Multiple analysis of three common genetic alterations associated with thrombophilia.

We have previously reported the use of a novel mini-sequencing protocol for detection of the factor V Leiden variant, the first nucleotide change (FNC) technology. This technology is based on a single nucleotide extension of a primer, which is hybridized immediately adjacent to the site of mutation. The extended nucleotide that carries a reporter molecule (fluorescein) has the power to discriminate the genotype at the site of mutation. More recently, the prothrombin 20210 and thermolabile methylene tetrahydrofolate reductase (MTHFR) 677 variants have been identified as possible risk factors associated with thrombophilia. This study describes the use of the FNC technology in a combined assay to detect factor V, prothrombin and MTHFR variants in a population of Australian blood donors, and describes the objective numerical methodology used to determine genotype cut-off values for each genetic variation. Using FNC to test 500 normal blood donors, the incidence of Factor V Leiden was 3.6% (all heterozygous), that of prothrombin 20210 was 2.8% (all heterozygous) and that of MTHFR was 10% (homozygous). The combined FNC technology offers a simple, rapid, automatable DNA-based test for the detection of these three important mutations that are associated with familial thrombophilia.     

Calcitonin gene-related peptide in the joint: contributions to pain and inflammation

Arthritis is the commonest cause of disabling chronic pain, and both osteoarthritis (OA) and rheumatoid arthritis (RA) remain major burdens on both individuals and society. Peripheral release of calcitonin gene-related peptide (CGRP) contributes to the vasodilation of acute neurogenic inflammation. Contributions of CGRP to the pain and inflammation of chronic arthritis, however, are only recently being elucidated. Animal models of arthritis are revealing the molecular and pathophysiological events that accompany and lead to progression of both arthritis and pain. Peripheral actions of CGRP in the joint might contribute to both inflammation and joint afferent sensitization. CGRP and its specific receptors are expressed in joint afferents and up-regulated following arthritis induction. Peripheral CGRP release results in activation of synovial vascular cells, through which acute vasodilatation is followed by endothelial cell proliferation and angiogenesis, key features of chronic inflammation. Local administration of CGRP to the knee also increases mechanosensitivity of joint afferents, mimicking peripheral sensitization seen in arthritic joints. Increased mechanosensitivity in OA knees and pain behaviour can be reduced by peripherally acting CGRP receptor antagonists. Effects of CGRP pathway blockade on arthritic joint afferents, but not in normal joints, suggest contributions to sensitization rather than normal joint nociception. CGRP therefore might make key contributions to the transition from normal to persistent synovitis, and the progression from nociception to sensitization. Targeting CGRP or its receptors within joint tissues to prevent these undesirable transitions during early arthritis, or suppress them in established disease, might prevent persistent inflammation and relieve arthritis pain.     

Hemicholinium-3 prevents the working memory impairments and the cholinergic hypofunction induced by ethylcholine aziridinium ion (AF64A)

The present study examined whether intraventricular administration of the potent high affinity choline transport (HAChT) inhibitor hemicholinium-3 (HC-3) would attenuate the memory impairments and the neurochemical deficits induced by i.c.v. ethylcholine aziridinium ion (AF64A). Male Sprague-Dawley rats were trained to perform a delayed-non-match to sample radial arm maze (RAM) task in which a 1-h delay was imposed between the fourth and fifth arm selections. Following 30 acquisition trials, animals were bilaterally injected with AF64A (3 nmol/side) or AF64A preceded by HC-3 (20 micrograms/side) into the lateral ventricles and allowed 7 days to recover before behavioral testing resumed. Control animals received either artificial cerebrospinal fluid or HC-3. AF64A-treated rats were significantly impaired in their performance of the RAM task as evidenced by fewer correct choices following the delay and more total errors to complete the task. This behavioral deficit was associated with a significant (32%) decrease in HAChT in the hippocampus. In contrast, animals pretreated with HC-3 exhibited no significant decreases in HAChT or decrements in RAM performance. These findings indicate that the memory deficits resulting from intraventricular administration of AF64A are a consequence of the compound's cholinotoxic properties and in particular its interaction with the HAChT carrier. Furthermore they demonstrate that a select alteration of septohippocampal cholinergic activity is sufficient to disrupt working memory processes.     

Chronic insomnia, quality-of-life, and utility scores: comparison with good sleepers in a cross-sectional international survey

Background

Chronic insomnia has a recognized impact on health-related quality-of-life (HRQoL) but data on utility scores across countries are lacking. The objective of the present study was to assess health related quality of life (HRQoL) and utility scores in individuals from three different countries (USA, France, and Japan), comparing sufferers of chronic insomnia to good sleepers.

Methods

A cross-sectional survey (SLEEPI-i) of 4067 persons in the US (n = 1298; 478 good sleepers and 820 patients with insomnia), France (n = 1858; 998 good sleepers and 860 patients with insomnia) and Japan (n = 911; 506 good sleepers and 405 patients with insomnia). Enrollment and data collection using consumer panels were web-based in the US and France, and gathered via a postal survey in Japan. People with chronic insomnia (>6 months) were selected based on Insomnia Severity Index scores (ISI). Severity of insomnia was assessed using the ISI score and HRQoL was assessed using the self-administered Short-Form SF-36 Health Survey. Utility scores were derived using the algorithm developed by Brazier et al. Multivariate analyses were used to adjust for potential confounding factors.

