Cellular Environment in a Bundle Modulates SEJP Characteristics in Detrusor Smooth Muscle.

Smooth muscle that ensheathes the urinary bladder wall is known as the detrusor. The detrusor has a bundled syncytial architecture where groups of electrically coupled cells form discrete bundles. Electrical activity recorded from detrusor cells is varied. Among the electrical signals recorded from the detrusor, spontaneous excitatory junction potentials (SEJPs) are events that are sub-threshold for spike generation. SEJPs are caused by spontaneous random release of neurotransmitter molecules from varicosities of innervating nerves. SEJPs recorded from different cells of the detrusor vary in amplitude and/or kinetics, and the reasons for variability are obscure. Our hypothesis was that variety in SEJP characteristics may be attributed to the biophysical micro-environment of a cell (in a bundle), where it arises. With the help of computational models, we show how cellular environment factor, such as size of a bundle significantly alters the amplitude as well as kinetics of SEJPs. These findings are congruent with experimental observations. Our results also suggest that characteristically different SEJPs may be observed in identical detrusor cells, with the difference arising from their neighbourhood rather than the inherent nature of the cells. Consequently, SEJP characteristics might be indicative of the cellular environment of electrophysiological recording.

Myeloid sarcoma of the periprostatic tissue and prostate: Case report and review of literature.

Myeloid sarcoma (MS) is a rare extramedullary tumor composed of immature cells of myeloid lineage that destroy the original tissue architecture in which it is found. It is most commonly identified in patients with acute myelogenous leukemia, and less often in myelodysplastic syndromes (MDSs) and other myeloproliferative disorders. It is most commonly reported in the periosteum, bone, skin, and lymph nodes but has been reported in many other sites of the body. Herein, we describe a case of MS involving the periprostatic tissue and review of literature of MS of the prostate. Our patient was initially diagnosed with MDS and was in remission following successful treatment. Six months later, the patient was diagnosed with prostate adenocarcinoma, and MS of the periprostatic tissue was incidentally discovered in the postprostatectomy pathology specimen. An extensive review of literature from 1997 to 2014 revealed a total of eight cases of MS involving the prostate. Of the eight cases of MS of the prostate, four were primary MS (absence of a history of leukemia) and four were secondary MS. Three received local radiation to the prostate with relief of obstructive symptoms, and one of them had a repeat prostate biopsy negative for leukemic cells. Despite being a rare entity, MS should be considered as a differential diagnosis of soft tissue masses, especially in patients with a history of hematological malignancies.

Relation of excess body weight and survival in patients with esophageal adenocarcinoma: a meta-analysis.

Excess body weight (body mass index >25 kg/m(2)) is common in patients with esophageal adenocarcinoma. In this study, a meta-analysis was performed by searching PubMed, Cochrane Library, EMBASE, and Science Direct databases from 1960 to June 2012. Data were extracted from studies comparing survival in obese (body mass index >30), overweight (body mass index 25-29), and normal-weight (body mass index 20-24) patients undergoing esophagectomy. A total of six studies with 1988 cases were suitable for this global meta-analysis. Compared with patients of normal weight, the hazard ratio of postoperational survival for overweight and obese patients was 0.79 (95% confidence interval 0.65-0.95, P = 0.108) and 0.80 (95% confidence interval 0.68-0.93, P = 1.00), respectably. Taken together, the excess body weight did not have the value of predicting survival for patients with esophageal adenocarcinoma.

Identification and characterization of novel polymorphisms in the basal promoter of the human transporter, MATE1.

