Subcortical brain volumes relate to neurocognition in schizophrenia and bipolar disorder and healthy controls

Background

Similar patterns of subcortical brain abnormalities and neurocognitive dysfunction have been demonstrated in schizophrenia and bipolar disorder, with more extensive findings in schizophrenia. It is unknown whether relationships between subcortical volumes and neurocognitive performance are similar or different between schizophrenia and bipolar disorder.

Methods

MRI scans and neuropsychological test performance were obtained from 117 schizophrenia or 121 bipolar spectrum disorder patients and 192 healthy control subjects. Using the FreeSurfer software, volumes of 18 selected subcortical structures were automatically segmented and analyzed for relationships with results from 7 neurocognitive tests.

Results

In schizophrenia, larger left ventricular volumes were related to poorer motor speed, and bilateral putamen volumes were related to poorer verbal learning, executive functioning and working memory performance. In bipolar disorder, larger left ventricular volumes were related to poorer motor speed and executive functioning. The relationship between left putamen volume and working memory was specific to schizophrenia. The relationships between left inferior lateral ventricles and motor speed and between right putamen volumes and executive functioning were similar in schizophrenia and bipolar disorder, and different from healthy controls. The results remained significant after corrections for use of antipsychotic medication. Significant structure-function relationships were also found when all subjects were combined into one group.

Conclusion

The present findings suggest that there are differences as well as similarities in subcortical structure/function relationships between patients with schizophrenia or bipolar disorder and healthy individuals. The observed differences further suggest that ventricular and putamen volume sizes may reflect severity of cognitive dysfunction in these disorders.     

Pharmacotherapy impacts functional connectivity among affective circuits during response inhibition in pediatric mania

Objective

The aim of the current study was to determine the influence of implicated affective circuitry disturbance in pediatric bipolar disorder (PBD) on behavioral inhibition. The differential influence of an antipsychotic and an anti-epileptic medication on the functional connectivity across affective and cognitive neural operations in PBD was examined.

Methods

This was a six-week double blind randomized fMRI trial of risperidone plus placebo vs. divalproex plus placebo for patients with mania (n = 22; 13.6 ± 2.5 years). Healthy controls (HC; n = 14, 14.5 ± 2.8 years) were also scanned for normative comparison. Participants performed a response inhibition fMRI task where a motor response, already ‘on the way’ to execution, had to be voluntarily inhibited on trials where a stop signal was presented. Independent component analysis was used to map functional connectivity across the whole brain.

Results

While there were no behavioral differences between the groups at pre- or post-drug trial, there was significant improvement on manic symptoms in the patient groups. All participants engaged an evaluative affective circuit (EAC: bilateral inferior frontal gyrus, middle frontal gyrus, anterior cingulate cortex (ACC), middle temporal gyrus, insulae, caudate and putamen) and a reactive affective circuit (RAC: bilateral occipital cortex, amygdala, medial frontal gyrus and insula) during task performance. Within the EAC, post-treatment and relative to HC, greater engagement was seen in left insula in risperidone group and left subgenual ACC in divalproex group. Within the RAC, greater baseline amygdala connectivity in patients did not alter with treatment.

Conclusion

EAC and RAC are two key circuits that moderate emotional influence on response inhibition in PBD. Risperidone and divalproex differentially engage the EAC. Limited change in amygdala activity with treatment in all patients indicates a likely trait deficit in PBD.     

Transgenic overexpression of a stable Plasminogen Activator Inhibitor-1 variant

Introduction

Plasminogen Activator Inhibitor-1 (PAI-1) is a member of the Serine Protease Inhibitor (SERPIN) gene family and a key regulator of fibrinolysis. PAI-1 is unique among SERPINs in its spontaneous transition to a latent, inactive state, with a half-life of approximately 2 hours under physiologic conditions. The biologic importance of the PAI-1 transition to latency is unknown. This study aimed to engineer transgenic overexpression of a stable murine PAI-1 variant to examine the physiologic effects in vivo from delayed transition of PAI-1 to latency.

