Autosomal recessive limb-girdle muscular dystrophy type 2G (LGMD2G) is an adult-onset myopathy characterized by distal lower limb weakness, calf hypertrophy and progressive decline in ambulation. The ...disease is caused by mutations in Tcap, a z-disc protein of skeletal muscle, although the precise mechanisms resulting in clinical symptoms are unknown. To provide a model for preclinical trials and for mechanistic studies, we generated knockout (KO) mice carrying a null mutation in the Tcap gene. Here we present the first report of a Tcap KO mouse model for LGMD2G and the results of an investigation into the effects of Tcap deficiency on skeletal muscle function in 4- and 12-month-old mice. Muscle histology of Tcap-null mice revealed abnormal myofiber size variation with central nucleation, similar to findings in the muscles of LGMD2G patients. An analysis of a Tcap binding protein, myostatin, showed that deletion of Tcap was accompanied by increased protein levels of myostatin. Our Tcap-null mice exhibited a decline in the ability to maintain balance on a rotating rod, relative to wild-type controls. No differences were detected in force or fatigue assays of isolated extensor digitorum longus (EDL) and soleus (SOL) muscles. Finally, a mechanical investigation of EDL and SOL indicated an increase in muscle stiffness in KO animals. We are the first to establish a viable KO mouse model of Tcap deficiency and our model mice demonstrate a dystrophic phenotype comparable to humans with LGMD2G.
There is no current cure for Duchenne muscular dystrophy (DMD), and palliative and prophylactic interventions to improve the quality of life of patients remain limited, with the exception of ...corticosteroids. This article describes 2 potential nutritional interventions for the treatment of DMD, green tea extract (GTE) and the branched-chain amino acid leucine, and their positive effects on physical activity. Both GTE and leucine are suitable for human consumption, are easily tolerated with no side effects, and, with appropriate preclinical data, could be brought forward to clinical trials rapidly.
Toxoplasma gondii is an intracellular protozoan parasite capable of causing devastating infections in immunocompromised and immunologically immature individuals. In this report, we demonstrate the ...relative independence of T. gondii from its host cell for aminoglycerophospholipid synthesis. The parasite can acquire the lipid precursors serine, ethanolamine, and choline from its environment and use them for the synthesis of its major lipids, phosphatidylserine (PtdSer), phosphatidylethanolamine (PtdEtn), and phosphatidylcholine (PtdCho), respectively. Dimethylethanolamine (Etn(Me)2), a choline analog, dramatically interfered with the PtdCho metabolism of T. gondii and caused a marked inhibition of its growth within human foreskin fibroblasts. In tissue culture medium supplemented with 2 mm Etn(Me)2, the parasite-induced lysis of the host cells was dramatically attenuated, and the production of parasites was inhibited by more than 99%. The disruption of parasite growth was paralleled by structural abnormalities in its membranes. In contrast, no negative effect on host cell growth and morphology was observed. The data also reveal that the Etn(Me)2-supplemented parasite had a time-dependent decrease in its PtdCho content and an equivalent increase in phosphatidyldimethylethanolamine, whereas other major lipids, PtdSer, PtdEtn, and PtdIns, remained largely unchanged. Relative to host cells, the parasites incorporated more than 7 times as much Etn(Me)2 into their phospholipid. These findings reveal that Etn(Me)2 selectively alters parasite lipid metabolism and demonstrate how selective inhibition of PtdCho synthesis is a powerful approach to arresting parasite growth.
In pregnancy-related atypical hemolytic uremic syndrome (p-aHUS), transferring recommendations for treatment decisions from nonpregnant cohorts with thrombotic microangiopathy (TMA) is difficult. ...Although potential causes of p-aHUS may be unrelated to inherent complement defects, peripartal complications such as postpartum hemorrhage (PPH) or (pre)eclampsia or Hemolysis, Elevated Liver enzymes and Low Platelets (HELLP) syndrome may be unrecognized drivers of complement activation.
To evaluate diagnostic and therapeutic decisions in the practical real-life setting, we conducted an analysis of a cohort of 40 patients from 3 German academic hospitals with a diagnosis of p-aHUS, stratified by the presence (n = 25) or absence (n = 15) of PPH.
