A SCA7 premutation may be a novel Mendelian modifier of MS course: A case report.

A proportion of patients with the phenotype of complex genetic disorders carry dominantly inherited Mendelian traits, exemplified by hereditary spastic paraparesis influencing pyramidal symptoms in some MS cases. We here describe a mutable ATXN7 gene, a SCA7 premutation, in a patient fulfilling contemporary definitions of primary progressive MS. His onset age, and onset with a severely progressive cerebellar ataxia syndrome, was outside the reported range of symptoms in a representative MS material. We suggest that an ATXN7 premutation is a novel genetic modifier of the course of MS.

Efficacy and safety of the dopaminergic stabilizer Pridopidine (ACR16) in patients with Huntington's disease.

OBJECTIVES: To evaluate the efficacy and safety of the dopaminergic stabilizer pridopidine (ACR16) in patients with Huntington's disease (HD). METHODS: In a randomized, double-blind, placebo-controlled, 4-week trial, patients with HD received pridopidine (50 mg/d, n = 28) or placebo (n = 30). The primary outcome measure was the change from baseline in weighted cognitive score, assessed by cognitive tests (Symbol Digit Modalities, verbal fluency, and Stroop tests). Secondary outcome measures included changes in the Unified Huntington's Disease Rating Scale, Hospital Anxiety and Depression Scale, Leeds Sleep Evaluation Questionnaire, Reitan Trail-Making Test A, and Clinical Global Impression of Change. Safety assessments were also performed. RESULTS: There was no significant difference between pridopidine and placebo in the change from baseline of the weighted cognitive score. However, secondary measures such as affective symptoms showed trends toward improvement, and there was significant improvement in voluntary motor symptoms compared with placebo (P < 0.05). Pridopidine was well tolerated, with a safety profile similar to placebo. CONCLUSIONS: Pridopidine shows promise as a treatment for some of the symptoms of HD. In this small-scale study, the most notable effect was improvement in voluntary motor symptoms. Larger, longer-term trials are warranted.

Parallel sequencing used in detection of mosaic mutations: comparison with four diagnostic DNA screening techniques.

We have made an evaluation of mutation detection techniques for their abilities to detect mosaic mutations. In this study, Sanger sequencing, single-strand conformation polymorphism (SSCP)/heteroduplex analysis (HD), protein truncation test (PTT), and denaturating high-performance liquid chromatography (DHPLC) were compared with parallel sequencing. In total DNA samples from nine patients were included in this study. Mosaic mutations were artificially constructed from seven of these samples, which were from heterozygote mutation carriers with the mutant allele present at 50%. The mutations analyzed were as follows: c.646C>T, c.2626C>T, c.2828C>A, c.1817_1818insA, c.2788dupA, c.416_419delAAGA, and c.607delC in the APC gene. The lowest degree of mutant alleles detected with SSCP/HD and DHPLC varied between 5% and 25%, and between 15% and 50% for Sanger sequencing. Three of the mutations were analyzed with PTT with considerable variations in detection levels (from 10 to 100%). Using parallel sequencing a detection frequency down to 1% was reached, but to achieve this high sensitivity sufficient coverage was required. Two patients with natural mosaic mutations were also included in this study. These two mutations had previously been identified with Sanger sequencing (NF2 c.1026_1027delGA) and SSCP/HD (APC c.2700_2701delTC). In conclusion, all the evaluated methods are applicable for mosaic mutation screening even though combinations of the conventional methods should be used to reach an adequate sensitivity. Sanger sequencing alone is not sensitive enough to detect low mosaic levels. Parallel sequencing seems to be the ultimate choice but the possibilities to use this technique is today limited by its complexity, economics, and availability of instruments.

High-resolution array-CGH profiling of germline and tumor-specific copy number alterations on chromosome 22 in patients affected with schwannomas.

Schwannomas may develop sporadically or in association with NF2 and schwannomatosis. The fundamental aberration in schwannomas is the bi-allelic inactivation of the NF2 gene. However, clinical and molecular data suggest that these tumors share a common pathogenetic mechanism related to as yet undefined 22q-loci. Linkage studies in schwannomatosis, a condition related to NF2, have defined a candidate 22q-locus and excluded the NF2 gene as the causative germline mutation. Thus, analysis of aberrations in schwannomas may lead to the identification of putative gene(s) involved in the development of schwannoma/schwannomatosis. We profiled a series of 88 schwannomas and constitutional DNA using a tiling path chromosome 22 array. Array-CGH is a suitable method for high-resolution discrimination between germline and tumor-specific aberrations. Previously reported frequencies of 22q-associated deletions in schwannomas display large discrepancies, ranging from 30% to 80%. We detected heterozygous deletions in 53% of schwannomas and the predominant pattern was monosomy 22. In addition, three tumors displayed terminal deletions and four harbored overlapping interstitial deletions of various sizes encompassing the NF2 gene. When profiling constitutional DNA, we identified eight loci that were affected by copy number variation (CNV). Some of the identified CNVs may not be phenotypically neutral and the possible role of these CNVs in the pathogenesis of schwannomas should be studied further. We observed a correlation between the breakpoint position, present in tumor and/or constitutional DNA and the location of segmental duplications. This association implicates these unstable regions in rearrangements occurring both in meiosis and mitosis.

Dermal exposure to monoterpenes during wood work.

