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Find video protocols related to scientific articles indexed in Pubmed.
A literature review and case series of accelerating fracture healing in postmenopausal osteoporotic working women.
J Orthop
PUBLISHED: 09-01-2014
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Majority of fractures do not cause significant long-term morbidity and mortality. A 10% of these fractures result in impaired fracture healing, drastically affecting quality of life in affected patients. Satisfactory healing of these osteoporotic fractures are critically important to functional recovery, morbidity, and quality of life. Some therapies for osteoporosis may affect the processes associated with bone repair. For example, bisphosphonates in experimental models are associated with increased callus size and mineralization, reduced callus remodeling, and improved mechanical strength. Local and systemic bisphosphonate treatment may improve implant fixation. No negative impact on fracture healing has been observed, even after major surgery or when administered immediately after fracture. For the osteoanabolic agent teriparatide, case reports and a randomized trial have produced mixed results, but they are consistent with a positive impact of teriparatide on fracture healing. At this point, therefore, there is no evidence that osteoporosis therapies are detrimental to fracture healing with some promising experimental evidence for positive effects on healing, notably for those agents whose actions are primarily anabolic.
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Enhanced Potency of a Broadly Neutralizing HIV-1 Antibody In Vitro Improves Protection against Lentiviral Infection In Vivo.
J. Virol.
PUBLISHED: 08-20-2014
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Over the past 5 years, a new generation of highly potent and broadly neutralizing HIV-1 antibodies has been identified. These antibodies can protect against lentiviral infection in nonhuman primates (NHPs), suggesting that passive antibody transfer would prevent HIV-1 transmission in humans. To increase the protective efficacy of such monoclonal antibodies, we employed next-generation sequencing, computational bioinformatics, and structure-guided design to enhance the neutralization potency and breadth of VRC01, an antibody that targets the CD4 binding site of the HIV-1 envelope. One variant, VRC07-523, was 5- to 8-fold more potent than VRC01, neutralized 96% of viruses tested, and displayed minimal autoreactivity. To compare its protective efficacy to that of VRC01 in vivo, we performed a series of simian-human immunodeficiency virus (SHIV) challenge experiments in nonhuman primates and calculated the doses of VRC07-523 and VRC01 that provide 50% protection (EC50). VRC07-523 prevented infection in NHPs at a 5-fold lower concentration than VRC01. These results suggest that increased neutralization potency in vitro correlates with improved protection against infection in vivo, documenting the improved functional efficacy of VRC07-523 and its potential clinical relevance for protecting against HIV-1 infection in humans.
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Enhanced neonatal Fc receptor function improves protection against primate SHIV infection.
Nature
PUBLISHED: 08-13-2014
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To protect against human immunodeficiency virus (HIV-1) infection, broadly neutralizing antibodies (bnAbs) must be active at the portals of viral entry in the gastrointestinal or cervicovaginal tracts. The localization and persistence of antibodies at these sites is influenced by the neonatal Fc receptor (FcRn), whose role in protecting against infection in vivo has not been defined. Here, we show that a bnAb with enhanced FcRn binding has increased gut mucosal tissue localization, which improves protection against lentiviral infection in non-human primates. A bnAb directed to the CD4-binding site of the HIV-1 envelope (Env) protein (denoted VRC01) was modified by site-directed mutagenesis to increase its binding affinity for FcRn. This enhanced FcRn-binding mutant bnAb, denoted VRC01-LS, displayed increased transcytosis across human FcRn-expressing cellular monolayers in vitro while retaining Fc?RIIIa binding and function, including antibody-dependent cell-mediated cytotoxicity (ADCC) activity, at levels similar to VRC01 (the wild type). VRC01-LS had a threefold longer serum half-life than VRC01 in non-human primates and persisted in the rectal mucosa even when it was no longer detectable in the serum. Notably, VRC01-LS mediated protection superior to that afforded by VRC01 against intrarectal infection with simian-human immunodeficiency virus (SHIV). These findings suggest that modification of FcRn binding provides a mechanism not only to increase serum half-life but also to enhance mucosal localization that confers immune protection. Mutations that enhance FcRn function could therefore increase the potency and durability of passive immunization strategies to prevent HIV-1 infection.
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Aerosol vaccination with AERAS-402 elicits robust cellular immune responses in the lungs of rhesus macaques but fails to protect against high-dose Mycobacterium tuberculosis challenge.
J. Immunol.
PUBLISHED: 07-14-2014
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Development of a vaccine against pulmonary tuberculosis may require immunization strategies that induce a high frequency of Ag-specific CD4 and CD8 T cells in the lung. The nonhuman primate model is essential for testing such approaches because it has predictive value for how vaccines elicit responses in humans. In this study, we used an aerosol vaccination strategy to administer AERAS-402, a replication-defective recombinant adenovirus (rAd) type 35 expressing Mycobacterium tuberculosis Ags Ag85A, Ag85B, and TB10.4, in bacillus Calmette-Guérin (BCG)-primed or unprimed rhesus macaques. Immunization with BCG generated low purified protein derivative-specific CD4 T cell responses in blood and bronchoalveolar lavage. In contrast, aerosolized AERAS-402 alone or following BCG induced potent and stable Ag85A/b-specific CD4 and CD8 effector T cells in bronchoalveolar lavage that largely produced IFN-?, as well as TNF and IL-2. Such responses induced by BCG, AERAS-402, or both failed to confer overall protection following challenge with 275 CFUs M. tuberculosis Erdman, although vaccine-induced responses associated with reduced pathology were observed in some animals. Anamnestic T cell responses to Ag85A/b were not detected in blood of immunized animals after challenge. Overall, our data suggest that a high M. tuberculosis challenge dose may be a critical factor in limiting vaccine efficacy in this model. However, the ability of aerosol rAd immunization to generate potent cellular immunity in the lung suggests that using different or more immunogens, alternative rAd serotypes with enhanced immunogenicity, and a physiological challenge dose may achieve protection against M. tuberculosis.
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Neutralizing antibodies to HIV-1 envelope protect more effectively in vivo than those to the CD4 receptor.
Sci Transl Med
PUBLISHED: 07-04-2014
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HIV-1 infection depends on effective viral entry mediated by the interaction of its envelope (Env) glycoprotein with specific cell surface receptors. Protective antiviral antibodies generated by passive or active immunization must prevent these interactions. Because the HIV-1 Env is highly variable, attention has also focused on blocking the HIV-1 primary cell receptor CD4. We therefore analyzed the in vivo protective efficacy of three potent neutralizing monoclonal antibodies (mAbs) to HIV-1 Env compared to an antibody against the CD4 receptor. Protection was assessed after mucosal challenge of rhesus macaques with simian/HIV (SHIV). Despite its comparable or greater neutralization potency in vitro, the anti-CD4 antibody did not provide effective protection in vivo, whereas the HIV-1-specific mAbs VRC01, 10E8, and PG9, targeting the CD4 binding site, membrane-proximal, and V1V2 glycan Env regions, respectively, conferred complete protection, albeit at different relative potencies. These findings demonstrate the protective efficacy of broadly neutralizing antibodies directed to the HIV-1 Env and suggest that targeting the HIV-1 Env is preferable to the cell surface receptor CD4 for the prevention of HIV-1 transmission.
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A fatal case of rapid gingival enlargement: Case report with brief review.
J Oral Maxillofac Pathol
PUBLISHED: 06-25-2014
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Myeloid sarcoma (MS) is a rare extramedullary tumor composed of primitive granulocytic cells. These lesions are commonly associated with other hematologic disorders such as myeloid leukemia and other myeloproliferative neoplasms. Although extremely rare in the oral cavity, this lesion was reported in gingiva, palate, buccal mucosa and extraction sockets. MS is an aggressive lesion associated with poor prognosis. Early identification and prompt treatment holds the key for increasing the disease-free period in these patients. In this context, we report a rare and aggressive case of MS, which ran a fatal course in a 45-year-old female patient.
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Choroidal thickness in macular telangiectasia type 2.
Retina (Philadelphia, Pa.)
PUBLISHED: 06-05-2014
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To assess the choroidal thickness changes in eyes with macular telangiectasia Type 2 and their relationship with the integrity of outer retinal structures and visual acuity.
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Pharmacokinetics and Efficacy of Bioerodible Dexamethasone Implant in Concanavalin A-induced Uveitic Cataract Rabbit Model.
Pharm. Res.
