Peter Agre, 2003 Nobel Prize winner in chemistry

Peter C. Agre, an American Society of Nephrology member, is the recipient of the 2003 Nobel Prize in Chemistry for his discovery of the aquaporin water channels. The function of many cells requires that water move rapidly into and out of them. There was only indirect evidence that proteinaceous channels provide this vital activity until Agre and colleagues purified aquaporin-1 from human erythrocytes and reported its cDNA sequence. They proved that aquaporin-1 is a specific water channel by cRNA expression studies in Xenopus oocytes and by functional reconstitution of transport activity in liposomes after the incorporation of the purified protein. These findings sparked a veritable explosion of work that affects several long-standing areas of investigation such as the biophysics of water permeation across cell membranes, the structural biology of integral membrane proteins, the physiology of fluid transport in the kidney and other organs, and the pathophysiological basis of inherited and acquired disorders of water balance. Agre's discovery of the first water channel has spurred a revolution in animal and plant physiology and in medicine.     

The roles of insulin and hyperglycemia in sepsis pathogenesis

Hyperglycemia is a risk marker of morbidity and mortality in acute critical illness, and insulin therapy seems to be beneficial in this patient group. Whether this is true for a population of sepsis patients, as such, has not been investigated in clinical trials, but evidence from in vitro studies and experimental sepsis suggests that this may be the case. The endocrinology of septic patients is characterized by a shift in the balance between insulin and its counter-regulatory hormones favoring the latter. This leads to prominent metabolic derangements composed of high release and low use of glucose, amino acids, and free fatty acids (FFA), resulting in increased blood levels of these substrates. Circulating, proinflammatory mediators further enhance this state of global catabolism. Increased levels of glucose and FFA have distinct effects on inflammatory signaling leading to additional release of proinflammatory mediators and endothelial and neutrophil dysfunction. Insulin has the inherent capability to counteract the metabolic changes observed in septic patients. Concomitantly, insulin therapy may act as a modulator of inflammatory pathways inhibiting the unspecific, inflammatory activation caused by metabolic substrates. Given these properties, insulin could conceivably be serving a dual purpose for the benefit of septic patients.     

Device-based left ventricular geometry change for heart failure treatment: developmental work and current status

Abstract Background: Device‐based left ventricular (LV) geometry change is a new concept in the treatment of heart failure that reduces LV wall stress and improves cardiac function by reducing effective LV radius. Ventricular geometry change is achieved by placement of three Myosplint® devices to bisect the LV and to create two smaller LV chambers. Methods and Results: Since the first animal experiment in June 1997, the Myosplint has been tested extensively in a series of animal studies using a pacing‐induced, canine dilated cardiomyopathy model. Device‐based LV geometry change decreased LV wall stress, improved systolic function, and maintained diastolic function, resulting in an improvement in myocardial energetics. An acute human feasibility study during heart transplant surgery was started in July 1999. While awaiting the arrival of the donor heart, the Myosplint was implanted in the recipient LV in 5 patients. The device was easily applied on a beating heart without complications related to the device or the procedure in any of the patients. LV wall stress was significantly decreased after tightening of the device. Clinical safety studies with chronic Myosplint implantation were begun in Germany in June 2000 and in the United States in February 2001. There have been a total of 21 patients receiving the implant without evidence of bleeding, muscle tearing, severe arrhythmia, or thrombus formation associated with the implant. Conclusions: Device‐based geometry change has been demonstrated to be practical, effective, and safe. (J CARD SURG 2003;18 (Suppl 2):S43‐S47)     

Flow associated (endothelium dependent) vasodilation and TSH-levels in young normotensive and normoglycemic subjects.

BACKGROUND: Endothelial dysfunction (ED) is regarded as an early step in the development of atherosclerosis. Recent experimental data showed a crosstalk between endothelial NO-synthase activity and thyrotropin production. Therefore we studied whether basal TSH can predict flow associated vasodilation (FAD) in a cohort of healthy young subjects with normal TSH levels. PATIENTS AND METHODS: FAD was evaluated in 60 normotensive and normoglycemic subjects (mean age 34 years; range 18-50). The mean thyrotropin level was 1.43 +/- 0.11 microU/ml (range 0.18-3.52 microU/ml). RESULTS: Comparing subjects in the upper, middle and lower tertile of TSH (2.38 +/- 0.14 microU/ml, 1.23 +/- 0.04 microU/ml and 0.65 +/- 0.06 microU/ml respectively) there was no difference in terms of the classical cardiovascular risk factor profiles (24 h blood pressure, HDL- and LDL-cholesterol, triglycerides, oral glucose load and body fat content). Regarding the vascular parameters, we could neither find an independent association with FAD (7.0 +/- 1.1%, 6.4 +/- 1.0% and 5.8 +/- 1.1% respectively) nor with endothelial independent vasodilation (after application of glycerol trinitrate GTN, 17.3 +/- 1.9%, 18.4 +/- 1.7% bzw. 17.5 +/- 1.6% respectively) between the groups. Furthermore, we could not find a significant association between free thyroid hormones (fT3/fT4) and FAD or GTN-induced vasodilation. CONCLUSION: TSH has no predictive value towards endothelial dysfunction in subjects with thyrotropin levels within the normal range.     

