Diffusion tensor imaging on teenagers, born at term with moderate hypoxic-ischemic encephalopathy

Hypoxic-ischemic encephalopathy (HIE) is graded with three levels of severity-mild, moderate and severe. The outcome of individuals with mild and severe grades can be reliably predicted from this scheme. Individuals with moderate degree are divided in outcome between those who suffer major neurologic problems (e.g., cerebral palsy) and those who are assumed to recover from the incident. It is however not clear if the recovery is complete and unquestionable. A group of adolescents who had been born at term, diagnosed with moderate HIE but had not developed cerebral palsy, were investigated with diffusion tensor imaging. Fractional anisotropy maps were used as a basis of comparison to a group of controls of the same age and gender distribution. In several white matter areas fractional anisotrophy was lower in the group of individuals with a history of moderate HIE. These areas include the internal capsules (bilaterally in the posterior limb and on the right in the anterior limb), the posterior and anterior corpus callosum as well as frontal inferior white matter areas. These results indicate that even in the absence of such major neurologic impairments as cerebral palsy, moderate HIE causes long term white matter disturbances which are not repaired by adolescence.     

Beta2-adrenergic receptor gene polymorphisms and pregnancy outcome

AIMS: The association between alleles at two loci of the polymorphic beta2-adrenergic receptor (beta2AR) gene and pregnancy outcome was determined. METHODS: In a case-control study, buccal swabs obtained from 159 mother-infant pairs after a preterm or term birth were analyzed by gene amplification and endonuclease digestion for polymorphisms at codons 16 and 27 of the beta2AR gene. RESULTS: Homozygosity for allele A at codon 16 (Arg-16) occurred in 26 (20.5%) of 127 mothers with a term birth and in none of the mothers who had a spontaneous preterm birth (p=0.002). Conversely, 24 of 32 (75.0%) mothers with a spontaneous preterm birth, as compared to 58 of 127 (45.7%) mothers with term births, were Arg-16/ allele G (Gly-16) heterozygotes (p=0.003). There was no relation between pregnancy outcome and infant genotype at codon 16 or maternal or infant genotypes at codon 27. The alleles at codon 16 and 27 were in linkage disequilibrium and the combinations of Arg-16-Gln-27 homozygosity (p=0.04) and Arg-16/Gly-16-Gln homozygous (p=0.01) were associated with a decreased and increased rate of spontaneous preterm birth, respectively. CONCLUSION: At codon 16 of the beta2-AR gene, maternal Arg-16 homozygosity protects against, and Gly-16 predisposes to spontaneous preterm birth.     

A randomised clinical trial evaluating the efficacy of physiotherapy after rotator cuff repair

The optimal form of rehabilitation after rotator cuff repair has yet to be determined. A randomised clinical trial was undertaken to compare outcomes for two forms of rehabilitation for this condition: individualised supervised physiotherapy treatment, and a standardised unsupervised home exercise regime. Fifty-eight volunteers with all sizes of operatively repaired rotator cuff tears were allocated randomly to one of the two treatment groups. All subjects received a standardised home exercise regime. Subjects who were randomised to the physiotherapy group received additional individualised treatment. Independent, blinded assessments of range of motion, muscle force and functional outcome measures were performed pre-operatively, and at six, 12 and 24 weeks postoperation. At six, 12 and 24 weeks post-operation, comparable outcomes were demonstrated for both rehabilitation groups. By 24 weeks post-operation, most subjects demonstrated outcomes that were consistent with a favourable recovery, regardless of rehabilitation mode. On the basis of these results, outcomes for subjects allocated to individualised physiotherapy treatment after rotator cuff repair are no better than for subjects allocated to a standardised home exercise regime.     

