Indication for molecular testing by multiplex ligation-dependent probe amplification in parkinsonism.

BACKGROUND AND PURPOSE: The monogenic forms of Parkinson's disease represent <10% of familial cases and a still lower frequency of sporadic cases. However, guidelines to orient genetic testing are lacking. The aim was to establish the interest of multiplex ligation-dependent probe amplification (MLPA) as a primary screening test and to propose clinical criteria to guide genetic diagnostic tests for patients with suspected Mendelian Parkinson's disease. METHODS: In all, 567 patients with parkinsonism from 547 unrelated families were recruited and two MLPAs were performed for each. All pathogenic G2019S variants in the LRRK2 gene were confirmed by Sanger sequencing and the PRKN gene was screened for a second mutation in the cases of one heterozygous structural variant in the PRKN gene. RESULTS: The performance of MLPA was 51/567 (9%) for the entire cohort and included 27 (4.8%) LRRK2 G2019S mutations, 19 (3.4%) PRKN mutations and five (0.9%) SNCA locus duplications. The variables significantly associated with a positive test in the total cohort were North African ancestry (p < 0.0001), female sex (p = 0.004) and younger age at onset (p < 0.0008). CONCLUSIONS: Retrospective analysis allowed us to refine our indication criteria: (i) North African ancestry, (ii) an age at onset <40 years or (iii) a familial history of parkinsonism with at least one affected first-degree relative. Our study highlights the interest of MLPA testing for other parkinsonism cases with a family history, especially for patients with dementia with Lewy bodies or a multiple-system-atrophy-like phenotype.

Does ultrasound-guidance improve the outcome of botulinum toxin injections in cervical dystonia?

PURPOSE: Ultrasound-guided injections of botulinum neurotoxin in cervical dystonia have a number of theoretical advantages. However, their action has never been compared to that of non-guided injections. The objectives of the study were to compare the outcome of botulinum neurotoxin type A treatment in patients with idiopathic, focal cervical dystonia, according to two methods: inspection and palpation of anatomical landmarks (non-guided group) or ultrasound guidance (ultrasound-guided group). METHODS: We included consecutive patients in this single-center, prospective, real-life, non-randomized study. The outcomes were evaluated one month after the injections: Cervical Dystonia Impact Profile 58 (main outcome), Toronto Western Spasmodic Torticollis Rating Scale-2 (pain and disability subscores), Toronto Western Spasmodic Torticollis Rating Scale-PSYCH, patient-rated Clinical Global Impression - Improvement and adverse events. We used propensity score methods for statistical analysis; ten predefined confounding factors were used to build the propensity score. RESULTS: Sixty-three patients were included in the non-guided group, and 60 other patients in the ultrasound-guided group. We found no difference in main and secondary outcomes between the two study groups. CONCLUSION: This is the first direct comparison between ultrasound-guided and non-guided botulinum neurotoxin type A injections in patients with cervical dystonia. We hypothesize that ultrasound guidance made it possible to obtain the same results in the most severe (or the most demanding) patients as in the best responders. Further studies are still needed to assess the impact of botulinum neurotoxin injections into deep cervical muscles.

Anatomy-guided injections of botulinum neurotoxin in neck muscles: how accurate is needle placement?

BACKGROUND AND PURPOSE: In cervical dystonia, the accuracy of botulinum neurotoxin (BoNT) injections may influence the response to the treatment. METHODS: We used ultrasound to evaluate the accuracy of anatomy-guided injections of BoNT in the neck muscles. RESULTS: A total of 56 consecutive patients and 332 injections were evaluated. The overall accuracy was 76.6%. The lowest accuracy (67.9%) was observed for the splenius capitis muscle. CONCLUSIONS: Anatomic guidance of BoNT injections in the neck muscles is often inaccurate. Imaging guidance may improve the accuracy of BoNT injections in cervical dystonia.

[Continuous subcutaneous infusion of apomorphine in Parkinson's disease: retrospective analysis of a series of 81 patients]. / Le traitement par apomorphine en perfusion continue sous-cutanée dans la maladie de Parkinson : analyse rétrospective d'une série de 81 patients.

