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The transmembrane protein TMEM16A forms a Ca(2+)-activated Cl(-) channel that is permeable to many anions, including SCN(-), I(-), Br(-), Cl(-), and HCO3 (-), and has been implicated in various physiological functions. Indeed, controlling anion permeation through the TMEM16A channel pore may be critical in regulating the pH of exocrine fluids such as the pancreatic juice. The anion permeability of the TMEM16A channel pore has recently been reported to be modulated by Ca(2+)-calmodulin (CaCaM), such that the pore of the CaCaM-bound channel shows a reduced ability to discriminate between anions as measured by a shift of the reversal potential under bi-ionic conditions. Here, using a mouse TMEM16A clone that contains the two previously identified putative CaM-binding motifs, we were unable to demonstrate such CaCaM-dependent changes in the bi-ionic potential. We confirmed the activity of CaCaM used in our study by showing CaCaM modulation of the olfactory cyclic nucleotide-gated channel. We suspect that the different bi-ionic potentials that were obtained previously from whole-cell recordings in low and high intracellular [Ca(2+)] may result from different degrees of bi-ionic potential shift secondary to a series resistance problem, an ion accumulation effect, or both.

Calcium-activated chloride channels (CaCC) encoded by family members of transmembrane proteins of unknown function 16 (TMEM16) have recently been intensely studied for functional properties as well as their physiological roles as chloride channels in various tissues. One technical hurdle in studying these channels is the well-known channel rundown that frequently impairs the precision of electrophysiological measurements for the channels. Using experimental protocols that employ fast-solution exchange, we circumvented the problem of channel rundown by normalizing the Ca(2+)-induced current to the maximally-activated current obtained within a time period in which the channel rundown was negligible. We characterized the activation of the TMEM16A-encoded CaCC (also called ANO1) by Ca(2+), Sr(2+), and Ba(2+), and discovered that Mg(2+) competes with Ca(2+) in binding to the divalent-cation binding site without activating the channel. We also studied the permeability of the ANO1 pore for various anions and found that the anion occupancy in the pore-as revealed by the permeability ratios of these anions-appeared to be inversely correlated with the apparent affinity of the ANO1 inhibition by niflumic acid (NFA). On the other hand, the NFA inhibition was neither affected by the degree of the channel activation nor influenced by the types of divalent cations used for the channel activation. These results suggest that the NFA inhibition of ANO1 is likely mediated by altering the pore function but not through changing the channel gating. Our study provides a precise characterization of ANO1 and documents factors that can affect divalent cation activation and NFA inhibition of ANO1.

Objective: Late-life depression (LLD) is a severe public health problem. Given that pharmacological treatments for LLD are limited by their side effects, development of efficient and tolerable nonpharmacological treatment for LLD is urgently required. This study investigated whether high-frequency external muscle stimulation could reduce depressive symptoms in LLD. Methods: Twenty-two older male veterans with major depression were recruited and randomized into a treatment (n = 9) or sham control group (n = 13). The groups received high-frequency external muscle stimulation or sham intervention 3 times per week for 12 weeks. Clinical symptoms and muscle strength were evaluated at baseline and every 2 weeks. Results: The 2 groups were homogeneous in age, baseline clinical symptoms, and muscle strength. The treatment group showed significant improvement in depression and anxiety scores and muscle strength (all P <.01), whereas the control group showed no significant change after the 12-week follow-up. Compared to the control group, the treatment group showed significant improvements in depression (Geriatric Depression Scale, P =.009; Hamilton Depression Rating Scale, P =.007) and anxiety scores (HAMA, P =.008) and muscle strength (all P <.001). Changes in depression and anxiety levels were significantly correlated with changes in muscle strength after the study. In the treatment group, we observed a trend of correlation between the reduction in depression and muscle strength gains. Conclusion: High-frequency external muscle stimulation appears to be an effective treatment for older patients with LLD. Large studies with more tests and/or conducted in different populations are warranted to validate these preliminary findings. [ABSTRACT FROM AUTHOR]