Histological signs of TMA were observed in 84.2% of all patients (100% vs. 72.7% in patients without or with PPH, respectively). Patients without PPH had a higher likelihood (20% vs. 0%) of pathogenic genetic abnormalities in the complement system although notably less than in other published cohorts. Four of 5 patients with observed renal cortical necrosis (RCN) after PPH received complement inhibition and experienced partially recovered kidney function. Patients on complement inhibition with or without PPH had an increased need for kidney replacement therapy (KRT) and plasma exchange (PEX). Because renal recovery was comparable among all patients treated with complement inhibition, a potential beneficial effect in this group of pregnancy-associated TMAs and p-aHUS is presumed.
Based on our findings, we suggest a pragmatic approach toward limited and short-term anticomplement therapy for patients with a clinical diagnosis of p-aHUS, which should be stopped once causes of TMA other than genetic complement abnormalities emerge.
Display omitted
Adolescence represents a pivotal stage in the development of positive or negative body image. Many influences exist during the teen years including transitions (eg, puberty) that affect one's body ...shape, weight status, and appearance. Weight status exists along a spectrum between being obese (ie, where one's body weight is in the 95th percentile for age and gender) to being underweight. Salient influences on body image include the media, which can target adolescents, and peers who help shape beliefs about the perceived body ideal. Internalization of and pressures to conform to these socially prescribed body ideals help to explain associations between weight status and body image. The concepts of fat talk and weight-related bullying during adolescence greatly contribute to an overemphasis on body weight and appearance as well as the development of negative body perceptions and dissatisfaction surrounding specific body parts. This article provides an overview of the significance of adolescent development in shaping body image, the relationship between body image and adolescent weight status, and the consequences of having a negative body image during adolescence (ie, disordered eating, eating disorders, and dysfunctional exercise). Practical implications for promoting a healthy weight status and positive body image among adolescents will be discussed.
Attempts to reduce high utilisation of mental health inpatient care by targeting the critical time of hospital discharge are rare. In this study, we test the effect of a needs-oriented discharge ...planning intervention on number and duration of psychiatric inpatient treatment episodes (primary), as well as on outpatient service use, needs, psychopathology, depression and quality of life (secondary).
Four hundred and ninety-one adults with a defined high utilisation of mental health care gave informed consent to participate in a multicentre RCT carried out at five psychiatric hospitals in Germany (Düsseldorf, Greifswald, Regensburg, Ravensburg and Günzburg). Subjects allocated to the intervention group were offered a manualised needs-led discharge planning and monitoring intervention with two intertwined sessions administered at hospital discharge and 3 months thereafter. Outcomes were assessed at four measurement points during a period of 18 months following discharge.
Intention-to-treat analyses showed no effect of the intervention on primary or secondary outcomes.
Process evaluation pending, the intervention cannot be recommended for implementation in routine care. Other approaches, e.g. team-based community care, might be more beneficial for people with persistent and severe mental illness.
The DRG-ÖRG IRP (Deutsche Röntgengesellschaft-Österreichische Röntgengesellschaft international radiomics platform) represents a web-/cloud-based radiomics platform based on a public-private ...partnership. It offers the possibility of data sharing, annotation, validation and certification in the field of artificial intelligence, radiomics analysis, and integrated diagnostics. In a first proof-of-concept study, automated myocardial segmentation and automated myocardial late gadolinum enhancement (LGE) detection using radiomic image features will be evaluated for myocarditis data sets.
The DRG-ÖRP IRP can be used to create quality-assured, structured image data in combination with clinical data and subsequent integrated data analysis and is characterized by the following performance criteria: Possibility of using multicentric networked data, automatically calculated quality parameters, processing of annotation tasks, contour recognition using conventional and artificial intelligence methods and the possibility of targeted integration of algorithms. In a first study, a neural network pre-trained using cardiac CINE data sets was evaluated for segmentation of PSIR data sets. In a second step, radiomic features were applied for segmental detection of LGE of the same data sets, which were provided multicenter via the IRP.
First results show the advantages (data transparency, reliability, broad involvement of all members, continuous evolution as well as validation and certification) of this platform-based approach. In the proof-of-concept study, the neural network demonstrated a Dice coefficient of 0.813 compared to the expert's segmentation of the myocardium. In the segment-based myocardial LGE detection, the AUC was 0.73 and 0.79 after exclusion of segments with uncertain annotation.The evaluation and provision of the data takes place at the IRP, taking into account the FAT (fairness, accountability, transparency) and FAIR (findable, accessible, interoperable, reusable) criteria.
