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Articles by Eugene Bart in JoVE

 JoVE Neuroscience

Creating Objects and Object Categories for Studying Perception and Perceptual Learning

1Brain and Behavior Discovery Institute, Georgia Health Sciences University, 2Vision Discovery Institute, Georgia Health Sciences University, 3Department of Opthalmology, Georgia Health Sciences University, 4Intelligent Systems Laboratory, Palo Alto Research Center, 5Pattern Recognition Systems, Palo Alto Research Center, 6Department of Psychology, University of Minnesota


JoVE 3358

We describe a novel methodology for creating naturalistic 3-D objects and object categories with precisely defined feature variations. We use simulations of the biological processes of morphogenesis and phylogenesis to create novel, naturalistic virtual 3-D objects and object categories that can then be rendered as visual images or haptic objects.

Other articles by Eugene Bart on PubMed

TGFbeta Affects Collagen Cross-linking Independent of Chondrocyte Phenotype but Strongly Depending on Physical Environment

Transforming growth factor beta (TGFbeta) is often used in cartilage tissue engineering to increase matrix formation by cells with various phenotypes. However, adverse effects of TGFbeta, such as extensive crosslinking in cultured fibroblasts, have also been reported. Our goal was to study effects of TGFbeta on collagen cross-linking and evaluating the role of cellular phenotype and physical environment. We therefore used four different cell populations in two very different physical environments: primary and expanded chondrocytes and fibroblasts embedded in alginate gel and attached to tissue culture plastic. Matrix production, collagen cross-linking, and alpha-smooth muscle actin (alphaSMA) were analyzed during 4 weeks with or without 2.5 ng/ mL TGFbeta2. TGFbeta2 did not affect collagen deposition by primary cells. In expanded cells, TGFbeta2 increased collagen deposition. Chondrocytes and fibroblasts in monolayer produced more collagen cross-links with TGFbeta2. In alginate, primary and expanded cells displayed an unexpected decrease in collagen cross-linking with TGFbeta2. alphaSMA was not present in alginate cultures and barely upregulated by TGFbeta2. Organized alphaSMA fibers were present in all monolayer cultures and became more pronounced with TGFbeta2. This study demonstrates that the physical environment determined by the substrate used co-determines the response of cells to TGFbeta. The presence of mechanical stress, determined with alphaSMA-staining, is probably responsible for the increase in collagen cross-linking upon addition of TGFbeta.

Cord Blood Banking

Comorbidity Between Balance and Anxiety Disorders: Verification in a Normal Population

Comorbidity between balance and anxiety disorders has been documented in clinical psychiatric and neurological samples. The authors aimed to determine whether the comorbidity of balance and anxiety disorders has an analogous representation in the normal population. Participants were 20 undergraduate students ages 22-29 years. The authors assigned them to high or low trait anxiety groups and performed a balance task in 3 experimental stages: baseline, training, and test. The baseline and test stages consisted of 4 wobbly and 4 stable trials each. The authors measured state anxiety in the form of auditory startle responses (ASRs) during the stable trials. In the baseline stage, the ASR amplitudes were higher in the high trait anxiety participants. In the test stage, the low trait anxiety participants performed the balance task better than the high trait anxiety participants did. These data suggest that the clinical entity designated as a comorbidity of balance and anxiety disorders has an analogous representation in the normal population.

[Ductal Adenocarcinoma, Four Years Follow-up]

Ductal adenocarcinoma of the prostate (DAP) is an unusual form of prostatic cancer rising in the light of the acini and prostatic ducts with preservation of their architecture. We report the case of a 78-year-old patient presenting a pure ductal adenocarcinoma of the prostate locally advanced, with a four years' follow-up. With this case, we report the principal aspects of the literature.

Aspects in Post-orthodontic Removal of Orthosystem Implants

Problems encountered in the removal of a temporary anchorage device, such as the Orthosystems implant, specially designed for orthodontic anchorage purposes after insertion at the palatal side of the maxilla, are presented and discussed.

Spontaneous Cure of American Cutaneous Leishmaniasis Due to Leishmania Naiffi in Two Dutch Infantry Soldiers

We report two Dutch infantry soldiers who acquired American cutaneous leishmaniasis (ACL) during military jungle training in Surinam. The lesions had existed for 3 and 5 months, respectively, before the soldiers presented for treatment. The lesions occurred on the head and right thigh, and were small, uncomplicated and symptomless. PCR for Leishmania revealed Leishmania naiffi in both patients. No treatment was given, and the lesions in both men healed spontaneously within 4 and 6 weeks, respectively, after presentation to our clinic. CL is one of the important 'tropical' diseases in The Netherlands, primarily due to the increasing numbers of cases in travellers and in military personnel serving overseas. ACL due to L. naiffi is thought to be a mild expression of CL with a self-limiting nature. Lesions seem to be single, mostly small, ulcerating and usually appear on the hands, arms and legs. No case of mucocutaneous leishmaniasis has yet been attributed to this parasite.

Room-temperature Intermediate Layer Bonding for Microfluidic Devices

In this work a novel room-temperature bonding technique based on chemically activated Fluorinated Ethylene Propylene (FEP) sheet as an intermediate between chemically activated substrates is presented. Surfaces of silicon and glass substrates are chemically modified with APTES bearing amine terminal groups, while FEP sheet surfaces are treated to form carboxyl groups and subsequently activated by means of EDC-NHS chemistry. The activation procedures of silicon, glass and FEP sheet are characterized by contact angle measurements and XPS. Robust bonds are created at room-temperature by simply pressing two amine-terminated substrates together with activated FEP sheet in between. Average tensile strengths of 5.9 MPa and 5.2 MPa are achieved for silicon-silicon and glass-glass bonds, respectively, and the average fluidic pressure that can be operated is 10.2 bar. Moreover, it is demonstrated that FEP-bonded microfluidic chips can handle mild organic solvents at elevated pressures without leakage problems. This versatile room-temperature intermediate layer bonding technique has a high potential for bonding, packaging, and assembly of various (bio-) chemical microfluidic systems and MEMS devices.

Echinococcus Vogeli Infection in a Hunter, French Guiana

Echinococcus vogeli infection in a hunter from the rain forest of French Guiana was confirmed by imaging and mitochondrial DNA sequence analysis. Serologic examination showed typical patterns for both alveolar and cystic echinococcosis. Polycystic echinococcis caused by E. vogeli may be an emerging parasitic disease in Central and South America.

Ferric Carboxymaltose in Patients with Heart Failure and Iron Deficiency

Iron deficiency may impair aerobic performance. This study aimed to determine whether treatment with intravenous iron (ferric carboxymaltose) would improve symptoms in patients who had heart failure, reduced left ventricular ejection fraction, and iron deficiency, either with or without anemia.

Treatment of Congestion in Congestive Heart Failure: Ultrafiltration is the Only Rational Initial Treatment of Volume Overload in Decompensated Heart Failure

What Should an Ideal Vaccine Postlicensure Safety System Be?

In 2007 the National Vaccine Program, along with the Centers for Disease Control and Prevention, the Food and Drug Administration, the National Institutes of Health, and the Health Resources and Services Administration, sponsored a public conference titled "Vaccine Safety Evaluation: Post Marketing Surveillance." The objective was to discuss enhanced approaches to postlicensure evaluation of vaccine safety, including active and passive surveillance systems and special studies. The conference participants reviewed the evolution of the assessment of vaccine safety, detailed current national approaches to postmarketing safety, and offered new approaches to evaluating vaccine safety. A number of the participants recommended that information systems be expanded to include reliable information on vaccination and health outcomes in large populations. We summarize the major meeting presentations and discussions.

Optimization of Stripline-based Microfluidic Chips for High-resolution NMR

We here report on the optimization, fabrication and experimental characterization of a stripline-based microfluidic NMR probe, realized in a silicon substrate. The stripline geometry was modelled in respect of rf-homogeneity, sensitivity and spectral resolution. Using these models, optimal dimensional ratios were found, which hold for every sample size. Based on the optimized parameters, a simple integrated stripline-based microfluidic chip was realized. The fabrication of this chip is described in detail. We achieved a sensitivity of 0.47 nmol/square root(Hz) and a resolution of 0.7 Hz. The rf-homogeneity (A(810 degrees)/A(90 degrees)) was 76% and was proved to be suitable for 2D-NMR analysis of glucose.

[Left Bundle of His Brunch Block As a Manifestation of the Syndrome of Dromotropic Insufficiency in Patients with Chronic Heart Failure]

Left bundle brunch block (LBBB) is met in approximately 20% of hospitalized patients and in 1/3 of outpatients with chronic heart failure (CHF). Abnormalites of impulse conduction in LBBB promote dyssynchronization, which represent a pathophysiological process which not only worsens ventricular function but also facilitates remodeling of the myocardium and development of CHF. As a result of dyssynchrony systolic and diastolic functions of the heart are impaired. This manifests as shortening of diastole of the left ventricle and dyssynchronous movement of interventricular septum (IVS) with a tendency to lowering of local and global ejection fraction (EF), and leads to significant metabolic and energetic consequences. Abnormal geometry and dilation of the heart in CHF promotes chaotic separation of early and late activated myocardial zones. This aggravates disturbances of conduction existing as a result of fibrosis and causes weakening of contractility and slowing of impulse conduction velocity. These morphological changes facilitate electrophysiological deviations and formation of abnormal conduction. LBBB is undoubtedly involved in development of sudden death of patients with CHF, but its effect on long term prognosis remains ambiguous and possibly the role of no small importance in this belongs to severe concomitant pathology and dysfunction of left ventricular myocardium.

Bordetella Pertussis Strains with Increased Toxin Production Associated with Pertussis Resurgence

Before childhood vaccination was introduced in the 1940s, pertussis was a major cause of infant death worldwide. Widespread vaccination of children succeeded in reducing illness and death. In the 1990s, a resurgence of pertussis was observed in a number of countries with highly vaccinated populations, and pertussis has become the most prevalent vaccine-preventable disease in industrialized countries. We present evidence that in the Netherlands the dramatic increase in pertussis is temporally associated with the emergence of Bordetella pertussis strains carrying a novel allele for the pertussis toxin promoter, which confers increased pertussis toxin (Ptx) production. Epidemiologic data suggest that these strains are more virulent in humans. We discuss changes in the ecology of B. pertussis that may have driven this adaptation. Our results underline the importance of Ptx in transmission, suggest that vaccination may select for increased virulence, and indicate ways to control pertussis more effectively.

A New Tripodal Ligand System with Steric and Electronic Modularity for Uranium Coordination Chemistry

The synthesis of a potentially redox active tripodal ligand containing a tris(aryloxide) functionalized mesitylene anchor, (((tBu)ArOH)(3)mes) (1), and its metalation with low-valent uranium to form [(((tBu)ArO)(3)mes)U] (1-U) is reported. The results from characterization by X-ray crystallography, spectroscopic studies, and computational analysis, as well as initial reactivity studies, support a +3 uranium oxidation state. Comparison to the previously synthesized complex, [(((tBu)ArO)(3)tacn)U] (2-U), featuring the redox-innocent triazacyclononane anchor reveals that changing the anchor from the flexible triazacyclononane to a rigid mesityl fragment increases the structural flexibility of the aryloxide substituents in complexes of 1. The synthesis and crystal structures of uranium(IV) amide complexes of 1-U and 2-U are discussed.

Concerns About Consensus Guidelines for QTc Interval Screening in Methadone Treatment

Cohesin Regulates VSG Monoallelic Expression in Trypanosomes

Antigenic variation allows Trypanosoma brucei to evade the host immune response by switching the expression of 1 out of approximately 15 telomeric variant surface glycoprotein (VSG) expression sites (ESs). VSG ES transcription is mediated by RNA polymerase I in a discrete nuclear site named the ES body (ESB). However, nothing is known about how the monoallelic VSG ES transcriptional state is maintained over generations. In this study, we show that during S and G2 phases and early mitosis, the active VSG ES locus remains associated with the single ESB and exhibits a delay in the separation of sister chromatids relative to control loci. This delay is dependent on the cohesin complex, as partial knockdown of cohesin subunits resulted in premature separation of sister chromatids of the active VSG ES. Cohesin depletion also prompted transcriptional switching from the active to previously inactive VSG ESs. Thus, in addition to maintaining sister chromatid cohesion during mitosis, the cohesin complex plays an essential role in the correct epigenetic inheritance of the active transcriptional VSG ES state.

Obtaining Adequate Surgical Margins in Breast-conserving Therapy for Patients with Early-stage Breast Cancer: Current Modalities and Future Directions

Inadequate surgical margins represent a high risk for adverse clinical outcome in breast-conserving therapy (BCT) for early-stage breast cancer. The majority of studies report positive resection margins in 20% to 40% of the patients who underwent BCT. This may result in an increased local recurrence (LR) rate or additional surgery and, consequently, adverse affects on cosmesis, psychological distress, and health costs. In the literature, various risk factors are reported to be associated with positive margin status after lumpectomy, which may allow the surgeon to distinguish those patients with a higher a priori risk for re-excision. However, most risk factors are related to tumor biology and patient characteristics, which cannot be modified as such. Therefore, efforts to reduce the number of positive margins should focus on optimizing the surgical procedure itself, because the surgeon lacks real-time intraoperative information on the presence of positive resection margins during breast-conserving surgery. This review presents the status of pre- and intraoperative modalities currently used in BCT. Furthermore, innovative intraoperative approaches, such as positron emission tomography, radioguided occult lesion localization, and near-infrared fluorescence optical imaging, are addressed, which have to prove their potential value in improving surgical outcome and reducing the need for re-excision in BCT.

Reactivity of NH4H2PO4 Toward LaCl3 in LiCl-KCl Melt Flux. Step by Step Formation of Monazite-like LaPO4

The synthesis of lanthanum phosphates in molten LiCl-KCL eutectic was chosen to address the preliminary treatment of chlorinated wastes containing fission products that are already present in a Li/Cl eutectic. The obtained monazite compound shows interesting properties to be considered as a good candidate to trap lanthanum for a long-time. The synthesis route based on LaCl(3) reaction with NH(4)H(2)PO(4) in a stoichiometric amount is a key point to obtain monazite as a pure phase. Hence, the salt composition is not modified during the synthesis reaction. The chemical reactivity of ammonium dihydrogenphosphate (NH(4)H(2)PO(4), hereafter abbreviated ADP) toward lanthanum chloride (LaCl(3)) in molten LiCl-KCl eutectic is probed by NMR spectroscopy to follow the formation of LaPO(4). Formally, a direct transformation of the two aforementioned precursors into LaPO(4), NH(4)Cl and HCl can be discarded on the basis of the low thermal stability of ADP. To shed some light on the formation of LaPO(4), in situ and ex situ NMR experiments were carried out on LiCl-KCl/LaCl(3)/ADP, as well as LiCl-KCl/ADP, KCl/ADP, and LiCl/ADP mixtures. First, the reactivity of the precursors in contact with the eutectic was studied from room temperature to 600 degrees C by means of (31)P, (35)Cl, and (139)La high temperature NMR. Second, ex situ room temperature magic angle spinning (MAS) and RadioFrequency driven recoupling (RFDR) (31)P solid-state NMR experiments were carried out on solid samples prepared in different conditions (i.e., temperature and atmosphere) and quenched at room temperature to identify frozen intermediate species in their metastable state. On the basis of this approach, we propose a model for the LaPO(4) formation based on a multistep mechanism which highlights the strong reactivity of ADP toward the alkaline salts but without final change in the composition of the solvent.

Molecular Profile of Ductal Carcinoma in Situ of the Breast in BRCA1 and BRCA2 Germline Mutation Carriers

Ductal carcinoma in situ (DCIS) is an established late precursor of sporadic invasive breast cancer and to a large extent parallels its invasive counterpart with respect to molecular changes and immunophenotype. Invasive breast cancers in germline BRCA1 and BRCA2 mutation carriers have a distinct "basal" and "luminal" immunophenotype, respectively, but the immunophenotype of their precursor lesions has hardly been studied, and this was the aim of this study.

Effect of Tidal Volume in Children with Acute Hypoxemic Respiratory Failure

To determine if tidal volume (VT) between 6 and 10 ml/kg body weight using pressure control ventilation affects outcome for children with acute hypoxemic respiratory failure (AHRF) or acute lung injury (ALI). To validate lung injury severity markers such as oxygenation index (OI), PaO2/FiO2 (PF) ratio, and lung injury score (LIS).

Ultrafiltration for Congestive Heart Failure

Relief of congestive symptoms is a primary goal in treating heart failure. Ultrafiltration is a tool that can be used to safely remove sodium and water from whole blood at a controlled rate. Ultrafiltration decreases symptoms, relieves congestion, and improves hemodynamics, neurohormonal balance, and exercise capacity. This article describes the importance of congestion as a therapeutic target in heart failure and outlines the development of ultrafiltration as a treatment to address this important physiologic state.

Genetic Diversity of the Cestode Echinococcus Multilocularis in Red Foxes at a Continental Scale in Europe

Alveolar echinococcosis (AE) is a severe helminth disease affecting humans, which is caused by the fox tapeworm Echinococcus multilocularis. AE represents a serious public health issue in larger regions of China, Siberia, and other regions in Asia. In Europe, a significant increase in prevalence since the 1990s is not only affecting the historically documented endemic area north of the Alps but more recently also neighbouring regions previously not known to be endemic. The genetic diversity of the parasite population and respective distribution in Europe have now been investigated in view of generating a fine-tuned map of parasite variants occurring in Europe. This approach may serve as a model to study the parasite at a worldwide level.

Differentiation Dependent Expression of TRPA1 and TRPM8 Channels in IMR-32 Human Neuroblastoma Cells

TRPA1 and TRPM8 are transient receptor potential (TRP) channels involved in sensory perception. TRPA1 is a non-selective calcium permeable channel activated by irritants and proalgesic agents. TRPM8 reacts to chemical cooling agents such as menthol. The human neuroblastoma cell line IMR-32 undergoes a remarkable differentiation in response to treatment with 5-bromo-2-deoxyuridine. The cells acquire a neuronal morphology with increased expression of N-type voltage gated calcium channels and neurotransmitters. Here we show using RT-PCR, that mRNA for TRPA1 and TRPM8 are strongly upregulated in differentiating IMR-32 cells. Using whole cell patch clamp recordings, we demonstrate that activators of these channels, wasabi, allyl-isothiocyanate (AITC) and menthol activate membrane currents in differentiated cells. Calcium imaging experiments demonstrated that AITC mediated elevation of intracellular calcium levels were attenuated by ruthenium red, spermine, and HC-030031 as well as by siRNA directed against the channel. This indicates that the detected mRNA level correlate with the presence of functional channels of both types in the membrane of differentiated cells. Although the differentiated IMR-32 cells responded to cooling many of the cells showing this response did not respond to TRPA1/TRPM8 channel activators (60% and 90% for AITC and menthol respectively). Conversely many of the cells responding to these activators did not respond to cooling (30%). This suggests that these channels have also other functions than cold perception in these cells. Furthermore, our results suggest that IMR-32 cells have sensory characteristics and can be used to study native TRPA1 and TRPM8 channel function as well as developmental expression.

Expression of MiR-21 and Its Targets (PTEN, PDCD4, TM1) in Flat Epithelial Atypia of the Breast in Relation to Ductal Carcinoma in Situ and Invasive Carcinoma

Flat epithelial atypia (FEA) of the breast is characterised by a few layers of mildly atypical luminal epithelial cells. Genetic changes found in ductal carcinoma in situ (DCIS) and invasive ductal breast cancer (IDC) are also found in FEA, albeit at a lower concentration. So far, miRNA expression changes associated with invasive breast cancer, like miR-21, have not been studied in FEA.

Sources of Error in Total Knee Arthroplasty

The purpose of this study was to identify the procedural steps in a total knee arthroplasty (TKA) in which technical errors occur and to quantify the magnitude of these errors. Forty-nine consecutive TKAs were performed using a traditional exposure and manual instrumentation. An image-free computer navigation system (OrthoPilot; Aesculap AG, Tuttlingen, Germany) was used to measure and compare femoral and tibial alignment at specific procedural points during the TKA; this data was then used to evaluate possible sources of error in the procedure. The femoral cut tended to be made in hyperextension, the tibial cut tended to be made in hyperextension and valgus, and the tibial component tended to be implanted in valgus. This study identified specific points during the performance of a TKA where technical errors occur. This information suggests technical considerations that can help a surgeon achieve more reproducible, durable, and successful outcomes for his or her patients.

[Alternative Treatments for Interstitial Cystitis]

Interstitial cystitis is the first cause of bladder pain. In case of failure of the usual treatments, several other modalities have been proposed. These therapeutic modalities are posterior sacral root neuromodulation, posterior tibial nerve stimulation, vanilloid agent intravesical instillation, intradetrusor botulinum toxin injections and surgery. A certain efficiency of each of these treatments in the interstitial cystitis has been reported. However, the evaluation of these treatments is limited and the level of evidence is too low to propose these treatments in routine.

