Janus kinase-2 signaling mediates apoptosis in rat cardiomyocytes

We tested the hypothesis that activation Jak2, which is prominently involved in the up-regulation of the renin-angiotensin system (RAS), constitutes a focal point in relaying signals triggered by a Angiotensin II (Ang II) and hypoxia/reoxygenation separately to cause an enhanced susceptibility of cardiac myocyte to apoptotic cell death. Ang II-treated adult cardiomyocytes in culture exhibited an increased level of apoptosis that accompanied activation of pro-apoptotic as well as anti-apoptotic signaling pathways. We observed increased phosphorylation of Jak2 kinase, Stat1, JNK, with increased expression of Bax protein, followed by an increase in caspase-1 and caspase-3 activity. Activation of these pro-apoptotic pathways was blocked by the Jak2 pharmacological inhibitor, Tyrphostin AG490. We also observed an increase in phosphorylation of cardioprotective pathway components, namely S6 ribosomal protein, and heat shock protein 27 (HSP27). Likewise, the oxidative stress, via the hypoxia/reoxygenation treatment of rat adult cardiomyocytes, produced apoptosis that was dependent upon activation of Jak2. The apoptotic response was not only reduced by Losartan, an inverse agonist of the AT1, receptor, but by treatment with AG490 as well. Taken together, these observations provide clear evidence in favor of Jak2 signaling as mediator of the apoptotic response in cardiomyocytes. However, there was a concomitant induction of cytoprotective signaling that presumably provides a negative feed-back to the deleterious effects of the agonist.     

A large 12-month extension study of an 8-week trial to evaluate the safety and efficacy of triple combination (TC) cream in melasma patients previously treated with TC cream or one of its dyads

This was a 12-month extension of a randomized, investigator-blinded, multicenter, 8-week trial with triple combination (TC) cream in facial melasma. A total of 585 patients were enrolled in the study and 569 patients received study medication. Three hundred eighty-nine patients completed 6 months of treatment and 327 patients completed 12 months of treatment. TC cream demonstrated a favorable safety profile: only 14 patients (2.5%) discontinued the study due to treatment-related adverse events (AEs). The 2 cases of skin atrophy were mild and did not lead to withdrawal. From the 23 cases of mild telangiectasia, only 2 resulted in discontinuation. All others were transient. Results confirmed those of a previous smaller study, with both physicians and patients reporting clinically significant improvements in melasma. By month 12, 80% of patients had lesions completely cleared or nearly cleared. Once daily application of TC cream applied intermittently over a long period is a safe, tolerable, and effective treatment for moderate to severe melasma of the face.     

Role of elastase-2 as an angiotensin II-forming enzyme in rat carotid artery

We have described the biochemical, enzymatic, and structural properties of a chymostatin-sensitive angiotensin (Ang) I-converting elastase-2 found in the rat mesenteric arterial bed perfusate. We determined the mRNA for elastase-2 and its relative role in generating Ang II in the rat isolated aorta and carotid artery rings. In carotid rings, the Ang I-induced vasoconstrictor effect was only partially inhibited by captopril or chymostatin, whereas that of tetradecapeptide renin substrate (TDP) was greatly inhibited by chymostatin but unaffected by captopril; however, Ang I- and TDP-induced effects were abolished by the combination of both inhibitors. Effects of [Pro11-D-Ala12]-Ang I (PDA), an Ang I-converting enzyme (ACE)-resistant biologically inactive precursor of Ang II were blocked by chymostatin or N-acetyl-Ala-Ala-Pro-Leu-chloromethylketone (elastase-2 inhibitor) in carotid artery. PDA failed to induce an effect in aortic rings, and Ang I-induced contractions were completely inhibited by captopril. The mRNA for rat elastase-2 was detected in aorta, carotid, and mesenteric arteries, although its expression was found to be less important in aorta. These findings indicate the presence of a functional alternative pathway to ACE for Ang II generation in rat carotid artery and represent strong evidence of a physiological role for elastase-2; however, its functional contribution to Ang II formation in aorta appears to be negligible.     

