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In JoVE (1)

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Articles by Marianne S. Carlon in JoVE

 JoVE Clinical and Translational Medicine

A Novel Surgical Approach for Intratracheal Administration of Bioactive Agents in a Fetal Mouse Model

1Molecular Virology and Gene Therapy, KU Leuven, 2Department of Woman and Child, KU Leuven, 3Neurobiology and Gene Therapy, KU Leuven, 4Division of Nuclear Medicine, KU Leuven, 5Biomedical NMR Unit/ MoSAIC, KU Leuven


JoVE 4219

We developed a novel surgical approach for intratracheal administration of bioactive agents into the mouse fetus. The delivery route is more efficient in targeting the fetal mouse lungs than the commonly used intra-amniotic injection. This procedure has to date not been described in a mouse model.

Other articles by Marianne S. Carlon on PubMed

Pulmonary Venous Admixture During Mechanical Ventilation with Varying FIO2 and PEEP

Many authors have indicated that high FIO2 (0.75-1.0) ventilation may increase pulmonary venous admixture. Reabsorption atelectasis is supposedly responsible for this adverse effect. The authors attempted to determine if increasing PEEP during high FIO2 ventilation could eliminate the detrimental influence of the latter. In 17 patients in respiratory failure, hemodynamic and respiratory variables were measured during ventilation with FIO2 0.50, 0.75, and 1.0 and PEEP varying from -3 to +5 cm H2O from baseline. Before exposure to FIO2 > 0.75, addition of PEEP resulted in a decrease of Qs/Qt from a mean of 26.6-21.9%. After exposure to FIO2 0.75-1.0, Qs/Qt remained at levels not different from baseline, even when PEEP 8 cm H2O above baseline was added. The authors conclude that ventilation with high FIO2 is not useful in determining Qs/Qt, and may prevent the improvement in pulmonary venous admixture associated with PEEP therapy.

Laser Monitoring of Mass Concentrations of Monodisperse Test Aerosols

Aerosol sampling is a complicated problem in aerosol physics. A technique described to monitor continuously the mass concentration of monodisperse test aerosols using a He-Ne laser. Good approximations are possible from Mie theory. The method is fast, accurate, and eliminates the need for precalibration of a standard sampler to monitor aerosol mass concentration over increments of time. It can be used for sampler efficiency measurements and wherever it is desired to monitor test aerosols of spherical droplets continuously, e.g., in studies of the human respiratory system for droplets larger than a few micrometers.

Aerosol Spectrometry in the Infrared

Aerosol spectrometry denotes a methodology for describing spectral effects of atmospheric constituents in quantitative, standardized, basic terms. It is based on the premise that most atmospheric constituents can be described (albeit in some cases very unconventionally) as specialized kinds of aerosols, some of which exhibit complex changes in spectral behavior between physical phases. Aerosol spectrometry permits an intuitive understanding of the spectral properties of atmospheric constituents and, very important, allows insights to be gained not found in traditional or purely mathematical treatments. The discussion includes liquid and solid particulate aerosols, special cases including Christiansen effects and isosbestics, and the phasetransitional behavior of liquid droplets in vapor. A study of the latter led to the finding that anomalous (continuum) IR absorption in water vapor could be attributed to liquidlike intermolecular hydrogen bonds in molecular complexes (clusters) long before this observation was made using traditional vapor spectrometric techniques.

Drug Associations in Hypokalemia

Evaluation of an "in Vivo" PaO2 and PaCO2 Monitor in the Management of Respiratory Failure

A commercially available gas-chromatograph (Sentorr Gas Analyzer, Ohio Medical Products, Madison, WI) was tested, featuring continuous measurement of in vivo PaO2 and PaCO2 by means of a thin, heparin-coated catheter, inserted through an indwelling arterial line. Gas tensions are displayed every 4 min. The probes had a tendency to break rather easily, and a considerable proportion of them was faulty. We measured 105 paired determinations of blood gases obtained from patients in respiratory failure requiring mechanical ventilation with a Corning IL 175 Analyzer and displayed by the Sentorr Gas Analyzer. A high correlation (p < 0.01) existed between the two sets of values, but an estimated error of 10-20% was found in the Sentorr data. After modifications of the respirator, changes of displayed values were already notable after 4 min and 90% completed by 8-12 min. The use of this device enabled us to considerably accelerate decision-making in the management of respiratory failure. Although techology still necessitates improvements, before widespread use of in vivo monitoring of PaO2 and PaCO2 is advisable, the concept has significant clinical potential and may represent a major advance in the management of respiratory failure.

High-frequency Jet Ventilation in Major Airway or Pulmonary Disruption

High-frequency jet ventilation is an experimental method of mechanical support, which achieves satisfactory alveolar ventilation and oxygenation at low peak-inspiratory pressures of 5 to 8 cm H2O and low end-expiratory pressures of 3 to 5 cm H2O. This characteristic was used to advantage in 23 patients with cancer, 12 of whom had tracheal or bronchial disruption complicated by pneumonia. Eight patients who could not be supported by conventional means were salvaged. Barotrauma complicated the very high peak airway pressures required to ventilate 8 of 11 patients with respiratory failure associated with diffuse interstitial pneumonia or pulmonary fibrosis. There were only 2 survivors despite temporary normalization of arterial blood gas values in 7 patients. Earlier use of high-frequency jet ventilation in patients with poor compliance may prevent pulmonary disruption in addition to deleterious hemodynamic and systemic effects of conventional high-pressure ventilation. Other applications under study include the role of jet ventilation in resection of the trachea or carina, and in major airway trauma.

Dopamine Administration in Oliguria and Oliguric Renal Failure

Oliguric renal failure significanlty worsens the prognosis of many critical illnesses, particularly in patients with respiratory failure. In 52 patients, a continuous infusion of dopamine, 1.5-2.5 micrograms/kg . min, was administered when creatine clearance (Ccr) fell below 40 ml/min and urinary output was less than 1 ml/kg . h despite normal intravascular volume. In 18 patients, a continuous infusion of furosemide (3-5 mg/kg . day) was also administered. Daily, two 3-h collections of urine and blood specimens were obtained to determine Ccr, osmolar clearance (Cosm), free water clearance (CH2O) and excreted fraction of filtered sodium (FENa); one collection was made during dopamine infusion and one while the infusion was suspended. Cardiac output and pulmonary venous admixture were also measured. The authors obtained 199 urine collections in 52 patients; considering the aggregate patient pouplation, urinary output increased by 42.3% (30.2 +/- 3.45 (SEM) ml/h), on dopamine infusion. Cosm, FENa, and Ccr were also higher on dopamine. CH2O and hemodynamic variables were not altered by dopamine infusion. When patients were startified on the basis of mechanical ventilatory support, Ccr and furosemide administration, dopamine infusion essentially caused the same changes in the variables studied as described for the aggregate patient population. Diuresis and sodium excretion increased significantly on dopamine even in those patients receiving furosemide infusion. The authors conclude that fluid and osmolar load can be eliminated more effectively in critically ill patients with continuous infusion of 1.5-2.5 micrograms/kg . min of dopamine.

The Seventies Evolution in Liver Surgery for Cancer

During the past decade, one of the major changes in the field of oncology has been in the surgical approach to primary and secondary cancer of the liver. As a result of data and experience gained in liver transplantation programs and with the application of vascular surgical principles, resectability rates have been increased. The present rate of 32% has been achieved with an overall 30-day operative mortality rate of 9%. More sophisticated intraoperative and postoperative supports have been essential in achieving these results. The median operating time is now 4 3/4 hours in length. Complications are minimal. The median postoperative hospital stay is now 13 days. During the past decade, 436 patients with liver tumors were treated by the authors. It has become apparent in this experience and in that reported by others that an increasing number of patients with primary liver cancer or metastatic cancer in the liver can be cured by surgery with minimal operative risk. Adjuvant chemotherapy may increase the salvage rate. Current therapeutic results are best evaluated after staging of the liver disease: Stage I (no involvement of margins of resection, hepatic vascular structures or bile ducts; all gross disease removed): 85% three-year survival estimate, using the Kaplan-Meier method, for individuals with primary liver cancer; 71% for those with metastatic colorectal cancer. Stages II and III (regional or extrahepatic spread): 22% three-year survival for individuals with primary liver cancer but no survivors at two years with metastatic colorectal cancer. These data permit better selection of patients who are most likely to benefit from surgery.

Infrared Water Vapor Continuum Absorption: Equilibria of Ions and Neutral Water Clusters

The temperature dependence of (C(o)(s))lambda, the self-broadening coefficient for the water vapor continuum absorption at wavelength lambda, can be modeled by the equilibrium ion product of water which is tabulated widely in physics texts and handbooks. A theoretical basis for this modeling is developed from water cluster theory, and it is shown that experimental values of (C(o)(s))lambda. could be seriously in error, especially at high temperatures, if the saturation ratio (fractional RH) of water vapor is not taken into account by the experimenter for reasons other than normalization of the coefficient for partial pressure of the sample. An explanation is suggested for the departure of (C(o)(s))lambda from the usual negative dependence on increasing water vapor temperature in some experiments. Figures are given showing equilibrium sizes and populations of neutral water clusters and ions in water vapor as functions of humidity and temperature, based in part on data of Bignell and other workers.

Mass Spectrometry of Ion-induced Water Clusters: an Explanation of the IR Continuum Absorption; Addenda

Comparison of Electronic and Manometric Central Venous Pressures. Influence of Access Route

Manometric central venous pressure (CVP) measurements are still routinely used as indicators of intravascular volume, particularly during surgery and when cardiorespiratory function is assumed to be normal. The difference between manometric measurements of CVP, from a 16-gauge polyvinylchloride catheter, and those obtained electronically from the level of the right atrium through the proximal port of a pulmonary artery catheter was studied in 40 patients admitted to the ICU. Despite correct position of the catheter tips and adequate respiratory oscillations, manometric measurements differed considerably from right atrial mean pressure determinations. The discrepancy was largest and the direction of change not predictable when the CVP catheters was inserted via an antecubital or right subclavian vein. When catheters were inserted from the left subclavian vein or the internal jugular, on the other hand, manometric CVP was consistently 4-6 cm H2O higher than the electronic pressure determination. If a manometric CVP catheter is to be used, the internal jugular or left subclavian routes appear preferable.

Technical Aspects and Clinical Implications of High Frequency Jet Ventilation with a Solenoid Valve

High frequency jet ventilation (HFJV) is an incompletely studied technique of mechanical respiratory support. The authors have built a ventilator based on a solenoid valve, that allows independent selection of respiratory rate and inspiratory/expiratory ratio. The ventilator can be synchronized to the heart rate. Humidification is provided by warm saline dripped in front of the injector nozzle, so that the jet stream itself acts as a nebulizer. Tube diameter, length, and deformability are fundamental determinants of inspiratory flow rate and wave form. Cannula kinking and inadequate humidification were the most significant sources of complications.

Recurrent Unilateral Lung Disease

A 25-year-old patient, with multiple pulmonary metastases from osteogenic sarcoma who two years ago developed respiratory failure with unilateral left lung involvement and was successfully treated with independent lung ventilation, was readmitted to an ICU with recurrent unilateral lung disease. Conventional therapy failed to reverse the respiratory failure; independent ventilation temporarily improved the patient's oxygenation. At autopsy, different involvement of the two lungs by the tumor was evident so that blood flow of the right lung and lymphatic flow of the left lung were impaired. When respiratory failure unresponsive to conventional therapy develops, anatomical abnormalities should be considered.

Clinical Experience with High Frequency Jet Ventilation

High frequency jet ventilation (HFJV) has been used in recent years in some forms of respiratory failure, where the presence of barotrauma limited the application of high peak inspiratory pressure. In the present report, the authors describe the clinical experience with 17 patients, who could not be supported with conventional mechanical support and were placed on HFJV. Rates of 100 breath/min, inspiratory/expiratory ratio of 1:2 and cannula size of 1.06--1.62 mm (18--14) gauge were used. Driving pressure required to maintain a PaCO2 of 40--45 torr was 14--45 psig; however, except in 2 patients who developed hemorrhagic tracheitis with subtotal obstruction of both mainstem bronchi, a driving pressure higher than 27 psig was never required, even when PEEP up to 32 cm H2O was used. Of 17 patients treated, 8 survived. In all cases, alveolar ventilation could be maintained within the desired range with high frequency ventilation, even in those patients who eventually died; mechanical support never provided better oxygenation or alveolar ventilation than high frequency ventilation. Hemodynamic function was essentially unchanged with high frequency ventilation; indeed, in three cases, inotropic support with dopamine could be discontinued after initiation of high frequency ventilation.

Present Status of High Frequency Ventilation

Prostaglandin Therapy in a Case of Refractory Stress Ulcer Bleeding

[Laryngeal Epithelium in Pre- and Postnatal Life. Experimental Study in Man and Guinea Pig]

Acute Respiratory Failure Due to 2'Deoxycoformycin

High-frequency Jet Ventilation: Theoretical Considerations and Clinical Observations

High-frequency jet ventilation (HFJV) described a technique of mechanical respiratory support based on the delivery of gases under conditions of constant flow and low pressure. Among the benefits ascribed to HFJV are lessened interference with hemodynamic function and reduced danger of barotrauma. The theoretical and technical aspects of HFJV are discussed and the clinical experience with 39 patients in respiratory failure reported. Synchronization of HFMV with heart rate was attempted in three patients. Cardiac output and ejection fraction increased in all of them. At present, results suggest that HFJV may be the ideal form of support for patients with major airway disruption. The available data also indicated that extensive clinical trials are warranted to define advantages and limits of this form of ventilation.

Acute Pulmonary Failure in Asymmetric Lung Disease: Approach to Management

Synthesis and Topical Antiinflammatory Potencies of a Series of 6-keto- and Delta 6-6-acyloxybetamethasone Derivatives

6-keto- and delta 6-6-acyloxybetamethasone esters were synthesized, and tested for topical antiinflammatory potency using a modification of the Tonelli croton ear assay. The introduction of a 6-keto group generally led to retention of topical antiinflammatory potencies when compared to the corresponding 6-desoxycorticoids. In contrast, introduction of the delta 6-6-acyloxy moiety into betamethasone 17,21-dipropionate reduced antiinflammatory potency.

[Role of HY Antigen in Human and Mammalian Gonadal Organogenesis (author's Transl)]

H-Y (histocompatibility Y) antigen plays a role in gonadal organogenesis, which is poorly understood. Indeed, it is not immunologically well-defined. The use of cytotoxicity tests cannot lead to a right quantification of its expression. In vertebrates, it is a marker of the heterogametic sex. As it is also detected in invertebrates, H-Y antigen is therefore ubiquitous and has a high phylogenic conservation. Its role, as an organizer of mammal testes, was carried out by controversial experiments of dissociation-reorganization, in gonadal cells. In gonads. H-Y antigen can be studied under 3 diverse aspects : secretion, fixation and expression, Recently, Ohno proposed a very attractive pattern of testicular and ovarian organogenesis. In males, organization of seminiferous tubules is the result of the interaction between H-Y antigen and its specific gonadal receptor. In females, primordial follicle formation is induced by the interaction between an hypothetic ovary-organizing antigen (similar to H-Y antigen) and the same specific receptor as in testis. These different hypotheses are discussed. In addition, it is underlined how expression of H-Y antigen (anchorage site of H-Y antigen on plasma membrane associated with beta 2-m) can be distinguished from its fixation on gonadal specific receptors. In view of controversial data, the masculinisation of bovine free-martin gonads by H-Y antigen is discussed. In XX males and XY females, H-Y expression which is variable is correlated with its gonadal organizing role. Finally, at present time location of H-Y structural and control genes remains unsolved. In view of all hypotheses postulated, it is not clearly demonstrated how H-Y antigen can act on gonadal organogenesis. Nevertheless, priority of cell-cell recognition, via H-Y antigen, has to be emphasized.