Involvement of TRPC3 Channels in Calcium Oscillations Mediated by OX(1) Orexin Receptors

Oscillations of intracellular Ca2+ provide a novel mechanism for sustained activation of cellular processes. Receptor-activated oscillations are mainly thought to occur through rhythmic IP3-dependent store discharge. However, as shown here in HEK293 cells 1 nM orexin-A (Ox-A) acting at OX1 receptors (OX1R) triggered oscillatory Ca2+ responses, requiring external Ca2+. These responses were attenuated by interference with TRPC3 channel (but not TRPC1/4) function using dominant negative constructs, elevated Mg2+ (a blocker of many TRP channels) or inhibition of phospholipase A2. These treatments did not affect Ca2+ oscillations elicited by high concentrations of Ox-A (100 nM) in the absence of external Ca2+. OX1R are thus able to activate TRPC(3)-channel-dependent oscillatory responses independently of store discharge.

[Structural-functional Peculiarities of the Heart and Survival of Elderly Patients with Chronic Heart Failure and Left Bundle Branch Block]

To study structural-functional characteristics of the heart and survival of elderly patients with chronic heart failure (CHF) and left bundle branch block (LBBB).

Development and Characterization of Clinical-grade 89Zr-trastuzumab for HER2/neu ImmunoPET Imaging

The anti-human epidermal growth factor receptor 2 (HER2/neu) antibody trastuzumab is administered to patients with HER2/neu-overexpressing breast cancer. Whole-body noninvasive HER2/neu scintigraphy could help to assess and quantify the HER2/neu expression of all lesions, including nonaccessible metastases. The aims of this study were to develop clinical-grade radiolabeled trastuzumab for clinical HER2/neu immunoPET scintigraphy, to improve diagnostic imaging, to guide antibody-based therapy, and to support early antibody development. The PET radiopharmaceutical (89)Zr-trastuzumab was compared with the SPECT tracer (111)In-trastuzumab, which we have tested in the clinic already.

[Mastocytosis: when Should It Be Considered?]

Mast cell disorders are defined by the accumulation of mast cells in one or more organ systems. Cutaneous forms are mainly observed in children whereas systemic forms are predominant in adults. Mast cells cause symptoms by the release of proinflammatory mediators or by infiltration of various organs. The measurement of serum tryptase has opened the possibility of screening for mastocytosis, which must be taken into consideration in case of severe anaphylactic reactions. Definite diagnosis is established based on a biopsy of skin or bone marrow. An activating mutation of stem cell factor receptor c-kit is often found. Treatment is based on control of the symptoms triggered by mast cell degranulation. Moreover, novel treatment options targeting mast cell proliferation become available for clinical use.

[Use of Autoantibodies in Clinical Practice]

Autoantibodies are frequently determined in unclear clinical situations and in the context of an inflammatory syndrome. The aim of this article is not to review all autoantibodies in details, but to discuss those used in clinical practice by describing their methods of detection and interpretation. Thus we will focus on antinuclear antibodies (ANA), which are typically associated with connective tissue diseases, as well as anti-neutrophil cytoplasmic antibodies (ANCA), which are useful in the diagnosis of ANCA-associated vasculitides. Due to its high sensitivity indirect immunofluorescence is used as a screening test; when positive, ELISA is performed to search for antibodies more specifically associated with certain auto-immune diseases.

[Therapeutic Strategies in Idiopatic Inflammatory Myopathies]

Idiopathic inflammatory myopathies, such as polymyositis and dermatomyositis, share common clinical features such as progressive, symmetrical muscle weakness prevailing in the lower limbs, associated sometimes with muscle pains. High CK and typical biopsy insure the diagnosis. Possible causes for secondary myopathies and associated diseases should be actively investigated. The search for autoantibodies helps to better classify inflammatory myopathies and to better define the prognosis of the myopathy. Glucocorticoids are the cornerstone of the early phase therapy. Glucocorticoid-sparing agents, such as azathioprine and methotrexate, are second line agents but can be readily prescribed. In case of therapeutic resistance, a rescue treatment (ciclosporine, immunoglobulins, rituximab, cyclophosphamide) could be considered.

Comparing Different Short-term Service Delivery Methods of Visual-motor Treatment for First Grade Students in Mainstream Schools

To compare the efficacy of three different short-term service delivery methods on first grade children with soft neurological signs who suffer from visual-motor difficulties. One hundred and forty seven first grade students who scored below the 21st percentile on the Visual-Motor Integration Test (VMI) were recruited from schools and randomly divided into three intervention groups and an additional control group. One group received Direct Treatment Model (DT), the second group received Collaborative-Consultation Treatment Model (CC) and the third group received a Combined Treatment Model (CT). The CC included treatment administered by teachers, after Collaborative-Consultation with an occupational therapist (OT). The CT included the two models (DT, CC), administered simultaneously. Pre- and post-intervention tests were administered to both groups. Students in all three intervention groups made significant gains in comparison to the control group suggesting that all three service delivery methods had the same effect on children's visual-motor skills. Therapists in school settings who are obliged to be more efficient are encouraged to use the CC or the CT service delivery methods which would enable them to treat more children during the same time-frame, with full confidence that the treatment goals will be achieved as if using the DT.

New Cellular Therapies: is There a Role for Transfusion Services?

Synthesis of Bis(imino)pyridine Iron Amide and Ammonia Compounds from an N-H Transfer Agent

Addition of the [NH] transfer reagent Hdbabh (dbabh = 2,3:5,6-dibenzo-7-azabicyclo[2.2.1]hepta-2,5-diene) to the bis(imino)pyridine iron bis(dinitrogen) complex, (((i)Pr)PDI)Fe(N(2))(2) (((i)Pr)PDI = 2,6-(2,6-(i)Pr(2)C(6)H(3)N horizontal lineCMe)(2)C(5)H(3)N), furnished the corresponding iron amide and ammonia compounds, resulting from cleavage of the strained amine. Isotopic labeling studies support N-H bond activation by a transient, parent imide, [(((i)Pr)PDI)FeNH].

Mapping of Transrectal Ultrasonographic Prostate Biopsies: Quality Control and Learning Curve Assessment by Image Processing

Mapping of transrectal ultrasonographic (TRUS) prostate biopsies is of fundamental importance for either diagnostic purposes or the management and treatment of prostate cancer, but the localization of the cores seems inaccurate. Our objective was to evaluate the capacities of an operator to plan transrectal prostate biopsies under 2-dimensional TRUS guidance using a registration algorithm to represent the localization of biopsies in a reference 3-dimensional ultrasonographic volume.

Comparison of Human and Rhesus Macaque T-cell Responses Elicited by Boosting with NYVAC Encoding Human Immunodeficiency Virus Type 1 Clade C Immunogens

Rhesus macaques (Macaca mulatta) have played a valuable role in the development of human immunodeficiency virus (HIV) vaccine candidates prior to human clinical trials. However, changes and/or improvements in immunogen quality in the good manufacturing practice (GMP) process or changes in adjuvants, schedule, route, dose, or readouts have compromised the direct comparison of T-cell responses between species. Here we report a comparative study in which T-cell responses from humans and macaques to HIV type 1 antigens (Gag, Pol, Nef, and Env) were induced by the same vaccine batches prepared under GMP and administered according to the same schedules in the absence and presence of priming. Priming with DNA (humans and macaques) or alphavirus (macaques) and boosting with NYVAC induced robust and broad antigen-specific responses, with highly similar Env-specific gamma interferon (IFN-gamma) enzyme-linked immunospot assay responses in rhesus monkeys and human volunteers. Persistent cytokine responses of antigen-specific CD4(+) and CD8(+) T cells of the central memory as well as the effector memory phenotype, capable of simultaneously eliciting multiple cytokines (IFN-gamma, interleukin 2, and tumor necrosis factor alpha), were induced. Responses were highly similar in humans and primates, confirming earlier data indicating that priming is essential for inducing robust NYVAC-boosted IFN-gamma T-cell responses. While significant similarities were observed in Env-specific responses in both species, differences were also observed with respect to responses to other HIV antigens. Future studies with other vaccines using identical lots, immunization schedules, and readouts will establish a broader data set of species similarities and differences with which increased confidence in predicting human responses may be achieved.

A Microfluidic High-resolution NMR Flow Probe

A microfluidic high-resolution NMR flow probe based on a novel stripline detector chip is demonstrated. This tool is invaluable for the in situ monitoring of reactions performed in microreactors. As an example, the acetylation of benzyl alcohol with acetyl chloride was monitored. Because of the uncompromised (sub-Hz) resolution, this probe holds great promise for metabolomics studies, as shown by an analysis of 600 nL of human cerebrospinal fluid.

Comparison of Dobutamine Stress Echocardiography, Dobutamine SPECT, and Adenosine SPECT Myocardial Perfusion Imaging in Patients with End-stage Renal Disease

We sought to assess and compare the diagnostic accuracy and prognostic value of dobutamine stress echocardiography (DSE), dobutamine SPECT, and adenosine SPECT myocardial perfusion imaging (MPI) in patients with end-stage renal disease (ESRD).

Validation of the 4B5 Rabbit Monoclonal Antibody in Determining Her2/neu Status in Breast Cancer

HER2 overexpression in breast cancer is associated with worse clinical outcome. To select patients for anti-Her2-based therapy immunohistochemistry is commonly performed as a first step to assess Her2 status. However, interobserver and interlaboratory variability can significantly compromise adequate assessment of Her2 status. In addition, immunohistochemistry does not always result in an unambiguous test result requiring additional testing for Her2 gene amplification. This study aimed to improve the reliability of Her2 immunohistochemistry by using rabbit monoclonal antibody 4B5 as an alternative to mouse monoclonal antibody CB11 routinely used in our laboratory. Therefore, 283 breast adenocarcinomas were included in a tissue microarray. Immunohistochemistry using the 4B5 and CB11 antibodies, and fluorescence and chromogenic in situ hybridization (FISH or CISH) were performed. Immunohistochemistry was scored by two independent investigators. We found that 4B5 staining was more distinct than CB11 staining. For CB11 staining, there were 12% (BV) and 5% (JW) 2+ scores compared with 4% (BV) and 2% (JW) for 4B5. There was a strong trend towards higher interobserver agreement for 4B5 compared with CB11 (4B5: kappa 0.87, 95% CI 0.79-0.96; CB11: kappa 0.77, 95% CI 0.66-0.88). There were no significant differences in sensitivity, specificity and predictive values between CB11 and 4B5. Our results indicate that the 4B5 antibody provides more robust assessment of immunohistochemical Her2/neu status and will reduce the number of gene amplification tests compared with CB11. However, for tumours with a 2+ score additional gene amplification measurement using FISH or CISH remains necessary.

Relationship Between Carotid Artery Stiffness Index, BNP and High-sensitivity CRP

Arterial stiffness is an independent predictor of cardiovascular morbidity and mortality. Brain natriuretic peptide (BNP) and high-sensitivity C-reactive protein (hs-CRP) are considered as novel biomarkers that are useful in the prediction of early cardiovascular risk. We studied the relationship between carotid artery stiffness index beta and the cardiovascular biomarkers BNP and hs-CRP in 55 consecutive subjects. Carotid artery stiffness was assessed using the stiffness index beta derived from brachial artery blood pressure measurement and carotid ultrasonography. Venous blood samples were obtained for BNP and hs-CRP. Pearson's correlation coefficient suggested a strong bivariate relationship between carotid stiffness index beta and age (r=0.56, P<0.0001), BNP (r=0.45, P<0.004) and hs-CRP (r=0.26, P=0.06), respectively. On multiple regression analysis, significant correlations were found between carotid stiffness index beta and age (P=0.004), BNP (P=0.027) and hs-CRP (P=0.029). These findings suggest that there is a relationship between intra-cardiac pressures (measured by BNP), vascular inflammation (measured by hs-CRP) and vascular stiffness. Cardiovascular biomarkers are thus associated with functional parameters of the vascular tree.

Construction of Health Preferences: a Comparison of Direct Value Assessment and Personal Narratives

Most terminally ill patients prefer to die at home rather than at an institution. However, patients are often insufficiently aware of the downsides of staying at home, which signals a need for effective decision aids.

P-gp and MRP1 Expression in Parathyroid Tumors Related to Histology, Weight and (99m)Tc-sestamibi Imaging Results

P-glycoprotein (P-gp) and multidrug resistance-associated protein (MRP) are membrane efflux pumps that may have a role in the kinetics of (99m)Tc-sestamibi (MIBI) in parathyroid tumors. P-gp and MRP1 expression in parathyroid tumors was studied and related to histology, weight and pre- and intraoperative MIBI imaging results.

Distinct Profiles of Cytotoxic Granules in Memory CD8 T Cells Correlate with Function, Differentiation Stage, and Antigen Exposure

Cytotoxic CD8 T cells exert their antiviral and antitumor activity primarily through the secretion of cytotoxic granules. Degranulation activity and cytotoxic granules (perforin plus granzymes) generally define CD8 T cells with cytotoxic function. In this study, we have investigated the expression of granzyme K (GrmK) in comparison to that of GrmA, GrmB, and perforin. The expression of the cytotoxic granules was assessed in virus-specific CD8 T cells specific to influenza virus, Epstein-Barr virus (EBV), cytomegalovirus (CMV), or human immunodeficiency virus type 1 (HIV-1). We observed a dichotomy between GrmK and perforin expression in virus-specific CD8 T cells. The profile in influenza virus-specific CD8 T cells was perforin(-) GrmB(-) GrmA(+/-) GrmK(+); in CMV-specific cells, it was perforin(+) GrmB(+) GrmA(+) GrmK(-/+); and in EBV- and HIV-1-specific cells, it was perforin(-/+) GrmB(+) GrmA(+) GrmK(+). On the basis of the delineation of memory and effector CD8 T cells with CD45RA and CD127, the GrmK(+) profile was associated with early-stage memory CD8 T-cell differentiation, the perforin(+) GrmB(+) GrmA(+) profile with advanced-stage differentiation, and the GrmB(+) GrmA(+) Grmk(+) profile with intermediate-stage differentiation. Furthermore, perforin and GrmB but not GrmA and GrmK correlated with cytotoxic activity. Finally, changes in antigen exposure in vitro and in vivo during primary HIV-1 infection and vaccination modulated cytotoxic granule profiles. These results advance our understanding of the relationship between distinct profiles of cytotoxic granules in memory CD8 T cells and function, differentiation stage, and antigen exposure.

Multi-locus Microsatellite Analysis Supports the Hypothesis of an Autochthonous Focus of Echinococcus Multilocularis in Northern Italy

Echinococcus multilocularis is characterised by a wide geographical distribution, encompassing three continents (North America, Asia and Europe) yet very low genetic variability is documented. Recently, this parasite has been detected in red foxes (Vulpes vulpes) circulating in an Alpine region of Italy, close to Austria. This finding raised the question as to whether an autochthonous cycle exists in Italy or whether the infected foxes originated from the neighbouring regions of Austria. Studies have shown that multi-locus microsatellite analysis can identify genomic regions carrying mutations that result in a local adaptation. We used a tandem repeated multi-locus microsatellite (EmsB) to evaluate the genetic differences amongst adult worms of E. multilocularis collected in Italy, worms from neighbouring Austria and from other European and extra-European countries. Fluorescent PCR was performed on a panel of E. multilocularis samples to assess intra-specific polymorphism. The analysis revealed four closed genotypes for Italian samples of E. multilocularis which were unique compared with the other 25 genotypes from Europe and the five genotypes from Alaska. An analysis in the Alpine watershed, comparing Italian adult worms with those from neighbouring areas in Austria, showed a unique cluster for Italian samples. This result supports the hypothesis of the presence of an autochthonous cycle of E. multilocularis in Italy. EmsB can be useful for 'tracking' the source of infection of this zoonotic parasite and developing appropriate measures for preventing or reducing the risk of human alveolar echinococcosis.

Reconstructing the Phylogenetic Relationships of the Earth's Most Diverse Clade of Freshwater Fishes--order Cypriniformes (Actinopterygii: Ostariophysi): a Case Study Using Multiple Nuclear Loci and the Mitochondrial Genome

The order Cypriniformes is the most diverse clade of freshwater fishes and is natively distributed on all continents except South America, Australia, and Antarctica. Despite the diversity of the group and the fundamental importance of these species in both ecosystems and human culture, relatively little has been known about their relationships relative to their diversity. In recent years, with an international effort investigating the systematics of the group, more information as to their genealogical relationships has emerged and species discovery and their descriptions have increased. One of the more interesting aspects of this group has been a traditional lack of understanding of the relationships of the families, subfamilies, and other formally or informally identified groups. Historical studies have largely focused on smaller groups of species or genera. Because of the diversity of this group and previously published whole mitochondrial genome evidence for relationships of major clades in the order, this clade serves as an excellent group to investigate the congruence between relationships reconstructed for major clades with whole mitogenome data and those inferred from a series of nuclear gene sequences. As descent has resulted in only one tree of life, do the phylogenetic relationships of these major clades converge on similar topologies using the large number of available characters through this suite of nuclear genes and previously published mitochondrial genomes? In this study we examine the phylogenetic relationships of major clades of Cypriniformes using previously published mitogenomes and four putative single-copy nuclear genes of the same or closely related species. Combined nuclear gene sequences yielded 3810bp, approximately 26% of the bp found in a single mitogenome; however homoplasy in the nuclear genes was measurably less than that observed in mitochondrial sequences. Relationships of taxa and major clades derived from analyses of nuclear and mitochondrial sequences were nearly identical and both received high support values. While some differences of individual gene trees did exist for species, it is predicted that these differences will be minimized with increased taxon sampling in future analyses.

[Primary Carcinoma of the Head of the Epididymis]

The authors report the case of a 44-year-old man in whom a poorly differentiated primary carcinoma of the head of the epididymis was discovered incidentally. Due to the rarity of this diagnosis, a comprehensive assessment was performed looking for a primary tumour, but without success. Despite early surgical resection, the patient developed lymph-node metastases. This exceptional tumour showed low sensitivity to chemotherapy. Malignant tumours of the epididymis are exceptional and require investigations to detect a primary tumour. Treatment is based on surgical resection, ideally via an inguinal incision, combined with chemotherapy adapted to the histological type.

Outlier Detection with the Kernelized Spatial Depth Function

Statistical depth functions provide from the "deepest" point a "center-outward ordering" of multidimensional data. In this sense, depth functions can measure the "extremeness" or "outlyingness" of a data point with respect to a given data set. Hence, they can detect outliers--observations that appear extreme relative to the rest of the observations. Of the various statistical depths, the spatial depth is especially appealing because of its computational efficiency and mathematical tractability. In this article, we propose a novel statistical depth, the kernelized spatial depth (KSD), which generalizes the spatial depth via positive definite kernels. By choosing a proper kernel, the KSD can capture the local structure of a data set while the spatial depth fails. We demonstrate this by the half-moon data and the ring-shaped data. Based on the KSD, we propose a novel outlier detection algorithm, by which an observation with a depth value less than a threshold is declared as an outlier. The proposed algorithm is simple in structure: the threshold is the only one parameter for a given kernel. It applies to a one-class learning setting, in which "normal" observations are given as the training data, as well as to a missing label scenario, where the training set consists of a mixture of normal observations and outliers with unknown labels. We give upper bounds on the false alarm probability of a depth-based detector. These upper bounds can be used to determine the threshold. We perform extensive experiments on synthetic data and data sets from real applications. The proposed outlier detector is compared with existing methods. The KSD outlier detector demonstrates a competitive performance.

A Rice Kinase-protein Interaction Map

Plants uniquely contain large numbers of protein kinases, and for the vast majority of the 1,429 kinases predicted in the rice (Oryza sativa) genome, little is known of their functions. Genetic approaches often fail to produce observable phenotypes; thus, new strategies are needed to delineate kinase function. We previously developed a cost-effective high-throughput yeast two-hybrid system. Using this system, we have generated a protein interaction map of 116 representative rice kinases and 254 of their interacting proteins. Overall, the resulting interaction map supports a large number of known or predicted kinase-protein interactions from both plants and animals and reveals many new functional insights. Notably, we found a potential widespread role for E3 ubiquitin ligases in pathogen defense signaling mediated by receptor-like kinases, particularly by the kinases that may have evolved from recently expanded kinase subfamilies in rice. We anticipate that the data provided here will serve as a foundation for targeted functional studies in rice and other plants. The application of yeast two-hybrid and TAPtag analyses for large-scale plant protein interaction studies is also discussed.

