Screening of innate immune receptors in neurodegenerative diseases: a similar pattern

In Alzheimer's disease (AD), Parkinson's disease (PD), dementia with Lewy bodies (DLB) and amyotrophic lateral sclerosis (ALS), neuroinflammatory responses are considered to contribute to neuronal injury. Recently, the innate immune receptors, toll-like receptors (TLRs) and the LPS receptor (CD14) have been related to neurodegeneration. In this study, we systematically assessed the expression of most TLRs and CD14 in AD, PD/DLB and ALS using murine models of these diseases and human post-mortem brain tissues. A common upregulation of TLR2 and CD14 was found in all three animal models. While these two receptors could also be detected in AD patient tissues, they were absent from DLB and ALS tissues. This uniform pattern of innate immune response in animal models of neurodegenerative diseases clearly indicates that this response is part of a non-specific neuroinflammatory effector phase rather than a disease-specific event. The less dynamic disease progression in humans and the location (extracellular versus intracellular) of the aggregated proteins deposits might explain the divergent results seen between animal models and human tissues.     

Intracardiac repair of dextro-transposition of the great arteries in the newborn period. Early and late results

Between November, 1978, and December, 1981, nine neonates with dextro-transposition of the great arteries (d-TGA) and intact ventricular septum underwent primary intracardiac repair (i.e., because of persistent hypoxemia following balloon atrial septostomy arterial Po2 between 17 and 27 mm Hg). Age and weight at operation ranged from 2 to 21 days (mean 6.7) and from 1,900 to 4,500 gm (mean 3,493), respectively. The Mustard procedure was used in the first three patients and the Senning technique in the last six. All operations were done with deep hypothermia and circulatory arrest lasting 43 to 88 minutes (mean 70). An associated patent ductus arteriosus was ligated in eight of the nine patients. There were no deaths. The patients have been followed up for an average of 23 months (range 1 to 36). All are asymptomatic and require no medication. In one patient, atrioventricular dissociation necessitated implantation of a pacemaker 2 weeks after operation. All others are in sinus rhythm with normal atrioventricular conduction. Hemodynamic and angiographic follow-up was obtained in seven patients 8 to 25 months postoperatively (average 14.5). Left ventricular pressure was less than 30 mm Hg and aortic oxygen saturation was greater than 90% in all patients. One of the patients who had the Mustard procedure had complete obstruction at the junction of the inferior vena cava and the lower limb of the baffle. No evidence of systemic venous obstruction was found in the patients who had the Senning procedure. Early primary intracardiac repair appears to be a satisfactory alternative in the treatment of neonates with persistent hypoxemia following balloon atrial septostomy.     

Primary adrenal and thyroid insufficiencies associated with hypopituitarism: a diagnostic challenge

Polyglandular syndromes have been described for many years but only one case of panhypopituitarism with adrenal and thyroid insufficiencies has been documented. We present a 69-year-old woman with the initial diagnosis of idiopathic primary hypopituitarism. An associated primary adrenal disease was suspected on low plasma aldosterone and increased plasma renin values during unjustified withdrawal of treatment. The complete absence of cortisol response to long-term ACTH administration confirmed the diagnosis. In addition, primary hypothyroidism was demonstrated by the absence of radioiodine uptake by the thyroid gland and the inability to increase T4 secretion after repeated TSH injections. The pattern of hypopituitarism and the coexistence of both adrenal and thyroid deficiencies provide strong evidence for the diagnosis of autoimmune polyglandular syndrome with hypophysitis.     

Postural adjustments to voluntary head motions during standing are modified following stroke

