Positive psychology psychoeducation makes a small impact on undergraduate student mental health: Further curriculum innovation and better well-being research needed.

OBJECTIVES: Courses on well-being are increasingly evaluated to see how they may promote mental health in college. We examined the impact of a course on students' well-being, anxiety, and depression. METHODS: Subjects were undergraduates enrolled in the "Science of Happiness," (SOH) (n = 105), and "Child and Adolescent Psychopathology," (CAP) (n = 114). Well-being measures included the PERMA Profiler and Satisfaction with Life Scale (SWLS) at the beginning and conclusion of the semester. The Depression Anxiety and Stress Scale - 21 items (DASS-21) measured psychopathology. RESULTS: There were significant improvements on the SWLS 1.28 (p = .038; d = .264) in SOH. There was no improvement for the PERMA Profiler in either group, and no differences between groups. There was no significant change on the DASS-21 for SOH subjects. CONCLUSIONS: Undergraduate courses that deliver positive psychology psychoeducation have a small effect size even in non-randomized studies. Future curriculum innovation is needed and better research to validate positive psychology psychoeducation.

Small molecule SWELL1 complex induction improves glycemic control and nonalcoholic fatty liver disease in murine Type 2 diabetes.

Type 2 diabetes is associated with insulin resistance, impaired pancreatic ß-cell insulin secretion, and nonalcoholic fatty liver disease. Tissue-specific SWELL1 ablation impairs insulin signaling in adipose, skeletal muscle, and endothelium, and impairs ß-cell insulin secretion and glycemic control. Here, we show that ICl,SWELL and SWELL1 protein are reduced in adipose and ß-cells in murine and human diabetes. Combining cryo-electron microscopy, molecular docking, medicinal chemistry, and functional studies, we define a structure activity relationship to rationally-design active derivatives of a SWELL1 channel inhibitor (DCPIB/SN-401), that bind the SWELL1 hexameric complex, restore SWELL1 protein, plasma membrane trafficking, signaling, glycemic control and islet insulin secretion via SWELL1-dependent mechanisms. In vivo, SN-401 restores glycemic control, reduces hepatic steatosis/injury, improves insulin-sensitivity and insulin secretion in murine diabetes. These findings demonstrate that SWELL1 channel modulators improve SWELL1-dependent systemic metabolism in Type 2 diabetes, representing a first-in-class therapeutic approach for diabetes and nonalcoholic fatty liver disease.

Localization and Control of Magnetic Suture Needles in Cluttered Surgical Site with Blood and Tissue.

Real-time visual localization of needles is necessary for various surgical applications, including surgical automation and visual feedback. In this study we investigate localization and autonomous robotic control of needles in the context of our magneto-suturing system. Our system holds the potential for surgical manipulation with the benefit of minimal invasiveness and reduced patient side effects. However, the nonlinear magnetic fields produce unintuitive forces and demand delicate position-based control that exceeds the capabilities of direct human manipulation. This makes automatic needle localization a necessity. Our localization method combines neural network-based segmentation and classical techniques, and we are able to consistently locate our needle with 0.73 mm RMS error in clean environments and 2.72 mm RMS error in challenging environments with blood and occlusion. The average localization RMS error is 2.16 mm for all environments we used in the experiments. We combine this localization method with our closed-loop feedback control system to demonstrate the further applicability of localization to autonomous control. Our needle is able to follow a running suture path in (1) no blood, no tissue; (2) heavy blood, no tissue; (3) no blood, with tissue; and (4) heavy blood, with tissue environments. The tip position tracking error ranges from 2.6 mm to 3.7 mm RMS, opening the door towards autonomous suturing tasks.

Towards Autonomous Control of Magnetic Suture Needles.