OBJECTIVES: Human multidrug and toxin extrusion member 1, MATE1 (SLC47A1), plays an important role in the renal and biliary excretion of endogenous and exogenous organic cations including many therapeutic drugs. In this study, we characterized the transcriptional effects of five polymorphic variants and six common haplotypes in the basal promoter region of MATE1 that were identified in 272 DNA samples from ethnically diverse US populations. METHODS: We measured luciferase activities of the six common promoter haplotypes of MATE1 using in-vitro and in-vivo reporter assays. RESULTS: Haplotypes that contain the most common variant (mean allele frequency in four ethnic groups: 0.322), g.-66T>C, showed a significant decrease in reporter activities compared to the reference. Two transcription factors, activating protein-1 (AP-1) and activating protein-2 repressor (AP-2rep), were predicted to bind to the promoter in the region of g.-66T>C. Results from electrophoretic mobility shift assays showed that the g.-66T allele, exhibited greater binding to AP-1 than the g.-66C allele. AP-2rep inhibited the binding of AP-1 to the MATE1 basal promoter region, and the effect was considerably greater for the g.-66T>C. These data suggest that the reduced transcriptional activity of g.-66T>C results from a reduction in the binding potency of the transcriptional activator, AP-1, and an enhanced binding potency of the repressor, AP-2rep to the MATE1 basal promoter region. Consistent with the reporter assays, MATE1 mRNA expression levels were significantly lower in kidney samples from individuals who were homozygous or heterozygous for g.-66T>C in comparison with samples from individuals who were homozygous for the g.-66T allele. CONCLUSION: Our study suggests that the rate of transcription of MATE1 is regulated by AP-1 and AP-2rep and that a common promoter variant, g.-66T>C may affect the expression level of MATE1 in human kidney, and ultimately result in variation in drug disposition and response.

Facial EMG as an index of affective response to nicotine.

Negative affect reduction has been postulated to be a key feature of cigarette smoking. In the present study, facial electromyography (EMG), heart rate (HR), and skin conductance response (SCR) were used to evaluate the affective significance of acute nicotine administration and overnight withdrawal. Smokers (N = 115) attended four 90-min laboratory assessment sessions scheduled approximately 3 days apart. The sessions provided a complete crossing of 2 prelaboratory deprivation conditions (12-hr deprived vs. nondeprived) with 2 drug conditions (nicotine vs. placebo nasal spray). During each session, smokers viewed affective slides while facial EMG, HR, and SCR were recorded. Results indicated that for women, nicotine nasal spray resulted in lower corrugator EMG activity during both smoking-deprived and nondeprived sessions, compared with placebo. However, nondeprived women also showed an increase in zygomaticus EMG when given nicotine compared with placebo spray, whereas smoking-deprived women demonstrated a decrease in the zygomaticus response to nicotine compared with placebo. With men, nicotine also appeared to lower corrugator during deprivation, but not nondeprivation, compared with placebo spray, though the contrast only approached significance. With zygomaticus EMG, nicotine spray decreased men's zygomaticus responding during nondeprivation but not during deprivation, compared with placebo spray. The HR results reflected the stimulatory properties of the drug rather than nicotine's affective properties, whereas SCR was unresponsive to our experimental manipulations. The corrugator EMG results support negative reinforcement models of smoking that postulate that acute nicotine use reduces withdrawal-driven negative affect.

A stem cell fusion model of carcinogenesis.

The origin of cancer remains enigmatic. Current models of carcinogenesis based on the gene mutation hypothesis have limitations in explaining many aspects of cancer. We put forward a new model of multistage carcinogenesis and propose that cancer development involves gene mutations and cell fusions. Specifically, cancer can result from a fusion between an "altered" pre-malignant cell and a bone marrow-derived stem cell (BMDSC). "Aneuploidy", which is a hallmark of malignancy, is a direct consequence of this cell fusion. The "stem cell fusion" model explains the remarkable similarities between malignant cells and BMDSC. This model also explains why non-mutagens can be carcinogens, and why non-mutagenic processes, such as wound healing and chronic inflammation, can promote malignant transformation. This model is readily testable. Cancer has been difficult to treat because of tissue heterogeneity and gene instability. However, if the malignant characteristics of cancer cells are derived from BMDSC, new conserved targets such as homing receptors for designing novel therapies may emerge.