PUBLISHED: 05-06-2014
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To advance therapy for the treatment of concurrent uveitis and post-cataract surgical inflammation; we evaluated pharmacokinetics and pharmacodynamics of Bioerodible Dexamethasone Implant (BDI) containing 0.3 mg of dexamethasone (DXM) in Concanavalin A (Con A) induced uveitis followed by phacoemulsification in New Zealand White (NZW) rabbits.
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Type I interferon responses in rhesus macaques prevent SIV infection and slow disease progression.
Nature
PUBLISHED: 04-11-2014
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Inflammation in HIV infection is predictive of non-AIDS morbidity and death, higher set point plasma virus load and virus acquisition; thus, therapeutic agents are in development to reduce its causes and consequences. However, inflammation may simultaneously confer both detrimental and beneficial effects. This dichotomy is particularly applicable to type I interferons (IFN-I) which, while contributing to innate control of infection, also provide target cells for the virus during acute infection, impair CD4 T-cell recovery, and are associated with disease progression. Here we manipulated IFN-I signalling in rhesus macaques (Macaca mulatta) during simian immunodeficiency virus (SIV) transmission and acute infection with two complementary in vivo interventions. We show that blockade of the IFN-I receptor caused reduced antiviral gene expression, increased SIV reservoir size and accelerated CD4 T-cell depletion with progression to AIDS despite decreased T-cell activation. In contrast, IFN-?2a administration initially upregulated expression of antiviral genes and prevented systemic infection. However, continued IFN-?2a treatment induced IFN-I desensitization and decreased antiviral gene expression, enabling infection with increased SIV reservoir size and accelerated CD4 T-cell loss. Thus, the timing of IFN-induced innate responses in acute SIV infection profoundly affects overall disease course and outweighs the detrimental consequences of increased immune activation. Yet, the clinical consequences of manipulation of IFN signalling are difficult to predict in vivo and therapeutic interventions in human studies should be approached with caution.
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Neuroprotective effect of a triterpenoid saponin isolated from Momordica cymbalaria Fenzl in diabetic peripheral neuropathy.
Indian J Pharmacol
PUBLISHED: 02-20-2014
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To investigate the neuroprotective potential of a saponin isolated from the roots of Momordica cymbalaria against peripheral neuropathy in streptozotocin-induced diabetic rats.
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Structure-based design of a fusion glycoprotein vaccine for respiratory syncytial virus.
Science
PUBLISHED: 11-02-2013
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Respiratory syncytial virus (RSV) is the leading cause of hospitalization for children under 5 years of age. We sought to engineer a viral antigen that provides greater protection than currently available vaccines and focused on antigenic site Ø, a metastable site specific to the prefusion state of the RSV fusion (F) glycoprotein, as this site is targeted by extremely potent RSV-neutralizing antibodies. Structure-based design yielded stabilized versions of RSV F that maintained antigenic site Ø when exposed to extremes of pH, osmolality, and temperature. Six RSV F crystal structures provided atomic-level data on how introduced cysteine residues and filled hydrophobic cavities improved stability. Immunization with site Ø-stabilized variants of RSV F in mice and macaques elicited levels of RSV-specific neutralizing activity many times the protective threshold.
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Immunological and virological mechanisms of vaccine-mediated protection against SIV and HIV.
Nature
PUBLISHED: 09-06-2013
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A major challenge for the development of a highly effective AIDS vaccine is the identification of mechanisms of protective immunity. To address this question, we used a nonhuman primate challenge model with simian immunodeficiency virus (SIV). We show that antibodies to the SIV envelope are necessary and sufficient to prevent infection. Moreover, sequencing of viruses from breakthrough infections revealed selective pressure against neutralization-sensitive viruses; we identified a two-amino-acid signature that alters antigenicity and confers neutralization resistance. A similar signature confers resistance of human immunodeficiency virus (HIV)-1 to neutralization by monoclonal antibodies against variable regions 1 and 2 (V1V2), suggesting that SIV and HIV share a fundamental mechanism of immune escape from vaccine-elicited or naturally elicited antibodies. These analyses provide insight into the limited efficacy seen in HIV vaccine trials.
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Collagen cross linking: current perspectives.
Indian J Ophthalmol
PUBLISHED: 08-09-2013
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Keratoconus is a common ectatic disorder occurring in more than 1 in 1,000 individuals. The condition typically starts in adolescence and early adulthood. It is a disease with an uncertain cause and its progression is unpredictable, but in extreme cases, vision deteriorates and can require corneal transplant surgery. Corneal collagen cross-linking (CCL) with riboflavin (C3R) is a recent treatment option that can enhance the rigidity of the cornea and prevent disease progression. Since its inception, the procedure has evolved with newer instrumentation, surgical techniques, and is also now performed for expanded indications other than keratoconus. With increasing experience, newer guidelines regarding optimization of patient selection, the spectrum of complications and their management, and combination procedures are being described. This article in conjunction with the others in this issue, will try and explore the uses of collagen cross-linking (CXL) in its current form.
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Magical NiTi expander.
BMJ Case Rep
PUBLISHED: 07-23-2013
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A 24-year-old male patient was referred to our department for expansion of the constricted maxillary arch as a presurgical procedure for the correction of congenital facial disfigurement. On examination, the patient had a convex profile, increased interlabial gap, tongue thrust, limited mouth opening, posterior crossbite, asymmetric V-shaped maxillary arch with severe constriction, crowding of anterior teeth in the maxillary arch and a massive open bite. Radiographic investigations included orthopantomograph and occlusal radiographs. The patient photographs and models were analysed. On careful evaluation, the treatment for maxillary arch expansion was planned with a nickel titanium (NiTi) slow maxillary expander along with fixed mechanotherapy for alignment of teeth. An unexpectedly successful outcome was appreciated from the treatment. An emphasis should be laid on selecting and treating the case of constricted arches with a surgical or non-surgical approach, as expansion can be achieved orthodontically by using NiTi expanders.
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High production rates sustain in vivo levels of PD-1high simian immunodeficiency virus-specific CD8 T cells in the face of rapid clearance.
J. Virol.
PUBLISHED: 07-03-2013
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Programmed Death 1 (PD-1) expression by human/simian immunodeficiency virus (HIV/SIV)-specific CD8 T cells has been associated with defective cytokine production and reduced in vitro proliferation capacity. However, the cellular mechanisms that sustain PD-1(high) virus-specific CD8 T cell responses during chronic infection are unknown. Here, we show that the PD-1(high) phenotype is associated with accelerated in vivo CD8 T cell turnover in SIV-infected rhesus macaques, especially within the SIV-specific CD8 T cell pool. Mathematical modeling of 5-bromo-2 deoxyuridine (BrdU) labeling dynamics demonstrated a significantly increased generation rate of PD-1(high) compared to PD-1(low) CD8 T cells in all memory compartments. Simultaneous analysis of Ki67 and BrdU kinetics revealed a complex in vivo turnover profile whereby only a small fraction of PD-1(high) cells, but virtually all PD-1(low) cells, returned to rest after activation. Similar kinetics operated in both chronic and acute SIV infection. Our data suggest that the persistence of PD-1(high) SIV-specific CD8 T cells in chronic infection is maintained in vivo by a mechanism involving high production coupled with a high disappearance rate.
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Neglected primary Ewings sarcoma of ethmoid presenting as surgical emergency.
Asian J Neurosurg
PUBLISHED: 06-07-2013
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We present a male child with primary Ewings sarcoma arising from ethmoid sinuses with intradural and extracranial extension (bilateral nasal cavities, orbits, and maxillary sinuses). This is a rare condition. He presented with recurrent episodes of epistaxis for 2 years, sudden onset rapidly progressive bilateral proptosis, with painful restriction of extraocular movements, and decreased visual acuity for 4 days. Sudden complete loss of vision following admission demanded emergency tumor decompression.
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Emphysematous pyelonephritis: A single center study.
Indian J Nephrol
PUBLISHED: 05-30-2013
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We present our experience of 22 cases of emphysematous pyelonephritis (EPN) treated from 1996 to 2012. Medical records were analyzed retrospectively for demographic profile, presence and duration of diabetes mellitus, and mode of clinical presentation. EPN was diagnosed based on demonstration of intra-renal gas by plain X-ray, ultrasound, and/or computed tomography (CT) scan. Details of medical treatment, reason for surgical intervention, and final outcome were recorded. Univariate analysis was performed to identify risk factors for mortality and P value of less than 0.05 was taken as significant. Twenty-two cases (6 males, 16 females) of EPN were diagnosed. Seven cases presented with acute pyelonephritis, seven cases with urosepsis, and the remaining eight patients with multi-organ dysfunction. CT grading of EPN was class IV in three, class III in four, class II in 14, and class I in one. All were initially managed medically with parenteral antibiotics. Ten patients needed additional surgical intervention. The overall survival rate was 86.3% (19/22). Among the risk factors analyzed higher CT grade, altered sensorium and thrombocytopenia were significantly associated with mortality. We conclude that a more conservative approach in managing EPN has become the standard of care. Patients having high CT grade of lesions (III and IV) with altered sensorium and thrombocytopenia at presentation are more likely to die due to the disease and may be better managed by an aggressive surgical plan.
