Pharmacokinetics of glutathione and its metabolites in normal subjects

To determine the loading and maintenance dosage of glutathione (GSH) for patients suffering from reactive oxygen species (ROS) injury such as acute paraquat intoxication, a kinetic study of reduced GSH was performed in synchrony with that of cysteine (Cys), cystine (Cys2), and methionine (Met). Human subject's porticipitation was voluntary. The effective dose of Cys, Cys2, and Met against ROS in fibroblast cells generated by paraquat was assessed using laser scanning confocal microscopy. Both Cys and Met suppressed ROS in a dose-dependent manner at concentrations of 1-1,000 microM; the concentration required to suppress ROS by 50% was 10 microM for Cys and 50 microM for Met. Using metabolite kinetics with the assumption that Cys and Met are the metabolites of GSH, expected concentrations of Cys and Met of above 20 and 50 microM were estimated when GSH was administered at 50 mg/kg body weights every 205.4 min for Cys and 427.4 min for Met.     

Auditory perceptual grouping and attention in dyslexia

Despite dyslexia affecting a large number of people, the mechanisms underlying the disorder remain undetermined. There are numerous theories about the origins of dyslexia. Many of these relate dyslexia to low-level, sensory temporal processing deficits. Another group of theories attributes dyslexia to language-specific impairments. Here, we show that dyslexics perform worse than controls on an auditory perceptual grouping task. The results show differences in performance between the groups that depend on sound frequency and not solely on parameters related to temporal processing. Performance on this task suggests that dyslexics' deficits may result from impaired attentional control mechanisms. Such deficits are neither modality nor language-specific and may help to reconcile differences between theories of dyslexia.     

An autosomal recessive limb girdle muscular dystrophy (LGMD2) with mild mental retardation is allelic to Walker-Warburg syndrome (WWS) caused by a mutation in the POMT1 gene

Mutations of the protein O-mannosyltransferase (POMT1) gene affect glycosylation of alpha-dystroglycan, leading to Walker-Warburg syndrome, a lethal disorder in early life with severe congenital muscular dystrophy, and brain and eye malformations. Recently, we described a novel form of recessive limb girdle muscular dystrophy with mild mental retardation, associated with an abnormal alpha-dystroglycan pattern in the muscle, suggesting a glycosylation defect. Here, we present evidence that this distinct phenotype results from a common mutation (A200P) in the POMT1 gene. Our findings further expand the phenotype of glycosylation disorders linked to POMT1 mutations. Furthermore, the A200P mutation is part of a conserved core haplotype, indicating an ancestral founder mutation.     

Vascular rings—presentation,investigation and outcome

Our aim was to determine the presentation of patients with vascular rings and evaluate the effectiveness of investigations. Surgical outcomes and respiratory sequelae were also examined. The design was a retrospective case note study over a 13-year period set in a tertiary childrens hospital. Children below the age of 16 years presenting with a vascular ring to the Royal Hospital for Sick Children, Glasgow were studied. Demographic data at presentation, including symptoms, were recorded. The ability of diagnostic investigations to identify the presence of a vascular ring was evaluated. Surgical outcomes were determined by measuring surgical complications and mortality. Respiratory sequelae were recorded by the presence of persistent symptoms or the need for tracheostomy or long-term ventilation following surgery. A total of 24 patients were identified with a median age at presentation of 4.5 months. Stridor was the commonest presenting symptom (14/24). Angiography, chest CT scanning and MRI were the most accurate imaging modalities (accurate in 100% of cases used). Chest X-ray films and echocardiography had the lowest detection rates. Surgical complications (4/24) and mortality (1/24) were low. A substantial number of patients available to follow-up (7/20) were still experiencing stridor 3 months post-operatively. Conclusion:Vascular rings are rare, however, often present with common symptoms. Most children present in early infancy, but a minority presents much later. The investigation of choice is a barium swallow followed by high-resolution computed tomography. Surgery is safe although a number of patients will have persisting symptoms.     

Nasopharyngeal carcinoma in the pediatric age group: the northern Israel (Rambam) medical center experience, 1989-2004

Nasopharyngeal carcinoma (NPC) is rare in children, accounting for less than 1% of all malignancies. Radiation therapy has been the mainstay of treatment of many years, but to improve survival, the use of chemotherapy has been advocated. This is a retrospective analysis of 13 patients less than 20 years of age treated for NPC the Rambam Medical Center during 1989 to 2004. Eight boys and five girls with a median age of 14.5 years (range 10-19) were included. Median follow up (including patients who died) was 6.15 years (range 1-15 years). Duration of symptoms was 1 to 24 months (median 5 months). Of the 13 patients, one patient had stage I, 6 had stage III, 5 had stage IV-A, and 1 had stage IV-B disease. Ten patients (77%) had undifferentiated carcinoma (WHO type III) and three patients (23%) had nonkeratinizing carcinoma (WHO type II). Most of the children received two or three courses of neoadjuvant multiagent chemotherapy consisting of cisplatin and 5-FU, followed by radiotherapy with doses in excess of 60 Gy. One child received concomitant chemoradiation. Ten of the 13 patients (77%) are alive without disease 6 years after diagnosis (range 1-15 years). One patient developed local and distant metastases 1 year after diagnosis and is currently receiving combined radiochemotherapy. Two patients died. Overall survival was 84%; event-free survival was 77%. Nine patients (69%) developed moderate to severe long-term complications. Pediatric NPC is curable by combined radiation and chemotherapy, with doses of radiation in excess of 60 Gy. Long-term follow-up is important for early detection of second malignancies as well as for radiation-induced endocrinologic deficiencies and other normal tissue complications.     