Reduction Chemistry of Aryl- and Alkyl-substituted Bis(imino)pyridine Iron Dihalide Compounds: Molecular and Electronic Structures of [(PDI)2Fe] Derivatives

Sodium amalgam reduction of the aryl-substituted bis(imino)pyridine iron dibromide complex, ((Et)PDI)FeBr2 ((Et)PDI = 2,6-(2,6-Et2-C6H3N=CMe)2C5H3N), under a dinitrogen atmosphere in pentane furnished the bis(chelate)iron compound, ((Et)PDI)2Fe. Characterization by X-ray crystallography established a distorted four-coordinate iron center with two kappa2-bis(imino)pyridine ligands. Reducing the steric demands of the imine substituent to either a less sterically encumbered aryl ring (e.g., C6H4-4-OMe) or an alkyl group (e.g., Cy, iPr, cis-myrtanyl) also yielded bis(chelate) compounds from sodium amalgam reduction of the corresponding dihalide. Characterization of the compounds with smaller imine substituents by X-ray diffraction established six-coordinate, pseudo-octahedral compounds. In one case, a neutral bis(chelate)iron compound was prepared by reduction of the corresponding iron dication, [(PDI)2Fe]2+, providing chemical confirmation of electrochemically generated species that were previously reported as too reducing to isolate. Magnetic measurements, metrical parameters from X-ray structures, Mössbauer spectroscopy, and open-shell, broken symmetry DFT calculations were used to establish the electronic structure of both types (four- and six-coordinate) of neutral bis(chelate) compounds. The experimentally observed S = 1 compounds are best described as having high-spin ferrous (S(Fe) = 2) centers antiferromagnetically coupled to two bis(imino)pyridine radical anions. Thus, the two-electron reduction of the diamagnetic, low-spin complex [(PDI)2Fe]2+ to [(PDI)2Fe] is ligand-based with a concomitant spin change at iron.

[Extrapulmonary Sarcoidosis: an Unrecognized Disease Entity?]

Sarcoidosis is a multi-systemic inflammatory disease of unknown etiology, histologically characterized by the presence of non caseating granulomas. The diagnostic suspicion relies on clinical, epidemiological, biological and radiological elements. It is confirmed by an evocative histology and by the exclusion of other granulomatous pathologies. The aim of this article is to expose some clinical manifestations of extrapulmonary sarcoidosis particularly the cardiac and abdominal involvements. A register was made on cases of sarcoidosis diagnosed in CHUV from 2000 to 2009. It demonstrates the rarity of the disease in the region of Lausanne and confirms the existence of purely extra-thoracic affections.

Fragment-based Learning of Visual Object Categories in Non-human Primates

When we perceive a visual object, we implicitly or explicitly associate it with an object category we know. Recent research has shown that the visual system can use local, informative image fragments of a given object, rather than the whole object, to classify it into a familiar category. We have previously reported, using human psychophysical studies, that when subjects learn new object categories using whole objects, they incidentally learn informative fragments, even when not required to do so. However, the neuronal mechanisms by which we acquire and use informative fragments, as well as category knowledge itself, have remained unclear. Here we describe the methods by which we adapted the relevant human psychophysical methods to awake, behaving monkeys and replicated key previous psychophysical results. This establishes awake, behaving monkeys as a useful system for future neurophysiological studies not only of informative fragments in particular, but also of object categorization and category learning in general.

Cutaneous Leishmaniasis (Leishmania Major Infection) in Dutch Troops Deployed in Northern Afghanistan: Epidemiology, Clinical Aspects, and Treatment

Cutaneous leishmaniasis caused by Leishmania major infection affected 172 (18.3%) of 938 Dutch military troops deployed in northern Afghanistan in 2005. The high attack rate was a result of initial insufficient availability of means of prevention and insufficient adherence to preventive measures. At presentation, the lymphatic system was involved in 24.8%. Treatment with intralesional injections of antimony with or without cryotherapy was satisfactory, but 19.5% of patients received secondary treatment with miltefosine. Six months after treatment, 128 (77.1%) of 166 treated patients were cured, 16 (9.6%) were lost to follow-up, and 22 (13.3%) already experienced cure at six weeks but were not seen at six months. Natural evolution played a role in this observational study, which showed cure of all patients seen at six months. In general, management of cutaneous leishmaniasis was feasible under field conditions.

Comparative Genomics of Prevaccination and Modern Bordetella Pertussis Strains

Despite vaccination since the 1950s, pertussis has persisted and resurged. It remains a major cause of infant death worldwide and is the most prevalent vaccine-preventable disease in developed countries. The resurgence of pertussis has been associated with the expansion of Bordetella pertussis strains with a novel allele for the pertussis toxin (Ptx) promoter, ptxP3, which have replaced resident ptxP1 strains. Compared to ptxP1 strains, ptxP3 produce more Ptx resulting in increased virulence and immune suppression. To elucidate how B. pertussis has adapted to vaccination, we compared genome sequences of two ptxP3 strains with four strains isolated before and after the introduction vaccination.

[Eosinophilic Esophagitis]

Eosinophilic esophagitis is a recent diagnosis, of growing interest and prevalence. It has to be considered by every physician when facing any adult or pediatric case of dysphagia, food impaction, and symptoms of GERD (gastroesophageal reflux disease) resistant to proton-pump inhibitor treatment. The diagnosis is made by combining clinical symptoms and endoscopic signs, supported by biopsies of the mucosa, which should show more than 15 eosinophils per high power field. The etiology seems to be of allergic origin, and a full immuno-allergic testing should be made. Recommendations for the treatment are to calm down the inflammatory process by proton-pump inhibitors, and to give topical steroids, keeping the systemic treatment for acute severe cases. In cases of esophageal stenoses, dilations can be undertaken, but with a high risk of recurrence.

Efficacy and Safety of Flavocoxid Compared with Naproxen in Subjects with Osteoarthritis of the Knee- a Subset Analysis

twice-daily flavocoxid, a cyclooxygenase and 5-lipoxygenase inhibitor with potent antioxidant activity of botanical origin, was evaluated for 12 weeks in a randomized, double-blind, active-comparator study against naproxen in 220 subjects with moderate-severe osteoarthritis (OA) of the knee. As previously reported, both groups noted a significant reduction in the signs and symptoms of OA with no detectable differences in efficacy between the groups when the entire intent-to-treat population was considered. This post-hoc analysis compares the efficacy of flavocoxid to naproxen in different subsets of patients, specifically those related to age, gender, and disease severity as reported at baseline for individual response parameters.

Detection of Water in the LCROSS Ejecta Plume

Several remote observations have indicated that water ice may be presented in permanently shadowed craters of the Moon. The Lunar Crater Observation and Sensing Satellite (LCROSS) mission was designed to provide direct evidence. On 9 October 2009, a spent Centaur rocket struck the persistently shadowed region within the lunar south pole crater Cabeus, ejecting debris, dust, and vapor. This material was observed by a second "shepherding" spacecraft, which carried nine instruments, including cameras, spectrometers, and a radiometer. Near-infrared absorbance attributed to water vapor and ice and ultraviolet emissions attributable to hydroxyl radicals support the presence of water in the debris. The maximum total water vapor and water ice within the instrument field of view was 155 ± 12 kilograms. Given the estimated total excavated mass of regolith that reached sunlight, and hence was observable, the concentration of water ice in the regolith at the LCROSS impact site is estimated to be 5.6 ± 2.9% by mass. In addition to water, spectral bands of a number of other volatile compounds were observed, including light hydrocarbons, sulfur-bearing species, and carbon dioxide.

The Potential of Molecular Diagnosis of Cutaneous Ectopic Schistosomiasis

A 28-year-old woman presented with extensive erythematous lesions on her back after visiting Malawi. Skin biopsies showed ova, which could belong to Schistosoma spp. Sequencing of the Schistosoma 28S rRNA gene, extracted and amplified from paraffin biopsies, identified DNA of Schistosoma haematobium. Cutaneous ectopic schistosomiasis can present with extensive lesions and should be considered in the differential diagnosis of skin lesions in returning travelers. Microscopy and serology are the classical methods to obtain a diagnosis. Alternatively, molecular methods can be a valuable new tool for diagnosis and species determination.

[Cardiopulmonary Exercise Testing in Patients with Pectus Excavatum]

The functional consequences of physiologic impairments due to pectus excavatum (PE) are not known. This study was conducted to determine the exercise performance in patients with this condition. This prospective study included all patients presenting for PE during a 5-year period. Patients had a chest CT scan to measure the PE severity index, resting pulmonary function tests, cardiopulmonary exercise testing (CPET) with gas exchange analysis and echocardiography. Thirty-two patients were included, with a mean age of 25.9 years. The mean PE severity index was 3.72 ± 0.87. The maximal oxygen uptake (VO(2-max)) was 78.6 ± 22.1% predicted. Only four out of the 32 patients had a normal CPET. In the remaining patients, we observed three main patterns of limitation: 18 patients had a marked limitation in increasing their tidal volume (41 ± 5% of FVC at VO(2-max) versus 51 ± 7.5%); five patients had abnormal gas exchange with increased P(A-a)O(2) at VO(2-max) (47 ± 23 mmHg versus 20 ± 7.5 mmHg) associated with a patent foramen ovale without elevation of right pressure. The five last patients had cardiovascular impairment with a decreased oxygen pulse at VO(2-max) (57 ± 9% versus 90 ± 20%). They exhibited the most severe limitation (VO(2-max) = 55 ± 10%; P = 0.003). CPET abnormalities were predicted by neither PE index severity nor the results of resting pulmonary function tests. PE is associated with abnormal CPET, including impairments in ventilatory, cardiovascular responses and/or gas exchange, which may be of importance in disease management.

Receptor Conversion in Distant Breast Cancer Metastases

When breast cancer patients develop distant metastases, the choice of systemic treatment is usually based on tissue characteristics of the primary tumor as determined by immunohistochemistry (IHC) and/or molecular analysis. Several previous studies have shown that the immunophenotype of distant breast cancer metastases may be different from that of the primary tumor ("receptor conversion"), leading to inappropriate choice of systemic treatment. The studies published so far are however small and/or methodologically suboptimal. Therefore, definite conclusions that may change clinical practice could not yet be drawn. We therefore aimed to study receptor conversion for estrogen receptor alpha (ERα), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) in a large group of distant (non-bone) breast cancer metastases by re-staining all primary tumors and metastases with current optimal immunohistochemical and in situ hybridization methods on full sections.

Rice Snl6, a Cinnamoyl-CoA Reductase-like Gene Family Member, is Required for NH1-mediated Immunity to Xanthomonas Oryzae Pv. Oryzae

Rice NH1 (NPR1 homolog 1) is a key mediator of innate immunity. In both plants and animals, the innate immune response is often accompanied by rapid cell death at the site of pathogen infection. Over-expression of NH1 in rice results in resistance to the bacterial pathogen, Xanthomonas oryzae pv. oryzae (Xoo), constitutive expression of defense related genes and enhanced benzothiadiazole (BTH)- mediated cell death. Here we describe a forward genetic screen that identified a suppressor of NH1-mediated lesion formation and resistance, snl6. Comparative genome hybridization and fine mapping rapidly identified the genomic location of the Snl6 gene. Snl6 is a member of the cinnamoyl-CoA reductase (CCR)-like gene family. We show that Snl6 is required for NH1-mediated resistance to Xoo. Further, we show that Snl6 is required for pathogenesis-related gene expression. In contrast to previously described CCR family members, disruption of Snl6 does not result in an obvious morphologic phenotype. Snl6 mutants have reduced lignin content and increased sugar extractability, an important trait for the production of cellulosic biofuels. These results suggest the existence of a conserved group of CCR-like genes involved in the defense response, and with the potential to alter lignin content without affecting development.

HIV-1 Drug Resistance Transmission Networks in Southwest Switzerland

To determine viral subtypes and resistance mutations to antiretroviral treatment (ART) in untreated HIV-1 acutely infected subjects from Southwest Switzerland. Clinical samples were obtained from the HIV primary infection cohort from Lausanne. Briefly, pol gene was amplified by nested PCR and sequenced to generate a 1 kb sequence spanning protease and reverse transcriptase key protein regions. Nucleotide sequences were used to assess viral genotype and ART resistance mutations. Blood specimens and medical information were obtained from 30 patients. Main viral subtypes corresponded to clade B, CRF02_AG, and F1. Resistant mutations to PIs consisted of L10V and accessory mutations 16E and 60E present in all F1 clades. The NNRTI major resistant mutation 103N was detected in all F1 viruses and in other 2 clades. Additionally, we identified F1 sequences from other 6 HIV infected and untreated individuals from Southwest Switzerland, harboring nucleotide motifs and resistance mutations to ART as observed in the F1 strains from the cohort. These data reveal a high transmission rate (16.6%) for NNRTI resistant mutation 103N in a cohort of HIV acute infection. Three of the 5 resistant strains were F1 clades closely related to other F1 isolates from HIV-1 infection untreated patients also coming from Southwest Switzerland. Overall, we provide strong evidence towards an HIV-1 resistant transmission network in Southwest Switzerland. These findings have relevant implications for the local molecular mapping of HIV-1 and future ART surveillance studies in the region.

Efficacy and Safety of Flavocoxid, a Novel Therapeutic, Compared with Naproxen: a Randomized Multicenter Controlled Trial in Subjects with Osteoarthritis of the Knee

Flavocoxid is a novel flavonoid-based "dual inhibitor" of the 5-lipoxygenase (5-LOX) enzyme and the cyclooxygenase (COX) enzymes. This study was designed to compare the effectiveness and safety of flavocoxid to naproxen in subjects with moderate to severe osteoarthritis (OA) of the knee.

Methylation Profiles of Hereditary and Sporadic Ovarian Cancer

Tumour suppressor gene silencing through promoter hypermethylation plays an important role in oncogenesis. Carcinogenesis of hereditary cancers usually differs from that of their sporadic counterparts, but methylation has hardly been studied in hereditary ovarian cancer. The aim of this study was to investigate promoter methylation of a set of common tumour suppressor genes in BRCA1-related ovarian cancer in comparison with sporadic ovarian cancer.

The Sustainability of Medical Morning Handover Reporting: Adherence in a Regional Hospital

The Medical Morning Handover Report is a form of clinical handover and is considered to be an essential mechanism for continuity of care and adverse event minimisation within a hospital environment. It is considered a significant Quality of Care activity recommended in Australian Medical Association clinical handover guidelines. The sustainability of such activities has not been reported.

Selective Interference with TRPC3/6 Channels Disrupts OX1 Receptor Signalling Via NCX and Reveals a Distinct Calcium Influx Pathway

TRPC channels play significant roles in the regulation of neuronal plasticity and development. The mechanism by which these nonselective cation channels exert their trophic actions appears to involve entry of Ca(2+) into the cells. Using a neuronal cell model (differentiated human IMR32 neuroblastoma cells), we demonstrate a central role for sodium entry via TRPC3/6 channels in receptor-mediated increases in intracellular calcium. These Na(+)-dependent Ca(2+) influxes, which were observed in a subpopulation of cells, were efficiently blocked by protein kinase C activation, by the Na(+)/Ca(2+) exchanger inhibitors, and by molecular disruption of TRPC3/6 channel function. On the other hand, another subpopulation of cells showed a Na(+)-independent Ca(2+) entry upon stimulation of the same receptors, orexin/hypocretin and bradykinin receptors. This second type of response was not affected by the above mentioned treatments, but it was sensitive to polyvalent cations, such as ruthenium red, spermine and Gd(3+). The data suggest that a NCX-TRPC channel interaction constitutes an important functional unit in receptor-mediated Ca(2+) influx in neuronal cells.

Development and Initial Validation of the Environmental Restriction Questionnaire (ERQ)

The purpose of this manuscript was to develop and test the psychometric properties of the Environmental Restriction Questionnaire (ERQ) a parent-reported questionnaire for measuring perceived environmental restrictions for young children participation. Reliability and homogeneity were tested by Cronbach's alpha and inter-item correlations. Construct validity was computed by factor analysis and known group differences analysis. Convergent and divergent validities were calculated by correlation with the Children Participation Questionnaire (CPQ). Participants were 290 children and their parent. Seventy-five children who were referred to occupational therapy evaluation as consequence of moderate developmental disabilities and 215 children without any disability (mean age ± standard deviation for total sample, 5 y, 3 mo ± .65 y; range, 3 y, 11 mo to 6 y, 10 mo). The ERQ has good internal reliability. Cronbach's alpha for the ERQ measures ranged between .75 and .91, indicating adequate homogeneity. Factor analysis yielded three factors that explained almost 48% of the total variance. Significant differences were found between known groups. Convergent and divergent validity were supported by various correlations with the Children Participation Questionnaire (CPQ). The ERQ has demonstrated good psychometric properties and can be used as a reliable and valid measure to assess perceived environmental restriction at the age of 4-6 y.

Crystallographic Evidence of a Base-free Uranium(IV) Terminal Oxo Species

The uranium(IV) terminal oxo species Tp*(2)U(O) has been synthesized by oxygen-atom transfer from pyridine-N-oxide to Tp*(2)U(2,2'-bipyridine), a trivalent uranium species with a monoanionic bipyridine ligand. Full characterization of the oxo species using (1)H NMR and IR spectroscopies, X-ray crystallography, and computational studies was performed.

Polaron Hopping in Nano-scale Poly(dA)-Poly(dT) DNA

We investigate the current-voltage relationship and the temperature-dependent conductance of nano-scale samples of poly(dA)-poly(dT) DNA molecules. A polaron hopping model has been used to calculate the I-V characteristic of nano-scale samples of DNA. This model agrees with the data for current versus voltage at temperatures greater than 100 K. The quantities G(0), i(0), and T(1d) are determined empirically, and the conductivity is estimated for samples of poly(dA)-poly(dT).

A Preliminary Study on the Effect of Methylphenidate on Motor Performance in Children with Comorbid DCD and ADHD

Attention Deficit Hyperactive Disorder (ADHD) and Developmental Coordination Disorder (DCD) are two developmental disorders with considerable comorbidity. The impact of Methylphenidate (MPH) on ADHD symptoms is well documented. However, the effects of MPH on motor coordination are less studied. We assessed the influence of MPH on motor performance of children with comorbid DCD and ADHD. Participants were 18 children (13 boys, mean age 8.3 years) diagnosed with comorbid DCD and ADHD. A structured clinical interview (K-SADS-PL) was used to determine psychopathology and the Movement Assessment Battery for Children-Checklist were used to determine criterion for motor deficits. The Movement Assessment Battery for Children (M-ABC) was administrated to all participants once under the influence of MPH and once under a placebo pill condition. The motor tests were administered on two separate days in a double-blinded design. Participants' motor performance with MPH was significantly superior to their performance in the placebo condition. Significant improvement was observed in all the M-ABC sub-tasks except for static balance performance. The findings suggest that MPH improves motor coordination in children with comorbid DCD and ADHD but clinically significant improvement was found in only 33% of the children.

A Role for PKD1 and PKD3 Activation in Modulation of Calcium Oscillations Induced by Orexin Receptor 1 Stimulation

The neuropeptides orexin-A/hypocretin-1 (Ox-A) and orexin-B/hypocretin-2 play an important role in the control of energy metabolism via either of two G-protein-coupled receptors, orexin receptor 1 (Ox1R) and 2. Despite its significant physiological functions, signaling via orexin receptors is still poorly characterized. The aim of this study was to improve our understanding of early signaling events triggered by the binding of Ox-A to Ox1R. Using phosphospecific antibodies, we observed that early kinase activation by Ox-A in a HEK293 cell line stably expressing Ox1R (HEKOx1R) included ERK1/2, PKCdelta, and PKD1. Elevation of intracellular Ca(2+) is a well-characterized response to Ox1R activation. Comparison of Ox-A-induced calcium elevation and PKD1 activation demonstrated that both responses are detectable soon after stimulation and increase in a dose-dependent manner, but inhibition of protein kinase C, when low Ox-A concentrations are used, affects them differently. PKD family of protein kinases has 3 members: PKD1, 2, and 3, which are all expressed in HEKOx1R cells. In response to stimulation of the cells with 1nM Ox-A, both PKD1 and PKD3 are activated and increased in the plasma membrane, pointing at a possible role for these kinases in that cell compartment. Overexpression of either kinase-dead PKD1 or kinase-dead PKD3 disrupts Ox-A-induced calcium oscillations demonstrating the functional role of these kinases in modulating physiological responses to Ox-A.

Expression of the Stem Cell Marker ALDH1 in the Normal Breast of BRCA1 Mutation Carriers

Evolutionary Divergence of Duplicate Copies of the Growth Hormone Gene in Suckers (actinopterygii: Catostomidae)

Catostomid fishes (suckers) have duplicate copies of the growth hormone gene and other nuclear genes, due to a genome duplication event early in the group's history. Yet, paralogs of GH in suckers are more than 90% conserved in nucleotide (nt) and amino acid (aa) sequence. Within paralogs across species, variation in nt and aa sequence averages 3.33% and 4.46% for GHI, and 3.22% and 2.43% for GHII, respectively. Selection tests suggest that the two GH paralogs are under strong purifying selection. Consensus trees from phylogenetic analysis of GH coding region data for 23 species of suckers, other cypriniform fishes and outgroups resolved cypriniform relationships and relationships among GHI sequences of suckers more or less consistently with analyses based on other molecular data. However, the analysis failed to resolve all sucker GHI and GHII sequences as monophyletic sister groups. This unexpected topology did not differ significantly from topologies constrained to make all GH sequences monophyletic. We attribute this result either to limitations in our GHII data set or convergent adaptive changes in GHII of tribe Catostomini.