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Self-assembling influenza nanoparticle vaccines elicit broadly neutralizing H1N1 antibodies.
Nature
PUBLISHED: 04-18-2013
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Influenza viruses pose a significant threat to the public and are a burden on global health systems. Each year, influenza vaccines must be rapidly produced to match circulating viruses, a process constrained by dated technology and vulnerable to unexpected strains emerging from humans and animal reservoirs. Here we use knowledge of protein structure to design self-assembling nanoparticles that elicit broader and more potent immunity than traditional influenza vaccines. The viral haemagglutinin was genetically fused to ferritin, a protein that naturally forms nanoparticles composed of 24 identical polypeptides. Haemagglutinin was inserted at the interface of adjacent subunits so that it spontaneously assembled and generated eight trimeric viral spikes on its surface. Immunization with this influenza nanoparticle vaccine elicited haemagglutination inhibition antibody titres more than tenfold higher than those from the licensed inactivated vaccine. Furthermore, it elicited neutralizing antibodies to two highly conserved vulnerable haemagglutinin structures that are targets of universal vaccines: the stem and the receptor binding site on the head. Antibodies elicited by a 1999 haemagglutinin-nanoparticle vaccine neutralized H1N1 viruses from 1934 to 2007 and protected ferrets from an unmatched 2007 H1N1 virus challenge. This structure-based, self-assembling synthetic nanoparticle vaccine improves the potency and breadth of influenza virus immunity, and it provides a foundation for building broader vaccine protection against emerging influenza viruses and other pathogens.
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Safety and tolerability of a live oral Salmonella typhimurium vaccine candidate in SIV-infected nonhuman primates.
Vaccine
PUBLISHED: 04-17-2013
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Nontyphoidal Salmonella (NTS) serovars are a common cause of acute food-borne gastroenteritis worldwide and can cause invasive systemic disease in young infants, the elderly, and immunocompromised hosts, accompanied by high case fatality. Vaccination against invasive NTS disease is warranted where the disease incidence and mortality are high and multidrug resistance is prevalent, as in sub-Saharan Africa. Live-attenuated vaccines that mimic natural infection constitute one strategy to elicit protection. However, they must particularly be shown to be adequately attenuated for consideration of immunocompromised subjects. Accordingly, we examined the safety and tolerability of an oral live attenuated Salmonella typhimurium vaccine candidate, CVD 1921, in an established chronic simian immunodeficiency virus (SIV)-infected rhesus macaque model. We evaluated clinical parameters, histopathology, and measured differences in mucosal permeability to wild-type and vaccine strains. Compared to the wild-type S. typhimurium strain I77 in both SIV-infected and SIV-uninfected nonhuman primate hosts, this live-attenuated vaccine shows reduced shedding and systemic spread, exhibits limited pathological disease manifestations in the digestive tract, and induces low levels of cellular infiltration in tissues. Furthermore, wild-type S. typhimurium induces increased intestinal epithelial damage and permeability, with infiltration of neutrophils and macrophages in both SIV-infected and SIV-uninfected nonhuman primates compared to the vaccine strain. Based on shedding, systemic spread, and histopathology, the live-attenuated S. typhimurium strain CVD 1921 appears to be safe and well-tolerated in the nonhuman primate model, including chronically SIV-infected rhesus macaques.
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Investigation on mechanism of Cr(VI) reduction and removal by Bacillus amyloliquefaciens, a novel chromate tolerant bacterium isolated from chromite mine soil.
Chemosphere
PUBLISHED: 03-11-2013
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A strain CSB 9 isolated from chromite mine soil of Sukinda, India was identified as Bacillus amyloliquefaciens based on biochemical and 16S rRNA gene sequencing. The strain exhibited relatively high tolerance to Cr(VI) (?900mgL(-1)) and fast reduction rate of 2.22mg Cr(VI) L(-1)h(-1), under optimized conditions of 100mgL(-1) Cr(VI), pH 7 and temperature 35°C within 45h. Mechanism of Cr(VI) reduction as well as nature and fate of the reduced product were studied to determine the scope of removal of reduced Cr(III) end product. AAS analyses of the culture products treated with Cr(VI) for 45h showed the distribution of Cr(III) in pellet and culture supernatant to be 37.4±1.7 and 62.6±3.4mgL(-1), respectively. In SEM images, the bacterial pellets with Cr(VI) treatment appeared coagulated, rough and porous whereas the pellets without Cr(VI) treatment appeared regular, smooth and non-porous in structure. SEM-EDX of the bacterial precipitates under Cr(VI) treatment revealed immobilization of Cr(III) species on the bacterial cell surface. Further Raman spectroscopy analysis confirmed the presence of Cr(III) species, with characteristic peak at around 600cm(-1). TEM-EDX study of the bacterial precipitates under Cr(VI) treatment showed intracellular deposition of Cr(III) which are in nanometric range. Further characterization of reduced product by XRD, FT-IR and SAED analyses suggested the formation of poorly crystalline end products. A Cr(VI) removal mechanism considering both the surface immobilization and intracellular accumulation of Cr(III) along with the formation of coagulated cell precipitate by living B. amyloliquefaciens was suggested.
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Association of lipid peroxidation with endothelial dysfunction in patients with overt hypothyroidism.
Exp. Clin. Endocrinol. Diabetes
PUBLISHED: 02-28-2013
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Hypothyroidism is associated with increased oxidative stress. The mechanism underlying the endothelial dysfunction in thyroid disease is not yet clear. This study aims to investigate lipid peroxidation and its association with endothelial dysfunction in overt hypothyroidism (OHT).Plasma malondialdehyde (MDA) as a marker of oxidative stress and plasma nitrates and asymmetric dimethyl arginine levels (ADMA) as markers of endothelial dysfunction were estimated in 25 OHT patients in comparison to 25 euthyroid controls. Plasma MDA, ADMA levels were significantly increased, whereas plasma nitrates were significantly decreased in the patient group compared to control group (p<0.01). Moreover, a significant positive association between plasma MDA and ADMA was found in the patient group (?=0.472, p=0.036). Our results reveal the presence of endothelial dysfunction in OHT patients as evidenced by decreased plasma nitrates and increased ADMA levels. Increased levels of MDA represent an increased generation of reactive oxygen species in these patients. A finding of significant direct relation of plasma MDA with ADMA indicates that oxidative stress has a strong impact on endothelial dysfunction in overt hypothyroidism. Further studies focusing on the role of oxidative stress in endothelial dysfunction and the effects of antioxidant supplementation on endothelial function in OHT patients are required.
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Development of a novel bioerodible dexamethasone implant for uveitis and postoperative cataract inflammation.
J Control Release
PUBLISHED: 01-05-2013
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Delivery of anti-inflammatory steroids concurrently to both anterior and posterior segments of the eye is a challenge. The anterior ocular structures limit topical delivery. Injection can be disproportionately and repeatedly invasive and selective for only one ocular hemisphere. We developed a novel implant that can compensate for the limited conveyance of topical medicine and reduce the repetitive invasiveness of injection from the capsular bag allowing dexamethasone (DXM) delivery to both the anterior and posterior chambers. To establish proof of concept, microparticles were prepared with PLGA [poly(d,l-lactide-co-glycolide), 50:50, MW. 7000-17000], hydroxypropyl methyl cellulose (HPMC), and DXM by oil-in-water emulsion/solvent evaporation technique. Zeatsizer Nano and SEM (scanning electron microscopy) results showed microspheres in the range of 8±1µm. The target load of DXM in the microparticles was ~20.0% with a % recovery of 99.9% (w/w). Dose related pharmacokinetics with near zero order kinetics was observed for up to 6 weeks in rabbits with intracapsular bag implants. DXM flow was bidirectional from the endocapsular space and significant concentrations were found in the anterior and posterior chambers after up to 6 weeks. Whereas, with topical drops the exposure was minimal in all the ocular tissues with greater systemic exposure. Intraocular pressure was normal in all of the study groups; slit lamp biomicroscopy examinations revealed that no cells or fibrin formation in the anterior and posterior chamber with implants but flare, cells and fibrin was present in the topical drops group. Histological examination revealed normal tissues and no signs of inflammation in all the groups. The implant did not migrate to the center of the eye or obstruct the visual axis. We believe these findings demonstrate the feasibility of drug delivery from the capsular bag to the anterior and posterior segments effectively compared to topical alternatives.
