Growth hormone secretagogues: characterization, efficacy, and minimal bioactive conformation.

Another class of growth hormone (GH) secretagogues has been discovered by altering the backbone structure of a flexible linear GH-releasing peptide (GHRP). In vitro and in vivo characterization confirms these GH secretagogues as the most potent and smallest (M(r) < 500) reported. Anabolic efficacy is demonstrated in rodents with intermittent delivery. A convergent model of the bioactive conformation of GHRPs is developed and is supported by the NMR structure of a highly potent cyclic analog of GHRP-2. The model and functional data provide a logical framework for the further design of low-molecular weight secretagogues and illustrate the utility of an interdisciplinary approach to elucidating potential bound-state conformations of flexible peptide ligands.     

Artificial neural networks improve the prediction of Kt/V, follow-up dietary protein intake and hypotension risk in haemodialysis patients.

BACKGROUND: Artificial neural networks (ANN) represent a promising alternative to classical statistical and mathematical methods to solve multidimensional non-linear problems. The aim of the study was to compare the performance of ANN in predicting the dialysis quality (Kt/V), the follow-up dietary protein intake and the risk of intradialytic hypotension in haemodialysis patients with that predicted by experienced nephrologists. METHODS: A combined retrospective and prospective observational study was performed in two Swiss dialysis units (80 chronic haemodialysis patients, 480 monthly clinical observations and biochemical test results). Using mathematical models based on linear and logistic regressions as background, ANN were built and then prospectively compared with the ability of six experienced nephrologists to predict the Kt/V and the follow-up protein catabolic rate (PCR) and to detect a Kt/V < 1.30, a follow-up PCR < 1.00 g/kg/day and the occurrence of hypotension. RESULTS: ANN compared with nephrologists gave a more accurate correlation between estimated and calculated Kt/V and follow-up PCR (P<0.001). The same superiority of ANN was also seen in the ability to detect a Kt/V < 1.30, a follow-up PCR < 1.00 g/kg/day and the occurrence of hypotension expressed as a percentage of correct answers, sensitivity, specificity and predictivity. CONCLUSIONS: The use of ANN significantly improves the ability of experienced nephrologists to estimate the Kt/V and the follow-up PCR and to detect a Kt/V < 1.30, a follow-up PCR < 1.00 g/kg/day and the occurrence of intradialytic hypotension.     

Immunohistochemical evaluation of uveal melanocytic tumors. Expression of HMB-45, S-100 protein, and neuron-specific enolase

The authors compared the immunohistochemical reactivity of 13 uveal nevi and 20 uveal melanomas for HMB-45, S-100 protein, and neuron-specific enolase (NSE) in formalin-fixed, paraffin-embedded sections. All 33 of the lesions were positive for HMB-45. The false-negative rates for S-100 protein and NSE were 21% and 18%, respectively. If only strongly positive reactions were considered, more than 50% of the tumors would be interpreted as negative for S-100 protein and NSE. Nevi stained with less intensity than melanomas using all three antibodies. The expression of HMB-45 appeared to be greater in active nevi than in inactive nevi. There was a weak association between S-100 protein reactivity and the ability of the uveal melanomas to metastasize (P = 0.1); however, the standard deviation of nucleolar area was a much better predictor (P = 0.02). These results indicate that pathologists will find HMB-45 to be a useful tool in differentiating uveal melanoma from nonmelanocytic tumors.     

Identification of Toxoplasma gondii in paraffin-embedded sections by the polymerase chain reaction

We used the polymerase chain reaction to amplify DNA fragments specific to Toxoplasma gondii. The sensitivity of the technique allowed for the detection of as few as ten cultured T. gondii tachyzoites. We applied the same amplification technique to deparaffinized ocular sections from two cases of ocular toxoplasmosis. Although toxoplasmic cysts could only be seen in one eye by optical microscopy, polymerase chain reaction allowed the identification of the parasite in both cases. Our study indicates the feasibility of a sensitive DNA-based assay to complement pathologic studies of an ocular parasitic disease.     

Clinical Profiles and Factors Associated with a Low Sodium Intake in the Population: An Analysis of the Swiss Survey on Salt

As a part of the salt controversy, it has been suggested that people with a low sodium intake have an increased risk of cardiovascular events. However, there is no clear explanation for this increased risk. We examined the socio-demographic, clinical profile, and behavioral factors associated with a low sodium intake in the Swiss subjects who participated in the Swiss Survey on Salt. Only 13.3% of the Swiss population eat less than 5 g of salt daily and among them 78.2% are women. Subjects with a low sodium intake eat and drink less as reflected by lower intakes of proteins, potassium, and calcium and a smaller urine volume. In addition, a low blood pressure, a normal body mass index, a low prevalence of obesity, a low serum uric acid, and less alcohol and cigarette consumption characterized this group, suggesting a rather low cardiovascular risk profile. Being single and doing most of the cooking at home are associated with a low intake of sodium, as well as a less frequent consumption of meat and fish when eating less than 5 g salt per day. However, the awareness of the effects of salt on health and cardiovascular risk, health concerns, and physical activity are similar in subjects eating more or less salt. In conclusion, we could not evidence clinical or behavioral factors that could significantly increase the risk of developing cardiovascular events in low salt eaters.     

