Dysferlin mutations in LGMD2B, Miyoshi myopathy, and atypical dysferlinopathies

DYSF encoding dysferlin is mutated in Miyoshi myopathy and Limb-Girdle Muscular Dystrophy type 2B, the two main phenotypes recognized in dysferlinopathies. Dysferlin deficiency in muscle is the most relevant feature for the diagnosis of dysferlinopathy and prompts the search for mutations in DYSF. DYSF, located on chromosome 2p13, contains 55 coding exons and spans 150 kb of genomic DNA. We performed a genomic analysis of the DYSF coding sequence in 34 unrelated patients from various ethnic origins. All patients showed an absence or drastic decrease of dysferlin expression in muscle. A primary screening of DYSF using SSCP or dHPLC of PCR products of each of 55 exons of the gene was followed by sequencing whenever a sequence variation was detected. All together, 54 sequence variations were identified in DYSF, 50 of which predicting either a truncated protein or one amino-acid substitution and most of them (34 out of 54) being novel. In 23 patients, we identified two pathogenic mutations, while only one was identified in 11 patients. These mutations were widely spread in the coding sequence of the gene without any mutational "hotspot."     

上海人群面肩肱型肌营养不良症相关位点的D4Z4多态性

目的 对上海人群4p35位点D4Z4重复序列进行研究，分析D4Z4的多态性。方法 191名正常上海人的基因组DNA经EooR I/Bln I双酶水解后，应用脉冲场凝胶电泳及Southem印迹测定其染色体4p35位点的D4Z4片段长度，并对短的D4Z4片段Kpn I酶进行部分酶切以计数其D4Z4串联重复序列数。结果 在191名正常上海人群中，有17人（占8.9％）携带短的D4Z4片段，其长度在22－34kb之间；其中16人携带的短D4Z4片段位于4q35位点，1人携带的短D4Z4片段为4q35→10q26。结论 面肩肱型肌营养不良症的发病虽与4q35位点D4Z4片段的串联重复序列数减少有关，但上海人群中携带4q35位点短的D4Z4片段个体的比例明显高于西方人群，提示其他因素可能也参与面肩肱型肌营养不良症的发病。     

Imaging Metal-on-Metal Hip Replacements: the Norwich Experience

Background

Adverse reaction to metal debris is a relatively recently described and often a silent complication of metal-on-metal (MOM) total hip replacements (THR). The Norfolk & Norwich University Hospital has been performing metal artefact reduction (MARS) MRI for 8 years in a variety of different types of MOM THR.

Questions/purposes

The aims of this review are to describe the experience of using MARS MRI in Norwich and to compare our experience with that published by other groups.

Methods

A MEDLINE keyword search was performed for studies including MRI in MOM THR. Relevant publications were reviewed and compared with published data from the Norfolk & Norwich University Hospital. The similarities and differences between these data were compared and possible explanations for these discussed.

Results

MARS MRI appears to be the most useful tool for diagnosing, staging and monitoring adverse reactions to metal debris (ARMD). There appears to be no clinically useful association between clinical and serological markers of disease and the severity of MR findings. Although severe early ARMD is associated with significant morbidity, mild disease is often stable for years. If patients with normal initial MR examinations develop ARMD, this usually occurs 7 years. A 1-year interval between MRI examinations is reasonable in asymptomatic patients.

Conclusions

There is a general international consensus that ARMD is prevalent in symptomatic and asymptomatic patients with MOM THR and that while appearances vary with the type of prosthesis, there are characteristic features that make MARS MRI essential for diagnosis, staging and surveillance of the disease.     

Pathobiology of Lomentospora prolificans: could this species serve as a model of primary antifungal resistance?

The number of fungal isolates resistant to antifungal drugs has increased dramatically over the last few years and has become an important concern for clinicians. Among these isolates, fungi showing multidrug resistance are particularly worrying because of the difficulties associated with their treatment. These factors hamper the successful recovery of patients and drastically raise mortality rates. Antifungal resistance is multifactorial and several mechanisms in different fungi have been described. There is a need to study these mechanisms in depth; however, the study of antifungal drug resistance separately for each individual species makes progress in the field very slow and tedious. The selection of a multiresistant microorganism as a model for understanding resistance mechanisms and extrapolating the results to other species could help in the search for a solution. In this mini-review, we describe the pathobiology of Lomentospora (Scedosporium) prolificans, paying special attention to its intrinsic resistance to all currently available antifungal agents. The characteristics of L. prolificans offer several advantages: the possibility of using a single microorganism for the study of resistance to different drugs, even cases of double and triple resistance; it is biologically safe for society in general as no new genetically–modified strains are needed for the experiments; it is homologous with other fungal species, and there is repetitiveness between different strains. In conclusion, we propose L. prolificans as a candidate for consideration as a fungal model for the study of resistance mechanisms against antifungal agents.     