Materials and Methods

Ten independent transgenic lines were generated with expression of a stable PAI-1 variant driven by the hybrid CMV/chicken β-actin promoter.

Results

Plasma PAI-1 levels in the transgenic founders ranged from 3.1 ± 0.1 ng/mL to 1268.8 ± 717.0 ng/mL. Quantitative PCR analysis in 3 transgenic lines demonstrated elevated PAI-1 mRNA in multiple tissues, with the highest increases observed in liver, brain, heart, and kidney. The fold-increase in PAI-1 mRNA over wild-type ranged from 2-fold to > 2000-fold. Immunohistochemistry showed increased PAI-1 in liver, kidney, heart, spleen, and lung. Histologic examination of transgenic mice showed no evidence of thrombosis. The two founders with the highest plasma PAI-1 levels failed to produce any transgenic offspring that survived to weaning, although genotyping of expired pups revealed successful transmission of the transgene.

Conclusion

These results suggest that high expression of a stable variant of PAI-1 may be lethal in mice, while more moderate expression is generally well tolerated and produces no apparent thrombosis.     

Factor XIII A subunit Val34Leu polymorphism in patients suffering atherothrombotic ischemic stroke

Introduction

Factor XIII (FXIII) is a key regulator of fibrinolysis and clot firmness. Val34Leu polymorphism of its potentially active A subunit (FXIII-A) leads to faster activation of FXIII, influences clot structure and provides a moderate protection against coronary artery disease. The effect of FXIII A subunit (FXIII-A) Val34Leu polymorphism on the risk of ischemic stroke (IS) has been investigated in a few studies with contradictory results. In spite of their fundamental difference in pathogenesis and hemostatic pathomechanism, only four small studies investigated the effect of FXIII-A Val34Leu polymorphism on the risk of atherothrombotic IS (AIS) separately from cardioembolic IS. Gender specific effect of the polymorphism on the risk of AIS has not been explored. In the present study we investigated the effect of FXIII-A Val34Leu polymorphism on the risk of AIS on a large patient population.

Materials and methods

A population control group of 1,146 randomly selected individuals, 496 patients surviving AIS and their age and sex-matched controls selected from the population control group were included in the study. FXIII-A Val34Leu genotype was determined on DNA samples, obtained from peripheral blood leukocytes, by fluorescence resonance energy transfer detection using melting curve analysis.

Results

Neither sex nor age affected the distribution of FXIII-A Val34Leu genotypes in population control group. No association was revealed between the risk of AIS and FXIII-A Leu34 carriership and homozygous or heterozygous presentation of Leu34 allele in either gender.

Conclusion

FXIII-A Val34Leu polymorphism fails to influence the risk of AIS.     

Psychopathology in offspring from families of alcohol dependent female probands: A prospective study

Background

Despite the importance of understanding the long-term outcome for children of alcohol dependent (AD) women, the available literature is largely based on offspring of AD fathers and few have utilized prospective designs that include child, adolescent and young adult assessments. Multiplex AD families in which multiple cases of AD are present provide an ideal setting for understanding developmental variants of the adult phenotype.

Method

Offspring from multiplex AD families identified through the mother or control families were evaluated multiple times during childhood and followed to young adulthood. Familial risk status and the presence of specific child/adolescent disorders were used as predictors of substance use disorder outcome by young adulthood.

Results

Offspring who were members of maternal multiplex families had elevated rates of child and young adulthood disorders. High risk offspring of alcohol dependent women were at increased risk for externalizing (Conduct Disorder and ADHD) and internalizing disorders (Major Depressive Disorder (MDD) and Anxiety Disorders). By young adulthood, offspring from these multiplex families had significantly greater odds of developing alcohol abuse or dependence (odds ratio [OR] = 3.63 [CI 1.36-9.64]) and drug abuse or dependence (OR = 4.23 [CI 1.73-10.32]). The prospective design of the study revealed that specific childhood disorders (Conduct Disorder, ADHD, MDD) increased the odds of subsequent development of substance use disorder (SUD).

