Patrick Maison

Motor and cognitive improvements in patients with Huntington's disease after neural transplantation.

BACKGROUND Huntingtons disease is a neurodegenerative disease of genetic origin that mainly affects the striatum. It has severe motor and cognitive consequences and, up to now, no treatment. Motor and cognitive functions can be restored in experimental animal models by means of intrastriatal transplantation of fetal striatal neuroblasts. We explored whether grafts of human fetal striatal tissue could survive and have detectable effects in five patients with mild to moderate Huntingtons disease. METHODS After 2 years of preoperative assessment, patients were grafted with human fetal neuroblasts into the right striatum then, after a year, the left striatum. Final results were assessed 1 year later on the basis of neurological, neuropsychological, neurophysiological, and psychiatric tests. The results obtained were compared with those of a cohort of 22 untreated patients at similar stages of the disease who were followed up in parallel. Repeated magnetic resonance imaging (MRI) and positron emission tomography (PET) scanning with fluorine-18-labelled fluorodeoxyglucose was also done to assess metabolic activity. FINDINGS The final PET-scan assessment showed increased metabolic activity in various subnuclei of the striatum in three of five patients, contrasting with the progressive decline recorded in the two other patients in the series, as seen in patients with untreated Huntingtons disease. Small areas of even higher metabolic activity, coregistering with spherical hyposignals on MRI were also present in the same three patients, suggesting that grafts were functional. Accordingly, motor and cognitive functions were improved or maintained within the normal range, and functional benefits were seen in daily-life activities in these three patients, but not in the other two. INTERPRETATION Fetal neural allografts could be associated with functional, motor, and cognitive improvements in patients with Huntingtons disease.

Effect of fetal neural transplants in patients with Huntington's disease 6 years after surgery: a long-term follow-up study

BACKGROUND Although we have shown in three out of five patients with Huntingtons disease that motor and cognitive improvements 2 years after intracerebral fetal neural grafts are correlated with recovery of brain metabolic activity in grafted striatal areas and connected regions of the cerebral cortex, neural grafts are not known to have protective effects on the host brain per se. We undertook long-term follow-up of previously reported patients with the disease to ascertain the nature and extent of any secondary decline after grafting. METHODS Five patients with Huntingtons disease from our pilot study were assessed annually with the unified Huntingtons disease rating scale, neuropsychological tests, and MRI, for up to 6 years after neural grafting. Resting cerebral activity was recorded at 2 and 6 years. FINDINGS Clinical improvement plateaued after 2 years and then faded off variably 4-6 years after surgery. Dystonia deteriorated consistently, whereas chorea did not. Cognitive performance remained stable on non-timed tests, whereas progression of motor disability was shown by deterioration on timed tests. Hypometabolism also affected the brain heterogeneously, sparing the benefits in the frontal cortex and at the precise location of the grafts, but showing a progressive deterioration in other areas. Two patients who had no benefit from grafting at 2 years continued to decline in the same way as non-grafted patients. INTERPRETATION Neuronal transplantation in Huntingtons disease provides a period of several years of improvement and stability, but not a permanent cure for the disease. Improvement of the surgical procedure and in patient selection could improve the therapeutic value, but neuroprotective treatment seems to be unavoidable in the disease.

Medications as Risk Factors of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis in Children: A Pooled Analysis

OBJECTIVE. The aim of this study was to determine the relation of medications to the risk of Stevens-Johnson syndrome and toxic epidermal necrolysis in children <15 years of age. METHODS. We conducted a pooled analysis by using data from 2 multicenter international case-control studies: the severe cutaneous adverse reaction (SCAR) study and the multinational severe cutaneous adverse reaction (EuroSCAR) study conducted in France, Germany, Italy, Portugal, the Netherlands, Austria, and Israel. We selected case subjects aged <15 years, hospitalized for Stevens-Johnson syndrome, Stevens-Johnson syndrome/toxic epidermal necrolysis-overlap, or toxic epidermal necrolysis, and age-, gender-, and country-matched hospital controls. Pooled crude odds ratios were estimated and adjusted for confounding by multivariate methods when numbers permitted. RESULTS. Our study included 80 cases and 216 matched controls. Antiinfective sulfonamides, phenobarbital, carbamazepine, and lamotrigine were strongly associated with the risk of Stevens-Johnson syndrome or toxic epidermal necrolysis. Significant associations were highlighted in univariate analysis for valproic acid and nonsteroidal antiinflammatory drugs as a group and for acetaminophen (paracetamol) in multivariate analysis. CONCLUSIONS. We confirmed 4 previously highly suspected drug risk factors for Stevens-Johnson syndrome/toxic epidermal necrolysis in children: antiinfective sulfonamides, phenobarbital, carbamazepine, and lamotrigine. Among more unexpected risk factors, we suspect that acetaminophen (paracetamol) use increases the risk of Stevens-Johnson syndrome or toxic epidermal necrolysis.

