Stress in Parents of Children With Genetically Determined Leukoencephalopathies: A Pilot Study.

Genetically determined leukoencephalopathies comprise a group of rare inherited white matter disorders. The majority are progressive diseases resulting in early death. We performed a cross-sectional pilot study including 55 parents from 36 families to assess the level of stress experienced by parents of patients with genetically determined leukoencephalopathies, aged 1 month to 12 years. Thirty-four mothers and 21 fathers completed the Parenting Stress Index-4th Edition. One demographic questionnaire was completed per family. Detailed clinical data was gathered on all patients. Statistical analysis was performed with total stress percentile score as the primary outcome. Mothers and fathers had significantly higher stress levels compared with the normative sample; 20% of parents had high levels of stress whereas 11% had clinically significant levels of stress. Mothers and fathers had comparable total stress percentile scores. We identified pediatric behavioral difficulties and gross motor function to be factors influencing stress in mothers. Our study is the first to examine parental stress in this population and highlights the need for parental support early in the disease course. In this pilot study, we demonstrated that using the Parenting Stress Index-4th Edition to assess stress levels in parents of patients with genetically determined leukoencephalopathies is feasible, leads to valuable and actionable results, and should be used in larger, prospective studies.

A fully validated simple new method for environmental monitoring by surface sampling for cytotoxics.

A wipe sampling procedure followed by a simple ultra-performance liquid chromatography - tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for simultaneous quantification of six cytotoxic drugs: 5-fluorouracil (5FU), doxorubicin (DOXO), epirubicin (EPI), ifosfamide (IF), cyclophosphamide (CP) and gemcitabine (GEM), as surrogate markers for occupational exposure. After a solid-phase extraction of wiping filter on 10 × 10 cm surface, the separation was performed within 6.5 min, using a gradient mobile phase and the analytes were detected by mass spectrometry in the multiple reaction ion monitoring mode. The method was validated according to the recommendations of the US Food and Drug Administration. The method was linear (r2 > 0.9912) between 2.5 and 200 ng per wiping sample (25 to 2000 pg/cm2) for 5FU, doxorubicin and epirubicin and between 0.2 and 40 ng per wiping sample (2 to 400 pg/cm2) for cyclophosphamide, ifosfamide and gemcitabine. The lower limits of quantification were 2.5 ng (25 pg/ cm2) for 5FU, doxorubicin and epirubicin, and 0.2 ng (2 pg/cm2) for CP, IF and GEM. Within-day and between-day imprecisions were <14.0, 10.6, 11.1, 8.7, 11.2 and 10.9% for 5-fluorouracil, doxorubicin, epirubicin, ifosfamide cyclophosphamide and gemcitabine, respectively. The inaccuracies did not exceed 2.7, 10.9, 1.1, 4.5, 1.6 and 2.9% for the studied molecules, respectively. This new sensitive validated method for surface contamination studies of cytotoxics was successfully applied on different localizations in hospital. This approach is particularly suitable to assess occupational exposure risk to cytotoxic drugs.

Atherosclerosis knowledge of general practice residents: Diagnosis and management in primary care.

OBJECTIVES: Cardiovascular diseases represent the leading cause of death worldwide. In a previous survey, we have shown that the management of patients with atherosclerosis by general practitioners depends on the locations of the disease. The aim of this survey was to assess general practice residents' (GPR) knowledge on three clinical presentations which are ischemic stroke, coronary artery disease (CAD), and peripheral artery disease (PAD). MATERIALS AND METHODS: Between May 2017 and September 2017, a national self-administered survey that we previously used to assess the GPs' knowledge was emailed to GPRs from French medicine faculties. The questionnaire was composed of three clinical cases dealing with transient ischemic attack (TIA), stable angina (SA) and intermittent claudication (IC). Each clinical case was explored by seven similar questions. The primary endpoint was the number of GPRs who correctly answered 5 of the 7 questions for each clinical case. RESULTS: Five hundred and fifty-three GPRs (10%) answered the questionnaire entirely. There is a significant difference between TIA knowledge (19.9% of correct answers) which is greater than SA knowledge (0.9%) and IC knowledge (0.4%). The diagnosis was correctly done by 525 (94.9%) GPRs for TIA, 513 (92.8%) for SA, and 532 (96.2%) for IC. The main difficulties encountered by the GPRs concerned complementary investigations and treatment. CONCLUSION: As for general practitioners, this study reveals a difference in GPRs' knowledge depending on the location of the atherosclerosis. Considering the results, the improvement of initial training and continuing medical education (CME) in general medicine would be desirable.