Results

In all countries, people with chronic insomnia (40% treated) reported lower SF-36 scores in each of eight domains compared with good sleepers (P < .0001). Chronic insomnia was associated with significantly lower utility scores compared with good sleepers (mean scores 0.63 versus 0.72 in the US, 0.57 versus 0.67 in France, and 0.67 versus 0.77 in Japan, P < .0001).

Conclusions

This survey suggests that chronic insomnia is associated with significant impairment of HRQoL and decreased utilities across the different geographical regions studied.     

Evaluation of deoxycoformycin in patients with advanced renal cell carcinoma

This study was conducted by the Eastern Cooperative Oncology Group (Paul P. Carbone, M.D., Chairman, CA 21115) and supported by Public Health Service Grants from the NCI, National Institutes of Health, and the Department of Health and Human Services.     

Corpus Callosotomy for Intractable Epilepsy: Seizure Outcome and Prognostic Factors

We reviewed the outcome of corpus callosal section in 64 adult and pediatric patients to identify factors associated with a good outcome: 48% of patients had a favorable outcome for overall seizure frequency. Improvement was noted in several seizure types and was most likely for drop attacks, particularly in the setting of a unilateral focal cerebral lesion or a true generalized epilepsy of Lennox-Gastaut type. Poor outcomes for drop attacks were more likely if there was associated severe intellectual handicap or bilateral independent spikes on interictal EEG. Complex partial seizures (CPS), most commonly of frontal lobe origin, also responded favorably. The complications of callosal section were usually mild and transient. New focal seizures occurred in only 2 patients and were not as frequent or disabling as preoperative seizure types. A worthwhile improvement in seizure outcome was achieved by completion of the callosotomy in 6 of 10 patients with unsatisfactory results from anterior callosotomy.     

Molecular diagnosis of inheritable neuromuscular disorders. Part I: Genetic determinants of inherited disease and their laboratory detection

Understanding of the genetic basis of inheritable neuromuscular disorders has grown rapidly over the last decade, resulting in improved classification and understanding of their pathogenesis. A consequence of these advances has been the development of genetic tests of blood specimens for the diagnosis of many of these diseases. For many patients, these blood tests have eliminated the need for other more invasive diagnostic tests such as muscle or nerve biopsy, and for some patients, reduced exposure to immunosuppressive medication and its complications. The first part of this review focuses on the nature of genetic disorders, the laboratory methods used in the performance of genetic tests, and general practical aspects of their use and interpretation. The second part discusses the applicability of these tests to the range of neuromuscular disorders.     

Distinct neural substrates for visual search amongst spatial versus temporal distractors

Whether the contribution of the superior parietal cortex (BA7) to attention-demanding tasks is strictly spatial in nature remains unresolved. We used functional magnetic resonance imaging to explore the behavioural and neuroanatomical correlates of non-spatial search for a conjunction of features within a stream of temporally-distracting stimuli. In addition, we compared these data to those from a conventional visuo-spatial search task, performed by the same subjects, in order to determine the specificity of right BA7 activation. Mode of stimulus-distribution (spatial versus temporal) and search type (target defined by a single feature or a conjunction of features) were manipulated in a 2 x 2 factorial design. Behaviourally, the temporal conjunction task was shown to index temporal selective attention. Accuracy of detecting a second target varied with the temporal proximity of two successive targets when subjects searched for a conjunction of features, but not a single feature. The temporal conjunction task activated a network of areas including right superior parietal cortex and bilateral regions of intraparietal sulcus, frontal operculum and putamen. The two latter regions were selectively activated by the attentional demands of the temporal conjunction task when compared directly to the attentional demands of the spatial conjunction task, implicating these regions specifically in selective attention among temporally-distracting stimuli. By comparison, only a very medial region of right BA7 was selectively activated by the spatial conjunction task. The more lateral region of BA7 previously reported by other groups was engaged to a similar degree by both spatial and temporal versions of the conjunction search task.     

Obstetric adversity and age at first presentation with schizophrenia: evidence of a dose-response relationship

OBJECTIVE: The purpose of the study was to determine if a dose-response relationship exists between obstetric adversity and age at first presentation with schizophrenia. METHOD: The Dublin Psychiatric Case Register was used to identify subjects with schizophrenia. Data on obstetric complications, social class of origin, and family history of psychiatric illness were obtained for those subjects. RESULTS: A total of 409 patients with ICD-9 schizophrenia were identified. Patients with a history of obstetric complications presented earlier to psychiatric services. As the number of complications increased, the mean age at first presentation decreased. This effect was independent of social class of origin and family history of psychiatric illness. CONCLUSIONS: Obstetric adversity exerts an independent influence on the age at first presentation with schizophrenia, in a dose-response manner. This finding supports the existence of a causal relationship between obstetric adversity and age at first presentation with schizophrenia.