Conclusions

Multiplex familial risk for alcohol dependence is a significant predictor of substance use disorders by young adulthood. Familial risk and an earlier childhood disorder may set the stage for later development of SUD.     

Spontaneous K-complexes in chronic psychophysiological insomnia

Objective

Spontaneous K-complexes are electroencephalographic features unique to non-rapid eye movement sleep. It has been suggested that this phasic event is a sleep-protective mechanism. Because insomnia sufferers report poor sleep quantity and quality, the objective of this study was to document the occurrence of spontaneous K-complexes in Stage 2 sleep of individuals with chronic insomnia. Specifically, the number and density of spontaneous K-complexes were studied in psychophysiological insomnia sufferers.

Setting

This study took place in a sleep and event-related potentials laboratory.

Design

Spontaneous K-complexes were scored during Stage 2 sleep on the second and third nights of a four-consecutive-nights protocol of polysomnographic recordings.

Participants

The sample included 14 participants suffering from psychophysiological insomnia (INS group; mean age=44.1 years) and 14 good sleepers (mean age=38.1 years). Participants underwent sleep and psychological evaluations. INS group participants met the diagnostic criteria for primary psychophysiological insomnia (mean duration of insomnia=9.6 years).

Intervention

Not applicable.

Results

The total number of spontaneous K-complexes and the density according to the total time spent in Stage 2 sleep (spontaneous K-complexes per minute) were compiled. Repeated-measures analyses of variance showed no significant difference in the number and density of spontaneous K-complexes between the INS group (313.98 and 2.66) and the GS group (361.10 and 2.88), respectively.

Conclusion

These results suggest no deficiency in the sleep-protective mechanism of psychophysiological insomnia sufferers in comparison with good sleepers, as measured by the spontaneous K-complexes' number and density.     

Risperidone and serum lipid profile changes in child and adolescent patients

Objectives

Atypical antipsychotics (AAPs) have been reported to cause metabolic dysregulation that can cause AAPs-related weight gain. The purpose of this study was to assess triglyceride, cholesterol, and weight changes among risperidone-treated children and youths.

Methods

Eighty-one subjects treated with risperidone for any psychiatric disturbances were included in the study. Fasting total low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC), and triglyceride (TG) levels were measured at the baseline and at the sixth month of treatment.

Results

TG, TC and LDL-C levels increased over time and reached statistical significance but there has been no change in HDL-C levels. Seven subjects (8.64%) crossed the threshold into clinically significant hypertriglyceridemia, four subjects (4.94%) crossed the threshold into clinically significant hypercholesterolemia, defined as going over the 95th percentile of published age normed plasma TG and TC levels, respectively. There was a positive correlation between TG and TC elevations and weight gain. There was no significant association with age, gender, diagnoses, risperidone dose and changes of serum TG, TC or LDL-C levels.

Conclusion

The present study identified significant associations between lipid dysregulation and risperidone treatment. Since there is little research available on long-term lipid profile follow-up with atypical antipsychotics treatment in children and youths, controlled studies in larger samples should be carried out to reveal the relationship between risperidone use and plasma lipid parameters in the pediatric population.     

