Don’t miss patients with atypical FMR1 mutations: dysmorphism and clinical features in a boy with a partially methylated FMR1 full mutation

Fragile X syndrome characterized by intellectual disability (ID), facial dysmorphism, and postpubertal macroorchidism is the most common monogenic cause of ID. It is typically induced by an expansion of a CGG repeat in the fragile X mental retardation 1 (FMR1) gene on Xq27 to more than 200 repeats. Only rarely patients have atypical mutations in the FMR1 gene such as point mutations, deletions, or unmethylated/partially methylated full mutations. Most of these patients show a minor phenotype or even appear clinically healthy. Here, we report the dysmorphism and clinical features of a 17-year-old boy with a partially methylated full mutation of approximately 250 repeats. Diagnosis was made subsequently to the evaluation of a FMR1 premutation as the cause for maternal premature ovarian failure. Dysmorphic evaluation revealed no strikingly long face, no prominent forehead/frontal bossing, no prominent mandible, no macroorchidism, and a head circumference in the lower normal range. Acquisition of a driving license for mopeds and unaccompanied rides by public transport in his home province indicate rather mild ID (IQ?=?58). Conclusion: This adolescent demonstrates that apart from only minor ID, patients with a partially methylated FMR1 full mutation present less to absent pathognomonic facial dysmorphism, thus emphasizing the impact of family history for a straightforward clinical diagnosis.     

CARS microscopy for the visualization of micrometer-sized iron oxide MRI contrast agents in living cells

Micrometer-sized iron oxide particles (MPIOs) attract increasing interest as contrast agents for cellular tracking by clinical Magnetic Resonance Imaging (MRI). Despite the great potential of MPIOs for in vivo imaging of labeled cells, little is known on the intracellular localization of these particles following uptake due to the lack of techniques with the ability to monitor the particle uptake in vivo at single-cell level. Here, we show that coherent anti-Stokes Raman scattering (CARS) microscopy enables non-invasive, label-free imaging of MPIOs in living cells with sub-micron resolution in three dimensions. CARS allows simultaneous visualization of the cell framework and the MPIOs, where the particles can be readily distinguished from other cellular components of comparable dimensions, and localized inside the cell.     

Use of population pharmacokinetic modeling and Monte Carlo simulation to describe the pharmacodynamic profile of cefditoren in plasma and epithelial lining fluid

Cefditoren is a broad-spectrum, oral cephalosporin that is highly active against clinically relevant respiratory tract pathogens, including multidrug-resistant Streptococcus pneumoniae. This study described its pharmacodynamic profile in plasma and epithelial lining fluid (ELF). Plasma and ELF pharmacokinetic data were obtained from 24 patients under fasting conditions. Cefditoren and urea concentrations were determined in plasma and bronchoalveolar lavage fluid by liquid chromatography-tandem mass spectrometry. Concentration-time profiles in plasma and ELF were modeled using a model with three disposition compartments and first-order absorption, elimination, and transfer. Pharmacokinetic parameters were identified in a population pharmacokinetic analysis (big nonparametric adaptive grid with adaptive gamma). Monte Carlo simulation (9,999 subjects) was performed with the ADAPT II program to estimate the probability of target attainment at which the free-cefditoren plasma concentrations (88%) protein binding and total ELF concentrations exceeded the MIC for 33% of the dosing interval for 400 mg cefditoren given orally every 12 h. After the Bayesian step, the overall fits of the model to the data were good, and plots of predicted versus observed concentrations for plasma and ELF showed slopes and intercepts very close to the ideal values of 1.0 and 0.0, respectively. In the plasma probability of target attainment analysis, the probability of achieving a time for which free, or unbound, plasma concentration exceeds the MIC of the organism for 33% of the dosing interval was <80% for a MIC of >0.06 mg/liter. Similar to plasma, the probability of achieving a time above the MIC of 33% was <80% for MIC of >0.06 mg/liter in ELF. Cefditoren was found to have a low probability of achieving a bacteriostatic effect against MICs of >0.06 mg/liter, which includes most S. pneumoniae isolates with intermediate susceptibility to penicillin, when given in the fasting state in both plasma and ELF.     

Sudden cardiac death: prevalence, pathogenesis, and prevention

Sudden cardiac death (SCD), also known as sudden arrest, is a major health problem worldwide. It is usually defined as an unexpected death from a cardiac cause occurring within a short time in a person with or without preexisting heart disease. The pathogenesis of SCD is complex and multifaceted. A dynamic triggering factor usually interacts with an underlying heart disease, either genetically determined or acquired, and the final outcome is the development of lethal tachyarrhythmias or, less frequently, bradycardia. It has increasingly been highlighted that a reliable clinical and diagnostic approach might be effective to unmask the most important genetic and environmental factors, allowing the construction of a rational personalized medicine framework that can be applied in both the preclinical and clinical settings of SCD. The aim of the present article is to provide a concise overview of prevalence, pathogenesis, clinical presentation, and diagnostic approach to this challenging disorder.     

Responsiveness of physical function outcomes following physiotherapy intervention for osteoarthritis of the knee: an outcome comparison study

Objective

To compare the responsiveness of two self-report measures and three physical performance measures of function following physiotherapy for osteoarthritis of the knee.