BACKGROUND: Continuous subcutaneous infusion of apomorphine (CAI) has shown efficacy in the treatment of motor fluctuations but its place in the therapeutic arsenal remains poorly defined in terms of indication, acceptability and long-term tolerance. Indeed, few studies have been carried out with a follow-up greater than 12 months. The main objective was to assess the quality of life of Parkinson's disease (PD) patients treated with CAI. We also evaluate the effectiveness on the motor fluctuations, the long-term tolerance of this treatment with its causes of discontinuation and the treatment regimens used. METHODS: We conducted a retrospective study of 81 PD patients treated with CAI between April 2003 and June 2012. Data were collected from medical records. A repeated measures analysis of variance by the linear mixed model was used (significance level: 5%). RESULTS: In August 2012, 27/81 patients were still treated with CAI with a mean duration of 28 months, 46/81 discontinued CAI (9 precociously), and 8 were lost to view. We didn't show improvement in the quality of life nor efficacy of CAI on the UPDRS IV score (P=0.54) and dyskinesia score (P=0.95). The CGI score patient also reflects this result with a majority response suggesting no significant change with CAI. We observed relative good cognitive and psychiatric tolerance. Adverse events were frequent but often benign. The average (±SD) rate of apomorphine was 3.15±1.71 mg/h and the oral dopaminergic treatment was decreased by 37.8%. DISCUSSION: The results are consistent with the literature except for the lack of efficiency on motor fluctuations which may be due to the use of too small doses of apomorphine. This seems to be a leading cause of discontinuation of CAI, especially when it is associated with side effects or important constraints. For better efficiency on motor fluctuations, we recommend the use of apomorphine at higher doses to obtain an optimal continuous dopaminergic stimulation.

[Primary prophylaxis of venous thromboembolism in ambulatory cancer patients treated with antineoplastic agents]. / Prophylaxie primaire de la maladie thromboembolique veineuse chez les patients cancéreux ambulatoires traités par les antinéoplasiques.

Apart from myeloma, primary prophylaxis of venous thromboembolism (VTE) in ambulatory cancer patients treated with chemotherapy is underused, despite its proven benefit for pancreatic cancer and to a lesser extent for lung cancer. This prophylaxis has been showed to be effective for myeloma, pancreas but in absolute numbers these cancers lead to a few venous thromboembolic events. Up to date, VTE risk scores cannot be used as a discriminatory criterion to select a high-risk population that could really benefit from this prevention. VTE depends in part on oncogenic mutations of tumor cells that result in an imbalance between activation and inhibition pathways that are involved in venous thrombus formation. So, stratification of risk of VTE in cancer patients could be considered from a clinical and molecular point of view and result in a tailored prophylaxis. This "personalized medicine" that is currently used for the anti-tumor treatment of many cancers and hematological malignancies, could lead to a more effective prophylaxis of VTE in cancer patients.

Engraftable human neural stem cells respond to developmental cues, replace neurons, and express foreign genes.

Stable clones of neural stem cells (NSCs) have been isolated from the human fetal telencephalon. These self-renewing clones give rise to all fundamental neural lineages in vitro. Following transplantation into germinal zones of the newborn mouse brain they participate in aspects of normal development, including migration along established migratory pathways to disseminated central nervous system regions, differentiation into multiple developmentally and regionally appropriate cell types, and nondisruptive interspersion with host progenitors and their progeny. These human NSCs can be genetically engineered and are capable of expressing foreign transgenes in vivo. Supporting their gene therapy potential, secretory products from NSCs can correct a prototypical genetic metabolic defect in neurons and glia in vitro. The human NSCs can also replace specific deficient neuronal populations. Cryopreservable human NSCs may be propagated by both epigenetic and genetic means that are comparably safe and effective. By analogy to rodent NSCs, these observations may allow the development of NSC transplantation for a range of disorders.

Comparison of the fat content and fat globule size distribution of breast milk from mothers delivering term and preterm.

The fat content and the fat globule size distribution of human preterm milk samples were analyzed and compared with data of previously analyzed samples of term milk. A negative correlation was found between the fat content and the gestational age. In both term and preterm milk three subpopulations of fat globules could be observed. The subpopulations of small (1 to 15 microns) and large globules (8 to 13 microns) were larger in preterm milk, but decreased slower throughout lactation. The average diameter was identical in both milks and increased with advancing lactation. The fat surface, which also depends on the fat content, increased with decreasing gestational age. However, no correlation between the specific fat surface area and the gestational age was found. Compared to human milk, commercial infant formulas have a smaller average fat globule diameter and a larger specific fat surface area.