Differential effects of antipsychotic medications on polyunsaturated fatty acid biosynthesis in rats: Relationship with liver delta6-desaturase expression

Polyunsaturated fatty acids (PUFA), a lipid family comprised of omega-3 (n-3) and n-6 fatty acids, are a critical component of cellular membranes, and recent in vitro studies have found that antipsychotic medications up-regulate genes responsible for PUFA biosynthesis. To evaluate this effect in vivo, rats were treated with risperidone (1.5, 3, 6mg/kg/day), paliperidone (1.5, 3, 6mg/kg/day), olanzapine (2.5, 5, 10mg/kg/day), quetiapine (5, 10, 20mg/kg/day), haloperidol (1, 3mg/kg/day) or vehicle through their drinking water for 40day. Effects on liver Fads1, Fads2, Elovl2, and Elovl5 mRNA expression, plasma indices of n-3 (plasma 22:6/18:3 and 20:5/18:3 ratios) and n-6 (plasma 20:4/18:2 and 20:3/18:2 ratios) biosynthesis, and peripheral (erythrocyte, heart) and central (frontal cortex) membrane PUFA composition were determined. Only risperidone and its metabolite paliperidone significantly and selectively up-regulated liver delta-6 desaturase (Fads2) mRNA expression, and robustly increased plasma indices of n-3 and n-6 fatty acid biosynthesis. In risperidone- and paliperidone-treated rats, plasma indices of n-3 and n-6 fatty acid biosynthesis were all positively correlated with liver Fads2 mRNA expression, but not Fads1, Elovl2, or Elovl5 mRNA expression. All antipsychotics at specific doses increased erythrocyte docosahexaenoic acid (DHA, 22:6n-3) composition, and all except quetiapine increased arachidonic acid (AA, 20:4n-6) composition. Risperidone, paliperidone, and olanzapine increased heart DHA and AA composition, and no antipsychotic altered frontal cortex DHA or AA composition. These in vivo data demonstrate that augmentation of PUFA biosynthesis is not common to all antipsychotic medications, and that risperidone and paliperidone uniquely increase delta-6 desaturase (Fads2) mRNA expression and most robustly increase PUFA biosynthesis and peripheral membrane composition.     

Effects of risperidone on glucose metabolism in Chinese patients with schizophrenia: a prospective study

Background

While most of the second generation antipsychotic agents are associated with abnormal glucose metabolism, previous studies have shown that risperidone has relatively little effect upon blood glucose levels. This study aimed to explore the effect of risperidone on the glucose-regulating mechanism of patients with schizophrenia by using the oral glucose tolerance test (OGTT), measuring insulin and C-peptide levels.

Methods

Thirty inpatients with schizophrenia taking risperidone were studied. All the patients were given a simplified OGTT at baseline and six weeks after treatment. Plasma glucose, insulin, and C-peptide concentrations were measured at fasting, then 1 and 2 h after OGTT respectively. Other data, including demographic characteristics and plasma drug concentrations, were also recorded.

Results

(1) There was no significant increase in the proportion of patients demonstrating abnormal plasma glucose levels compared with baseline (p = 1.000, McNemar test); (2) risperidone was associated with elevated insulin concentrations (p = 0.013), C-peptide levels (p = 0.020), insulin/glucose ratio (p = 0.020) and BMI (p < 0.01); (3) no sex differences in glucose-related measures were observed.

Conclusion

Risperidone treatment may be associated with alterations in glucose-regulating mechanisms in patients with schizophrenia.     

A porcine model of massive, totally occlusive, pulmonary embolism

Background

A reliable, animal model of massive, totally occlusive, pulmonary embolism (PE) is lacking.

Objectives

To design an animal model of totally occlusive PE and to challenge the model by a plasminogen activator.

Methods

In eight anaesthetized pigs (~ 90 kg) a massive preformed autologous thrombus was injected into the caval vein. One animal was autopsied to assess the extent of injected clot, whereas in the other animals extracorporeal life support (ECLS) was initiated and continued for three hours. These animals received 100 mg rt-PA. Blood gases, coagulation tests, creatine kinase (CK), lactate dehydrogenase (LDH), end-tidal CO2, systemic and pulmonary artery blood pressures and flow were registered.