This paper proposes a magnetic needle steering controller to manipulate mesoscale magnetic suture needles for executing planned suturing motion. This is an initial step towards our research objective: enabling autonomous control of magnetic suture needles for suturing tasks in minimally invasive surgery. To demonstrate the feasibility of accurate motion control, we employ a cardinally-arranged four-coil electromagnetic system setup and control magnetic suture needles in a 2-dimensional environment, i.e., a Petri dish filled with viscous liquid. Different from only using magnetic field gradients to control small magnetic agents under high damping conditions, the dynamics of a magnetic suture needle are investigated and encoded in the controller. Based on mathematical formulations of magnetic force and torque applied on the needle, we develop a kinematically constrained dynamic model that controls the needle to rotate and only translate along its central axis for mimicking the behavior of surgical sutures. A current controller of the electromagnetic system combining with closed-loop control schemes is designed for commanding the magnetic suture needles to achieve desired linear and angular velocities. To evaluate control performance of magnetic suture needles, we conduct experiments including needle rotation control, needle position control by using discretized trajectories, and velocity control by using a time-varying circular trajectory. The experiment results demonstrate our proposed needle steering controller can perform accurate motion control of mesoscale magnetic suture needles.

Surgical ablation of atrial fibrillation concomitant to coronary-artery bypass grafting provides cost-effective mortality reduction.

BACKGROUND: Data on the longitudinal impact of surgical ablation (SA) for atrial fibrillation (AF) in patients undergoing coronary artery bypass grafting (CABG) remain limited. This study examined 2-year risk-adjusted mortality and total hospital costs in Medicare beneficiaries with AF requiring CABG with or without SA. METHODS: CABG was performed in 3745 Medicare beneficiaries with AF in 2013, with concomitant SA in 17% (626 of 3745). Risk-adjusted mortality, morbidity, and cost during the first 2 postoperative years for patients with SA and those without SA were compared. A piecewise Cox proportional hazard model (0-90 days and 91-729 days) was used to risk-adjust mortality. RESULTS: Compared with the no SA group, the SA group had lower rates of heart failure before surgery (31% vs 36%), chronic lung disease (27% vs 33%), renal failure (4% vs 7%), and urgent or emergent presentation (34% vs 49%) (all P < .05). Risk-adjusted index admission costs were higher with SA (rate ratio [RR], 1.11; P < .01), as were readmissions for AF (hazard ratio [HR], 1.14; 95% confidence interval [CI], 1.00-1.29; P = .04) and pacemaker/defibrillator implantation (HR, 1.37; 95%, 1.08-1.74; P = .01). Risk-adjusted inpatient days and inpatient costs were similar after 2 years (RR, 0.97; P = .31 and RR = 1.04; P = .17, respectively); however, the risk-adjusted hazard for late mortality (91-729 days) was significantly lower with SA (HR, 0.71; 95% CI, 0.52-0.97; P = .03). CONCLUSIONS: In patients with AF requiring CABG, SA was associated with a 29% lower risk-adjusted hazard for late mortality. Index hospital costs were higher with SA, but total inpatient costs were not different in the 2 groups after 2 years. SA appears to be a cost-effective intervention to enhance late 2-year survival in patients with AF undergoing CABG.

Prevalence of atrial fibrillation before cardiac surgery and factors associated with concomitant ablation.