Reported associations between coffee consumption and an increased risk of pancreatic cancer could be due to residual confounding by smoking and/or biased recall of coffee consumption in retrospective studies. Studying associations prospectively in never smokers should minimize these problems, but thus far such studies have included relatively small numbers of cases. In our study, 309,797 never‐smoking women self‐reported typical daily coffee consumption at a mean age of 59.5 years (SD 5.0 years) and were followed up for a median of 13.7 years (IQR: 12.2–14.9) through record linkage to national health cancer and death registries. During this period, 962 incident cases of pancreatic cancers were registered. Cox regression was used to calculate adjusted relative risks [RRs] of incident pancreatic cancer with 95% confidence intervals [CIs] in relation to coffee consumption at baseline. After adjustment for potential confounding factors, including body mass index and alcohol consumption, RRs of pancreatic cancer in never‐smokers who reported usually consuming 1–2, 3–4, and ≥ 5 cups of coffee daily, compared to nondrinkers of coffee, were 1.02 (CI 0.83–1.26), 0.96 (0.76–1.22), and 0.87 (0.64–1.18), respectively (trend p = 0.2). A meta‐analysis of results from this cohort and 3 smaller prospective studies found little or no statistically significant association between coffee consumption and pancreatic cancer risk in never smokers (summary RR = 1.00, CI 0.86–1.17 for ≥2 vs. zero cups of coffee per day). What's new? Reported associations between coffee consumption and pancreatic cancer risk could be due to residual confounding by smoking or recall bias of coffee consumption in retrospective studies. In this large prospective study and meta‐analysis restricted to never‐smokers, we found no significant association between coffee consumption and pancreatic cancer risk. [ABSTRACT FROM AUTHOR]

Background: The role of diet in breast cancer aetiology is unclear; recent studies have suggested associations may differ by estrogen receptor status.Methods: Baseline diet was assessed in 2000-04 using a validated questionnaire in 691 571 postmenopausal UK women without previous cancer, who had not changed their diet recently. They were followed by record linkage to national cancer and death databases. Cox regression yielded adjusted relative risks for breast cancer for 10 food items and eight macronutrients, subdivided mostly into five categories of baseline intake. Trends in risk across the baseline categories were calculated, assigning re-measured intakes to allow for measurement error and changes in intake over time; P-values allowed for multiple testing.Results: Women aged 59.9 (standard deviation (SD 4.9)) years at baseline were followed for 12 (SD 3) years; 29 005 were diagnosed with invasive breast cancer. Alcohol intake had the strongest association with breast cancer incidence: relative risk (RR) 1.08 [99% confidence interval (CI) 1.05-1.11] per 10 g/day higher intake, P = 5.8 × 10-14. There were inverse associations with fruit: RR 0.94 (99% CI 0.92-0.97) per 100 g/day higher intake, P = 1.1 × 10-6, and dietary fibre: RR 0.91 (99% CI 0.87-0.96) per 5 g/day increase, P = 1.1 × 10-4. Fruit and fibre intakes were correlated (ρ = 0.62) and were greater among women who were not overweight, so residual confounding cannot be excluded. There was no heterogeneity for any association by estrogen receptor status.Conclusions: By far the strongest association was between alcohol intake and an increased risk of breast cancer. Of the other 17 intakes examined, higher intakes of fruit and fibre were associated with lower risks of breast cancer, but it is unclear whether or not these associations are causal. [ABSTRACT FROM AUTHOR]

Background: Migraine is associated with syncope. We investigated risk factors for syncope and burden of syncope in migraine patients.Methods: Participants were recruited from a headache clinic. All participants provided information on lifestyle, co-morbidity, syncope, headache and suicide, and completed the MIDAS and HADS questionnaires. Genetic data were available for a subset of participants. Risk of syncope in relation to participant's characteristics and migraine susceptibility loci, and risks of psychological disorders associated with syncope, were calculated using logistic regression.Results: Underweight, regular tea intake, diabetes mellitus, and migraine with aura were associated with increased syncope risks, with adjusted ORs of 1.76 (95% CI 1.03-3.03), 1.84 (95% CI 1.22-2.79), 4.70 (95% CI 1.58-13.95), and 1.78 (95% CI 1.03-3.10), respectively. Preliminary results showed that rs11172113 in LRP1 was associated with syncope risks. Comorbid syncope in migraine patients was associated with increased risks of depression (OR 1.95, 95% CI 1.18-3.22) and suicide attempt (OR 2.85, 95% CI 1.48-5.48).Conclusion: Our study showed the potential roles of vascular risk factors in the association between migraine and syncope. Modifiable risk factors for syncope in patients with migraine include body mass index and tea intake. The debilitating psychological impact of co-morbid syncope in migraine patients warrants clinical attention of treating physicians. [ABSTRACT FROM AUTHOR]