It could be shown that the DRG-ÖRP IRP can be used as a crystallization point for the generation of further individual and joint projects. The execution of quantitative analyses with artificial intelligence methods is greatly facilitated by the platform approach of the DRG-ÖRP IRP, since pre-trained neural networks can be integrated and scientific groups can be networked.In a first proof-of-concept study on automated segmentation of the myocardium and automated myocardial LGE detection, these advantages were successfully applied.Our study shows that with the DRG-ÖRP IRP, strategic goals can be implemented in an interdisciplinary way, that concrete proof-of-concept examples can be demonstrated, and that a large number of individual and joint projects can be realized in a participatory way involving all groups.
· The DRG-ÖRG IRP is a web/cloud-based radiomics platform based on a public-private partnership.. · The DRG-ÖRG IRP can be used for the creation of quality-assured, structured image data in combination with clinical data and subsequent integrated data analysis.. · First results show the applicability of left ventricular myocardial segmentation using a neural network and segment-based LGE detection using radiomic image features.. · The DRG-ÖRG IRP offers the possibility of integrating pre-trained neural networks and networking of scientific groups..
· Overhoff D, Kohlmann P, Frydrychowicz A et al. The International Radiomics Platform - An Initiative of the German and Austrian Radiological Societies. Fortschr Röntgenstr 2021; 193: 276 - 287.
Summary
The intracellular protozoan Toxoplasma gondii lacks a de novo mechanism for cholesterol synthesis and therefore must scavenge this essential lipid from the host environment. In this study, we ...demonstrated that T. gondii diverts cholesterol from low‐density lipoproteins for cholesteryl ester synthesis and storage in lipid bodies. We identified and characterized two isoforms of acyl‐CoA:cholesterol acyltransferase (ACAT)‐related enzymes, designated TgACAT1α and TgACAT1β in T. gondii. Both proteins are coexpressed in the parasite, localized to the endoplasmic reticulum and participate in cholesteryl ester synthesis. In contrast to mammalian ACAT, TgACAT1α and TgACAT1β preferentially incorporate palmitate into cholesteryl esters and present a broad sterol substrate affinity. Mammalian ACAT‐deficient cells transfected with either TgACAT1α or TgACAT1β are restored in their capability of cholesterol esterification. TgACAT1α produces steryl esters and forms lipid bodies after transformation in a Saccharomyces cerevisiae mutant strain lacking neutral lipids. In addition to their role as ACAT substrates, host fatty acids and low‐density lipoproteins directly serve as Toxoplasma ACAT activators by stimulating cholesteryl ester synthesis and lipid droplet biogenesis. Free fatty acids significantly increase TgACAT1α mRNA levels. Selected cholesterol esterification inhibitors impair parasite growth by rapid disruption of plasma membrane. Altogether, these studies indicate that host lipids govern neutral lipid synthesis in Toxoplasma and that interference with mechanisms of host lipid storage is detrimental to parasite survival in mammalian cells.
Chronic obstructive pulmonary disease (COPD) results from a progressive decline in lung function, which is thought to be the consequence of airway inflammation. We hypothesized that antiinflammatory ...therapy with inhaled corticosteroids would slow this decline.
We enrolled 1116 persons with COPD whose forced expiratory volume in one second (FEV1) was 30 to 90 percent of the predicted value in a 10-center, placebo-controlled, randomized trial of inhaled triamcinolone acetonide administered at a dose of 600 microg twice daily. The primary outcome measure was the rate of decline in FEV1 after the administration of a bronchodilator. The secondary outcome measures included respiratory symptoms, use of health care services, and airway reactivity. In a substudy of 412 participants, we measured bone density in the lumbar spine and femur at base line and one and three years after the beginning of treatment.
The mean duration of follow-up was 40 months. The rate of decline in the FEV1 after bronchodilator use was similar in the 559 participants in the triamcinolone group and the 557 participants in the placebo group (44.2+/-2.9 vs. 47.0+/-3.0 ml per year, P= 0.50). Members of the triamcinolone group had fewer respiratory symptoms during the course of the study (21.1 per 100 person-years vs. 28.2 per 100 person-years, P=0.005) and had fewer visits to a physician because of a respiratory illness (1.2 per 100 person-years vs. 2.1 per 100 person-years, P=0.03). Those taking triamcinolone also had lower airway reactivity in response to methacholine challenge at 9 months and 33 months (P=0.02 for both comparisons). After three years, the bone density of the lumbar spine and the femur was significantly lower in the triamcinolone group (P < or = 0.007).
Inhaled triamcinolone does not slow the rate of decline in lung function in people with COPD, but it improves airway reactivity and respiratory symptoms and decreases the use of health care services for respiratory problems. These benefits should be weighed against the potential long-term adverse effects of triamcinolone on bone mineral density.
PDF