OBJECTIVE: Surgical ablation for atrial fibrillation concomitant with cardiac surgery is now a Class I recommendation for selected patients. Understanding how the revised recommendations will affect appropriate use of surgical ablation is challenging because the reported prevalence of preoperative atrial fibrillation depends on the definition used. The objective was to determine the prevalence of atrial fibrillation in the 3 years before cardiac surgery and the rate of concomitant surgical ablation. METHODS: Patients with and without a diagnosis of atrial fibrillation in the 3 years before surgical coronary artery bypass, aortic valve replacement, or mitral valve replacement/repair were identified in the 2014 Medicare Standard Analytical File. RESULTS: Patients had prior atrial fibrillation in 28.4% of 79,134 cardiac surgeries. Prior atrial fibrillation was associated with risk factors for increased cardiac surgical morbidity/mortality, including recent heart failure, renal failure, and lung disease. Black patients were less likely to have prior atrial fibrillation but more likely to have had infrequent care for it. Isolated coronary artery bypass had the lowest prevalence but highest absolute number of prior atrial fibrillation cases. Concomitant surgical ablation was performed in 22.1% of patients with prior atrial fibrillation. Patients with mitral valve surgery were 3-fold more likely to receive surgical ablation. Women were less likely to have prior atrial fibrillation but less likely to have surgical ablation when they did. CONCLUSIONS: Medicare beneficiaries had a substantially higher prevalence of atrial fibrillation diagnoses in the 3 years before cardiac surgery than previously published rates of preoperative atrial fibrillation. Concomitant surgical ablation was performed in less than one-quarter of patients with atrial fibrillation undergoing cardiac surgery for other indications.

Risky business: linking Toxoplasma gondii infection and entrepreneurship behaviours across individuals and countries.

Disciplines such as business and economics often rely on the assumption of rationality when explaining complex human behaviours. However, growing evidence suggests that behaviour may concurrently be influenced by infectious microorganisms. The protozoan Toxoplasma gondii infects an estimated 2 billion people worldwide and has been linked to behavioural alterations in humans and other vertebrates. Here we integrate primary data from college students and business professionals with national-level information on cultural attitudes towards business to test the hypothesis that T. gondii infection influences individual- as well as societal-scale entrepreneurship activities. Using a saliva-based assay, we found that students (n = 1495) who tested IgG positive for T. gondii exposure were 1.4× more likely to major in business and 1.7× more likely to have an emphasis in 'management and entrepreneurship' over other business-related emphases. Among professionals attending entrepreneurship events, T. gondii-positive individuals were 1.8× more likely to have started their own business compared with other attendees (n = 197). Finally, after synthesizing and combining country-level databases on T. gondii infection from the past 25 years with the Global Entrepreneurship Monitor of entrepreneurial activity, we found that infection prevalence was a consistent, positive predictor of entrepreneurial activity and intentions at the national scale, regardless of whether previously identified economic covariates were included. Nations with higher infection also had a lower fraction of respondents citing 'fear of failure' in inhibiting new business ventures. While correlational, these results highlight the linkage between parasitic infection and complex human behaviours, including those relevant to business, entrepreneurship and economic productivity.

One-year mortality and costs associated with surgical ablation for atrial fibrillation concomitant to coronary artery bypass grafting.

OBJECTIVES: While surgical ablation (SA) for persistent atrial fibrillation (AF) can reduce recurrence of AF, its impact on longitudinal survival and health-care costs remains controversial. This study defines the clinical outcomes and costs associated with SA in patients with prior AF undergoing coronary artery bypass grafting (CABG). METHODS: A total of 3745 Medicare beneficiaries with prior AF who underwent CABG in 2013 were divided into 2 groups: those with and those without concomitant SA. Risk-adjusted early (0-90 days) and late (91-364 days) postoperative outcomes and inpatient costs were compared. RESULTS: SA was performed in 17% of CABG patients with prior AF. Preoperative characteristics favoured patients with SA: emergent presentation (15% vs 22%), heart failure in the 2 weeks prior to CABG (31% vs 36%), chronic lung disease (27% vs 33%) and renal failure (4% vs 7%) (all P < 0.05). Risk-adjusted operative mortality and perioperative stroke rates were similar in the 2 groups. Risk-adjusted survival was similar through 90 days, but significantly better with SA after 90 days [hazard ratio (HR) = 0.58; P = 0.03]. At 1 year, the risk-adjusted incidence of cardiovascular implantable electronic device implantation was greater with SA (HR = 1.20; P = 0.01). Risk-adjusted costs for the CABG admission (HR = 1.11; P < 0.01) and inpatient care through 1 year (HR = 1.06; P = 0.02) were also greater with SA. CONCLUSIONS: In the US Medicare population, SA was performed in 17% of CABG-AF patients in 2013. Operative risks for mortality and stroke did not increase with SA but costs did. Patients receiving SA, however, had significantly better risk-adjusted late survival.