[Comparison Between the Clinical and Pathological Classifications of Cervical Metastatic Lymphadenopathies]

High-frequency Jet Ventilation. A Prospective Randomized Evaluation

Three hundred nine patients were randomly allocated to two ventilatory protocols; 157 patients were supported with a volume-cycled ventilator (VCV) (Bear Medical BEAR 1) and 152 with a high-frequency jet ventilatory (HFJV) developed at our institution. The two ventilators were compared for safety, reliability, ease of use, and efficacy in maintaining gas exchange. On VCV, end points of therapy were: fractional concentration of oxygen in the inspired gas (FIo2) less than or equal to 0.40; arterial oxygen pressure (PaO2) greater than or equal to 70 mm Hg; cardiac index (CI) greater than or equal to 3.5 L/min/sq m; and spontaneous respiratory rate less than or equal to eight breaths per minute. On HFJV, end points were: FIo2 less than or equal to 0.45; arterial oxygen saturation greater than or equal to 0.90; and CI greater than or equal to 3.5 L/min/sq m. Spontaneous ventilation and pulmonary venous admixture reduction were the goals on VCV, with oxygen transport the goal on HFJV, Total duration of use of the ventilators was approximately 800 days with both types of devices; there were no technical failures, and the incidence of barotrauma was less than 5 percent. The end point of mechanical ventilation was reached by a significantly higher percentage of the patients randomized to HFJV. Patients who failed to reach the therapeutic goal within 24 hours were crossed over to the other form of support. Those crossed from VCV to HFJV improved more rapidly and in greater number than those crossed from HFJV to VCV. When survival and total duration of stay in the intensive care unit were considered, there was no difference between VCV and HFJV. Considering data on gas exchange, VCV provided a higher PaO2 at equivalent positive end-respiratory pressure than HFJV. Alveolar ventilation was slightly better on HFJV. Differences were statistically but not clinically significant. On HFJV, oxygenation and ventilation were maintained with lower peak inspiratory pressures and smaller tidal volumes than those required for VCV. This investigation proves that HFJV is a safe and reliable method to provide mechanical support which does not, at this time, offer obvious benefits over VCV.

Atypical Mesothelial Cells in Peritoneal Dialysis Fluid

Naloxone in Septic Shock

Naloxone, 0.3 mg/kg of a 10 mg/ml solution, was administered as a single bolus to patients in septic shock if their systolic blood pressure (BP) was less than 100 mm Hg or MAP less than 70 mm Hg with evidence of renal or cerebral hypoperfusion. Patients with chronic or acute (less than 12 h) administration of narcotics were excluded. Ten patients received naloxone; 5 patients had significant increases in blood pressure; 5 had no response. Maximal response in BP occurred by 15 min, and lasted 45-165 min. Responders could not be separated by nonresponders by analysis of baseline, hemodynamics, or prior steroid therapy; nonresponders were hemodynamically compromised greater than 24 h; responders less than or equal to 8. Two patients in each group were chronically on high-dose steroids and responded to a 2nd smaller dose of naloxone when effects of initial bolus had ended. Naloxone, 0.3 mg/kg, can reverse endorphin-mediated hypotension in acute septic shock in patients who have received chronic steroid therapy.

Physiologic Implications of High Frequency Jet Ventilation Techniques

High Frequency Jet Ventilation in Experimental Airway Disruption

Anecdotal observations suggest that high frequency jet ventilation (HFJV) is beneficial in major airway disruption. Quantitative evaluation is, however, unavailable. In 12 healthy mongrel dogs, a tracheal window of increasing size, from 0.5 x 1 cm to 1.5 x 2 cm, was opened. Dogs were supported on volume-cycled ventilation (VCV) and on HFJV, using injector cannulas of 1.06 and 1.62 mm internal diameter. The tracheal window was then closed and an upper lobectomy performed, followed by total pneumonectomy. Arterial blood gases were obtained after 10 min in each experimental condition. VCV could maintain life-supporting blood gases only with the tracheal window of 0.5 x 1 cm. HFJV, delivered with a 1.06-mm injector cannula, was adequate with a tracheal window of 1 x 1 cm, or after a lobectomy. In all experimental conditions, HFJV delivered with a 1.62-mm injector effectively maintained alveolar ventilation and arterial oxygenation. Gas transport on HFJV is based, in part, on the principles of jet mixing and entrainment; increasingly large tidal volumes can be delivered under conditions of low and constant pressure. Air leaks through pathological openings remain constant even when tidal volume is increased, so that alveolar ventilation can be adequately maintained.

[Acute Myocardial Infarct in the Aged]

Tidal Volume and Airway Pressure on High Frequency Jet Ventilation

The principle of jet injector indicates that large tidal volumes may be delivered on high frequency jet ventilation (HFJV) without increasing airway pressure. Fifteen dogs were ventilated on HFJV in 2 separate experiments. In the first one, tidal volume was maintained constant at 10 ml/kg, while PEEP, respiratory rate, and cannula size were changed in 16 different experimental conditions. In the second experiment, driving pressure was progressively increased from 5 to 45 psig, and PEEP, respiratory rate, and injector size were changed in 32 experimental conditions. Mean airway pressure, tidal volume, driving pressure, thoracic aortic mean pressure, and abdominal aortic mean pressure were the variables measured. Tidal volume linearly increased with driving pressure, while airway pressure only increased when tidal volume exceeded 25 ml/kg. Blood pressure was inversely related to mean airway pressure. Tidal volume was twice as high with the 1.62 mm injector, as compared to the 1.06 mm injector, although resistances are 6 times higher with the smaller injector. The difference is related to the higher entrainment, which is observed when jet flow velocity increases, as is the case when the injector cannula is smaller. The experiments confirmed that HFJV follows the physical principles of jet mixing and entrainment.

Mesonephric Origin of the Gonadal Primitive Medulla in Chick Embryos

The development of the gonadal primitive medulla in embryonic chick gonads was studied with the light microscope, using serial longitudinal sections from 72 h to 108 h of incubation. The sex of embryos was established from karyotypes. At 72 h, the germinal epithelium in the genital ridges was thickened. The nephrogenic cord was not differentiated into nephrons underneath, although the surrounding mesonephros displayed renal corpuscles and tubules. Clusters and trabeculae of mobilized mesonephric cells piled up under the germinal epithelium, forming the rudiment of the primitive medulla. From 78 h onwards, nephrotome-like structures existed in the mesenchyme underlying the germinal epithelium. Mesonephric cells became detached from their ventral walls and incorporated into the rudiment of the medulla. Finally, at 90 h, when the gonads were constituted, the primitive medulla was definitively formed without any contribution of the germinal epithelium. Adrenal cortical cells, also originating from the mesonephric blastema, showed tight relationships with the gonadal medullarian structures. Our observations support the concept of the mesonephric origin of the gonadal components having male potentialities in birds.

[Activity of Serum Enzymes in Intracoronary Thrombolysis: Preliminary Study]

[Primary Eosinophilic Granuloma of the Lymph Nodes. Case Report]

Clinical Experience with High Frequency Jet Ventilation

Novel 17 Alpha-chloro-17 Beta-sulfinyl Steroids As Specific Inhibitors of Sebaceous Gland Activity: Potential Antiacne Agents

The preparation and antisebaceous gland activities of a series of 17 alpha-chloro-17 beta-sulfinyl steroids are described. They were obtained from the corresponding 17 alpha-sulfides by chlorination and oxidation with iodobenzene dichloride in aqueous pyridine at -40 degrees C. A single-crystal X-ray structure determination of 17 alpha-chloro-17 beta-(benzylsulfinyl)-1,4-androstadiene-3,11-dione (4) established the absolute configuration at sulfur to be R. From an analysis of their CD spectra, some of the other alpha-chloro sulfoxides were also assigned the same absolute stereochemistry at sulfur. Inhibition of sebaceous gland activity, after topical application of the test compounds, was determined in hamsters and found to reach a maximum with 4. The 17 beta-sulfone and 17 alpha-sulfide corresponding to 4 were less potent. Subcutaneous administration of 4 produced no antiandrogenic effects in either hamsters or rats.

Ventilation at Supraphysiologic Frequencies. Theoretical, Technical, Experimental, and Clinical Basis

Critical Care Nurse and High-frequency Ventilation

As the treatment of respiratory failure becomes more sophisticated and technical, the critical care nurse is faced with many challenges. High-frequency ventilation is a modality of respiratory support employing principles different from those of conventional ventilation. For these reasons, the nurse must be familiar with the indications for its use and the practical management of the ventilated patient. This paper addresses those aspects of respiratory support which have the greatest impact on nursing care.

High-frequency Jet Ventilation: Technical Implications

A variety of technical decisions are required for the proper selection and safe and efficacious application of high-frequency jet ventilation (HFJV). Criteria for analyzing the performance of an HFJV system are presented, along with discussions of some of the more common respiratory measurements and their applicability to HFJV.

Role of High-frequency Jet Ventilation in the Management of Respiratory Failure

Hemodynamic Effects of Continuous Positive-pressure Ventilation and High-frequency Jet Ventilation with Positive End-expiratory Pressure in Normal Dogs

The hemodynamic effects of high-frequency jet ventilation (HFJV) at 60, 120, 240, and 480 breath/min, and conventional ventilation at 15 breath/min were compared in 6 anesthetized, paralyzed dogs, at 0, 10, and 20 cm H2O of positive end-expiratory pressure (PEEP). On HFJV at the same inspired oxygen, PaCO2, and PEEP levels, hemodynamic function improved significantly. Cardiac output was higher, whereas transmural CVP and pulmonary vascular resistances were lower. The improvement was primarily related to a decrease in mean airway pressure, particularly at higher PEEP levels. When PEEP was applied, hemodynamic function improved even when mean airway pressure was maintained constant. The findings suggest that lung volume was smaller during HFJV, and/or that lung volume changes during each respiratory cycle contributed to differences in venous return and ventricular function.

Experimental Evaluation of High-frequency Jet Ventilation

The consensus of available studies indicates that high-frequency jet ventilation (HFJV) can adequately ventilate animals in respiratory failure, although a clear superiority to volume-cycled ventilation (VCV) cannot be established. HFJV is probably useful in the presence of airway disruption and in tracheal or pulmonary surgery. Clinical trials and additional bench and animal studies must be performed, to reach a full understanding of the potential benefits of this technique.

Pneumatic-to-electrical Analog for High-frequency Jet Ventilation of Disrupted Airways

A pneumatic-to-electrical circuit analog is used to describe 2 separate mechanisms by which high-frequency jet ventilators sustain ventilation and oxygenation in the presence of large airway disruptions. The frequency-dependent mechanism is based on variations in the pneumatic equivalent to capacitive reactance. The pressure-dependent mechanism models lung defects on a voltage-controlled resistor. The electrical circuit model is also used to explain the factors leading to gas trapping and inadvertent positive end-expiratory pressure during high-frequency jet ventilation.

Development of High-frequency Ventilation Techniques

Early Prediction of Outcome of Respiratory Failure. Comparison of High-frequency Jet Ventilation and Volume-cycled Ventilation

Data from a prospective randomized investigation comparing volume-cycled ventilation and high-frequency jet ventilation were reexamined to determine whether improvement of respiratory and hemodynamic function, as well as ultimate outcome (death or survival), could be predicted early in the course of the disease. End points were selected for the ratio of the arterial oxygen pressure over the fractional concentration of oxygen in the inspired gas (PaO2/FIO2), the arterial oxygen saturation (SaO2), the arterial carbon dioxide tension (PaCO2), and the cardiac index. Patients were assigned to "success" or "failure" groups, according to the values recorded for those end points 24 hours after institution of mechanical ventilation. Values obtained from initiation of mechanical ventilation to 16 hours later were divided into four time groups. Differences between patients who "succeeded" and "failed" were compared at each time interval. Ultimate outcome was also compared. The PaCO2 and cardiac index were poor predictors of survival. Early values did not foretell the progression of these variables. The PaO2/FIO2 and SaO2 effectively discriminated, at all time intervals, between patients who succeeded and failed on volume-cycled ventilation. On high-frequency jet ventilation, significant differences were evident only after eight hours of support. With both types of ventilator, patients who reached the end point of oxygenation at 24 hours survived in far greater numbers than those who did not. On the basis of this investigation, it appears justified to attempt high-frequency jet ventilation in patients who do not rapidly improve on volume-cycled ventilation. Institution of high-frequency jet ventilation as the initial support method may not be advisable, since failure does not become apparent for many hours.

Medical and Nursing Implications of High-frequency Jet Ventilation

Airway Humidification with High-frequency Jet Ventilation

Humidification of inspired gases is indispensible to prevent serious injury to the tracheal mucosa of patients on mechanical ventilation. High-frequency jet ventilation (HFJV), recently introduced for the management of some forms of respiratory failure, presents unusual technical problems of humidification. The present investigation evaluated a technique to humidify jet gases by delivering small droplets of normal saline in front of the injector cannula, and utilizing the jet flow to nebulize the fluids administered. One millicurie of technetium-99m sulfur colloid (Tc-99m) was diluted in 10 ml of saline and infused in the airway of nine patients supported on HFJV. Six patients were orotracheally intubated and three were tracheostomized. A portable gamma camera was used to determine the distribution of radioactive contrast in the airway every 200 sec. When the injector catheter was directed upward, as was the case in tracheostomized patients, contrast material accumulated in the ventilator lines, and visualization of the airway was limited to the trachea. In orotracheally intubated patients, the injector catheter was generally directed downward, and radioactive contrast material extended beyond the major bronchi. The radioactive tracer reached the most distal airway location in patients with the lowest PaCO2 values. Thus, when humidification systems rely on jet-stream nebulization of fluids, the position of the injector cannula should facilitate saline flow by gravity. In the presence of poor alveolar ventilation, the concomitant risk of inadequate humidification should be considered.

Origin of the Somatic Components in Chick Embryonic Gonads

[Histologic Grading of Malignancy in Epidermoid Carcinoma of the Larynx. Review of the Literature and Proposal of a Structural Grading]

Prognostic Correlations of Operable Carcinoma of the Rectum

Various histologic factors correlated to survival were studied in 124 patients radically operated on for rectal carcinoma in order to establish valid prognostic criteria. The total survival rate after five years was 63 percent, while in stage B1 it was 89 percent, in B2, 61 percent, and in C1, 47 percent (P less than 0.05). With regard to histotype, the survival was 83 percent in the papillary subtype of adenocarcinoma, while in the tubular subtype it was 62 percent, and 29 percent in the mucinous type (P = not significant). Vascular invasion negatively affected survival (41 percent); however, when there was no invasion, the prognosis was better (71 percent) (P less than 0.01). In evaluating histologic grading and lymphoglandular reactivity, the difference in survival rates was not statistically significant. The marked peri- and intratumoral lymphocytic infiltration gave a very good prognosis (92 percent) contrary to when reactivity was moderate (59 percent) or even absent (51 percent) (P less than 0.01). Finally, the expanding type tumor, with reference to Ming's classification of gastric carcinoma, had a much better prognosis (75 per cent) than the infiltrative type (40 percent) (P less than 0.01).

'APACHES,' Chiefs, and Indians

High-frequency Jet Ventilation During Thoracic Surgical Procedures

[Myocardial Infarct Before 45 Years of Age: Significance of the Coronarographic Study in Asymptomatic Patients]

The aim of our study was to evaluate the significance of coronary arteriography in young asymptomatic patients after myocardial infarction. Among a total of 586 consecutive patients who underwent left ventriculography and coronary angiography because of coronary heart disease during the period from January 1984 to June 1986, we selected 51 patients (8.7%) under 45 years of age (range 28-45 years) and without angina, dyspnea or electrocardiographic signs of myocardial ischemia during bicycle ergometric stress test. These patients, 50 males (98.0%) and 1 female (2.0%) were angiographically evaluated from 1 to 12 months after a first myocardial infarction. Coronary occlusions greater than or equal to 70% were found in 44 patients (86.3%): 36 of them (70.6%) had single-vessel disease, 6 (11.8%) double-vessel disease and only 2 (3.9%) triple-vessel disease; no coronary obstructions greater than or equal to 50% of the left main coronary artery were found. Among the 7 patients without critical stenoses (13.7%) 3 had "normal" coronary arteries, 3 noncritical stenoses and one presented an anomalous origin of the left circumflex artery from the right sinus of Valsalva. Only 1 patient underwent surgery. In conclusion, in young asymptomatic patients after a myocardial infarction coronary arteriography may identify a small group either without or with minor atherosclerotic involvement of the coronary tree, while the presence of a localized disease is confirmed in most patients. Therefore, in this selected subgroup, coronary angiography has a limited usefulness in defining high-risk patients possibly requiring surgical treatment.

Pulmonary Embolus-induced Disseminated Intravascular Coagulation

Pulmonary embolus as a cause of disseminated intravascular coagulation has only recently been recognized. The hemorrhagic disorder reported in the past was associated with little or no bleeding. We report a case of pulmonary embolus associated with life-threatening disseminated intravascular coagulation.

Endoscopic Treatment of Stenosis Following Stapler Anastomosis

The papillotomy knife, introduced by an endoscope, was employed to treat stenosis following stapler anastomosis, and to cut the stenotic ring in three points along its circumference.

Evaluation of a Closed-tracheal Suction System

A new tracheo-bronchial closed-suction system has been recently introduced. The Trach Care catheter can be connected to the endotracheal tube of a patient on mechanical ventilation and be left in place as long as 24 h. Thus, suctioning does not require disconnection from the mechanical ventilator. We evaluated the benefits of this new system in 20 patients receiving mechanical ventilation; ten patients required PEEP of 10 cm H2O and under, while the other ten patients needed PEEP over 10 cm H2O to maintain acceptable oxygenation. PaCO2, arterial oxygen saturation, and alveolar-arterial oxygen tension difference were measured before and after suctioning, using a conventional catheter and the Trach Care closed-suction method. Oxygenation only deteriorated when the open technique was used in patients receiving over 10 cm H2O of PEEP. The changes were statistically, but not clinically, significant. The Trach Care system is approximately 25 times as expensive as conventional suctions catheter, so its use cannot be justified economically. A potential advantage of the technique is preventing the dissemination of contaminated secretions, which are dispersed when the patient is disconnected from the ventilator and inspiratory gas flow persists. While no universal advantage of the closed-suction system was found, potential benefits may be considered on a case-by-case basis.