[Cardiac Involvement in Connective Tissue Disease: the Example of Systemic Lupus Erythematosus]

When we think of cardiac affection in the context of systemic lupus erythematosus (SLE), we usually refer to pericarditis first. As frequent as this affection is, it is actually not the only cardio-vascular problem that occurs with this systemic inflammatory disease. Are the cardiac events--ranging from multiple heart valve involvements to increased cardiovascular risks--clinically significant? And are they involving a specific follow-up, treatment or support? We are therefore trying to evaluate these questions in order to give some recommendations to any practitioners following up a lupus patient, or a patient suffering from any other inflammatory systemic disease.

[Immunization Guidelines Regarding Patients with a Chronic Disease]

Some chronic diseases--like renal failure, liver insufficiency, chronic lung disease, cardiac involvement, diabetes mellitus, asplenia--present limited defects of the immune system and/or a higher risk of infection; therefore, patients with such pathologies should get selective vaccinations. The efficacy of immunization decreases with disease progression; for this reason, these patients should be immunized as soon as possible. At the beginning of their disease, these patients do not need a specialized treatment and are followed by the general practitioner alone who is in charge of immunizing them as well as contact people of any immunocompromised patient. OFSP's regular vaccinations programme is recommended, as well as selective vaccinations against influenza, pneumococci and viral hepatitis, depending on the underlying chronic disease.

[Prevention of Transmissible Diseases]

The Sympathorenal Axis in Hypertension and Heart Failure

Excessive sympathetic drive is undoubtedly a major contributing factor to the pathophysiology of hypertension and heart failure. Much of the excessive sympathetic drive in these conditions is directed to the kidney, where it leads to inappropriate sodium retention, renin stimulation, and diminished renal function. Less well appreciated is the role the kidney itself plays in the generation of increased sympathetic activity by way of the renal somatic afferent nerves. The kidney therefore is both target and contributor to increased sympathetic activity in these conditions. Although some current pharmacotherapy indirectly targets this "sympathorenal axis," resistant hypertension remains a common problem, and the prognosis in heart failure remains poor, especially in more severe cases. It is now possible to directly target this axis via procedures, which directly interrupt renal sympathetic efferent and afferent signaling. Other procedures involving chronic carotid nerve stimulation may indirectly influence renal sympathetic tone and so improve renal sodium handling. These techniques have demonstrated early promise in hypertension and offer significant potential in heart failure as well. Should their early promise be borne out in controlled studies, the "sympathorenal axis" will have been proven to be a key element in the pathophysiology of these 2 very common, and dangerous, conditions.

Discordant Molecular and Morphological Evolution in Buffalofishes (Actinopterygii: Catostomidae)

Buffalofishes (Genus Ictiobus) are large, robust-bodied suckers adapted to large rivers and lakes of North America. Currently recognized species are readily diagnosed by morphological characters, and the group is known from fossils dating back to the Miocene. However, sympatrically occurring species in the Mississippi River Basin are known to hybridize in nature and in the laboratory. Here we describe patterns of morphological (morphometric) and DNA sequence variation (mitochondrial and nuclear genes) across the geographic ranges of extant species of genus Ictiobus. We show that Ictiobus species form more of less discrete entities based on body morphometry, consistent with current taxonomy. However, except for I. labiosus, there is extensive sharing of alleles of nuclear and mitochondrial genes among species, and the species do not form reciprocally monophyletic groups in nuclear or mitochondrial gene trees. Moreover, the pattern is not confined to the broad area of sympatry in the Mississippi River Basin. We attribute this to a long history of introgressive hybridization and gene flow among species inhabiting the present-day Mississippi River Basin, and recent colonization of the Great Lakes, Hudson Bay drainage and gulf coastal rivers east and west of the Mississippi River by introgressed Mississippi River Basin stocks.

Lympho-vascular Invasion in BRCA Related Breast Cancer Compared to Sporadic Controls

Germline mutations in the BRCA1 gene predispose to the development of breast cancer, exhibiting a specific histological phenotype. Identification of possible hallmarks of these tumors is important for selecting patients for genetic screening and provides inside in carcinogenetic pathways.Since BRCA1-associated breast cancers have pushing borders that prevent them from easily reaching vessels and are often of the medullary (like) type that is known to have a low rate of lympho-vascular invasion (LVI), we hypothesized that absence of LVI could characterize BRCA1 related breast cancer.

Insights into the Mechanism of Carbonate Formation Through Reductive Cleavage of Carbon Dioxide with Low-valent Uranium Centers

The low-valent U(III) complexes [((t-BuArO)3mes)U] and [((AdArO)3N)U] react with CO2 to form the bridging carbonate complexes [{((t-BuArO)3mes)U}2(mu-kappa2:kappa2-CO3)] and [{((AdArO)3N)U}2(mu-eta1:kappa2-CO3)]. Uranium(IV) bridging oxo complexes have been determined to be the intermediate in these transformations.

First Cases of Cutaneous Leishmaniasis Caused by Leishmania (Viannia) Naiffi Infection in Surinam

Cutaneous leishmaniasis in Surinam is generally caused by infection by Leishmania guyanensis. We report three cases of infection with Leishmania (Viannia) naiffi, a Leishmania species not described from Surinam before. Treatment with pentamidine proved to be effective.

Analysis of Genes Differentially Expressed During Retinal Degeneration in Three Mouse Models

An estimated 100,000 people in the US alone have retinitis pigmentosa. This disease, caused by the loss of rods and cones, results in blindness. With the intention of identifying common cell death pathways that result in RP, the pattern of global gene expression in three different mouse models of retinal degeneration was analyzed using DNA arrays. The models used were opsin ( Delta255-256 ), a transgenic mouse line that expresses a mutant form of opsin with a deletion of an isoleucine at either position 255 or 256; the Bouse C mouse, whereby normal opsin is over-expressed by over 2 folds; MOT1, a model that expresses SV-40 T antigen downstream of opsin promoter and leads to retinal degeneration. We found that, at least in the 2 models of retinal degeneration that are characterized by rhodopsin abnormalities, death is due to the TNF pathway. In addition, there are a number of unknown genes not yet annotated in each of the models that could be promising in revealing novel functions in photoreceptors.

Overexpression of the Endoplasmic Reticulum Chaperone BiP3 Regulates XA21-mediated Innate Immunity in Rice

Recognition of pathogen-associated molecular patterns by pattern recognition receptors (PRRs) activates the innate immune response. Although PRR-mediated signaling events are critical to the survival of plants and animals, secretion and localization of PRRs have not yet been clearly elucidated. Here we report the in vivo interaction of the endoplasmic reticulum (ER) chaperone BiP3 with the rice XA21 PRR, which confers resistance to the Gram negative bacterium, Xanthomonas oryzae pv. oryzae (Xoo). We show that XA21 is glycosylated and is primarily localized to the ER and also to the plasma membrane (PM). In BiP3-overexpressing rice plants, XA21-mediated immunity is compromised, XA21 stability is significantly decreased, and XA21 proteolytic cleavage is inhibited. BiP3 overexpression does not affect the general rice defense response, cell death or brassinolide-induced responses. These results indicate that BiP3 regulates XA21 protein stability and processing and that this regulation is critical for resistance to Xoo.

Non-ionic Surfactant Modified Ligand Exchange Chromatography Using Copper (II) Complex of N,N-dimethyl-L-phenylalanine As the Chiral Additive for Enantioselective Amino Acids Separation

The influence of non-ionic surfactants on the selectivity and retention in the ligand exchange chromatography for the enantioselective separation of racemic mixtures of the amino acids dl-methionine, dl-leucine, dl-valine and dl-tyrosine applying chiral mobile phases was investigated, whereas five different surfactants were tested as modifiers. The experiments were carried out using a commercially available non-chiral RP-C8 column and the copper (II) complex of N,N-dimethyl-l-phenylalanine as the chiral additive. Varying the surfactant concentrations the retention factors and the selectivity could be controlled and in general no negative influence on the separation (due to surfactant adsorption on the non-chiral stationary phase) occurred. Changing the temperature the van't Hoff plots were obtained and the thermodynamic parameters calculated. Temperature had influence on the selectivity for each surfactant and lowered the retention times as expected.

Development and Initial Validation of the Children Participation Questionnaire (CPQ)

To develop and test the psychometric properties of a parent-reported questionnaire measuring participation of preschool children (Children Participation Questionnaire; CPQ) aged 4-6 years in their everyday activities.

The Cell Envelope Subtilisin-like Proteinase is a Virulence Determinant for Streptococcus Suis

Streptococcus suis is a major swine pathogen and zoonotic agent that mainly causes septicemia, meningitis, and endocarditis. It has recently been suggested that proteinases produced by S. suis (serotype 2) are potential virulence determinants. In the present study, we screened a S. suis mutant library created by the insertion of Tn917 transposon in order to isolate a mutant deficient in a cell surface proteinase. We characterized the gene and assessed the proteinase for its potential as a virulence factor.

Serum Creatinine As Stratified in the RIFLE Score for Acute Kidney Injury is Associated with Mortality and Length of Stay for Children in the Pediatric Intensive Care Unit

To evaluate the ability of the RIFLE criteria to characterize acute kidney injury in critically ill children.

An Original Field Evaluation Test for Chronic Obstructive Pulmonary Disease Population: the Six-minute Stepper Test

The aim of this study was to evaluate a new field test, the six-minute stepper test (6-MST), by studying its reproducibility, sensitivity and validity.

Synthesis and Characterization of a Uranium(III) Complex Containing a Redox-active 2,2'-bipyridine Ligand

Hydrotris(3,5-dimethylpyrazolyl)borate uranium(III) diiodide derivatives have been prepared as an entry into low-valent uranium chemistry with these ligands. The bis(tetrahydrofuran) adduct, Tp*UI(2)(THF)(2) (1) (Tp* = hydrotris(3,5-dimethylpyrazolyl)borate), was synthesized by addition of sodium hydrotris(3,5-dimethylpyrazolyl)borate (NaTp*) to an equivalent of UI(3)(THF)(4). Addition of 2,2'-bipyridine (2,2'-bpy) to 1 displaced the THF molecules producing Tp*UI(2)(2,2'-bpy) (2). Both derivatives were characterized by (1)H NMR and IR spectroscopies, magnetic measurements, and X-ray crystallography. Reduction of both species was attempted with two equivalents of potassium graphite. The reduction of 1 did not result in a clean product, but rather decomposition and ligand redistribution. However, compound 2 was reduced to form Tp*(2)U(2,2'-bpy), 3, which is composed of a uranium(III) ion with a radical monoanionic bipyridine ligand. This was confirmed by X-ray crystallography, which revealed distortions in the bond lengths of the bipyridine consistent with reduction. Further support was obtained by (1)H NMR spectroscopy, which showed resonances shifted far upfield, consistent with radical character on the 2,2'-bipyridine ligand. Future studies will explore the reactivity of this compound as well as the consequences for redox-activity in the bipyridine ligand.

Cost Effectiveness of Cord Blood Versus Bone Marrow and Peripheral Blood Stem Cells

Umbilical cord blood (CB) has become, since its first successful use more than two decades ago, an increasingly important source of blood stem cells. In this light, an overview of current usage of CB in the field of unrelated hematopoietic blood stem cell transplantation (HSCT) is given. The three main sources of hematopoietic stem cells: bone marrow (BM), peripheral blood stem cells (PBSC), and cord blood (CB) are compared as regards their current quantitative usage in HSCT. A cost analysis of the named three hematopoietic blood stem cell (HSC) sources, taking into account various factors, is undertaken. The health economical comparison shows significant differences between CB on the one side, and BM and PBSC on the other. The consequences for the public health side and propositions for a possible health care policy, especially regarding future resource allocation towards the different choices for HSCT products, are discussed. An outlook on the possible future usage of BM, PBSC, and CB and its implications on health systems, donor registries, and CB banks is given.

[Duodenogastric Reflux and Gastric Pathology in the Elderly Patients]

To determine the frequency of duodenogastric reflux (DGR), and to assess the changes in the gastric mucosa in the presence of bile reflux.

The Genomic Echinococcus Microsatellite EmsB Sequences: from a Molecular Marker to the Epidemiological Tool

In the field of molecular and epidemiological parasitology, characterization of fast evolving genetic markers appears as an important challenge to consider the diversity and genetic structure of parasites. The study of respective populations can help us to understand their adaptive strategies to survive and perpetuate the species within different host populations, all trying to resist infection. In the past, the relative monomorphic features of Echinococcus multilocularis, the causative agent of alveolar echinococcosis and a severe human parasitic disease, did not stimulate studies dealing with the genetic variability of Echinococcus species or respective populations. A recently developed, characterized and validated original multilocus microsatellite, named EmsB, tandemly repeated in the genome, offered an additional opportunity for this line of investigation. We have compiled in this review new insights brought by this molecular tracker on the transmission activity of Echinococcus among different hosts and at different geographical scales.

Transition from Pediatric to Adult Diabetes Care: Smooth or Slippery?

The purpose of this study is to evaluate the practices of diabetes health care providers concerning the transition from pediatric to adult diabetes care. The information presented here may help increase awareness of the organization of transitional care for young people with diabetes and prevent the loss of follow-up during this vulnerable period in their lives.

Miltefosine Treatment of Leishmania Major Infection: an Observational Study Involving Dutch Military Personnel Returning from Northern Afghanistan

In a retrospective, observational study involving 34 patients with Leishmania major infection, 31 of whom had experienced unsuccessful treatment with intralesional antimony (ilSb(v)), miltefosine proved effective. Thirty patients experienced cure after receipt of miltefosine, 3 after receipt of additional ilSb(v), and 1 after 28 daily intravenous injections of antimony. Temporary diminution of ejaculate volume was reported by 21 patients.

The Efficacy and Safety of Enhanced External Counterpulsation in Patients with Peripheral Arterial Disease

Peripheral arterial disease (PAD) is common in patients with severe coronary artery disease (CAD) and is considered a relative contraindication to external enhanced counterpulsation (EECP), but there are no data that define the efficacy and safety of EECP in patients with PAD. The International EECP Patient Registry (IEPR) was used to compare initial post-therapy and 2-year follow-up clinical outcomes and adverse event rates in patients with and without PAD. From January 2002 to October 2004, 2126 patients were enrolled in the IEPR, of whom 493 (23%) had a history of PAD. Immediately following EECP, the reduction in angina (> or = 1 Canadian Cardiovascular Society class) was similar in patients with and without PAD (76.6% vs 79.0%, p = 0.27) as was improvement in the Duke Activity Score Index (DASI) score (+4.7% vs +6.1%, p < 0.001). Both angina reduction and DASI score improvement were sustained at 2 years. PAD patients discontinued EECP more frequently (12.0% vs 8.5%, p < 0.05), but lower extremity ulceration did not occur more frequently in patients with PAD (3.7% vs 2.7%, p = 0.26). Rates of death (17.1% vs 8.6%, p < 0.001) and myocardial infarction (9.5% vs 5.0%, p < 0.001) were, as expected, higher in patients with PAD compared to patients without PAD at 2 years. In conclusion, while PAD patients constitute a high-risk cohort with known higher adverse event rates, EECP led to similar short- and long-term improvements in angina and quality of life for individuals with PAD compared to those without PAD.

Efficiency of the Home Parental Programme in Visual-motor Home Activity Among First-grade Children

The objectives of this study were to assess the efficacy of the home parental programme (HPP) in improving children's visual-motor skills, and to assess parent satisfaction with the programme.

Ten Years Down the Road: Predictors of Driving Cessation

Recent prospective studies have found that cognition is a more salient predictor of driving cessation than physical performance or demographic factors among community-dwelling older adults. However, these studies have been limited to 5 years of follow-up. The current study used data from the Maryland Older Drivers Project to examine predictors of driving cessation in older adults over a 10-year period.

Development and Initial Validation of the Performance Skills Questionnaire (PSQ)

The objectives of this study was to develop and test the psychometric properties of the Performance Skills Questionnaire (PSQ), addressed to measure performance skills of preschoolers, as reported by their parents. Participants included 231 children ranging in age from 4 to 6 years old, with mild to moderate developmental disabilities and 240 children without disabilities at same age range. Internal consistency, test-retest, construct validity, and divergent and convergent validity were assessed. The PSQ has shown good internal reliability, and temporal stability. Construct validity was supported by factor analysis which yielded 3 factors that explained almost 52% of the total variance. Significant differences were found between known groups. Convergent and divergent validity were supported by significant correlations with Visual-Motor Integration (VMI) test, and the Children Participation Questionnaire (CPQ). The PSQ is a unique tool that measures performance skills based on preschool children's everyday function. Results provide evidence in support of the PSQ as a reliable and psychometrically sound instrument.

Phylogenetic Relationships of Catostomid Fishes (Actinopterygii: Cypriniformes) Based on Mitochondrial ND4/ND5 Gene Sequences

Family Catostomidae is a diverse group of benthic freshwater fishes that are distributed across North America and in parts of East Asia. In this study, the phylogenetic relationships of Catostomidae is examined using 3436 nucleotides of mitochondrial ND4 and ND5 protein coding genes and intervening tRNAs. All 13 genera and 60 species of catostomids were sampled to represent diversity of the family. Catostomidae and its four subfamilies were found to be monophyletic; however, relationships of the subfamilies are not strongly supported with bootstrapping. The analysis provides strong support for recognizing four tribes in subfamily Catostominae.

Swiss Blood Stem Cells: More Than Just a Registry

Swiss Transfusion SRC, division Swiss Blood Stem Cells (SBSC), is an important national organization for all matters relating to blood stem cells. Not only has its name changed several times over the years but also its role has developed steadily and today goes beyond registry alone. For example, on order of and in close collaboration with transplant doctors, the organization searches for suitable donors worldwide. Searching for unrelated donors for Swiss patients and organizing the deliveries of the transplant tissues for Swiss and foreign patients are the most time-consuming procedures at SBSC. Additionally, the organization pays special attention to the problem of donor follow-up. Here it has made important contributions to the field of data collection (minimal data set) and helped to strengthen international coordination. As of January 2011, the organization has a new structure, because it has joined forces with the SRC Blood Transfusion Service. The new organization will be called Swiss Transfusion SRC, but SBSC remains as a main operational unit of the new organization. In 2009, SBSC implemented a successful new strategy to increase the numbers of donors: donors can now register online. This step led to a remarkable increase of donor numbers from 2009 to 2010.

[Hiking and Useful Advices to Patients (part 1)]

The attraction of walking as a pastime has grown enormously in Switzerland over the past few years. Synonym of health and well-being, this activity carries some risks which more and more patients are questioning; answering these questions is not always obvious, so we wanted to tackle the subject. Risks linked to certain animals will be covered. One of these risks is insect stings, particularly wasps and bees. This is a major problem which affects the whole population and more seriously those who are allergic, accounting for around 5% of the population. Another problem: snake bites. In Switzerland, there are about 20-25 bites each year. Poisoning from these can be divided into two categories: local or systemic. The effects are multiple and diverse, ranging from renal failure to discrasia to hypovolemic shock. Pre-hospitalisation measures are of paramount importance in the treatment.

Potentiation of a P53-SLP Vaccine by Cyclophosphamide in Ovarian Cancer: A Single-arm Phase II Study

The purpose of the current phase II single-arm clinical trial was to evaluate whether pretreatment with low-dose cyclophosphamide improves immunogenicity of a p53-synthetic long peptide (SLP) vaccine in patients with recurrent ovarian cancer. Patients with ovarian cancer with elevated serum levels of CA-125 after primary treatment were immunized four times with the p53-SLP vaccine. Each immunization was preceded by administration of 300 mg/m(2) intravenous cyclophosphamide as a means to affect regulatory T cells (Tregs). Vaccine-induced p53-specific interferon-gamma (IFN-γ)-producing T cells evaluated by IFN-γ ELISPOT were observed in 90% (9/10) and 87.5% (7/8) of evaluable patients after two and four immunizations, respectively. Proliferative p53-specific T cells, observed in 80.0% (8/10) and 62.5% (5/8) of patients, produced both T-helper 1 and T-helper-2 cytokines. Cyclophosphamide induced neither a quantitative reduction of Tregs determined by CD4(+) FoxP3(+) T cell levels nor a demonstrable qualitative difference in Treg function tested in vitro. Nonetheless, the number of vaccine-induced p53-specific IFN-γ-producing T cells was higher in our study compared to a study in which a similar patient group was treated with p53-SLP monotherapy (p ≤ 0.012). Furthermore, the strong reduction in the number of circulating p53-specific T cells observed previously after four immunizations was currently absent. Stable disease was observed in 20.0% (2/10) of patients, and the remainder of patients (80.0%) showed clinical, biochemical and/or radiographic evidence of progressive disease. The outcome of this phase II trial warrants new studies on the use of low-dose cyclophosphamide to potentiate the immunogenicity of the p53-SLP vaccine or other antitumor vaccines.

Organ Procurement from Donors Deceased from Cardiac Death: a Single-center Efficiency Assessment

Organ donation after cardiac death has been used for kidney and liver procurement in France since 2006. Until recently, most teams relied on in situ cold perfusion to prepare the donor before organ retrieval. Our team has used since 2007 normothermic abdominal recirculation. While this technique is presumed to be more difficult to implement, it also ensures a lower rate of primary nonfunction when compared to in situ cold perfusion. We present the efficiency results of our organ donation after cardiac death program. After 3 years, we have been able to establish a program in which we use normothermic abdominal recirculation in 97% of donors after cardiac death. The yearly efficiency of this program is comparable to the national efficiency of organ procurement from conventional deceased donors in France.

