Accounting for flow dependence of respiratory resistance during exercise

Studies of airway function during exercise have produced conflicting results both in healthy and diseased subjects. Respiratory resistance (Rrs) was measured using an impulse oscillation technique. A flow/resistance curve was established for each of 16 healthy males during voluntary hyperventilation (VHV) at rest. Then, Rrs and flow were measured immediately (t(0)) and 90 sec (t(90)) after exercise on a cycle ergometer at 60, 70, and 80% of maximal aerobic power. The flow/resistance relationship at rest during VHV was used to assess the flow dependence of Rrs. Rrs at t(0) was higher than at rest (P <0.01) but lower than Rrs obtained at matched flow during VHV (P <0.05). In healthy subjects, the linear increase in Rrs with VHV indicates airflow dependency of Rrs following Rohrer's equation. The relative decrease in Rrs with exercise suggests bronchodilation. The bronchodilating effect disappeared promptly when exercise was stopped suggesting that it may have been related to a reflex mechanism.     

Routine questioning about non-consenting sex: a survey of practice in Australasian sexual health clinics

The objectives of the study were, 1. To ascertain if sexual health physicians and practitioners believe a question concerning a past history of non-consensual sex should be asked routinely and are asking it. 2. To identify whether sexual health services have established protocols to integrate this question into practice. 3. To identify the barriers to this becoming part of a routine sexual health history. A questionnaire covering demographics, protocols and practice around asking the question and reasons for not asking was sent to all (20) sexual health clinics in New Zealand and 7 sexual health clinics in Australia, inviting participation from all staff who took routine sexual health histories. Twenty-seven sexual health clinics participated with a total of 122 (69% response rate) questionnaires completed and returned. One hundred and thirteen (93%) participants believed it was a relevant question to ask. Seventy-eight (63%) said asking the question was encouraged, and routinely or mostly asked the question. Only 40 (33%) identified their workplace had a written policy and 52 (43%) had not received specific training in asking the question. The majority who asked routinely said their client never or rarely objected and that it did not often add significantly to the time. The main reasons for not asking were the belief it was nothing to do with the person's presenting complaint, concern the client would find it too disturbing, inadequate training, and lack of time. Sexual health clinics should develop protocols and guidelines and provide appropriate training to ensure that routine questioning about non-consenting sex is integrated into safe practice.     

No effect of MDR1 C3435T variant on loperamide disposition and central nervous system effects

BACKGROUND: The MDR1 gene encodes the efflux transporter P-glycoprotein, which is highly expressed in the small intestine and in the blood-brain barrier. A major function of P-glycoprotein is to limit the absorption and central nervous system exposure of numerous xenobiotics. A genetic polymorphism in the MDR1 gene (C3435T) has been associated with changes in the intestinal expression level and function of P-glycoprotein. The aim of this study was to investigate the effect of this polymorphism on disposition and brain entry of the P-glycoprotein substrate loperamide. METHODS: Healthy white volunteers were genotyped for the MDR1 C3435T polymorphism, and a 16-mg oral dose of loperamide was administered to 8 subjects with the 3435TT genotype and 8 subjects with the 3435CC genotype. Plasma levels of loperamide were determined by liquid chromatography-tandem mass spectrometry. Loperamide-induced respiratory depression was detected as the ventilatory response to carbon dioxide and was used as a measure of central nervous system side effects. RESULTS: We found no significant difference in loperamide pharmacokinetics between individuals homozygous for the C and the T alleles in position 3435 of MDR1, as follows: peak plasma drug concentration, 3164 +/- 1053 pg/mL and 3021 +/- 984 pg/mL; area under the concentration-time curve from 0 to 8 hours, 14414 +/- 4756 pg. h/mL and 14923 +/- 6466 pg. h/mL; and time to peak plasma drug concentration, 3.9 +/- 1.4 hours and 3.9 +/- 2.6 hours for the MDR1 3435CC and 3435TT genotypes, respectively (P >.05, for all parameters). Hypercapnic ventilatory response changed only minimally after ingestion of loperamide (the coefficient of variation during the 0- to 8-hour period was 21% +/- 14% for the sample population), and there was no MDR1 3435 genotype-related effect on respiratory response. Carriers of the 2 major MDR1 haplotypes, MDR1*1 and MDR1*13, did not differ in their response to loperamide. CONCLUSION: There was no association between the MDR1 C3435T variation and plasma levels or central nervous system effects of the P-glycoprotein substrate loperamide in a white study population. The MDR1 haplotype structure was quite variable and supports the use of haplotypes instead of single nucleotide polymorphisms in determining clinical consequences of genetic variation.     