Safety of sofosbuvir-based regimens after liver transplantation: longitudinal assessment of renal function in the prospective ANRS CO23 CUPILT study.

BACKGROUND: In liver transplant recipients with hepatitis C virus recurrence, there is concern about renal safety of sofosbuvir-based regimens. Changes in serum creatinine or in the estimated glomerular filtration rate (eGFR) under treatment are used to look for possible renal toxicity. However, serum creatinine and eGFR are highly variable. AIM: To analyse renal function trajectory with numerous assays of serum creatinine over a long period of time. METHODS: In a multicentre cohort of 139 patients, the eGFR was obtained from serum creatinine using the Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) equation. Slopes of eGFR were defined as a change in eGFR during a period divided by time. Pre-treatment, on-treatment and post-treatment periods were 9 months, 3-9 months and 4.5 months. Interactions between eGFR slopes and the pre-treatment eGFR, use of ribavirin or mycophenolate mofetil, and stage of fibrosis were addressed. On-treatment eGFR slopes were separated in tertiles. Pre- and post-treatment eGFR slopes were compared globally and according to tertiles. RESULTS: The post-treatment eGFR slope was significantly better than pre-treatment eGFR slope (+0.18 (IQR -0.76 to +1.32) vs -0.11 (IQR -1.01 to +0.73) mL/min/1.73 m2 /month, P = 0.03) independently of the pre-treatment eGFR (P = 0.99), ribavirin administration (P = 0.26), mycophenolate mofetil administration (P = 0.51) and stage of fibrosis (F3 and F4 vs lower stages, P = 0.18; F4 vs lower stages, P = 0.08; F4 Child-Pugh B and C vs lower stages, P = 0.38). Tertiles of on-treatment eGFR slopes were -1.71 (IQR -2.54 to -1.48), -0.78 (IQR -1.03 to -0.36) and +0.75 (IQR +0.28 to +1.47) mL/min/1.73 m2 /month. Pre- and post-treatment eGFR slopes were not significantly different according to tertiles (respectively, P = 0.34, 0.08, 0.73). CONCLUSION: The eGFR varies during treatment and gives a confusing picture of the renal safety of sofosbuvir-based regimens. In contrast, longitudinal assessment of the eGFR shows a rising trajectory over longer time, meaning that these therapies are safe for the kidneys in our cohort of liver transplant recipients.

[Simplified Protocols for Cholera Diagnosis in the National Public Health Laboratory, Port-au-Prince, Haiti]. / Protocoles simplifiés de diagnostic du choléra au Laboratoire national de santé publique, Port-au-Prince, Haïti.

While the incidence of cholera is decreasing in Haiti, the time required to render stool culture results with antibiogram using the standard method practiced at the National Public Health Laboratory (LNSP) remains at an average of 80 hours. This delay can be further lengthened by the process of rendering the analysis reports to the sites of care which significantly delays the community responses to cholera. Through this study, we have aimed to assess the reliability of partial results. We have studied 250 stool samples that were analyzed between January and September 2017 at the LNSP by determining the specificity, positive predictive value and positive likelihood ratio of i) the identification of yellowish colonies and ii) the identification of yellowish colonies with a positive oxidase assay in comparison to the stool culture. Compared to the entire process, the identification of yellowish colonies showed a specificity of 56%, a positive predictive value of 69% and a positive likelihood ratio of 2.27. The identification of yellowish colonies with a positive oxidase assay showed a specificity of 77%, a positive predictive value of 81% and a positive likelihood ratio of 4.31. The communication of partial results at these steps would likely guide community interventions despite a relative decrease in reliability of the results.