Case of Embolization by a Sheared Pulmonary Artery Catheter Tip

Reinventing the Triangular Wheel

Oral Contraceptives and Dysmenorrhea

[Evaluation of Flow Reserve in Internal Mammary Artery in Situ Bypass]

The internal mammary artery, when used as a conduit for coronary artery bypass, offers a better long-term patency and survival rate than the saphenous vein. However, concern exists that the flow through the internal mammary artery may be inadequate during periods of peak myocardial demand. This flow was investigated in 18 consecutive patients who were selected for coronary bypass of the left anterior descending artery using the internal mammary artery. All patients were evaluated post-operatively within 12 months by means of graded maximal stress test, cardiac catheterization and exercise thallium-201 scintigraphy. Significant improvement in work capacity, maximal rate-pressure product, effort angina and ECG abnormalities during exercise stress testing were observed following internal mammary artery myocardial revascularization. The patency rate for internal mammary artery grafts was 100% (vs 85% for vein grafts); during the followup period, occlusion of a saphenous vein bypass or development of a new stenosis in a native coronary artery was noted in five patients, and two patients were classified as having partial revascularization. Ischemia, demonstrated by perfusion deficits at peak stress which disappeared in the 3-hour delayed film, was documented in 7.4% (4/54) of the areas supplied by internal mammary artery grafts, compared to 31% (13/42) of the regions revascularized using saphenous vein conduits. Although this result was not statistically significant, a definite trend is suggested. We conclude that ischemia demonstrated by stress thallium scintigraphy in the post-operative period is uncommon when an internal mammary artery graft has been used. This suggests that adequate coronary flow exists at peak myocardial demand during exercise.

An Automated Mechanism for Protection of Mass Spectrometry Sampling Tubing

The usefulness of medical mass spectrometers in intensive care units can be limited by too frequent obstruction of the tubing that transports gases from the patients to the analyzing unit. To overcome this problem, we developed an automated system consisting of an infrared light sensor and a three-way valve. One port of the three-way valve connects to 2.4-m disposable tubing that collects gases from the patient's airway. The second port is connected to a mass spectrometer analyzing unit through 30-m permanently installed tubing. The third port is connected to a pressurized oxygen source. An infrared light sensor is placed on the shorter tubing, between the patient and the three-way valve. When increased optical density is detected, due to entrainment of respiratory secretions, the three-way valve is activated. Gas flow is closed between the patient and the mass spectrometer and opened between the pressurized oxygen source and patient tubing to flush its contents. During the six years that the protection system has been in use, the frequency with which the disposable gas collection tubing is changed has been halved. Furthermore, periodic tests of delay and response times, performed at each bedside station, indicate that permanent connection tubing only needed cleaning at 2- to 3-year intervals. The system has decreased the cost of operating our mass spectrometers while also reducing periods of unavailability due to equipment failure.

[Residual Cystic Duct: a Frequent Cause of Reintervention of the Bile Ducts]

Capnography in Mechanically Ventilated Patients

Capnography, the science of CO2 waveforms analysis, can play a role in the management of mechanically ventilated patients. Mass spectrometers are the devices most commonly used to collect sequentially and examine CO2 waveforms from multiple patients in the ICU or operating rooms. We present here a review of some clinical and technical problems, which may be resolved efficiently and expeditiously through the use of mass spectrometry and capnography. Mechanical failures, especially those that lead to rebreathing of exhaled gases, can be readily detected. The patient's progress during weaning and the consequences of changes in mechanical assistance can be virtually and noninvasively determined. An expanded role of capnography in mechanically ventilated patients can increase the use of mass spectrometers in the ICU.

Charity and Accountability

Admitting Cancer Patients to the Intensive Care Unit

The allocation of critical care resources must follow criteria of distributive justice. Because most societies cannot indefinitely expand medical care costs, difficult decisions on the quality and quantity of care that can be rendered to each patient are inevitable. Data on which objective decisions can be based are currently being gathered at many levels. It is reasonable to anticipate that over the next few years regulations will be formulated to decide which patients can be admitted to the ICU. Critical care physicians have the right and obligation to be involved in all aspects of these decision-making processes.

[Short- and Medium-term Study of Arterial Grafts and Native Coronary Circulation After in Situ Implant of the Internal Mammary Artery]

The internal mammary artery (IMA) is being increasingly utilized as a conduit for myocardial revascularization, based on its higher long-term patency. The aim of this study is the serial assessment of the changes of native coronary vessels after IMA coronary anastomosis. Twenty-six consecutive patients (24 males and 2 females, mean age 56.4 years) received an IMA graft on the left anterior descending (LAD) artery. IMA coronary anastomosis was single in 11 patients and double (LAD and diagonal branch) in the remaining 15 cases. In 23 patients (88.5%) at least one associated saphenous vein graft was inserted. Post-operatively, no new Q waves or low-output syndromes were observed. Follow-up angiographic study, including selective opacification of the IMA graft, was carried out after 1 month and after 1 year. The cumulative patency rate of IMA grafts was 97.7% after 1 month. The LAD stenosis proximal to the IMA anastomosis progressed to total occlusion in 6 patients (28.5%), all of them with a preoperative stenosis ranging from 90 to 99%; its diameter remained unchanged in 6 patients (28.5%), while a reduction of the coronary narrowing greater than or equal to 20% was observed in 9 patients (43%). Preoperatively, the LAD stenosis of the latter groups ranged from 70 to 90%. Severity of residual stenosis and relative diameters of LAD artery and IMA graft influenced the competitive flow distribution through these vessels.(ABSTRACT TRUNCATED AT 250 WORDS)

Isotonic Nasogastric Tube Feedings: Do They Cause Diarrhea?

NG tube feedings in hospitalized patients, whether in a ward or ICU, are considered a common etiology of diarrhea. To evaluate the accuracy of this assumption, 13 hospitalized postoperative patients with head and neck cancer, 11 ICU patients, and five healthy volunteers were given isotonic, low-residue, lactose-free tube feedings starting at 30 kcal/kg.day. There was no prior history of diarrhea in any patient studied. There was a significant difference in both albumin levels and diarrhea incidence in the three groups (analysis of variance, p less than .05). Diarrhea occurred in four of 11 ICU patients while receiving feedings, but not in the healthy volunteers or non-ICU patients. The four patients with diarrhea had an average albumin level of 2.8 g/dl, while the other ICU patients had an average albumin of 2.6 g/dl. We conclude that isotonic NG tube feedings do not cause diarrhea in healthy volunteers or postoperative head and neck cancer patients. However, in some mechanically ventilated ICU patients, this regimen may cause diarrhea even though no risk factors can be clearly identified.

Assist Control Versus Synchronized Intermittent Mandatory Ventilation During Acute Respiratory Failure

Controversy persists as to the relative advantages and disadvantages of synchronized intermittent mandatory ventilation (SIMV) vs. assist/control ventilation (A/C) in the management of acute respiratory failure. In an effort to resolve these differences, we evaluated differences in hemodynamic, metabolic, ventilatory, and oxygenation variables during ventilation with both SIMV and A/C using a crossover protocol in critically ill patients without chronic obstructive pulmonary disease. Despite differences in ventilation, resting energy expenditure, and oxygen delivery in specific subgroups of patients, we found no evidence to support any clear-cut advantage of SIMV or A/C in the acute management of respiratory failure. Careful assessment of individual patients may indicate which patient might benefit from each modality of support.

Quest for the Philosopher's Stone

Just Say No

Hypertonic Nasogastric Tube Feedings: Do They Cause Diarrhea?

Hypertonic NG tube feeding in hospitalized patients, whether on the hospital ward or in the ICU, is considered a common etiology of diarrhea. To evaluate the accuracy of this assumption, five normal volunteers, ten hospitalized postoperative patients with head and neck cancer, and 24 ICU patients were given hypertonic (690 mosm), low residue, lactose-free tube feedings starting at 30 kcal/kg.day. There was no prior history of diarrhea in any of the groups studied. There was a significant difference in albumin levels between the three groups, with an average albumin of 2.8 g/dl in the ICU patient group; different from 4.5 g/dl present in both the normal volunteer and non-ICU hospitalized patient groups (general linear models procedure from SAS, p less than .05) (Duncan test). Diarrhea was not present in the normal volunteers or non-ICU patients during the feedings, but did occur in 3/24 ICU patients. This difference was not significant. The three patients with diarrhea had an average albumin level of 3.0 g/dl, while the other ICU patients had an average albumin of 2.7 g/dl. We conclude that hypertonic NG tube feedings do not cause diarrhea in normal volunteers or postoperative head and neck cancer patients. However, in a small statistically insignificant percent of mechanically ventilated ICU patients, this regimen may cause diarrhea although no risk factors can be identified.

Age and Utilization of Intensive Care Unit Resources of Critically Ill Cancer Patients

Older patients, patients with malignancies, and those admitted to ICUs utilize a disproportionate amount of hospital resources. To evaluate the combined impact of age and a diagnosis of malignancy on ICU utilization and outcome, we reviewed the care provided to all 1,212 patients admitted to a medical/surgical ICU in a hospital specializing in the treatment of cancer between January 1, 1986 and December 31, 1987. Patients between 19 and 64 yr (young) were compared with those between 65 and 74 yr (young-old) and with those greater than or equal to 75 yr (old-old) with respect to utilization of nutritional support (total parenteral nutrition [TPN]), mechanical ventilation (MV), pulmonary artery (PA) catheterization, dialysis (D), and blood products (B). Mean length of stay (LOS) in the ICU, primary diagnosis, outcome, and average daily severity of illness scores (ADTIS) were also compared. Old-old patients represented 14% of all ICU patients and young-old patients represented 28%; 64% of old-old and 61% of young-old patients had solid tumors, compared with 36% of younger patients. The ICU mortality of the two older groups was significantly lower than that of the younger patients (17%, 27%, and 30%, respectively). The use of TPN, PA catheters, and D was similar for all three groups, but older patients used less MV and B than the younger patients (p less than .0001, chi2 analysis). The two older groups also had similar LOS and lower average daily Therapeutic Intervention Scoring Systems (TISS) scores than their younger cohort.(ABSTRACT TRUNCATED AT 250 WORDS)

[Gallopamil Infusion for Treatment of Prinzmetal Angina]

The efficacy of a new calcium channel blocker, gallopamil, has been tested via a single blind, self-controlled versus placebo protocol in 9 consecutive patients admitted to our Coronary Care Unit because of repeated daily attacks of Prinzmetal variant angina. Exclusion criteria were age (greater than 65 years) bradycardia (less than 50 beats/min), recent myocardial infarction, heart failure, sinoatrial or atrioventricular block. After a 24 hours run-in period on saline drip, gallopamil was administered as 0.03 mg/kg bolus followed by continuous infusion at 0.02 mg/kg/h for the first 24 hours and 0.03 mg/kg/h for the last 48 hours. Treatment was then stopped and the patients were again kept on saline infusion for the next 30 hours. Holter monitoring was recorded during run-in, on third day of treatment and 6 hours after gallopamil withdrawal. Anginal attacks were significantly reduced in number by therapy (-63%, -91%, -84% in the 3 days of treatment). Holter monitoring during gallopamil infusion showed a statistically significant reduction in silent (-98%) and symptomatic (-93%) ischemic episodes (IE). During the last 24 hours of the washout period we observed a statistically significant increase in silent ischemic episodes. While no transient ST segment elevation was recorded in 3 patients, in 1 patient symptomatic IE were increased of 150% with respect to the run-in period. On the whole we observed complete suppression of IE in 7 patients (78%) at the third day of treatment with gallopamil. In 2 patients (22%) a greater than 75% reduction was observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Intravenous Glycerol Infusions: Effect on Free Fatty Acid Metabolism

The plasma-free fatty acid response to intravenous glycerol infused at 250 and 500 mumol/min was determined in five normal volunteers in the postabsorptive state. There was a drop in free fatty acid concentration in all five subjects (one-way ANOVA, p less than 0.01) after the glycerol infusion with no change in insulin concentration compared to the post-absorptive state. These results suggest that intravenous glycerol infusions decrease free fatty acid concentrations in the post-absorptive state by an insulin-independent mechanism. When pharmacologic nonisotopic glycerol infusions are used to determined lipolytic rate, simultaneous measurement of free fatty acid concentrations should be interpreted with caution.

[Dilated Cardiomyopathy. Multivariate Discriminant Analysis of Main Hemodynamic-angiographic Indices]

The study group consisted of 47 consecutive patients (38 men and 9 women) aged between 16 and 56 years with dilated cardiomyopathy studied invasively between January 1980 and December 1986. Follow-up observation (40 +/- 29 months) showed that 28 patients were mildly symptomatic (group 1) and 19 patients were severely symptomatic (group 2: eight of them died due to intractable congestive heart failure). At univariate analysis, group 2 was characterized by higher pulmonary vascular resistance, larger end-diastolic and end-systolic left ventricular volumes, increased left ventricular mass, lower ratio of mass to volume index, depressed angiographic ejection fraction, lower ratio of end-systolic stress and peak systolic pressure to volume index. Multivariate analysis was used to determine which combination of factors might be a better effective predictor of prognosis in these patients: the most important factors were mass to volume index ratio (M/V) and end-systolic stress to volume index ratio (sigma TS/VTS). An equation was developed that can be applied to the prognosis of patients with dilated cardiomyopathy (F = 7.41573 M/V + 0.87805 sigma TS/VTS - 10.34571). A score system was devised on the basis of the summed-up value of these two parameters. When the patients were assigned (according to the score) to one of the previously mentioned two groups, the classification proved to be correct in 98% of the cases. Thus, these factors can accurately predict the development of congestive heart failure or the risk of death in patients with dilated cardiomyopathy, who are reasonable candidates for cardiac transplantation.

Frequency Response of the Peripheral Sampling Sites of a Clinical Mass Spectrometer

Mass spectrometers are used in ICUs and ORs to measure the concentration of medical and anesthetic gases gathered from multiple sites. This investigation was designed to determine the accuracy of a clinical system, which included 12 ICU bedside stations monitored by a medical mass spectrometer (Perkin-Elmer RMS III, Pomona, CA). Each site station was connected to the analyzing unit via two Teflon tubes, one permanently installed, 30-m long, and the second disposable, 2.4-m long. A gas mixture containing 95% O2 and 5% CO2, alternating with room air, was delivered to a solenoid valve and from there to the connecting tubes. Gas flow-rate, delay time, rise time, and peak and trough concentrations were determined for each gas at solenoid cycling frequencies of 25, 50, and 100/min. After the first set of measurements, the 30-m tubes were thoroughly cleaned and all measurements repeated. In addition, the authors also measured CO2 delay and rise times when the gas was delivered to the mass spectrometer through an unused 30-m tube or a new 2.4-m tube. Gas flow-rate increased from 143 +/- 12 ml/min (mean +/- SD) to 238 +/- 9 ml/min after the tubes were cleaned. Delay time was identical for all gases at all solenoid cycling rates but decreased significantly (P less than 0.05), from 11.5 +/- 0.3 to 4.8 +/- 0.7 s after the ceiling tubes were cleaned. As solenoid valve rate increased, the difference between measured and actual gas concentration increased. The lowest accuracy was 63.6 +/- 2.1%, for CO2 at 100 cycles/min.(ABSTRACT TRUNCATED AT 250 WORDS)

Case of the Day. Ultrasound. Omental "cake" of Metastatic Adenocarcinoma

Transesophageal Echocardiography for Assessing the Cause of Hypotension

Successful Management of CMV Pneumonia in a Mechanically Ventilated Patient

We report a case of severe respiratory failure due to cytomegalovirus pneumonitis in a patient who underwent an allogeneic bone marrow transplant, who was successfully treated with the combination of ganciclovir and high-dose intravenous immune globulin. We also reviewed the rationale for the use of combination therapy with an antiviral agent and immunotherapy. Because of the bone marrow toxicity of ganciclovir, an aggressive diagnostic approach, including bronchoalveolar lavage and open lung biopsy, may be necessary to establish a definitive diagnosis prior to institution of therapy.