OBJECTIVE: To compare postural adjustments to voluntary head motions during standing between stroke and healthy subjects. DESIGN: Quasi-experimental design involving two groups: stroke patients (n=8) and age-matched healthy controls (n=5). BACKGROUND: Massive sensory stimulation from the visual, vestibular and neck proprioceptive systems is conveyed during a voluntary head motion. It remains to be investigated how stroke patients integrate this sensory information and generate appropriate postural adjustments to maintain standing balance. METHODS: Eight stroke patients and five healthy age-matched subjects performed fast head motions (up, down, right, left, or none) in random sequence during standing. Body kinematics in 3-D, horizontal displacement of the center of pressure and the body center of mass, as well as bilateral vertical ground reaction forces and activation of tibialis anterior, medial gastrocnemius, vastus lateralis and semitendinosus muscles, were acquired and analyzed. RESULTS: Stroke patients moved their heads at lower velocities while maintaining similar range of motion as compared to healthy subjects. Stroke patients showed larger difference in center of pressure and center of mass excursions and larger root-mean-square values for center of pressure and center of mass displacement and velocity during all directions of head motions. Stroke patients presented disrupted loading patterns to avoid weight bearing of the paretic limb, in contrast to the typical and direction-specific loading patterns observed in healthy subjects during head motions. CONCLUSIONS: Stroke patients manifest altered postural adjustments to voluntary head motions during standing. It suggests that sensorimotor integration processes for stance and balance are impaired by a stroke. RELEVANCE: Head motions are expected to produce little displacement in body center of mass, as the mass of the head is relatively small as compared to the rest of the body. However, the complex information channeled from vestibular, visual and neck proprioceptive afferents must be processed by the central nervous system in relation to the motor commands, such that head motions can be executed smoothly and rapidly while maintaining standing balance. The altered postural adjustments to head motions observed in stroke patients suggest an underlying impairment in sensorimotor integration.     

Cost-effectiveness of immunization strategies for the control of serogroup C meningococcal disease

This study compares the cost-effectiveness of a control strategy for serogroup C meningococcal disease (CMD) relying on surveillance and implementation of a mass immunization campaign effective 1 year after the beginning of an epidemic with strategies based on routine immunization, using either three doses of serogroup C conjugate vaccine given in early infancy or one dose at 1 year of age. The simulation model is based on 25 birth cohorts followed up to age 24 years, and seven epidemiological scenarios including low and high level endemicity, and one to five epidemics over a 49-year period. Epidemiological and cost data were mainly collected in the province of Quebec, Canada. Results indicate that the most effective strategy is a three-dose routine program, with the least effective strategy being mass immunization. A one-dose routine program is the most cost-effective strategy in most likely scenarios. In a societal perspective with a vaccine purchase price of CDN$ 50 per dose, the average incremental cost of the one-dose strategy would be $ 190,000 per case averted, US$ 23,000 per life-year gained, and US$ 42,000 per QALY gained. If vaccine-induced immunity is waning rapidly, mass immunization or routine vaccination with booster dose(s) would be the best control options.     

Follow-up of adverse drug reactions from peginterferon alfa-2b-ribavirin therapy

STUDY OBJECTIVE: To investigate the adverse drug reactions (ADRs) from peginterferon alfa-2b plus ribavirin in patients infected with the hepatitis C virus (HCV). DESIGN: Prospective, observational, pharmacovigilance study. SETTING: Gastroenterology department of a French university hospital. PATIENTS: A cohort of consecutive outpatients who were treated with peginterferon alfa-2b plus ribavirin for viral hepatitis. INTERVENTION: During the 1-year period of HCV therapy visits, a medical staff member trained in pharmacovigilance interviewed the patients about all ADRs and their use of other drugs. The ADRs assessed as serious were confirmed from regular review of the medical records. MEASUREMENTS AND MAIN RESULTS: A total of 87 patients were treated for HCV. Among these, peginterferon alfa-2b plus ribavirin therapy was started in 51 patients; one patient was lost to follow-up after 1 month. The ADRs were assessed as serious in 10 patients (20%): suicide (one patient), hospitalization (three patients), and definitive discontinuation of peginterferon alfa-2b plus ribavirin (six patients). The ADRs contributed to or were the main reason for withdrawing HCV drugs in 8 patients (16%). Dosage reductions of ribavirin and/or peginterferon alfa-2b were required in 10 patients (20%) and seemed less frequent than that needed in clinical trials. Compared with results of clinical trials, a similar frequency of hair loss, higher frequency of injection-site reactions, lower frequency of depression or insomnia, and higher frequency of endocrine ADRs or blurred vision were detected. CONCLUSION: Results suggest some differences in the frequencies of ADRs compared with data from clinical trials. A longer period of monitoring is warranted to improve knowledge about ADRs of pegylated interferon. A medical staff member trained in pharmacovigilance is useful to collect quantitative and qualitative data about ADRs.     

