Enhanced paracrine FGF10 expression promotes formation of multifocal prostate adenocarcinoma and an increase in epithelial androgen receptor

Enhanced mesenchymal expression of FGF10 led to the formation of multifocal PIN or prostate cancer. Inhibition of epithelial FGFR1 signaling using DN FGFR1 led to reversal of the cancer phenotype. A subset of the FGF10-induced carcinoma was serially transplantable. Paracrine FGF10 led to an increase in epithelial androgen receptor and synergized with cell-autonomous activated AKT. Our observations indicate that stromal FGF10 expression may facilitate the multifocal histology observed in prostate adenocarcinoma and suggest the FGF10/FGFR1 axis as a potential therapeutic target in treating hormone-sensitive or refractory prostate cancer. We also show that transient exposure to a paracrine growth factor may be sufficient for the initiation of oncogenic transformation.     

Activation of latent TGF-β1 by low-power laser in vitro correlates with increased TGF-β1 levels in laser-enhanced oral wound healing

The term Laser "Photobiomodulation" was coined to encompass the pleiotropic effects of low-power lasers on biological processes. The purpose of this study was to investigate whether transforming growth factor (TGF)-beta had a role in mediating the biological effects of low-power far-infrared laser irradiation. We assayed for in vitro activation using various biological forms of cell-secreted, recombinant, and serum latent TGF-beta using the p3TP reporter and enzyme-linked immunosorbent assays. We demonstrate here that low-power lasers are capable of activating latent TGF-beta1 and -beta3 in vitro and, further, that it is capable of "priming" these complexes, making them more amenable to physiological activation present in the healing milieu. Using an in vivo oral tooth extraction-healing model, we observed an increased TGF-beta1, but not beta3, expression by immunohistochemistry immediately following laser irradiation while TGF-beta3 expression was increased after 14 days, concomitant with an increased inflammatory infiltrate. All comparisons were performed between laser-irradiated wounds and nonirradiated wounds in each subject essentially using them as their own control (paired T-test p<0.05). Low-power laser irradiation is capable of activating the latent TGF-beta1 complex in vitro and its expression pattern in vivo suggests that TGF-beta play a central role in mediating the accelerated healing response.     

Impact of inflammation on the relationship among alcohol consumption, mortality, and cardiac events: the health, aging, and body composition study

BACKGROUND: Uncertainty remains about the overall survival benefit of alcohol consumption and the mechanisms underlying the cardioprotective effect of light to moderate alcohol intake. Recent evidence suggests an anti-inflammatory effect of light to moderate alcohol consumption. We investigated the relationship of alcohol intake with all-cause mortality and cardiac events and evaluated whether this relationship is mediated or modified by inflammatory markers. METHODS: The analysis included 2487 subjects, aged 70 to 79 years, without baseline coronary heart disease (CHD) or heart failure (HF), participating in the Health, Aging, and Body Composition study. All-cause mortality and incident cardiac events (CHD and HF) were detected during a mean follow-up of 5.6 years. Alcohol consumption and serum levels of interleukin-6 (IL-6) and C-reactive protein (CRP) were assessed at baseline. RESULTS: A total of 397 participants died, and 383 experienced an incident cardiac event. Compared with never or occasional drinkers, subjects drinking 1 to 7 drinks per week had lower age-, sex-, and race-adjusted incidences of death (27.4 vs 20.1 per 1000 person-years, respectively) and cardiac events (28.9 vs 20.8 per 1000 person-years). After adjustment for confounders, compared with never or occasional drinkers, light to moderate drinkers (1-7 drinks per week) showed a decreased risk of death (hazard ratio [HR], 0.75; 95% confidence interval [CI], 0.56-1.00) and cardiac events (HR, 0.72; CI, 0.54-0.97). Adjustment for potential mediators, and particularly inflammatory marker levels, did not affect the strength of this association. CONCLUSION: Light to moderate alcohol consumption was associated with significantly lower rates of cardiac events and longer survival, independent of its anti-inflammatory effect.     

The otolaryngologic manifestations in children with eosinophilic esophagitis

Objectives

(1) To describe the incidence of eosinophilic esophagitis (EoE) in the population of patients undergoing esophagoscopy with biopsy by a pediatric otolaryngology service. (2) To elucidate the demographics, presenting symptoms, and endoscopic findings in children with EoE.

Design

Case series.

Patients/methods

The reports of esophageal biopsy specimens taken over 5 years in 2429 patients were reviewed. Ninety-two patients who received their initial diagnosis of EoE by the pediatric otolaryngology service with specimens showing 15 or greater eosinophils per high power field (HPF) were included.