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New rhodamine nitroxide based fluorescent probes for intracellular hydroxyl radical identification in living cells.
Org. Lett.
PUBLISHED: 12-16-2011
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The synthesis, characteristics, and biological applications of a series of new rhodamine nitroxide fluorescent probes that enable imaging of hydroxyl radicals (•OH) in living cells are described. These probes are highly selective for •OH in aqueous solution, avoiding interference from other reactive oxygen species (ROS), and they facilitate •OH imaging in biologically active samples. The robust nature of these probes (high specificity and selectivity, and facile synthesis) offer distinct advantages over previous methods for •OH detection.
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Fluorescent uranyl ion lidded cucurbit[5]uril capsule.
Inorg Chem
PUBLISHED: 11-30-2011
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A novel fluorescent complex {(UO(2))(2)(CB5)}(NO(3))(4)·4HNO(3).3H(2)O (U2CB5) is obtained from cucurbit[5]uril (CB5) and uranyl nitrate under ambient temperature conditions. The crystal structure revealed that two uranyl ions are coordinated to the two open portals of CB5 giving a closed molecular capsule, which further connected through CB5 molecules to give two-dimensional frameworks. The U2CB5 complex was further investigated by NMR, FTIR and TGA techniques. The Fluorescence of uranyl ion was found to be enhanced due to complexation with cucurbituril.
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DNA vaccination elicits protective immune responses against pandemic and classic swine influenza viruses in pigs.
Clin. Vaccine Immunol.
PUBLISHED: 09-14-2011
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Swine influenza is a highly contagious viral infection in pigs that significantly impacts the pork industry due to weight loss and secondary infections. There is also the potential of a significant threat to public health, as was seen in 2009 when the pandemic H1N1 influenza virus strain emerged from reassortment events among avian, swine, and human influenza viruses within pigs. As classic and pandemic H1N1 strains now circulate in swine, an effective vaccine may be the best strategy to protect the pork industry and public health. Current inactivated-virus vaccines available for swine influenza protect only against viral strains closely related to the vaccine strain, and egg-based production of these vaccines is insufficient to respond to large outbreaks. DNA vaccines are a promising alternative since they can potentially induce broad-based protection with more efficient production methods. In this study we evaluated the potentials of monovalent and trivalent DNA vaccine constructs to (i) elicit both humoral and gamma interferon (IFN-?) responses and (ii) protect pigs against viral shedding and lung disease after challenge with pandemic H1N1 or classic swine H1N1 influenza virus. We also compared the efficiency of a needle-free vaccine delivery method to that of a conventional needle/syringe injection. We report that DNA vaccination elicits robust serum antibody and cellular responses after three immunizations and confers significant protection against influenza virus challenge. Needle-free delivery elicited improved antibody responses with the same efficiency as conventional injection and should be considered for development as a practical alternative for vaccine administration.
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Aerosolized adenovirus-vectored vaccine as an alternative vaccine delivery method.
Respir. Res.
PUBLISHED: 09-06-2011
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Conventional parenteral injection of vaccines is limited in its ability to induce locally-produced immune responses in the respiratory tract, and has logistical disadvantages in widespread vaccine administration. Recent studies suggest that intranasal delivery or vaccination in the respiratory tract with recombinant viral vectors can enhance immunogenicity and protection against respiratory diseases such as influenza and tuberculosis, and can offer more broad-based generalized protection by eliciting durable mucosal immune responses. Controlled aerosolization is a method to minimize vaccine particle size and ensure delivery to the lower respiratory tract. Here, we characterize the dynamics of aerosolization and show the effects of vaccine concentration on particle size, vector viability, and the actual delivered dose of an aerosolized adenoviral vector. In addition, we demonstrate that aerosol delivery of a recombinant adenoviral vaccine encoding H1N1 hemagglutinin is immunogenic and protects ferrets against homologous viral challenge. Overall, aerosol delivery offers comparable protection to intramuscular injection, and represents an attractive vaccine delivery method for broad-based immunization campaigns.
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The timing of death in patients with tuberculosis who die during anti-tuberculosis treatment in Andhra Pradesh, South India.
BMC Public Health
PUBLISHED: 07-24-2011
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India has 2.0 million estimated tuberculosis (TB) cases per annum with an estimated 280,000 TB-related deaths per year. Understanding when in the course of TB treatment patients die is important for determining the type of intervention to be offered and crucially when this intervention should be given. The objectives of the current study were to determine in a large cohort of TB patients in India:- i) treatment outcomes including the number who died while on treatment, ii) the month of death and iii) characteristics associated with "early" death, occurring in the initial 8 weeks of treatment.
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The TRIM5 gene modulates penile mucosal acquisition of simian immunodeficiency virus in rhesus monkeys.
J. Virol.
PUBLISHED: 07-20-2011
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There is considerable variability in host susceptibility to human immunodeficiency virus type 1 (HIV-1) infection, but the host genetic determinants of that variability are not well understood. In addition to serving as a block for cross-species retroviral infection, TRIM5 was recently shown to play a central role in limiting primate immunodeficiency virus replication. We hypothesized that TRIM5 may also contribute to susceptibility to mucosal acquisition of simian immunodeficiency virus (SIV) in rhesus monkeys. We explored this hypothesis by establishing 3 cohorts of Indian-origin rhesus monkeys with different TRIM5 genotypes: homozygous restrictive, heterozygous permissive, and homozygous permissive. We then evaluated the effect of TRIM5 genotype on the penile transmission of SIVsmE660. We observed a significant effect of TRIM5 genotype on mucosal SIVsmE660 acquisition in that no SIV transmission occurred in monkeys with only restrictive TRIM5 alleles. In contrast, systemic SIV infections were initiated after preputial pocket exposures in monkeys that had at least one permissive TRIM5 allele. These data demonstrate that host genetic factors can play a critical role in restricting mucosal transmission of a primate immunodeficiency virus. In addition, we used our understanding of TRIM5 to establish a novel nonhuman primate penile transmission model for AIDS mucosal pathogenesis and vaccine research.
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Randomized double-masked controlled trial comparing pain scores with and without the use of supplementary 2% lidocaine gel in LASIK.
Am. J. Ophthalmol.
PUBLISHED: 05-19-2011
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To compare pain scores with and without supplementary topical 2% lidocaine gel in patients undergoing simultaneous bilateral laser-assisted in situ keratomileusis (LASIK) under topical anesthesia using 0.5% proparacaine eye drops.
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Dual pro-drugs of 2-C-methyl guanosine monophosphate as potent and selective inhibitors of hepatitis C virus.
Bioorg. Med. Chem. Lett.
PUBLISHED: 05-10-2011
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We have previously reported the power of combining a 5-phosphoramidate ProTide, phosphate pro-drug, motif with a 6-methoxy purine pro-drug entity to generate highly potent anti-HCV agents, leading to agents in clinical trial. We herein extend this work with the disclosure that a variety of alternative 6-substituents are tolerated. Several compounds exceed the potency of the prior 6-methoxy leads, and in almost every case the ProTide is several orders of magnitude more potent than the parent nucleoside. We also demonstrate that these agents act as pro-drugs of 2-C-methyl guanosine monophosphate. We have also reported the novel use of hepatocyte cell lysate as an ex vivo model for ProTide metabolism.
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Immune and Genetic Correlates of Vaccine Protection Against Mucosal Infection by SIV in Monkeys.