Le temps nécessaire au rendu des résultats de culture des selles avec antibiogramme par la méthode classique pratiquée au Laboratoire national de santé publique (LNSP) d'Haïti s'étale sur une durée de 80 heures en moyenne. Ce délai peut être encore allongé par le processus de rendu des rapports d'analyse aux sites de prise en charge, ce qui retarde de manière significative les réponses communautaires face au choléra. Cette étude vise à évaluer la fiabilité de résultats partiels par rapport au processus complet. Nous avons inclus 250 échantillons de selles analysés au LNSP de janvier à septembre 2017 en déterminant la spécificité, la valeur prédictive positive et le rapport de vraisemblance positif de l'identification des colonies jaunâtres et de l'identification des colonies jaunâtres oxydase positive. Par rapport au processus complet de culture des selles, l'identification des colonies jaunâtres a montré une spécificité de 56 %, une valeur prédictive positive de 69 % et un rapport de vraisemblance positif de 2,27. Quant à l'identification des colonies jaunâtres oxydase positive, la spécificité est de 77 %, la valeur prédictive positive de 81 % et le rapport de vraisemblance positif de 4,31. La communication de résultats partiels aux équipes de terrain à ces étapes serait utile pour guider les interventions en dépit d'une relative diminution de leur fiabilité par rapport au gold standard.

Involvement of cortical fast-spiking parvalbumin-positive basket cells in epilepsy.

GABAergic interneurons of the parvalbumin-positive fast-spiking basket cells subtype (PV INs) are important regulators of cortical network excitability and of gamma oscillations, involved in signal processing and cognition. Impaired development or function of PV INs has been associated with epilepsy in various animal models of epilepsy, as well as in some genetic forms of epilepsy in humans. In this review, we provide an overview of some of the experimental data linking PV INs dysfunction with epilepsy, focusing on disorders of the specification, migration, maturation, synaptic function, or connectivity of PV INs. Furthermore, we reflect on the potential therapeutic use of cell-type specific stimulation of PV INs within active networks and on the transplantation of PV INs precursors in the treatment of epilepsy and its comorbidities.

LPIN1 deficiency with severe recurrent rhabdomyolysis and persistent elevation of creatine kinase levels due to chromosome 2 maternal isodisomy.

Fatty acid oxidation disorders and lipin-1 deficiency are the commonest genetic causes of rhabdomyolysis in children. We describe a lipin-1-deficient boy with recurrent, severe rhabdomyolytic episodes from the age of 4 years. Analysis of the LPIN1 gene that encodes lipin-1 revealed a novel homozygous frameshift mutation in exon 9, c.1381delC (p.Leu461SerfsX47), and complete uniparental isodisomy of maternal chromosome 2. This mutation is predicted to cause complete lipin-1 deficiency. The patient had six rhabdomyolytic crises, with creatine kinase (CK) levels up to 300,000 U/L (normal, 30 to 200). Plasma CK remained elevated between crises. A treatment protocol was instituted, with early aggressive monitoring, hydration, electrolyte replacement and high caloric, high carbohydrate intake. The patient received dexamethasone during two crises, which was well-tolerated and in these episodes, peak CK values were lower than in preceding episodes. Studies of anti-inflammatory therapy may be indicated in lipin-1 deficiency.

Genetics and function of neocortical GABAergic interneurons in neurodevelopmental disorders.

A dysfunction of cortical and limbic GABAergic circuits has been postulated to contribute to multiple neurodevelopmental disorders in humans, including schizophrenia, autism, and epilepsy. In the current paper, I summarize the characteristics that underlie the great diversity of cortical GABAergic interneurons and explore how the multiple roles of these cells in developing and mature circuits might contribute to the aforementioned disorders. Furthermore, I review the tightly controlled genetic cascades that determine the fate of cortical interneurons and summarize how the dysfunction of genes important for the generation, specification, maturation, and function of cortical interneurons might contribute to these disorders.

Vagus nerve stimulation in pediatric epileptic syndromes.