Increasing use of gonadotropin-releasing hormone agonists for the treatment of localized prostate carcinoma

BACKGROUND: The role of androgen deprivation therapy in prostate carcinoma is controversial in earlier stages of disease. The authors examined the time trends and patterns of use for androgen deprivation in the form of gonadotropin-releasing hormone (GnRH) agonists or orchiectomy, in population-based tumor registries. METHODS: Data were obtained from the linked Surveillance, Epidemiology and End Results-Medicare database. A total of 100,274 men with prostate carcinoma diagnosed from 1991 through 1999 were selected. The main outcome was the proportion of men who received >/= 1 dose of a GnRH agonist in the first 6 months of diagnosis. This was plotted by year and stratified for age, grade, stage as well as primary versus adjuvant usage. Multiple logistic regression was used to examine predictors of GnRH agonist use in the subset of patients with localized cancer. RESULTS: There was a consistent increase in GnRH agonist use by year for all ages, stages, and grades. Even in men >/= 80 years with localized stage and low to moderate grade tumors, primary GnRH agonist use increased over the study period, from 3.7% in 1991 to 30.9% in 1999 (P < 0.001). The multivariable analysis showed that significant variability in GnRH agonist use existed among SEER geographic regions. CONCLUSIONS: The use of GnRH agonists for prostate carcinoma increased dramatically during the 1990s. This increase occurred across all stages and histologic grades of prostate carcinoma, and was greatest in patients >/= 80 years.     

A critical review of biomarkers used for monitoring human exposure to lead: advantages, limitations, and future needs

Lead concentration in whole blood (BPb) is the primary biomarker used to monitor exposure to this metallic element. The U.S. Centers for Disease Control and Prevention and the World Health Organization define a BPb of 10 microg/dL (0.48 micromol/L) as the threshold of concern in young children. However, recent studies have reported the possibility of adverse health effects, including intellectual impairment in young children, at BPb levels < 10 microg/dL, suggesting that there is no safe level of exposure. It appears impossible to differentiate between low-level chronic Pb exposure and a high-level short Pb exposure based on a single BPb measurement; therefore, serial BPb measurements offer a better estimation of possible health outcomes. The difficulty in assessing the exact nature of Pb exposure is dependent not so much on problems with current analytical methodologies, but rather on the complex toxicokinetics of Pb within various body compartments (i.e., cycling of Pb between bone, blood, and soft tissues). If we are to differentiate more effectively between Pb stored in the body for years and Pb from recent exposure, information on other biomarkers of exposure may be needed. None of the current biomarkers of internal Pb dose have yet been accepted by the scientific community as a reliable substitute for a BPb measurement. This review focuses on the limitations of biomarkers of Pb exposure and the need to improve the accuracy of their measurement. We present here only the traditional analytical protocols in current use, and we attempt to assess the influence of confounding variables on BPb levels. Finally, we discuss the interpretation of BPb data with respect to both external and endogenous Pb exposure, past or recent exposure, as well as the significance of Pb determinations in human specimens including hair, nails, saliva, bone, blood (plasma, whole blood), urine, feces, and exfoliated teeth.     

Ethnicity/race in the Pró-Saúde Study: comparative results of two methods of self-classification in Rio de Janeiro, Brazil

Variations in classification systems related to color/race and the contextual dependence of their utilization are two challenges for researchers conducting health studies within an ethnic/racial framework. A comparison was made between the results obtained by two distinct approaches to racial self-classification -- a closed question (using categories from the IBGE, or National Census Bureau) and an open-ended question -- in a cohort study of employees at a university in Rio de Janeiro. According to the closed question, 54.0% of the 3,717 respondents classified themselves as white, 30.0% as brown (or mixed-race), and 16.0% as black. According to answers to the open-ended question, the proportions were 53.0%, 25.0%, and 22.0%, respectively, when the terms "moreno", "mesti?o", and "mulato" were grouped under the "brown" category. Despite the high level of agreement (kappa = 0.80; 95%CI: 0.78-0.82), a sizeable numbers of black and brown respondents (open-ended question) chose "whitening" categories available in the list supplied by the IBGE. The use of ethnic/racial categories in health studies can both reveal information on health inequalities in Brazil and also contribute to the formulation of public health policies adequately informed by the specificities of Brazilian society.     

Tracheoesophageal fistula in an intubated patient. Treatment through exclusion and esophageal patch

Currently, acquired benign tracheoesophageal fistulas are mainly iatrogenic lesions produced by prolonged tracheal intubation. Their occurrence in intubated patients is infrequent but devastating and their therapeutic resolution is highly complex. We present the case of a patient with an extensive tracheoesophageal fistula following tracheal intubation that was surgically treated through esophageal exclusion (cervical esophagostomy and suture-stapling of the distal esophagus) and closure of the tracheal defect using the posterior esophageal wall.     

Solid-pseudopapillary tumor of pancreas

Solid-pseudopapillary tumor of pancreas is a very rare neoplasm of low malignant potential and unknown origin. It generally occurs in young women and the prognosis is usually good after complete surgical removal. Two cases of solid pseudopapillary tumor with distinct disease duration are reported.