Sci Transl Med
PUBLISHED: 05-06-2011
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The RV144 vaccine trial in Thailand demonstrated that an HIV vaccine could prevent infection in humans and highlights the importance of understanding protective immunity against HIV. We used a nonhuman primate model to define immune and genetic mechanisms of protection against mucosal infection by the simian immunodeficiency virus (SIV). A plasmid DNA prime/recombinant adenovirus serotype 5 (rAd5) boost vaccine regimen was evaluated for its ability to protect monkeys from infection by SIVmac251 or SIVsmE660 isolates after repeat intrarectal challenges. Although this prime-boost vaccine regimen failed to protect against SIVmac251 infection, 50% of vaccinated monkeys were protected from infection with SIVsmE660. Among SIVsmE660-infected animals, there was about a one-log reduction in peak plasma virus RNA in monkeys expressing the major histocompatibility complex class I allele Mamu-A*01, implicating cytotoxic T lymphocytes in the control of SIV replication once infection is established. Among Mamu-A*01-negative monkeys challenged with SIVsmE660, no CD8(+) T cell response or innate immune response was associated with protection against virus acquisition. However, low levels of neutralizing antibodies and an envelope-specific CD4(+) T cell response were associated with vaccine protection in these monkeys. Moreover, monkeys that expressed two TRIM5 alleles that restrict SIV replication were more likely to be protected from infection than monkeys that expressed at least one permissive TRIM5 allele. This study begins to elucidate the mechanisms of vaccine protection against immunodeficiency viruses and highlights the need to analyze these immune and genetic correlates of protection in future trials of HIV vaccine strategies.
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Association of hemopexin in tear film and conjunctival macrophages with vernal keratoconjunctivitis.
Arch. Ophthalmol.
PUBLISHED: 04-13-2011
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Vernal keratoconjunctivitis (VKC) is a chronic allergic inflammatory disease with unclear etiology and pathogenesis. We investigated the tear film proteome of patients with VKC to understand the pathologic characteristics of VKC.
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The right sided syndrome, congenital absence of kidney and testis.
Saudi J Kidney Dis Transpl
PUBLISHED: 03-23-2011
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Unilateral renal agenesis (URA) is a developmental defect associated with ano-malies of the genitourinary system. The associations vary from absence of testis alone to high anorectal anomalies in other patients. We present two interesting patients with URA, encountered recently. Our first case was diagnosed with URA at the age of 11 years, which was detected on sonography, when he presented with pain abdomen. The presence of an epididymal cyst masked the absence of ipsilateral testes leading to delay in the diagnosis. Our second case was diagnosed with URA during the neonatal period when he presented with anorectal agenesis. He underwent abdomino-anal pull-through operation and later clinical course was complicated by recurrent cystitis, secondary vesicoureteral reflux and hydroureteronephrosis of solitary kidney, progressing to chronic kidney disease.
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Ready preparation of furanosyl n-pentenyl orthoesters from corresponding methyl furanosides.
J. Org. Chem.
PUBLISHED: 03-07-2011
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The 3,5-di-O-benzoyl n-pentenyl orthoesters of the four pentofuranoses have been prepared. The first key intermediate in each case is the methyl pentofuranoside(s), and a user-friendly procedure for the preparation of each, based on the Callam-Lowary precedent, is described, whereby formation of the crucial ?/? anomeric mixture is optimized. The mixture is used directly to prepare the corresponding perbenzoylated pentofuranosyl bromide(s) and then the title compounds.
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CD8+ cellular immunity mediates rAd5 vaccine protection against Ebola virus infection of nonhuman primates.
Nat. Med.
PUBLISHED: 02-14-2011
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Vaccine-induced immunity to Ebola virus infection in nonhuman primates (NHPs) is marked by potent antigen-specific cellular and humoral immune responses; however, the immune mechanism of protection remains unknown. Here we define the immune basis of protection conferred by a highly protective recombinant adenovirus virus serotype 5 (rAd5) encoding Ebola virus glycoprotein (GP) in NHPs. Passive transfer of high-titer polyclonal antibodies from vaccinated Ebola virus-immune cynomolgus macaques to naive macaques failed to confer protection against disease, suggesting a limited role of humoral immunity. In contrast, depletion of CD3(+) T cells in vivo after vaccination and immediately before challenge eliminated immunity in two vaccinated macaques, indicating a crucial requirement for T cells in this setting. The protective effect was mediated largely by CD8(+) cells, as depletion of CD8(+) cells in vivo using the cM-T807 monoclonal antibody (mAb), which does not affect CD4(+) T cell or humoral immune responses, abrogated protection in four out of five subjects. These findings indicate that CD8(+) cells have a major role in rAd5-GP-induced immune protection against Ebola virus infection in NHPs. Understanding the immunologic mechanism of Ebola virus protection will facilitate the development of vaccines for Ebola and related hemorrhagic fever viruses in humans.
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Assessing the Impact of Tiotropium on Lung Function and Physical Activity in GOLD Stage II COPD Patients who are Naïve to Maintenance Respiratory Therapy: A Study Protocol.
Open Respir Med J
PUBLISHED: 01-26-2011
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Physical activity status is increasingly recognized as a reliable predictor of mortality and hospitalization in patients with chronic obstructive pulmonary disease (COPD). The reduction in physical activity occurs earlier in the clinical course of COPD than previously appreciated, possibly arising from breathlessness, reduced exercise tolerance, and adoption of a more sedentary lifestyle. To date, no clinical trial has evaluated the impact of pharmacotherapy on both lung function and physical activity. We recently designed a study that evaluates the impact of tiotropium (a once-daily inhaled anticholinergic) on lung function and physical activity in a maintenance/treatment-naïve Global Initiative for Chronic Obstructive Lung Disease (GOLD) Stage II COPD cohort. Previous studies have demonstrated that tiotropium improves lung function and exercise tolerance; whether these benefits translate into improvements in physical activity is the focus of the current work. Here we describe the rationale and challenges in developing and implementing this study and review its unique features and novel design, including: utility of direct activity monitoring in multicenter clinical trials; importance of behavioral-modification techniques (including motivational interviewing to improve patient self-efficacy and adherence for a healthy, more active lifestyle); utility of individualized activity plans that provide an integrated approach with pharmacotherapy and behavioral modification to help patients achieve a more active lifestyle.
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Synthesis of new compounds related to the commercial fungicide tricyclazole.
Pest Manag. Sci.
PUBLISHED: 01-21-2011
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Tricyclazole is a commercial fungicide used to control rice blast. As part of re-registration activities, samples of metabolites and process impurities are required. In addition, isotopically labeled tricyclazole samples are also required.
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Genital tract sequestration of SIV following acute infection.
PLoS Pathog.
PUBLISHED: 01-13-2011
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We characterized the evolution of simian immunodeficiency virus (SIV) in the male genital tract by examining blood- and semen-associated virus from experimentally and sham vaccinated rhesus monkeys during primary infection. At the time of peak virus replication, SIV sequences were intermixed between the blood and semen supporting a scenario of high-level virus "spillover" into the male genital tract. However, at the time of virus set point, compartmentalization was apparent in 4 of 7 evaluated monkeys, likely as a consequence of restricted virus gene flow between anatomic compartments after the resolution of primary viremia. These findings suggest that SIV replication in the male genital tract evolves to compartmentalization after peak viremia resolves.
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Adjunctive effect of acupuncture to refractive correction on anisometropic amblyopia: one-year results of a randomized crossover trial.
Ophthalmology
PUBLISHED: 01-06-2011
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To evaluate the safety and adjunctive effect of acupuncture added to refractive correction for anisometropic amblyopia in younger children.
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Randomized controlled trial of patching vs acupuncture for anisometropic amblyopia in children aged 7 to 12 years.
Arch. Ophthalmol.
PUBLISHED: 12-15-2010
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To compare the effectiveness of 2-hour daily patching with the effectiveness of acupuncture in treating anisometropic amblyopia in children aged 7 to 12 years who have worn optimal spectacles for at least 16 weeks.
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Genetic immunization in the lung induces potent local and systemic immune responses.
Proc. Natl. Acad. Sci. U.S.A.
PUBLISHED: 12-06-2010
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Successful vaccination against respiratory infections requires elicitation of high levels of potent and durable humoral and cellular responses in the lower airways. To accomplish this goal, we used a fine aerosol that targets the entire lung surface through normal respiration to deliver replication-incompetent recombinant adenoviral vectors expressing gene products from several infectious pathogens. We show that this regimen induced remarkably high and stable lung T-cell responses in nonhuman primates and that it also generated systemic and respiratory tract humoral responses of both IgA and IgG isotypes. Moreover, strong immunogenicity was achieved even in animals with preexisting antiadenoviral immunity, overcoming a critical hurdle to the use of these vectors in humans, who commonly are immune to adenoviruses. The immunogenicity profile elicited with this regimen, which is distinct from either intramuscular or intranasal delivery, has highly desirable properties for protection against respiratory pathogens. We show that it can be used repeatedly to generate mucosal humoral, CD4, and CD8 T-cell responses and as such may be applicable to other mucosally transmitted pathogens such as HIV. Indeed, in a lethal challenge model, we show that aerosolized recombinant adenoviral immunization completely protects ferrets against H5N1 highly pathogenic avian influenza virus. Thus, genetic immunization in the lung offers a powerful platform approach to generating protective immune responses against respiratory pathogens.
