Operative GABAergic inhibition in hippocampal CA1 pyramidal neurons in experimental epilepsy

Patch–clamp recordings of CA1 interneurons and pyramidal cells were performed in hippocampal slices from kainate- or pilocarpine-treated rat models of temporal lobe epilepsy. We report that γ-aminobutyric acid (GABA)ergic inhibition in pyramidal neurons is still functional in temporal lobe epilepsy because: (i) the frequency of spontaneous GABAergic currents is similar to that of control and (ii) focal electrical stimulation of interneurons evokes a hyperpolarization that prevents the generation of action potentials. In paired recordings of interneurons and pyramidal cells, synchronous interictal activities were recorded. Furthermore, large network-driven GABAergic inhibitory postsynaptic currents were present in pyramidal cells during interictal discharges. The duration of these interictal discharges was increased by the GABA type A antagonist bicuculline. We conclude that GABAergic inhibition is still present and functional in these experimental models and that the principal defect of inhibition does not lie in a complete disconnection of GABAergic interneurons from their glutamatergic inputs.     

Influence of sex on disease severity in patients with rheumatoid arthritis

OBJECTIVE: To determine whether patient's sex influences the severity of rheumatoid arthritis (RA) in terms of clinical severity or need for treatments. METHODS: This was a retrospective, single-center study. We compared 133 male patients with 133 female patients presenting with RA and matched for disease duration. Data collection included demographic characteristics, pattern of joint involvement, extraarticular manifestations, medical treatment, and joint surgery. Biological measures, HLA genotypes, Larsen radiological scores on radiographs of hands and feet, and Health Assessment Questionnaire (HAQ) results were obtained. RESULTS: Mean disease duration was 7.4 +/- 6.9 years. Concerning clinical pattern of involvement, sicca syndrome was more frequent in women than in men (p = 0.0003). There were no significant differences concerning absence or presence of at least one disease associated gene (HLA-DRB1*01 or *04) in our patients; however, women more often carried 2 disease associated genes (21% vs 11%). No other difference in clinical, biological, or radiological indicators was noted between the 2 populations. Concerning treatment, there was no difference for large joint arthroplasties; female patients underwent significantly more distal joint arthrodesis, 6.7% vs 1.5% (p = 0.03); they were prescribed slightly more disease modifying drugs, 3.33 vs 2.83 (p = 0.04); and showed a trend toward more large joint arthrodesis, 15% vs 7.5% (p = 0.05), and metacarpophalangeal joint arthroplasties, 5.2% vs 0.7% (p = 0.08). CONCLUSION: When patients are matched for RA duration, sex has little effect on the disease pattern and severity, yet women undergo more distal joint surgery.     

Inefficacy of infliximab in primary Sjögren's syndrome: results of the randomized, controlled Trial of Remicade in Primary Sjögren's Syndrome (TRIPSS)

OBJECTIVE: There is no effective treatment for patients with primary Sj?gren's syndrome (SS). Since tumor necrosis factor alpha (TNF alpha) could be a key element in the pathogenesis of primary SS, we conducted a multicenter, randomized, double-blind, placebo-controlled trial to evaluate the effect of infliximab in primary SS. METHODS: A total of 103 patients with primary SS were randomly assigned to receive infliximab infusions (5 mg/kg) or placebo at weeks 0, 2, and 6 and were followed up for 22 weeks. All patients fulfilled the new American-European Consensus Group criteria for SS and had active disease as assessed by values >50 mm on 2 of 3 visual analog scales (VAS) (0-100 mm) that evaluated joint pain, fatigue, and buccal, ocular, skin, vaginal, or bronchial dryness. A favorable overall response was defined as the patient having > or =30% improvement between weeks 0 and 10 in the values on 2 of the 3 VAS. Secondary end points were values on each VAS separately, the number of tender and swollen joints, the basal salivary flow rate, results of the Schirmer test for lacrimal gland function, the focus score on labial salivary gland biopsy, the level of C-reactive protein, and the erythrocyte sedimentation rate evaluated at weeks 0, 10, and 22, as well as quality of life evaluated by use of the generic Short Form 36 questionnaire administered at weeks 0, 10, and 22. RESULTS: At week 10, 26.5% of patients receiving placebo and 27.8% of patients treated with infliximab had a favorable overall response (P = 0.89), and at week 22, 20.4% of the placebo group and 16.7% of the infliximab group had a favorable response (P = 0.62). In addition, the 2 groups did not differ in any of the secondary end points over the 22 weeks of the trial. Severe adverse events reported in the infliximab group did not differ from those observed in previous studies. CONCLUSION: This randomized, double-blind, placebo-controlled study of an anti-TNF agent did not show any evidence of efficacy of infliximab in primary SS.     

