Calcineurin/NFAT Activation-Dependence of Leptin Synthesis and Vascular Growth in Response to Mechanical Stretch.

Background and Aims: Hypertension and obesity are important risk factors of cardiovascular disease. They are both associated with high leptin levels and have been shown to promote vascular hypertrophy, through the RhoA/ROCK and ERK1/2 phosphorylation. Calcineurin/NFAT activation also induces vascular hypertrophy by upregulating various genes. This study aimed to decipher whether a crosstalk exists between the RhoA/ROCK pathway, Ca2+/calcineurin/NFAT pathway, and ERK1/2 phosphorylation in the process of mechanical stretch-induced vascular smooth muscle cell (VSMC) hypertrophy and leptin synthesis. Methods and Results: Rat portal vein (RPV) organ culture was used to investigate the effect of mechanical stretch and exogenous leptin (3.1 nM) on VSMC hypertrophy and leptin synthesis. Results showed that stretching the RPV significantly upregulated leptin secretion, mRNA, and protein expression, which were inhibited by the calcium channel blocker nifedipine (10 µM), the selective calcineurin inhibitor FK506 (1 nM), and the ERK1/2 inhibitor PD98059 (1 µM). The transcription inhibitor actinomycin D (0.1 µM) and the translation inhibitor cycloheximide (1 mM) significantly decreased stretch-induced leptin protein expression. Mechanical stretch or leptin caused an increase in wet weight changes and protein synthesis, considered as hypertrophic markers, while they were inhibited by FK506 (0.1 nM; 1 nM). In addition, stretch or exogenous leptin significantly increased calcineurin activity and MCIP1 expression whereas leptin induced NFAT nuclear translocation in VSMCs. Moreover, in response to stretch or exogenous leptin, the Rho inhibitor C3 exoenzyme (30 ng/mL), the ROCK inhibitor Y-27632 (10 µM), and the actin depolymerization agents Latrunculin B (50 nM) and cytochalasin D (1 µM) reduced calcineurin activation and NFAT nuclear translocation. ERK1/2 phosphorylation was inhibited by FK506 and C3. Conclusions: Mechanical stretch-induced VSMC hypertrophy and leptin synthesis and secretion are mediated by Ca2+/calcineurin/NFAT activation. RhoA/ROCK and ERK1/2 activation are critical for mechanical stretch-induced calcineurin activation.

Diffuse leukoencephalopathy in a 29-year-old male with hypertensive emergency.

Severe hypertension is associated with multiple symptoms that reflect the end-organ damage effect of rapidly increasing blood pressure. Encephalopathy is a manifestation of the clinical spectrum of hypertensive emergencies. Hypertensive encephalopathy was initially described as part of the posterior reversible encephalopathy syndrome, which mostly involved the parieto-occipital white matter of the brain. A more detailed review of this syndrome reveals many cases where the brain abnormalities are distributed in a more random pattern. We describe a case of diffuse leukoencephalopthy in a young male who presented with altered mental status, ataxia, and blurred vision. This is the most diffuse brain involvement ever described in hypertensive statuses.

Prostate Cancer in the Arab World: A View From the Inside.

The rates of prostate cancer vary by more than 50-fold across different international populations. The aim of this review was to explore the differences in epidemiology and risk factors between the Middle Eastern Arab countries and some of the developed countries in Europe and North America. The age-standardized incidence rate of prostate cancer in the Arab countries is still lower than that in the Western countries, but is steadily increasing with time. Several factors come into play to explain this difference. There are health care systems-related factors such as the lack of good population-based registries, and population-related factors. The latter include the relatively young age structure in the Arab countries, lower reported androgen and prostate-specific antigen levels in Arab men, the effect of genetic differences on prostate cancer risk, the metabolic syndrome paradox, and the protective effect of the Mediterranean diet on a subset of the Arab population. In conclusion, the study of prostate cancer in the Arab world represents a challenge with the currently available cancer care systems and the increase in the burden of the disease. A multinational prospective study to investigate the epidemiology of prostate cancer in the Middle East, with specific attention to country/geographic variability along with a comparative analysis to that of the Western hemisphere is needed.

Preoperative lymphocyte-to-monocyte ratio predicts clinical outcome in patients undergoing radical cystectomy for transitional cell carcinoma of the bladder: a retrospective analysis.

BACKGROUND: Inflammation is a critical component of tumorigenesis, and many cancers arise from sites of infection, chronic irritation, and inflammation. Inflammatory cytokines triggered by tumors alter hematologic components, including neutrophil, lymphocyte, and monocyte counts. The neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios have been shown to be valuable prognostic markers in various types of cancers, including bladder cancer. Risk stratification based on clinicopathologic data is insufficient to support treatment-related choices in patients with bladder cancer. Novel prognostic markers are therefore needed. An elevated pretreatment lymphocyte-to-monocyte ratio (LMR) is reportedly associated with improved overall survival (OS) and a longer time to treatment recurrence (TTR) in some types of cancers. However, these data are lacking in patients with bladder cancer. The aim of the present study was to investigate the effect of the preoperative LMR on OS and TTR in a cohort of patients with bladder cancer. METHODS: Sixty-eight patients with transitional cell carcinoma of the bladder were included in this retrospective analysis. The associations between a high and low LMR with OS and TTR were analyzed using Kaplan-Meier curves and compared by the log-rank test. RESULTS: In our study cohort, an elevated preoperative LMR was significantly associated with an increased TTR (P = 0.001) and OS (P = 0.020). Patients with an LMR of ≤2.87 showed a median TTR of 2.0 years (95% CI, 0.27-3.73), whereas patients with an LMR of >2.87 had a median TTR of 11.1 years (95% CI, 2.31-19.88) (P = 0.001). Patients with an LMR of ≤2.81 showed a median OS of 2.7 years (95% CI, 0.63-4.70), whereas patients with an LMR of >2.81 had a median OS of 6.0 years (95% CI, 3.60-8.40) (P = 0.020). The clinical stage at diagnosis was the only clinicopathologic feature associated with the LMR, while tumor invasion depth showed borderline significance. CONCLUSIONS: The LMR is an easily measured and inexpensive prognostic marker that was significantly correlated with OS and TTR in the present retrospective analysis. However, because of the small sample size in this study, larger multicenter, prospective studies are needed.