Serum and cystic fluid CA 19–9 determinations as a diagnostic help in liver cysts of uncertain nature

Abstract: The distinction between hepatobiliary cystadenoma or cystadenocarcinoma and simple hepatic cyst complicated by intracystic hemorrhage may prove difficult to determine on the sole basis of clinical and radiological features because of the presence of intracystic structures and septations well-demonstrated by ultrasound examination in both situations. We investigated four patients with various types of hepatic cysts, in whom diagnostic difficulties led to further investigations. In this small group, CA 19–9 serum levels were abnormal only in the two patients with cystadenoma or cystadenocarcinoma. Cystic fluid CA 19–9 values were also five times higher in cystadenoma and cystadenocarcinoma than in other benign lesions. Our data thus suggest that the determination of serum and cyst fluid CA 19–9 may be of help in distinguishing between hemorrhagic simple cyst and cystadenoma or cystadenocarcinoma.     

Tubular aggregate myopathy and Stormorken syndrome: Mutation spectrum and genotype/phenotype correlation

Calcium (Ca²⁺) acts as a ubiquitous second messenger, and normal cell and tissue physiology strictly depends on the precise regulation of Ca²⁺ entry, storage, and release. Store‐operated Ca²⁺ entry (SOCE) is a major mechanism controlling extracellular Ca²⁺ entry, and mainly relies on the accurate interplay between the Ca²⁺ sensor STIM1 and the Ca²⁺ channel ORAI1. Mutations in STIM1 or ORAI1 result in abnormal Ca²⁺ homeostasis and are associated with severe human disorders. Recessive loss‐of‐function mutations impair SOCE and cause combined immunodeficiency, while dominant gain‐of‐function mutations induce excessive extracellular Ca²⁺ entry and cause tubular aggregate myopathy (TAM) and Stormorken syndrome (STRMK). TAM and STRMK are spectra of the same multisystemic disease characterized by muscle weakness, miosis, thrombocytopenia, hyposplenism, ichthyosis, dyslexia, and short stature. To date, 42 TAM/STRMK families have been described, and here we report five additional families for which we provide clinical, histological, ultrastructural, and genetic data. In this study, we list and review all new and previously reported STIM1 and ORAI1 cases, discuss the pathomechanisms of the mutations based on the known functions and the protein structure of STIM1 and ORAI1, draw a genotype/phenotype correlation, and delineate an efficient screening strategy for the molecular diagnosis of TAM/STRMK.     

Creatine supplementation prevents acute strength loss induced by concurrent exercise

Purpose

To investigate the effect of creatine (CR) supplementation on the acute interference induced by aerobic exercise on subsequent maximum dynamic strength (1RM) and strength endurance (SE, total number of repetitions) performance.

Methods

Thirty-two recreationally strength-trained men were submitted to a graded exercise test to determine maximal oxygen consumption (VO_2max: 41.56 ± 5.24 ml kg^?1 min^?1), anaerobic threshold velocity (AT_v: 8.3 ± 1.18 km h^?1), and baseline performance (control) on the 1RM and SE (4 × 80 % 1RM to failure) tests. After the control tests, participants were randomly assigned to either a CR (20 g day^?1 for 7 days followed by 5 g day^?1 throughout the study) or a placebo (PL-dextrose) group, and then completed 4 experimental sessions, consisting of a 5-km run on a treadmill either continuously (90 % AT_v) or intermittently (1:1 min at vVO_2max) followed by either a leg- or bench-press SE/1RM test.

Results

CR was able to maintain the leg-press SE performance after the intermittent aerobic exercise when compared with C (p > 0.05). On the other hand, the PL group showed a significant decrease in leg-press SE (p ≤ 0.05). CR supplementation significantly increased bench-press SE after both aerobic exercise modes, while the bench-press SE was not affected by either mode of aerobic exercise in the PL group. Although small increases in 1RM were observed after either continuous (bench press and leg press) or intermittent (bench press) aerobic exercise in the CR group, they were within the range of variability of the measurement. The PL group only maintained their 1RM.

Conclusions

In conclusion, the acute interference effect on strength performance observed in concurrent exercise may be counteracted by CR supplementation.