Increased long-term mortality in patients with cardiovascular implantable electronic device infections.

BACKGROUND: Device infection is associated with increased mortality in patients receiving cardiovascular implantable electronic device (CIED) therapy. However, long-term mortality associated with CIED infections has not been systematically analyzed in larger studies. This study sought to determine the long-term mortality associated with CIED infection in a large cohort of Medicare beneficiaries. METHODS: We used a retrospective study design to analyze 3-year mortality in 200,219 Medicare fee-for-service patients admitted for CIED generator implantation, replacement, or revision between January 1, 2007 and December 31, 2007. Multivariate analysis adjusting for age, sex, race, and 28 comorbidities was performed to determine the relative risk (RR) of death in the 12 quarters following CIED infection. RESULTS: Patients with CIED infection, compared to device recipients without infection, had increased mortality that persisted for at least 3 years after the admission quarter for all device types: pacemakers (PMs: 53.8% vs 33%; P < 0.001), implantable cardioverter defibrillator (ICD: 47.7% vs 31.6%; P < 0.001), and cardiac resynchronization therapy-defibrillator (CRT-D: 50.8% vs 36.5%; P < 0.001). After adjusting for patient demographics and comorbidities, significantly increased RR of death following CIED infection persisted for at least 3 years following PM infection, and for at least 2 years with single- and dual-chamber ICD infection. CONCLUSIONS: CIED recipients who develop device infection have increased, device-dependent, long-term mortality even after successful treatment of infection. The etiology of this persistent increased risk of death associated with CIED infection is unknown and merits further investigation.

KCNQ1, KCNE2, and Na+-coupled solute transporters form reciprocally regulating complexes that affect neuronal excitability.

Na(+)-coupled solute transport is crucial for the uptake of nutrients and metabolic precursors, such as myo-inositol, an important osmolyte and precursor for various cell signaling molecules. We found that various solute transporters and potassium channel subunits formed complexes and reciprocally regulated each other in vitro and in vivo. Global metabolite profiling revealed that mice lacking KCNE2, a K(+) channel ß subunit, showed a reduction in myo-inositol concentration in cerebrospinal fluid (CSF) but not in serum. Increased behavioral responsiveness to stress and seizure susceptibility in Kcne2(-/-) mice were alleviated by injections of myo-inositol. Suspecting a defect in myo-inositol transport, we found that KCNE2 and KCNQ1, a voltage-gated potassium channel α subunit, colocalized and coimmunoprecipitated with SMIT1, a Na(+)-coupled myo-inositol transporter, in the choroid plexus epithelium. Heterologous coexpression demonstrated that myo-inositol transport by SMIT1 was augmented by coexpression of KCNQ1 but was inhibited by coexpression of both KCNQ1 and KCNE2, which form a constitutively active, heteromeric K(+) channel. SMIT1 and the related transporter SMIT2 were also inhibited by a constitutively active mutant form of KCNQ1. The activities of KCNQ1 and KCNQ1-KCNE2 were augmented by SMIT1 and the glucose transporter SGLT1 but were suppressed by SMIT2. Channel-transporter signaling complexes may be a widespread mechanism to facilitate solute transport and electrochemical crosstalk.

Comparison of mortality in women versus men with infections involving cardiovascular implantable electronic device.