Vagal nerve stimulation (VNS) has shown promising results in various cohorts of non-surgical refractory epilepsy in adults and children. However studies report a significant delay between implantation and clinical response. We describe a cohort of 28 children and adolescents prospectively followed, classified by epileptic syndromes and treated with VNS using a 6-week rapid ramping protocol between January 2000 and March 2005. Our cohort showed favorable outcome within 6 months which was sustained at 24 months: 68% (19/28) showing >or=50% reduction in seizure frequency, including 14% (4/28) who became seizure-free. VNS was particularly efficacious in children with cryptogenic generalized and partial epilepsies. Although adverse events occurred in 68% (19/28) of patients, most were transient. In conclusion, rapid ramping is associated with an early and lasting response in most children but with a slightly higher side-effect rate.

A novel founder SCN4A mutation causes painful cold-induced myotonia in French-Canadians.

BACKGROUND: Myotonia is observed in classic congenital myotonia caused by CLCN1 mutations and in sodium-channel myotonia (SCM) due to SCN4A mutations. METHODS: We assessed 66 electrically proven cases of myotonia belonging to 17 French-Canadian families living in the Saguenay Lac St-Jean area of Quebec, a region well known for its genetic founder effects. The CLCN1 gene was sequenced in one affected member of each family. SCN4A exons with known SCM mutations were subsequently sequenced in families where no CLCN1 mutations were found. RESULTS: Six families, 33% of cases (22/66), presenting classic congenital myotonia phenotypes were found to carry two previously identified CLCN1 mutations. In the other 11 families comprising 66% of cases (44/66), a new dominant SCN4A mutation in exon 24 (M1476I) was uncovered and segregated with a variable SCM phenotype. Although all carriers of this novel mutation had electrical myotonia, some were asymptomatic (25%) and age at onset was variable in the others (5 to 67, mean 21). Cold aggravated myotonia was observed in 41% of cases and painful myotonia in 18%. Additional features observed include aggravation of symptoms with pregnancies (7%), localized muscle swelling (2%), myotonic reactions to anesthesia (2%), and food-induced paralysis (2%). CONCLUSIONS: This cohort is the largest described with a variable sodium-channel myotonia phenotype caused by a single SCN4A mutation. The clinical variability observed in this cohort underlines the phenotypic heterogeneity of SCN4A mutations and suggests that variants in other genes likely modulate clinical expression.

Progress in understanding processes underlying occupational accidents on the level based on case studies.

The purpose of this work was to further the knowledge of contexts surrounding accidents on the level in occupational situations with a view to proposing suitable actions for the prevention of these accidents. The study, undertaken at three establishments belonging to a national rail transport company, was based on quantitative and qualitative analysis of accident-on-the-level data available at the establishments concerned, typology of these accidents, interviews with victims and activity analysis. Understanding accidents on the level through building scenarios makes it possible to consider the relevance of prevention actions, such as workplace or environmental design/remediation and machine access system design. Moreover, it also makes it possible to consider curtailing the injury-causing aspect of the physical environment by reducing its 'aggressiveness'. Finally, the prospects emerging from this work in the research field are discussed.

[Long-term development of blood pressure profile in hypertensive hemodialysis patients]. / Devenir à long terme du profil tensionnel des patients hémodialysés hypertendus.

OBJECTIVE: The prognostic value of nocturnal blood pressure (BP) in hemodialysis patients has been well established. The aim of this study was to evaluate the long-term outcome of ambulatory BP in hypertensive hemodialysis patients. DESIGN AND METHODS: Medical records of all hemodialysis patients seen for uncontrolled hypertension between 1993 and 1999 and who underwent an ambulatory blood pressure measurements (ABPM) were retrospectively studied. Uncontrolled hypertension was defined as office BP = 140/90 mmHg and 24 h ABP = 125/80 mmHg. Patients who underwent a second ABPM after an interval of at least 1 year were included in the study. Demographic characteristics, medical history, cardiovascular risk factors and treatments were recorded for each patient. A t-test (bilateral) was used to compare BP. RESULTS: 26 patients were included (545 +/- 18.9 years; 14 men). 7 had previous history of cardiovascular disease and 2 were diabetic. At the end of the follow-up (29 +/- 12.8 months), 9 patients (36%) had 24 h BP < 125/80 mmHg. A significant decrease in diurnal and nocturnal BP was observed (p < 0.05). No significant change was observed for office systolic BP and predialytic BP. CONCLUSION: Our data show that a long-term decrease in nocturnal BP can be obtained in hypertensive patients on hemodialysis. With respect to the prognostic value of this criteria, randomised trials could be carried out to determine whether nocturnal BP is superior to office BP as a target for antihypertensive therapy in this population.

