Germline mutation in BRAF codon 600 is compatible with human development: de novo p.V600G mutation identified in a patient with CFC syndrome

Champion KJ, Bunag C, Estep AL, Jones JR, Bolt CH, Rogers RC, Rauen KA, Everman DB. Germline mutation in BRAF codon 600 is compatible with human development: de novo p.V600G mutation identified in a patient with CFC syndrome. BRAF, the protein product of BRAF, is a serine/threonine protein kinase and one of the direct downstream effectors of Ras. Somatic mutations in BRAF occur in numerous human cancers, whereas germline BRAF mutations cause cardio‐facio‐cutaneous (CFC) syndrome. One recurrent somatic mutation, p.V600E, is frequently found in several tumor types, such as melanoma, papillary thyroid carcinoma, colon cancer, and ovarian cancer. However, a germline mutation affecting codon 600 has never been described. Here, we present a patient with CFC syndrome and a de novo germline mutation involving codon 600 of BRAF, thus providing the first evidence that a pathogenic germline mutation involving this critical codon is not only compatible with development but can also cause the CFC phenotype. In vitro functional analysis shows that this mutation, which replaces a valine with a glycine at codon 600 (p.V600G), leads to increased ERK and ELK phosphorylation compared to wild‐type BRAF but is less strongly activating than the cancer‐associated p.V600E mutation.     

The effect of balneotherapy on antioxidant, inflammatory, and metabolic indices in patients with cardiovascular risk factors (hypertension and obesity)—A randomised, controlled, follow-up study

Introduction

The primary objective of our study was to explore the changes of antioxidant, inflammatory, and metabolic parameters in obese and hypertension people patients during balneotherapy and to evaluate the safety of balneotherapy in these participants.

Methods

Following randomisation, 22 obese and 20 hypertensive patients underwent balneotherapy with thermal water of 38 °C temperature, in 15 sessions of 30 minutes. An additional 22 obese and 20 hypertensive patients served as controls. Antioxidant, inflammatory, and metabolic parameters were determined at baseline, as well as post-treatment and at the end of follow-up (at 15 weeks).

Results

As regards changes observed in hypertensive patients subjected to balneotherapy, differences could be detected between baseline and post-treatment albumin and haemoglobin A_1c levels only; however, these were no longer significant after 3 months. Although the difference between transferrin levels determined at the end of balneotherapy and 3 months later was significant, it remained within the physiological range, as well as it was accompanied by normal serum iron level and therefore, it was considered irrelevant. C-reactive protein levels of balneotherapy patients decreased significantly after treatment.In obese patients, haemoglobin A_1c level decreased after balneotherapy, but this difference was not observed either after 3 months. Similarly, both transferrin and C-reactive protein levels changed from baseline, but not between groups.

Conclusions

This study contributes important information regarding the safety of balneotherapy in hypertensive and obese diabetics by showing no alterations of antioxidant, inflammatory, or metabolic indices. The findings of this study confirm that balneotherapy is not contraindicated for hypertensive or obese patients.     

Synovial fluid β-endorphin level in avascular necrosis,rheumatoid arthritis,and osteoarthritis of the femoral head and knee. A controlled pilot study

The goal of this study is to determine and compare the β-endorphin levels in the synovial fluid of patients with different joint disorders (avascular necrosis, AVN; osteoarthritis, OA; and rheumatoid arthritis, RA of the hip or knee). Eighty-seven patients were involved in our study with an average age of 62 years. Thirty-three patients had AVN (18 hips, 15 knees). Twenty-three patients were diagnosed with OA (14 hips, 9 knees), and 31 patients suffered from RA (12 hips, 19 knees). We measured the β-endorphin levels of the synovial fluids -harvested from surgery—with radioimmunoassay. No significant difference was found in the β-endorphin levels of the synovial fluid from AVN comparing to OA and RA, however β-endorphin level was significantly higher in RA group than among patients with OA (p = 0.01). Synovial β-endorphin level was slightly lower in knee comparing to hip joint p = (0.06). When examining the different joints separately in compliance with diagnoses, we concluded that the synovial β-endorphin level from AVN was between the values of OA and RA without significant difference, whereas it was significantly higher in the knee of RA, than of OA groups (p = 0.05 knee, p = 0.2 hip). Our results confirmed those experiments which stated that there is a significant increase in synovial β-endorphin level in patients with inflammatory autoimmune diseases (e.g., RA), comparing to the level measured in degenerative conditions (e.g., OA).     