Results

All animals went into circulatory arrest within 2 minutes after injection of the thrombus. In the animal where ECLS was not started, autopsy relieved a totally occlusive embolus of the pulmonary artery. The ECLS maintained a systemic blood flow of 6-8 L/min with adequate oxygenation and CO2-removal. However, lactate increased and base-excess became negative. Ddimer increased, fibrinogen decreased, and CK and LDH increased. All seven animals were weaned from ECLS. Despite the rt-PA treatment, the animals had at that time low end tidal CO2/PaCO2 ratio and increased mean pulmonary arterial pressure, suggesting a significant amount of embolic material remaining in the pulmonary artery.

Conclusion

This model of massive, totally occlusive, pulmonary embolism mimics well fatal PE seen in the clinic, and has the potential for use in testing of new therapeutic interventions.     

Open adjunctive ziprasidone associated with weight loss in obese and overweight bipolar disorder patients

Objective

To assess effectiveness and tolerability of open adjunctive ziprasidone for weight loss in obese/overweight patients with bipolar disorders (BD) in diverse mood states, taking weight gain-implicated psychotropic medications.

Method

22 obese and three overweight BD patients (20 female; 10 BD-I, 14 BD-II, 1 BD-NOS) with mean ± SD baseline body mass index (BMI) of 31.8 ± 2.5 kg/m² received ZIP (mean final dose 190 ± 92 mg/day) for mean of 79.2 ± 23.2 days. Weight was assessed at six weekly and three biweekly visits. Subjects entered the study in diverse mood states. At baseline, 21 were taking second-generation antipsychotics, 7 lithium, and 1 valproate, which could be reduced/discontinued at investigators’ discretion.

Results

Weight and BMI decreased from baseline to endpoint by 4.5 ± 3.4 kg and 1.6 ± 1.2 kg/m², respectively, at weekly rates of 0.37 kg and 0.13 kg/m², respectively (all p < 0.00001). 48% of patients had at least 5% weight loss. Obesity rate decreased from 88% to 35% (p < 0.0001). Waist circumference decreased 1.6 inches (p = 0.0001). Overall, mood did not change. Patients with at least moderate baseline mood symptoms experienced significant mood improvement, despite 72% patients decreasing/discontinuing weight gain-implicated psychotropic medications. Seven patients discontinued ZIP early: 3 for weight loss inefficacy, and 1 each for viral gastroenteritis, loss of consciousness, pneumonia with hypomania, and lost to follow up.

Conclusion

Open adjunctive ziprasidone may be effective for weight loss in obese/overweight BD patients taking weight gain-implicated psychotropic medications. These preliminary data should be considered with caution due to the open uncontrolled design, small sample size, and brief duration.     

Moderate exercise improves depression parameters in treatment-resistant patients with major depressive disorder

Background

Treatment-resistant major depressive disorder (MDD) is a complex condition, with very low remission rates. Physical exercise has been used, with some encouraging results, as an alternative therapy in other depressive disorders. This study assessed the impact on depression and functioning parameters of a moderate intensity exercise program, as an adjuvant to pharmacotherapy, in treatment-resistant MDD patients.

Methods

150 individuals with treatment-resistant MDD, defined as taking combined therapy in doses considered adequate for 9-15 months, without showing clinical remission, were initially screened. 33 were randomized to one of two groups: usual pharmacotherapy (N = 11) and usual pharmacotherapy plus aerobic exercise (N = 22). The exercise program consisted of home-based 30-45 min/day walks, 5 days/week, for 12 weeks, being 1 walk per week supervised.

Results

The exercise group showed improvement of all depression and functioning parameters, as indicated by lower HAMD17, BDI and CGI-S and higher GAF (p < 0.05) at last observation compared both to baseline values and to control group. At the end of the study none of the participants in the control group showed response or remission, whilst in the exercise group 21% of participants showed response and 26% remission, although these differences were not statistically significant.