Cardiac Effects of Growth Hormone in Adults With Growth Hormone Deficiency A Meta-Analysis

Background—Growth hormone (GH) treatment may improve morphological and functional cardiac parameters in adults with GH deficiency (GHD). However, clinical trials reported to date involved few patients and yielded variable effects. Methods and Results—We systematically reviewed blinded, placebo-controlled, randomized clinical trials of GH treatment in adults with GHD and open studies in patients with GHD before and after GH treatment, evaluating the effects of GH on cardiac parameters assessed by echocardiography. Sixteen trials (9 blinded and 7 open), involving a total of 468 patients, were identified in 3 bibliographic databases. GH dosage, duration of treatment, and study populations varied among the studies. We conducted a combined analysis of effects on left ventricular mass (LVM), interventricular septum thickness (IVS), left ventricular posterior wall (LVPW), left ventricular end-systolic (LVESD) and diastolic (LVEDD) diameters, stroke volume, E/A ratio, isovolumic relaxation time (IRT), and fractional shortening. Overall effect size was used to evaluate significance, and weighted mean difference between GH and control was given to appreciate size of the effect. GH treatment was associated with a significant increase in LVM: +10.8 (SD: 9.3) g (P =0.02); IVS: +0.28 (0.38) mm (P <0.001), LVPW: 0.98 (0.22) mm (P =0.05), LVEDD: +1.34 (1.13) mm (P <0.001), and stroke volume: +10.3 (8.7) mL (P <0.001). A trend toward a difference in fractional shortening was observed: +1.1 (1.1)% (P =0.06). Overall effect sizes were not significant for LVESD, E/A, and IRT. Conclusions—GH treatment is associated with a significant positive effect on LVM, IVS, LVPW, LVEDD, and stroke volume, as assessed by echocardiography, in adults with GHD.

Place of Cabergoline in Acromegaly: A Meta-Analysis

CONTEXT Cabergoline is widely considered to be poorly effective in acromegaly. OBJECTIVE The aim of this study was to obtain a more accurate picture of the efficacy of cabergoline in acromegaly, both alone and in combination with somatostatin analogs. DESIGN We systematically reviewed all trials of cabergoline therapy for acromegaly published up to 2009 in four databases (PubMed, Pascal, Embase, and Google Scholar). We identified 15 studies (11 prospective) with a total of 237 patients; none were randomized or placebo-controlled. A meta-analysis was conducted on individual data (n = 227). RESULTS Cabergoline was used alone in nine studies. Fifty-one (34%) of the 149 patients achieved normal IGF-I levels. In multivariate analysis, the decline in IGF-I was related to the baseline IGF-I concentration (β = 1.16; P <0.001), treatment duration (β = 0.28; P < 0.001), and baseline prolactin concentration (β = -0.18; P = 0.01), and with a trend toward a relation with the cabergoline dose (β = 0.38; P =0.07). In five studies, cabergoline was added to ongoing somatostatin analog treatment that had failed to normalize IGF-I. Forty patients (52%) achieved normal IGF-I levels. The change in IGF-I was significantly related to the baseline IGF-I level (β = 0.74; P < 0.001) but not to the dose of cabergoline, the duration of treatment, or the baseline prolactin concentration. CONCLUSION This meta-analysis suggests that cabergoline single-agent therapy normalizes IGF-I levels in one third of patients with acromegaly. When a somatostatin analog fails to control acromegaly, cabergoline adjunction normalizes IGF-I in about 50% of cases. This effect may occur even in patients with normoprolactinemia.

Antihypertensive classes, cognitive decline and incidence of dementia: a network meta-analysis.

Objectives: Prevention of cognitive decline and dementia with blood pressure lowering treatments has shown inconsistent results. We compared the effects of different classes of antihypertensive drugs on the incidence of dementia, and on cognitive function. Methods: We conducted a systematic review and included 19 randomized trials (18 515 individuals) and 11 studies (831 674 individuals) analysing the effects of antihypertensive treatment on cognition and on the incidence of dementia, respectively, in hypertensive patients without prior cerebrovascular disorders. Network meta-analysis was used for the comparison of antihypertensive classes. Results: Antihypertensive treatment, regardless of the drug class, had benefits on overall cognition [effect size 0.05, 95% confidence interval (CI) 0.02–0.07] and all cognitive functions except language. Antihypertensive treatment reduced the risk of all-cause dementia by 9%, with reference to the control group (hazard ratio 0.91, 95% CI 0.89–0.94), when randomized trials and observationnal studies were combined (n = 15). Result was not significant with randomized trials alone (n = 4). Angiotensin II receptor blockers (ARBs) had larger benefits than placebo on overall cognition (adjusted effect size 0.60 ± 0.18, P = 0.02). ARBs were more effective than &bgr;-blockers (0.67 ± 0.18, P = 0.01), diuretics (0.54 ± 0.19, P = 0.04) and angiotensin-converting enzyme inhibitors (0.47 ± 0.17, P = 0.04) in rank. The mean change in blood pressure did not differ significantly between the different antihypertensive drug classes. Conclusion: Our results support the notion that antihypertensive treatment has beneficial effects on cognitive decline and prevention of dementia, and indicate that these effects may differ between drug classes with ARBs possibly being the most effective.