[Primary treatment of Parkinson's disease: the application of the March 2000 consensus rules in the Nord Pas-de-Calais area]. / Traitement initial de la maladie de Parkinson: étude sur l'application des règles de consensus de mars 2000 dans la région Nord Pas-de-Calais.

INTRODUCTION: For Parkinson's disease, the choice of the initial treatment is essentially between L-Dopa and dopaminergic agonists. Selegilin, anticholinergic and amantadine can be used for subjects with moderate symptoms. The first French consensus conference, held in 2000, elaborated decision-making rules which take into account both the age and disease severity. The aim of our study was to evaluate the impact of these recommendations on treatments prescribed for de novo parkinsonian patients in the Nord-Pas de Calais area, comparing initial prescriptions before and after the conference. METHODS: Three groups of 50 patients whose diagnosis of Parkinson's disease had been establish in three periods (1985-1992, 1993-1999, and after July 2000, date of the national publication of the consensus) were constituted. RESULTS: For these 3 groups, the initial treatment complied with the 2000 recommendations for 58, 84 and 82 percent of the patients respectively. The prescriptions of agonists increased progressively while the prescriptions of L-Dopa decreased for younger patients, in concordance with the consensus, but also for older patients, in opposition with the recommendations, though without any increase in the incidence of side effects. The non dopaminergic treatments were almost discarded as initial treatment. CONCLUSION: Prescription habits have gradually changed over the past 10 years. Changes were linked to the elaboration of the national consensus conference guidelines and to the apparent desire to decrease L-Dopa prescriptions.

[Systemic lupus erythematosus presenting with recurrent psychiatric disturbances]. / Troubles psychiatriques itératifs révélateurs d'un lupus érythémateux disséminé.

INTRODUCTION: There is a wide range of non-specific symptoms that can reveal neurolupus, sometimes making diagnosis difficult. OBSERVATION: A 29-year-old man presented, from 1996 to 2002, three episodes of mood disorders with hetero-aggression, preceded by seizures, which resolved completely. Repeated investigations were negative except for lymphopenia, an inflammatory cerebrospinal fluid and some rare non-specific areas of high intensity signals in the white matter on the brain MRI. After a six-year course, the patient was considered to have a severe mood disorder related to a schizoid personality. A new dot-blot search for antinuclear antibodies detected anti-Sm antibodies was positive, leading to the diagnosis of neuropsychiatric lupus since the patient's symptoms fulfilling four of the American Rheumatism Association criteria (neuropsychiatric events, lymphopenia, antinuclear and anti-Sm antibodies). The patient was given monthly pulses of cyclophosphamide and remained symptom free one year after the last flare up. CONCLUSIONS: Lupus can rarely be revealed by long-standing isolated psychiatric disorders. Search for auto-antibodies, using highly specialized techniques (western blot, dot blot) should be a routine practice since antibody titres fluctuate during the course of the disease; elevated titres may correlate with exacerbations. Considering the prominence and severity of these behavior disorders, systemic diseases may often be misdiagnosed.

High insulinlike growth factor I is associated with cognitive decline in Huntington disease.

OBJECTIVE: The somatotropic axis (growth hormone [GH] and insulinlike growth factor I [IGFI]) play a role in the cognitive deficits seen with aging, GH deficiency, and neurodegenerative disorders such as Alzheimer disease. We recently reported elevations in basal plasma GH and IGFI levels in patients with Huntington disease (HD). Here, our objective was to determine whether somatotropic axis abnormalities predicted cognitive dysfunction in HD. METHODS: In this prospective cohort study of 109 patients with genetically documented HD, aged 21 to 85 years, we determined fasting blood levels of total IGFI, GH, and insulinlike factor binding protein 3 at baseline, and we used the cognitive Unified Huntington's Disease Rating Scale to assess cognitive impairment at baseline and for up to 5 years subsequently. Associations were evaluated using mixed linear model analysis. RESULTS: Higher plasma IGFI concentrations were associated with greater cognitive decline (beta Stroop Words, -6.01, p = 0.003; beta Stroop Color, -4.41, p = 0.01; beta Stroop Color/Words, -3.86, p = 0.02; beta Symbol Digit Modalities, -3.69, p = 0.03; and beta verbal fluency, -5.01, p = 0.03). Higher free IGFI concentrations and higher GH concentrations in men also predicted greater cognitive decline. CONCLUSIONS: Our findings in patients with HD suggest that a high IGFI level at baseline may be associated with greater subsequent declines in executive function and attention.

