Mutations in TIMM50 cause severe mitochondrial dysfunction by targeting key aspects of mitochondrial physiology

3‐Methylglutaconic aciduria (3‐MGA‐uria) syndromes comprise a heterogeneous group of diseases associated with mitochondrial membrane defects. Whole‐exome sequencing identified compound heterozygous mutations in TIMM50 (c.[341 G>A];[805 G>A]) in a boy with West syndrome, optic atrophy, neutropenia, cardiomyopathy, Leigh syndrome, and persistent 3‐MGA‐uria. A comprehensive analysis of the mitochondrial function was performed in fibroblasts of the patient to elucidate the molecular basis of the disease. TIMM50 protein was severely reduced in the patient fibroblasts, regardless of the normal mRNA levels, suggesting that the mutated residues might be important for TIMM50 protein stability. Severe morphological defects and ultrastructural abnormalities with aberrant mitochondrial cristae organization in muscle and fibroblasts were found. The levels of fully assembled OXPHOS complexes and supercomplexes were strongly reduced in fibroblasts from this patient. High‐resolution respirometry demonstrated a significant reduction of the maximum respiratory capacity. A TIMM50‐deficient HEK293T cell line that we generated using CRISPR/Cas9 mimicked the respiratory defect observed in the patient fibroblasts; notably, this defect was rescued by transfection with a plasmid encoding the TIMM50 wild‐type protein. In summary, we demonstrated that TIMM50 deficiency causes a severe mitochondrial dysfunction by targeting key aspects of mitochondrial physiology, such as the maintenance of proper mitochondrial morphology, OXPHOS assembly, and mitochondrial respiratory capacity.     

Does the procedure of arthrography affect the range of movement in patients with locking of the temporomandibular joint?

The aim of this study was to investigate whether arthrography itself altered the range of mandibular movements, in a group of patients with locking of the temporomandibular joint (TMJ). The clinical records of a series of 161 patients who were diagnosed with locking of the TMJ were retrospectively analysed. Mouth opening had improved in 57 out of 161 patients (35%). Twenty-three patients (14%) had improved by 5 mm or less. Nineteen patients (11%) had improved by more than 5 mm but less than 10 mm, whereas 15 patients (9%) had improved by more than 10 mm. Of the patients who experienced an improved mouth opening, only nine (15%) had improved from their pre-arthrography restricted maximum opening to beyond the lower limit of normal. This suggests that the injection of contrast medium had an effect on the range of vertical opening in patients with displacement of the disc without reduction.     

Gene expression analysis in cells of the dentine-pulp complex in healthy and carious teeth

Knowledge of the molecular events that occur in carious disease has so far been constrained due to difficulties in obtaining sufficient quantities of the dental tissues and cells involved. Our histological findings indicate that a pulp-odontoblast cellular complex can be obtained from carious and healthy human teeth when exposed to low-temperatures prior to pulpal extirpation and from rodent teeth processed at room-temperature. In contrast, pulpal tissue extracted from room-temperature processed human teeth and low-temperature processed rodent teeth resulted in the odontoblast layer remaining attached to the pulp chamber. Semi-quantitative RT-PCR (sq-RT-PCR) analysis confirmed that markers previously shown to be preferentially expressed in odontoblasts, namely dentin sialophosphoprotein (DSPP) and Nestin, amplified more readily from the extracted pulp-odontoblast complex, as compared to pulpal tissue alone, in both human and rodent samples. Subsequent gene expression analysis of collagen-1alpha and collagen-3alpha indicated levels were significantly higher in carious pulpal tissue. In addition, analysis characterising the expression of members of the transforming growth factor and bone morphogenic protein families and their receptors indicated in general, that these genes were expressed by healthy odontoblasts and up-regulated in both pulpal cells and odontoblasts in response to carious injury. Use of this temperature-sensitive dental tissue preparation procedure allows detection of differential gene expression in odontoblasts and other pulpal cells in healthy and carious tissue.     

Prevalence and classification of HIV-associated oral lesions

OBJECTIVES: An International Workshop addressed the prevalence and classification of HIV/AIDS associated oral lesions.
DESIGN: Five questions provided the framework for discussion and literature review. What is the prevalence of oral lesions in children and adults? Should the accepted classification of HIV-related oral lesions be modified in the light of recent findings? Why is there a gender difference in the prevalence of oral lesions in developed and developing countries? Are there unusual lesions present in developing countries? Is there any association between modes of transmission and the prevalence of oral lesions?
RESULTS: Workshop discussion emphasized the urgent need for assistance in the development of expertise to obtain accurate global prevalence data for HIV-associated oral lesions. Oral candidiasis has been consistently reported as the most prevalent HIV-associated oral lesion in all ages. Penicilliosis marneffei, a newly described fungal infection, has emerged in South-east Asia. Oral hairy leukoplakia and Kaposi's sarcoma appear to be associated with male gender and male-to-male HIV transmission risk behaviours. These lesions occur only rarely in children.
CONCLUSIONS: Additional prevalence data are needed from developing countries prior to substantially altering the 1993 ECC/WHO Classification of oral lesions associated with adult HIV infection. The workshop confirmed current oral disease diagnostic criteria.     