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Discovery of a series of phosphonic acid-containing thiazoles and orally bioavailable diamide prodrugs that lower glucose in diabetic animals through inhibition of fructose-1,6-bisphosphatase.
J. Med. Chem.
PUBLISHED: 12-02-2010
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Oral delivery of previously disclosed purine and benzimidazole fructose-1,6-bisphosphatase (FBPase) inhibitors via prodrugs failed, which was likely due to their high molecular weight (>600). Therefore, a smaller scaffold was desired, and a series of phosphonic acid-containing thiazoles, which exhibited high potency against human liver FBPase (IC(50) of 10-30 nM) and high selectivity relative to other 5-adenosinemonophosphate (AMP)-binding enzymes, were discovered using a structure-guided drug design approach. The initial lead compound (30j) produced profound glucose lowering in rodent models of type 2 diabetes mellitus (T2DM) after parenteral administration. Various phosphonate prodrugs were explored without success, until a novel phosphonic diamide prodrug approach was implemented, which delivered compound 30j with good oral bioavailability (OBAV) (22-47%). Extensive lead optimization of both the thiazole FBPase inhibitors and their prodrugs culminated in the discovery of compound 35n (MB06322) as the first oral FBPase inhibitor advancing to human clinical trials as a potential treatment for T2DM.
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Soluble HIV-1 Env trimers in adjuvant elicit potent and diverse functional B cell responses in primates.
J. Exp. Med.
PUBLISHED: 08-02-2010
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Broadly neutralizing antibodies (bNAbs) against the HIV-1 envelope glycoproteins (Envs) have proven difficult to elicit by immunization. Therefore, to identify effective Env neutralization targets, efforts are underway to define the specificities of bNAbs in chronically infected individuals. For a prophylactic vaccine, it is equally important to define the immunogenic properties of the heavily glycosylated Env in healthy primates devoid of confounding HIV-induced pathogenic factors. We used rhesus macaques to investigate the magnitude and kinetics of B cell responses stimulated by Env trimers in adjuvant. Robust Env-specific memory B cell responses and high titers of circulating antibodies developed after trimer inoculation. Subsequent immunizations resulted in significant expansion of Env-specific IgG-producing plasma cell populations and circulating Abs that displayed increasing avidity and neutralization capacity. The neutralizing activity elicited with the regimen used was, in most aspects, superior to that elicited by a regimen based on monomeric Env immunization in humans. Despite the potency and breadth of the trimer-elicited response, protection against heterologous rectal simian-HIV (SHIV) challenge was modest, illustrating the challenge of eliciting sufficient titers of cross-reactive protective NAbs in mucosal sites. These data provide important information for the design and evaluation of vaccines aimed at stimulating protective HIV-1 immune responses in humans.
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Induction of broadly neutralizing H1N1 influenza antibodies by vaccination.
Science
PUBLISHED: 07-15-2010
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The rapid dissemination of the 2009 pandemic influenza virus underscores the need for universal influenza vaccines that elicit protective immunity to diverse viral strains. Here, we show that vaccination with plasmid DNA encoding H1N1 influenza hemagglutinin (HA) and boosting with seasonal vaccine or replication-defective adenovirus 5 vector encoding HA stimulated the production of broadly neutralizing influenza antibodies. This prime/boost combination increased the neutralization of diverse H1N1 strains dating from 1934 to 2007 as compared to either component alone and conferred protection against divergent H1N1 viruses in mice and ferrets. These antibodies were directed to the conserved stem region of HA and were also elicited in nonhuman primates. Cross-neutralization of H1N1 subtypes elicited by this approach provides a basis for the development of a universal influenza vaccine for humans.
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Comparative efficacy of hemagglutinin, nucleoprotein, and matrix 2 protein gene-based vaccination against H5N1 influenza in mouse and ferret.
PLoS ONE
PUBLISHED: 03-02-2010
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Efforts to develop a broadly protective vaccine against the highly pathogenic avian influenza A (HPAI) H5N1 virus have focused on highly conserved influenza gene products. The viral nucleoprotein (NP) and ion channel matrix protein (M2) are highly conserved among different strains and various influenza A subtypes. Here, we investigate the relative efficacy of NP and M2 compared to HA in protecting against HPAI H5N1 virus. In mice, previous studies have shown that vaccination with NP and M2 in recombinant DNA and/or adenovirus vectors or with adjuvants confers protection against lethal challenge in the absence of HA. However, we find that the protective efficacy of NP and M2 diminishes as the virulence and dose of the challenge virus are increased. To explore this question in a model relevant to human disease, ferrets were immunized with DNA/rAd5 vaccines encoding NP, M2, HA, NP+M2 or HA+NP+M2. Only HA or HA+NP+M2 vaccination conferred protection against a stringent virus challenge. Therefore, while gene-based vaccination with NP and M2 may provide moderate levels of protection against low challenge doses, it is insufficient to confer protective immunity against high challenge doses of H5N1 in ferrets. These immunogens may require combinatorial vaccination with HA, which confers protection even against very high doses of lethal viral challenge.
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A virus-like particle vaccine for epidemic Chikungunya virus protects nonhuman primates against infection.
Nat. Med.
PUBLISHED: 01-20-2010
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Chikungunya virus (CHIKV) has infected millions of people in Africa, Europe and Asia since this alphavirus reemerged from Kenya in 2004. The severity of the disease and the spread of this epidemic virus present a serious public health threat in the absence of vaccines or antiviral therapies. Here, we describe a new vaccine that protects against CHIKV infection of nonhuman primates. We show that selective expression of viral structural proteins gives rise to virus-like particles (VLPs) in vitro that resemble replication-competent alphaviruses. Immunization with these VLPs elicited neutralizing antibodies against envelope proteins from alternative CHIKV strains. Monkeys immunized with VLPs produced high-titer neutralizing antibodies that protected against viremia after high-dose challenge. We transferred these antibodies into immunodeficient mice, where they protected against subsequent lethal CHIKV challenge, indicating a humoral mechanism of protection. Immunization with alphavirus VLP vaccines represents a strategy to contain the spread of CHIKV and related pathogenic viruses in humans.
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Physical inactivity in patients with COPD, a controlled multi-center pilot-study.
Respir Med
PUBLISHED: 01-15-2010
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Physical activity (PA) has been reported to be reduced in severe chronic obstructive pulmonary disease (COPD). Studies in moderate COPD are currently scarce. The aim of the present study was to investigate physical activity in daily life in patients with COPD (n=70) and controls (n=30).
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Effect of open air drying, LPG based drier and pretreatments on the quality of Indian gooseberry (aonla).
J Food Sci Technol
PUBLISHED: 01-13-2010
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The aonla fruits (whole fruit, pricking, splits, segments) were subjected to pretreatments like blanching, osmotic dehydration with salt (2%) and sugar (40%) in different experiments before drying to obtain a product with better keeping quality. An LPG based drier (CRIDA drier) with capacity to dry 50 kg of fresh Indian gooseberry (aonla) was used. Nutritional quality and rehydration characteristics of CRIDA drier dried products were higher and free from contamination. Drying time was shortest for blanched and osmotically dehydrated segments dried in CRIDA drier and the product had better vitamin C retention, rehydration characteristics and sensory acceptability compared to sun or cabinet drier dried product. The additional expenditure spent on gas in CRIDA drier is compensated by reduced labour cost and higher price for the better quality product. Alternate energy sources like biogas and biomass can be used as fuel in the CRIDA drier.
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Fructose-1,6-bisphosphatase Inhibitors. 2. Design, synthesis, and structure-activity relationship of a series of phosphonic acid containing benzimidazoles that function as 5-adenosinemonophosphate (AMP) mimics.
J. Med. Chem.
PUBLISHED: 01-09-2010
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Efforts to enhance the inhibitory potency of the initial purine series of fructose-1,6-bisphosphatase (FBPase) inhibitors led to the discovery of a series of benzimidazole analogues with human FBPase IC(50)s < 100 nM. Inhibitor 4.4 emerged as a lead compound based on its potent inhibition of human liver FBPase (IC(50) = 55 nM) and significant glucose lowering in normal fasted rats. Intravenous administration of 4.4 to Zucker diabetic fatty rats led to rapid and robust glucose lowering, thereby providing the first evidence that FBPase inhibitors could improve glycemia in animal models of type 2 diabetes.
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Envelope vaccination shapes viral envelope evolution following simian immunodeficiency virus infection in rhesus monkeys.