Device infection is a complication of implantable cardioverter-defibrillator (ICD) therapy that significantly increases mortality. Risk factors associated with death and ICD infection are poorly understood. The purpose of this study was to identify patient characteristics associated with death after cardiovascular implantable electronic device (CIED) infection. This is a retrospective cohort study of 64,903 Medicare fee-for-service patients who received an ICD in 2007, including 1,855 with device infection. Long-term survival was significantly reduced with CIED infection (71.6% vs 85.0%, p <0.001). Regression analysis accounting for age, race, gender, and 28 co-morbidities identified only 2 patient characteristics associated with decreased long-term survival with CIED infection: female gender and human immunodeficiency virus/acquired immunodeficiency syndrome. In patients with CIED infection, women had substantially reduced long-term survival compared with men (67.3% vs 72.9%, p <0.02). The risk-adjusted hazard ratio for long-term mortality with device infection in women compared with that in men increased significantly from 0.86 (95% confidence interval [CI] 0.82 to 0.91) to 1.25 (95% CI 1.02 to 1.53), corresponding to a risk increase of >45%. Importantly, a substantial portion of this excess mortality occurred after the index admission for infection, when the hazard ratio for death in women compared with that in men increased from 0.86 (95% CI 0.82 to 0.91) to 1.20 (95% CI 0.96 to 1.51) with CIED infection, despite little gender difference in admission length of stay, disposition, and cost. In conclusion, women are significantly more likely than men to die with CIED infection. A substantial part of this excess mortality occurs after discharge. It will be important to identify and address the cause(s) of this gender difference in mortality.

Mortality and cost associated with cardiovascular implantable electronic device infections.

BACKGROUND: Cardiovascular implantable electronic device (CIED) therapy can reduce morbidity and mortality, but this benefit can be diminished by CIED infection. Currently, there are limited published data on the mortality and cost associated with CIED infection. METHODS: We analyzed the risk-adjusted total and incremental admission mortality, long-term mortality, admission length of stay (LOS), and admission cost associated with infection in a retrospective cohort of 200 219 Medicare fee-for-service patients admitted for CIED generator implantation, replacement, or revision between January 1, 2007, and December 31, 2007. RESULTS: There were a total of 5817 admissions with infection. Infection was associated with significant increases in adjusted admission mortality (rate ratios, 4.8-7.7; standardized rates, 4.6%-11.3%) and long-term mortality (rate ratios, 1.6-2.1; standardized rates, 26.5%-35.1%), depending on CIED type. Importantly, approximately half of the incremental long-term mortality occurred after discharge. The adjusted LOS was significantly longer with infection (length of stay mean ratios, 2.5-4.0; standardized length of stay, 15.5-24.3 days), depending on CIED type. The standardized adjusted incremental and total admission costs with infection were $14 360 to $16 498 and $28 676 to $53 349, respectively, depending on CIED type. The largest incremental cost with infection was intensive care, which accounted for more than 40% of the difference. Adjusted long-term mortality rate and cost ratios with infection were significantly greater for pacemakers than for implantable cardioverter/defibrillators or cardiac resynchronization therapy/defibrillator devices. CONCLUSIONS: Infection associated with CIED procedures resulted in substantial incremental admission mortality and long-term mortality that varied with the CIED type and occurred, in part, after discharge. Almost half of the incremental admission cost was for intensive care.

KCNE2 forms potassium channels with KCNA3 and KCNQ1 in the choroid plexus epithelium.

Cerebrospinal fluid (CSF) is crucial for normal function and mechanical protection of the CNS. The choroid plexus epithelium (CPe) is primarily responsible for secreting CSF and regulating its composition by mechanisms currently not fully understood. Previously, the heteromeric KCNQ1-KCNE2 K(+) channel was functionally linked to epithelial processes including gastric acid secretion and thyroid hormone biosynthesis. Here, using Kcne2(-/-) tissue as a negative control, we found cerebral expression of KCNE2 to be markedly enriched in the CPe apical membrane, where we also discovered expression of KCNQ1. Targeted Kcne2 gene deletion in C57B6 mice increased CPe outward K(+) current 2-fold. The Kcne2 deletion-enhanced portion of the current was inhibited by XE991 (10 µM) and margatoxin (10 µM) but not by dendrotoxin (100 nM), indicating that it arose from augmentation of KCNQ subfamily and KCNA3 but not KCNA1 K(+) channel activity. Kcne2 deletion in C57B6 mice also altered the polarity of CPe KCNQ1 and KCNA3 trafficking, hyperpolarized the CPe membrane by 9 ± 2 mV, and increased CSF [Cl(-)] by 14% compared with wild-type mice. These findings constitute the first report of CPe dysfunction caused by cation channel gene disruption and suggest that KCNE2 influences blood-CSF anion flux by regulating KCNQ1 and KCNA3 in the CPe.

