ATM-dependent DNA damage surveillance in T-cell development and leukemogenesis: the DSB connection

Summary:  The immune system is capable of recognizing and eliminating an enormous array of pathogens due to the extremely diverse antigen receptor repertoire of T and B lymphocytes. However, the development of lymphocytes bearing receptors with unique specificities requires the generation of programmed double strand breaks (DSBs) coupled with bursts of proliferation, rendering lymphocytes susceptible to mutations contributing to oncogenic transformation. Consequently, mechanisms responsible for monitoring global genomic integrity must be activated during lymphocyte development to limit the oncogenic potential of antigen receptor locus recombination. Mutations in ATM (ataxia-telangiectasia mutated), a kinase that coordinates DSB monitoring and the response to DNA damage, result in impaired T-cell development and predispose to T-cell leukemia. Here, we review recent evidence providing insight into the mechanisms by which ATM promotes normal lymphocyte development and protects from neoplastic transformation.     

Melioidosis: an important cause of pneumonia in residents of and travellers returned from endemic regions.

Melioidosis is endemic in South East Asia, Asia and northern Australia. Infection usually follows percutaneous inoculation or inhalation of the causative bacterium, Burkholderia pseudomallei, which is present in soil and surface water in the endemic region. While 20-36% of melioidosis cases have no evident predisposing risk factor, the vast majority of fatal cases have an identified risk factor, the most important of which are diabetes, alcoholism and chronic renal disease. Half of all cases present with pneumonia, but there is great clinical diversity, from localised skin ulcers or abscesses without systemic illness to fulminant septic shock with multiple abscesses in the lungs, liver, spleen and kidneys. At least 10% of cases present with a chronic respiratory illness (sick > 2 months) mimicking tuberculosis and often with upper lobe infiltrates and/or cavities on chest radiography. As with tuberculosis, latency with reactivation decades after infection can also occur, although this is rare. Confirmation of diagnosis is by culture of B. pseudomallei from blood, sputum, throat swab or other samples. Microbiology laboratories need to be informed of the possibility of melioidosis, as those not familiar with it can misidentify the organism. Antibiotic therapy is initial intensive therapy with i.v. ceftazidime or meropenem or imipenem +/- cotrimoxazole for > or = 10 days, followed by eradication therapy with cotrimoxazole +/- doxycycline +/- chloramphenicol (first 4 weeks only) for > or = 3 months. Melioidosis has been increasingly recognised in returning travellers in Europe and recently melioidosis and colonisation with B. pseudomallei have been documented in cystic fibrosis patients visiting or resident in endemic areas.     

Pharmacokinetics of Moxifloxacin in Rabbits After Intravenous,Subcutaneous and a Long‐acting Poloxamer 407 Gel Formulation Administration

The pharmacokinetics (PK) of moxifloxacin in healthy white New Zealand rabbits was studied following intravenous (IV) and subcutaneous (SC) administration routes as well as a SC long‐acting poloxamer 407 gel formulation (SC‐P407). Moxifloxacin concentrations were determined by high‐performance liquid chromatography assay with fluorescence detection. Mean half‐life for IV, SC and SC‐P407 routes was 2.15, 5.41 and 11.09 h. Clearance value after IV dosing was 0.78 l/kg/h. After SC administration, the mean absolute bioavailability was 117% and the C_max was 1.61 ± 0.49 mg/l. After SC‐P407 administration, the bioavailability was 44% and the C_max 1.83 was ±0.62 mg/l. No adverse effects were observed in any of the rabbits following IV, SC and SC‐P407 administration of moxifloxacin. Minimal inhibitory concentrations of moxifloxacin against different strains of Staphylococcus aureus from different european countries were used to compute the main pharmacodynamic (PD) surrogate markers of efficacy. The high tolerability of this SC‐P407 formulation and the favourable PK behaviour such as the long half‐life, acceptable bioavailability and excellent PK–PD ratios achieved indicate that it is likely to be effective in rabbits.     

Anxiety in medically III patients

Anxiety disorders and anxiety symptoms are highly prevalent in the general population and more so in the medically ill. They have a number of negative consequences for these patients and may worsen the outcome of the medical illness and increase health care utilization. In the evaluation of these patients, it is of paramount importance to identify the etiology of the anxiety and, in particular, to differentiate primary from secondary anxiety. Management includes medications (especially benzodiazepines and selective serotonin reuptake inhibitors) and psychotherapy (particularly cognitive-behavioral therapy).     

Right aortic arch detected in fetal life.