Administration of Gallopamil by Long-term Venous Infusion in Spontaneous Angina. A Single-blind, Self-controlled Study Versus Placebo

In order to assess the efficacy and tolerability of gallopamil (D-600, CAS 16662-47-8) by long-term venous infusion in the treatment of spontaneous angina, 15 consecutive patients were studied in a single-blind, self-controlled trial versus placebo. Following a 24-h Holter ECG recording of the patients receiving a saline infusion (run-in phase), i.v. administration of gallopamil was started at a dose of 0.02 mg/kg/h preceded by a 0.03 mg/kg bolus. After 24 h, the dosage was increased to 0.03 mg/kg/h and the infusion was maintained for another 48 h. The Holter ECG recording was repeated in the last 24 h of treatment and after 6 h from withdrawal (washout phase). The reduction in the number of angina attacks, as shown by a comparison between the average of the two placebo periods (run-in and washout phases) and the three days of treatment, was 68.2%, 92.5%, and 87%, respectively. Consumption of glyceryl trinitrate decreased by 92.5% on each one of the three days of treatment. The reduction in the number of ischemic episodes (IEs) with symptomatic (-91.6%) and silent (-98.0%) ST elevation, and with symptomatic (-100%) and silent (-90%) ST depression, also proved significant. Heart rate decreased only moderately. One patient showed a mild first-degree heart block, while another suffered a transient episode of isorhythmic A-V dissociation. In conclusion, when administered by venous infusion, gallopamil has been found to be well tolerated and highly effective in the treatment of spontaneous angina.(ABSTRACT TRUNCATED AT 250 WORDS)

Use of Neural Network Analysis to Classify Electroencephalographic Patterns Against Depth of Midazolam Sedation in Intensive Care Unit Patients

The electroencephalographic (EEG) analog signal is complex and cannot easily be described by univariate variables. Clear visual changes in the EEG power spectrum can be present with little or no change in univariate variable values. A method that could produce a single value based on the total data available in the EEG power spectrum would be very useful in monitoring EEG changes. Neural network analysis is a technique that can take multiple inputs and produce a single output value using complicated processing patterns that require training to establish. We examined the usefulness of a series of neural network models to classify 63 EEG patterns against sedation level in 26 mechanically ventilated patients requiring midazolam for long-term sedation. During a stable period of sedation, a 4- to 60-minute period of EEG data was obtained concurrently with a sedation level from 1 (follows commands) to 7 (no or gag response to suctioning of the endotracheal tube). The EEG power spectrum was divided into equal frequency bands, and the log absolute powers in each of these bands were used as inputs for a series of neural network models. The output target was the sedation level associated with each set of EEG data. Networks were trained on a subset of EEG power/sedation score data pairs, and the ability to classify the remaining data pairs was tested. Using a t-test comparison with a random set of sedation levels, we found that trained neural network models classified EEG patterns against sedation level successfully (p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Thermodilution Cardiac Output: Proximal Lumen Versus Right Ventricular Port

To assess the accuracy of thermodilution cardiac output measurements from the right ventricular port vs. the central venous port. In addition, waveform patterns were evaluated in 50 right-heart catheters to determine the actual location of the right ventricular port.

Tension Pneumocephalus: Treatment with Controlled Decompression Via a Closed Water-seal Drainage System. Case Report

The successful treatment of a patient with tension pneumocephalus by controlled decompression via external drainage is described. The advantage of the technique includes the immediate release of high pressure and the capability of maintaining constant low pressure to enable and facilitate sealing of dural tears. The method has been used in three other patients, leading to resolution of the tension pneumocephalus without recurrence or other complications.

Tuberculosis Control. Will Our Legal System Guard Our Health and Will the ADA Hamper Our Control Efforts?

Quantified Ultrastructural Study of Spermatozoa in Unexplained Failure of in Vitro Fertilization

Failure of in vitro fertilization or very low cleavage rates may occur even though oocyte and semen parameters seem satisfactory. Quantified ultrastructural study of spermatozoa was performed in such cases of failure (n = 6) or low cleavage rate (< 20%; n = 4). Through 1 to 11 retrievals, the number of inseminated oocytes ranged from 14 to 145. The results were compared to those of six fertile men. Quantification was achieved by cataloguing cell defects of the spermatozoon heads and mid-/principal pieces of the flagella. Using the data from each specimen, the percentages of total cellular abnormalities in the head/mid-/principal pieces were established. At the level of the head overall percentages for six groups of defects were determined. The overall percentage of combined head abnormalities, defined as the presence of at least three of these six defects on the same spermatozoon head, was established. Statistical differences among control and patient groups were analyzed by nonparametric Mann-Whitney U test. The percentages of anomalies of the midpiece and of the principal piece were not significantly different between patients and controls. Motility assessed by spermogram was considered "functionally uncompromised." In eight patients the percentage of cell alterations of the head (93-100 vs 77.3 +/- 6.4%) and the percentage of combined anomalies of the head (78.1-100 vs 60.8 +/- 8.5%) were significantly different between patients and controls. In two cases, the percentages established for all head parameters considered were not globally different from those observed in controls. Thus in 8 cases of 10, electron microscopy with quantified analysis supplied valuable evidence about the poor quality of these sperm samples judged as normal under light microscopy and may provide an explanation for their impaired fertilizability.(ABSTRACT TRUNCATED AT 250 WORDS)

Ventilatory Support During Magnetic Resonance Imaging

Ventilatory support during magnetic resonance imaging is difficult because metallic objects on ventilatory support devices can interfere with the imaging field and/or become magnetized and move inside the patient or become flying projectiles. We report the successful MRI examination of an intubated respirator-dependent pediatric patient. Ventilatory support was carried out with a plastic ambu bag, exhalation valve circuit, and tubing.

Room-temperature Thermodilution Cardiac Output: Central Venous Vs Right Ventricular Port

To assess the accuracy of room-temperature thermodilution cardiac output measurements from the right ventricular port. In addition, waveform patterns were evaluated to determine the actual location of the right ventricular port.

Subzonal Sperm Insemination and Total or Extreme Asthenozoospermia: an Effective Technique for an Uncommon Cause of Male Infertility

To assess the value of subzonal insemination (SUZI) in cases of total or extreme asthenozoospermia.

Urinary Creatinine Excretion in the ICU: Low Excretion Does Not Mean Inadequate Collection

It has been assumed that a urinary creatinine excretion rate of less than 10 mg/kg per day means an inadequately collected urine sample.

The Effects of Midazolam on the EEG During Sedation of Critically Ill Patients

Patients who require mechanical ventilation are often sedated with midazolam. As clinical signs of sedation are often confusing or nonexistent, and there are few adverse side effects when large doses are infused over a period of days, substantial drug accumulation can result in these critically ill patients, despite the short half-life of midazolam. An objective monitor of sedation would help maintain sedation at a constant level despite changing pharmacokinetic values in patients. We undertook this study to describe the electroencephalographic changes which occur with intravenous midazolam in critically ill patients, and to determine if a relationship exists between these changes and the depth of sedation as measured using a clinical scoring method. A series of 31 critically ill patients who required intravenous midazolam during mechanical ventilation were studied. Four different levels of sedation were defined ranging from execution of verbal commands to no response to suctioning through the tracheal tube or sternal rub. Electroencephalographic recordings were obtained in patients on a daily basis and a concurrent sedation level was determined. High frequency electroencephalogram activity decreased as sedation level increased. This was reflected in decreases in the spectral edge (17.61 to 10.56 Hz (p = 0.0024)), the median frequency (4.27 to 2.56 Hz (p = 0.0278)), and the logarithm of the absolute power in the beta 1 (p = 0.0012), and beta 2 (p < 0.0001) bands. An incidental finding of asymmetry in power between right and left frontal electrodes was observed, with right-sided power being 9-18% greater (p < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Left Atrial Thrombus Following Liver Resection with Veno-venous Bypass: Use of Transesophageal Echocardiography to Guide Resuscitation

Cost-effectiveness of Monoclonal Antibodies to Gram-negative Endotoxin in the Treatment of Gram-negative Sepsis in ICU Patients

To evaluate the fiscal impact and the cost-effectiveness of monoclonal antibodies against gram-negative endotoxin (MAbGNE) in the treatment of presumed gram-negative sepsis.

Prediction Equation Estimates of Creatinine Clearance in the Intensive Care Unit

To assess the accuracy of 4 mathematical equations used to estimate creatinine clearance versus the 24-h creatinine clearance in ICU patients.

[Epidural Anesthesia and Prevention of Autonomic Hyperreflexia in a Paraplegic Parturient]

Pregnancy in a patient suffering from high spinal cord lesions is unusual and can lead to serious autonomic hyperreflexia during delivery. Epidural anaesthesia has been suggested as a means of decreasing such a risk. This clinical report presents the case of a paraplegic patient with lesions above the T3 level who had spinal anaesthesia for a Caesarean section. Her first delivery, six years earlier and without spinal anaesthesia was complicated by serious autonomic hyperreflexia with severe hypertension, seizures and inhalation. These symptoms were at first interpreted as eclampsia. For the Caesarean section, spinal anaesthesia using 0.25% bupivacaine in divided doses presented no difficulty, in spite of important lordosis, and permitted the delivery of a newborn with an Apgar score of 10 at one minute. The upper sympathetic level reached (T4-T6) was assessed by the discontinuing of muscular spasticity and contractures elicited by cutaneous stimuli. At the present time, spinal anaesthesia is the best method for preventing autonomic hyperreflexia. General anaesthesia, especially with halothane, is effective, but requires a deeper anaesthesia with the risk of serious hypotension and its possible repercussions on the fetus. Moreover it does not decrease the risk of autonomic hyperreflexia during the postoperative period.

Phase Diagram of the Two Component Body-centered Solid-on-solid Model

Calcification Rates in Corals

Networks of Steps on Crystal Surfaces

[Heart Rupture During Maximal Exercise Test Before Hospital Discharge After Acute Myocardial Infarction]

A 64 years old patient performed a maximal exercise testing 13 days after inferoposterior myocardial infarction (no thrombolytic treatment had been performed). The patient presented at days 1-4 an intermittent Mobitz 1 and 2:1 heart block, with normal ventricular rate. No other complications were present. The ECG at entry and before stress test showed a complete right bundle block. The test was stopped at 30 sec of 75 watts. The systolic blood pressure increased from 130 to 155 mm Hg and heart rate from 84 to 145/min (93% of predicted heart rate). No arrhythmias and anginal pain were noted. The leads with pathologic Q wave showed elevation of the ST segment, whereas V1-V2 and aVL leads a depression of the ST segment. During recovery the patient developed electromechanical dissociation. The echocardiogram showed significant pericardial effusion. Cardiopulmonary resuscitation and pericardiocentesis were ineffective. Necropsy confirmed left ventricular inferior wall rupture and haemopericardium.

Hemolytic-uremic Syndrome Without Evidence of Microangiopathic Hemolytic Anemia on Peripheral Blood Smear

We report the case of an 18-year old man with hemolytic-uremic syndrome (HUS) having a classic clinical presentation and diagnostic renal pathology without evidence of microangiopathic hemolytic anemia (MAHA) by peripheral blood smear. Indirect evidence of hemolysis was suggested by mild anemia, elevation of serum lactate dehydrogenase, and examination of the patient's bone marrow. We postulate that in this case the inability to detect schistocytes in the peripheral smear reflected a low degree of hemolysis. Review of the literature revealed that evidence of fragmented erythrocytes by peripheral smear is not always present in HUS, yet this observation has received little attention. Thus, the diagnosis of HUS need not include overt evidence of MAHA as is traditionally taught.

Cardiopulmonary Risk Index Does Not Predict Complications After Thoracic Surgery

The preoperative cardiopulmonary risk index (CPRI) is a multifactorial index intended to predict postoperative outcome after thoracic surgery. It combines cardiac and pulmonary information into one parameter that ranges from 1 to 10, with 10 being the worst. A CPRI > or = 4 has been advocated as an effective predictor of postoperative pulmonary and cardiac complications. This study prospectively evaluates the predictive value of CPRI in a large population of patients undergoing thoracic surgery.

Quantitative Methanol-burning Lung Model for Validating Gas-exchange Measurements over Wide Ranges of FIO2

The methanol-burning lung model has been used as a technique for generating a predictable ratio of carbon dioxide production (VCO2) to oxygen consumption (VO2) or respiratory quotient (RQ). Although an accurate RQ can be generated, quantitatively predictable and adjustable VO2 and VCO2 cannot be generated. We describe a new burner device in which the combustion rate of methanol is always equal to the infusion rate of fuel over an extended range of O2 concentrations. This permits the assembly of a methanol-burning lung model that is usable with O2 concentrations up to 100% and provides continuously adjustable and quantitative VO2 (69-1,525 ml/min) and VCO2 (46-1,016 ml/min) at a RQ of 0.667.

The Evolution of Mating Systems in Tropical Reef Corals

The life histories of tropical reef corals (Scleractinia) include two traits that can strongly bias mating systems towards inbreeding: (1) most species express both sexes simultaneously, creating the potential for self-fertilization; and (2) there is philopatric dispersal of planktonic or demersal larvae. Recent studies have confirmed that all hermaphrodite species with broad dispersal potential are either completely, or almost completely, self-incompatible. By contrast, species with limited dispersal potential have high, but variable, rates of self-fertilization. This interspecific variation in coral mating systems is similar to that found in terrestrial plants. Understanding the selective forces that drive mating-system variation in marine environments will undoubtedly broaden our understanding of the evolution of inbreeding and outbreeding in sessile plants and animals.

Preventing Renal Failure in Critically Ill Patients

[Ultrasonographic Study of Detrusor Thickness in Patients with Obstruction]

The diagnostic work up of patients with symptomatic benign prostatic hyperplasia is not always useful for diagnosing bladder outlet obstruction, especially if they are compared with pressure-flow studies. The authors make a review of the literature and a clinical study to demonstrate that alternative less invasive methods (ultrasound estimated bladder weight) can often replace pressure/flow studies.

Mechanical Ventilation and the Diseased Lung

System of Automated Gas-exchange Analysis for the Investigation of Metabolic Processes

Conventional gas-exchange instruments are confined to the measurement of O(2) consumption (VO(2)) and CO(2) production (VCO(2)) and are subject to a variety of errors. This handicaps the performance of these devices at inspired O(2) fraction (FI(O(2))) > 0.40 and limits their applicability to indirect calorimetry only. We describe a device based on the automation of the Douglas bag technique that is capable of making continuous gas-exchange measurements of multiple species over a broad range of experimental conditions. This system is validated by using a quantitative methanol-burning lung model modified to provide reproducible (13)CO(2) production. The average error for VO(2) and VCO(2) over the FI(O(2)) range of 0.21-0.8. is 2.4 and 0.8%, respectively. The instrument is capable of determining the differential atom% volume of known references of (13)CO(2) to within 3.4%. This device reduces the sources of error that thwart other instruments at FI(O(2)) > 0. 40 and demonstrates the capacity to explore other expressions of metabolic activity in exhaled gases related to the excretion of (13)CO(2).

Mechanical Ventilators and Respiratory Centers

Disorder Induced Cross-over Effects at Quantum Critical Points

Critical properties of quantum spin chains with varying degrees of disorder are studied at zero temperature by analytical and extensive density matrix renormalization methods. Generally the phase diagram is found to contain three phases. The weak disorder regime, where the critical behavior is controlled by the fixed points of the pure system, and the strong disorder regime, which is attracted by an infinite randomness fixed point, are separated by an intermediate disorder regime, where dynamical scaling is anisotropic and the static and dynamical exponents are disorder dependent.

Universal Phase Boundary Shifts for Corner Wetting and Filling

The phase boundaries for corner wetting (filling) in square and diagonal lattice Ising models are exactly determined and show a universal shift relative to wetting near the bulk criticality. More generally, scaling theory predicts that the filling phase boundary shift for wedges and cones is determined by a universal scaling function R(d)(psi) depending only on the opening angle 2psi. R(d)(psi) is determined exactly in d = 2 and approximately in higher dimensions using nonclassical local functional and mean-field theory. Detailed numerical transfer matrix studies of the magnetization profile in finite-size Ising squares support the conjectured connection between filling and the strong-fluctuation regime of wetting.

Generalized Contact Process with N Absorbing States

We investigate the critical properties of a one-dimensional stochastic lattice model with n (permutation symmetric) absorbing states. We analyze the cases with n/=3 with exponents z=nu( ||)/nu( perpendicular)=2, nu( perpendicular)=1, and beta=1. These exponents coincide with those of the multispecies (bosonic) branching annihilating random walks. For n=3 we also show that, upon breaking the symmetry to a lower one (Z2), one gets a transition either in the directed percolation, or in the parity conserving class, depending on the choice of parameters.

Crossover Behavior for Long Reptating Polymers

The Rubinstein-Duke model for polymer reptation is analyzed by means of density matrix renormalization techniques. It is found that the crossover in the scaling behavior of polymer renewal time (or viscosity) arises from the competing effect of the contribution due to tube length fluctuations and higher-order corrections, which are of opposite sign. Experiments which ought to emphasize both contributions are suggested. The exponent describing the subleading scaling behavior of the diffusion coefficient is also investigated.