Interventions

The demographic data, history, presenting symptoms, and endoscopic findings were reviewed retrospectively for the patients.

Main outcome measure

The percentage of children diagnosed with EoE of all children undergoing esophageal biopsy.

Results

A total of 92 children were diagnosed with EoE (3.8% of total children biopsied). The mean age at biopsy was 4.4 years, much lower than previously reported in the literature (approximately 8 years); 73% were boys and 27% girls. The main presenting symptom was cough (46%) followed by hoarseness, throat clearing, burping/vomiting, and abdominal pain. Forty three percent had a history of asthma and 17% a history of GERD. Half of patients had esophageal edema, a third were normal, and only a quarter had mucosal furrowing on endoscopic examination.

Conclusions

EoE is increasingly diagnosed as a clinical entity with a distinct symptom profile and etiology. Increased understanding of EoE and its predisposing factors requires a multidisciplinary approach to diagnosis and management involving the pediatric otolaryngologist.     

Attitudes and practices of medical graduates in Delhi towards gifts from the pharmaceutical industry

Pharmaceutical companies use a variety of strategies, including gifts, to influence physicians. In December 2009, the Medical Council of India amended the Code of Medical Ethics to ban medical professionals from accepting gifts from pharmaceutical companies. In view of this ban, it is important to find out the magnitude and contours of the problem amongst Indian medical professionals. We aimed to study, through an e-mail based survey, the attitudes and practices of young resident doctors and interns from two medical colleges of New Delhi regarding acceptance of gifts from the pharmaceutical industry. We e-mailed the questionnaire to 150 fresh graduates. We found that the majority of graduates agreed with existing guidelines: they accepted low cost gifts but considered expensive gifts unrelated to patient welfare unethical. Despite the low response rate, this study is important because data from India on attitudes and practices of medical professionals regarding gifts from the pharmaceutical industry are virtually non-existent.     

Road to Alzheimer's disease: the pathomechanism underlying

Alzheimer's disease (AD), the most common cause of dementia, results from the interplay of various deregulated mechanisms triggering a complex pathophysiology. The neurons suffer from and slowly succumb to multiple irreversible damages, resulting in cell death and thus memory deficits that characterize AD. In spite of our vast knowledge, it is still unclear as to when the disease process starts and how long the perturbations continue before the disease manifests. Recent studies provide sufficient evidence to prove amyloid β (Aβ) as the primary cause initiating secondary events, but Aβ is also known to be produced under normal conditions and to possess physiological roles, hence, the questions that remain are: What are the factors that lead to abnormal Aβ production? When does Aβ turn into a pathological molecule? What is the chain of events that follows Aβ? The answers are still under debate, and further insight may help us in creating better diagnostic and therapeutic options in AD. The present article attempts to review the current literature regarding AD pathophysiology and proposes a pathophysiologic cascade in AD.     

17p13.3 microduplications are associated with split-hand/foot malformation and long-bone deficiency (SHFLD)

Split-hand/foot malformation with long-bone deficiency (SHFLD) is a relatively rare autosomal-dominant skeletal disorder, characterized by variable expressivity and incomplete penetrance. Although several chromosomal loci for SHFLD have been identified, the molecular basis and pathogenesis of most SHFLD cases are unknown. In this study we describe three unrelated kindreds, in which SHFLD segregated with distinct but overlapping duplications in 17p13.3, a region previously linked to SHFLD. In a large three-generation family, the disorder was found to segregate with a 254 kb microduplication; a second microduplication of 527 kb was identified in an affected female and her unaffected mother, and a 430 kb microduplication versus microtriplication was identified in three affected members of a multi-generational family. These findings, along with previously published data, suggest that one locus responsible for this form of SHFLD is located within a 173 kb overlapping critical region, and that the copy gains are incompletely penetrant.     

Revisiting Immune Exhaustion During HIV Infection

Chronic immune activation is a hallmark of HIV infection, yet the underlying triggers of immune activation remain unclear. Persistent antigenic stimulation during HIV infection may also lead to immune exhaustion, a phenomenon in which effector T cells become dysfunctional and lose effector functions and proliferative capacity. Several markers of immune exhaustion, such as PD-1, LAG-3, Tim-3, and CTLA-4, which are also negative regulators of immune activation, are preferentially upregulated on T cells during HIV infection. It is not yet clear whether accumulation of T cells expressing activation inhibitory molecules is a consequence of general immune or chronic HIV-specific immune activation. Importantly, however, in vitro blockade of PD-1 and Tim-3 restores HIV-specific T-cell responses, indicating potential for immunotherapies. In this review we discuss the evolution of our understanding of immune exhaustion during HIV infection, highlighting novel markers and potential therapeutic targets.