Angiotensin II receptor antagonists - antihypertensive agents

Blockade of the renin-angiotensin system (RAS) is now recognised as an effective approach for the treatment of hypertension and congestive heart failure (CHF). Today, it is possible to antagonise the effects of angiotensin II more specifically by blocking its receptors using non-peptide receptor antagonists. These compounds, which at first were used to identify the various subtypes of angiotensin II receptors, are now available clinically. Some of them have recently been launched on the market and several others are preregistered for the treatment of hypertension. These new molecules are as effective as angiotensin converting enzyme (ACE) inhibitors at lowering blood pressure in hypertensive patients, and appear to have similar systemic and renal haemodynamic properties in patients with CHF and renal diseases. Large-scale clinical trials such as the LIFE, the ELITE and the RENAAL studies are now underway to investigate the long-term benefits of one of these agents in hypertension, heart failure and Type II diabetic nephropathy. The major clinical advantage of AT1 receptor antagonists is that, in contrast to ACE inhibitors, they do not induce cough. With the more widespread use of AT1 receptor antagonists, two unresolved questions remains unanswered: what is the role of AT2 receptors? Are the unblocked effects of angiotensin II on AT2 receptor sites of any clinical relevance to the safety profile or efficacy of AT1 receptor antagonists? Another interesting question is whether the combination of an ACE inhibitor with an AT1 receptor antagonist is advantageous. Studies attempting to answer these questions are underway and will certainly enable researchers to define more precisely the role and the advantages of these new specific non-peptide AT1 receptor antagonists in the treatment of hypertension and heart failure.     

Inflammatory cellular kinetics in sympathetic ophthalmia a study of 29 traumatized (exciting) eyes

An immunohistochemical study was conducted on 29 cases of sympathetic ophthalmia (SO). Monoclonal antibodies against T, B, NK cells, macrophages, and MHC class II antigen (HLA-DR) were used. The choroidal infiltrate in 20 eyes was predominantly T cell while B cell predominated in four cases. All eyes with a B cell predominance came from males. A predominance of B cells was correlated to a longer duration of the disease (> 9 months) and in eyes showing phthisical changes. There was no correlation between a predominance of B cells with age, race, corticosteroid treatment or histological type (typical or atypical). These findings suggest that, although SO is a T cell mediated disease, the predominance of B cells in some cases may represent the end stage of the disease process, or seems a secondary pathological process. The kinetic change in cell populations during the disease may have therapeutic implication.     

Antibody SPC-54 provides acute in vivo blockage of the murine protein C system

Multiple protective effects of pharmacological activated protein C (APC) are reported in several organ pathologies. To help evaluate the endogenous murine PC system, we characterized a rat monoclonal anti-mouse PC antibody, SPC-54, which inhibited the amidolytic and anticoagulant activities of murine APC by > 95%. SPC-54 blocked active site titration of purified APC using the active site titrant, biotinylated FPR-chloromethylketone, showing that SPC-54 blocks access to APC's active site to inhibit all enzymatic activity. A single injection of SPC-54 (10 mg/kg) neutralized circulating PC in mice for at least 7 days, and immunoblotting and immuno-precipitation with protein G-agarose confirmed that SPC-54 in vivo was bound to PC in plasma. Pre-infusion of SPC-54 in tissue factor-induced murine acute thromboembolism experiments caused a major decrease in mean survival time compared to controls (7 min vs. 42.5 min, P = 0.0016). SPC-54 decreased lung perfusion in this model by 54% when monitored by vascular perfusion methodologies using infrared fluorescence of Evans blue dye. In LD50 endotoxemia murine models, SPC-54 infused at 7 hr after endotoxin administration increased mortality from 42% to 100% (P < 0.001). In summary, monoclonal antibody SPC-54 ablates in vitro and in vivo APC protective functions and enzymatic activity. The ability of SPC-54 to block the endogenous PC/APC system provides a powerful tool to understand better the role of the endogenous PC system in murine injury models and in cell bioassays and also to neutralize the enzymatic activities of murine APC in any assay system.