Growth hormone as a risk for premature mortality in healthy subjects: data from the Paris prospective study

The influence of growth hormone on mortality in adults is well known in conditions such as growth hormone deficiency and acromegaly. 1 2 In both diseases the excess mortality is principally from cardiovascular disorders, but the occurrence of malignant disorders has also been reported in acromegaly.2 To our knowledge the long term effect of physiological growth hormone on mortality in healthy adults has not been reported. We studied 864 policemen aged 48 to 52 years who did not have cardiovascular disease, diabetes, or glucose intolerance and who had complete data in the Paris prospective study.3 They were examined between 1967 and 1973 then followed for mortality until January 1989. The body mass index (weight(kg)/(height(m)2)), ratio of iliac to thigh circumference (a marker of central fat distribution), heart rate, and both diastolic and systolic blood pressures were measured and smoking habits determined. Blood samples were taken at fasting to measure cholesterol and triglyceride concentrations and mean corpuscular volume, and both at fasting …

Neuroendocrine Disturbances in Huntington's Disease

Background Huntingtons disease (HD) is a severe inherited neurodegenerative disorder characterized, in addition to neurological impairment, by weight loss suggesting endocrine disturbances. The aims of this study were to look for neuroendocrine disturbances in patients with Huntingtons disease (HD) and to determine the relationship with weight loss seen in HD Methods and Finding We compared plasma levels of hormones from the five pituitary axes in 219 patients with genetically documented HD and in 71 sex- and age-matched controls. Relationships between hormone levels and disease severity, including weight-loss severity, were evaluated. Growth hormone (GH) and standard deviation score of insulin-like growth factor 1 (SDS IGF-1) were significantly higher in patients than in controls (0.25 (0.01–5.89) vs. 0.15 (0.005–4.89) ng/ml, p = 0.013 and 0.16±1.02 vs. 0.06±0.91, p = 0.039; respectively). Cortisol was higher (p = 0.002) in patients (399.14±160.5 nmol/L vs. 279.8±130.1 nmol/L), whereas no differences were found for other hormone axes. In patients, elevations in GH and IGF-1 and decreases in thyroid-stimulating hormone, free triiodothyronine and testosterone (in men) were associated with severity of impairments (Independence scale, Functional score, Total Functional Capacity, Total Motor score, Behavioral score). Only GH was independently associated with body mass index (β = −0.26, p = 0.001). Conclusion Our data suggest that the thyrotropic and in men gonadotropic axes are altered in HD according to the severity of the disease. The somatotropic axis is overactive even in patients with early disease, and could be related to the weight loss seen in HD patients.

Long-term persistence of vaccine-derived aluminum hydroxide is associated with chronic cognitive dysfunction

Macrophagic myofasciitis (MMF) is an emerging condition, characterized by specific muscle lesions assessing long-term persistence of aluminum hydroxide within macrophages at the site of previous immunization. Affected patients mainly complain of arthromyalgias, chronic fatigue, and cognitive difficulties. We designed a comprehensive battery of neuropsychological tests to prospectively delineate MMF-associated cognitive dysfunction (MACD). Compared to control patients with arthritis and chronic pain, MMF patients had pronounced and specific cognitive impairment. MACD mainly affected (i) both visual and verbal memory; (ii) executive functions, including attention, working memory, and planning; and (iii) left ear extinction at dichotic listening test. Cognitive deficits did not correlate with pain, fatigue, depression, or disease duration. Pathophysiological mechanisms underlying MACD remain to be determined. In conclusion, long-term persistence of vaccine-derived aluminum hydroxide within the body assessed by MMF is associated with cognitive dysfunction, not solely due to chronic pain, fatigue and depression.

Trends in Antimicrobial Drug Use in the Community—France, 1981–1992

Trends in the use of antimicrobials in France between 1980-1981 and 1991-1992 were analyzed. Data were obtained from surveys of health and ambulatory care, which were based on national probability samples. In a 3-month period in 1980, 17% of the population of France was treated with an antibiotic, compared with 25% in 1991 (P < .001). The frequency of respiratory tract infections with a presumed viral etiology that were diagnosed and treated with antibiotics increased by 86% for adults and 115% for children in the 11-year period. The proper use of cephalosporins must be encouraged, and vigilance is required in view of the increased improper use of fluoroquinolones, mainly for respiratory tract infections with a presumed viral etiology.