Synthesis and Characterization of (smif)2M(n) (n = 0, M = V, Cr, Mn, Fe, Co, Ni, Ru; N = +1, M = Cr, Mn, Co, Rh, Ir; Smif =1,3-di-(2-pyridyl)-2-azaallyl)

A series of Werner complexes featuring the tridentate ligand smif, that is, 1,3-di-(2-pyridyl)-2-azaallyl, have been prepared. Syntheses of (smif)(2)M (1-M; M = Cr, Fe) were accomplished via treatment of M(NSiMe(3))(2)(THF)(n) (M = Cr, n = 2; Fe, n = 1) with 2 equiv of (smif)H (1,3-di-(2-pyridyl)-2-azapropene); ortho-methylated ((o)Mesmif)(2)Fe (2-Fe) and ((o)Me(2)smif)(2)Fe (3-Fe) were similarly prepared. Metatheses of MX(2) variants with 2 equiv of Li(smif) or Na(smif) generated 1-M (M = Cr, Mn, Fe, Co, Ni, Zn, Ru). Metathesis of VCl(3)(THF)(3) with 2 Li(smif) with a reducing equiv of Na/Hg present afforded 1-V, while 2 Na(smif) and IrCl(3)(THF)(3) in the presence of NaBPh(4) gave [(smif)(2)Ir]BPh(4) (1(+)-Ir). Electrochemical experiments led to the oxidation of 1-M (M = Cr, Mn, Co) by AgOTf to produce [(smif)(2)M]OTf (1(+)-M), and treatment of Rh(2)(O(2)CCF(3))(4) with 4 equiv Na(smif) and 2 AgOTf gave 1(+)-Rh. Characterizations by NMR, EPR, and UV-vis spectroscopies, SQUID magnetometry, X-ray crystallography, and DFT calculations are presented. Intraligand (IL) transitions derived from promotion of electrons from the unique CNC(nb) (nonbonding) orbitals of the smif backbone to ligand π*-type orbitals are intense (ε ≈ 10,000-60,000 M(-1)cm(-1)), dominate the UV-visible spectra, and give crystals a metallic-looking appearance. High energy K-edge spectroscopy was used to show that the smif in 1-Cr is redox noninnocent, and its electron configuration is best described as (smif(-))(smif(2-))Cr(III); an unusual S = 1 EPR spectrum (X-band) was obtained for 1-Cr.

CSAT's QT Interval Screening in Methadone Report: Outrageous Fortune or Sea of Troubles?

New England Souvenirs

A 54-year-old woman presented with 2 weeks of fever after a trip to the Northeastern United States. Except for an erythematous skin lesion on her right shoulder, no physical abnormality was detected. We diagnosed concomitant borreliosis and babesiosis. Both infections were possibly acquired by one bite from Ixodes scapularis.

Measuring Participation Within the Environment

Intraoperative Tumor-specific Fluorescence Imaging in Ovarian Cancer by Folate Receptor-α Targeting: First In-human Results

The prognosis in advanced-stage ovarian cancer remains poor. Tumor-specific intraoperative fluorescence imaging may improve staging and debulking efforts in cytoreductive surgery and thereby improve prognosis. The overexpression of folate receptor-α (FR-α) in 90-95% of epithelial ovarian cancers prompted the investigation of intraoperative tumor-specific fluorescence imaging in ovarian cancer surgery using an FR-α-targeted fluorescent agent. In patients with ovarian cancer, intraoperative tumor-specific fluorescence imaging with an FR-α-targeted fluorescent agent showcased the potential applications in patients with ovarian cancer for improved intraoperative staging and more radical cytoreductive surgery.

Moving Beyond the Status Quo: Excellence in Prognostication Requires Both Science and Art

Highly Conserved Tyrosine 37 Stabilizes Desensitized States and Restricts Calcium Permeability of ATP-gated P2X3 Receptor

Tyrosine 37 in the first transmembrane (TM1) domain is highly conserved in ATP-gated P2X receptors suggesting its fundamental role. We tested whether Y37 contributes to the desensitization of P2X3 receptors, which is currently not well understood. By combining electrophysiological, imaging and modeling approaches, we studied desensitization of various Y37 P2X3 mutants and potential partners of Y37. Unlike the membrane current of the WT receptor, which desensitized in seconds, Y37A mutant current did not fully desensitize even after minutes-long applications of β,γ-meATP, α,β-meATP, ATP or 2MeS-ATP. The fractional calcium current was enhanced in the Y37A mutant. Y37F did not rescue the native P2X3 phenotype indicating a role for the hydroxyl group of Y37 for the WT receptor. Homology modeling indicated I318 or I319 in TM2 as potential partners for Y37 in the receptor closed state. We tested this hypothesis by creating a permanent interaction between the two residues via disulfide bond. Whereas single Y37C, I318C and I319C mutants were functional, the double mutants Y37C-I318C and Y37C-I319C were non-functional. Using a cyclic model of receptor operation, we suggest that the conserved tyrosine 37 links TM1 to TM2 of adjacent subunit to stabilize desensitized states and restricts calcium permeability through the ion channel.

Promise of Extended-release Naltrexone is a Red Herring

Prevalence of Metabolic Syndrome Components in a Population of Bank Employees from St. Petersburg, Russia

The aim of this study was to assess prevalence of metabolic syndrome and its components according to different criteria in the population of bank employees in St. Petersburg, Russia.

DNA/NYVAC Vaccine Regimen Induces HIV-specific CD4 and CD8 T-cell Responses in Intestinal Mucosa

In the present study, we have investigated the anatomic distribution in blood and gut mucosal tissues of memory poxvirus-specific CD4 and CD8 T cells in subjects vaccinated with smallpox and compared it with vector (NYVAC)-specific and HIV insert-specific T-cell responses induced by an experimental DNA-C/ NYVAC-C vaccine regimen. Smallpox-specific CD4 T-cell responses were present in the blood of 52% of the subjects studied, while smallpox-specific CD8 T cells were rarely detected (12%). With one exception, smallpox-specific T cells were not measurable in gut tissues. Interestingly, NYVAC vector-specific and HIV-specific CD4 and CD8 T-cell responses were detected in almost 100% of the subjects immunized with DNA-C/NYVAC-C in blood and gut tissues. The large majority (83%) of NYVAC-specific CD4 T cells expressed α4β7 integrins and the HIV coreceptor CCR5. These results demonstrate that the experimental DNA-C/NYVAC-C HIV vaccine regimen induces the homing of potentially protective HIV-specific CD4 and CD8 T cells in the gut, the port of entry of HIV and one of the major sites for HIV spreading and the depletion of CD4 T cells.

Synthesis, Characterization, and Multielectron Reduction Chemistry of Uranium Supported by Redox-active α-diimine Ligands

Uranium compounds supported by redox-active α-diimine ligands, which have methyl groups on the ligand backbone and bulky mesityl substituents on the nitrogen atoms {(Mes)DAB(Me) = [ArN═C(Me)C(Me)═NAr], where Ar = 2,4,6-trimethylphenyl (Mes)}, are reported. The addition of 2 equiv of (Mes)DAB(Me), 3 equiv of KC(8), and 1 equiv of UI(3)(THF)(4) produced the bis(ligand) species ((Mes)DAB(Me))(2)U(THF) (1). The metallocene derivative, Cp(2)U((Mes)DAB(Me)) (2), was generated by the addition of an equimolar ratio of (Mes)DAB(Me) and KC(8) to Cp(3)U. The bond lengths in the molecular structure of both species confirm that the α-diimine ligands have been doubly reduced to form ene-diamide ligands. Characterization by electronic absorption spectroscopy shows weak, sharp transitions in the near-IR region of the spectrum and, in combination with the crystallographic data, is consistent with the formulation that tetravalent uranium ions are present and supported by ene-diamide ligands. This interpretation was verified by U L(III)-edge X-ray absorption near-edge structure (XANES) spectroscopy and by variable-temperature magnetic measurements. The magnetic data are consistent with singlet ground states at low temperature and variable-temperature dependencies that would be expected for uranium(IV) species. However, both complexes exhibit low magnetic moments at room temperature, with values of 1.91 and 1.79 μ(B) for 1 and 2, respectively. Iodomethane was used to test the reactivity of 1 and 2 for multielectron transfer. While 2 showed no reactivity with CH(3)I, the addition of 2 equiv of iodomethane to 1 resulted in the formation of a uranium(IV) monoiodide species, ((Mes)DAB(Me))((Mes)DAB(Me2))UI {3; (Mes)DAB(Me2) = [ArN═C(Me)C(Me(2))NAr]}, which was characterized by single-crystal X-ray diffraction and U M(4)- and M(5)-edge XANES. Confirmation of the structure was also attained by deuterium labeling studies, which showed that a methyl group was added to the ene-diamide ligand carbon backbone.

Prediction of Participation and Sensory Modulation of Late Preterm Infants at 12 Months: a Prospective Study

The aim of the study was to prospectively assess the differences in participation and sensory modulation between late preterm infants (LPI) and term babies, and to predict it by LPI characteristics. The study population includes 124 late preterm infants at gestational age between 34 and 35 6/7 weeks who were born at the same medical center. The control group comprised of 33 term babies (18 boys, 15 girls), born during the same period and location (mean age 12.47, SD = 0.73). Sensory modulation was assessed by the test of sensory functions in infants and the infant/toddler sensory profile and for assessment of participation and parents' satisfaction we used questionnaires. Term infants had better sensory modulation than LPI. Approximately 10% of the sensory modulation of participants in the study was explained by gestational age and head circumference. LPI participation and parental satisfaction decreased in the LPI group. Among all the explanatory variables only multiple gestations and head circumference contributed to the explained variance of participation (16%), and parents' satisfaction (13%). At age of 1 year, children born as late preterm are at increased risk of developing sensory modulation disorder, showing less participation, and resulting in less parental satisfaction.

Variation in Clinical Presentation and Genotype of Causative Leishmania Major Strain in Cutaneous Leishmaniasis in North and South Afghanistan

A different clinical picture and therapeutic response were observed when data from Leishmania major-infected Dutch military personnel stationed in southern (N = 8) and northern (N = 169) Afghanistan were analyzed. Clinical presentation of cutaneous leishmaniasis in personnel in the south was milder and seemed to respond better to antileishmanial treatment; molecular analyses of parasite isolates seem to indicate that these differences may be genetic.

What the 'Moonwalk' Illusion Reveals About the Perception of Relative Depth from Motion

When one visual object moves behind another, the object farther from the viewer is progressively occluded and/or disoccluded by the nearer object. For nearly half a century, this dynamic occlusion cue has been thought to be sufficient by itself for determining the relative depth of the two objects. This view is consistent with the self-evident geometric fact that the surface undergoing dynamic occlusion is always farther from the viewer than the occluding surface. Here we use a contextual manipulation ofa previously known motion illusion, which we refer to as the'Moonwalk' illusion, to demonstrate that the visual system cannot determine relative depth from dynamic occlusion alone. Indeed, in the Moonwalk illusion, human observers perceive a relative depth contrary to the dynamic occlusion cue. However, the perception of the expected relative depth is restored by contextual manipulations unrelated to dynamic occlusion. On the other hand, we show that an Ideal Observer can determine using dynamic occlusion alone in the same Moonwalk stimuli, indicating that the dynamic occlusion cue is, in principle, sufficient for determining relative depth. Our results indicate that in order to correctly perceive relative depth from dynamic occlusion, the human brain, unlike the Ideal Observer, needs additional segmentation information that delineate the occluder from the occluded object. Thus, neural mechanisms of object segmentation must, in addition to motion mechanisms that extract information about relative depth, play a crucial role in the perception of relative depth from motion.

Speech Recognition in Noise with Active and Passive Hearing Protectors: a Comparative Study

The perceived negative influence of standard hearing protectors on communication is a common argument for not wearing them. Thus, "augmented" protectors have been developed to improve speech intelligibility. Nevertheless, their actual benefit remains a point of concern. In this paper, speech perception with active earplugs is compared to standard passive custom-made earplugs. The two types of active protectors included amplify the incoming sound with a fixed level or to a user selected fraction of the maximum safe level. For the latter type, minimal and maximal amplification are selected. To compare speech intelligibility, 20 different speech-in-noise fragments are presented to 60 normal-hearing subjects and speech recognition is scored. The background noise is selected from realistic industrial noise samples with different intensity, frequency, and temporal characteristics. Statistical analyses suggest that the protectors' performance strongly depends on the noise condition. The active protectors with minimal amplification outclass the others for the most difficult and the easiest situations, but they also limit binaural listening. In other conditions, the passive protectors clearly surpass their active counterparts. Subsequently, test fragments are analyzed acoustically to clarify the results. This provides useful information for developing prototypes, but also indicates that tests with human subjects remain essential.

Phylogeny of the Gudgeons (Teleostei: Cyprinidae: Gobioninae)

The members of the cyprinid subfamily Gobioninae, commonly called gudgeons, form one of the most well-established assemblages in the family Cyprinidae. The subfamily is a species-rich group of fishes, these fishes display diverse life histories, appearances, and behavior. The phylogenetic relationships of Gobioninae are examined using sequence data from four loci: cytochrome b, cytochrome c oxidase I, opsin, and recombination activating gene 1. This investigation produced a data matrix of 4114 bp for 162 taxa that was analyzed using parsimony, maximum likelihood, and Bayesian inference methods. The phylogenies our analyses recovered corroborate recent studies on the group. The subfamily Gobioninae is monophyletic and composed of three major lineages. We find evidence for a Hemibarbus-Squalidus group, and the tribes Gobionini and Sarcocheilichthyini, with the Hemibarbus-Squalidus group sister to a clade of Gobionini-Sarcocheilichthyini. The Hemibarbus-Squalidus group includes those two genera; the tribe Sarcocheilichthyini includes Coreius, Coreoleuciscus, Gnathopogon, Gobiocypris, Ladislavia, Paracanthobrama, Pseudorasbora, Pseudopungtungia, Pungtungia, Rhinogobio, and Sarcocheilichthys; the tribe Gobionini includes Abbottina, Biwia, Gobio, Gobiobotia, Huigobio, Microphysogobio, Platysmacheilus, Pseudogobio, Romanogobio, Saurogobio, and Xenophysogobio. The monotypic Acanthogobio is placed into the synonymy of Gobio. We tentatively assign Belligobio to the Hemibarbus-Squalidus group and Mesogobio to Gobionini; Paraleucogobio and Parasqualidus remain incertae sedis. Based on the topologies presented, the evolution of swim bladder specializations, a distinctive feature among cyprinids, has occurred more than once within the subfamily.

SNP-based Typing: a Useful Tool to Study Bordetella Pertussis Populations

To monitor changes in Bordetella pertussis populations, mainly two typing methods are used; Pulsed-Field Gel Electrophoresis (PFGE) and Multiple-Locus Variable-Number Tandem Repeat Analysis (MLVA). In this study, a single nucleotide polymorphism (SNP) typing method, based on 87 SNPs, was developed and compared with PFGE and MLVA. The discriminatory indices of SNP typing, PFGE and MLVA were found to be 0.85, 0.95 and 0.83, respectively. Phylogenetic analysis, using SNP typing as Gold Standard, revealed false homoplasies in the PFGE and MLVA trees. Further, in contrast to the SNP-based tree, the PFGE- and MLVA-based trees did not reveal a positive correlation between root-to-tip distance and the isolation year of strains. Thus PFGE and MLVA do not allow an estimation of the relative age of the selected strains. In conclusion, SNP typing was found to be phylogenetically more informative than PFGE and more discriminative than MLVA. Further, in contrast to PFGE, it is readily standardized allowing interlaboratory comparisons. We applied SNP typing to study strains with a novel allele for the pertussis toxin promoter, ptxP3, which have a worldwide distribution and which have replaced the resident ptxP1 strains in the last 20 years. Previously, we showed that ptxP3 strains showed increased pertussis toxin expression and that their emergence was associated with increased notification in The Netherlands. SNP typing showed that the ptxP3 strains isolated in the Americas, Asia, Australia and Europe formed a monophyletic branch which recently diverged from ptxP1 strains. Two predominant ptxP3 SNP types were identified which spread worldwide. The widespread use of SNP typing will enhance our understanding of the evolution and global epidemiology of B. pertussis.

Evidence for Association of Hyperprolinemia with Schizophrenia and a Measure of Clinical Outcome

There are multiple genetic links between schizophrenia and a deficit of proline dehydrogenase (PRODH) enzyme activity. However, reports testing for an association of schizophrenia with the resulting proline elevation have been conflicting. The objectives of this study were to investigate whether hyperprolinemia is associated with schizophrenia, and to measure the relationship between plasma proline, and clinical features and symptoms of schizophrenia. We performed a cross-sectional case-control study, comparing fasting plasma proline in 90 control subjects and 64 schizophrenic patients and testing for association of mild to moderate hyperprolinemia with schizophrenia. As secondary analyses, the relationship between hyperprolinemia and five measures of clinical onset, symptoms and outcome were investigated. Patients had significantly higher plasma proline than matched controls (p<0.0001), and categorical analysis of gender adjusted hyperprolinemia showed a significant association with schizophrenia (OR 6.15, p=0.0003). Hyperprolinemic patients were significantly older at their first hospitalization (p=0.015 following correction for multiple testing). While plasma proline level was not related to total, positive or negative symptoms, hyperprolinemic status had a significant effect on length of hospital stay (p=0.005), following adjustment for race, BPRS score, and cross-sectional time from admission to proline measurement. Mild to moderate hyperprolinemia is a significant risk factor for schizophrenia, and may represent an intermediate phenotype in the disease. Hyperprolinemic patients have a significantly later age of first psychiatric hospitalization, suggestive of later onset, and hospital stays 46% longer than non-hyperprolinemic subjects. These findings have implications in the etiology of schizophrenia, and for the clinical management of these patients.

[Hyperuricemia in Chronic Heart Failure]

Development of hyperuricemia is associated with excessive body mass, insulin resistance, metabolic syndrome, overuse of diuretics, elderly age, and abnormal renal function. Data are accumulated on existence of links between elevated uric acid level and arterial hypertension, diabetes mellitus, ischemic heart disease, and chronic heart failure (CHF). Hyperuricemia has been found in 60% of patients hospitalized because of decompensation of CHF. In CHF isolated hyperuricemia (irrespective of the state of renal function and administration of drugs) appears to be a marker of altered oxidative metabolism characterized by elevation of levels of free radicals which damage cardiomyocytes and vascular endothelium inducing disturbances of myocardial contractility and vasoconstriction. Hyperuricemia associated with insulin resistance, tissue hypoxia, elevated production of cytokines and free radicals can negatively affect cardiovascular system and worsen prognosis in patients with CHF.

[What to Expect from Allergy Tests?]

Diagnosis in allergology is facing novel challenges because of the availability not only of purified or recombinant allergens, but also of multitests such as allergen micro-arrays. These new diagnostic opportunities contribute to a better understanding of crossreactivities between respiratory and food allergens. In comparison to current diagnosis based on whole allergen extracts, this novel generation of specific IgE tests is expected to provide better information on the risk of reaction to allergens as well as on its severity. However these new technologies are expensive, and will have to be carefully analyzed in terms of medical usefulness and public health costs.

[Allergen Specific Immunotherapy: Review of New Perspectives]

Allergic diseases constitute a health problem worldwide. More than just a treatment option, the classical desensitization (SIT--Specific immunotherapy) by subcutaneous injection has profiled over time as a unique approach, able to attenuate the immune response to allergic stimuli proved. For a long time conservative, desensitization has now progressed in the knowledge of allergens, in the understanding of the mechanisms involved in immune response and in production techniques. From recombinants to alternative routes of allergen delivery, this article gives an overview of new perspectives and assesses SIT in order to provide guidance to the general physician before choosing to initiate such treatment or not in patients with respiratory allergy.

[Hymenoptera Venom Allergy: New Diagnostic Tools and Management]

Anaphylactic reactions to hymenoptera venoms are common and, in our latitudes, mainly concern wasps and bees. Recently, molecular biology techniques have contributed to identifying and to sequencing the major allergens of insect venoms and led to the production of recombinant allergens. Assays for specific IgE directed against these recombinant allergens have recently been made available in clinical practice. They provide considerable assistance in identifying the insect responsible for an anaphylactic reaction, in particular when standard tests are positive for both wasp and bee. This article focuses on these new laboratory tests and also reviews the management of patients experiencing an anaphylactic reaction after hymenoptera sting.

