Missorting of the Aquaporin-2 mutant E258K to multivesicular bodies/lysosomes in dominant NDI is associated with its monoubiquitination and increased phosphorylation by PKC but is due to the loss of E258

To stimulate renal water reabsorption, vasopressin induces phosphorylation of Aquaporin-2 (AQP2) water channels at S256 and their redistribution from vesicles to the apical membrane, whereas vasopressin removal results in AQP2 ubiquitination at K270 and its internalization to multivesicular bodies (MVB). AQP2-E258K causes dominant nephrogenic diabetes insipidus (NDI), but its subcellular location is unclear, and the molecular reason for its involvement in dominant NDI is unknown. To unravel these, AQP2-E258K was studied in transfected polarized Madin–Darby canine kidney (MDCK) cells. In MDCK cells, AQP2-E258K mainly localized to MVB/lysosomes (Lys). Upon coexpression, wild-type (wt) AQP2 and AQP2-E258K formed multimers, which also localized to MVB/Lys, independent of forskolin stimulation. Orthophosphate labeling revealed that forskolin increased phosphorylation of wt-AQP2 and AQP2-E258K but not AQP2-S256A, indicating that the E258K mutation does not interfere with the AQP2 phosphorylation at S256. In contrast to wt-AQP2 but consistent with the introduced protein kinase C (PKC) consensus site, AQP2-E258K was phosphorylated by phorbol esters. Besides the 29-kDa band, however, an additional band of about 35 kDa was observed for AQP2-E258K only, which represented AQP2-E258K uniquely monoubiquitinated at K228 only. Analysis of several mutants interfering with AQP2-E258K phosphorylation, and/or ubiquitination, however, revealed that the MVB/lysosomal sorting of AQP2-E258K occurred independent of its monoubiquitination or phosphorylation by PKC. Instead, our data reveal that the loss of the E258 in AQP2-E258K is fundamental to its missorting to MVB/Lys and indicate that this amino acid has an important role in the proper structure formation of the C-terminal tail of AQP2.     

Associations between the ankle-brachial index and cardiovascular and all-cause mortality are similar in individuals without and with type 2 diabetes: nineteen-year follow-up of a population-based cohort study

OBJECTIVE

In the general population, a low ankle-brachial index (ABI) (<0.9) is strongly associated with (cardiovascular) mortality. However, the association between the ABI and mortality may be weaker in individuals with diabetes, as ankle pressures may be elevated by medial arterial calcification and arterial stiffening, which occur more frequently in diabetes. Therefore, the aim of this study was to compare the association between ABI and mortality in individuals without and with diabetes.

RESEARCH DESIGN AND METHODS

We studied the associations between ABI and cardiovascular and all-cause mortality in 624 individuals from the Hoorn study, a population-based cohort of 50- to 75-year-old individuals (155 with diabetes and 469 without) followed for a median period of 17.2 years. Data were analyzed using Cox proportional hazards models.

RESULTS

During the follow-up period, 289 of 624 (46.3%) participants died (97 of 155 with and 192 of 469 without diabetes and 52 of 65 with and 237 of 559 without ABI <0.9): 85 (29.4%) of CVD (30 of 155 with and 55 of 469 without diabetes and 20 of 65 with and 65 of 559 without ABI <0.9). A low ABI was strongly associated with cardiovascular mortality (relative risk 2.57 [95% CI 1.50–4.40]) and all-cause mortality (2.02 [1.47–2.76]), after adjustment for Framingham risk factors. The associations of the ABI with mortality did not differ between individuals without and with diabetes for cardiovascular (P_interaction = 0.45) or all-cause (P_interaction = 0.63) mortality.