Genetic dissection reveals unexpected influence of beta subunits on KCNQ1 K+ channel polarized trafficking in vivo.

Targeted deletion of the Kcne2 potassium channel ß subunit gene ablates gastric acid secretion and predisposes to gastric neoplasia in mice. Here, we discovered that Kcne2 deletion basolaterally reroutes the Kcnq1 α subunit in vivo in parietal cells (PCs), in which the normally apical location of the Kcnq1-Kcne2 channel facilitates its essential role in gastric acid secretion. Quantitative RT-PCR and Western blotting revealed that Kcne2 deletion remodeled fundic Kcne3 (2.9±0.8-fold mRNA increase, n=10; 5.3±0.4-fold protein increase, n=7) but not Kcne1, 4, or 5, and resulted in basolateral Kcnq1-Kcne3 complex formation in Kcne2(-/-) PCs. Concomitant targeted deletion of Kcne3 (creating Kcne2(-/-)Kcne3(-/-) mice) restored PC apical Kcnq1 localization without Kcne1, 4, or 5 remodeling (assessed by quantitative RT-PCR; n=5-10), indicating Kcne3 actively, basolaterally rerouted Kcnq1 in Kcne2(-/-) PCs. Despite this, Kcne3 deletion exacerbated gastric hyperplasia in Kcne2(-/-) mice, and both hypochlorhydria and hyperplasia in Kcne2(+/-) mice, suggesting that Kcne3 up-regulation was beneficial in Kcne2-depleted PCs. The findings reveal, in vivo, Kcne-dependent α subunit polarized trafficking and the existence and consequences of potassium channel ß subunit remodeling.

Implantation success and infection in cardiovascular implantable electronic device procedures utilizing an antibacterial envelope.

BACKGROUND: Cardiovascular implantable electronic device (CIED) infection rates are increasing faster than implantation rates. More effective antimicrobial prophylaxis may help reduce CIED infections and improve clinical outcomes. The AIGIS(Rx)(®) antibacterial envelope is a polymer mesh implanted in the generator pocket with the CIED. After implantation it releases two antibiotics, minocycline and rifampin, that have been shown to reduce infections associated with other medical devices. The purpose of this retrospective cohort study is to determine the rate of CIED implantation success and CIED infection in procedures utilizing the antibacterial envelope. METHODS: This study enrolled consecutive CIED procedures utilizing the antibacterial envelope at 10 US academic, community, and Veterans Affairs medical centers. Procedures following an explantation for a prior CIED infection or off-label use of the antibacterial envelope were excluded. RESULTS: The 624 eligible procedures (age 70 ± 13 years, 68.1% men, 27.2% renal insufficiency, 35.4% oral anticoagulant use, 67.8% replacement/revision procedures) utilized pacemakers (35%), implantable cardioverter-defibrillators (ICD)(29%), and cardiac resynchronization therapy with defibrillator devices (CRT-D)(36%). Nearly half of the patients (49%) had at least three predefined risk factors for CIED infection. CIED implantation was successful in 621 procedures (99.5%[95% confidence interval (CI) 98.8-99.9]). There were three major infections (0.48%[95%CI 0.17-1.40]) after 1.9 ± 2.4 months follow-up. The infections followed one ICD revision and two CRT-D replacements. There were seven deaths; none was a result of the antibacterial envelope or the CIED procedure. CONCLUSIONS: CIED procedures that utilized an antibacterial envelope had a high rate of CIED implantation success (>99%). Although the follow-up to date is short, there was also a low rate of infection (<0.50%) in this population at high risk for CIED infection.

