Smad3-dependent induction of plasminogen activator inhibitor-1 in astrocytes mediates neuroprotective activity of transforming growth factor-beta 1 against NMDA-induced necrosis

The intravenous injection of the serine protease, tissue-type plasminogen activator (t-PA), has shown to benefit stroke patients by promoting early reperfusion. However, it has recently been suggested that t-PA activity, in the cerebral parenchyma, may also potentiate excitotoxic neuronal death. The present study has dealt with the role of the t-PA inhibitor, PAI-1, in the neuroprotective activity of the cytokine TGF-beta1 and focused on the transduction pathway involved in this effect. We demonstrated that PAI-1, produced by astrocytes, mediates the neuroprotective activity of TGF-beta 1 against N-methyl-D-aspartate (NMDA) receptor-mediated excitotoxicity. This t-PA inhibitor, PAI-1, protected neurons against NMDA-induced neuronal death by modulating the NMDA-evoked calcium influx. Finally, we showed that the activation of the Smad3-dependent transduction pathway mediates the TGF-beta-induced up-regulation of PAI-1 and subsequent neuroprotection. Overall, this study underlines the critical role of the t-PA/PAI-1 axis in the regulation of glutamatergic neurotransmission.     

New Zealand community attitudes toward people with epilepsy

PURPOSE: International surveys on knowledge and attitudes toward people with epilepsy suggest that public opinion is improving in many countries. This study aimed to discover how New Zealand compared with other countries, and how subgroups within the New Zealand population compared with each other, by conducting a survey of community knowledge and attitudes toward epilepsy. METHODS: Telephone interviews were conducted on a random sample of 400 persons older than 17 years, drawn from a mid-sized provincial town and its hinterland. RESULTS: Ninety-five percent of respondents had heard or read about epilepsy; 73% knew someone with epilepsy; and 67% had seen an epileptic seizure. Somewhat less knowledgeable were young people, the less educated, lower socioeconomic status (SES), and those of Maori or non-European ethnicity. Attitudes toward people with epilepsy were favorable, with only 5% objecting to their child marrying a person who sometimes had seizures. Less-positive attitudes were found among some older people. CONCLUSIONS: Compared with those in other Western countries, New Zealanders are well informed about epilepsy, and their attitudes toward it are mainly positive. Continuing public education about epilepsy is still necessary, especially among the young, the non-European, and older people.     

Prophylaxis of radiation-associated mucositis in conventionally treated patients with head and neck cancer: a double-blind, phase III, randomized, controlled trial evaluating the clinical efficacy of an antimicrobial lozenge using a validated mucositis scoring system.

PURPOSE: Mucositis occurs in almost all patients treated with radiotherapy for head and neck cancer. The aim of this multicenter, double-blind, prospective, randomized trial was to evaluate the clinical efficacy of an economically viable antimicrobial lozenge (bacitracin, clotrimazole, and gentamicin [BcoG]) in the alleviation of radiation-induced mucositis in patients with head and neck cancer. PATIENTS AND METHODS: One hundred thirty-seven eligible patients were randomized to treatment with either antimicrobial lozenge (69 patients) or placebo lozenge (68 patients). The primary end point of the study was the time to development of severe mucositis from the start of radiotherapy. Secondary end points included severity and duration of mucositis, pain measurement, radiation therapy interruption, and quality of life. Mucositis was scored using a validated mucositis scoring system. RESULTS: Toxicity profiles were similar between the two arms of the study. The median time to development of severe mucositis from the start of radiotherapy was 3.61 weeks on BCoG and 3.96 weeks on placebo (P =.61). There were no statistically significant differences between the arms in the extent of severe mucositis as measured by physician, in oral toxicities as recorded by patients, or in radiotherapy delays. CONCLUSION: This study was conducted on the basis of a pilot study that demonstrated the BCoG lozenge to be tolerable and microbiologically efficacious. A validated mucositis scoring system was used. However, in this group of patients treated with conventional radiotherapy, the lozenge did not impact significantly on the severity of mucositis. Whether such a lozenge would be beneficial in treatment situations where rate of severe mucositis is higher (ie, in patients treated with unconventional fractionation or with concomitant chemotherapy) is unknown.     

Tropisetron plus dexamethasone is more effective than tropisetron alone for the prevention of postoperative nausea and vomiting in children undergoing tonsillectomy

The 5-HT3 antagonists are effective in reducing postoperative nausea and vomiting (PONV) associated with paediatric tonsillectomy. Although prophylactic tropisetron can reduce the incidence of PONV by half, the resulting level of over 40% is still unacceptably high. The aim of this study was to evaluate the effect of adding dexamethasone to tropisetron. In a blinded study, 59 children (mean age 6.1 years) were administered 0.1 mg.kg-1 up to 2 mg of tropisetron and 66 children (mean age 5.7 years) received the same dose of tropisetron plus 0.5 mg.kg-1 up to 8 mg of dexamethasone. Both drugs were given intravenously during induction of anaesthesia for tonsillectomy. During the inpatient stay of 24 h, the incidence of postoperative vomiting in the tropisetron alone group was 53% compared with 26% in the combination group (P=0.002, chi-squared). A significant reduction in nausea from 53% to 30% was also observed (P=0.02). Parents completed a daily diary for 5 days following discharge. Delayed vomiting occurred in 27% and 11% of the tropisetron and combination therapy groups, respectively (P=0.025) Sixteen percent and 9%, respectively, required medical attention (P=0.27). Tropisetron plus dexamethasone is more effective than tropisetron alone in reducing the incidence of PONV following paediatric tonsillectomy.     