Zipping and Collapse of Diblock Copolymers

Using exact enumeration methods and Monte Carlo simulations, we study the phase diagram relative to the conformational transitions of a diblock copolymer in two dimensions. The polymer is made of two homogeneous strands of monomers of different species which are joined to each other at one end. We find that, depending on the values of the energy parameters in the model, there is either a first order collapse from a swollen phase to a compact phase of spiral type, or a continuous transition to an intermediate zipped phase followed by a first order collapse at lower temperatures. Critical exponents of the zipping transition are computed, and their exact values are conjectured on the basis of a mapping onto percolation geometry, thanks to recent results on path-crossing probabilities.

Critical Properties of the Reaction-diffusion Model 2A-->3A, 2A-->0

The steady-state phase diagram of the one-dimensional reaction-diffusion model 2A-->3A, 2A-->0 is studied through the non-Hermitian density matrix renormalization group. In the absence of single-particle diffusion the model reduces to the pair-contact process, which has a phase transition in the universality class of directed percolation (DP) and an infinite number of absorbing steady states. When single-particle diffusion is added, the number of absorbing steady states is reduced to 2 and the model no longer shows DP critical behavior. The exponents theta=nu(parallel)/nu(perpendicular) and beta/nu(perpendicular) are calculated numerically. The value of beta/nu(perpendicular) is close to the value of the parity conserving universality class, in spite of the absence of local conservation laws.

Risk Based Characterisation of Contaminated Industrial Site Using Multivariate and Geostatistical Tools

Human and ecological risk assessment requires the sources, distribution, mobility and environmental behaviour of contaminants to be investigated on a site-specific basis. It often deals with data sets which are relatively small and affected by sampling gaps. In the case of a polycyclic aromatic hydrocarbon (PAH) contaminated industrial site, Kriging interpolation of spatial data and principal component analysis (PCA) proved useful for extracting additional value from the data set. Kriging was adopted for assessing the horizontal and vertical distribution and transport of PAHs in soil. PCA was applied to PAH concentration and relative abundance in soil samples and interpreted on the basis of the PAH physico-chemical and bio-degradation properties. It revealed correlation with the products of a neighbouring factory and the weathering of the lighter PAHs. The geo- and multivariate statistical results were coupled with the previous hydrogeological characterisation of the site to develop a site-conceptual model for use in the exposure scenario modelling for risk assessment.

Incipient Speciation Across a Depth Gradient in a Scleractinian Coral?

A few marine cases have demonstrated morphological and genetic divergence in the absence of spatial barriers to gene flow, suggesting that the initial phase of speciation is possible without geographic isolation. In the Bocas del Toro Archipelago of the Atlantic Coast of Panama, we found two morphotypes of the scleractinian coral Favia fragum with opposing depth distributions. One morphotype fit the classical description of F. fragum and was most abundant at 3 m depth. A second morphotype was distinguished by raised corallites and was restricted to < or = 1 m depth. The two morphotypes overlapped in distribution at 1 m depth. Multivariate analysis of polyp-level characters (shape and distribution of septa within corallites) divided samples into two groups corresponding to initial qualitative observations of colony shape and corallite relief. To determine whether reduced gene flow maintains morphological variation, we measured the frequencies of alleles at five allozyme loci in both morphotypes at three sites 1-2 km distant. While there were significant differences in allele frequencies between morphotypes within sites, there were also frequency differences among sites at most loci, with the exception of nearly fixed alleles at the PGM locus. Extremely low heterozygosity permitted us to use haplotypes to compare genetic distance between morphotypes and among sites. Comparisons between haplotype data and a null model assuming gene flow between morphotypes showed that the two morphotypes shared significantly fewer haplotypes than expected, and average genetic distance between morphotypes was significantly greater than expected. Partitioning haplotype variation with analysis of molecular variance demonstrated that 35% of the variation was explained by morphotype, whereas 28% of the variation was explained by site. Two PGM heterozygotes and several individuals homozygous for rare PGM alleles are consistent with hybridization, and perhaps introgression by selfing within morphotypes. We consider three hypotheses for this morphological and genetic divergence in F. fragum: (1) intraspecific polymorphism, (2) incipient species, (3) biological species; and discuss the role of reproductive characters in a divergence-with-gene flow mechanism of speciation.

Would Euclid Approve of How We Select Mechanical Ventilators?

Scaling in DNA Unzipping Models: Denaturated Loops and End Segments As Branches of a Block Copolymer Network

For a model of DNA denaturation, exponents describing the distributions of denaturated loops and unzipped end segments are determined by exact enumeration and by Monte Carlo simulations in two and three dimensions. The loop distributions are consistent with first-order thermal denaturation in both cases. Results for end segments show a coexistence of two distinct power laws in the relative distributions, which is not foreseen by a recent approach in which DNA is treated as a homogeneous network of linear polymer segments. This unexpected feature, and the discrepancies with such an approach, are explained in terms of a refined scaling picture in which a precise distinction is made between network branches representing single-stranded and effective double-stranded segments.

Roles of Stiffness and Excluded Volume in DNA Denaturation

The nature and the universal properties of DNA thermal denaturation are investigated by Monte Carlo simulations. For suitable lattice models we determine the exponent c describing the decay of the probability distribution of denaturated loops of length l, P approximately l(-c). If excluded volume effects are fully taken into account, c = 2.10(4) is consistent with a first order transition. The stiffness of the double stranded chain has the effect of sharpening the transition, if it is continuous, but not of changing its order and the value of the exponent c, which is also robust with respect to inclusion of specific base-pair sequence heterogeneities.

[Cardiac Rehabilitation and Secondary Prevention]

The last few years, a series of Guidelines, Reports, Review and Recommendations have confirmed that the scientific world is focusing on Cardiac Rehabilitation and Secondary Prevention. However, despite the scientific evidence, cultural problems, apparent economic limitations and organizational difficulties, continue to slow the development of Cardiac Rehabilitation. The main fault lies with the medical community and its cultural preparation. In the past 10 years the attention of the cardiologist has been focused on the early thrombolytic treatment and on primary coronary angioplasty while the secondary prevention has not always been a priority. Despite the many barriers against the development of Cardiac Rehabilitation, it would seem that it is important to improve the training of the future doctor and cardiologist by including the primary and secondary prevention and the clinical application of physical therapy in the university studies and in the courses of specialization. If the politicians are aware of the reduction in costs, even the cardiologists should realize that certain results can be obtained in a cost-effective manner, and surely that Cardiac Rehabilitation is more cost-effective with respect to thrombolytic treatment, bypass or hypolipidaemic drugs.

[GICR and ANMCO for Cardiac Rehabilitation Development in Veneto]

Reparametrizing the Loop Entropy Weights: Effect on DNA Melting Curves

Recent advances in the understanding of the melting behavior of double-stranded DNA with statistical mechanics methods lead to improved estimates of the weight factors for the dissociation events of the chains, in particular for interior loop melting. So far, in the modeling of DNA melting, the entropy of denaturated loops has been estimated from the number of configurations of a closed self-avoiding walk. It is well understood now that a loop embedded in a chain is characterized by a loop closure exponent c which is higher than that of an isolated loop. Here we report an analysis of DNA melting curves for sequences of a broad range of lengths (from 10 to 10(6) base pairs) calculated with a program based on the algorithms underlying MELTSIM. Using the embedded loop exponent we find that the cooperativity parameter is one order of magnitude bigger than current estimates. We argue that in the melting region the double helix persistence length is greatly reduced compared to its room temperature value, so that the use of the embedded loop closure exponent for real DNA sequences is justified.

Pulling Reptating Polymers by One End: Magnetophoresis in the Rubinstein-Duke Model

We consider the magnetophoresis problem within the Rubinstein-Duke model, i.e., a reptating polymer pulled by a constant field applied to a single end of a chain. Extensive density matrix renormalization calculations are presented of the drift velocity and the profile of the chain for various strengths of the driving field and chain lengths. We show that the velocities and the average densities of the stored length are well described by simple interpolating crossover formulas, derived under the assumption that the difference between the drift and curvilinear velocities vanishes for sufficiently long chains. The profiles, which describe the average shape of the reptating chain, also show such interesting features as some nonmonotonic behavior of the link densities for sufficiently strong pulling fields. We develop a description in which a distinction is made between links entering at the pulled head and at the unpulled tail. At weak fields the separation between the head zone and the tail zone meanders through the whole chain, while the probability of finding it close to the edges drops off. At strong fields the tail zone is confined to a small region close to the unpulled edge of the polymer.

Secondary Migration of a Central Venous Catheter. A Case Report

A case of central venous catheter (CVC) secondary migration in a patient with Hodgkin's lymphoma is reported. The catheter was inserted in the right internal jugular vein with anterior approach. The correct position of the catheter tip in the superior vena cava was confirmed by X-ray. Secondary migration to the right subclavian vein, without displacement at the point of insertion, was reported 8 days later by a chest X-ray performed for worsening of the respiratory condition. CVC was removed and reinserted with the same procedure. The correct position of the catheter tip was confirmed by thoracic radiography till 10 days later. Epidemiological data present in the literature and secondary migration predisposing factors are reported.

Universality in the Pair Contact Process with Diffusion

The pair contact process with diffusion is studied by means of multispin Monte Carlo simulations and density matrix renormalization group calculations. Effective critical exponents are found to behave nonmonotonically as functions of time or of system length and extrapolate asymptotically towards values consistent with the directed percolation universality class. We argue that an intermediate regime exists where the effective critical dynamics resembles that of a parity conserving process.

Beneficial Effects of Exercise Beyond the Pain Threshold in Intermittent Claudication

The quality of life and autonomy may be severely hampered in patients with intermittent claudication, but the amputation rate is very low. Supervised exercise training is effective, but still very rarely employed. Many authors think that in these patients exercise over the pain threshold may be dangerous. The aim of this study was to assess whether supervised, 3-month duration, 3 times/week, beyond the pain threshold exercise training is safe and whether it improves both the performance and quality of life in patients with claudication.

Interstrand Distance Distribution of DNA Near Melting

The distance distribution between complementary base pairs of the two strands of a DNA molecule is studied near the melting transition. Scaling arguments are presented for a generalized Poland-Scheraga-type model that includes self-avoiding interactions. At the transition temperature and for a large distance r, the distribution decays as 1/r(kappa) with kappa=1+(c-2)/nu. Here nu is the self-avoiding walk correlation length exponent and c is the exponent associated with the entropy of an open loop in the chain. Results for the distribution function just below the melting point are also presented. Numerical simulations that fully take into account the self-avoiding interactions are in good agreement with the scaling approach.

NO Way to Warm the Big Toe

Characterization of Contaminated Soil and Groundwater Surrounding an Illegal Landfill (S. Giuliano, Venice, Italy) by Principal Component Analysis and Kriging

The characterization of a hydrologically complex contaminated site bordering the lagoon of Venice (Italy) was undertaken by investigating soils and groundwaters affected by the chemical contaminants originated by the wastes dumped into an illegal landfill. Statistical tools such as principal components analysis and geostatistical techniques were applied to obtain the spatial distribution of chemical contaminants. Dissolved organic carbon (DOC), SO4(2-) and Cl- were used to trace the migration of the contaminants from the top soil to the underlying groundwaters. The chemical and hydrogeological available information was assembled to obtain the schematic of the conceptual model of the contaminated site capable to support the formulation of major exposure scenarios, which are also provided.

Unbinding of Mutually Avoiding Random Walks and Two-dimensional Quantum Gravity

We analyze the unbinding transition for a two-dimensional lattice polymer in which the constituent strands are mutually avoiding random walks. At low temperatures the strands are bound and form a single self-avoiding walk. We show that unbinding in this model is a strong first order transition. The entropic exponents associated with denaturated loops and end-segment distributions show sharp differences at the transition point and in the high temperature phase. Their values can be deduced from some exact arguments relying on a conformal mapping of copolymer networks into a fluctuating geometry, i.e., in the presence of quantum gravity. An excellent agreement between analytical and numerical estimates is observed for all cases analyzed.

[Is It Time to Renew and Potentiate the Regional Representativeness of the GICR Agency?]

Ecological Risk Assessment of Persistent Toxic Substances for the Clam Tapes Philipinarum in the Lagoon of Venice, Italy

Because of contamination of sediments of the Lagoon of Venice, Italy, by inorganic pollutants (e.g., arsenic, cadmium, chromium, copper, lead, mercury, nickel, and zinc) and organic pollutants (e.g., polychlorobiphenyls), as well as the ecological and economical relevance of the edible clam Tapes philipinarum, an ecological risk assessment was undertaken to ascertain the extent of bioaccumulation that would pose a significant risk. Risk was estimated by means of toxic units and hazard quotient approaches, by comparing the exposure concentration with the effect concentration. Clam exposure was estimated by applying previous results based on bioaccumulation spatial regression models. In addition, a comparison was made between sum of dioxin-like polychlorinated biphenyl (PCB) congeners and total PCB bioaccumulation provided by spatial regression models and by a partitioning model. The effect concentrations were calculated as tissue screening concentrations, as the product of pollutant sediment quality criteria and the bioaccumulation factor. Finally, the cumulative risk posed by selected inorganic pollutants and total PCBs was estimated and a map of risk was drawn. The resulting chemicals of potential ecological concern were mercury, cadmium, arsenic, and nickel, as well as, to a lesser extent, total PCBs.

Effect of a Contaminated Site (the San Giuliano Landfill, Venice, Italy) on the Interaction Between Water Bodies in a Coastal Aquifer System

A complex multiple aquifer system affected by a contaminated site and exposed to tidal effects was investigated to develop the hydrogeological conceptual model of the study case. Two water bodies were identified, from top to down: a surface aquifer unaffected by tidal events, and a semiconfined aquifer partly communicating with the brackish lagoon waters. By using the Cl(-)/SO4(2-) ratio and the DOC (Dissolved Organic Carbon) concentration, as well as by applying the kriking to the piezometric levels results, the groundwater flow directions and the hydraulic gradients within the investigated aquifers were also identified. Based on the overall results, a schematic of the conceptual model for the whole aquifer system was provided which allows to visualize the communication between the different water bodies.

[Repeated Thromboembolism During Pregnancy with Constitutional Antithrombin Deficiency]

We report the case of a twenty-three-year old woman with constitutional antithrombin deficiency, who had oral anticoagulation since she was four years old. During her first pregnancy, after the introduction of unfractionated heparin prophylactic therapy, she presented a first venous thromboembolism at nine weeks, and a second one with low-molecular-weight heparin therapy at nineteen weeks. Because of a severe antithombin deficiency, regular infusions of antithrombin concentrates were necessary until delivery to ensure effective anticoagulation by heparin. Patients with antithrombin deficiency have a very high risk of venous thromboses during the pregnancy and post-partum. We discuss the significant points of management for this period.

Regression Models to Predict Water-soil Heavy Metals Partition Coefficients in Risk Assessment Studies

Risk assessment studies apply fate and transport models to predict the behaviour of chemicals in the environment. The definition of physico-chemical properties is crucial to predict the mobility of pollutants and heavy metals in particular within the environmental compartments. The conservative approach normally adopted at a screening level in attributing a value to the K(d) value, results in an extremely variable mobility in soil. In this paper a regression model to estimate rapidly the K(d) for heavy metals is proposed and applied to Pb, allowing a considerable reduction (3-4 orders of magnitude) of the estimation uncertainty. The application of a stepwise forward multiple regression to literature data provided a pH-dependent regression equation of the soil-water distribution coefficient (K(d)) for Pb: log K(d)=1.99+0.42 pH.

[Cardiac Rehabilitation in the Region of Veneto]

In Italy there has been a progressive shifting of the legislative and fiscal activity from a national level to a regional one. In the Venetian district a series of documents, also concerning the cardiac rehabilitation, has been produced. A document elaborated in 1999 contains a detailed account of eligibility criteria for cardiac rehabilitation as well as of structural and organizational requirements. Other documents contain the updated price lists for admission episode (DRG 462) or days of stay in hospital and diurnal hospital activity, according to the type of structure which supplies the service. For outpatients, cardiac rehabilitation is identified by the code 93.36 and the ticket fare is 19,50 Euro. In the enclosure no.6 of the Sanitary Regional Plan, still under definitive approval, it is stated that for each Intensive Therapy there will be a functional connector with a cardiac rehabilitation service which, except for few Centers, will carry on its activity with outpatients. At present the regional Cardiac Rehabilitation includes 3 complex units (for in- and outpatients) and 13 simple units (for outpatients only), with a total of 3031 patients rehabilitated in 2004.

A Method for Risk Assessment for Three Contaminated Sites in Northern Italy

A stepwise human health risk assessment procedure carried out using American Society for Testing and Materials methodology was applied to three contaminated sites located in northern Italy: an uncontrolled landfill, an abandoned industrial site and an industrial waste contaminated land. Two different tiers of analysis were performed by means of the analytical model RBCA Tool Kit and the numerical model API-DSS, respectively. The latter was applied according to both a deterministic and a probabilistic risk analysis. The comparison of the two approaches highlighted the great benefit provided by probabilistic analysis for the risk assessment based on site specific parameters and more complex models, in particular for groundwater exposure route. Finally, the risk-based site specific target levels were compared to the generic regulatory threshold limits fixed by the Italian regulation. The comparison showed the regulatory limits generally too restrictive for non-carcinogenic substances but less protective for carcinogenic chemicals, outlining the need of a site-specific risk assessment especially for carcinogenic substances.