Morphological Variation of the Palatal Organ and Chewing Pad of Catostomidae (teleostei: Cypriniformes)

We studied the morphology and shape variation of the palatal organ and chewing pad of sucker fishes, family Catostomidae. The palatal organ is a muscularized structure that forms a large mass on the roof of the posterior part of the buccopharyngeal cavity in cypriniform fishes. It functions in coordination with the branchial arches to separate food items from inorganic debris during feeding. The palatal organ exhibits considerable variability in morphology among catostomids. It is shorter, narrower, and thinner in species of the subfamily Cycleptinae (e.g., Cycleptus elongatus) than in other catostomid subfamilies. The thickest and widest palatal organ is seen in species of the subfamily Ictiobinae (e.g., Ictiobus cyprinellus). The shape and size of the palatal organ generally varies between these extremes in species of subfamily Catostominae (e.g., Catostomus and Moxostoma species). Principal components analysis and analysis of variance has differentiated means of various palatal organ measurements for each monophyletic subfamily and tribe of Catostomidae with statistical significance. These results corroborate previously established typological classification of catostomids based on pharyngeal tooth count, pharyngeal tooth morphology, and diet. A keratinized chewing pad forms on the posterior surface of the palatal organ in catostomids or on a skeletal process in cyprinids and serves as an occlusion surface for pharyngeal teeth. The chewing pad is lunate in catostomids and generally ovoid in cyprinids. It is absent from the species of loaches (e.g., botiids, cobitids, and nemacheilids) and gyrinocheilids examined. A synonymy of terms used in the past to describe the palatal organ and chewing pad of Cypriniformes is provided.

Management of Stress Urinary Incontinence Following Prostate Surgery with Minimally Invasive Adjustable Continence Balloon Implants: Functional Results from a Single Center Prospective Study

We determined the functional results and morbidity of balloon (ProACTâ„¢) implants for the treatment of male stress urinary incontinence after prostate surgery.

[Chagas Disease in the Netherlands: an Estimate of the Number of Patients]

A total of 8-10 million persons are infected worldwide with Trypanosoma cruzi, the causative parasite of Chagas disease, most of whom are inhabitants of Latin America. Due to the increased migration of peoples, Chagas disease has been on the uprise outside Latin America, including in Europe. The course of Chagas, also called American trypanosomiasis, runs in 2 phases: an acute phase lasting approximately 2 months, and a chronic phase in which symptoms may appear years after infection. Without treatment, the patient will remain infected for life. The acute phase is usually asymptomatic; in the chronic phase of American trypanosomiasis, severe gastro-intestinal and cardiac abnormalities may develop, finally with fatal course. In the Netherlands, the number of immigrants who would serologically test positive for American trypanosomiasis is estimated to be between 726 and 2929. Healthcare providers in the Netherlands may encounter patients who have Chagas disease more and more frequently. The screening of pregnant women and blood donors at risk for American trypanosomiasis should be considered.

Unsupervised Organization of Image Collections: Taxonomies and Beyond

We introduce a nonparametric Bayesian model, called TAX, which can organize image collections into a tree-shaped taxonomy without supervision. The model is inspired by the Nested Chinese Restaurant Process (NCRP) and associates each image with a path through the taxonomy. Similar images share initial segments of their paths and thus share some aspects of their representation. Each internal node in the taxonomy represents information that is common to multiple images. We explore the properties of the taxonomy through experiments on a large (~10(4)) image collection with a number of users trying to locate quickly a given image. We find that the main benefits are easier navigation through image collections and reduced description length. A natural question is whether a taxonomy is the optimal form of organization for natural images. Our experiments indicate that although taxonomies can organize images in a useful manner, more elaborate structures may be even better suited for this task.

Enhancing Surgical Vision by Using Real-time Imaging of αvβ3-integrin Targeted Near-infrared Fluorescent Agent

This study was designed to improve the surgical procedure and outcome of cancer surgery by means of real-time molecular imaging feedback of tumor spread and margin delineation using targeted near-infrared fluorescent probes with specificity to tumor biomarkers. Surgical excision of cancer often is confronted with difficulties in the identification of cancer spread and the accurate delineation of tumor margins. Currently, the assessment of tumor borders is afforded by postoperative pathology or, less reliably, intraoperative frozen sectioning. Fluorescence imaging is a natural modality for intraoperative use by directly relating to the surgeon's vision and offers highly attractive characteristics, such as high-resolution, sensitivity, and portability. Via the use of targeted probes it also becomes highly tumor-specific and can lead to significant improvements in surgical procedures and outcome.

Mu-opioid Receptor A118G Polymorphism in Healthy Volunteers Affects Hypothalamic-pituitary-adrenal Axis Adrenocorticotropic Hormone Stress Response to Metyrapone

The mu-opioid receptor encoded by the gene OPRM1 plays a primary role in opiate, alcohol, cocaine and nicotine addiction. Studies using opioid antagonists demonstrate that the mu-opioid receptor (MOP-r) also mediates the hypothalamic-pituitary-adrenal (HPA) axis stress response. A common polymorphism in exon one of the MOP-r gene, A118G, has been shown to significantly alter receptor function and MOP-r gene expression; therefore, this variant likely affects HPA-axis responsivity. In the current study, we have investigated whether the presence of the 118AG variant genotype affects HPA axis responsivity to the stressor metyrapone, which transiently blocks glucocorticoid production in the adrenal cortex. Forty-eight normal and healthy volunteers (32 men, 16 women) were studied, among whom nine men and seven women had the 118AG genotype. The 118G allele blunted the adrenocorticotropic hormone (ACTH) response to metyrapone. Although there was no difference in basal levels of ACTH, subjects with the 118AG genotype had a more modest rise and resultant significantly lower ACTH levels than those with the prototype 118AA at the 8-hour time point (P < 0.02). We found no significant difference between genders. These findings suggest a relatively greater tonic inhibition at hypothalamic-pituitary sites through the mu-opioid receptor and relatively less cyclical glucocorticoid inhibition in subjects with the 118G allele.

Selecting Potential Targetable Biomarkers for Imaging Purposes in Colorectal Cancer Using TArget Selection Criteria (TASC): A Novel Target Identification Tool

Peritoneal carcinomatosis (PC) of colorectal origin is associated with a poor prognosis. However, cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy is available for a selected group of PC patients, which significantly increases overall survival rates up to 30%. As a consequence, there is substantial room for improvement. Tumor targeting is expected to improve the treatment efficacy of colorectal cancer (CRC) further through 1) more sensitive preoperative tumor detection, thus reducing overtreatment; 2) better intraoperative detection and surgical elimination of residual disease using tumor-specific intraoperative imaging; and 3) tumor-specific targeted therapeutics. This review focuses, in particular, on the development of tumor-targeted imaging agents. A large number of biomarkers are known to be upregulated in CRC. However, to date, no validated criteria have been described for the selection of the most promising biomarkers for tumor targeting. Such a scoring system might improve the selection of the correct biomarker for imaging purposes. In this review, we present the TArget Selection Criteria (TASC) scoring system for selection of potential biomarkers for tumor-targeted imaging. By applying TASC to biomarkers for CRC, we identified seven biomarkers (carcinoembryonic antigen, CXC chemokine receptor 4, epidermal growth factor receptor, epithelial cell adhesion molecule, matrix metalloproteinases, mucin 1, and vascular endothelial growth factor A) that seem most suitable for tumor-targeted imaging applications in colorectal cancer. Further cross-validation studies in CRC and other tumor types are necessary to establish its definitive value.

[Non-rheumatic Myocarditis in Practice of Outpatient Therapist and Cardiologist]

Non-rheumatic myocarditis occurs in therapeutic and cardiological practice both at prehospital and hospital stages. Diagnosis of this myocarditis at early stages is difficult. The course and outcome of this disease and its present-day treatment are outlined to help clinical and cardiological practitioners.

Phylogenetic Relationships of the North American Cyprinid Subgenus Hydrophlox

Notropis is one of the largest genera of North American fishes and is composed of a number of morphologically diagnosed subgroups; however, the validity of many has not been tested in a phylogenetic framework. One such subgroup is the subgenus Hydrophlox, which is composed of brilliantly colored species that engage in the symbiotic reproductive behavior of nest association. Although they have long been recognized as a cohesive group due to their nuptial coloration and fin tuberculation, very little is known about the relationships of species within Hydrophlox. We tested the monophyly of Hydrophlox using a mitochondrial marker (ND2) and two nuclear markers (ITS1 and RH), with Maximum Parsimony and Bayesian inference approaches. A well supported clade of "core"Hydrophlox was recovered and is composed of five taxa: Notropis chiliticus, Notropis rubricroceus, Notropis lutipinnis, Notropis chlorocephalus, and Notropis chrosomus. Hydrophlox s.l. is paraphyletic with respect to three taxa: Notropis baileyi, Notropis leuciodus and Notropis nubilus. While there was some discordance among the individual marker topologies, a combined evidence analysis recovered a topology that incorporated elements from all single-gene trees. Our analyses suggest that Hydrophlox is composed of five nominal species and additional undescribed diversity exists within this clade.

[Allergy-immunology. Do We Have to Be Afraid of Biological Agents?]

Biologicals are now fully part of our daily therapeutic strategies. However, even if their high specificity seems to induce less risk compared to older or classical immunosuppressive drugs, there are not harmless especially regarding infectious but also immunological and allergic issues. Recent attempts to better characterize the different types of reactions to biologicals should be reported, allowing us better understanding of the risk to maintain these therapies or defining how to improve the methods to use them.

How Do Young Children with DCD Participate and Enjoy Daily Activities?

Developmental problems may decrease participation of children. The objective of this study was to evaluate multidimensional aspects of participation amongst preschool children with and without DCD. Participants included 63 children with mean age of 4.96 years (SD=0.62; range=4.02-6.35 years). Twenty one children were diagnosed with DCD, 21 children without DCD who were referred to OT due to mild developmental problems, and 21 children from mainstream public kindergartens whom did not require any developmental intervention. All three groups were matched for age, gender, and socioeconomic status. Children were administered the M-ABC2 and their parents completed the PSQ questionnaire. Results indicate significant differences in level of independence and subjective measures of participation (enjoyment and parents' satisfaction) between the DCD group and the two other groups. The results indicate that from a young age, and in comparison to their peers, the participation of children with DCD is compromised. The integration of the DSM diagnostic criteria and the ICF perception of health enables us to capture the full scope of DCD and its complexity.

Effects of Prone and Supine Positions on Sleep State and Stress Responses in Preterm Infants

The purpose of the study is to assess the influence of prone or supine position on sleep states and on withdrawal and approach reactions of preterm infants.

Functionalization of Carbon Dioxide and Carbon Disulfide Using a Stable Uranium(III) Alkyl Complex

A rare uranium(III) alkyl complex, Tp*(2)U(CH(2)Ph) (2) (Tp* = hydrotris(3,5-dimethylpyrazolyl)borate), was synthesized by salt metathesis from Tp*(2)UI (1) and KCH(2)Ph and fully characterized using (1)H NMR, infrared, and electronic absorption spectroscopies as well as X-ray crystallography. This complex has a uranium-carbon distance of 2.57(2) Å, which is comparable to other uranium alkyls reported. Treating this compound with either carbon dioxide or carbon disulfide results in insertion into the uranium-carbon bond to generate Tp*(2)U(κ(2)-O(2)CCH(2)Ph) (3) and Tp*(2)U(SC(S)CH(2)Ph) (4), respectively. These species, characterized spectroscopically and by X-ray crystallography, feature new carboxylate and dithiocarboxylate ligands. Analysis by electronic absorption spectroscopy supports the trivalent oxidation state of the uranium center in both of these derivatives. Addition of trimethylsilylhalides (Me(3)SiX; X = Cl, I) to 3 results in the release of the free silyl ester, Me(3)SiOC(O)CH(2)Ph, forming the initial uranium monohalide species, Tp*(2)UX, which can then be used over multiple cycles for the functionalization of carbon dioxide.

Diuretic Strategies in Patients with Acute Decompensated Heart Failure

Loop diuretics are an essential component of therapy for patients with acute decompensated heart failure, but there are few prospective data to guide their use.

Expression of the Stem Cell Marker ALDH1 in BRCA1 Related Breast Cancer

The BRCA1 protein makes mammary stem cells differentiate into mature luminal and myoepithelial cells. If a BRCA1 mutation results in a differentiation block, an enlarged stem cell component might be present in the benign tissue of BRCA1 mutation carriers, and these mammary stem cells could be the origin of BRCA1 related breast cancer. Since ALDH1 is a marker of both mammary stem cells and breast cancer stem cells, we compared ALDH1 expression in malignant tissue of BRCA1 mutation carriers to non-carriers.

Dominant TNF-α+ Mycobacterium Tuberculosis-specific CD4+ T Cell Responses Discriminate Between Latent Infection and Active Disease

Rapid diagnosis of active Mycobacterium tuberculosis (Mtb) infection remains a clinical and laboratory challenge. We have analyzed the cytokine profile (interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α) and interleukin-2 (IL-2)) of Mtb-specific T cells by polychromatic flow cytometry. We studied Mtb-specific CD4+ T cell responses in subjects with latent Mtb infection and active tuberculosis disease. The results showed substantial increase in the proportion of single-positive TNF-α Mtb-specific CD4+ T cells in subjects with active disease, and this parameter was the strongest predictor of diagnosis of active disease versus latent infection. We validated the use of this parameter in a cohort of 101 subjects with tuberculosis diagnosis unknown to the investigator. The sensitivity and specificity of the flow cytometry-based assay were 67% and 92%, respectively, the positive predictive value was 80% and the negative predictive value was 92.4%. Therefore, the proportion of single-positive TNF-α Mtb-specific CD4+ T cells is a new tool for the rapid diagnosis of active tuberculosis disease.

Participation Patterns of School-aged Children with and Without DCD

Participation is recognized as a key to one's health and well-being and is considered to be a vital part of the development of children and youth. The purpose of this study was to examine the participation patterns of children with and without Developmental Coordination Disorder (DCD) in their out-of-school-time (OST) activities, and to see whether there is a relationship between the children's motor abilities and their choices and participation.

Immunodeficiency in a Child with Partial Trisomy 6p

AIM: We present a mentally retarded boy with partial trisomy of the short arm of chromosome 6 as a result of an interstitial tandem duplication of 6p12.2-p21.31 and immunodeficiency. Patients with mental retardation because of a chromosomal disorder or eponymous syndrome often experience recurrent respiratory tract infections as a result of their associated anatomical or neurological abnormalities. However, associated immune defects may also significantly contribute to their susceptibility to infections. Timely recognition and appropriate treatment of their immunodeficiency will greatly improve quality of life in these patients. CONCLUSION: Immunodeficiency may be the direct cause of recurrent respiratory tract infections in patients with mental retardation because of a chromosomal disorder or eponymous syndrome, even in the face of feeding difficulties and multiple episodes of aspiration, as is illustrated in this boy with partial trisomy 6p.

Humoral Response to the Influenza A H1N1/09 Monovalent AS03-adjuvanted Vaccine in Immunocompromised Patients

Few data are available regarding the immunogenicity and safety of the pandemic influenza vaccine in immunocompromised patients. We evaluated the humoral response to the influenza A H1N1/09 vaccine in solid-organ transplant (SOT) recipients, in patients with human immunodeficiency virus (HIV) infection, and in healthy individuals.

To "pump Up" Quality of Life and Exercise Performance Studies in Patients with Left Ventricular Assist Devices

Using Video-capture Virtual Reality for Children with Acquired Brain Injury

To assess the use of a video-capture projected VR system for children with acquired brain injury (ABI), and to compare their performance to that of matched healthy controls.

Hoover Sign

Development and Validation of the Documentation of Occupational Therapy Session During Intervention (D.O.T.S.I.)

To developed and validate a form for Documentation of Occupational Therapy Session during Intervention (D.O.T.S.I) based on the OTPF. This form may fill the need for more consistent and detailed documentation of the intervention process.

Randomized, Crossover Study Evaluating Patient Preference and the Impact on Quality of Life of Urisheaths Vs Absorbent Products in Incontinent Men

• To evaluate the impact of urisheaths vs absorbent products (APs) on quality of life (QoL) in men with moderate to severe urinary incontinence (UI).

Approach and Management of Primary Ectopic Breast Carcinoma in the Axilla: Where Are We? A Comprehensive Historical Literature Review

Primary ectopic breast carcinoma is a rare disease and, at present, no specific guidelines on its diagnosis and treatment are available. The purpose of this article is to review the world literature in English on primary ectopic breast carcinoma located in the armpit and to offer guidelines for diagnosis and treatment. Data for this review were identified by searches of MEDLINE, PubMed, The Cochrane Library, ACNP (Italian catalogue of journals) and references from relevant articles using relevant search terms and data published in the previous reviews. Primary ectopic breast carcinoma of the axilla mostly affects women of over 40 (range 28-90 yrs) years of age. The most frequent histological diagnosis is invasive ductal carcinoma not otherwise specified (NOS) (72%). Because of its rareness, in most cases, the diagnosis is delayed for on average 40.5 months. This disease is rare, but a high level of suspicion for carcinoma is mandatory when confronted with a tumour in this area. Once diagnosed, patients should undergo staging, and prognostic and adjuvant treatment procedures identical to orthotopic breast carcinoma guidelines. There are some limitations for the staging. Loco-regional treatment, on indication, combined with endocrine therapy and/or chemotherapy seems the treatment of choice.

Can Personal and Environmental Factors Explain Dimensions of Child Participation?

One of the main goals of paediatric occupational therapists and other health professionals is to enhance child participation in age-related activities within their communities. According to theoretical models, the act of participation has numerous dimensions, affected by personal and environmental factors. However, there have been relatively few studies undertaken to validate this theory. The purpose of this study was to explore the extent to which personal and environmental factors explain each of five distinct dimensions of child participation, which are: diversity, intensity, independence, enjoyment and subsequent parental satisfaction.

[Anxiety-depressive States in Elderly Patients with Chronic Heart Failure]

Aim of the study was determination of factors of social desadaptation, which negatively affect psychoemotional status and quality of life ofelderly patients with chronic heart failure (CHF). We included into the study 248 patients aged 60-85 years and 82 patients aged 39-59years with NYHA class II-IV CHF. General state of patients we assessed with the help of clinical state assessment scale (CSAS), presence and severity of anxiety and depression -with hospital anxiety and depression scale, exercise tolerance - with 6 minute walk test. Patients of both groups were comparable by sex, severity of the CHF course quality of life, concomitant pathology, and treatment. Clinically manifest depression was found in 22.8% of patients aged 60 years and older and in 16% of patients younger than 60 years (p=0.460), clinically manifest anxiety was found in 22.8% and 20%, respectively (p=0.945). Risk factors of anxiety-depressive state in elderly patients were disability (relative risk [RR] 3.05, 95% confidence interval [CI] 1.04-8.97, p =0.042), insufficient education (RR 2.44, 95%CI 1.08-5.34; p=0.0320, and severe CHF according to CSAS (OR 1.22, 95%CI 1.07-1.4; p=0.003). According to data of multifactorial analysis disability (RR 1.78, 95%CI 1.01-3.13; p=0.045) and severe CHF (RR 1.17, 95%CI 1.07-1.27; p=0.001) were independently related to anxiety-depressive state in elderly patients. Conclution. Thus social dysadaptation and medical factors turned out to be leading parameters determining worsening of quality of life and development of anxiety-depressive state in elderly patients with CHF.

Hyaluronan in Cytosol - Microinjection-based Probing of Its Existence and Suggested Functions

Hyaluronan (HA) is a large glycosaminoglycan produced by the hyaluronan synthases (HASs), enzymes normally active at plasma membrane. While hyaluronan is delivered into the extracellular space, intracellular hyaluronan is also seen, mostly in vesicular structures, but there are also reports on its presence in the cytosol and specific locations and functions there. We probed the possibility of HA localization and functions in cytosol by microinjecting fluorescent HA binding complex (fHABC), HA fragments and hyaluronidase into cytosol. Microinjection of fHABC did not reveal HA-specific intracellular binding sites. Likewise, specific cytosolic binding sites for HA were not detected, as microinjected fluorescent HA composed of 4 to 8 monosaccharide units (HA4-HA8) were evenly distributed throughout the cells, including nucleus, but excluded from membrane-bound organelles. The largest HA tested (~HA120 or ~25 kDa) did not enter nucleus, and HA10-HA28 were progressively excluded from parts of nuclei resembling nucleoli. In contrast, HA oligosaccharides endocytosed from medium remained in vesicular compartments. The activity of hyaluronan synthesis was estimated by measuring the hyaluronan coat on GFP-HAS3-transfected MCF-7 cells. Microinjection of HA4 reduced coat size at 4 h, but increased at 24 h after injection, while larger HA-oligosaccharides and hyaluronidase had no influence. As a positive control, microinjection of glucose increased coat size. In summary, no evidence for the presence or function of HA in cytosol was obtained. Also, the synthesis of HA and the active site of HAS were not accessible to competition, binding and degradation by cytosolic effectors, while synthesis responded to increased substrate supply.