CONCLUSIONS

In the Hoorn Study, associations between ABI and cardiovascular and all-cause mortality were similar in individuals without and with diabetes. Future studies should investigate, in both individuals without and with diabetes, whether measurement of ABI can be used to guide treatment decisions.Identifying individuals with a high risk of cardiovascular morbidity and mortality remains challenging, as many high-risk individuals are asymptomatic (1). The ankle-brachial blood pressure index (ABI) is a marker for systemic atherosclerosis, is strongly associated with mortality (2), and may thus improve identification of high-risk individuals. However, the validity of the ABI may be decreased in diabetes, as ankle pressures may be elevated by medial arterial calcification and arterial stiffening, which occur more frequently in diabetes (3). In diabetes, the ABI may thus fall within the normal range (≥0.9 to ≤1.4) when both atherosclerosis and arterial stiffening and calcifications of the lower limbs occur within the same individual. Therefore, the aim of this study was to investigate whether the associations between the ABI and cardiovascular and all-cause mortality are similar or, in fact, weaker in individuals with diabetes than in individuals without diabetes. We investigated the ABI at several cutoff points (ABI <0.9, <1.0, and <1.1) and as a continuous variable because development of atherosclerosis in the lower limbs is a continuous process (4). In addition, we investigated whether alternatives for the ABI, such as the toe-brachial index (TBI) and Doppler flow curves of the lower extremities, were more strongly associated with mortality than the ABI in individuals with diabetes, as these techniques may be less affected by arterial calcifications and stiffening than the ABI.     

The type I interferon response during viral infections: a "SWOT" analysis

The type I interferon (IFN) response is a strong and crucial moderator for the control of viral infections. The strength of this system is illustrated by the fact that, despite some temporary discomfort like a common cold or diarrhea, most viral infections will not cause major harm to the healthy immunocompetent host. To achieve this, the immune system is equipped with a wide array of pattern recognition receptors and the subsequent coordinated type I IFN response orchestrated by plasmacytoid dendritic cells (pDCs) and conventional dendritic cells (cDCs). The production of type I IFN subtypes by dendritic cells (DCs), but also other cells is crucial for the execution of many antiviral processes. Despite this coordinated response, morbidity and mortality are still common in viral disease due to the ability of viruses to exploit the weaknesses of the immune system. Viruses successfully evade immunity and infection can result in aberrant immune responses. However, these weaknesses also open opportunities for improvement via clinical interventions as can be seen in current vaccination and antiviral treatment programs. The application of IFNs, Toll-like receptor ligands, DCs, and antiviral proteins is now being investigated to further limit viral infections. Unfortunately, a common threat during stimulation of immunity is the possible initiation or aggravation of autoimmunity. Also the translation from animal models to the human situation remains difficult. With a Strengths-Weaknesses-Opportunities-Threats ("SWOT") analysis, we discuss the interaction between host and virus as well as (future) therapeutic options, related to the type I IFN system.     

Questioning the Role of a Neutropenic Diet following Hematopoetic Stem Cell Transplantation

The use of a neutropenic diet (ND) after hematopoietic stem cell transplantation (HSCT) was instituted more than 30 years ago as a means of preventing infection from organisms colonizing the gastrointestinal tract. Evidence supporting this practice is lacking, however, and the actual efficacy of the ND remains unknown. Institutional policy at Northwestern Memorial Hospital discontinued the use of ND in 2006. We conducted a retrospective study of 726 consecutive HSCT recipients, 363 who received an ND and 363 who received a general hospital diet, to determine the incidence of microbiologically confirmed infections during and after transplantation. Our findings indicate a higher rate of infections in the HSCT recipients who received an ND.     

Applicability of two brief evidence-based interventions to improve sleep quality in inpatient mental health care

The present study explored the applicability of two brief evidence-based interventions to improve sleep quality in inpatient psychiatry. The study involved three comparable admission wards of a psychiatric hospital. Stimulus control was introduced at the first ward, and music-assisted relaxation at the second. At the third ward, no intervention was introduced. A mixed-method study was employed. We found that nurses share the opinion that both interventions can be applied, but patients are hard to motivate. They perceived the lack of available time, busyness at the ward, and the lack of cooperation of patients as the main obstacles. The perception of a successful implementation is correlated with the perception of gained attention for sleep problems, the perception of increased care options, and the impression of effectiveness. Qualitative data showed that the effectiveness of the interventions was compromised by operational issues, commitment issues, adaptation to contextual limitations, and conflicting individual beliefs. We concluded that music-assisted relaxation is applicable in inpatient psychiatry. The application of stimulus control met with insurmountable operational issues. The nursing team is a very important factor for the implementation of evidence-based interventions at ward level. The lack of a shared urge for change and responsibility for continuity are important factors contributing to failure.     