Acute Renal Failure and Severe Neurotoxicity Following Valacyclovir

Screening Ecological Risk Assessment for the Benthic Community in the Venice Lagoon (Italy)

According to the risk hypothesis: the sediment as source of potential risk for the benthic community, an Ecological Risk Assessment (ERA) based on the quotient method was undertaken. The exposure of the benthic community to different classes of pollutants (metals, chlorinated organic compounds and polynuclear aromatic hydrocarbons) was inferred by estimating the pollutant stocks in the top 15-cm sediment of the whole Venice lagoon, after application of geostatistic techniques. The risk was calculated by comparing the sediment exposure profiles with the ecotoxicological benchmarks for benthic organisms. Kriging based maps of the spatial distribution of the estimated risk for the benthic community over the whole lagoon were obtained. The highest risk, found in the areas nearest to the sources of contamination (e.g., the industrial district of Porto Marghera and the river mouths), was posed by mercury (40% of the sampling stations showed exposure levels higher than the Probable Effect Level), arsenic and nickel (75% of the sampling stations exceeded the Threshold Effect Level).

Exons, Introns, and DNA Thermodynamics

The genes of eukaryotes are characterized by protein coding fragments, the exons, interrupted by introns, i.e., stretches of DNA which do not carry useful information for protein synthesis. We have analyzed the melting behavior of randomly selected human cDNA sequences obtained from genomic DNA by removing all introns. A clear correspondence is observed between exons and melting domains. This finding may provide new insights into the physical mechanisms underlying the evolution of genes.

The Use of Etched, Chemically Modified, Rectangular Capillaries As a Separation Medium for Open Tubular Capillary Electrochromatography

The use of etched, chemically modified, capillaries with a rectangular inner channel for open tubular electrochromatography is investigated. Comparisons of separation capabilities are made between circular and rectangular capillaries undergoing the same etching and chemical modification processes. With the long dimension of the rectangular column aligned in the direction of the optical light path, the relative sensitivities of the two capillary geometries are evaluated. The electrochromatographic properties of two catechins found in tea are investigated on the rectangular etched octadecyl-modified capillary.

"If You Cannot Measure It, You Cannot Improve It"

Intravascular Large B-cell Lymphoma Involving Hemangiomas: an Unusual Presentation of a Rare Neoplasm

We report the clinicopathological features of two cases of intravascular large B-cell lymphoma involving cutaneous hemangiomas. The cases were identified from the consultation files of two of the authors. Both patients were women, 64 and 55 years of age, who presented with long-standing cutaneous hemangiomas of the posterior scalp and left shoulder, respectively. The lesions were brought to medical attention by an increase in size and change in color. Biopsies and immunohistochemical evaluation of the hemangiomas revealed extensive involvement by intravascular large B-cell lymphoma. The neoplastic cells were diffusely positive for CD20 in both cases and negative for CD3, pan-cytokeratin (AE1/AE3), epithelial membrane antigen, S-100, Factor VIII-related antigen, CD34 and CD31. Disease was limited to the hemangiomas in both patients. Treatment consisted of chemotherapy (both patients) and adjuvant radiation therapy (one patient). One patient had a recurrence of disease 33 months after initial diagnosis, leading to an autologous stem cell transplant. The other patient is without evidence of disease 27 months after initial diagnosis. Although this is a rare neoplasm, it is important to consider intravascular large B-cell lymphoma in the differential diagnosis of vascular lesions containing intravascular neoplastic cells.

[Why Cardiovascular Rehabilitation Services Should Include Patients with Intermittent Claudication?]

Chronic peripheral arterial disease represents a frequent and underestimated localization of atherosclerosis and its management often appears to be inadequate. The association with ischemic heart disease, the weighty prevalence of coronary disease risk factors, the high cardiovascular rate of morbidity and mortality, the sharp reduction in the tenor of life and the well-being supervised physical training efficacy constitute the main reasons that transform Cardiac Rehabilitation into an ideal setting for the treatment of patients suffering from intermittent claudication. Thanks to the cultural patrimony of cardiologists, together with other professionals, such as psychologists, dietitians, physiotherapists and nurses, it is possible to initiate an multi-comprehensive treatment program. Besides, this type of management may decrease both morbidity and mortality as well as reduce symptoms and improve the patients' quality of life.

Physical-chemistry-based Analysis of Affymetrix Microarray Data

We analyze publicly available data on Affymetrix microarray spike-in experiments on the human HGU133 chipset in which sequences are added in solution at known concentrations. The spike-in set contains sequences of bacterial, human, and artificial origin. Our analysis is based on a recently introduced molecular-based model (Carlon, E.; Heim, T. Physica A 2006, 362, 433) that takes into account both probe-target hybridization and target-target partial hybridization in solution. The hybridization free energies are obtained from the nearest-neighbor model with experimentally determined parameters. The molecular-based model suggests a rescaling that should result in a "collapse" of the data at different concentrations into a single universal curve. We indeed find such a collapse, with the same parameters as obtained previously for the older HGU95 chip set. The quality of the collapse varies according to the probe set considered. Artificial sequences, chosen by Affymetrix to be as different as possible from any other human genome sequence, generally show a much better collapse and thus a better agreement with the model than all other sequences. This suggests that the observed deviations from the predicted collapse are related to the choice of probes or have a biological origin rather than being a problem with the proposed model.

Comment on "Solving the Riddle of the Bright Mismatches: Labeling and Effective Binding in Oligonucleotide Arrays"

In a recent paper [Phys. Rev. E 68, 011906 (2003)], Naef and Magnasco suggested that the "bright" mismatches observed in Affymetrix microarray experiments are caused by the fluorescent molecules used to label RNA target sequences, which would impede target-probe hybridization. Their conclusion is based on the observation of "unexpected" asymmetries in the affinities obtained by fitting microarray data from publicly available experiments. We point out here that the observed asymmetry is due to the inequivalence of RNA and DNA, and that the reported affinities are consistent with stacking free energies obtained from melting experiments of unlabeled nucleic acids in solution. The conclusion of Naef and Magnasco is therefore based on an unjustified assumption.

Decision Support-oriented Selection of Remediation Technologies to Rehabilitate Contaminated Sites

A methodology for selecting remediation technologies is presented as part of a decision support system for the rehabilitation of contaminated sites. It includes 2 steps: In the 1st step, a pool of suitable technologies is selected within a technologies database according to their applicability to site-specific conditions; in the 2nd step, the selected technologies: are ranked according to a multicriteria decision analysis (MCDA) approach. The MCDA was applied to allow for a transparent procedure and for the integration of expert analyses. The methodology was implemented in a previously developed georeferenced information system-based decision support system for the rehabilitation of contaminated sites and then applied to a case study (Porto Marghera, Venice, Italy). On the basis of the obtained results, the proposed methodology appeared suitable to select remediation technologies according to both technical features and requirements of available technologies, as well as site-specific environmental conditions of the site of concern, such as chemical contamination levels and remediation objectives.

[Consensus Statement of Multisocietary Task Force Prescription of Physical Exercise in the Cardiological Environment--executive Summary (fourth Part)]

[Is Obesity Still a Coronary Risk Factor?]

Although obesity and, in particular, abdominal obesity is clearly a risk factor for developing coronary artery disease, once coronary artery disease has been established, the correlation of obesity with total mortality, cardiovascular mortality, myocardial infarction, and revascularization is unclear and still remains a matter of debate. The relationship between obesity and mortality in patients with coronary artery disease has so far only been investigated by posthoc analysis of cohort studies, which have produced contradictory results. When a higher percentage body fat has been found to be a strong independent predictor of event-free survival, the phenomenon has been described as an 'obesity paradox' or 'reverse epidemiology'. A recent meta-analysis, appearing in the August 19 issue of Lancet on 250,152 patients with documented coronary artery disease, suggests that after grouping 40 cohort studies with adjusted risks, overweight patients were consistently associated with a better survival and lower cardiovascular events than patients with a low body mass index, whereas obesity was associated with a higher total mortality only in patients with history of coronary artery bypass graft, and severe obesity was associated with a significantly higher cardiovascular mortality but not with an increased risk for total mortality. Far from proving that obesity is harmless, these findings suggest that alternative methods might be required to better characterize individuals who truly have excess body fat and that additional studies with different methods are needed. Moreover, still unknown is the unique contribution of higher muscle-to-fat ratio, which may be merely a surrogate of increased physical fitness. Future research is needed to assess the link between high muscle mass, high body fat and clinical outcomes.

[Consensus Statement of Multisocietary Task Force--prescription of Physical Exercise in the Cardiological Environment (third Part)]

Stability Domains of Actin Genes and Genomic Evolution

In eukaryotic genes, the protein coding sequence is split into several fragments, the exons, separated by noncoding DNA stretches, the introns. Prokaryotes do not have introns in their genomes. We report calculations of the stability domains of actin genes for various organisms in the animal, plant, and fungi kingdoms. Actin genes have been chosen because they have been highly conserved during evolution. In these genes, all introns were removed so as to mimic ancient genes at the time of the early eukaryotic development, i.e., before intron insertion. Common stability boundaries are found in evolutionarily distant organisms, which implies that these boundaries date from the early origin of eukaryotes. In general, the boundaries correspond with intron positions in the actins of vertebrates and other animals, but not much for plants and fungi. The sharpest boundary is found in a locus where fungi, algae, and animals have introns in positions separated by one nucleotide only, which identifies a hot spot for insertion. These results suggest that some introns may have been incorporated into the genomes through a thermodynamically driven mechanism, in agreement with previous observations on human genes. They also suggest a different mechanism for intron insertion in plants and animals.

[Pseudomeigs Syndrome in a Patient with Krukenberg's Tumor]

We report the case of a fiftyone-year-old woman with a past medical history of Linfoma no Hodking and a gastric adenocarcinoma with signet ring cells. She came to our institution with a twenty month history of dysnea secondary to pleural effussion, bilateral lower extremity edema and probably had ascitis. On CT and US two bilateral pelvic masses were found and biopsied. The anatomopathological analysis showed bilateral ovarian implants from signet ring cell adenocarcinoma (Krukenberg tumor). This patient developed a PseudoMeigs syndrome consisting on malignant ovarian tumor asociated with ascitis and pleural effusion without malignant cells. Oncological patients who present with ascitis and benign pleural effusion, the diagnosis of PseudoMeigs syndrome should be considered.

Thermodynamic Behavior of Short Oligonucleotides in Microarray Hybridizations Can Be Described Using Gibbs Free Energy in a Nearest-neighbor Model

While designing oligonucleotide-based microarrays, cross-hybridization between surface-bound oligos and non-intended labeled targets is probably the most difficult parameter to predict. Although literature describes rules-of-thumb concerning oligo length, overall similarity, and continuous stretches, the final behavior is difficult to predict. The aim of this study was to investigate the effect of well-defined mismatches on hybridization specificity using CodeLink Activated Slides and to study quantitatively the relation between hybridization intensity and Gibbs free energy (DeltaG), taking the mismatches into account. Our data clearly showed a correlation between the hybridization intensity and DeltaG of the oligos over 3 orders of magnitude for the hybridization intensity, which could be described by the Langmuir model. As DeltaG was calculated according to the nearest-neighbor model, using values related to DNA hybridizations in solution, this study clearly shows that target-probe hybridizations on microarrays with a three-dimensional coating are in quantitative agreement with the corresponding reaction in solution. These results can be interesting for some practical applications. The correlation between intensity and DeltaG can be used in quality control of microarray hybridizations by designing probes and corresponding RNA spikes with a range of DeltaG values. Furthermore, this correlation might be of use to fine-tune oligonucleotide design algorithms in a way to improve the prediction of the influence of mismatching targets on microarray hybridizations.

[Consensus Statement of Multisocietary Task Force--prescription of Physical Exercise in the Cardiological Environment (second Part)]

[Consensus Statement of Multisocietary Task Force--prescription of Physical Exercise in the Cardiological Environment (First Part)]

DESYRE: DEcision Support SYstem for the REhabilitation of Contaminated Megasites

DESYRE (DEcision Support sYstem for the REqualification of contaminated sites) is a GIS-based decision support system (DSS) specifically developed to address the integrated management and remediation of contaminated megasites (i.e., large contaminated areas or impacted areas characterized by multiple site owners and multiple stakeholders). In the DESYRE conceptual design and development the main aspects pertaining to a remediation process--analysis of social and economic benefits and constrains, site characterization, risk assessment, selection of best available technologies, creation of sets of technologies to be applied, analysis of the residual risk, and comparison of different remediation scenarios--were included. The DESYRE DSS is a GIS-based software composed of 6 interconnected modules. In the characterization module, chemical and hydrogeological data are organized in a relational database and contaminants' distributions are mapped by using geostatistic tools. The socioeconomic module addresses the socioeconomic constraints though a fuzzy logic analysis to select the best land use. The risk assessment module is divided into 2 phases. In the preremediation phase, an original procedure allows assessing and representing the spatial distribution of risks posed by contaminants in soil and groundwater, providing a risk-based zoning of the site. Then, in the technology assessment module, a selection of suitable technologies and creation of different technology sets, taking into account both technical requirements and site-specific features, are performed by experts supported by multicriteria decision analysis tools. In the postremediation risk assessment, a simulation of applied technologies provides residual risk maps with related uncertainty maps. Finally, in the decision module, alternative remediation scenarios are described by a set of indices and can be compared and ranked by interested stakeholders using multicriteria decision analysis methodologies. The paper highlights original procedural steps and functionalities of DESYRE nd analyzes its main points of strength and potentialities, as well as limits.

Development of a Site-specific Ecological Risk Assessment for Contaminated Sites: Part II. A Multi-criteria Based System for the Selection of Bioavailability Assessment Tools

A comparison procedure based on Multi-Criteria Decision Analysis (MCDA) and expert judgment was developed in order to allow the comparison of bioavailability tests to implement the chemical Line of Evidence (LoE) within a TRIAD based site-specific Ecological Risk Assessment framework including three tires of investigation. The proposed methodology was included in the Module 1 of the Decision Support System DSS-ERAMANIA and the obtained rank supported the selection of a suitable set of available tests to be applied to the case study. A simplified application of the proposed procedure is described and results obtained by the system software are discussed.

The Possibilities for the EU-wide Use of Similar Ecological Risk-based Soil Contamination Assessment Tools

Soil degradation, e.g. due to soil contamination, is a serious problem in Europe. Therefore, the European Commission believes that a comprehensive EU strategy for soil protection is required. With the purpose of supporting the European soil policy, the possibilities for a common approach in the EU-wide use of ecological risks assessment methodologies are explored. For over ten years now, ecological procedures used in different countries have been discussed in international fora. More recently, within the framework of the HERACLES network a review of ecological risk assessment tools was performed, among other things. From this study it can be concluded that the inclusion of ecological risk assessment in soil quality standards shows an increasing interest in many EU Member States. The study also shows that there are many procedures for ecological risk assessment readily available in several EU countries and will be readily available in even more Member States in the nearby future. Besides, this study clearly shows quite some variation in the ecological risk assessment tools and in the resulting soil quality standards in the different countries. Therefore, an effort was made to look for potential harmonisation of these tools within the European Union. Risk assessment tools used in soil quality assessment include both political and scientific elements, which are often interwoven. Insofar differences in the existing tools originate from geographical or cultural differences between Member States or from political choices, harmonisation is not at all regarded an option. Nevertheless, several differences between existing ecological risk assessment tools have been identified, that merely originate from scientific or technical aspects. These tools could be standardized, which means that there could be a uniform tool to be used everywhere throughout the EU. The development of these harmonised risk assessment tools will imply an intensive international cooperation, with the purpose of at least making the existing differences between those tools from the Member States transparent and to investigate the possibilities for coming to similar tools from a scientific/technical perspective.

[Short and Medium Term Functional Capacity After Single Cycle of Controlled Physical Training in Subjects with Claudication]

Previous studies have shown the positive effect of exercise rehabilitation in patients with claudication, but uncertainties remain surrounding the optimal exercise program strategy and the persistence of the benefits over time. The purpose of the present study has been to prospectively assess the feasibility of short-course intensive supervised exercise training beyond pain threshold and to verify the maintenance of walking capacity during a medium term follow-up.