Facial appearance in persistent hyperinsulinemic hypoglycemia

Persistent hyperinsulinism is the most common cause of recurrent hypoglycemia in infancy because of inappropriate oversecretion of insulin by the pancreas. Pancreatic lesions can be either focal or diffuse, and they have distinct molecular bases. We have studied the facial features in 17 unrelated patients presenting with neonatal (n = 8) or infancy-onset (n = 9) hyperinsulinism. Hyperinsulinism was related to focal adenomatous hyperplasia (n = 7), diffuse hyperinsulinism (n = 5), non-operated hyperinsulinism (n = 2), and hyperinsulinism with hyperammonemia (n = 3). SUR1 or Kir6.2 mutations were found in six of seven focal adenomatous hyperplasia and three of five diffuse hyperinsulinism. A loss of the maternal allele from chromosome 11p15 in the lesion was found in all focal adenomatous hyperplasia. GLUD1 mutations were found in all patients with hyperammonemia. Large birth weight (mean > 3,800 g) was consistently observed (11/17) but protruding tongue, exomphalos, or visceromegaly were never noted and Wiedemann-Beckwith syndrome could always be ruled out. All patients presented with high forehead, small nasal tip, and short columella giving the impression that the nose is large and bulbous, smooth philtrum, and thin upper lip. A square appearance to the face was more obvious in younger patients. These specific facial features, observed in patients with hyperinsulinism of various molecular mechanisms, could be the consequence of fetal intoxication by insulin. However, to date, facial anomalies have not been noted in infants of diabetic mothers and inversely, malformations that are commonly reported in infants of diabetic mothers were not present in our hyperinsulinemic patients.     

Increased expression of metabotropic glutamate receptor subtype 1 on spinothalamic tract neurons following spinal cord injury in the rat

Spinal cord injury (SCI) leads to an increase in metabotropic glutamate receptor subtype 1 (mGluR1) immunoreactivity in the peri-lesion area. The increased expression of mGluR1 parallels the development of thermal hyperalgesia and mechanical allodynia and has been suggested to contribute to the development and maintenance of chronic central pain (CCP) syndromes resulting from SCI. However, expression of mGluR1 has not been directly shown to increase on cells in the pain pathway. Therefore, the expression of mGluR1 on spinothalamic tract (STT) neurons was quantified using confocal imaging and densiometric analysis in normal, sham, and SCI rats. Contusion SCI produced an increase in mGluR1 expression on STT cells in both the cervical enlargement and the spinal section just rostral to contusion SCI. These results suggest that mGluR1 is expressed on neurons that modulate pain transmission and expression on these cells increases following injury, supporting the hypothesis that mGluR1 contributes to CCP following SCI.     

Focusing on local health needs and promoting new partnerships

Government reports have stressed the importance of community-based interventions in addressing health inequalities. This article discusses the pivotal role played by a health visitor and school nurse team in identifying the health needs of a local community and working in partnership with local people, key community groups, health and youth workers to address these specific needs. A health needs assessment highlighted the need for a parenting programme to support parents in managing young children's behaviour, a forum for teenagers to socialize and access pertinent health information and health days to raise public awareness of key community health issues. To date the parenting programme and the youth club have been implemented. Evaluation has considered how accessible, appropriate, efficient and effective they have been and the knowledge and skills gained by participants. This community development demonstrates how health promotion works through effective community action.     

Generic carbamazepine-induced subacute adrenal insufficiency?

Iatrogenic causes of adrenal insufficiency in Addison's disease are exceptional. We report the case of a patient with a history of epilepsy (taking carbamazepine, Tégrétol LP) and Addison's disease (treated by hydrocortisone (HDC) 30 mg/d, Dectancyl 0,5 mg/d, Florinef 50 mg/d). Recent digestive disorders required emergency hospitalization. The physical examination was normal and laboratory tests showed hyponatremia, hyperkalemia, and elevated serum ACTH. The course was rapidly favorable after rehydration and up-titration of the drug regimen. No triggering factor was identified, but the Tégrétol LP had been replaced for 3 months by a generic drug with the same quantity of active ingredients and the same bioavailability, but with a different excipient (the generic drug was not encapsulated). Could these differences have increased the serum level of carbamazepine and lead to more rapide HDC metabolism by enzymatic induction? Could poorer digestive tolerance have decreased HDC absorption? The hypothesis of carbamazepine overdosage is unlikely because the assay remained within the therapeutic range and hyperkaliemia would favor adrenal decompensation. In conclusion, this single case cannot prove drug interaction but does point out the importance of being prudent when modifying a well--tolerated regimen in a patient with Addison's disease.     

Isolation of differentially expressed genes in NPM-ALK-positive anaplastic large cell lymphoma

In this study, we used subtractive suppression hybridization to compare gene expression between an ALK-positive anaplastic large cell lymphoma (ALCL)-derived cell line and a clinical case of ALK-negative ALCL. Construction and screening of a subtracted library resulted in the cloning of 29 cDNAs which were differentially expressed. Most of these clones corresponded to novel genes with unknown function (EST) or to genes implicated in the differentiation, activation or signalling of T cells such as Ran/TC4, interleukin 1-receptor, thymosin beta4, thymosin beta10, moesin and cytohesin-1. Other genes involved in the regulation of apoptosis, such as human inhibitor of apoptosis-1 (HIAP-1), Bax inhibitor-1 and MCL-1, or DNA repair, such as poly (ADP-ribose) polymerase 1 (PARP-1), X-associated protein-1 (XAP-1), SUMO-1 (sentrin-1) and RanGTPase-activating protein 1 (RanGAP-1), were isolated. Interestingly, we found that both RNA and protein levels of human sterol isomerase (hSI), also referred to as emopamil binding protein (EBP), were overexpressed in ALK+ tumours. This protein is involved in the biosynthesis of cholesterol and may be activated by NPM-ALK. Overall, our results suggest that all the genes described above are upregulated in the NPM-ALK-driven transformation process, and that moesin and cytohesin-1 may be more specifically implicated in a signalling pathway involving PLCgamma and PI3K.