Cryptococcal meningitis in a patient with X-linked hyper-IgM1 syndrome

A case is reported of cryptococcal meningitis in a 27-y-old male suffering from X-linked hyper-IgM1 syndrome. This congenital disorder is characterized by multiple infections of the respiratory and gastrointestinal tracts, but also opportunistic infections commonly seen in patients with cell-mediated immunity. His clinical recovery was good but the need for life-long secondary chemoprophylaxis to prevent relapses is unknown.     

Efficacy of telephone and mail intervention in patient compliance with antihypertensive drugs in hypertension. ETECUM-HTA study

OBJECTIVE: To study the efficacy of telephone and mail intervention in therapeutic compliance among patients with mild to moderate hypertension. DESIGN: A prospective controlled multicenter clinical trial. SETTING: Eighty-five primary care centers in Spain, with a duration of 6 months. PATIENTS: A total of 636 patients with newly diagnosed or uncontrolled hypertension were included. Interventions. The patients were randomized and distributed between the following groups: (i) control (CG) - under routine clinical management; (ii) mail intervention (MIG) - received a mailed message reinforcing compliance and reminding of the visits (15 days, 2 and 4 months); (iii) telephone intervention (TIG) - received a telephone call at 15 days, then at 7 and 15 weeks. MAIN OUTCOME MEASURE: Five visits were scheduled, with the measurement of blood pressure and counting of tablets. Compliers were defined as subjects showing 80-110% drug consumption. Calculations were made of mean percentage compliance (MPC) and compliers, mean blood pressure and percentage controlled subjects. RESULTS: Five hundred and thirty-eight patients completed the study (261 males); 85.5% were compliers (CI = 82.5-88.5; n = 460). The MPC was 95.1+/-19.6% (CI = 93.28-96.92). The CG consisted of 182 individuals, MIG = 172 and TIG = 184. Compliers represented 69.2% of the CG (CI 62.5-75.9%), 91.3% (CI = 87.1-95.5) of the MIG (p = 0.0001) and 96.2% of the TIG (CI 93.5-98.9%); the final MPC was 89.6%+/-15 in CG, 96.6%+/-12 in MIG and 99.1+/-26.8 in TIG (p = 0.0001). The percentage of controlled subjects was 47.2% in CG (CI = 40-54.4), 61.3% in MIG (CI = 54.1-68.5%) and 63.3% in TIG (CI = 56.4-70.2%) (p<0.05). CONCLUSIONS: TIG and MIG are effective measures for improving patient compliance in hypertension.     

Higher cortisol levels in spring and fall in patients with major depression

BACKGROUND: Multiple lines of evidence suggest that there are seasonal effects on mood and behavior, and that these effects are related to serotonergic and hypothalamic-pituitary-adrenal (HPA) function. This study sought to determine whether there is a seasonal effect on clinical parameters, baseline cortisol and prolactin levels, and cortisol and prolactin responses to fenfluramine administration in subjects with major depression. METHODS: In all, 136 subjects with major depression entered the study. Sixty-two subjects who had a major depressive episode (MDE) in Spring or in Fall (the Spring/Fall group) were compared to 74 subjects who had MDE in Winter or in Summer (the Winter/Summer group). Demographic and clinical parameters were assessed and recorded. Clinical parameters included depression, aggression, impulsivity, hopelessness, hostility, and current suicide ideation rating scales, suicide attempt status, and number and maximum lethality of suicide attempts. Cortisol and prolactin levels were drawn before fenfluramine administration and hourly for 5 h thereafter. Cortisol and prolactin levels were computed as the area under the curve of hourly cortisol measurements. RESULTS: Baseline cortisol levels were significantly higher in the Spring/Fall group compared to the Winter/Summer group (14.1+/-4.5 ng/ml vs. 12.5+/-4.4 ng/ml, df=132, t=2.16, p=0.03). There were no seasonal effects on baseline prolactin levels, or post-challenge cortisol and prolactin levels. CONCLUSIONS: The Spring/Fall group and the Winter/Summer group may represent different subtypes of major depression. Future studies need to both confirm our results and elucidate the mechanism of the circannual effect on biological function in depressed patients. The results of our study underline the importance of considering seasonality in psychobiology.