Nocturnal blood pressure and 24-hour pulse pressure are potent indicators of mortality in hemodialysis patients.

BACKGROUND: Cardiovascular (CV) complications are the leading cause of mortality in hemodialysis patients. The role of arterial hypertension on the prognosis of CV in hemodialysis patients is not as clear as in the general population. The purpose of this study was to investigate the prognostic role of ambulatory blood pressure (BP) on CV mortality in treated hypertensive hemodialysis patients. METHODS: Fifty-seven treated hypertensive hemodialysis patients (56.87 +/- 16.22 years, 30 men) were prospectively studied. All patients initially underwent an ambulatory BP monitoring between two dialysis sessions. The outcome event studied was CV death; kidney transplantation and deaths not related to CV disease were censored. RESULTS: The duration of follow-up was 34.4 +/- 20.39 months, during which 10 CV and 8 non-CV fatal events occurred. In the 10 patients who died from CV complications, age, previous CV events, ambulatory systolic BP, ambulatory pulse pressure (PP), and life-long smoking level were significantly higher, and the office diastolic BP was lower at the time of inclusion than in those who did not die from CV complications (N = 47). Based on Cox analysis and after adjustment for age, sex, and previous CV events, a low office diastolic BP [relative risk (RR) 0.49, 95% CI, 0.25 to 0.93, P = 0.03], an elevated 24-hour PP (RR 1.85, 95% CI, 1.28 to 2.65, P = 0.009), and an elevated nocturnal systolic BP (RR 1.41, 95% CI, 1.08 to 1.84, P = 0.01) were predictors of CV mortality (RR associated with a 10 mm Hg increase in BP and in PP). CONCLUSION: This study demonstrates that nocturnal BP and 24-hour PP are independent predictors of CV mortality in treated hypertensive hemodialysis patients. Randomized trials are needed to investigate whether nocturnal BP and 24-hour PP are superior to office BP as targets for antihypertensive therapy in this high-risk group.

Influence of nycthemeral blood pressure pattern in treated hypertensive patients on hemodialysis.

Arterial hypertension in end-stage renal disease (ESRD) patients is characterized by an altered nycthemeral blood pressure (BP) rhythm and an increased pulse pressure, and it could be suggested that this association of risk factors plays a major role in the cardiovascular prognosis of this population. The aim of this study was to determine the influence of nycthemeral BP pattern on arterial distensibility and pulsatile components of BP in treated hypertensive patients on regular hemodialysis. Forty-two hypertensive patients were included, and all underwent ambulatory BP and pulse wave velocity (PWV) measurements between the femoral and carotid arteries. The patients were divided into two groups according to the magnitude of the nocturnal fall in BP: dippers and non-dippers. The groups were similar in gender, age, duration of hemodialysis, body mass index, body size, history of cardiovascular complications, class and number of antihypertensive drugs used per patient. PWV was significantly higher in non-dippers. For the whole population, a stepwise regression analysis showed that PWV and erythropoietin therapy were independently related to the impaired nycthemeral BP pattern. In addition to its pressor effect, erythropoietin could have a deleterious influence on the ambulatory BP profile of treated hypertensive patients in ESRD. Arterial distensibility and nycthemeral BP impairment are linked, and these cardiovascular risk factors should be taken into account together for the management of hypertensive hemodialysis patients.

Evaluation of a mini-cascade impactor for sampling exposure chamber atmospheres.

Andersen 4-stage mini-cascade impactors, designed primarily for personnel dosimetry, were tested for suitability of characterizing solid-particle aerosols within inhalation exposure chambers. Performances were assessed by comparing their particle-size separating capabilities against cyclone separators and Andersen 8-stage ambient cascade impactors. Data reveal excellent agreement between respirable (ACGIH) mass fractions, and mass median aerodynamic diameters, measured with the mini-samplers and the larger laboratory cascade impactors. Cyclone data did not correlate as well. Findings indicate that where accurate particle characterization at low sampling flow rates is desired, compact mini-cascade impactors are appropriate instruments.