Dual-Stage Picolinic Acid-Derived Inhibitors of Toxoplasma gondii

Toxoplasma gondii causes a prevalent human infection for which only the acute stage has an FDA-approved therapy. To find inhibitors of both the acute stage parasites and the persistent cyst stage that causes a chronic infection, we repurposed a compound library containing known inhibitors of parasitic hexokinase, the first step in the glycolysis pathway, along with a larger collection of new structural derivatives. The focused screen of 22 compounds showed a 77% hit rate (>50% multistage inhibition) and revealed a series of aminobenzamide-linked picolinic acids with submicromolar potency against both T. gondii parasite forms. Picolinic acid 23, designed from an antiparasitic benzamidobenzoic acid class with challenging ADME properties, showed 60-fold-enhanced solubility, a moderate LogD_7.4, and a 30% improvement in microsomal stability. Furthermore, isotopically labeled glucose tracing revealed that picolinic acid 23 does not function by hexokinase inhibition. Thus, we report a new probe scaffold to interrogate dual-stage inhibition of T. gondii.     

Diversity of Francisella tularensis Schu4 antigens recognized by T lymphocytes after natural infections in humans: identification of candidate epitopes for inclusion in a rationally designed tularemia vaccine

The T lymphocyte antigens, which may have a role in protection against tularemia, were predicted by immunoinformatics analysis of Francisella tularensis Schu4. Twenty-seven class II putative promiscuous epitopes and 125 putative class I supertype epitopes were chosen for synthesis; peptides were tested in vitro for their ability to bind HLA and to induce immune responses from PBMCs of 23 previously infected subjects. While the immune responses of individual subjects showed heterogeneity, 95% of the subjects responded strongly to a pool of 27 promiscuous peptides; 25%, 33%, and 44% of subjects responded to pools of 25 A2, A24, and B7 peptides, respectively. These data can aid in the development of novel epitope-based and subunit tularemia vaccines.     

NoiseChem: an European Commission research project on the effects of exposure to noise and industrial chemicals on hearing and balance

Exposure to multiple physical and chemical agents is common in occupational environments but workplace hazards and occupational safety criteria for combined exposures are lacking. NoiseChem is an European Commission research project examining the effects of exposure to noise and chemicals on hearing and balance. Partners in Sweden, Finland, France, Denmark, UK and Poland with expert guidance from partners in the USA will examine workers and study the mechanisms of action in animals to determine the levels of risk associated with joint exposure to noise and solvents. This paper briefly outlines the project details.     

NoiseChem: An European Commission research project on the effects of exposure to noise and industrial chemicals on hearing and balance

Exposure to multiple physical and chemical agents is common in occupational environments but workplace hazards and occupational safety criteria for combined exposures is lacking. NoiseChem is an European Commission research project examining the effects of exposure to noise and chemicals on hearing and balance. Partners in Sweden, Finland, France, Denmark, UK and Poland with expert guidance from partners in USA will examine workers and study the mechanisms of action in animals to determine the levels of risk associated with joint exposure to noise and solvents. This paper briefly outlines the project details.     

Urethral pressure variations in healthy females during rest and sleep

Recent studies have shown the occurrence of rhythmic urethral pressure variations (UPV) in the normal female urethra in the awake state. The nature of these variations still needs further elucidation. In this study we investigated the changes in urethral pressure (UP) and in UPV as they occur in healthy females awake and asleep. UPV, intravesical-(IVP) and rectal pressure (RP), together with anal electromyography (EMG) and electroencephalography (EEG) were measured in 10 healthy fertile female volunteers. The registration was done in the awake state, during falling asleep and during sleep. During falling asleep the average urethral pressure as well as the UPV amplitude and frequencies decreased and remained at a lower stable level during sleep. Urethral pressure and its variations seemed to be interrelated since the UPV frequency and amplitude decreased when the average UP decreased. From this study it appears that urethral pressure is influenced by extrinsic factors such as the waking, resting and sleeping states. Although some extrinsic modulation of urethral pressure variations occurs, their persistance in sleep suggests their local nature.