Platelet activity and antibody titers after exposure to streptokinase or streptococcal infection

INTRODUCTION: Streptokinase use, in acute myocardial infarction, is hindered by failure to reperfuse (60%) and early reocclusion (16%). This phenomenon may, among other causes, be due to systemic inactivation of streptokinase, as well as streptokinase-induced platelet aggregation and clot propagation from antibodies to streptokinase produced after streptokinase administration or streptococcal infections. The purpose of this study was to determine the incidence of streptokinase-induced, antibody-mediated, platelet activation and aggregation after administration of SK or development of a streptococcal infection. MATERIALS AND METHODS: We included 45 normal volunteers (Control group), as well as 45 patients who had received streptokinase (Streptokinase group) and 13 who had suffered a severe streptococcal infection (Streptococcal infection group) within the past 3 years. Extent of streptokinase-induced, antibody-mediated, platelet activation and aggregation, as well as anti-streptokinase antibody and streptokinase resistance titers (lowest streptokinase concentration to cause clot lysis within 10 min) were measured. RESULTS: Whereas streptokinase-induced, antibody-mediated, platelet activation was observed in 49% of streptokinase patients and in only 17% and 15% of streptococcal infection patients and normal volunteers (p<0.05 Streptokinase vs. Control and Streptokinase vs. Streptococcal infection), streptokinase-induced platelet aggregation was observed in 23% of streptokinase patients and streptococcal infection patients, and in none of the control patients (p<0.05). CONCLUSIONS: Streptokinase-induced, antibody-mediated, platelet activation and aggregation occur in patients with high titers of anti-streptokinase antibody and may play a role in failure of streptokinase therapy. Streptococcal infection patients behave like streptokinase patients in terms of the reactivity of their platelets to subsequent streptokinase dose in vitro.     

185. Wandsklerosierung der Speiseröhre,ein neues Verfahren zur Therapie der akuten und drohenden Oesophagusvaricenblutung im Kindesalter

Zusammenfassung Die Resultate der chirurgischen Therapie der Oesophagusvaricenblutung im Kindesalter durch Shunt- oder Venensperroperationen haben bisher enttäuscht. Auf der Suche nach neuen Behandlungsmöglichkeiten haben wir die Fibrosklerosierung der Oesophagusschleimhaut erprobt. Durch Injektion sklerosierender Substanzen in das Epithel der terminalen Speiser6hre bleibt der pathophysiologische Kollateralkreislauf erhalten, die blutungsgefährdeten Krampfadern werden unter Narbengewebe versenkt and können nicht mehr rupturieren and bluten. — 21 Kinder im Alter von 2–14 Jahren werden behandelt. Die Sklerosierung erfolgte 15mal im blutungsfreien Intervall and 6mal bei konservativ unstillbarer Blutung; sie konnte gestoppt and Blutungsrezidive konnten verhindert werden. Durch Anwendung der Fibrosklerosierung der Speiser6hre wird somit Zeit gewonnen, um die immer empfehlenswerte Shuntoperation erst im Jugendalter durchzuführen.     

Influence of HCV or HBV coinfection on adverse drug reactions to antiretroviral drugs in HIV patients

Objective To compare the profile of adverse drug reactions (ADRs) to antiretroviral (ARV) drugs in patients coinfected with hepatitis C virus (HCV) or hepatitis B virus (HBV) versus non-coinfected patients with human immunodeficiency virus (HIV) infection. Methods We used the French Pharmacovigilance Database from 2000 to 2002. Selected patients were classified into four groups: HIV+HCV, HIV+HBV, HIV+HBV+HCV and HIV patients. We compared patients’ characteristics and profiles of ADRs to ARV drugs between the four groups. Results We identified 1,068 HIV, 172 HIV+HCV, 72 HIV+HBV and 26 HIV+HBV+HCV patients with 2,398, 446, 183 and 70 ADRs related to ARV drugs, respectively. The “seriousness” of these ADRs was similar in HIV and coinfected patients but death related to the ADRs was more frequent in HIV+HCV (9.4%) than in HIV (3.6%) patients (p<0.001). “Liver and bile system disorders” were more frequently reported in HIV+HCV and HIV+HBV patients than in HIV patients (17.3% and 20.8%, respectively, versus 8.9%, p<0.001). In HIV+HBV patients, the occurrence of these ADRs was independently associated in a logistic regression model to male gender [odds ratio (OR): 9.28, 95% confidence interval (CI): 2.74–31.36], exposure to zalcitabine (OR: 17.82, 95% CI: 1.49–212.95) or efavirenz (OR: 5, 95% CI: 1.44–17.33). “Red blood cell disorders” were also more frequent in HIV+HCV (7.4%) than in HIV (4.4%) patients (p<0.01). Conclusion Hepatic or haematological (mainly anaemia) ADRs to ARV drugs are more frequent in coinfected patients than in HIV patients. This study underlines the importance of hepatitis B or C in the occurrence of ADRs in HIV patients on ARV drugs.