Idiopathic hypertrophic cranial pachymeningitis treated by oral methotrexate: a case report and review of literature.

Idiopathic hypertrophic cranial pachymeningitis (IHCP) is a rare clinical entity, characterized by a chronic inflammation causing thickening of the dura. Adequate therapeutic management is still a matter of debate. We present a patient with an IHCP, non-responsive to corticotherapy. Oral methotrexate was introduced (12.5 mg weekly) and total remission was observed after 6 weeks, both clinically and after neuro-imaging. We conclude that methotrexate can be effective and a therapeutical option in patients with IHCP who are resistant to corticotherapy or present major side-effects of chronic corticosteroids use.

[Therapy of acute myocardial infarct (1994-1996) at non-university hospitals in Switzerland (CHAMI Study)]. / Die Therapie des akuten Herzinfarkts (1994-1996) an nicht-universitären Spitälern in der Schweiz (CHAMI-Studie).

The CHAMI study (Confederatio Helvetica Acute Myocardial Infarction) recorded the therapies administered for acute myocardial infarction in 520 consecutive patients between October 1994 and February 1996 at 10 non-academic hospitals in Switzerland. The patients in this group consisted of 363 men and 157 women with an average age of 63.2 years. The prescribed medications administered from the day of hospital admission until the day of discharge were recorded. In the acute phase, the patients were given the following therapy: thrombolytic agents 40%, i.v. nitrates 65%, i.v. beta-blockers 22%, aspirin 95%, oral beta-blockers 36%, ACE inhibitors 14%. Impressive was the lower distribution of thrombolytic agents and beta-blockers among the older patients (age > 70) (thrombolytic agents 52.1% vs 28.4%; oral beta-blockers 44.0% vs 29.1%) and in particular among women (thrombolytic agents 26.8% vs 46%; oral beta-blockers 29.3% vs 39.7%) in men. Therapy at hospital discharge consisted, inter alia, of aspirin (73%), beta-blockers (54%), ACE inhibitors (3%), and lipid lowering agents (10%). The hospital mortality was 12.6%. The CHAMI study provided the participating hospitals with a quality control comparison with other participating centers and impressively demonstrated with the example of the lipid lowering agents, that the significance of secondary prophylaxis is assigned too little importance in contrast to acute therapy.

Low molecular weight heparin-loaded polymeric nanoparticles: formulation, characterization, and release characteristics.

The aim of the present work was to investigate the preparation of low molecular weight heparin (LMWH) nanoparticles (NP) as potential oral heparin carriers. The NP were formulated using an ultrasound probe by water-in-oil-in-water (w/o/w) emulsification and solvent evaporation with two biodegradable polymers [poly-epsilon-caprolactone, PCL and poly(D,L-lactic-co-glycolic acid) 50/50, PLGA] and two non-biodegradable positively charged polymers (Eudragit RS and RL) used alone or in combination. The mean diameter of LMWH-loaded NP ranged from 240 to 490 nm and was dependent on the reduced viscosity of the polymeric organic solution. The surface potential of LMWH NP prepared with Eudragit polymers used alone or blended with PCL and PLGA was changed dramatically from strong positive values obtained with unloaded NP to negative values. The highest encapsulation efficiencies were observed when Eudragit polymers took part in the composition of the polymeric matrix, compared with PCL and PLGA NP exhibiting low LMWH entrapment. The in vitro LMWH release in phosphate buffer from all formulations ranged from 10 to 25% and was more important (two- to threefold) when esterase was added into the dissolution medium. The in vitro biological activity of released LMWH, determined by the anti-factor Xa activity with a chromogenic substrate, was preserved after the encapsulation process, making these NP good candidates for oral administration.