Translational behavioral research in respiratory medicine

Human behavior can prevent or invite disease and is a major determinant of treatment success. Consequently, many efforts have been directed toward developing interventions to promote behaviors essential to managing or preventing respiratory disease. The process of developing, testing, and disseminating health behavior interventions should closely follow the translational research paradigm. However, most behavioral investigators have failed to adequately apply the translational research paradigm to behavioral research. The final stage of translation, consisting of testing the effectiveness of interventions in broad clinical settings after efficacy has been demonstrated in randomized controlled trials, is too often omitted. Additionally, the important task of understanding why any given health behavior intervention succeeds with some people but fails to change behavior in others is inconsistently pursued and seldom used to develop the robust theories of behavior change needed to improve respiratory health. Bringing health behavior research through the full translational process has the potential to significantly enhance respiratory health with specific behavioral targets, including smoking cessation, obesity prevention, TB control, and adherence to a multitude of respiratory treatments.     

Oseltamivir-resistant influenza A 2009 H1N1 virus in immunocompromised patients

Please cite this paper as: Couturier et al. (2010). Oseltamivir-resistant influenza A 2009 H1N1 virus in immunocompromised patients. Influenza and Other Respiratory Viruses 4(4), 199–204. Background First-line treatment of influenza A 2009 H1N1 relies on neuraminidase inhibitors such as oseltamivir. Resistance conferred by the H275Y neuraminidase gene mutation is concerning and likely to increase. Objectives To characterize oseltamivir resistance in a hospital-based patient population. Patients and Methods All available respiratory specimens positive for influenza A by direct fluorescent antibody, RT-PCR, or culture from patients at the University of Utah 5/09-12/09 were collected. Specimens were confirmed as 2009 H1N1 by the Utah Department of Health. RT-PCR and pyrosequencing were used to test for the H275Y mutation (CDC protocol). Pyro Mark Q24 AQ software (Qiagen, Valencia, CA, USA) was used to allow for quantitative H275Y mutation analysis. Medical records of patients with resistant virus were reviewed. Results We tested 191 influenza A virus-positive samples from 187 unique patients. Fifty (27%) patients were hospitalized. Four patient specimens (2·1%) were found to carry the H275Y mutation. Three patients were hospitalized, representing 6% of inpatient samples tested. Three patients had undergone hematopoietic stem cell transplant in the past year. Two patients died. Their influenza viruses were confirmed to be oseltamivir-resistant at an independent reference laboratory and through the Center for Disease Control and Prevention (CDC). One patient reported no history of prior oseltamivir exposure. Conclusions Widespread oseltamivir resistance among 2009 H1N1 remains a potential threat. Rapid techniques, such as pyrosequencing, which has the additional benefit of identifying mixed mutant populations of virus, may play a key role in identifying at-risk individuals and potentially unsuspected cases. Targeted surveillance of immunocompromised patients will be critical toward improving future influenza planning and therapy.     

Transmodal comparison of auditory,motor, and visual post-processing with and without intentional short-term memory maintenance

Objective

To elucidate the contributions of modality-dependent post-processing in auditory, motor and visual cortical areas to short-term memory.

Methods

We compared late negative waves (N700) during the post-processing of single lateralized stimuli which were separated by long intertrial intervals across the auditory, motor and visual modalities. Tasks either required or competed with attention to post-processing of preceding events, i.e. active short-term memory maintenance.

Results

N700 indicated that cortical post-processing exceeded short movements as well as short auditory or visual stimuli for over half a second without intentional short-term memory maintenance. Modality-specific topographies pointed towards sensory (respectively motor) generators with comparable time-courses across the different modalities. Lateralization and amplitude of auditory/motor/visual N700 were enhanced by active short-term memory maintenance compared to attention to current perceptions or passive stimulation. The memory-related N700 increase followed the characteristic time-course and modality-specific topography of the N700 without intentional memory-maintenance.

Conclusions

Memory-maintenance-related lateralized negative potentials may be related to a less lateralised modality-dependent post-processing N700 component which occurs also without intentional memory maintenance (automatic memory trace or effortless attraction of attention). Encoding to short-term memory may involve controlled attention to modality-dependent post-processing.

Significance

Similar short-term memory processes may exist in the auditory, motor and visual systems.     

Computer-aided surgical planning in the treatment of soft-tissue sarcoma

INTRODUCTION

Soft-tissue sarcoma resections are often highly complex procedures that demand meticulous pre-operative planning in order to maximise the potential for complete excision with clear margins, while preserving vital neurovascular structures and muscle groups.

SUBJECTS AND METHODS

We present a computer-aided model for surgical planning using Microsoft Powerpoint as a tool for cross referencing magnetic resonance images and normal anatomical diagrams.

RESULTS

Using this system the operator follows a sequence of pre-planned steps, minimising intra-operative decision making and unexpected adverse events. Four case studies are discussed.

CONCLUSIONS

The visual plan optimises the potential to meet surgical and oncological goals, and serves as an excellent nct to the operation note for documentation of the procedure.