Kv7.2 regulates the function of peripheral sensory neurons

The Kv7 (KCNQ) family of voltage‐gated K⁺ channels regulates cellular excitability. The functional role of Kv7.2 has been hampered by the lack of a viable Kcnq2‐null animal model. In this study, we generated homozygous Kcnq2‐null sensory neurons using the Cre‐Lox system; in these mice, Kv7.2 expression is absent in the peripheral sensory neurons, whereas the expression of other molecular components of nodes (including Kv7.3), paranodes, and juxtaparanodes is not altered. The conditional Kcnq2‐null animals exhibit normal motor performance but have increased thermal hyperalgesia and mechanical allodynia. Whole‐cell patch recording technique demonstrates that Kcnq2‐null sensory neurons have increased excitability and reduced spike frequency adaptation. Taken together, our results suggest that the loss of Kv7.2 activity increases the excitability of primary sensory neurons. J. Comp. Neurol. 522:3262–3280, 2014. © 2014 Wiley Periodicals, Inc.     

Potentially traumatic events and serious life stressors are prospectively associated with frequency of doctor visits and overnight hospital visits

Objective

Cumulative lifetime exposure to potentially traumatic events and serious life stressors has been linked with both mental and physical health problems; however, less is known about the association between exposure to potentially traumatic events and serious life stressors with health care use. We investigated whether a higher number of potentially traumatic events and serious life stressors were prospectively associated with an increased number of doctor visits and nights spent in the hospital.

Methods

Participants were drawn from the Health and Retirement Study, a prospective and nationally representative study of adults aged 50 + in the United States (n = 7168). We analyzed the data using a generalized linear model with a gamma distribution and log link.

Results

A higher number of potentially traumatic events and serious life stressors were associated with an increased number of doctor visits and nights spent in the hospital. On a 10-point scale, each additional potentially traumatic event or serious life stressor was associated with an 8% increase in doctor visits after controlling for sociodemographic factors (RR = 1.08, 95% CI = 1.06–1.11; p < .001). Each additional potentially traumatic event or serious life stressor was also associated with an 18% increase in the number of nights spent in the hospital after controlling for sociodemographic factors (RR = 1.18, 95% CI = 1.10–1.27; p < .001).

Conclusion

Exposure to potentially traumatic events and serious life stressors is associated with increased doctor visits and nights spent in the hospital, which may have important implications for the current standard of care.     

Suicidality in Non-Treatment Seeking Young Adults with Subsyndromal Gambling Disorder

Gambling Disorder is associated with elevated rates of suicidal thoughts and acts. However, virtually nothing is known about suicidality in people with subsyndromal forms of gambling disorder. A total of 174 non-treatment seeking subjects were recruited for a study of impulsivity and met criteria for a subsyndromal form of DSM-5 gambling disorder (31.0 % females; mean age = 21.7 ± 3.61 years). Subjects were categorized as being ‘at risk of suicide’ or ‘no suicide risk’ based on the Mini-International Neuropsychiatric Interview (MINI). Those with and without suicidality were compared on clinical and cognitive measures. 32 (18.4 %) met MINI criteria for suicidality. Suicidality was significantly associated with mood and anxiety disorders, greater rates of nicotine consumption, and relative impairments in decision-making and cognitive flexibility. These findings suggest that decision-making impairments may be implicated in the development of both gambling problems and suicidality. Future work should address causality, neural correlates, and tailored suicide prevention strategies for people with, or at risk for, disordered forms of gambling.     