Myocardial perfusion defects and associated systemic ventricular dysfunction in congenitally corrected transposition of the great arteries

Background—Patients with systemic ventricles of right ventricular morphology are at high risk of contractile dysfunction, the cause of which has not been fully elucidated.
Objective—To assess whether ischaemia or infarction contributes to ventricular impairment in unoperated patients with uncomplicated congenitally corrected transposition of the great arteries (TGA) by studying myocardial perfusion and function.
Setting—Paediatric and adult congenital cardiac clinics of a tertiary referral centre.
Patients—Five patients with congenitally corrected TGA but without associated structural cardiac defects (aged 3.5 to 34 years).
Interventions—Maximal exercise stress testing using standard or modified Bruce protocols. Sestamibi (technetium-99m methoxy isobutyl isonitrile) scanning after isotope injection at maximal exercise and rest.
Main outcome measures—Maximum exercise capacity; right ventricular myocardial perfusion, regional wall motion, and thickening; right ventricular ejection fraction.
Results—The two youngest patients (3.5 and 11 years) had normal exercise capacity for age, while the others had reduced exercise performance. Sestamibi scanning showed reversible myocardial ischaemia in four patients and fixed defects indicating infarction in five. Irreversible defects were mostly associated with impaired wall motion and thickening. The ejection fraction was normal (65%) in the youngest patient but < 55% in the others (mean (SD) 47(11)%).
Conclusions—Patients with unoperated congenitally corrected TGA have a high prevalence of myocardial perfusion defects, with consequent abnormalities of regional wall motion and thickening, and impaired ventricular contractility. These data suggest that ischaemia and infarction are important in the pathogenesis of ventricular failure in this condition.

Keywords: congenitally corrected transposition of the great arteries;  ventricular dysfunction;  myocardial perfusion;  sestamibi scanning     

Malaria and human immunodeficiency virus infection as risk factors for anemia in infants in Kisumu,western Kenya

The role of maternal and pediatric infection with human immunodeficiency virus type 1 (HIV-1) and malaria as risk factors for anemia was determined in a birth cohort of infants born to mothers participating in a study of the interaction between placental malaria and HIV infection, in Kisumu, Kenya. Between June 1996 and April 2000, 661 infants born to 467 HIV-seropositive and 194 HIV-seronegative mothers were monitored monthly from birth. At each visit a questionnaire was completed and a blood sample was collected for the determination of hemoglobin levels and detection of malaria and HIV. Anemia was common and increased from 13.6% at one month to 75% at six months and remained high throughout the second half of infancy. Placental malaria, infant malaria, and HIV infection of the infant were all associated with infant anemia in a multivariate model, adjusting for other co-variates found to be associated with infant anemia. The HIV-infected infants with malaria parasitemia had lower mean hemoglobin levels compared with HIV-uninfected infants, or HIV-infected infants without malaria, suggesting that HIV-infected infants are particularly vulnerable to the adverse consequences of malaria at this age. Early detection and prompt treatment of infant malaria and treatment of anemia as part of the study protocol failed to prevent most of the infants from becoming anemic. Although not proven effective in this study, micronutrient supplementation should be prospectively assessed in HIV-infected infants as a means of preventing anemia.     

Assessment of renal flow and flow reserve in humans.

OBJECTIVES: The purpose of this work was to establish the normal range of maximal renal hyperemic response in humans and to identify the ideal renal vasodilatory stimuli. BACKGROUND: Stenotic renovascular atherosclerosis is increasingly treated by percutaneous transluminal renal intervention but with an unpredictable outcome. This may be due to hemodynamically non-significant stenosis or the presence of irreversible damage to the glomerular circulation. We propose that the renovascular hyperemic response may help identify appropriate patients. METHODS: In 28 normotensive patients, quantitative angiographic measurements of the renal artery were obtained, and renal artery pressure and flow velocity were continuously recorded after various hyperemic agents. RESULTS: In a first group of 11 patients, a significant increase in renal artery average peak velocity (APV) was observed after intrarenal (IR) bolus injection of 600 microg isosorbide dinitrate (41 +/- 19%), 30 mg papaverine (50 +/- 34%), 50 microg dopamine (94 +/- 54%), 0.8 microg x kg(-1) fenoldopam (80 +/- 25%), and during IR infusion of 1 microg x kg(-1) x min(-1) fenoldopam (86 +/- 28%). A second group of 17 patients received intravenous infusion of dopamine (3, 5, 10, 20, 30, and 40 microg x kg(-1) x min(-1)). The 3 and 5 microg x kg(-1) x min(-1) of dopamine modestly reduced renal resistance index (RI) (-13 +/- 15% and -25 +/- 20%, respectively). At higher dosages, no further decline in RI was observed. No significant change in vessel diameter was observed before and after the administration of the pharmacological stimuli suggesting that changes in APV corresponded with changes in absolute renal blood flow. CONCLUSIONS: The normal renal flow reserve averages approximately 2 in humans with normal renal function. An IR bolus injection of 50 microg x kg(-1) of dopamine is the most convenient means to elicit maximal renal hyperemia.     