Statin Therapy Enhance Benefit of Exercise Training in Patients with Claudication Intermittens

Modeling Background Intensity in DNA Microarrays

DNA microarrays are devices that are able, in principle, to detect and quantify the presence of specific nucleic acid sequences in complex biological mixtures. The measurement consists in detecting fluorescence signals from several spots on the microarray surface onto which different probe sequences are grafted. One of the problems of the data analysis is that the signal contains a noisy background component due to nonspecific binding. We present a physical model for background estimation in Affymetrix Genechips. It combines two different approaches. The first is based on the sequence composition, specifically its sequence-dependent hybridization affinity. The second is based on the strong correlation of intensities from locations which are the physical neighbors of a specific spot on the chip. Both effects are incorporated in a background estimator which contains 24 free parameters, fixed by minimization on a training data set. In all data analyzed the sequence-specific parameters, obtained by minimization, are found to strongly correlate with empirically determined stacking free energies for RNA-DNA hybridization in solution. Moreover, there is an overall agreement with experimental background data and we show that the physics-based model that we propose performs on average better than purely statistical approaches for background calculations. The model thus provides an interesting alternative method for background subtraction schemes in Affymetrix Genechips.

On the Relationship Between Perfect Matches and Mismatches in Affymetrix Genechips

A relationship which links the fluorescence intensity histograms for perfect match (PM) and mismatch (MM) probes in Affymetrix Genechips is derived using inputs from physical-chemistry as the Langmuir and the Nearest Neighbor models. This relationship is in good agreement with experimental data from few dozens of chips belonging to about 10 different organisms. Principles of physical-chemistry impose some constant value for the average ratios of PM and MM intensities. Experimental data, however, show quite some variations in these parameters, although they follow the same inequalities as expected from hybridization free energies for oligonucleotides melting in solution. It is suggested that the anomalous experiment to experiment differences are due to 1) problems with chip design and 2) excessive fragmentation of the target in solution. The histogram analysis developed may be a useful preprocessing step to evaluate the global quality of the experimental data, prior to the calculation of the gene expression level.

Fifteen New Microsatellite Markers for the Reef Coral Favia Fragum and a New Symbiodinium Microsatellite

Sixteen new microsatellite loci were isolated from the Tropical Atlantic coral Favia fragum. One locus amplified with pure zooxanthellae DNA template, revealing a symbiont (Symbiodinium) origin. We genotyped 48 short and 45 tall ecomorphs of F. fragum from the Bocas del Toro region of Panama. For 15 host loci, allelic diversity ranged from three to 23 with an average of 5.75 alleles per locus. Analysis of genotypic data revealed significant heterozygote deficits at all loci and linkage disequilibrium between loci, as did a previous study of the two ecomorphs with allozymes. We found evidence for null alleles at four of the host loci in the form of locus-specific polymerase chain reaction failure; however, extreme inbreeding via self-fertilization is likely to explain the large departures from Hardy-Weinberg equilibrium.

Exercise Prescription for the Prevention and Treatment of Cardiovascular Diseases: Part II

Epidemiological, clinical and laboratory studies have provided definitive evidence that physical activity is able to improve fitness and reduce cardiovascular morbidity and mortality. Moreover, physical exercise also seems to significantly reduce the risk of developing other chronic diseases such as obesity, osteoporosis, diabetes, tumours and depression. Promoting physical activity in the general population is therefore one of the primary objectives of our healthcare institutions. Although the benefits of an active lifestyle have been demonstrated by numerous scientific data, only a few numbers of Italians and Europeans take up regular physical exercise. To promote physical activity, both in the general population and in subjects affected by cardiovascular diseases, the Italian Federation of Sports Medicine, the Italian Society of Sports Cardiology, the Italian Association of Hospital Cardiologists, the Italian Society of Cardiology, the Italian Association of Out-of-Hospital Cardiologists and the Italian Group of Cardiac Rehabilitation have promoted the constitution of a Task Force made up of experts in the fields of sports cardiology. The document produced by the Task Force is intended for healthcare professionals, and deals with the role of physical activity in the prevention and treatment of cardiovascular diseases. It examines the beneficial effects of physical activity on the cardiovascular system, while analysing the possible risks involved and how they can be avoided. The rational principles underlying the prescription of physical activity in the cardiologic setting are described, as are the modalities for prescribing such activity.

Exercise Prescription for the Prevention and Treatment of Cardiovascular Diseases: Part I

Epidemiological, clinical and laboratory studies have provided definitive evidence that physical activity is able to improve fitness and reduce cardiovascular morbidity and mortality. Moreover, physical exercise also seems to significantly reduce the risk of developing other chronic diseases such as obesity, osteoporosis, diabetes, tumours and depression. Promoting physical activity in the general population is therefore one of the primary objectives of our healthcare institutions. Although the benefits of an active lifestyle have been demonstrated by numerous scientific data, only a few numbers of Italians and Europeans take up regular physical exercise. To promote physical activity, both in the general population and in subjects affected by cardiovascular diseases, the Italian Federation of Sports Medicine, the Italian Society of Sports Cardiology, the Italian Association of Hospital Cardiologists, the Italian Society of Cardiology, the Italian Association of Out-of-Hospital Cardiologists and the Italian Group of Cardiac Rehabilitation have promoted the constitution of a Task Force made up of experts in the fields of sports cardiology. The document produced by the Task Force is intended for healthcare professionals and deals with the role of physical activity in the prevention and treatment of cardiovascular diseases. It examines the beneficial effects of physical activity on the cardiovascular system, while analysing the possible risks involved and how they can be avoided. The rational principles underlying the prescription of physical activity in the cardiologic setting are described, as are the modalities for prescribing such activity.

Role of Sedation and Analgesia in Mechanical Ventilation

A Spatial Risk Assessment Methodology to Support the Remediation of Contaminated Land

When soil and groundwater contaminations occur over large areas, remediation measures should be spatially prioritized on the basis of the risk posed to human health and in compliance with technological and budget constraints. Within this scope, the application of human health risk assessment algorithms in a spatially resolved environment raises a number of methodological and technical complexities. In this paper, a methodology is proposed and applied in a case study to support the entire formulation process of remediation plans, encompassing hazard assessment, exposure assessment, risk characterisation, uncertainty assessment and allocation of risk reduction measures. In the hazard assessment, it supports the selection of Contaminants of Concern (CoC) with regard to both their average concentrations and peak concentrations, i.e. hot spots. In the exposure assessment, it provides a zoning of the site based on the geostatistical mapping of contaminant. In the risk characterisation, it generates vector maps of Risk Factors on the basis of the risk posed by multiple substances and allows the interrogation of most relevant CoC and exposure pathways for each zone of the site. It also supports the Monte Carlo based probabilistic estimation of the Risk Factors and generates maps of the associated uncertainty. In the risk reduction phase, it supports the formulation of remediation plans based on the stepwise spatial allocation of remediation interventions and the on-time simulation of risk reduction performances. The application of this methodology is fully supported by an easy-to-use and customized Geographical Information System and does not require high expertise for interpretation. The proposed methodology is the core module of a Decision Support System (DSS) that was implemented in the DESYRE software aimed at supporting the risk-based remediation of megasites.

Linear Model for Fast Background Subtraction in Oligonucleotide Microarrays

One important preprocessing step in the analysis of microarray data is background subtraction. In high-density oligonucleotide arrays this is recognized as a crucial step for the global performance of the data analysis from raw intensities to expression values.

Comparative Analysis of Paw Pad Structure in the Clouded Leopard (Neofelis Nebulosa) and Domestic Cat (Felis Catus)

The Clouded leopard (Neofelis nebulosa) is a medium-sized highly arboreal cat. This study compares the structure of the digital, metacarpal and metatarsal pads of the manus and pes in N. nebulosa to that of the domestic cat (Felis catus). Covered by a stratified squamous cornified epithelium, the pads have a supple deposit of subepidermal fat that is partitioned by collagen fibers and extensively anchored to the muscle tendon sheaths. In both animals, a pes metatarsal pad suspensory ligament originates from the Mm. flexores digitorum profundi tendon and forms 3-4 small branches that project through the dermal fat layer and attach to the pad epidermis. In the cat manus, four tendons of equal size extend from the M. flexor digitorum superficialis (FDS) to form the manica flexoria in digits 2-4 from which extends a metacarpal pad suspensory ligament (MPSL) on digits 2 and 5 that extends into the tela subcutanea and epidermis. On digits 3 and 4 MPSL extends directly from the FDS tendon itself. In contrast, manus FDS tendons 1 and 5 in N. nebulosa were thin and either project directly to the tela subcutanea (tendon 1) or connect with the manica flexoria forming a metacarpal pad suspensory ligament (tendon 5). Tendons 2-4 connect with the manica flexoria from which MPSL project into the tela subcutanea and epidermis. In both species, the suspensory ligaments may serve to contract the pad to conform to the under lying substrate, thus enhancing the animal's ability to grip branches while climbing.

The Effects of Mismatches on Hybridization in DNA Microarrays: Determination of Nearest Neighbor Parameters

Quantifying interactions in DNA microarrays is of central importance for a better understanding of their functioning. Hybridization thermodynamics for nucleic acid strands in aqueous solution can be described by the so-called nearest neighbor model, which estimates the hybridization free energy of a given sequence as a sum of dinucleotide terms. Compared with its solution counterparts, hybridization in DNA microarrays may be hindered due to the presence of a solid surface and of a high density of DNA strands. We present here a study aimed at the determination of hybridization free energies in DNA microarrays. Experiments are performed on custom Agilent slides. The solution contains a single oligonucleotide. The microarray contains spots with a perfect matching (PM) complementary sequence and other spots with one or two mismatches (MM) : in total 1006 different probe spots, each replicated 15 times per microarray. The free energy parameters are directly fitted from microarray data. The experiments demonstrate a clear correlation between hybridization free energies in the microarray and in solution. The experiments are fully consistent with the Langmuir model at low intensities, but show a clear deviation at intermediate (non-saturating) intensities. These results provide new interesting insights for the quantification of molecular interactions in DNA microarrays.

Inverse Langmuir Method for Oligonucleotide Microarray Analysis

An algorithm for the analysis of Affymetrix Genechips is presented. This algorithm, referred to as the Inverse Langmuir Method (ILM), estimates the binding of transcripts to complementary probes using DNA/RNA hybridization free energies, and the hybridization between partially complementary transcripts in solution using RNA/RNA free energies. The balance between these two competing reactions allows for the translation of background-subtracted intensities into transcript concentrations.

Thermodynamic Scaling Behavior in Genechips

Affymetrix Genechips are characterized by probe pairs, a perfect match (PM) and a mismatch (MM) probe differing by a single nucleotide. Most of the data preprocessing algorithms neglect MM signals, as it was shown that MMs cannot be used as estimators of the non-specific hybridization as originally proposed by Affymetrix. The aim of this paper is to study in detail on a large number of experiments the behavior of the average PM/MM ratio. This is taken as an indicator of the quality of the hybridization and, when compared between different chip series, of the quality of the chip design.

A Systematic Review of the Psychometric Properties of Quality of Life Measures for School Aged Children with Cerebral Palsy

This systematic review aimed to evaluate the psychometric properties and clinical utility of all condition specific outcome measures used to assess quality of life (QOL) in school aged children with cerebral palsy (CP).

Unwinding Dynamics of Double-stranded Polymers

We consider the unwinding of two lattice polymer strands of length N that are initially wound around each other in a double-helical conformation and evolve through Rouse dynamics. The problem relates to quickly bringing a double-stranded polymer well above its melting temperature, i.e., the binding interactions between the strands are neglected, and the strands separate from each other as it is entropically favorable for them to do so. The strands unwind by rotating around each other until they separate. We find that the process proceeds from the ends inward; intermediate conformations can be characterized by a tightly wound inner part, from which loose strands are sticking out, with length l∼t(0.39). The total time needed for the two strands to unwind scales as a power of N as τ(u)∼N(2.57±0.03). We present a theoretical argument, which suggests that during this unwinding process, these loose strands are far out of equilibrium.

Elastic Lattice Polymers

We study a model of "elastic" lattice polymer in which a fixed number of monomers m is hosted by a self-avoiding walk with fluctuating length l . We show that the stored length density ρm≡1-/m scales asymptotically for large m as ρm=ρ∞(1-θ/m+…) , where θ is the polymer entropic exponent, so that θ can be determined from the analysis of ρm. We perform simulations for elastic lattice polymer loops with various sizes and knots, in which we measure ρm. The resulting estimates support the hypothesis that the exponent θ is determined only by the number of prime knots and not by their type. However, if knots are present, we observe strong corrections to scaling, which help to understand how an entropic competition between knots is affected by the finite length of the chain.

Hybridisation Thermodynamic Parameters Allow Accurate Detection of Point Mutations with DNA Microarrays

We consider mixtures of two DNA sequences t and t' differing by a single nucleotide, which are analyzed by an Agilent custom DNA microarray. In particular we focus on the case in which t, the "wild type", is predominantly abundant and t' the "mutant" is at very low concentrations compared to t. We show that by using appropriately designed arrays it is possible to accurately quantify the presence of t' even at low relative concentrations (≈1%). The detection method is based on thermodynamic models of DNA hybridisation and on the analysis of a large number of hybridisation intensities from probes containing one or two mismatches with respect to t and t'.

Efficient Gene Transfer into the Mouse Lung by Fetal Intratracheal Injection of RAAV2/6.2

Fetal gene therapy is one of the possible new therapeutic strategies for congenital or perinatal diseases with high mortality or morbidity. We developed a novel delivery strategy to inject directly into the fetal mouse trachea. Intratracheal (i.t.) injection at embryonic day 18 (E18) was more efficient in targeting the fetal lung than conventional intra-amniotic (i.a.) delivery. Viral vectors derived from adeno-associated virus serotype 6.2, with tropism for the airway epithelium and not earlier tested in the fetal mouse lung, were injected into the fetal trachea. Bioluminescence (BL) imaging (BLI) was combined with magnetic resonance (MR) imaging (MRI) for noninvasive and accurate localization of transgene expression in vivo. Histological analysis for β-galactosidase (β-gal) revealed 17.5% of epithelial cells transduced in the conducting airways and 1.5% in the alveolar cells. Stable gene expression was observed up to 1 month after injection. This study demonstrates that direct injection of rAAV2/6.2 in the fetal mouse trachea is superior to i.a. delivery for transducing the lung. Second, as stable gene transfer was detected up to 1 postnatal month, this approach may be useful to evaluate fetal gene therapy for pulmonary diseases such as cystic fibrosis, requiring both substantial numbers of transduced cells as well as prolonged gene expression to obtain a stable phenotypic effect.

Breakdown of Thermodynamic Equilibrium for DNA Hybridization in Microarrays

Test experiments of hybridization in DNA microarrays show systematic deviations from the equilibrium isotherms. We argue that these deviations are due to the presence of a partially hybridized long-lived state, which we include in a kinetic model. Experiments confirm the model predictions for the intensity vs free-energy behavior. The existence of slow relaxation phenomena has important consequences for the specificity of microarrays as devices for the detection of a target sequence from a complex mixture of nucleic acids.

Three Cases of Severe Metformin-related Lactic Acidosis

Fetal Surgery is a Clinical Reality

An increasing number of fetal anomalies are being diagnosed prior to birth, some of them amenable to fetal surgical intervention. We discuss the current clinical status and recent advances in endoscopic and open surgical interventions. In Europe, fetoscopic interventions are widely embraced, whereas the uptake of open fetal surgery is much less. The indications for each access modality are different, hence they cannot substitute each other. Although the stage of technical experimentation is over, most interventions remain investigational. Today there is level I evidence that fetoscopic laser surgery for twin-to-twin transfusion syndrome is the preferred therapy, but this operation actually takes place on the placenta. In terms of surgery on the fetus, an increasingly frequent indication is severe congenital diaphragmatic hernia as well as myelomeningocele. Overall maternal safety is high, but rupture of the membranes and preterm delivery remain a problem. The increasing application of fetal surgery and its mediagenicity has triggered the interest to embark on fetal surgical therapy, although the complexity as well as the overall rare indications are a limitation to sufficient experience on an individual basis. We plead for increased exchange between high volume units and collaborative studies; there may also be a case for self-regulation. Inclusion of patients into trials whenever possible should be encouraged rather than building up casuistic experience.

From Hybridization Theory to Microarray Data Analysis: Performance Evaluation

Several preprocessing methods are available for the analysis of Affymetrix Genechips arrays. The most popular algorithms analyze the measured fluorescence intensities with statistical methods. Here we focus on a novel algorithm, AffyILM, available from Bioconductor, which relies on inputs from hybridization thermodynamics and uses an extended Langmuir isotherm model to compute transcript concentrations. These concentrations are then employed in the statistical analysis. We compared the performance of AffyILM and other traditional methods both in the old and in the newest generation of GeneChips.