OBJECTIVE: To evaluate the prenatal distribution, associated conditions and outcome of the different types of right aortic arch (RAA) detected in fetal life. METHODS: This was a retrospective review of all cases of RAA detected prenatally between 1998 and 2005 in two tertiary referral centers. RESULTS: In the study period 71 cases of RAA were detected; 26 (37%) had RAA with aberrant left subclavian artery, 23 (32%) had RAA with mirror-image branching, 20 (28%) had RAA of unknown type and two (3%) had double aortic arch. While 20/26 cases with RAA and aberrant left subclavian artery were isolated findings, all 23 cases with RAA and mirror-image branching were associated with cardiac defects, namely tetralogy of Fallot (43%) or pulmonary atresia with ventricular septal defect (22%). Of the 20 cases with RAA, 19 of unknown type were associated with heterotaxy syndromes and had additional cardiac malformations and ambiguities of the situs. The two cases with DAA were isolated findings. Seven cases in our series (10%) had a microdeletion 22q11 and these were significantly associated with extracardiac malformations. The outcome in our series depended solely on the associated cardiac and extracardiac malformations, with the exception of one infant with isolated DAA, in whom a surgical correction was warranted. CONCLUSIONS: RAA detected in fetal life is associated frequently with other cardiac/non-cardiac malformations, heterotaxy syndromes and microdeletions 22q11. The associated conditions vary depending on the branching type of the brachiocephalic vessels and the presence of extracardiac malformations.     

Revascularized fibula for tibia replacement in adamantinoma

Adamantinoma of long bones is one of the rarest of malignant bone tumors; it is commonly located in the middle or lower third of the diaphysis of the tibia. A case with multiple occurrences affecting both the tibia and fibula is presented. En bloc resection with wide operative margins was performed, and a large tibial defect of 23 cm was effectively bridged by a revascularized free fibular flap. At 13 months follow-up, there was no sign of local recurrence or metastasis, and the patient was mobile.     

Volume et profil de consommation d’alcool des élèves et des camarades scolaires comme prédicteurs de l’agression et de la victimisation: une analyse multiniveaux auprès d’adolescents suisses

Volume and profile of alcohol consumption among students and classmates as predictors of aggression and victimization: a multilevel analysis among Swiss adolescents

Objective:  

To test the effects of the volume of alcohol consumption and drinking patterns on alcohol-related aggression and victimization, both at the individual and class levels.     

Audio spectrum and sound pressure levels vary between pulse oximeters

PURPOSE: The variable-pitch pulse oximeter is an important intraoperative patient monitor. Our ability to hear its auditory signal depends on its acoustical properties and our hearing. This study quantitatively describes the audio spectrum and sound pressure levels of the monitoring tones produced by five variable-pitch pulse oximeters. METHODS: We compared the Datex-Ohmeda Capnomac Ultima, Hewlett-Packard M1166A, Datex-Engstrom AS/3, Ohmeda Biox 3700, and Datex-Ohmeda 3800 oximeters. Three machines of each of the five models were assessed for sound pressure levels (using a precision sound level meter) and audio spectrum (using a hanning windowed fast Fourier trans-form of three beats at saturations of 99%, 90%, and 85%). RESULTS: The widest range of sound pressure levels was produced by the Hewlett-Packard M1166A (46.5 +/- 1.74 dB to 76.9 +/- 2.77 dB). The loudest model was the Datex-Engstrom AS/3 (89.2 +/- 5.36 dB). Three oximeters, when set to the lower ranges of their volume settings, were indistinguishable from background operating room noise. Each model produced sounds with different audio spectra. Although each model produced a fundamental tone with multiple harmonic overtones, the number of harmonics varied with each model; from three harmonic tones on the Hewlett-Packard M1166A, to 12 on the Ohmeda Biox 3700. There were variations between models, and individual machines of the same model with respect to the fundamental tone associated with a given saturation. CONCLUSION: There is considerable variance in the sound pressure and audio spectrum of commercially-available pulse oximeters. Further studies are warranted in order to establish standards.     

Conversion from mycophenolate mofetil to enteric-coated mycophenolate sodium in liver transplant patients presenting gastrointestinal disorders: a pilot study.

Gastrointestinal (GI) disorders are one of the main adverse events in patients treated by mycophenolic acid (MPA). The aim of this prospective study was to evaluate the effect of conversion from mycophenolate mofetil (MMF) to enteric-coated mycophenolate sodium (EC-MPS) in liver transplant patients presenting GI side-effects Since January 2003, stable liver transplant patients receiving MMF and presenting GI disorders, without evidence of other origin than MMF were enrolled. Conversion was performed without a washout period at an equimolar daily dosage. Thirty-six patients were included after a median delay of 45 months after liver transplantation (LT) (16 women and 20 men, median age of 47 years). Diarrhoea was the main clinical symptom (n = 28, 77.7%). At the time of inclusion, patients were treated with MMF since 18 months (range 3-28) and GI disorders were known for 9 months (range 3-12). After a median follow-up of 12 months after conversion, GI disorders were resolved in 20 patients (55%), improved in 6 patients (17%) and not modified or worsened in 10 patients (28%). Our results strongly suggest that conversion from MMF to EC-MPS in liver transplant patients can improve gastrointestinal disorders in a majority of the patients, and therefore might be considered as the best therapeutic option.