Setting

Single centre study in acute hospital setting.

Methods

Patients referred for physiotherapy with osteoarthritis of the knee were recruited. The Western Ontario and McMaster Universities (WOMAC), Lequesne Algofunctional Index (LAI), timed-up-and-go test (TUGT), timed-stand test (TST) and six-minute walk test (6MWT) were administered at first and final physiotherapy visits. Wilcoxon Signed Rank tests were used to determine the effect of physiotherapy on each outcome. Responsiveness was calculated using effect size, standardised response mean and a median-based measure of responsiveness due to some outlying data.

Results

Thirty-nine patients with a mean age of 65.3 (standard deviation 6.9) years were investigated before and after a course of exercise-based physiotherapy. There was a significant improvement in all outcomes except the WOMAC scores. All measures demonstrated small effect sizes for all statistics (<0.50), except the 6MWT which was in the moderate range for one of the indices (standardised response mean 0.54). The LAI was more responsive than the WOMAC total score and the WOMAC physical function subscale for all responsiveness statistics, whilst the 6MWT was more responsive than the TST and the TUGT. The median-based effect size index produced the smallest effect sizes for all measures (0.1 to 0.43).

Conclusion

These results can be used to guide decision making about which physical function outcome measures should be used to evaluate effectiveness of rehabilitation of people with osteoarthritis of the knee at group level in a clinical setting.     

<Emphasis Type="Italic">Pseudomonas aeruginosa</Emphasis> carriage,colonization, and infection in ICU patients

Objective We evaluated whether Pseudomonas aeruginosa associated nosocomial infections in our ICU originate mainly from patients' endogenous flora or from exogenous cross-transmission. Design and setting A 6-month prospective surveillance survey was performed according to standardized protocols at the interdisciplinary ICU of the Azienda Ospedaliera Cannizzaro. Patients The study analyzed 121 patients and focused on three different states: carriage upon admission, colonization of sterile sites, and infections during ICU stay. Results We identified 138 P. aeruginosa isolates from 45 patients. The cumulative incidence of P. aeruginosa sustained colonization in the ICU was 29.9/100 patients, and the incidence density was 16.2/1,000 patient-days. The cumulative incidence of P. aeruginosa-sustained infections in the ICU was 36.7/100 patients, and the incidence density was 19.9/1,000 patient-days. The most frequent infection type was ventilator-associated pneumonia. PFGE analysis of P. aeruginosa isolates led to the identification of a major clone represented by 60.8% of isolates involving 45.9% of patients. The impact of cross-transmission, i.e., the preventable proportion of P. aeruginosa acquisition, was estimated to be at least 59.5% of all colonization or infection episodes. Acquisition of multidrug-resistant P. aeruginosa was significantly associated with cross-transmission. Conclusions Our results suggest that the ICU personnel and environment served as reservoirs for cross-transmission and emphasize the importance of exogenous acquisition of multidrug-resistant P. aeruginosa, of reduction in antibiotic pressure, and prompt enforcement of infection control measures. This work was supported by grants to A. A. from the University of Catania, Italy.     

Role of transforming growth factor beta in rat bladder smooth muscle cell proliferation

Conditions associated with hypertrophy of the urinary bladder have repeatedly been associated with an increased urinary excretion of transforming growth factor (TGF) beta in both rats and patients. Because TGFbeta can have both growth-promoting and -inhibiting effects, we have studied its effects on cell growth and death in primary cultures of rat bladder smooth muscle cells. TGFbeta1, TGFbeta2, or TGFbeta3 did not cause apoptosis, but all three isoforms inhibited DNA synthesis with similar potency (EC(50) of approximately 0.1 ng/ml) and efficacy. Such inhibition was antagonized by a specific TGFbeta receptor antagonist and independent of the presence of serum. Mitogen-activated protein kinases (MAPKs) are involved in the control of cell growth, and all three TGFbeta isoforms inhibited activation of the extracellular signal-regulated kinase, c-Jun NH(2)-terminal kinase, and p38 MAPK subfamilies. Nevertheless, the inhibitory effects of the TGFbeta isoforms on DNA synthesis were not affected by presence of inhibitors of the three MAPK pathways. TGFbeta did not alter cell size as measured by flow cytometry or mitochondrial activity, an integrated measure of cell size and number. We conclude that our data do not support the hypothesis that TGFbeta is a mediator of rat bladder hypertrophy.     

Human monoclonal antibody as prophylaxis for SARS coronavirus infection in ferrets

SARS coronavirus continues to cause sporadic cases of severe acute respiratory syndrome (SARS) in China. No active or passive immunoprophylaxis for disease induced by SARS coronavirus is available. We investigated prophylaxis of SARS coronavirus infection with a neutralising human monoclonal antibody in ferrets, which can be readily infected with the virus. Prophylactic administration of the monoclonal antibody at 10 mg/kg reduced replication of SARS coronavirus in the lungs of infected ferrets by 3.3 logs (95% CI 2.6-4.0 logs; p<0.001), completely prevented the development of SARS coronavirus-induced macroscopic lung pathology (p=0.013), and abolished shedding of virus in pharyngeal secretions. The data generated in this animal model show that administration of a human monoclonal antibody might offer a feasible and effective prophylaxis for the control of human SARS coronavirus infection.