Ubiquitin-proteasomal degradation of COX-2 in TGF-β stimulated human endometrial cells is mediated through endoplasmic reticulum mannosidase I

Cyclooxygenase (COX)-2 is a key regulatory enzyme in the production of prostaglandins (PG) during various physiological processes. Mechanisms of COX-2 regulation in human endometrial stromal cells (human endometrial stromal cells) are not fully understood. In this study, we investigate the role of TGF-β in the regulation of COX-2 in human uterine stromal cells. Each TGF-β isoform decreases COX-2 protein level in human uterine stromal cells in Smad2/3-dependent manner. The decrease in COX-2 is accompanied by a decrease in PG synthesis. Knockdown of Smad4 using specific small interfering RNA prevents the decrease in COX-2 protein, confirming that Smad pathway is implicated in the regulation of COX-2 expression in human endometrial stromal cells. Pretreatment with 26S proteasome inhibitor, MG132, significantly restores COX-2 protein and PG synthesis, indicating that COX-2 undergoes proteasomal degradation in the presence of TGF-β. In addition, each TGF-β isoform up-regulates endoplasmic reticulum (ER)-mannosidase I (ERManI) implying that COX-2 degradation is mediated through ER-associated degradation pathway in these cells. Furthermore, inhibition of ERManI activity using the mannosidase inhibitor (kifunensine), or small interfering RNA-mediated knockdown of ERManI, prevents TGF-β-induced COX-2 degradation. Taken together, these studies suggest that TGF-β promotes COX-2 degradation in a Smad-dependent manner by up-regulating the expression of ERManI and thereby enhancing ER-associated degradation and proteasomal degradation pathways.     

Abnormal activation of autophagy-induced crinophagy in Paneth cells from patients with Crohn's disease

Autophagy-related 16 like-1 (ATG16L-1), immunity-related GTPase-M (IRGM), and nucleotide-binding oligomerization domain-containing 2 (NOD2) regulate autophagy, and variants in these genes have been associated with predisposition to Crohn's disease (CD). However, little is known about the role of autophagy in CD. Intestinal biopsies from untreated pediatric patients with CD, celiac disease, or ulcerative colitis were analyzed by immunohistochemistry and electron microscopy. We observed that autophagy was specifically activated in Paneth cells from patients with CD, independently of mucosal inflammation or disease-associated variants of ATG16L1 or IRGM. In these cells, activation of autophagy was associated with a significant decrease in number of secretory granules and features of crinophagy. These observations might account for the disorganization of secretory granules previously reported in Paneth cells from patients with CD.     

Subclinical Thyroid Dysfunction and the Risk of Heart Failure Events: An Individual Participant Data Analysis From 6 Prospective Cohorts

BACKGROUND: American College of Cardiology/American Heart Association guidelines for the diagnosis and management of heart failure recommend investigating exacerbating conditions such as thyroid dysfunction, but without specifying the impact of different thyroid-stimulation hormone (TSH) levels. Limited prospective data exist on the association between subclinical thyroid dysfunction and heart failure events. METHODS AND RESULTS: We performed a pooled analysis of individual participant data using all available prospective cohorts with thyroid function tests and subsequent follow-up of heart failure events. Individual data on 25 390 participants with 216 248 person-years of follow-up were supplied from 6 prospective cohorts in the United States and Europe. Euthyroidism was defined as TSH of 0.45 to 4.49 mIU/L, subclinical hypothyroidism as TSH of 4.5 to 19.9 mIU/L, and subclinical hyperthyroidism as TSH <0.45 mIU/L, the last two with normal free thyroxine levels. Among 25 390 participants, 2068 (8.1%) had subclinical hypothyroidism and 648 (2.6%) had subclinical hyperthyroidism. In age- and sex-adjusted analyses, risks of heart failure events were increased with both higher and lower TSH levels (P for quadratic pattern <0.01); the hazard ratio was 1.01 (95% confidence interval, 0.81-1.26) for TSH of 4.5 to 6.9 mIU/L, 1.65 (95% confidence interval, 0.84-3.23) for TSH of 7.0 to 9.9 mIU/L, 1.86 (95% confidence interval, 1.27-2.72) for TSH of 10.0 to 19.9 mIU/L (P for trend <0.01) and 1.31 (95% confidence interval, 0.88-1.95) for TSH of 0.10 to 0.44 mIU/L and 1.94 (95% confidence interval, 1.01-3.72) for TSH <0.10 mIU/L (P for trend=0.047). Risks remained similar after adjustment for cardiovascular risk factors. CONCLUSION: Risks of heart failure events were increased with both higher and lower TSH levels, particularly for TSH ≥10 and <0.10 mIU/L.