Opinions and attitudes of the UK's GDPs and specialists in oral surgery, oral medicine and surgical dentistry on oral cancer screening

OBJECTIVE: To survey two broad areas of oral cancer awareness and management of patients at risk of oral cancer by specialists in oral surgery, oral medicine, surgical dentistry and general dental practitioners (GDPs) in the UK. The first of these included knowledge and awareness of aetiological factors, changing patterns of disease, and screening/detection programmes including their effectiveness. The second included oral cancer detection methods, advice on avoidance of high-risk activity and self-examination, and referral pattern of GDPs. DESIGN AND METHOD: A pretested, 44-item questionnaire, a covering letter, a brief outline of the research protocol and return, stamped envelope were mailed in March 2003. A sample of 200 GDPs whose names were obtained from the General Dental Council's main list and 305 dental specialist names obtained from specialist's list in surgical dentistry, oral medicine and oral surgery were selected randomly. Information on oral cancer awareness and practice, screening practice and education was obtained. RESULTS: The response rate was 66.9%. The knowledge of the dental specialists was consistent with that in reports of current aetiological studies on oral cancer. However there were gaps in the GDP's knowledge and ascertainment of oral cancer risk factors. Over 70% of the dental specialists provided counselling advice on the risks of tobacco and alcohol habits compared with 41.2% of GDPs. More GDPs (52.4%) than specialists (35.4%) believed that oral cancer screening on a national basis would be effective in decreasing the mortality of oral cancer. Over 95% of all respondents used a visual examination for oral cancer screening and 89.9% of all respondents strongly believed that visual screening is effective in the early detection of oral cancer. CONCLUSION: The results showed that GDPs had knowledge gaps in their awareness of oral cancer risk factors and the application of preventive measures. Most dental health providers in the UK perform visual screening of the oral mucosa for their patients. Opinion was equivocal as to whether a nationally based screening programme similar to cervical cancer would be effective in improving the mortality and morbidity of oral cancer.     

Echoes of things to come. Ultrasound in UK emergency medicine practice

Ultrasound is widely used in the US and continental Europe in the immediate assessment of patients after blunt abdominal trauma. There are also now other recognised "primary" indications for ultrasound in emergency medicine.

In this paper current evidence supporting the implementation and use of emergency ultrasound in these primary conditions and possible other indications are assessed. The issues surrounding introduction of the technology into the practice of emergency medicine in this country are considered. It is accepted that further debate is necessary but the establishment of a robust evidence base in the UK will help to clarify the place of ultrasound.

     

Systematic review of enhanced recovery after gastro-oesophageal cancer surgery

Introduction

Fast track methodology or enhanced recovery schemes have gained increasing popularity in perioperative care. While evidence is strong for colorectal surgery, its importance in gastric and oesophageal surgery has yet to be established. This article reviews the evidence of enhanced recovery schemes on outcome for this type of surgery.

Methods

A systematic literature search was conducted up to March 2014. Studies were retrieved and analysed using predetermined criteria.

Results

From 34 articles reviewed, 18 eligible studies were identified: 7 on gastric and 11 on oesophageal resection. Three randomised controlled trials, five case-controlled studies and ten case series were identified. The reported protocols included changes to each stage of the patient journey from pre to postoperative care. The specific focus following oesophageal resections was on early mobilisation, a reduction in intensive care unit stay, early drain removal and early (or no) contrast swallow studies. Following gastric resections, the emphasis was on reducing epidural anaesthesia along with re-establishing oral intake in the first three postoperative days and early removal of nasogastric tubes.In the papers reviewed, mortality rates following fast track surgery were 0.8% (9/1,075) for oesophageal resection and 0% (0/329) for gastric resection. The reported morbidity rate was 16.5% (54/329) following gastric resection and 38.6% (396/1,075) following oesophageal resection. Length of stay was reduced in both groups compared with conventional recovery groups in comparative studies.

Conclusions

The evidence for enhanced recovery schemes following gastric and oesophageal resection is weak, with only three (low volume) published randomised controlled trials. However, the enhanced recovery approach appears safe and may be associated with a reduction in length of stay.     

Return to sporting activity after Birmingham hip resurfacing arthroplasty: Mid term results

Background:

Hip resurfacing arthroplasty (HRA) is primarily indicated for young, active patients with disabling coxarthrosis who wish to remain active and return to sports after surgery. Relatively few prospective studies have assessed return to sporting activity and impact of gender and age on this.

Materials and Methods:

Seventy-nine consecutive patients treated with HRA were included. Patients were reviewed clinically and radiologically. Function was assessed using the modified University of California Los Angeles (UCLA) activity score. The Oxford, Harris and WOMAC hip scores were calculated.

Results:

Average age at the time of surgery was 54.9 years (range 34.5–73.6 years). Average preoperative and postoperative UCLA scores were 4 and 7.6 respectively. Patients were involved in 2 (0–4) sporting activities preoperatively and 2 (0–5) postoperatively. Preoperative and postoperative Oxford Hip Scores, Harris Hip Score and WOMAC scores were 40, 46 and 51 and 16, 94 and 3 respectively (P < 0.0001). Patients returned to sports at an average of 3 months postoperatively.

Conclusion:

Patients were able to return to sports by 3 months and perform the same number of activities at preoperative intensity. Activity levels are maintained up to the medium term with few complications.