Aortic connective tissue in ageing--a biochemical study

The biochemical analysis of samples of aortic connective tissue was carried out in 22 subjects from 9 to 84 years old. Aortic samples were taken at necropsy performed after sudden or, more often, traumatic death. The results suggest that aging of the aorta is accompanied by an increase both in collagen content and in total sugar content when expressed as mg/cm2 while the elastin content, when expressed in the same way, does not undergo any variation.     

Validation of 20-meter corridor for the 6-minute walk test in men on liver transplantation waiting list

Background

Guidelines established by the American Thoracic Society recommend the use of corridors 30 m in length for the 6-minute walk test (6MWT). However, not all institutions have such long corridors, which hinders or prevents 6MWT performance and use of its benefits.

Objective

To compare the distances walked by male patients with cirrhosis on the liver transplantation waiting list, we performed 6MWT on corridors 20 and 30 m long.

Methods

This prospective study included 10 patients on the waiting list for liver transplantation. They underwent 2 walk tests: the first test in a 20 m corridor and the second in a 30 m corridor. We assessed physiologic variables (heart rate, oxygen saturation, arterial blood pressure) and the subjective sensation of dyspnea at rest at 6 and 9 minutes after each walk. Statistical analysis was performed using the Wilcoxon test.

Results

Data are expressed as mean ± sd. Patient age was 59 ± 10 years. The distances walked by the patients were shorter than those predicted for their age and gender (586 ± 45 m) in both tests, no significant difference was observed between the first and the second 6MWT (437 ± 101 m vs 465 ± 80 m; P = .131) or among the physiologic variables.

Conclusion

We concluded that a 20 m corridor can be used safely and effectively as an alternative to 30 m for the 6MWT for male patients with cirrhosis on the liver transplantation waiting list.     

Itk tyrosine kinase substrate docking is mediated by a nonclassical SH2 domain surface of PLCγ1

Interleukin-2 tyrosine kinase (Itk) is a Tec family tyrosine kinase that mediates signaling processes after T cell receptor engagement. Activation of Itk requires recruitment to the membrane via its pleckstrin homology domain, phosphorylation of Itk by the Src kinase, Lck, and binding of Itk to the SLP-76/LAT adapter complex. After activation, Itk phosphorylates and activates phospholipase C-γ1 (PLC-γ1), leading to production of two second messengers, DAG and IP₃. We have previously shown that phosphorylation of PLC-γ1 by Itk requires a direct, phosphotyrosine-independent interaction between the Src homology 2 (SH2) domain of PLC-γ1 and the kinase domain of Itk. We now define this docking interface using a combination of mutagenesis and NMR spectroscopy and show that disruption of the Itk/PLCγ1 docking interaction attenuates T cell signaling. The binding surface on PLCγ1 that mediates recognition by Itk highlights a nonclassical binding activity of the well-studied SH2 domain providing further evidence that SH2 domains participate in important signaling interactions beyond recognition of phosphotyrosine.     

Atrazine and cancer incidence among pesticide applicators in the agricultural health study (1994-2007)

Background: Atrazine is a triazine herbicide used widely in the United States. Although it is an animal carcinogen, the mechanism in rodents does not appear to operate in humans. Few epidemiologic studies have provided evidence for an association.Methods: The Agricultural Health Study (AHS) is a prospective cohort that includes 57,310 licensed pesticide applicators. In this report, we extend a previous AHS analysis of cancer risk associated with self-reported atrazine use with six additional years of follow-up and more than twice as many cancer cases. Using Poisson regression, we calculated relative risk estimates and 95% confidence intervals for lifetime use of atrazine and intensity-weighted lifetime days, which accounts for factors that impact exposure.Results: Overall, 36,357 (68%) of applicators reported using atrazine, among whom there were 3,146 cancer cases. There was no increase among atrazine users in overall cancer risk or at most cancer sites in the higher exposure categories compared with the lowest. Based on 29 exposed cases of thyroid cancer, there was a statistically significant risk in the second and fourth quartiles of intensity-weighted lifetime days. There was a similar pattern for lifetime days, but neither the risk estimates nor the trend were statistically significant and for neither metric was the trend monotonic.Conclusions: Overall, there was no consistent evidence of an association between atrazine use and any cancer site. There was a suggestion of increased risk of thyroid cancer, but these results are based on relatively small numbers and minimal supporting evidence.     

HLA control of interferon production in the human mixed lymphocyte culture

This report describes studies of interferon production in the human mixed lymphocyte culture. Similar levels of interferon were detectable in two-way, unidirectional, and double-irradiated mixed lymphocyte culture combinations. Following an initial lag period of 1-2 days interferon production showed a peak response on days 3-4 and, in most combinations, was detectable through day 7 of the mixed lymphocyte culture. Interferon-gamma was the predominant type of interferon produced, along with a minor component of interferon activity detectable in some culture combinations which appeared similar to interferon-alpha. Interferon was not produced in HLA identical sibling combinations except for one brother-sister pair who were the donor and recipient of a kidney allograft. Interferon was produced in sibling and unrelated individual combinations that expressed HLA-A, HLA-B, or HLA-DR region incompatibility, with higher concentrations of interferon detectable in the HLA-DR region imcompatible combinations.     

Chemical synthesis and characterization of J46 peptide, an atypical class IIa bacteriocin from Lactococcus lactis subsp. cremoris J46 Strain

Bacteriocin J46 is a 27-residue polypeptide produced by Lactococcus lactis subsp. cremoris J46 in fermented milk. The natural form of J46 (nJ46) exhibits a broad antimicrobial spectrum. Herein, we produced the synthetic form of J46 (sJ46) by solid-phase chemical synthesis. The biochemical and physico-chemical properties of sJ46, as well as its antimicrobial activity, were found to be identical to those of its natural counterpart nJ46. It showed a potent antimicrobial activity against both lactic acid bacteria and other Gram-positive microorganisms. (1)H-NMR conformational analysis of sJ46 indicates that it adopts a flexible random coil structure.     

Dihydropyrrole[2,3-d]pyridine derivatives as novel corticotropin-releasing factor-1 antagonists: mapping of the receptor binding pocket by in silico docking studies

In an effort to discover novel CRF-1 receptor antagonists exhibiting improved physicochemical properties, a dihydropirrole[2,3]pyridine scaffold was designed and explored in terms of the SAR of the substitution at the pendent phenyl ring and the nature of the heterocyclic moieties present in the upper region of the molecule. Selective and potent compounds have been discovered endowed with reduced ClogP with respect to compounds known in the literature. Of particular relevance was the finding that the in vitro affinity of the series was maintained by reducing the overall lipophilicity. The results achieved by this exploration enabled the formulation of a novel hypothesis on the nature of the receptor binding pocket of this class of CRF-1 receptor antagonists, making use of in silico docking studies of the putative nonpeptidic antagonist binding site set up in house by homology modeling techniques.     

Efficacy of duloxetine for the treatment of depression: relationship to most recent antidepressant trial

To describe and examine, in a sample of depressed outpatients, the relationship between level of response to a previous SSRI or SNRI antidepressant trial and subsequent response to duloxetine hydrochloride. Data collected from a multicenter trial that evaluated the safety and efficacy of duloxetine for the treatment of major depressive disorder were analyzed to determine the relationship between response to previous antidepressant treatment and degree of response to duloxetine. Time to first response, first remission, sustained response, and sustained remission during the first 12 weeks of duloxetine treatment were compared across patient groups. Principal Observations: Response and remission with duloxetine treatment ranged between 57 and 68% and 29 and 57%, respectively, and did not differ significantly across previous response levels.