Development of insulin resistance by nitrate tolerance in conscious rabbits

Clinical evidence has been raised to suggest that transdermal nitroglycerin increases the sensitivity of peripheral tissues to the hypoglycemic effect of insulin. In this study we determined whether development of tolerance to the hypotensive effect of nitroglycerin also resulted in tolerance to the insulin-sensitizing effect in rabbits. Intravenous glucose disposal and hyperinsulinemic euglycemic glucose clamp studies were performed on naive and hemodynamic nitrate tolerant conscious New Zealand white rabbits. These rabbits were exposed to continuous "patch on" with nitroglycerin (0.07 mg/kg/h) or placebo patches over 7 days. Nitroglycerin treatment of 7 days produced a lack of hypotensive response to a single intravenous bolus of 30 microg/kg nitroglycerin, which caused a significant decrease in mean arterial blood pressure in control rabbits. A six-hour exposure to transdermal nitroglycerin significantly increased insulin sensitivity determined by hyperinsulinemic (100 microU/ml) euglycemic (5.5 mmol/l) glucose clamping as compared with that seen in rabbits treated with placebo patches. A significant decrease in insulin sensitivity was observed in the nitroglycerin patch-treated animals both in the presence and after the removal of the last patch when the patches were applied over 7 days. We conclude that acutely nitrate patches improve insulin sensitivity whereas a 7-day chronic treatment schedule that results in hemodynamic nitrate tolerance also produces insulin resistance.     

Olanzapine versus clozapine in treatment-resistant or treatment-intolerant schizophrenia

Clozapine has been the gold standard for treatment of patients with refractory schizophrenia but is associated with serious safety liabilities. This has prompted the search for therapeutic alternatives for treatment-resistant schizophrenia. The objective of this study was to compare the efficacy and safety of olanzapine versus clozapine in schizophrenic patients who failed to respond adequately to antipsychotic medication or who experienced intolerable adverse effects associated with the medication. This 18-week, randomized, double-blind, parallel study compared treatment with either olanzapine (5-25 mg/day, n=75) or clozapine (100-500 mg/day, n=72) in patients with schizophrenia who were nonresponsive to, or intolerant of, standard acceptable antipsychotic therapy. At the 18-week endpoint, no statistically significant differences were found between olanzapine and clozapine in any efficacy measure used: Positive and Negative Syndrome Scale (PANSS) total, positive, negative, or general psychopathology or Clinical Global Impression severity (CGI-S). Response rates based on the criteria of Kane et al. [Arch. Gen. Psychiatry 45 (1988) 789] were also not significantly different between olanzapine-treated (57.9%) and clozapine-treated patients (60.8%). There were no significant differences in measurements of extrapyramidal symptoms or electrocardiography, and no clinically and statistically significant changes were seen in vital signs or laboratory measures in either group. Both treatments were well tolerated. Olanzapine demonstrated similar efficacy to clozapine in patients who had failed previous treatment because of lack of efficacy (treatment resistance) or intolerable side effects (treatment intolerance). Olanzapine therefore presents a safe alternative in the treatment of refractory schizophrenia.     

Spinal implantation of hNT neurons and neuronal precursors: graft survival and functional effects in rats with ischemic spastic paraplegia

Transient spinal ischemia, a complication associated with aortic cross-clamp may lead to spastic paraplegia. Once fully developed this deficit is permanent. Quantitative histopathological assessments and pharmacological studies show that the ischemic spasticity is secondary to the loss of lumbar GABA and glycinergic inhibitory interneurons. In the present study, we investigated whether human hNT neurons or committed Sprague-Dawley rat spinal neuronal precursors (SNPs) when grafted into previously ischemic spinal segments depleted of inhibitory neurons would restore local inhibitory tone and ameliorate spasticity. Rats with functionally and electrophysiologically defined spasticity that received spinal graft of hNT neurons or neuronal precursors and immunosuppressive treatment displayed a progressive recovery of motor function that correlated with the improvement of otherwise exacerbated peripheral motor response evoked by stimulation of motor cortex. In contrast, in control, medium-injected or oligodendrocyte-grafted animals no significant therapeutic effect was seen. Stereological quantification of grafted neurons revealed 1-2% survival at three months after transplantation. These surviving neurons displayed a robust axo-dendritic sprouting and expression of markers typical of mature neurons including NSE, NeuN and synaptophysin. In both treatment groups a subpopulation of grafted neurons developed GABA immunoreactivity. These data provide evidence that a region specific grafting of hNT neurons or other neuronally committed cells, which have a potential to develop inhibitory neurotransmitter phenotype, represent an effective treatment modality to modulate ischemia-induced spastic paraplegia.     