J. Virol.
PUBLISHED: 11-11-2009
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The evolution of envelope mutations by replicating primate immunodeficiency viruses allows these viruses to escape from the immune pressure mediated by neutralizing antibodies. Vaccine-induced anti-envelope antibody responses may accelerate and/or alter the specificity of the antibodies, thus shaping the evolution of envelope mutations in the replicating virus. To explore this possibility, we studied the neutralizing antibody response and the envelope sequences in rhesus monkeys vaccinated with either gag-pol-nef immunogens or gag-pol-nef immunogens in combination with env and then infected with simian immunodeficiency virus (SIV). Using a pseudovirion neutralization assay, we demonstrate that envelope vaccination primed for an accelerated neutralizing antibody response following virus challenge. To monitor viral envelope evolution in these two cohorts of monkeys, full-length envelopes from plasma virus isolated at weeks 37 and 62 postchallenge were sequenced by single genome amplification to identify sites of envelope mutations. We show that env vaccination was associated with a change in the pattern of envelope mutations. Prevalent mutations in sequences from gag-pol-nef vaccinees included deletions in both variable regions 1 and 4 (V1 and V4), whereas deletions in the env vaccinees occurred only in V1. These data show that env vaccination altered the focus of the antibody-mediated selection pressure on the evolution of envelope following SIV challenge.
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Endothelial cell loss and surgically induced astigmatism after sutureless large-incision manual cataract extraction (SLIMCE).
Arch. Ophthalmol.
PUBLISHED: 10-14-2009
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To describe a modified manual cataract extraction technique, sutureless large-incision manual cataract extraction (SLIMCE), and to report its clinical outcomes.
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Current progress in the pharmacological therapy of fibromyalgia.
Expert Opin Investig Drugs
PUBLISHED: 09-08-2009
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Fibromyalgia (FM) is a chronic musculoskeletal pain disorder often associated with fatigue, dyscognition, and sleep disturbances. Recent research advances highlight a critical role for aberrant central pain processing in FM, and, consistent with these data, the first three drugs approved by the FDA for FM over the past 2 years have a predominantly central mode of action. The first drug, pregabalin, may counteract central pain transmission by inhibiting presynaptic release of excitatory neurotransmitters, including substance P and glutamate. The serotonin-norepinephrine reuptake inhibitors duloxetine and milnacipran have been approved more recently and are believed to reduce pain by increasing serotonin and norepinephrine concentrations in descending inhibitory pain pathways. Agents with multiple other mechanisms of action are in development and promise an assortment of therapeutic options for this complex disorder in the near future.
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Systemic and mucosal T-lymphocyte activation induced by recombinant adenovirus vaccines in rhesus monkeys.
J. Virol.
PUBLISHED: 08-05-2009
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The administration of vectors designed to elicited cell-mediated immune responses may have other consequences that are clinically significant. To explore this possibility, we evaluated T-cell activation during the first 2 months after recombinant adenovirus serotype 5 (rAd5) prime or boost immunizations in rhesus monkeys. We also evaluated the kinetics of T-lymphocyte activation in both the systemic and the mucosal compartments after rAd5 administration in monkeys with preexisting immunity to Ad5. The rAd5 immunization induced lower-frequency Gag epitope-specific CD8+ T cells in the colonic mucosa than in the peripheral blood. There was evidence of an expansion of the simian immunodeficiency virus Gag-specific CD8+ T-cell responses, but not the Ad5 hexon-specific T-cell responses, following a homologous rAd5 boost. A striking but transient T-lymphocyte activation in both the systemic and the mucosal compartments of rhesus monkeys was observed after rAd5 immunization. These findings indicate that the administration of a vaccine vector such as Ad5 can induce a global activation of T cells.
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T-cell vaccination reduces simian immunodeficiency virus levels in semen.
J. Virol.
PUBLISHED: 07-29-2009
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Recent findings suggest that most sexual transmission of human immunodeficiency virus type 1 (HIV-1) occurs during the acute phase of infection when viral replication is most intense. Here, we show that vaccine-elicited cellular immune responses can significantly reduce simian immunodeficiency virus levels in the semen during the period of primary infection in monkeys. A vaccine that decreases the quantity of HIV-1 in the semen of males during primary infection might decrease HIV-1 transmission in human populations and therefore affect the spread of AIDS.
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Monitoring HIV vaccine trial participants for primary infection: studies in the SIV/macaque model.
AIDS
PUBLISHED: 06-25-2009
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The ability to detect and quantify acute HIV-1 infection prior to seroconversion would be an important tool for use in HIV vaccine clinical efficacy trials. We have utilized the SIV/rhesus monkey model to evaluate whether samples more easily obtained than peripheral blood might be used for intensive monitoring of vaccine trial participants.
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TLR9 agonist, but not TLR7/8, functions as an adjuvant to diminish FI-RSV vaccine-enhanced disease, while either agonist used as therapy during primary RSV infection increases disease severity.
Vaccine
PUBLISHED: 03-06-2009
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Agonists for TLR7, TLR8, and TLR9 have been shown to enhance vaccine immunogenicity. We evaluated the impact of TLR activation on RSV disease in a murine model by administering TLR7/8 and TLR9 agonists during FI-RSV immunization or RSV infection. CpG administered during immunization reduced disease following challenge as evidenced by decreased lung pathology, illness, and cytokines. In marked contrast, TLR7/8 agonist had little impact. To evaluate potential therapeutic use, TLR agonists were administered during primary infection. Although type 2 cytokine responses decreased and type 1 cytokines and MIP-1-alpha/beta increased, both TLR7/8 and TLR9 agonists increased clinical symptoms and pulmonary inflammation when administered during primary infection. Thus, TLR9-induced signaling during FI-RSV immunization reduced vaccine-enhanced disease whereas immunostimulatory properties of TLR agonists enhanced disease severity when used during RSV infection. Immunomodulation elicited by TLR9 agonist confirms the adjuvant potential of TLR agonists during RSV immunization. However, in contrast to work done with HIV-1 vaccines, the inability of TLR7/8 agonist to boost type 1 vaccine-induced RSV immunity demonstrates pathogen-TLR specificity. These data reveal that the timing of administration of immunomodulatory agents is critical. Furthermore, these data underscore that amplification of anti-viral immune responses may result in immunopathology rather than immune-mediated protection.
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Effects of platelet-derived growth factor, vitamin D and parathyroid hormone on osteoblasts derived from cancer patients on chronic bisphosphonate therapy.
Int. J. Mol. Med.
PUBLISHED: 02-13-2009
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Bisphosphonates consist of a family of pyrophosphate analogues that are currently being used to treat metastatic bone diseases as well as systemic bone diseases such as osteoporosis. There is accumulating evidence suggesting that patients treated with these bisphosphonates can develop, particularly with invasive dental procedures, osteonecrosis of the jaw. This present study investigated the ability of osteoblastic cells obtained from the alveolar bone of patients on long term intravenous bisphosphonate therapy to respond to agents normally involved in bone regulation and repair. The effects of platelet-derived growth factor-BB (PDGF-BB), 1,25-dihydroxycholecalciferol [1,25(OH)2VitaminD3] and parathyroid hormone (PTH) on basic parameters of cell viability, proliferation, and differentiation were studied. Osteoblastic cells from a diagnosed necrotic alveolar bone specimen obtained with consent from a multiple myeloma female patient, and a non-necrotic sample from a breast cancer female patient both on chronic bisphosphonate therapy (zolendronic acid) were successfully cultured. Cells from an alveolar bone specimen obtained from a female donor with no known medical conditions were also studied for comparative responses. The cells were exposed to 1,25(OH)2D3, PDGF, or PTH under various incubation conditions. The osteoblastic cell differentiation marker, alkaline phosphatase activity, was assayed using a biochemical analysis. Cell viability was assessed with an MTT assay which measures mitochondrial activity and cell proliferation with a tritiated thymidine assay. This study on osteoblastic cells grown from a necrotic alveolar bone from a multiple myeloma patient and a non-necrotic sample from a breast cancer patient, both on long term bisphosphonate treatment, suggests that viable cells from the bone are responsive to agents such as PTH, PDGF and 1,25(OH)2D3 with changes in alkaline phosphatase activity, proliferation and viability suggestive of normal osteoblastic cell responses observed in cultures from a donor of the same gender and age, but not on bisphosphonate treatment. This work provides a rationale for clinical studies to further assess whether the osteonecrosis that sometimes develops in patients treated with bisphosphonates, can be controlled or prevented by close attention to the levels of bone/calcium regulatory agents and/or, in some cases, therapeutic intervention with PDGF to restore regenerative processes that may be compromised at the necrotic site.
