Dynamic regulation of airway surface liquid pH by TMEM16A and SLC26A4 in cystic fibrosis nasal epithelia with rare mutations

Copyright \ua9 2023 the Author(s). Published by PNAS. In cystic fibrosis (CF), defects in the CF transmembrane conductance regulator (CFTR) channel lead to an acidic airway surface liquid (ASL), which compromises innate defence mechanisms, predisposing to pulmonary failure. Restoring ASL pH is a potential therapy for people with CF, particularly for those who cannot benefit from current highly effective modulator therapy. However, we lack a comprehensive understanding of the complex mechanisms underlying ASL pH regulation. The calcium-activated chloride channel, TMEM16A, and the anion exchanger, SLC26A4, have been proposed as targets for restoring ASL pH, but current results are contradictory and often utilise nonphysiological conditions. To provide better evidence for a role of these two proteins in ASL pH homeostasis, we developed an efficient CRISPR-Cas9-based approach to knock-out (KO) relevant transporters in primary airway basal cells lacking CFTR and then measured dynamic changes in ASL pH under thin-film conditions in fully differentiated airway cultures, which better simulate the in vivo situation. Unexpectantly, we found that both proteins regulated steady-state as well as agonist-stimulated ASL pH, but only under inflammatory conditions. Furthermore, we identified two Food and Drug Administration (FDA)-approved drugs which raised ASL pH by activating SLC26A4. While we identified a role for SLC26A4 in fluid absorption, KO had no effect on cyclic adenosine monophosphate (cAMP)-stimulated fluid secretion in airway organoids. Overall, we have identified a role of TMEM16A in ASL pH homeostasis and shown that both TMEM16A and SLC26A4 could be important alternative targets for ASL pH therapy in CF, particularly for those people who do not produce any functional CFTR

Meta-analysis of four new genome scans for lipid parameters and analysis of positional candidates in positive linkage regions

Lipid levels in plasma strongly influence the risk for coronary heart disease. To localise and subsequently identify genes affecting lipid levels, we performed four genome-wide linkage scans followed by combined linkage/association analysis. Genome-scans were performed in 701 dizygotic twin pairs from four samples with data on plasma levels of HDL- and LDL-cholesterol and their major protein constituents, apolipoprotein AI (ApoAI) and Apolipoprotein B (ApoB). To maximise power, the genome scans were analysed simultaneously using a well-established meta-analysis method that was newly applied to linkage analysis. Overall LOD scores were estimated using the means of the sample-specific quantitative trait locus (QTL) effects inversely weighted by the standard errors obtained using an inverse regression method. Possible heterogeneity was accounted for with a random effects model. Suggestive linkage for HDL-C was observed on 8p23.1 and 12q21.2 and for ApoAI on 1q21.3. For LDL-C and ApoB, linkage regions frequently coincided (2p24.1, 2q32.1, 19p13.2 and 19q13.31). Six of the putative QTLs replicated previous findings. After fine mapping, three maximum LOD scores mapped within 1cM of major candidate genes, namely APOB (LOD =2.1), LDLR (LOD =1.9) and APOE (LOD =1.7). APOB haplotypes explained 27% of the QTL effect observed for LDL-C on 2p24.1 and reduced the LOD-score by 0.82. Accounting for the effect of the LDLR and APOE haplotypes did not change the LOD score close to the LDLR gene but abolished the linkage signal at the APOE gene. In conclusion, application of a new meta-analysis approach maximised the power to detect QTLs for lipid levels and improved the precision of their location estimate. © 2005 Nature Publishing Group. All rights reserved

Selective serotonin reuptake inhibitors in the treatment of generalized anxiety disorder

Selective serotonin reuptake inhibitors have proven efficacy in the treatment of panic disorder, obsessive–compulsive disorder, post-traumatic stress disorder and social anxiety disorder. Accumulating data shows that selective serotonin reuptake inhibitor treatment can also be efficacious in patients with generalized anxiety disorder. This review summarizes the findings of randomized controlled trials of selective serotonin reuptake inhibitor treatment for generalized anxiety disorder, examines the strengths and weaknesses of other therapeutic approaches and considers potential new treatments for patients with this chronic and disabling anxiety disorder

Measurement invariance of the center for epidemiological studies depression scale (CES-D) among chinese and dutch elderly