The dermal exposure to the suspected allergenic monoterpenes [small alpha]-pinene, [small beta]-pinene and [capital Delta](3)-carene was assessed with a patch sampling technique. The patch used was made of activated charcoal sandwiched between two layers of cotton cloth. Patches were fastened at 12 different spots on a sampling overall and at the front of a cap to estimate the potential exposure of the body. Fastening two patches on a cotton glove, one patch representing the dorsal side and one patch representing the palm of the hand respectively, assessed the exposure on the hands. Sampling was carried out during collecting of pine and spruce boards in sawmills and during sawing of pine wood pieces in joinery shops respectively. The potential dermal exposure of the total body was 29.0-1 890 mg h(-1) with a geometric mean (GM) of 238 mg h(-1) during sawing. During collecting the GM was estimated to 100 mg h(-1) with a range of 12.2-959 mg h(-1). The hands had a mean exposure of 9.24 mg h(-1) during sawing and 3.25 mg h(-1) during collecting respectively. The good correlation between the mass of contamination on the individual body parts and the potential body exposure indicates that sampling can be performed on one body part to give a good estimation of the potential body exposure. Monoterpenes were detected at patches fastened underneath the protective clothing indicating a contamination of the skin of the worker. The patch used may overestimate the dermal exposure.

Dermal exposure to styrene in the fibreglass reinforced plastics industry.

OBJECTIVES: The aim of this study was to assess the potential dermal exposure to styrene in the fibreglass reinforced plastics industry. METHODS: Assessment was performed during spraying and rolling using a patch sampling technique. The patch was made of charcoal sandwiched between two layers of cotton fabric. Samplers were fastened at 12 different spots on a sampling overall, each spot representing a body area. One patch was fastened at the front of a cap. A patch fastened to a string worn around the neck assessed the exposure at chest level inside the clothing. Patches were fastened to cotton gloves at sites representing the dorsal side and the palm of the hand to evaluate exposure on these areas. Following sampling the patches were solvent desorbed and styrene was analysed by gas chromatography flame ionization detection. RESULTS: The potential body exposure for the participating individuals was between 544 and 17 100 mg/h with a geometric mean (GM) of 3780 mg/h. The legs, arms and outer chest in general had the highest exposures. The left and right hands had mean (GM) exposures of 344 and 433 mg/h, respectively. Styrene was determined for the patch at the inside of the clothing, indicating contamination of the dermal layer. CONCLUSIONS: The charcoal patch can be used to evaluate potential exposure to styrene. The results indicate that the dermal layer of the worker is exposed to styrene. Precautions should be performed to reduce dermal exposure.

Dermal exposure to terpenic resin acids in Swedish carpentry workshops and sawmills.

OBJECTIVES: The aim of this study was to evaluate dermal exposure to the resin acids abietic acid, dehydroabietic acid and 7-oxodehydroabietic acid during collecting in sawmills and during sawing in carpentry workshops, respectively. METHODS: Sampling was performed by fastening patches at 12 different areas on a sampling overall, one patch on the front of a cap, one patch on the chest inside the clothing and one patch on the inner lower right leg. Exposure of the hands was assessed by fastening patches on cotton gloves representing the dorsal sides and the palms of the left and right hands. Sampling was performed on 30 different occasions in the sawmills and in the carpentry workshops with mean sampling times of 120 and 59 min, respectively. The acids were solvent desorbed from the patches. Identification and quantification of the resin acids was performed by gas chromatography-mass spectrometry. RESULTS: The geometric means (GMs) of the potential body exposures to abietic acid, dehydroabietic acid and 7-oxodehydroabietic acid during sawing and collecting of wood from pine and spruce were 3346 and 17 247 micro g/h, respectively. The GM of the potential exposure on the hands was 3020 micro g/h in the carpentry workshops and 4365 micro g/h in the sawmills. Resin acids were detected on the inner chest and inner lower front right leg, respectively. CONCLUSIONS: There is a potential dermal exposure to terpenic resin acids in carpentry workshops as well as in sawmills. The hands have the highest exposure during sawing as well as during collecting. There is a spatial distribution of contaminants, with the outer chest, arms and legs showing the highest exposures. Resin acids also contaminated the inner chest and inner lower leg. It is necessary to take action to reduce dermal exposure to these allergenic substances.

Excitatory Amino Acid Pathway from the Hippocampus to the Prefrontal Cortex. Contribution of AMPA Receptors in Hippocampo-prefrontal Cortex Transmission.

Previous experiments in the rat have demonstrated that field CA1 and the subiculum project to the prefrontal cortex and that this direct unilateral pathway is excitatory. In the present study, anatomical and electrophysiological approaches were used to determine the transmitter mediating the excitatory responses in prefrontal cortex neurons to low-frequency stimulation of the hippocampus. The method of selective retrograde d-[3H]aspartate labelling was used to identify putative glutamatergic and/or aspartatergic hippocampal afferent fibres to the prefrontal cortex. Unilateral microinjection of d-[3H]aspartate into the prelimbic area of the prefrontal cortex resulted in the retrograde labelling of a fraction of hippocampal neurons. Some labelled cell bodies were distributed in field CA1 and the subiculum but larger numbers of neurons were detected in the ventral and intermediary subiculum. In a second series of experiments, the excitatory transmission from the hippocampus to the prefrontal cortex was pharmacologically analysed to provide further evidence for the involvement of glutamate and/or aspartate in the pathway. All prefrontal cortex neurons responding to the stimulation of the hippocampus were activated by selective agonists of the glutamate receptor subtypes alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) and N-methyl-d-aspartate (NMDA), and these effects were selectively antagonized by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and 2-amino-5-phosphonopentanoic acid (APV) respectively. Most of the excitatory responses of prefrontal cortex neurons to single and paired-pulse stimulation of the hippocampus were antagonized by CNQX. APV only affected the excitatory response in a few cells. These results suggest that the hippocampal input to the prefrontal cortex utilizes glutamate and/or aspartate as a transmitter. Even though prefrontal cortex neurons responding to the stimulation of the hippocampus appear to have both AMPA and NMDA receptors, low-frequency stimulation of the hippocampo-prefrontal cortex pathway activates cortical neurons mostly through AMPA receptors.