Increased Uracil Insertion in DNA is Cytotoxic and Increases the Frequency of Mutation, Double Strand Break Formation and VSG Switching in Trypanosoma Brucei

Deoxyuridine 5'-triphosphate pyrophosphatase (dUTPase) and uracil-DNA glycosylase (UNG) are key enzymes involved in the control of the presence of uracil in DNA. While dUTPase prevents uracil misincorporation by removing dUTP from the deoxynucleotide pool, UNG excises uracil from DNA as a first step of the base excision repair pathway (BER). Here, we report that strong down-regulation of dUTPase in UNG-deficient Trypanosoma brucei cells greatly impairs cell viability in both bloodstream and procyclic forms, underscoring the extreme sensitivity of trypanosomes to uracil in DNA. Depletion of dUTPase activity in the absence of UNG provoked cell cycle alterations, massive dUTP misincorporation into DNA and chromosomal fragmentation. Overall, trypanosomatid cells that lack dUTPase and UNG activities exhibited greater proliferation defects and DNA damage than cells deficient in only one of these activities. To determine the mutagenic consequences of uracil in DNA, mutation rates and spectra were analyzed in dUTPase-depleted cells in the presence of UNG activity. These cells displayed a spontaneous mutation rate 9-fold higher than the parental cell line. Base substitutions at A:T base pairs and deletion frequencies were both significantly enhanced which is consistent with the generation of mutagenic AP sites and DNA strand breaks. The increase in strand breaks conveyed a concomitant increase in VSG switching in vitro. The low tolerance of T. brucei to uracil in DNA emphasizes the importance of uracil removal and regulation of intracellular dUTP pool levels in cell viability and genetic stability and suggests potential strategies to compromise parasite survival.

Small Mutations in Bordetella Pertussis Are Associated with Selective Sweeps

Bordetella pertussis is the causative agent of pertussis, a highly contagious disease of the human respiratory tract. Despite high vaccination coverage, pertussis has resurged and has become one of the most prevalent vaccine-preventable diseases in developed countries. We have proposed that both waning immunity and pathogen adaptation have contributed to the persistence and resurgence of pertussis. Allelic variation has been found in virulence-associated genes coding for the pertussis toxin A subunit (ptxA), pertactin (prn), serotype 2 fimbriae (fim2), serotype 3 fimbriae (fim3) and the promoter for pertussis toxin (ptxP). In this study, we investigated how more than 60 years of vaccination has affected the Dutch B. pertussis population by combining data from phylogeny, genomics and temporal trends in strain frequencies. Our main focus was on the ptxA, prn, fim3 and ptxP genes. However, we also compared the genomes of 11 Dutch strains belonging to successful lineages. Our results showed that, between 1949 and 2010, the Dutch B. pertussis population has undergone as least four selective sweeps that were associated with small mutations in ptxA, prn, fim3 and ptxP. Phylogenetic analysis revealed a stepwise adaptation in which mutations accumulated clonally. Genomic analysis revealed a number of additional mutations which may have a contributed to the selective sweeps. Five large deletions were identified which were fixed in the pathogen population. However, only one was linked to a selective sweep. No evidence was found for a role of gene acquisition in pathogen adaptation. Our results suggest that the B. pertussis gene repertoire is already well adapted to its current niche and required only fine tuning to persist in the face of vaccination. Further, this work shows that small mutations, even single SNPs, can drive large changes in the populations of bacterial pathogens within a time span of six to 19 years.

Ammonia Control and Neurocognitive Outcome Among Urea Cycle Disorder Patients Treated with Glycerol Phenylbutyrate

BACKGROUND: Glycerol phenylbutyrate is under development for treatment of urea cycle disorders (UCDs), rare inherited metabolic disorders manifested by hyperammonemia and neurological impairment. METHODS: We report the results of a pivotal phase 3, randomized, double-blind, crossover trial comparing ammonia control, assessed as 24-hour area under the curve (NH(3) -AUC(0-24hr) ), and pharmacokinetics during treatment with glycerol phenylbutyrate versus sodium phenylbutyrate (NaPBA) in adult UCD patients and the combined results of 4 studies involving short- and long- term glycerol phenylbutyrate treatment of UCD patients ages 6 and above. RESULTS: Glycerol phenylbutyrate was non-inferior to NaPBA with respect to ammonia control in the pivotal study, with mean (SD) NH(3) -AUC(0-24hr) of 866 (661) versus 977 (865) μmolùh/L for glycerol phenylbutyrate and NaPBA, respectively. Among 65 adult and pediatric patients completing 3 similarly designed short term comparisons of glycerol phenylbutyrate versus NaPBA, NH(3) -AUC(0-24hr) was directionally lower on glycerol phenylbutyrate in each study, similar among all subgroups, and significantly lower (p<0.05) in the pooled analysis, as was plasma glutamine. The 24-hour ammonia profiles were consistent with slow release behavior of glycerol phenylbutyrate and better overnight ammonia control. During 12 months of open label glycerol phenylbutyrate treatment, average ammonia was normal in adult and pediatric patients and executive function among pediatric patients, including behavioral regulation, goal setting, planning and self-monitoring, was significantly improved. CONCLUSIONS: Glycerol phenylbutyrate exhibits favorable pharmacokinetics and ammonia control relative to NaPBA in UCD patients, and long-term glycerol phenylbutyrate treatment in pediatric patients was associated with improved executive function (ClinicalTrials.gov NCT00551200, NCT00947544, NCT00992459, NCT00947297). (HEPATOLOGY 2012.).

Urinary Phenylacetylglutamine As Dosing Biomarker for Patients with Urea Cycle Disorders

We have analyzed pharmacokinetic data for glycerol phenylbutyrate (also GT4P or HPN-100) and sodium phenylbutyrate with respect to possible dosing biomarkers in patients with urea cycle disorders (UCD).

The Profile of Performance Skills and Emotional Factors in the Context of Participation Among Young Children with Developmental Coordination Disorder

Participation is a person's involvement in daily activities in a variety of environments, roles and life situations. Children with Developmental Coordination Disorder (DCD) experience difficulties in gaining academic achievements or in their engagement in activity of daily living. Motor difficulties have a negative effect on the ability to participate, as well as on various affective components. Senses of coherence, effort and hope have not yet been assessed, within the context of participation, in children with DCD. The purpose of the present study is to look into the relations between participation and senses of coherence, effort and hope among children with DCD, in comparison to typically developed children. Fifty subjects aged 5-6years participated in the study, 25 of whom are children diagnosed with DCD, the other 25 being typical children. The DCD diagnosis was established according to the DSM-IV criteria and the M-ABC test. All children completed the coherence questionnaire for children as well as the children's questionnaire on effort and hope. Parents completed the Children Participation Questionnaire (CPQ), and the Performance Skills Questionnaire (PSQ). Children with DCD had lower performance skills, lower sense of coherence, hope, and effort than their peers. They less enjoy their participation and their parents are less satisfied in comparison to control group. Significant correlations were found between sense of coherence and hope to participation. Process skills were found to be the main predictor for explaining child's participation. While treating children with DCD we have to consider also socio-psychological aspects that may be weakened.

Invariant Recognition of Visual Objects: Some Emerging Computational Principles

Invariant Object Recognition Based on Extended Fragments

Visual appearance of natural objects is profoundly affected by viewing conditions such as viewpoint and illumination. Human subjects can nevertheless compensate well for variations in these viewing conditions. The strategies that the visual system uses to accomplish this are largely unclear. Previous computational studies have suggested that in principle, certain types of object fragments (rather than whole objects) can be used for invariant recognition. However, whether the human visual system is actually capable of using this strategy remains unknown. Here, we show that human observers can achieve illumination invariance by using object fragments that carry the relevant information. To determine this, we have used novel, but naturalistic, 3-D visual objects called "digital embryos." Using novel instances of whole embryos, not fragments, we trained subjects to recognize individual embryos across illuminations. We then tested the illumination-invariant object recognition performance of subjects using fragments. We found that the performance was strongly correlated with the mutual information (MI) of the fragments, provided that MI value took variations in illumination into consideration. This correlation was not attributable to any systematic differences in task difficulty between different fragments. These results reveal two important principles of invariant object recognition. First, the subjects can achieve invariance at least in part by compensating for the changes in the appearance of small local features, rather than of whole objects. Second, the subjects do not always rely on generic or pre-existing invariance of features (i.e., features whose appearance remains largely unchanged by variations in illumination), and are capable of using learning to compensate for appearance changes when necessary. These psychophysical results closely fit the predictions of earlier computational studies of fragment-based invariant object recognition.

NYVAC Immunization Induces Polyfunctional HIV-specific T-cell Responses in Chronically-infected, ART-treated HIV Patients

We report the results of the Theravac-01 phase I trial, which was conducted to evaluate the safety and immunogenicity of a poxvirus-based vector, NYVAC, expressing Gag, Pol, Nef, and Env from an HIV clade B isolate. NYVAC-B vaccine was injected intra-muscularly into ten HIV-infected patients successfully treated with antiretroviral therapy, twice on day 0 and again at week 4. Safety and immunogenicity were monitored for 48 weeks. HIV-specific T-cell responses following immunization were quantitatively analyzed using an IFN-γ ELISPOT assay and qualitatively characterized for their functional profile (including multiple cytokines secretion plus cytotoxic and proliferation capacity) by polychromatic flow cytometry. Our results indicate that the NYVAC-B vaccine is safe and highly immunogenic, as indicated by increased HIV-specific T-cell responses in virtually all vaccinees. Interestingly, both an expansion of preexisting T-cell responses, and the appearance of newly detected HIV-specific CD4(+) and CD8(+) T-cell responses were observed. Furthermore, immunization mostly induced an increase in Gag-specific T-cell responses. In conclusion, NYVAC-B immunization induces broad, vigorous, and polyfunctional HIV-specific T-cell responses, suggesting that poxvirus-based vaccine regimens may be instrumental in the therapeutic HIV vaccine field.

Support of the 'fallopian Tube Hypothesis' in a Prospective Series of Risk-reducing Salpingo-oophorectomy Specimens

OBJECTIVE: To determine the prevalence, localisation and type of occult (non)invasive cancer in risk-reducing salpingo-oophorectomy (RRSO) specimens in BRCA-mutation carriers and high-risk women from BRCA-negative families. METHODS: A consecutive series of RRSO specimens of asymptomatic, screen-negative high-risk women were prospectively collected in our tertiary multidisciplinary cancer clinic from January 2000 until March 2012. All high-risk women in this study underwent genetic testing on BRCA-mutations. The surgico-pathological protocol comprised complete resection of ovaries and fallopian tubes, transverse sectioning at 2-3mm (sectioning and extensively examining the fimbrial end [SEE-FIM] protocol from 2006) and double independent pathology review of morphologically deviant sections. RESULTS: Three hundred and sixty RRSOs were performed in 188 BRCA1-carriers, 115 BRCA2-carriers and 57 BRCA-negative women at a median age of 44.0years. Four occult invasive cancers were detected in BRCA-carriers (1.3%, 95%-confidence interval (CI) 0.03-2.61), all in BRCA1-carriers >40years of age. All cancers, of which two tubal and two ovarian cancers, were FIGO-stage I/II. Three non-invasive serous intraepithelial carcinomas (STICs) were detected in BRCA-carriers (1.0%, 95%-CI 0.00-2.10). In BRCA-negative women one STIC was found (1.8%, 95%-CI 0.00-5.16), however she carried an unclassified variant in BRCA2. Total follow-up after RRSO was 1691 woman-years, in which one BRCA1-carrier developed peritoneal cancer (0.3%, 95%-CI 0.00-0.82). CONCLUSIONS: A low prevalence of occult invasive cancer (1.1%) was found in young asymptomatic, screen-negative women at increased ovarian cancer risk undergoing RRSO. This study adds to the advice to perform RRSO in BRCA1-carriers before the age of 40. Our findings support the hypothesis of the fallopian tube as the primary site of origin of pelvic high-grade serous cancer.

The CCRC Conundrum

Third Target of Rapamycin Complex Negatively Regulates Development of Quiescence in Trypanosoma Brucei

African trypanosomes are protozoan parasites transmitted by a tsetse fly vector to a mammalian host. The life cycle includes highly proliferative forms and quiescent forms, the latter being adapted to host transmission. The signaling pathways controlling the developmental switch between the two forms remain unknown. Trypanosoma brucei contains two target of rapamycin (TOR) kinases, TbTOR1 and TbTOR2, and two TOR complexes, TbTORC1 and TbTORC2. Surprisingly, two additional TOR kinases are encoded in the T. brucei genome. We report that TbTOR4 associates with an Armadillo domain-containing protein (TbArmtor), a major vault protein, and LST8 to form a unique TOR complex, TbTORC4. Depletion of TbTOR4 caused irreversible differentiation of the parasite into the quiescent form. AMP and hydrolysable analogs of cAMP inhibited TbTOR4 expression and induced the stumpy quiescent form. Our results reveal unexpected complexity in TOR signaling and show that TbTORC4 negatively regulates differentiation of the proliferative form into the quiescent form.

Maintenance Medication for Opiate Addiction: the Foundation of Recovery

Illicit use of opiates is the fastest growing substance use problem in the United States, and the main reason for seeking addiction treatment services for illicit drug use throughout the world. It is associated with significant morbidity and mortality related to human immunodeficiency virus, hepatitis C, and overdose. Treatment for opiate addiction requires long-term management. Behavioral interventions alone have extremely poor outcomes, with more than 80% of patients returning to drug use. Similarly poor results are seen with medication-assisted detoxification. This article provides a topical review of the three medications approved by the Food and Drug Administration for long-term treatment of opiate dependence: the opioid-agonist methadone, the partial opioid-agonist buprenorphine, and the opioid-antagonist naltrexone. Basic mechanisms of action and treatment outcomes are described for each medication. Results indicate that maintenance medication provides the best opportunity for patients to achieve recovery from opiate addiction. Extensive literature and systematic reviews show that maintenance treatment with either methadone or buprenorphine is associated with retention in treatment, reduction in illicit opiate use, decreased craving, and improved social function. Oral naltrexone is ineffective in treating opiate addiction, but recent studies using extended-release naltrexone injections have shown promise. Although no direct comparisons between extended-release naltrexone injections and either methadone or buprenorphine exist, indirect comparison of retention shows inferior outcome compared with methadone and buprenorphine. Further work is needed to directly compare each medication and determine individual factors that can assist in medication selection. Until such time, selection of medication should be based on informed choice following a discussion of outcomes, risks, and benefits of each medication.

Exploring the Relationships Between Patient Characteristics and Their Dialysis Care Experience

BackgroundPrevious studies have shown that it is possible for patient experience to be influenced by factors that are not attributable to health-care. Therefore, if patient experience is to be used as an accurate indicator of clinical performance, then it is important to understand its determinants.MethodsWe used data from 840 dialysis patients who completed a validated patient experience survey. We created a potential theoretical framework based on available clinical knowledge to hypothesize the relationships between 13 demographic, socio-economic and health status factors and three outcome measures: global rating of the dialysis centre and the patient experience with the nephrologist's and nurses' care. The theoretical framework guided the selection of confounding variables for each determinant, which were then entered as terms in multivariable linear regression models.ResultsPatients who were of older age, of non-European decent, and who had a lower educational level, lower albumin level, with better self-rated health and who were without co-morbidities reported higher global ratings with the dialysis centre than their counterparts. Past myocardial infarction and better self-rated health were found to be determinants of a more positive experience while in the nephrologist's care. A more positive experience with nurses' care was associated with factors including older age, Dutch origin background, lower educational level, lower albumin levels and better self-rated health.ConclusionsSeveral characteristics of dialysis patients influence the way they rate and experience their care. When using the patient experience and ratings as indicators of clinical performance, they should be adjusted for such factors as identified in our study. This will facilitate a meaningful comparison of dialysis centres, and enable informed decision making by patients, insurers and policy makers.

[Initial Training in Regional Anesthesia for the French Residents: A Nationwide Survey]

To assess both level and type of the initial training on regional anesthesia for French residents after the publication of formalized recommendations of experts on training and practice in regional anesthesia in 2006.

Complication and Failure Rates of Tooth-supported Fixed Dental Prostheses After 7 to 19 Years in Function

The aims of this study were to reexamine patients who had received fixed dental prostheses (FDPs) more than 10 years prior, list the frequencies of observed technical and biologic failures and complications, and calculate the estimated failure and complication rates at 10 and 15 years.

High-throughput Genomic Sequencing of Cassava Bacterial Blight Strains Identifies Conserved Effectors to Target for Durable Resistance

Cassava bacterial blight (CBB), incited by Xanthomonas axonopodis pv. manihotis (Xam), is the most important bacterial disease of cassava, a staple food source for millions of people in developing countries. Here we present a widely applicable strategy for elucidating the virulence components of a pathogen population. We report Illumina-based draft genomes for 65 Xam strains and deduce the phylogenetic relatedness of Xam across the areas where cassava is grown. Using an extensive database of effector proteins from animal and plant pathogens, we identify the effector repertoire for each sequenced strain and use a comparative sequence analysis to deduce the least polymorphic of the conserved effectors. These highly conserved effectors have been maintained over 11 countries, three continents, and 70 y of evolution and as such represent ideal targets for developing resistance strategies.

Determining Sensitivity and Specificity of HER2 Testing in Breast Cancer Using a Tissue Micro-array Approach

Overexpression of the human epidermal growth factor receptor 2 (HER2) as a result of HER2 gene amplification is associated with a relatively poor prognosis in breast cancer and is predictive of HER2-targeting therapy response. False-positive rates of up to 20% for HER2 testing have been described. HER2-testing laboratories are therefore encouraged to participate in external quality control schemes in order to improve HER2-testing standardization.

Validation of the Israeli Version of the Rivermead Behavioral Memory Test for Children Following Acquired Brain Injury

OBJECTIVE:: To further validate the Rivermead Behavioral Memory Test for Children (RBMT-C) for use in children with acquired brain injury (ABI). We hypothesized that the RBMT-C could differentiate between children with and without ABI. We also hypothesized that construct validity would be supported by significant correlations with additional cognitive tests. METHOD:: A total of 58 children (6-11 years old), comprising 29 children diagnosed as having ABI (15 girls, 14 boys) and 29 healthy children (15 girls, 14 boys), participated. Children were administered the RBMT-C and the Dynamic Occupational Therapy Cognitive Assessment for Children (DOTCA-Ch). The Functional Independence Measure for Children (WeeFIM) was completed by the staff members. RESULTS:: There were significant differences in memory between children with ABI and the healthy children [t (35) = 4.94, P < .00]. Significant correlations were found between memory as measured by the RBMT-C and cognitive status as measured by the DOTCA-Ch, as well as cognitive function scores in the WeeFIM supporting convergent validity. Nonsignificant correlations were found between the motor function scores (WeeFIM) and the memory scores (RBMT-C), supporting divergent validity. CONCLUSIONS:: The study results suggest that the RBMT-C can differentiate between children with and without memory difficulties. However, further studies are needed to establish the Israeli version validity.

Background Morbidity in HIV Vaccine Trial Participants from Various Geographic Regions As Assessed by Unsolicited Adverse Events

Recently, more clinical trials are being conducted in Africa and Asia, therefore, background morbidity in the respective populations is of interest. Between 2000 and 2007, the International AIDS Vaccine Initiative sponsored 19 Phase 1 or 2A preventive HIV vaccine trials in the US, Europe, Sub-Saharan Africa and India, enrolling 900 healthy HIV-1 uninfected volunteers.

Defeating Leishmania Resistance to Miltefosine (hexadecylphosphocholine) by Peptide-mediated Drug Smuggling: a Proof of Mechanism for Trypanosomatid Chemotherapy

Miltefosine (hexadecylphosphocholine, HePC), the first orally active drug successful against leishmaniasis, is especially active on the visceral form of the disease. Resistance mechanisms are almost exclusively associated to dysfunction in HePC uptake systems. In order to evade the requirements of its cognate receptor/translocator, HePC-resistant Leishmania donovani parasites (R40 strain) were challenged with constructs consisting of an ω-thiol-functionalized HePC analogue conjugated to the cell-penetrating peptide (CPP) Tat(48-60), either through a disulfide or a thioether bond. The conjugates enter and kill both promastigote and intracellular amastigote forms of the R40 strain. Intracellular release of HePC by reduction of the disulfide-based conjugate was confirmed by means of double tagging at both the CPP (Quasar 670) and HePC (BODIPY) moieties. Scission of the conjugate, however, is not mandatory, as the metabolically more stable thioether conjugate retained substantial activity. The disulfide conjugate is highly active on the bloodstream form of Trypanosoma b. brucei, naturally resistant to HePC. Our results provide proof-of-mechanism for the use of CPP conjugates to avert drug resistance by faulty drug accumulation in parasites, as well as the possibility to extend chemotherapy into other parasites intrinsically devoid of membrane translocation systems.

[Common Variable Immune Deficiency: What You Need to Know]

Common variable immune deficiency is the most frequent primary immune deficiency, characterized mainly by a disorder of B lymphocytes differentiation and a deficit in immunoglobulins. The clinical manifestations include recurrent infections, non-infectious lung and digestive involvements, autoimmune diseases, and an increased susceptibility to cancers. Recent breakthroughs have been made in the understanding of some genetic mechanisms of the disease. Replacement therapy with intravenous immunoglobulins remains the treatment of choice, which allows significant improvement in the survival and quality of life. However progress should be made in the understanding of the pathophysiology and in the early detection of this disease, since a delay in the diagnosis may have harmful consequences in terms of morbidity and mortality.

[Sjögren's Syndrome: a New Approach to Treatment]

Södgren's syndrome treatment has essentially been based on symptomatic approach and has been of limited efficacy. Novel biological therapies targeting B cells, a key player in the pathophysiology of the syndrome, have recently been tested in controlled clinical trials and raise the hope of improving glandular and extraglandular manifestations of Söigren's syndrome.