Background: Although previous studies using non- elderly groups have assessed the factorial invariance of the Center for Epidemiological Studies Depression Scale (CES-D) across different groups with the same social-cultural backgrounds, few studies have tested the factorial invariance of the CES-D across two elderly groups from countries with different social cultures. The purposes of this study were to examine the factorial structure of the CES-D, and test its measurement invariance across two different national elderly populations. Methods. A total of 6806 elderly adults from China (n = 4903) and the Netherlands (n = 1903) were included in the final sample. The CES-D was assessed in both samples. Three strategies were used in the data analysis procedure. First, a confirmatory factor analysis (CFA) was carried out to determine the factor structures of the CES-D that best fitted the two samples. Second, the best fitting model was incorporated into a multi-group CFA model to test measurement invariance of the CES-D across the two population groups. Third, latent mean differences between the two groups were tested. Results: The results of confirmatory factor analysis (CFA) showed: 1) in both samples, Radloff's four-factor model resulted in a significantly better fit and the four dimensions (somatic complaints, depressed affect, positive affect, and interpersonal problems) of the CES-D seem to be the most informative in assessing depressive symptoms compared to the single-, three-, and the second-order factor models; and 2) the factorial structure was invariant across the populations under study. However, only partial scalar and uniqueness invariance of the CES-D items was supported. Latent means in the partial invariant model were lower for the Dutch sample, compared to the Chinese sample. Conclusions: Our findings provide evidence of a valid factorial structure of the CES-D that could be applied to elderly populations from both China and the Netherlands, producing a meaningful comparison of total scores between the two elderly groups. However, for some specific factors and items, caution is required when comparing the depressive symptoms between Chinese and Dutch elderly groups. © 2011 Zhang et al; licensee BioMed Central Ltd

Ten-year trends in benzodiazepine use in the Dutch population

Background In the past decades knowledge on adequate treatment of affective disorders and awareness of the negative consequences of long-term benzodiazepine use increased. Therefore, a decrease in benzodiazepine use is expected, particularly in prolonged use. The aim of this study was to assess time trends in benzodiazepine use. Methods and material Data from the Longitudinal Aging Study Amsterdam (LASA) were used to investigate trends in benzodiazepine use between 1992 and 2002 in two population-based samples aged 55-64 years. Differences between the two samples with respect to benzodiazepine use and to sociodemographic, physical health and mental health characteristics were described and tested with chi- square tests and logistic regression analyses. Results Benzodiazepine use remained stable over 10 years, with 7.8% in LASA-1 (n = 874) and 7.9% in LASA-2 (n = 919) (p = 0.90) with a persisting preponderance in women and in people with low education, low income, chronic physical diseases, functional limitations, cognitive impairment, depression, anxiety complaints, sleep problems and when using antidepressants. Long-term use remained high with 70% in 1992 and 80% in 2002 of total benzodiazepine use. Conclusion In the Dutch population aged 55-64, overall benzodiazepine use remained stable from 1992 to 2002, with a high proportion of long-term users, despite the effort to reduce benzodiazepine use and the renewal of the guidelines. More effort should be made to decrease prolonged benzodiazepine use in this middle-aged group, because of the increasing risks with ageing. © The Author(s) 2011

Interpersonal psychotherapy (IPT) for late-life depression in general practice: uptake and satisfaction by patients, therapists and physicians

<p>Abstract</p> <p>Background</p> <p>Interpersonal Psychotherapy (IPT) is recommended in most depression treatment guidelines and proved to be a suitable treatment for elderly depressed patients. Despite the favorable results of IPT in research populations, the dissemination to general practice is surprisingly limited. Little is known about uptake and satisfaction when this therapy is introduced into real-life general practice.</p> <p>Methods</p> <p>Motivation and evaluation of patients, GPs and therapists were recorded and organizational barriers described alongside a randomized controlled trial. IPT, given by mental health workers, was compared with usual general practitioner (GP) care. Included were patients (≥55 years) who met the DSM-IV criteria for major depressive disorder.</p> <p>Results</p> <p>Patients were motivated for the psychotherapy intervention: of the 205 eligible patients, 143 (70%) entered the study, and of the 69 patients who were offered IPT, 77% complied with the treatment. IPT proved to be an attractive therapy for patients as well as for therapists from mental health organizations. General practitioners evaluated the intervention positively afterwards, mainly because of the time-limited and structured approach. Organizational barriers: no IPT therapists were available; an IPT trainer and supervisor had to be trained and training materials had to be developed and translated. Additionally, there was a lack of office space in some general practices; for therapists from private practices it was not feasible to participate because of financial reasons. IPT was superior to usual care in patients with moderate to severe depression.</p> <p>Conclusion</p> <p>As we succeeded in delivering IPT in primary care practice, and as IPT was superior to usual care, there are grounds to support the implementation of IPT for depressed elderly patients within general practice, as long as the practices have room for the therapists and financial barriers can be overcome. Consolidation may be achieved by making this intervention available through practice nurses or community psychiatric nurses who deliver IPT as part of a more comprehensive depression management program.</p

Emergent complex neural dynamics

A large repertoire of spatiotemporal activity patterns in the brain is the basis for adaptive behaviour. Understanding the mechanism by which the brain's hundred billion neurons and hundred trillion synapses manage to produce such a range of cortical configurations in a flexible manner remains a fundamental problem in neuroscience. One plausible solution is the involvement of universal mechanisms of emergent complex phenomena evident in dynamical systems poised near a critical point of a second-order phase transition. We review recent theoretical and empirical results supporting the notion that the brain is naturally poised near criticality, as well as its implications for better understanding of the brain