Conclusion

A 12 week, home-based exercise program of 30-45 min/day walks, 5 days/week, improved depression and functioning parameters in treatment-resistant MDD patients, and contributed to remission of 26% of these patients. Moderate intensity exercise may be a helpful and effective adjuvant therapy for treatment-resistant MDD.     

Antidepressant-like effect of pioglitazone in the forced swimming test in mice: the role of PPAR-gamma receptor and nitric oxide pathway

In this study, the potential antidepressant-like effects of pioglitazone and the possible involvement of peroxisome proliferator-activated receptor gamma (PPARγ) and nitric oxide system in antidepressant effects of pioglitazone were determined using forced swimming test (FST) in mice.

Method

After assessment of locomotor activity in open-field test, mice were forced to swim individually and the immobility time of the last 4 min was evaluated. Pioglitazone was administered orally with doses (5, 10, 20 and 30 mg/kg) 2 and 4 h before FST. To assess the involvement of PPARγ in the possible antidepressant effect of pioglitazone, GW9662, a PPARγ antagonist (2 mg/kg) was administered before pioglitazone (20 mg/kg). For determination of possible role of nitric oxide pathway in this effect, a non-specific NOS inhibitor, Nω-nitro-l-arginine methyl ester (l-NAME, 10 mg/kg, i.p.), a specific iNOS inhibitor, aminoguanidine (50 mg/kg, i.p.), or a NO precursor, l-arginine (750 mg/kg, i.p.) was co-administered with pioglitazone, either 2 or 4 h before FST.

Results

The immobility time significantly decreased after pioglitazone administration (20 and 30 mg/kg). GW-9662 significantly reversed antidepressant effect of pioglitazone administered 2 and 4 h prior to FST. Co-administration of non-effective doses of pioglitazone and l-NAME revealed antidepressant-like effect in FST; while, co-administration of non-effective doses of aminoguanidine and pioglitazone did not affect the immobility time. l-Arginine also reversed the antidepressant-like effect of pioglitazone.

Conclusion

The antidepressant-like effect of pioglitazone on mice in the FST is mediated at least in part through PPARγ receptors and nitric oxide pathway.     

Risk of affective disorders following prenatal exposure to severe life events: a Danish population-based cohort study

Objective

To examine the effect of prenatal exposure to severe life events on risk of affective disorders in the offspring.

Methods

In a cohort of 1.1 million Danish births from May 1978 until December 1997, mothers were considered exposed if one (or more) of their close relatives died or was diagnosed with serious illness up to 6 months before conception or during pregnancy. Offspring were followed up from their 10th birthday until their death, migration, onset of affective disorder or 31 December 2007; hospital admissions were identified by linkage to the Central Psychiatric Register. Log-linear Poisson regression was used for data analysis.

Results

The risk of affective disorders was increased in male offspring whose mothers were exposed to severe life events during the second trimester (adjusted RR 1.55 [95% CI 1.05-2.28]). There was an increased risk of male offspring affective disorders in relation to maternal exposure to death of a relative in the second trimester (adjusted RR 1.74 [95% CI 1.06-2.84]) or serious illness in a relative before pregnancy (adjusted RR 1.44 [95% CI 1.02-2.05]). There was no evidence for an association between prenatal exposure to severe life events and risk of female offspring affective disorders.

Conclusions

Our population-based study suggests that prenatal maternal exposure to severe life events may increase the risk of affective disorders in male offspring. These findings are consistent with studies of populations exposed to famine and earthquake disasters which indicate that prenatal environment may influence the neurodevelopment of the unborn child.     

Effects of acute paliperidone palmitate treatment in subjects with schizophrenia recently treated with oral risperidone

Objective

To examine efficacy and safety of acute treatment with paliperidone palmitate in subjects with schizophrenia whose disease remained symptomatic despite recent treatment with oral risperidone.