Alpha-fetoprotein,the major fetal serum protein,is not essential for embryonic development but is required for female fertility

The alpha-fetoprotein gene (Afp) is a member of a multigenic family that comprises the related genes encoding albumin, alpha-albumin, and vitamin D binding protein. The biological role of this major embryonic serum protein is unknown although numerous speculations have been made. We have used gene targeting to show that AFP is not required for embryonic development. AFP null embryos develop normally, and individually transplanted homozygous embryos can develop in an AFP-deficient microenvironment. Whereas mutant homozygous adult males are viable and fertile, AFP null females are infertile. Our analyses of these mice indicate that the defect is caused by a dysfunction of the hypothalamic/pituitary system, leading to anovulation.     

Structural and functional remodeling of the left atrium: clinical and therapeutic implications for atrial fibrillation

Left atrial (LA) structural and functional remodeling reflects a spectrum of pathophysiological changes that have occurred in response to specific stressors. These changes include alterations at the levels of ionic channels, cellular energy balance, neurohormonal expression, inflammatory response, and physiologic adaptations. There is convincing evidence demonstrating an important pathophysiological association between LA remodeling and atrial fibrillation (AF). Measures that will prevent, attenuate, or halt these processes of LA remodeling may have a major public health impact with respect to the epidemic of AF. In this review, we describe the mechanisms involved in LA remodeling and highlight the existing and potential therapeutic options for its reversal, and implications for AF development.     

Management and treatment of hepatitis C virus in patients with HIV and hepatitis C virus coinfection: A practical guide for health care professionals

Concomitant HIV and hepatitis C virus (HCV) is a common yet complex coinfection. The present document is a practical guide for treating HCV infection in people coinfected with HIV. Effective antiretroviral therapies have prolonged survival rates for HIV-infected people over the past decade, which have made latent complications of HCV major causes of morbidity and mortality in these patients. Advances in the treatment of HCV (eg, combined pegylated interferon and ribavirin) offer the possibility of eradicating HCV infection in coinfected persons. The treatment of HCV must be considered in all cases. Intensive management of the adverse effects of HCV treatment is one of the factors for the success of these therapies. HCV eradication is predicted to decrease the mortality associated with coinfection and reduce the toxicity of HIV treatment.     

Risks of new-onset allergic sensitization and airway inflammation after early age swimming in chlorinated pools

Rationale

Irritant chlorination products in swimming pools can cause respiratory problems in swimmers but their possible implication in allergies development is still unclear.

Objectives

To assess prospectively whether early-life attendance at chlorinated pools increases the risks of IgE sensitization and of airways inflammation later during childhood.

Methods

We conducted a two-year prospective study among 196 kindergarten children (mean age of 5.7 years, 54% of boys). We measured exhaled nitric oxide (eNO) and aeroallergen-specific IgE in nasal mucosa. Parents completed a questionnaire about the child's health, chlorinated pool attendance and potential confounders.

Main Results

Ever swimming at indoor or outdoor chlorinated pools before the age of three years was associated with higher odds for new-onset IgE sensitization to house dust mite (adjusted odds ratio [aOR] 2.93, 95% confidence interval [CI] 1.14–7.55) and for new-onset increased eNO (>15 ppb; aOR, 4.54, 95% CI 1.48–13.9). For both outcomes, aORs increased dose-dependently with time spent in chlorinated pools with values reaching, respectively, 3.60 (95% CI 1.21–10.7) and 5.92 (95% CI 1.72–20.5) when the cumulative pool attendance exceeded 60 h These risks appeared independently of each other, of parental history of allergies and of pre-existing diseases, including eczema, which at baseline was more prevalent in early swimmers (aOR, 2.91; 95% CI 1.23–6.89). Such associations were not seen with IgE sensitization to pollen or cat allergens.

Conclusion

Attendance at chlorinated swimming pools in early life is associated with higher risks of new-onset airways inflammation and IgE sensitization to house dust mite, independently of other risk factors.