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The efficacy and safety of milnacipran for treatment of fibromyalgia. a randomized, double-blind, placebo-controlled trial.
J. Rheumatol.
PUBLISHED: 01-10-2009
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To evaluate the safety and efficacy of milnacipran, a dual norepinephrine and serotonin reuptake inhibitor, in the treatment of fibromyalgia (FM).
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Partial protection of Simian immunodeficiency virus (SIV)-infected rhesus monkeys against superinfection with a heterologous SIV isolate.
J. Virol.
PUBLISHED: 01-07-2009
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Although there is increasing evidence that individuals already infected with human immunodeficiency virus type 1 (HIV-1) can be infected with a heterologous strain of the virus, the extent of protection against superinfection conferred by the first infection and the biologic consequences of superinfection are not well understood. We explored these questions in the simian immunodeficiency virus (SIV)/rhesus monkey model of HIV-1/AIDS. We infected cohorts of rhesus monkeys with either SIVmac251 or SIVsmE660 and then exposed animals to the reciprocal virus through intrarectal inoculations. Employing a quantitative real-time PCR assay, we determined the replication kinetics of the two strains of virus for 20 weeks. We found that primary infection with a replication-competent virus did not protect against acquisition of infection by a heterologous virus but did confer relative control of the superinfecting virus. In animals that became superinfected, there was a reduction in peak replication and rapid control of the second virus. The relative susceptibility to superinfection was not correlated with CD4(+) T-cell count, CD4(+) memory T-cell subsets, cytokine production by virus-specific CD8(+) or CD4(+) cells, or neutralizing antibodies at the time of exposure to the second virus. Although there were transient increases in viral loads of the primary virus and a modest decline in CD4(+) T-cell counts after superinfection, there was no evidence of disease acceleration. These findings indicate that an immunodeficiency virus infection confers partial protection against a second immunodeficiency virus infection, but this protection may be mediated by mechanisms other than classical adaptive immune responses.
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"Toxic Pancreatitis with an Intra-Abdominal Abscess which was Caused by Organophosphate Poisoning (OP)".
J Clin Diagn Res
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Organophosphate insecticides are the potent inhibitors of the acetylcholinesterase enzyme which lead to an increased acetylcholine activity, which are responsible for symptoms such as abdominal pain, diarrhoea, vomiting and hypersalivation. We are reporting on a young male with acute organophosphate poisoning, who presented with unusual complications like toxic pancreatitis with an intraabdominal abscess.
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Ameloblastic fibroma.
J Oral Maxillofac Pathol
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Ameloblastic fibroma is a rare odontogenic tumor comprising neoplastic epithelial and mesenchymal tissues. This lesion was previously considered to be a benign lesion with very limited recurrence rate and malignant transformation. However, recent reports have suggested that this lesion has the potential for recurrence and malignant transformation. In this brief report, we report a case of AF in the context of its high cellularity on histopathological examination.
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A new era in corneal transplantation: paradigm shift and evolution of techniques.
Hong Kong Med J
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Penetrating keratoplasty is the replacement of a diseased cornea with a full-thickness donor graft. In the last century, this gold standard procedure was long established as the treatment of choice for various corneal diseases. The classical indications for a penetrating keratoplasty entailed optical, tectonic, therapeutic, and cosmetic issues. Over the past decade however, surgical advances have now enabled operations involving the cornea to be performed with a major shift in emphasis, such that penetrating keratoplasty has given way to lamellar (layered) keratoplasty. This review provides the latest updates on developments in the field of corneal transplantation and the nomenclature of different types of component surgery, particularly from the perspective of Hong Kong.
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Correlation between genotypic (V3 population sequencing) and phenotypic (Trofile ES) methods of characterizing co-receptor usage of HIV-1 from 200 treatment-naïve HIV patients screened for Study A4001078.
Antiviral Res.
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Assessment of HIV-1 co-receptor usage is essential to identify patients who are likely to respond to maraviroc (MVC)-containing regimens. Co-receptor usage of plasma virus from all treatment-naïve patients screened for a MVC clinical trial was assessed using phenotypic and genotypic methodologies to evaluate concordance between testing methods and to assess the quantity of CXCR4-using (non-R5) virus in samples giving discordant results. Co-receptor usage was prospectively measured using the enhanced sensitivity Trofile assay (Trofile ES) to screen patients for enrollment in Study A4001078. Population and deep sequencing methodologies were utilized retrospectively to analyze all screening samples, with co-receptor usage determined using the geno2pheno algorithm. Concordance between methods was explored using descriptive statistics. The quantity of non-R5 virus in all samples was measured using deep sequencing. Trofile ES and matched genotype results were obtained for 199screening samples. Concordance of Trofile ES with population genotyping (5.75% false-positive rate [FPR]) and deep sequencing (3.5% FPR; 2% non-R5 threshold) was 91.7% and 89.6%, respectively. Population genotype data were available for all samples with non-reportable Trofile ES results; the distribution of co-receptor usage in this set was consistent with that in the overall population: 75% (12/16) R5 and 25% (4/16) non-R5. The majority of samples contained non-R5 plasma HIV-1 RNA estimated at either <1 log(10) (62.0%) or ?4 log(10) (30.5%) copies/mL; the absolute amount of detectable non-R5 virus remained stable between screening and baseline visits. Samples originally classified as non-R5 by Trofile ES but R5 by population sequencing had a relatively low absolute amount of non-R5 virus (mean 2.1%, median 0.1%). The determination of co-receptor usage using either Trofile ES or genotyping methodologies showed similar frequencies of R5 and non-R5 virus in this treatment-naïve study population. For both concordant and discordant samples, population sequencing appropriately identified R5 samples with low levels of non-R5-using virus.
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Severe and recurrent interface hemorrhage after endothelial keratoplasty.
Optom Vis Sci
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To report the occurrence and management of recurrent hemorrhage after Descemet stripping endothelial keratoplasty (DSEK) in a patient with pseudophakic bullous keratopathy.
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Oral manifestations of human immunodeficiency virus in children: An institutional study at highly active antiretroviral therapy centre in India.
J Oral Maxillofac Pathol
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More than 1000 children are newly infected with Human immunodefi ciency virus (HIV) every day, and of these more than half will die as a result of AIDS due to lack of access to HIV treatment. HIV disease varies considerably in children. Among those infected prenatally, some experience few or no symptoms for years, whereas in others the disease progresses rapidly. The risk factors that influence the development of such oral manifestations include, low CD4+ T cell count, xerostomia and lack of highly active antiretroviral therapy (HAART).
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CD4 T follicular helper cell dynamics during SIV infection.
J. Clin. Invest.
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CD4 T follicular helper (TFH) cells interact with and stimulate the generation of antigen-specific B cells. TFH cell interaction with B cells correlates with production of SIV-specific immunoglobulins. However, the fate of TFH cells and their participation in SIV-induced antibody production is not well understood. We investigated the phenotype, function, location, and molecular signature of TFH cells in rhesus macaques. Similar to their human counterparts, TFH cells in rhesus macaques represented a heterogeneous population with respect to cytokine function. In a highly differentiated subpopulation of TFH cells, characterized by CD150lo expression, production of Th1 cytokines was compromised while IL-4 production was augmented, and cells exhibited decreased survival, cycling, and trafficking capacity. TFH cells exhibited a distinct gene profile that was markedly altered by SIV infection. TFH cells were infected by SIV; yet, in some animals, these cells actually accumulated during chronic SIV infection. Generalized immune activation and increased IL-6 production helped drive TFH differentiation during SIV infection. Accumulation of TFH cells was associated with increased frequency of activated germinal center B cells and SIV-specific antibodies. Therefore, chronic SIV does not disturb the ability of TFH cells to help B cell maturation and production of SIV-specific immunoglobulins.
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Feasibility and effectiveness of provider initiated HIV testing and counseling of TB suspects in Vizianagaram district, South India.
PLoS ONE
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Though internationally recommended, provider initiated HIV testing and counseling (PITC) of persons suspected of tuberculosis (TB) is not a policy in India; HIV seroprevalence among TB suspects has never been reported. The current policy of PITC for diagnosed TB cases may limit opportunities of early HIV diagnosis and treatment. We determined HIV seroprevalence among persons suspected of TB and assessed feasibility and effectiveness of PITC implementation at this earlier stage in the TB diagnostic pathway.
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