Methods

Post hoc analysis of a 13-week, double-blind, placebo-controlled study of subjects with symptomatic schizophrenia randomized to paliperidone palmitate 39, 156, or 234 mg (25, 100, or 150 mg equivalents of paliperidone) or placebo. Paliperidone palmitate subjects received a 234-mg day 1 dose, followed by their assigned dose on day 8 and monthly thereafter. Subjects treated with oral risperidone within 2 weeks before randomization regardless of duration were included. Assessments: PANSS, CGI-S, PSP scores; AEs. ANCOVA models with LOCF methodology evaluated treatment group differences.

Results

216 subjects received prior oral risperidone (paliperidone palmitate 39 mg, n = 53; 156 mg, n = 58; 234 mg, n = 48; placebo, n = 57). Median prior risperidone use was 22 days. Significant improvement was observed with paliperidone palmitate 156-mg or 234-mg versus placebo in least-squares mean (SE) score change at end point in PANSS total (156 mg, −15.8 [3.0], p = 0.0001; 234 mg, −17.6 [3.2], p = 0.0001), CGI-S (156 mg, −0.9 [0.2], p = 0.0068; 234 mg, −1.1 [0.2], p = 0.0003), and PSP (156 mg, 10.7 [2.3], p = 0.0061; 234 mg, 12.9 [2.4], p = 0.0009). Most common AEs (≥ 10%) in any paliperidone palmitate group were insomnia, anxiety, and headache.

Conclusions

In subjects with schizophrenia who recently received oral risperidone but who remained symptomatic, acute treatment with monthly doses of 156-mg and 234-mg paliperidone palmitate significantly improved clinical symptoms, global illness ratings, and functioning compared with placebo, with no unexpected safety findings.     

Utilisation du lorazépam injectable dans le traitement de l’état de mal épileptique : étude comparative au sein d’hôpitaux pédiatriques francophones

Background

Injectable lorazepam (IL) is marketed in many countries but in France is only available within the framework of a compassionate use program for refractory status epilepticus. This study aims to evaluate the differences of pediatric use and status of IL in the hospitals of the Mother-Child French-speaking Network (Réseau mère-enfant de la francophonie, i.e., RMEF).

Methods

Inclusion criteria are: firstly, RMEF member; secondly, one site per town; thirdly, all the Assistance publique-Hôpitaux de Paris hospitals. After a phone-recruitment in each selected hospital, a survey was sent by e-mail. The data collected concerned the number of beds in the hospital, the official status of IL, its place in the therapeutic strategy, inhospital consumption in 2008 (in milligram) and the therapeutic alternatives.

Results

Among the 18 hospitals selected, 17 were contacted and 12 (70%) replied. IL is not marketed in Tunisia and Lebanon. In Switzerland, Canada and Belgium, IL is marketed and used in all the polled hospitals (6.2 to 48.0 mg per bed). In France, only the Robert Debré Hospital uses it (3.2 mg per bed). In the countries where it is marketed, IL was firstly prescribed for the studied indication. In the other countries, injectable diazepam was the first line treatment (six out of eight hospitals).

Discussion/conclusion

France is the only country where IL is available though not marketed. The pharmacokinetic data favor use of IL instead of its principal therapeutic alternative (injectable diazepam) but no currently available evidence concludes that IL is superior to diazepam in the management of pediatric status epilepticus. The official indication of IL in France (last intention) is in contradiction with its use in the countries where it is marketed and with the data of the literature in favor of the first intention. This works presents the first evaluation on the use of IL in pediatric status epilepticus in the RMEF hospitals. It highlights the discrepancies in the management of status epilepticus in comparable pediatric hospitals.     

Anopheline anti-platelet protein from a malaria vector mosquito has anti-thrombotic effects in vivo without compromising hemostasis

Introduction

The saliva of blood-feeding animals (e.g., mosquitoes, ticks, bats) has pharmacological activities that facilitate efficient blood-sucking. We previously identified a unique anti-platelet protein, anopheline anti-platelet protein (AAPP), from the salivary gland of female Anopheles stephensi (human malaria vector mosquito). AAPP specifically blocks platelet adhesion to collagen by binding directly to collagen and subsequently aggregating platelets. To examine the potential of AAPP as a therapeutic agent, we investigated the in vivo anti-thrombotic effects of AAPP.