Targeted deletion of Kcne2 causes gastritis cystica profunda and gastric neoplasia.

Gastric cancer is the second leading cause of cancer death worldwide. Predisposing factors include achlorhydria, Helicobacter pylori infection, oxyntic atrophy and TFF2-expressing metaplasia. In parietal cells, apical potassium channels comprising the KCNQ1 alpha subunit and the KCNE2 beta subunit provide a K(+) efflux current to facilitate gastric acid secretion by the apical H(+)K(+)ATPase. Accordingly, genetic deletion of murine Kcnq1 or Kcne2 impairs gastric acid secretion. Other evidence has suggested a role for KCNE2 in human gastric cancer cell proliferation, independent of its role in gastric acidification. Here, we demonstrate that 1-year-old Kcne2(-/-) mice in a pathogen-free environment all exhibit a severe gastric preneoplastic phenotype comprising gastritis cystica profunda, 6-fold increased stomach mass, increased Ki67 and nuclear Cyclin D1 expression, and TFF2- and cytokeratin 7-expressing metaplasia. Some Kcne2(-/-) mice also exhibited pyloric polypoid adenomas extending into the duodenum, and neoplastic invasion of thin walled vessels in the sub-mucosa. Finally, analysis of human gastric cancer tissue indicated reduced parietal cell KCNE2 expression. Together with previous findings, the results suggest KCNE2 disruption as a possible risk factor for gastric neoplasia.

Kcne2 deletion uncovers its crucial role in thyroid hormone biosynthesis.

Thyroid dysfunction is a global health concern, causing defects including neurodevelopmental disorders, dwarfism and cardiac arrhythmia. Here, we show that the potassium channel subunits KCNQ1 and KCNE2 form a thyroid-stimulating hormone-stimulated, constitutively active, thyrocyte K+ channel required for normal thyroid hormone biosynthesis. Targeted disruption of Kcne2 in mice impaired thyroid iodide accumulation up to eightfold, impaired maternal milk ejection, halved milk tetraiodothyronine (T4) content and halved litter size. Kcne2-deficient mice had hypothyroidism, dwarfism, alopecia, goiter and cardiac abnormalities including hypertrophy, fibrosis, and reduced fractional shortening. The alopecia, dwarfism and cardiac abnormalities were alleviated by triiodothyronine (T3) and T4 administration to pups, by supplementing dams with T(4) before and after they gave birth or by feeding the pups exclusively from Kcne2+/+ dams; conversely, these symptoms were elicited in Kcne2+/+ pups by feeding exclusively from Kcne2-/- dams. These data provide a new potential therapeutic target for thyroid disorders and raise the possibility of an endocrine component to previously identified KCNE2- and KCNQ1-linked human cardiac arrhythmias.

MinK-dependent internalization of the IKs potassium channel.