An economic model of 2-hour post-dose ciclosporin monitoring in renal transplantation

BACKGROUND: Monitoring of microemulsion ciclosporin (cyclosporine; Neoral) by 2-hour post-dose drug concentrations (C2) is an accurate measure of ciclosporin absorption efficiency and exposure, and appears superior to trough (C0) monitoring for prediction of rejection risk. A predictive decision model was used to determine if this approach also reduces total treatment costs in the first 12 months after renal transplantation. METHODS: Parameter estimates for key clinical events were derived from the literature and from prospective pharmacokinetic studies comprising 234 adult HLA-non-identical renal graft recipients at seven Canadian centres. Patients were treated with microemulsion ciclosporin (Neoral), corticosteroids and azathioprine or mycophenolate mofetil. Using the perspective of the Canadian healthcare provider, total treatment costs for the C2 versus the C0 strategy were modelled over 12 months, and then remodelled using conservative estimates to extend the timeframe to 5 years. Health resources were valued in 1999 Canadian dollars. RESULTS: The incidence of acute rejection was estimated to be 25% at 1 year in patients monitored by C0 and 18% in those monitored by C2. Patient survival was considered to be independent of monitoring strategy, and graft loss was predicted to be 1.4% lower in the C2 group. The studies suggested no important differences in comorbidity and the costs of C0 and C2 monitoring and ambulatory-based adverse events were held equivalent. Using these inputs, the average cost per patient for the first year post-transplant was Can dollars 46,857 for C0 monitoring and Can dollars 45,306 for C2 monitoring, rising to Can dollars 146,879 and Can dollars 142,569 after 5 years. The predicted cost for initial hospitalisation was Can dollars 11,280 for C0 and Can dollars 10,806 for C2 monitoring. The cost of maintenance immunosuppressive drug use, graft loss and dialysis was Can dollars 19,098 in the C0 group and Can dollars 18,612 in the C2 group, while acute rejection treatment costs were Can dollars 2169 and Can dollars 1577, respectively. An additional Can dollars 14,310 was consumed by other events, including repeat hospitalisation, for each group. Sensitivity analysis indicated that the most influential parameters affecting savings due to C2 monitoring were a reduction in the duration of initial and follow-up hospitalisations and reduced risks of acute rejection and subsequent graft loss. CONCLUSIONS: Compared with traditional trough concentration monitoring, ciclosporin monitoring at 2 hours post-dose produced a predicted saving of Can dollars 1551 during the first year after renal transplant. Although modelling assumptions become more restrictive over time, this projection allows a preliminary assessment of the long-term economic impact of the routine use of C2 monitoring.     

Leukocyte esterase activity in vaginal fluid of pregnant and non-pregnant women with vaginitis/vaginosis and in controls

OBJECTIVES: To determine the leukocyte esterase (LE) activity in vaginal lavage fluid of women with acute and recurrent vulvovaginal candidosis (VVC and RVVC respectively), bacterial vaginosis (BV), and in pregnant and non-pregnant women without evidence of the three conditions. Also to compare the result of LE tests in women consulting at different weeks in the cycle and trimesters of pregnancy. The LE activity was correlated to vaginal pH, number of inflammatory cells in stained vaginal smears, type of predominating vaginal bacteria and presence of yeast morphotypes. METHODS: One hundred and thirteen women with a history of RVVC, i.e. with at least four attacks of the condition during the previous year and who had consulted with an assumed new attack of the condition, were studied. Furthermore, we studied 16 women with VVC, 15 women with BV, and 27 women attending for control of cytological abnormalities, who all presented without evidence of either vaginitis or vaginosis. Finally, 73 pregnant women were investigated. The LE activity in vaginal fluid during different weeks in the cycle of 53 of the women was measured. RESULTS: In the non-pregnant women, an increased LE activity was found in 96, 88, 73 and 56% of those with RVVC, VVC and BV and in the non-VVC/BV cases, respectively. In 73% of pregnant women in the second trimester, and 76% of those in the third, the LE test was positive. In all groups of non-pregnant women tested, the LE activity correlated with the number of leukocytes in vaginal smears, but it did not in those who were pregnant. There was no correlation between LE activity and week in cycle. The vaginal pH showed no correlation to LE activity in any of the groups studied. CONCLUSIONS: The use of commercial LE dipsticks has a limited value in the differential diagnosis of RVVC, VVC and BV. There is no correlation between the LE activity in vaginal secretion on one hand and vaginal pH, week in the menstrual cycle and trimester in pregnancy on the other. Women with BV often have signs of inflammation as evidenced by a positive LE test and inflammatory cells in genital smears.