Materials and Methods

Effects of AAPP on whole blood/platelet aggregation in mice were examined. AAPP was also challenged in an established model of pulmonary thromboembolism in mice. We simultaneously investigated the side-effects of the protein (prolongation of bleeding time and coagulation time). Aspirin was used as a positive control for comparison of anti-thrombotic effects.

Results and Conclusions

AAPP inhibited whole blood aggregation induced by collagen at 10 mg/kg body weight. AAPP prevented pulmonary death at a lower dose (3 mg/kg) without prolongation of bleeding time compared with aspirin (100 mg/kg) that compromised hemostasis. AAPP and aspirin did not affect coagulation time. These results indicate that AAPP has great potential as a new anti-platelet agent with a better risk/benefit ratio than that seen with aspirin (the most widely used anti-platelet agent).     

Le suicide dans la maladie de Huntington : état actuel des connaissances

Objectives

In 1872, George Huntington was the first to describe a genetic disease combining three types of disorder symptoms viz: motor, cognitive - evolving to cortical dementia and psychiatric. The purpose of this paper is to provide a selective review of the major issues and findings concerning suicide in Huntington's disease. The aim was to understand why patients with Huntington's disease have a higher suicide rate than those suffering from other neuro-developmental diseases.

Materials and methods

The present review is based on a MEDLINE survey of the relevant literature. The terms used in the search were: “Suicide”, “predictive genetic testing”, “suicidal risk factors” and “suicide attempt” all in combination with “Huntington's disease”. All abstracts were read and potentially relevant articles were examined in full. Various other important cross-references were included.

Results

Most of the authors found that suicidal occurrence in Huntington patients was four times higher than that in the general population. No specific individual risk factor was found except a lack of offspring and of psychological support. This review also considered the patient's attitude towards predictive genetic testing and its results. Reactions varied from psychological relief to paradoxical suicidal resurgence.

Conclusion

This paper emphasizes the need of appropriate psychiatric care for Huntington's patients in order to try to prevent suicidal behaviour.     

Myelin structure is unaltered in chemotherapy-induced peripheral neuropathy

Purpose

Alterations in mRNA for myelin proteins are reported in animal models of chemotherapy-induced peripheral neuropathies (CIPN); however, ultrastructural changes in aldehyde-fixed and plastic-embedded myelin are not evident by electron microscopy. Therefore, we used X-ray diffraction (XRD) to investigate more subtle changes in myelin sheath structure from unfixed nerves.

Experimental design

We used in vivo chronic animal models of CIPN in female Wistar rats, administering cisplatin (CDDP 2 mg/kg, i.p. twice/week), paclitaxel (PT 10 mg/kg, i.v. once/week) or bortezomib (0.20 mg/kg, i.v. three times/week) over a total period of 4 weeks. Animal weights were monitored, and tail nerve conduction velocity (NCV) was determined at the end of the treatments to assess the occurrence of peripheral neuropathy. Sciatic nerves were collected and the myelin structure was analyzed using electron microscopy (EM) and XRD.

Results

All the rats treated with the chemotherapy agents developed peripheral neuropathy, as indicated by a decrease in NCV values; however, light and electron microscopy indicated no severe pathological alterations of the myelin morphology. XRD also did not demonstrate significant differences between sciatic nerves in treated vs. control rats with respect to myelin period, relative amount of myelin, membrane structure, and regularity of membrane packing.

Conclusions

These results indicate that experimental peripheral neuropathy caused by CDDP, PT, and bortezomib—which are among the most widely used chemotherapy agents—does not significantly affect the structure of internodal myelin in peripheral nerve.