Peer Reviewed: Causal Beliefs and Perceptions of Risk for Diabetes and Cardiovascular Disease, the Netherlands, 2007

Introduction

Understanding people''s perceptions of disease risk and how these perceptions compare with actual risk models may improve the effectiveness of risk communication. This study examined perceived disease risk and causal beliefs for type 2 diabetes and cardiovascular disease (CVD), the relationship between self-reported risk factors and perceived disease risk, and the influence of causal beliefs on perceived disease risk in people at increased risk.

Methods

The sample (n = 255) consisted of people who were at increased risk for diabetes and CVD (aged 57-79 y). Participants completed a postal questionnaire assessing risk factors, perceived risk, and causal beliefs for diabetes and CVD. We used regression analyses to examine the relationship between risk factors and perceived disease risk and to explore how causal beliefs affect the relationship between risk factors and perceived disease risk.

Results

Associations between risk factors and perceived diabetes and CVD risks were weak. Perceived risk, causal beliefs, and explained variance of risk factors on perceived risk were lower for diabetes than for CVD. Stronger beliefs concerning 1) overweight as a cause of diabetes and 2) smoking as a cause of CVD strengthened the association between these risk factors and perceived disease risk.

Conclusion

Although participants seemed to have some understanding of disease causation, they only partially translated their risk factors into accurate perceptions of risk. To improve understanding of risk information, health professionals may need to educate patients on how personal risk factors can contribute to the development of diabetes and CVD.     

Recognition, management and outcome of psychological disorders in primary care: a naturalistic follow-up study

This article addresses the issues of recognition and labelling of psychological disorders (PDs) by general practitioners (GPs), and the association of recognition with management and outcome. Nearly 2000 attenders of 25 GPs were screened with the GHQ and a stratified sample of 296 patients was examined twice, using the Present State Examination (PSE) and Groningen Social Disability Schedule (GSDS). Prevalence rates of PDs according to the GHQ, GP and PSE were 46%, 26% and 15% respectively. For the 1450 'new' patients, i.e. patients who had no PD diagnosed by their GP in the 12 months prior to the enrollment visit, these rates were 38%, 14%, and 10%. GPs missed half of the PSE cases and typically assigned non-specific diagnoses to recognized cases. Depressions were more readily recognized than anxiety disorders, and the detection rates for severe disorders were higher than those for less severe disorders. Recognition was strongly associated with management and outcome. Recognized as compared to non-recognized cases were more likely to receive mental health interventions from their GP and had better outcomes in terms of both psychopathology and social functioning. Initial severity, psychological reasons for encounter, recency of onset, diagnostic category, and psychiatric comorbidity were related to both better recognition and outcome. However, these variables could not account for the association of recognition with management and outcome, but some did modify the association. A causal model of the relationships is presented and possible reasons for non-recognition and for the beneficial effects of recognition are discussed.     

Effectiveness of a Cognitive Behavioral Therapy-Based Indicated Prevention Program for Children with Elevated Anxiety Levels: a Randomized Controlled Trial

Childhood anxiety is a problem not only because of its negative consequences on the well-being of children but also because of its adverse effects on society and its role in mental disorders later in life. Adequate prevention might be the key in tackling this problem. The effectiveness of Coping Cat, as an indicated CBT-based prevention program in Dutch primary school children, was assessed by means of a randomized controlled trial. In total, 141 children aged 7–13 with elevated levels of anxiety and their mothers were included and randomly assigned to an intervention group and a waiting list control group. After screening, all participants completed baseline, post-intervention, and 3-month follow-up assessments. The results showed that Coping Cat, as an indicated prevention program, reduces children’s self-reported anxiety symptoms, with Cohen’s effect size d of 0.66 at the 3-month follow-up. A moderating effect was found for baseline anxiety level; specifically, children with high levels of baseline anxiety who received the Coping Cat program had lower anxiety levels at follow-up compared to children with high levels of anxiety in the control condition. No moderating effects of gender or age were found. An unexpected decline in anxiety levels from screening to pre-assessment was found in both groups, and this decline was stronger in the experimental group. These promising results warrant the implementation of Coping Cat as an indicated prevention program.