[Allergy to Beta-lactam Antibiotics]

Beta-lactam antibiotics allergies are common. Up to 10% of the population describe a former allergy to penicillins. However only 10 to 15% of these individuals are actually allergic. In most cases, beta-lactam antibiotics will be avoided and replaced by other antibiotics such as quinolones. This fear of a serious allergic reaction has an economic impact and may lead to the emergence of antibiotic resistance. A thorough allergic work-up can accurately determine true allergic patients. Most of the patients with a proven allergy will be able to tolerate other antibiotics belonging to the beta-lactam family. This article focuses on the management of beta-lactam allergic patients.

Molecular Detection of Plasmodium Knowlesi in a Dutch Traveler by Real-time PCR

Plasmodium knowlesi infection with low parasitemia presents a diagnostic challenge, as rapid diagnostic tests are often negative and identification to the species level by microscopy is difficult. P. knowlesi malaria in a traveler is described, and real-time PCR is demonstrated to support fast and reliable diagnosis and identification to the species level.

A Slippery Slope?

NUP-1 Is a Large Coiled-coil Nucleoskeletal Protein in Trypanosomes with Lamin-like Functions

A unifying feature of eukaryotic nuclear organization is genome segregation into transcriptionally active euchromatin and transcriptionally repressed heterochromatin. In metazoa, lamin proteins preserve nuclear integrity and higher order heterochromatin organization at the nuclear periphery, but no non-metazoan lamin orthologues have been identified, despite the likely presence of nucleoskeletal elements in many lineages. This suggests a metazoan-specific origin for lamins, and therefore that distinct protein elements must compose the nucleoskeleton in other lineages. The trypanosomatids are highly divergent organisms and possess well-documented but remarkably distinct mechanisms for control of gene expression, including polycistronic transcription and trans-splicing. NUP-1 is a large protein localizing to the nuclear periphery of Trypanosoma brucei and a candidate nucleoskeletal component. We sought to determine if NUP-1 mediates heterochromatin organization and gene regulation at the nuclear periphery by examining the influence of NUP-1 knockdown on morphology, chromatin positioning, and transcription. We demonstrate that NUP-1 is essential and part of a stable network at the inner face of the trypanosome nuclear envelope, since knockdown cells have abnormally shaped nuclei with compromised structural integrity. NUP-1 knockdown also disrupts organization of nuclear pore complexes and chromosomes. Most significantly, we find that NUP-1 is required to maintain the silenced state of developmentally regulated genes at the nuclear periphery; NUP-1 knockdown results in highly specific mis-regulation of telomere-proximal silenced variant surface glycoprotein (VSG) expression sites and procyclin loci, indicating a disruption to normal chromatin organization essential to life-cycle progression. Further, NUP-1 depletion leads to increased VSG switching and therefore appears to have a role in control of antigenic variation. Thus, analogous to vertebrate lamins, NUP-1 is a major component of the nucleoskeleton with key roles in organization of the nuclear periphery, heterochromatin, and epigenetic control of developmentally regulated loci.

Synthesis of U(IV) Imidos from Tp*2U(CH2Ph) (Tp* = Hydrotris(3,5-dimethylpyrazolyl)borate) by Extrusion of Bibenzyl

Addition of organic azides, N(3)R (R = 2,4,6-trimethylphenyl (Mes), phenyl (Ph), 1-adamantyl (Ad)), to a solution of the uranium(III) alkyl complex, Tp*(2)U(CH(2)Ph) (Tp* = hydrotris(3,5-dimethylpyrazolyl)borate) (1), results in the formation of a family of uranium(iv) imido derivatives, Tp*(2)U(NR) (2-R). Notably, these complexes were synthesized in high yields by coupling of the benzyl groups to form bibenzyl. The uranium(IV) imido derivatives, 2-Mes, 2-Ph, and 2-Ad, were all characterized by both (1)H NMR and IR spectroscopy, and 2-Mes and 2-Ad were also characterized by X-ray crystallography. In the molecular structure of 2-Mes, typical κ(3)-coordination of the Tp* ligands was observed; however in the case of 2-Ad, one pyrazole ring of a Tp* ligand has rotated away from the metal centre, forcing a κ(2)-coordination of the pyrazoles. This results in a uranium-hydrogen interaction with the Tp* B-H. Treating these imido complexes with para-tolualdehyde results in multiple bond metathesis, forming the terminal uranium(IV) oxo complex, Tp*(2)U(O), and the corresponding imine.

Carbon-carbon Reductive Elimination from Homoleptic Uranium(IV) Alkyls Induced by Redox-active Ligands

The synthesis, characterization, and reactivity of the homoleptic uranium(IV) alkyls U(CH(2)C(6)H(5))(4) (1-Ph), U(CH(2)-p-CH(3)C(6)H(4))(4) (1-p-Me), and U(CH(2)-m-(CH(3))(2)C(6)H(3))(4) (1-m-Me(2)) are reported. The addition of 4 equiv of K(CH(2)Ar) (Ar = Ph, p-CH(3)C(6)H(4), m-(CH(3))(2)C(6)H(3)) to UCl(4) at -108 °C produces 1-Ph in good yields and 1-p-Me and 1-m-Me(2) in moderate yields. Further characterization of 1-Ph by X-ray crystallography confirmed η(4)-coordination of each benzyl ligand to the uranium center. Magnetic studies produced an effective magnetic moment of 2.60 μ(B) at 23 °C, which is consistent with a tetravalent uranium 5f(2) electronic configuration. Addition of 1 equiv of the redox-active α-diimine (Mes)DAB(Me) ((Mes)DAB(Me) = [ArN═C(Me)C(Me)═NAr]; Ar = 2,4,6-trimethylphenyl (Mes)) to 1-Ph results in reductive elimination of 1 equiv of bibenzyl (PhCH(2)CH(2)Ph), affording ((Mes)DAB(Me))U(CH(2)C(6)H(5))(2) (2-Ph). Treating an equimolar mixture of 1-Ph and 1-Ph-d(28) with (Mes)DAB(Me) forms the products from monomolecular reductive elimination, 2-Ph, 2-Ph-d(14), bibenzyl, and bibenzyl-d(14). This is confirmed by (1)H NMR spectroscopy and GC/MS analysis of both organometallic and organic products. Addition of 1 equiv of 1,2-bis(dimethylphosphino)ethane (dmpe) to 1-Ph results in formation of the previously synthesized (dmpe)U(CH(2)C(6)H(5))(4) (3-Ph), indicating the redox-innocent chelating phosphine stabilizes the uranium center in 3-Ph and prevents reductive elimination of bibenzyl. Full characterization for 3-Ph, including X-ray crystallography, is reported.

Echinococcus Multilocularis in Svalbard, Norway: Microsatellite Genotyping to Investigate the Origin of a Highly Focal Contamination

Echinococcus multilocularis is a threatening cestode involved in the human alveolar echinococcosis. The parasite, mainly described in temperate regions of the Northern hemisphere was described for the first time in 1999 in the High Arctic Svalbard archipelago, Norway. The origin of this contamination could be due to an anthropogenic introduction from mainland Europe by domestic dogs or with the introduction of the sibling vole, perhaps from mainland Russia (St. Petersburg area), or with roaming Arctic foxes, known as the main definitive host of the parasite in Arctic regions. The genetic diversity of E. multilocularis in Svalbard was investigated here for the first time by genotyping using EmsB microsatellite and compared to other genotyped populations in the main worldwide endemic areas. We found low polymorphism amongst the 27 metacestode isolates from sibling voles trapped in the core of the distribution area of the vole on Svalbard. E. mutilocularis Arctic populations, using the Arctic fox as the definitive host, were genetically separated from European temperate populations that use the red fox, but closely related to St. Lawrence Island samples from Alaska. The result is inconsistent with the hypothesis of an anthropogenic introduction from mainland Europe, but can be seen as consistent with the hypothesis that Arctic foxes introduced E. multilocularis to Svalbard.

Development of the A§E Test Battery for Assessment of Pitch Perception in Speech

OBJECTIVES: The auditory speech sounds evaluation 2009 test battery for assessment of speech pitch perception is presented. It was designed to (a) assess perception of pitch in linguistic contexts without the confounds of secondary acoustic cues, (b) be usable with listeners from different language backgrounds, and (c) be suitable for use in a clinical setting. The need for this test battery arises from increased awareness of the importance of prosody in clinical practice, and the development of methods for improving pitch perception in listeners with profound hearing losses. METHODS: Identification and discrimination tasks based on linguistic contexts were developed to establish listeners' just noticeable differences (JNDs) for pitch changes. Stimuli were pseudosentences and pseudowords based on speech from a female speaker, overlain with stylized pitch contours. Target pitch excursions were varied from the 200 Hz baseline to a maximum of 349 Hz. Ninety normal-hearing listeners participated in test validation that assessed goals (a)-(c), established test-retest reliability, and gathered normative data. RESULTS: The JNDs on non-linguistic, control tasks were lower than on linguistic ones, showing that non-linguistic tasks may overestimate pitch perception in speech. Listeners from different language backgrounds scored comparably on most linguistic tasks, and test-retest differences were non-significant. Test usability as evidenced by task duration and subject experience seemed satisfactory for clinical use.

Prognostic Value of Estrogen Receptor α and Progesterone Receptor Conversion in Distant Breast Cancer Metastases

Changes in the receptor profile of primary breast cancers to their metastases (receptor conversion) have been described for the estrogen receptor α (ERα) and progesterone receptor (PR). The purpose of this study was to evaluate the impact of receptor conversion for ERα and PR on survival in a large group of distant non-bone breast cancer metastases.

Cardiorenal Rescue Study in Acute Decompensated Heart Failure: Rationale and Design of CARRESS-HF, for the Heart Failure Clinical Research Network

Worsening renal function is common among patients hospitalized for acute decompensated heart failure (ADHF). When this occurs, subsequent management decisions often pit the desire for effective decongestion against concerns about further worsening renal function. There are no evidence-based treatments or guidelines to assist in these difficult management decisions. Ultrafiltration is a potentially attractive alternative to loop diuretics for the management of fluid overload in patients with ADHF and worsening renal function.

Hypersensitivity Pneumonitis Induced by Shiitake Mushroom Spores

Hypersensitivity pneumonitis (HP) is a pulmonary granulomatosis involving an immunoallergic mechanism caused by chronic inhalation of antigens, most frequently organic substances, as well as chemicals. We report the first European case of hypersensitivity pneumonitis due to the inhalation of Shiitake mushroom spores. A 37-year-old French Caucasian man with a one-month history of persistent dry cough, shortness of breath and loss of weight was admitted to our hospital on December 2010. Anamnesis showed he was involved in mushroom production beginning in the summer of 2010. His temperature on admission was 36.6°C and he had a normal blood pressure (135/90 mmHg). Bilateral fine crackles were audible in the base of both lungs. Pulmonary function tests showed a mild restrictive pattern with decreased DLco and a PaO(2) of 65 mmHg, Chest CT scan revealed reticulo-nodular shadows, slight ground glass opacities, liner atelectasis, and subpleural opacities in both lung fields. Bronchoscopy was normal but cytological examination of BAL revealed a predominant lymphocytosis (55%). Serum precipitins to the Shiitake mushroom spores were positive (3 precipitins arcs with high intensity) and as a result we advised the patient to cease his mushroom production activities. The diagnosis of hypersensitivity pneumonitis due to inhalation of Shiitake mushroom spores was established as a result of the improvement of all of his clinical symptoms, i.e., cough, weight loss, bilateral fine crackles, mild restrictive pattern of pulmonary function, and reticulo-nodular shadows on chest CT, once exposure was eliminated. Recent interest in exotic mushrooms varieties, e.g., Shiitake, in developed countries because of their possible medicinal properties might increase the potential risk of HP among mushrooms workers. Therefore, healthcare professionals have to take this new potential respiratory disease into account.

Computational Insights into Uranium Complexes Supported by Redox-active α-diimine Ligands

The electronic structures of two uranium compounds supported by redox-active α-diimine ligands, ((Mes)DAB(Me))(2)U(THF) (1) and Cp(2)U((Mes)DAB(Me)) (2) ((Mes)DAB(Me) = [ArN═C(Me)C(Me)═NAr]; Ar = 2,4,6-trimethylphenyl (Mes)), have been investigated using both density functional theory and multiconfigurational self-consistent field methods. Results from these studies have established that both uranium centers are tetravalent, that the ligands are reduced by two electrons, and that the ground states of these molecules are triplets. Energetically low-lying singlet states are accessible, and some transitions to these states are visible in the electronic absorption spectrum.

Superior Methadone Treatment Outcome in Hmong Compared with Non-Hmong Patients

The Hmong are a distinct ethnic group from Laos. Little is known about how opiate-addicted Hmong respond to methadone maintenance treatment. Therefore, opium-addicted Hmong (exclusive route of administration: smoking) attending an urban methadone maintenance program in Minneapolis, MN, were matched by gender and date of admission with predominately heroin-addicted non-Hmong (predominant route of administration: injection) attending the same program, and both groups were evaluated for 1-year treatment retention, stabilization dose of methadone, and urine drug screen results. Hmong had greater 1-year treatment retention (79.8%) than non-Hmong (63.5%; p < .01). In both groups, methadone dose was significantly associated with retention (p = .005). However, Hmong required lower doses of methadone for stabilization (M = 49.0 vs. 77.1 mg; p < .0001). For both groups, positive urine drug screens were associated with stopping treatment. Further research to determine levels of tolerance and psychosocial and pharmacogenetic factors contributing to differences in methadone treatment outcome and dosing in Hmong may provide further insight into opiate addiction and its treatment.

A Different Perspective on the Phylogenetic Relationships of the Moxostomatini (Cypriniformes: Catostomidae) Based on Cytochrome-b and Growth Hormone Intron Sequences

We have examined phylogenetic relationships of suckers of tribe Moxostomatini (Cypriniformes, Catostomidae) using cytochrome-b and Growth Hormone gene intron sequences. Phylogenies were significantly different from recent estimates of relationships based primarily on morphology (Smith, 1992) and cytochrome-b sequences (Harris et al., 2002). Overall, there was little support for many basal nodes in the phylogeny, however it was clear that Scartomyzon and Moxostoma were not monophyletic, despite morphological evidence provided Robins and Raney (1956, 1957), Jenkins (1970), and Smith (1992). Growth Hormone sequences provided good support for a monophyletic Western Scartomyzon lineage and thus suggested a single ancestral invasion of Scartomyzon-like fishes into drainages of Texas and Mexico. Phylogenetic relationships of Western Scartomyzon are structured geographically and do not conform well to current taxonomy.

Cutaneous Leishmaniasis Acquired in Jura, France

Reductive Heterocoupling Mediated by Cp*2U(2,2'-bpy)

Trivalent Cp*(2)U(2,2'-bpy) (2) (Cp* = C(5)Me(5), 2,2'-bpy = 2,2'-bipyridine), which has a monoanionic bipyridine, was treated with p-tolualdehyde (a), furfuraldehyde (b), acetone (c), and benzophenone (d). Reduction of the C[double bond, length as m-dash]O bond followed by radical coupling with bipyridine forms the U(iv) derivatives [Cp*(2)U(2,2'-bpy)(OCRR')] (3a-d).

Folate Status and Homocysteine Levels During a 24-week Oral Administration of a Folate-containing Oral Contraceptive: a Randomized, Double-blind, Active-controlled, Parallel-group, US-based Multicenter Study

This study investigated the effects of adding levomefolate calcium 0.451 mg (the calcium salt of L-5-methyltetrahydrofolate; Metafolin®) to an oral contraceptive containing ethinylestradiol (EE) 20 mcg/drospirenone (drsp) 3 mg on folate levels in healthy women seeking contraception.

Structural Comparison of Cytochromes P450 2A6, 2A13, and 2E1 with Pilocarpine

Human xenobiotic-metabolizing cytochrome P450 (CYP) enzymes can each bind and monooxygenate a diverse set of substrates, including drugs, often producing a variety of metabolites. Additionally, a single ligand can interact with multiple CYP enzymes, but often the protein structural similarities and differences that mediate such overlapping selectivity are not well understood. Even though the CYP superfamily has a highly canonical global protein fold, there are large variations in the active site size, topology, and conformational flexibility. We have determined how a related set of three human CYP enzymes bind and interact with a common inhibitor, the muscarinic receptor agonist drug pilocarpine. Pilocarpine binds and inhibits the hepatic CYP2A6 and respiratory CYP2A13 enzymes much more efficiently than the hepatic CYP2E1 enzyme. To elucidate key residues involved in pilocarpine binding, crystal structures of CYP2A6 (2.4 Å), CYP2A13 (3.0 Å), CYP2E1 (2.35 Å), and the CYP2A6 mutant enzyme, CYP2A6 I208S/I300F/G301A/S369G (2.1 Å) have been determined with pilocarpine in the active site. In all four structures, pilocarpine coordinates to the heme iron, but comparisons reveal how individual residues lining the active sites of these three distinct human enzymes interact differently with the inhibitor pilocarpine.

Perceived Environmental Restrictions for the Participation of Children with Mild Developmental Disabilities

Aim  In light of the International Classification of Functioning, and Health (ICF) model, to assess whether parents of children with mild developmental disabilities perceived various environmental factors as barriers to their child's participation, and whether these factors have a unique contribution to the total explained variance of participation, beyond personal factors. Methods  Seventy-nine kindergarten children (mean age 5.20 ± 0.52 years old) with mild developmental disabilities and their parents participated in the study. Three questionnaires measuring the child's participation, performance skills and environmental factors were completed by the parents. Results  Parents perceived environmental factors as slightly restricting to their child's participation. Associations were found between home and education factors and the dimensions of child participation - independence, enjoyment and parental satisfaction. Although parents perceived human environmental factors as more restricting than physical factors at home, regression analysis revealed that the latter was found to affect the child participation dimension of independence beyond the contribution of personal factors. Interpretation  These findings are the first, to our knowledge, to support the contribution of environmental factors to the participation of young children with mild developmental disabilities. The results show that environmental factors have significant slight contribution to child's independence in participation beyond other predictors (i.e. personal factors). Therefore, it is recommended to include environmental restrictions measurement in the child evaluation process to facilitate effective intervention programs.

Nonrandom Distribution of Cryptic Repeating Triplets of Purines and Pyrimidines (RNY)(n) in Gp120 of HIV Type1

We have analyzed purine (R) and pyrimidine (Y) codon patterns in variable and constant regions of HIV-1 gp120 in seven patients infected with different HIV-1 subtypes and naive to antiretroviral therapy. We have calculated the relative frequency of each in-frame codon RNY, YNR, RNR, and YNY (N=any nucleotide) in variable and constant regions of gp120, in the sequence within indels and at indels' flanking sites. Our data show that hypervariable regions V1, V2, V4, and V5 are characterized by the presence of long stretches of RNY codons constituting the majority of the sequence portion within insertions/deletions. In full-length gp120 and within inserted/deleted fragments the number of AVT (V=A, C, G) codons did not exceed 50% of the total RNY codons. RNY strings in variable regions spanned up to 21 codons and were always in frame. In contrast, RNY strings in constant regions were mostly out of frame and their length was limited to five codons. The frequency of the codon RNY was found to be significantly higher in variable regions (p<0.0001; t-test), within indels, and at indels' flanking sites (p<0.0001; χ(2) test). Analysis of the distribution of RNY strings equal to or longer than five codons in the full genome of HXB2 also shows that these sequences are mostly out of frame, unless they contain a potential N-glycosylation site or an asparagine. These data suggest that cryptic repeats of RNY may play a role in the genesis of multiple base insertions and deletions in hypervariable regions of gp120.

Transvenous Phrenic Nerve Stimulation for the Treatment of Central Sleep Apnoea in Heart Failure

Periodic breathing with central sleep apnoea (CSA) is common in heart failure patients and is associated with poor quality of life and increased risk of morbidity and mortality. We conducted a prospective, non-randomized, acute study to determine the feasibility of using unilateral transvenous phrenic nerve stimulation for the treatment of CSA in heart failure patients.

Personal and Environmental Pathways to Participation in Young Children with and Without Mild Motor Disabilities

Participation in everyday activities has a positive influence upon health and well-being and is considered as an outcome measure. According to recent models child participation is the product of the dynamic interaction between health states and both individual and environmental factors. Children with mild developmental disabilities often present decreased participation in everyday activities. The purpose of this study was to explore the extent to which individual and environmental factors explain the participation of young children, with and without mild motor disabilities.

The Effect of Chemotherapy on Expression of Folate Receptor-alpha in Ovarian Cancer

Folate receptor alpha (FR-α) has been identified as a potential target in ovarian cancer for diagnostic and therapeutic purposes, based on its overexpression in serous epithelial ovarian carcinoma. The effect of chemotherapy on FR-α expression may be important in the applicability of FR-α directed agents in the case of residual tumor tissue. The objective of this study was to assess FR-α expression in ovarian carcinoma and to evaluate whether FR-α expression is altered by chemotherapy.

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