Muscle phenotype in patients with myotonic dystrophy type 1

Introduction: The pathogenesis of muscle involvement in patients with myotonic dystrophy type 1 (DM1) is not well understood. In this study, we characterized the muscle phenotype in patients with confirmed DM1. Methods: In 38 patients, muscle strength was tested by hand‐held dynamometry. Myotonia was evaluated by a handgrip test and by analyzing the decrement of the compound muscle action potential. Muscle biopsies were assessed for morphological changes and Na⁺‐K⁺ pump content. Results: Muscle strength correlated with a decline in Na⁺‐K⁺ pump content (r = 0.60, P < 0.001) and with CTG expansion. CTG expansion did not correlate with severity of myotonia, proximal histopathological changes, or Na⁺‐K⁺ pump content. Histopathologically, we found few centrally placed nuclei (range 0.2–6.9%). Conclusions: The main findings of this study are that muscle weakness correlated inversely with CTG expansion and that central nuclei are not a prominent feature of proximal muscles in DM1. Muscle Nerve 47:409‐415, 2013     

The impact of modified mania assessment scale (MAS-M) implementation on the use of mechanical restraint in psychiatric units

Abstract

Background and aim: During recent years, there has been an increased focus on reducing use of mechanical restraint in psychiatric care. Studies show that implementing an assessment tool could potentially prevent or decrease the number of episodes of mechanical restraint. This study aims to examine the association between use of the Danish assessment tool for psychiatric inpatients diagnosed with mania (MAS-M) and mechanical restraint to highlight if number, type, and duration of restraint could be prevented or reduced by this procedure.

Materials and method: This historical cohort study included psychiatric inpatients diagnosed with bipolar disorder and hospitalized with symptoms of mania at the departments of affective disorders during the years 2012–2015. Logistic regression was used in the statistical analyses.

Result: A total of 218 patients were included, 74 of whom were scored with MAS-M. Thirty-five episodes of mechanical restraint were recorded. A crude OR of 1.58 (95% CI: 0.75–3.30) of the association was estimated. The study showed a tendency toward patients scored with MAS-M being more frequently restrained with both belt and straps, however, in shorter duration, compared to the control group.

Conclusion: This study reported relevant clinical information concerning staff’s use of MAS-M, however, did not show a significant association between the use of MAS-M and mechanical restraint. Nevertheless, conflicting results about the impact of MAS-M on preventing and reducing these coercive measures have been highlighted, suggesting that more complex factors influence the use of mechanical restraint. No causal effect was examined thus further studies are needed.     

Phosphorylation of rat aquaporin‐4 at Ser111 is not required for channel gating

Aquaporin 4 (AQP4) is the predominant water channel in the mammalian brain and is mainly expressed in the perivascular glial endfeet at the brain‐blood interface. AQP4 has been described as an important entry and exit site for water during formation of brain edema and regulation of AQP4 is therefore of therapeutic interest. Phosphorylation of some aquaporins has been proposed to regulate their water permeability via gating of the channel itself. Protein kinase (PK)‐dependent phosphorylation of Ser¹¹¹ has been reported to increase the water permeability of AQP4 expressed in an astrocytic cell line. This possibility was, however, questioned based on the crystal structure of the human AQP4. Our study aimed to resolve if Ser¹¹¹ was indeed a site involved in phosphorylation‐mediated gating of AQP4. The water permeability of AQP4‐expressing Xenopus oocytes was not altered by a range of activators and inhibitors of PKG and PKA. Mutation of Ser¹¹¹ to alanine or aspartate (to prevent or mimic phosphorylation) did not change the water permeability of AQP4. PKG activation had no effect on the water permeability of AQP4 in primary cultures of rat astrocytes. Molecular dynamics simulations of a phosphorylation of AQP4.Ser¹¹¹ recorded no phosphorylation‐induced change in water permeability. A phospho‐specific antibody, exclusively recognizing AQP4 when phosphorylated on Ser¹¹¹, failed to detect phosphorylation in cell lysate of rat brain stimulated by conditions proposed to induce phosphorylation of this residue. Thus, our data indicate a lack of phosphorylation of Ser¹¹¹ and of phosphorylation‐dependent gating of AQP4.     

Systematic identification and stratification of help-seeking school-aged youth with mental health problems: a novel approach to stage-based stepped-care

We investigated whether a novel visitation model for school-aged youth with mental health problems based on a stage-based stepped-care approach facilitated a systematic identification and stratification process without problems with equity in access. The visitation model was developed within the context of evaluating a new transdiagnostic early treatment for youth with anxiety, depressive symptoms, and/or behavioural problems. The model aimed to identify youth with mental health problems requiring an intervention, and to stratify the youth into three groups with increasing severity of problems. This was accomplished using a two-phase stratification process involving a web-based assessment and a semi-structured psychopathological interview of the youth and parents. To assess problems with inequity in access, individual-level socioeconomic data were obtained from national registers with data on both the youth participating in the visitation and the background population. Altogether, 573 youth and their parents took part in the visitation process. Seventy-five (13%) youth had mental health problems below the intervention threshold, 396 (69%) were deemed eligible for the early treatment, and 52 (9%) had symptoms of severe mental health problems. Fifty (9%) youth were excluded for other reasons. Eighty percent of the 396 youth eligible for early treatment fulfilled criteria of a mental disorder. The severity of mental health problems highlights the urgent need for a systematic approach. Potential problems in reaching youth of less resourceful parents, and older youth were identified. These findings can help ensure that actions are taken to avoid equity problems in future mental health care implementations.