AIMS: KCNQ1-MinK potassium channel complexes (4alpha:2beta stoichiometry) generate IKs, the slowly activating human cardiac ventricular repolarization current. The MinK ancillary subunit slows KCNQ1 activation, eliminates its inactivation, and increases its unitary conductance. However, KCNQ1 transcripts outnumber MinK transcripts five to one in human ventricles, suggesting KCNQ1 also forms other heteromeric or even homomeric channels there. Mechanisms governing which channel types prevail have not previously been reported, despite their significance: normal cardiac rhythm requires tight control of IKs density and kinetics, and inherited mutations in KCNQ1 and MinK can cause ventricular fibrillation and sudden death. Here, we describe a novel mechanism for this control. METHODS AND RESULTS: Whole-cell patch-clamping, confocal immunofluorescence microscopy, antibody feeding, biotin feeding, fluorescent transferrin feeding, and protein biochemistry techniques were applied to COS-7 cells heterologously expressing KCNQ1 with wild-type or mutant MinK and dynamin 2 and to native IKs channels in guinea-pig myocytes. KCNQ1-MinK complexes, but not homomeric KCNQ1 channels, were found to undergo clathrin- and dynamin 2-dependent internalization (DDI). Three sites on the MinK intracellular C-terminus were, in concert, necessary and sufficient for DDI. Gating kinetics and sensitivity to XE991 indicated that DDI decreased cell-surface KCNQ1-MinK channels relative to homomeric KCNQ1, decreasing whole-cell current but increasing net activation rate; inhibiting DDI did the reverse. CONCLUSION: The data redefine MinK as an endocytic chaperone for KCNQ1 and present a dynamic mechanism for controlling net surface Kv channel subunit composition-and thus current density and gating kinetics-that may also apply to other alpha-beta type Kv channel complexes.

Targeted deletion of kcne2 impairs ventricular repolarization via disruption of I(K,slow1) and I(to,f).

Mutations in human KCNE2, which encodes the MiRP1 potassium channel ancillary subunit, associate with long QT syndrome (LQTS), a defect in ventricular repolarization. The precise cardiac role of MiRP1 remains controversial, in part, because it has marked functional promiscuity in vitro. Here, we disrupted the murine kcne2 gene to define the role of MiRP1 in murine ventricles. kcne2 disruption prolonged ventricular action potential duration (APD), suggestive of reduced repolarization capacity. Accordingly, kcne2 (-/-) ventricles exhibited a 50% reduction in I(K,slow1), generated by Kv1.5--a previously unknown partner for MiRP1. I(to,f), generated by Kv4 alpha subunits, was also diminished, by approximately 25%. Ventricular MiRP1 protein coimmunoprecipitated with native Kv1.5 and Kv4.2 but not Kv1.4 or Kv4.3. Unexpectedly, kcne2 (-/-) ventricular membrane fractions exhibited 50% less mature Kv1.5 protein than wild type, and disruption of Kv1.5 trafficking to the intercalated discs. Consistent with the reduction in ventricular K(+) currents and prolonged ventricular APD, kcne2 deletion lengthened the QT(c) under sevoflurane anesthesia. Thus, targeted disruption of kcne2 has revealed a novel cardiac partner for MiRP1, a novel role for MiRPs in alpha subunit targeting in vivo, and a role for MiRP1 in murine ventricular repolarization with parallels to that proposed for the human heart.

The KCNE2 potassium channel ancillary subunit is essential for gastric acid secretion.

Genes in the KCNE family encode single transmembrane domain ancillary subunits that co-assemble with voltage-gated potassium (Kv) channel alpha subunits to alter their function. KCNE2 (also known as MiRP1) is expressed in the heart, is associated with human cardiac arrhythmia, and modulates cardiac Kv alpha subunits hERG and KCNQ1 in vitro. KCNE2 and KCNQ1 are also expressed in parietal cells, leading to speculation they form a native channel complex there. Here, we disrupted the murine kcne2 gene and found that kcne2 (-/-) mice have a severe gastric phenotype with profoundly reduced parietal cell proton secretion, abnormal parietal cell morphology, achlorhydria, hypergastrinemia, and striking gastric glandular hyperplasia arising from an increase in the number of non-acid secretory cells. KCNQ1 exhibited abnormal distribution in gastric glands from kcne2 (-/-) mice, with increased expression in non-acid secretory cells. Parietal cells from kcne2 (+/-) mice exhibited normal architecture but reduced proton secretion, and kcne2 (+/-) mice were hypochlorhydric, indicating a gene-dose effect and a primary defect in gastric acid secretion. These data demonstrate that KCNE2 is essential for gastric acid secretion, the first genetic evidence that a member of the KCNE gene family is required for normal gastrointestinal function.