The Quantitative Genetics of Incipient Speciation: Heritability and Genetic Correlations of Skeletal Traits in Populations of Diverging Favia Fragum Ecomorphs

Recent speciation events provide potential opportunities to understand the microevolution of reproductive isolation. We used a marker-based approach and a common garden to estimate the additive genetic variation in skeletal traits in a system of two ecomorphs within the coral species Favia fragum: a Tall ecomorph that is a seagrass specialist, and a Short ecomorph that is most abundant on coral reefs. Considering both ecomorphs, we found significant narrow-sense heritability (h(2) ) in a suite of measurements that define corallite architecture, and could partition additive and nonadditive variation for some traits. We found positive genetic correlations for homologous height and length measurements among different types of vertical plates (costosepta) within corallites, but negative correlations between height and length within, as well as between costosepta. Within ecomorphs, h(2) estimates were generally lower, compared to the combined ecomorph analysis. Marker-based estimates of h(2) were comparable to broad-sense heritability (H) obtained from parent-offspring regressions in a common garden for most traits, and similar genetic co-variance matrices for common garden and wild populations may indicate relatively small G × E interactions. The patterns of additive genetic variation in this system invite hypotheses of divergent selection or genetic drift as potential evolutionary drivers of reproductive isolation.

Computing Equilibrium Concentrations for Large Heterodimerization Networks

We consider a chemical reaction network governed by mass action kinetics and composed of N different species which can reversibly form heterodimers. A fast iterative algorithm is introduced to compute te equilibrium concentrations of such networks. We show that the convergence is guaranteed by the Banach fixed point theorem. As a practical example of relevance for a quantitative analysis of microarray data, we consider a reaction network formed by N~10(6) mutually hybridizing different mRNA sequences. We show that, despite the large number of species involved, the convergence to equilibrium is very rapid for most species. The origin of slow convergence for some specific subnetworks is discussed. This provides some insights for improving the performance of the algorithm.

The Inability to Perform a 6 Minute Walking Test After Cardio-thoracic Surgery is a Marker of Clinical Severity and Poor Outcome. Data from the ISYDE-2008 Italian Survey

Can AFLP Genome Scans Detect Small Islands of Differentiation? The Case of Shell Sculpture Variation in the Periwinkle Echinolittorina Hawaiiensis

Genome scans have identified candidate regions of the genome undergoing selection in a wide variety of organisms, yet have rarely been applied to broadly dispersing marine organisms experiencing divergent selection pressures, where high recombination rates can reduce the extent of linkage disequilibrium (LD) and the ability to detect genomic regions under selection. The broadly dispersing periwinkle Echinolittorina hawaiiensis exhibits a heritable shell sculpture polymorphism that is correlated with environmental variation. To elucidate the genetic basis of phenotypic variation, a genome scan using over 1000 AFLP loci was conducted on smooth and sculptured snails from divergent habitats at four replicate sites. Approximately 5% of loci were identified as outliers with Dfdist, whereas no outliers were identified by BayeScan. Closer examination of the Dfdist outliers supported the conclusion that these loci were false positives. These results highlight the importance of controlling for Type I error using multiple outlier detection approaches, multitest corrections and replicate population comparisons. Assuming shell phenotypes have a genetic basis, our failure to detect outliers suggests that the life history of the target species needs to be considered when designing a genome scan.

Nonequilibrium Effects in DNA Microarrays: a Multiplatform Study

It has recently been shown that in some DNA microarrays the time needed to reach thermal equilibrium may largely exceed the typical experimental time, which is about 15 h in standard protocols (Hooyberghs et al. Phys. Rev. E2010, 81, 012901). In this paper we discuss how this breakdown of thermodynamic equilibrium could be detected in microarray experiments without resorting to real time hybridization data, which are difficult to implement in standard experimental conditions. The method is based on the analysis of the distribution of fluorescence intensities I from different spots for probes carrying base mismatches. In thermal equilibrium and at sufficiently low concentrations, log I is expected to be linearly related to the hybridization free energy ΔG with a slope equal to 1/RT(exp), where T(exp) is the experimental temperature and R is the gas constant. The breakdown of equilibrium results in the deviation from this law. A model for hybridization kinetics explaining the observed experimental behavior is discussed, the so-called 3-state model. It predicts that deviations from equilibrium yield a proportionality of log I to ΔG/RT(eff). Here, T(eff) is an "effective" temperature, higher than the experimental one. This behavior is indeed observed in some experiments on Agilent arrays [Hooyberghs et al. Phys. Rev. E2010, 81, 012901 and Hooyberghs et al. Nucleic Acids Res. 2009, 37, e53]. We analyze experimental data from two other microarray platforms and discuss, on the basis of the results, the attainment of equilibrium in these cases. Interestingly, the same 3-state model predicts a (dynamical) saturation of the signal at values below the expected one at equilibrium.

Efficient and Stable Transduction of Dopaminergic Neurons in Rat Substantia Nigra by RAAV 2/1, 2/2, 2/5, 2/6.2, 2/7, 2/8 and 2/9

Dysfunction of the nigrostriatal system is the major cause of Parkinson's disease (PD). This brain region is therefore an important target for gene delivery aiming at disease modeling and gene therapy. Recombinant adeno-associated viral (rAAV) vectors have been developed as efficient vehicles for gene transfer into the central nervous system. Recently, several serotypes have been described, with varying tropism for brain transduction. In light of the further development of a viral vector-mediated rat model for PD, we performed a comprehensive comparison of the transduction and tropism for dopaminergic neurons (DNs) in the adult Wistar rat substantia nigra (SN) of seven rAAV vector serotypes (rAAV 2/1, 2/2, 2/5, 2/6.2, 2/7, 2/8 and 2/9). All vectors were normalized by titer and volume, and stereotactically injected into the SN. Gene expression was assessed non-invasively and quantitatively in vivo by bioluminescence imaging at 2 and 5 weeks after injection, and was found to be stable over time. Immunohistochemistry at 6 weeks following injection revealed the most widespread enhanced green fluorescence protein expression and the highest number of positive nigral cells using rAAV 2/7, 2/9 and 2/1. The area transduced by rAAV 2/8 was smaller, but nevertheless almost equal numbers of nigral cells were targeted. Detailed confocal analysis revealed that serotype 2/7, 2/9, 2/1 and 2/8 transduced at least 70% of the DNs. In conclusion, these results show that various rAAV serotypes efficiently transduce nigral DNs, but significant differences in transgene expression pattern and level were observed.

Estimation of Mating Systems in Short and Tall Ecomorphs of the Coral Favia Fragum

We used 15 microsatellite markers to estimate the selfing rate (s), outcrossing rate (t(O) ) and hybridization between partially sympatric ecomorphs (t(H) ) of the coral Favia fragum. Genotyping of progeny arrays revealed complete self-fertilization in the Tall ecomorph and low outcrossing (t(O)  + t(H)  < 1%) in the Short ecomorph. Further, all larvae could be assigned with high probability to the same population as their parental dam, indicating no hybridization between ecomorphs (t(H)  = 0). Despite low ecological estimates of outcrossing, Q values from highly structured adult populations indicated that 9% of the adult samples were the products of outcrossing, and an additional 11% were hybrids. Reproductive isolation appears to have a strong geographical component, as we did not detect hybrids at a second site where the two ecomorphs were distributed in complete microallopatry. Adult estimates of gene flow within ecomorphs may be positively biased by ecomorph-specific patterns of inbreeding depression, but cryptic gene flow between ecomorphs is most likely explained by undetected outcrossing and the fact that hybrid lineages persist after repeated generations of self-fertilization. Our microsatellite data show that phenotypic differences between ecomorphs are maintained in sympatry despite evidence for hybridization.

Protection of Pigs Against Chlamydia Trachomatis Challenge by Administration of a MOMP-based DNA Vaccine in the Vaginal Mucosa

Plasmid DNA (pWRG7079::MOMP) expressing the major outer membrane protein of a human Chlamydia trachomatis serovar E strain was tested for the ability to induce an immune response and protect against experimental genital infection with the same serovar. The vaccine was tested in pigs, as they are genetically and physiologically related to humans and suitable for studying C. trachomatis infection of the genital system. To increase the immune response, GM-CSF, LTA and B and CpG motives were used as adjuvants. GM-CSF was administered seven days before immunization, while the other adjuvants were administered together with the vaccine. Ten pigs were randomly divided into two groups. One group received an intravaginal primo-vaccination and a booster of 500 μg pWRG7079::MOMP, while the other group received the placebo vaccine pWRG7079. All animals were challenged with 10(8) TCID(50) of C. trachomatis serovar E. Pigs immunized with the DNA vaccine showed significantly less macroscopic lesions, vaginal excretion and chlamydial replication in the genital tract, as compared to placebo-vaccinated controls. However, infection could not be completely cleared.

The West Pacific Diversity Hotspot As a Source or Sink for New Species? Population Genetic Insights from the Indo-Pacific Parrotfish Scarus Rubroviolaceus

We used a population genetic approach to quantify major population subdivisions and patterns of migration within a broadly distributed Indo-Pacific parrotfish. We genotyped 15 microsatellite loci in Scarus rubroviolaceus collected from 20 localities between Africa and the Americas. A STRUCTURE model indicates the presence of four major populations: Eastern Pacific, Hawaii, Central-West Pacific and a less well-differentiated Indian Ocean. We used the isolation and migration model to estimate splitting times, population sizes and migration patterns between sister population pairs. To eliminate loci under selection, we used BayeScan to select loci for three isolation and migration models: Eastern Pacific and Central-West Pacific, Hawaii and the Central-West Pacific, and Indian Ocean and the Central-West Pacific. To test the assumption of a stepwise mutation model (SMM), we used likelihood to test the SMM against a two-phase model that allowed mutational complexity. A posteriori, minor departures from SMM were estimated to affect ≤2% of the alleles in the data. The data were informative about the contemporary and ancestral population sizes, migration rates and the splitting time in the eastern Pacific/Central-West Pacific comparison. The model revealed a splitting time ∼17,000 BP, a larger contemporary N(e) in the Central-West Pacific than in the eastern Pacific and a strong bias of east to west migration. These characteristics support the Center of Accumulation model of peripatric diversification in low-diversity peripheral sites and perhaps migration from those sites to the western Pacific diversity hotspot.

Differences in Habitual Physical Activity Levels of Young People with Cerebral Palsy and Their Typically Developing Peers: a Systematic Review

Purpose: To systematically review and compare the daily habitual physical activity levels and sedentary times of young people with cerebral palsy to their typically developing peers and to physical activity guidelines. Method: After searching electronic databases, two reviewers independently applied criteria. Studies were required to include young people with cerebral palsy (up to 18 years) and to quantitatively measure habitual physical activity, defined as activity across at least one day. Data extraction was independently verified, and quality analysis completed by two reviewers. Results: Of 895 identified studies, six moderate to high quality studies were included. There were four measures of habitual physical activity. Participants were aged 5 to 18 years and typically had moderate to high gross motor function. Across all ages and levels of motor function, young people with cerebral palsy participated in 13% to 53% less habitual physical activity than their peers. Levels of activity were approximately 30% lower than guidelines. Sedentary times were twice the maximum recommended amount. Conclusions: Young people with cerebral palsy participate in significantly lower levels of habitual physical activity than their peers, and less than recommended guidelines. Long-term negative health consequences of inactivity such as metabolic dysfunction, cardiovascular disease and poor bone density are therefore more likely. [Box: see text].

Fractional Brownian Motion and the Critical Dynamics of Zipping Polymers

We consider two complementary polymer strands of length L attached by a common-end monomer. The two strands bind through complementary monomers and at low temperatures form a double-stranded conformation (zipping), while at high temperature they dissociate (unzipping). This is a simple model of DNA (or RNA) hairpin formation. Here we investigate the dynamics of the strands at the equilibrium critical temperature T=T_{c} using Monte Carlo Rouse dynamics. We find that the dynamics is anomalous, with a characteristic time scaling as τ∼L^{2.26(2)}, exceeding the Rouse time ∼L^{2.18}. We investigate the probability distribution function, velocity autocorrelation function, survival probability, and boundary behavior of the underlying stochastic process. These quantities scale as expected from a fractional Brownian motion with a Hurst exponent H=0.44(1). We discuss similarities to and differences from unbiased polymer translocation.

[Atherosclerosis of the Lower Extremities As a Linked Comorbidity in Patients Admitted for Cardiac Rehabilitation (THINKPAD): Rationale, Design, and Study Group]

Peripheral arterial disease (PAD) is a frequent comorbidity among patients entering cardiac rehabilitation (CR) programmes and an important source of disability and impaired prognosis. The prevalence of PAD across the wide range of conditions for CR is poorly understood, as far as its impact on drug optimization and intervention delivered. The "ATHerosclerosis of the lower extremities as a liNKed comorbidity in Patients Admitted for carDiac rehabilitation" (THINKPAD) study was carried out by the Italian Association for Cardiovascular Prevention, Rehabilitation and Epidemiology (GICR-IACPR) in order to explore PAD both as a comorbidity and a primary indication at the entry of CR. The study was a retrospective case series. In the study period (from May 1, 2012 to June 30, 2012), data on consecutive patients discharged from 17 CR units in Northern Italy were collected. Web-based electronic case report forms (e-CRF), accessible in a dedicated section of the IACPR website (www.iacpr.it), were used for data entry, and data were transferred via web to a central database. The data collection instrument was designed with a multiple choice format, with jump menus or select boxes and obligatory items. A sample size of 1,300 subjects is expected, with first data available by the end of 2012.

Molecules and Fossils Reveal Punctuated Diversification in Caribbean "faviid" Corals

Even with well-known sampling biases, the fossil record is key to understanding macro-evolutionary patterns. During the Miocene to Pleistocene in the Caribbean Sea, the fossil record of scleractinian corals shows a remarkable period of rapid diversification followed by massive extinction. Here we combine a time-calibrated molecular phylogeny based on three nuclear introns with an updated fossil stratigraphy to examine patterns of radiation and extinction in Caribbean corals within the traditional family Faviidae.

Probing Hybridization Parameters from Microarray Experiments: Nearest-neighbor Model and Beyond

In this article, it is shown how optimized and dedicated microarray experiments can be used to study the thermodynamics of DNA hybridization for a large number of different conformations in a highly parallel fashion. In particular, free energy penalties for mismatches are obtained in two independent ways and are shown to be correlated with values from melting experiments in solution reported in the literature. The additivity principle, which is at the basis of the nearest-neighbor model, and according to which the penalty for two isolated mismatches is equal to the sum of the independent penalties, is thoroughly tested. Additivity is shown to break down for a mismatch distance below 5 nt. The behavior of mismatches in the vicinity of the helix edges, and the behavior of tandem mismatches are also investigated. Finally, some thermodynamic outlying sequences are observed and highlighted. These sequences contain combinations of GA mismatches. The analysis of the microarray data reported in this article provides new insights on the DNA hybridization parameters and can help to increase the accuracy of hybridization-based technologies.

Fractional Brownian Motion and the Critical Dynamics of Zipping Polymers

We consider two complementary polymer strands of length L attached by a common-end monomer. The two strands bind through complementary monomers and at low temperatures form a double-stranded conformation (zipping), while at high temperature they dissociate (unzipping). This is a simple model of DNA (or RNA) hairpin formation. Here we investigate the dynamics of the strands at the equilibrium critical temperature T=T(c) using Monte Carlo Rouse dynamics. We find that the dynamics is anomalous, with a characteristic time scaling as τ∼L(2.26(2)), exceeding the Rouse time ∼L(2.18). We investigate the probability distribution function, velocity autocorrelation function, survival probability, and boundary behavior of the underlying stochastic process. These quantities scale as expected from a fractional Brownian motion with a Hurst exponent H=0.44(1). We discuss similarities to and differences from unbiased polymer translocation.

Impact of Intensive Upper Limb Rehabilitation on Quality of Life: a Randomized Trial in Children with Unilateral Cerebral Palsy

The aim of this study was to determine whether constraint-induced movement therapy is more effective than bimanual training in improving the quality of life of children with unilateral cerebral palsy (CP).

Hip and Thigh Anatomy of the Clouded Leopard (Neofelis Nebulosa) with Comparisons to the Domestic Cat (Felis Catus)

The clouded leopard (N. nebulosa) is an endangered felid native to Southeast Asia. It is considered to be the largest and most acrobatic of the arboreal cats. To date, published studies have focused on cranial morphology, particularly osteology and dentition. This study describes the hip and thigh morphology of N. nebulosa and compares it to the domestic cat (F. catus). A number of statistically significant differences were observed between N. nebulosa and F. catus that were primarily associated with muscle attachment surface areas rather than differences in overall morphology. F. catus had proportionally larger attachment areas for Mm. gluteus profundus, tensor fasciae latae, and biceps femoris, while N. nebulosa had larger attachment areas for Mm. gluteus medius, rectus femoris, and semitendinosus. By comparison, surface area analysis of nonfelid species (C. latrans and V. vulpes) showed more differences when compared to felids demonstrating that this analytical technique is useful for differentiating closely-related species from more distant ones. These results suggest that muscle map area analysis may be useful for comparing phylogenetic relationships between and within groups of different species and may also suggest variations in locomotor habits.

Fatal Mitral Valve Endocarditis Following a Papanicolaou Test

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