     

In vivo evaluation of PEGylated <Superscript>64</Superscript>Cu-liposomes with theranostic and radiotherapeutic potential using micro PET/CT

Purpose

The objective of this study was to evaluate the potential of PEGylated ⁶⁴Cu-liposomes in clinical diagnostic positron emission tomography (PET) imaging and PEGylated ¹⁷⁷Lu-liposomes in internal tumor radiotherapy through in vivo characterization and dosimetric analysis in a human xenograft mouse model.

Methods

Liposomes with 5 and 10 mol% PEG were characterized with respect to size, charge, and ⁶⁴Cu- and ¹⁷⁷Lu-loading efficiency. The tumor imaging potential of ⁶⁴Cu-loaded liposomes was evaluated in terms of in vivo biodistribution, tumor accumulation and tumor-to-muscle (T/M) ratios, using PET imaging. The potential of PEGylated liposomes for diagnostic and therapeutic applications was further evaluated through dosimetry analysis using OLINDA/EXM software. The ⁶⁴Cu-liposomes were used as biological surrogates to estimate the organ and tumor kinetics of ¹⁷⁷Lu-liposomes.

Results

High remote loading efficiency (>95 %) was obtained for both ⁶⁴Cu and ¹⁷⁷Lu radionuclides with PEGylated liposomes, and essentially no leakage of the encapsulated radionuclide was observed upon storage and after serum incubation for 24 h at 37 °C. The 10 mol% PEG liposomes showed higher tumor accumulation (6.2?±?0.2 %ID/g) than the 5 mol% PEG liposomes, as evaluated by PET imaging. The dosimetry analysis of the ⁶⁴Cu-liposomes estimated an acceptable total effective dose of 3.3·10^?2 mSv/MBq for diagnostic imaging in patients. A high absorbed tumor dose (114 mGy/MBq) was estimated for the potential radiotherapeutic ¹⁷⁷Lu-liposomes.

Conclusion

The overall preclinical profile of PEGylated ⁶⁴Cu-liposomes showed high potential as a new PET theranostic tracer for imaging in humans. Dosimetry results predicted that initial administered activity of 200 MBq of ⁶⁴Cu-liposomes should be acceptable in patients. Work is in progress to validate the utility of PEGylated ⁶⁴Cu-liposomes in a clinical research programme. The high absorbed tumor dose (114 mGy/MBq) estimated for ¹⁷⁷Lu-liposomes and the preliminary dosimetric studies justify further therapeutic and dosimetry investigation of ¹⁷⁷Lu-liposomes in animals before potential testing in man.

     

IgE expression pattern in lung: relation to systemic IgE and asthma phenotypes

BACKGROUND: IgE-mediated responses contribute to allergy and asthma. Little is understood regarding the relationship of tissue IgE to systemic IgE, inflammation or clinical outcomes. OBJECTIVES: To evaluate local IgE expression and cellular inflammation in the proximal and distal lung of normal subjects and subjects with asthma of varying severity and relate those tissue parameters to systemic IgE levels, atopy, lung function, and history of severe exacerbations of asthma. METHODS: Tissue from more than 90 subjects with eosinophilic (SAeo(+)) and noneosinophilic (SAeo(-)) severe asthma, mild asthma and normal subjects were immunostained for IgE, signal-amplifying isoform of IgE receptor (FcepsilonRIbeta) and markers of mast cells, eosinophils, and lymphocytes. Tissue expression of IgE, FcepsilonRIbeta, cellular inflammation, serum IgE, and atopy were compared. Regression models were used to determine the relationship of local and systemic IgE to lung function and severe exacerbations of asthma. RESULTS: Mast cell-bound IgE was present along airways but absent in lung parenchyma. Although the groups were similar in systemic/serum IgE and atopy, local/tissue IgE was highest in SAeo(+) and correlated with eosinophils and lymphocytes (r(s) = 0.52, P < .0001; and r(s) = 0.23, P = .03, respectively). Higher local IgE was associated with better lung function, but also with more severe exacerbations of asthma. CONCLUSION: Local IgE appears to be primarily a component of responses within the mucosal immune compartment and is related to cellular inflammation, lung function, and clinical outcomes in asthma. CLINICAL IMPLICATIONS: Local/airway IgE-related processes rather than systemic markers of atopy may be relevant in determining clinical outcomes in asthma.     

Chronic complaints after simple sutured repair for umbilical or epigastric hernias may be related to recurrence

Purpose

Umbilical and epigastric hernia repairs are minor, but are commonly conducted surgical procedures. Long-term results have only been sparsely investigated. Our objective was to investigate the risk of chronic complaints after a simple sutured repair for small umbilical and epigastric hernias.

Methods

A retrospective cohort study with a 5-year questionnaire and clinical follow-up was conducted. Patients undergoing primary elective, open non-mesh umbilical or epigastric sutured hernia repair were included. Patients completed a structured questionnaire regarding chronic complaints during work and leisure activities using a verbal rating scale. The primary outcome was chronic complaints.

Results

A total of 295 patients were included for analysis after a median of 5.0-year (range 2.8–8.0) follow-up period. Follow-up results were achieved from 262 of the included patients (90 % response rate). Up till 5.8 % of the patients reported moderate or severe pain and discomfort. Work and leisure activities were restricted in 8.5 and 10.0 % of patients, respectively. Patients with chronic complaints had a higher incidence of recurrence (clinical and reoperation), than patients with none or mild complaints (78.6 vs. 22.2 % (P?<?0.001)). The recurrence rate was significantly higher after a repair with absorbable suture (20.1 %) compared with non-absorbable suture repair (4.2 %) (P?<?0.001).

Conclusion

We found that chronic complaints after a simple sutured umbilical or epigastric repair was in the level of 5.5 % and could in part be explained by recurrence. Furthermore, absorbable suture should be omitted to reduce risk of recurrence.