The effects of photoperiod and feeding on the diurnal rhythm of circulating thyroid hormones in the red drum, Sciaenops ocellatus

Available data in cyprinid and salmonid species indicate that nutrient intake sustains thyroidal rhythmicity and that time of feeding may influence the amplitude, but not the phase, of diurnal thyroid hormone cycles. Several experiments were conducted to characterize the nature of thyroidal rhythmicity in a more derived perciform teleost, the red drum. These studies were designed to test the following hypotheses: (1) that feeding time will alter the amplitude of the thyroid hormone rhythm without altering its phase and (2) that food deprivation will diminish the amplitude of the thyroid hormone rhythm. Circulating T(4) levels in this species exhibit high-amplitude diurnal rhythms, whereas circulating T(3) levels fluctuate within a more narrow range. Fish were reared under a 12L:12D photoperiod and fed 5% body weight once daily either at dawn or at dusk. Feeding time had no discernible effect on the phase of the T(4) cycle, but altered the amplitude of the cycle. Dawn-fed fish had significantly greater mean peak levels of T(4) than dusk-fed fish, although there was no difference in daily mean levels in both groups of fish. When red drum were deprived of food, significant declines in plasma glucose, HSI, and liver glycogen content occurred within 3 days. When red drum were sampled once per day after 3, 7, or 11 days of food deprivation there were no consistent changes in circulating T(4) and T(3) levels compared to those of fed controls. However, significant declines in circulating T(4) and T(3) levels in response to food deprivation were detected with a diurnal sampling protocol. Within 3 days of food deprivation, T(4) levels were significantly reduced compared to those in fed controls and not significantly different from T(4) levels after 10 days of food deprivation. T(3) levels exhibited a stepwise decline in circulating levels during food deprivation. These data indicate that both feeding time and nutrient status exert their effects on thyroid hormone rhythms by modifying the amplitude of these cycles. These data also underscore the importance of incorporating a consideration of endocrine rhythmicity into sampling protocols.     

Urinary albumin excretion rate and puberty in non-diabetic children and adolescents

Slightly elevated urinary albumin excretion rate (microalbuminuria) is a marker of early diabetic nephropathy, but it is unclear if the established definition of microalbuminuria (20–200 μg/min) is correct for children and adolescents. We investigated the albumin excretion rate, albumin/creatinine ratio and urinary albumin concentration in 150 healthy schoolchildren and adolescents to (a) obtain a reference value for albumin excretion rate, (b) relate albumin excretion to pubertal stages and (c) evaluate albumin/creatinine ratio and morning albumin concentration as screening methods for elevatcd albumin excretion rate. Albumin concentration was measured by immunoturbidimetry in timed overnight urine samples. The albumin excretion showed a skewed distribution (geometric mean 3.2 μg/min, 95 percentile 15.1 μg/min). In girls, a peak in the albumin excretion rate was found at the pubertal stage 4 (Tanner) and in boys at stage 5. Albumin/creatinine ratio of 2.5 mg/mmol as a scrccning level for elevatcd albumin cxcrction (15 μg/min) showed a high positivc (0.88) and negative (0.99) predictive value.     

A polymorphic tetranucleotide repeat in the CYP19 gene and male breast cancer

The CYP19 gene codes for the aromatase enzyme that is involved in the synthesis of oestrogens. This case-control study examines the relationship between a tetranucleotide repeat sequence in the CYP19 gene and the development of male breast cancer. No significant differences were found between male breast cancer cases and controls.     

Risk-adapted therapy for clinical stage I-II Hodgkin's disease: 7-years results of radiotherapy alone for low-risk disease, and ABVD and radiotherapy for high-risk disease

Treatment outcomes were documented for 204 adult patients with clinical Stage I-II Hodgkin's disease who were treated with risk-adapted ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine) and radiotherapy (RT) at the Toronto-Sunnybrook Regional Cancer Centre between 1984 and 1994. Forty-nine patients with clinical Stage I disease (excluding bulky mediastinal presentations) and 50 patients with a combination of clinical Stage IIA disease, age 50 years or less, and favourable pathology (lymphocyte predominant or nodular sclerosing histology) were identified as low risk and treated with RT alone to 35 Gy. One hundred and five high-risk patients were treated with chemotherapy (86 with ABVD) followed by RT to 25 Gy. The 7-year cause-specific, overall and disease-free survivals were 95%, 90% and 75% respectively for the low-risk cohort, and 91%, 90% and 88% respectively for the high-risk cohort. In-field relapses accounted for 50% of the failures in both groups. Sixteen of 24 (67%) patients with RT failure and 6/14 (43%) with combined modality therapy (CMT) failure were salvaged. Twenty-eight per cent of the patients treated with RT and 21% of those treated with CMT developed hypothyroidism by 7 years. Fatal complications were recorded in 6% of the low-risk patients managed with RT and 8% of high-risk patients managed with CMT. Septic death and second malignancy accounted for the majority of treatment-related fatalities. Risk-adapted therapy emphasizing RT alone for selected patients with favourable prognostic factors and CMT based on ABVD provides excellent long-term disease control. Further treatment refinements, including the wider application of CMT with lower doses of chemotherapy and RT, will be required to reduce the rate of fatal complications to more acceptable levels.