Expression of apoptosis inhibitor protein Mcl1 linked to neuroprotection in CNS neurons.

Mcl1 is a Bcl2-related antiapoptotic protein originally isolated from human myeloid leukemia cells. Unlike Bcl2, expression has not been reported in CNS neurons. We isolated Mcl1 in a direct screen for candidate modifier genes of neuronal vulnerability by differential display of mRNAs upregulated following prolonged seizures in two mouse strains with contrasting levels of hippocampal cell death. Mcl1 is widely expressed in neurons, and transcription is rapidly induced in both strains. In resistant C57Bl/6J mice, Mcl1 protein levels remain persistently elevated in hippocampal pyramidal neurons after seizures, but fall rapidly in C3H/HeJ hippocampus, coinciding with extensive neuronal apoptosis. DNA damage and caspase-mediated cell death were strikingly increased in Mcl1-deficient mice when compared to +/+ littermates after similar seizures. We identify Mcl1 as a neuronal gene responsive to excitotoxic insult in the brain, and link relative levels of Mcl1 expression to inherited differences in neuronal thresholds for apoptosis.

Clinical utility of dorsal sural nerve conduction studies.

A technique of testing sensory nerve conduction of the dorsal sural nerve in the foot was used in 38 normal subjects and 70 patients with peripheral neuropathies. The normal dorsal sural sensory nerve action potential (SNAP) had a mean amplitude of 8.9 microV (range 5-15 microV), mean latency to negative peak of 4.0 ms (range 3.2-4.7 ms), and mean conduction velocity of 34.8 m/s (range 30-44 m/s). Optimal placement of the recording electrodes to obtain a maximal nerve action potential was proximal to digits 4 and 5. Cooling to below 25 degrees C prolonged the latency but did not decrease the SNAP amplitude. Among the patients with peripheral neuropathy, dorsal sural SNAP was absent in 68 (97%), whereas only 54 (77%) showed abnormalities of sural sensory conduction. The diagnostic sensitivity of sensory nerve conduction studies in peripheral neuropathies may be significantly improved by the use of this technique for evaluating the action potential of the dorsal sural nerve.

A cluster of three novel Ca2+ channel gamma subunit genes on chromosome 19q13.4: evolution and expression profile of the gamma subunit gene family.

The CACNG1 gene on chromosome 17q24 encodes an integral membrane protein that was originally isolated as the regulatory gamma subunit of voltage-dependent Ca2+ channels from skeletal muscle. The existence of an extended family of gamma subunits was subsequently demonstrated upon identification of CACNG2 (22q13), CACNG3 (16p12-p13), and CACNG4 and CACNG5 (17q24). In this study, we describe a cluster of three novel gamma subunit genes, CACNG6, CACNG7, and CACNG8, located in a tandem array on 19q13.4. Phylogenetic analysis indicates that this array is paralogous to the cluster containing CACNG1, CACNG5, and CACNG4, respectively, on chromosome 17q24. We developed sensitive RT-PCR assays and examined the expression profile of each member of the gamma subunit gene family, CACNG1-CACNG8. Analysis of 24 human tissues plus 3 dissected brain regions revealed that CACNG1 through CACNG8 are all coexpressed in fetal and adult brain and differentially transcribed among a wide variety of other tissues. The expression of distinct complements of gamma subunit isoforms in different cell types may be an important mechanism for regulating Ca2+ channel function.

The familial incidence of symptoms of scotopic sensitivity/Irlen syndrome: comparison of referred and mass-screened groups.

The familial incidence of Scotopic Sensitivity/Irlen Syndrome was investigated in two samples. One sample involved parents and siblings of 126 children identified with symptoms who had been referred for screening. The other sample involved parents and siblings of 33 children who had been identified with symptoms through mass screening of all children in Grades 3 to 6 at two local schools. Two different samples were taken to investigate the possibility of parental referral bias. Familial incidence may be inflated in a referred sample because some parents may be aware of their own symptoms and actively seek assistance. For the sample of children referred for screening, there was an 81% chance of either one or both parents showing similar symptoms and a 76% chance of siblings being similarly affected. For the sample of children identified through school screening, there was an 85%, chance of either one or both parents showing similar symptoms and a 54% chance of siblings being similarly affected. The data confirm previous estimates of incidence and suggest that Scotopic Sensitivity/Irlen Syndrome may be a genetically-based deficit in visual processing.

Scotopic sensitivity/Irlen syndrome and the use of coloured filters: a long-term placebo controlled and masked study of reading achievement and perception of ability.

This study investigated the effects of using coloured filters on reading speed, accuracy, and comprehension as well as on perception of academic ability. A double-masked, placebo-controlled crossover design was used, with subjects being assessed over a period of 20 mo. There were three treatment groups (Placebo filters, Blue filters, and Optimal filters) involving 113 subjects with "reading difficulties", ranging in age from 9.2 yr. to 13.1 yr. and with an average discrepancy between chronological age and reading age of 1.8 yr. The 35 controls (who did not use coloured filters) ranged in age from 9.4 yr. to 12.9 yr., with an average discrepancy between chronological age and reading age of 2.1 yr. The treatment groups increased at a significantly greater rate than the control group in reading accuracy and reading comprehension but not for speed of reading. For self-reported perception of academic ability, two of the three treatment groups showed significantly greater increases than the control group. The larger improvements for treatment groups in reading comprehension may be related to a reduction in print and background distortions allowing attention to be directed to the processing of continuous text rather than to the identification of individual words. A reduction in print distortion, however, may not be sufficient to generate improved word-identification skills without additional remedial support, and this may be indicated by the nonsignificant increase in rate of reading.

Scotopic sensitivity/Irlen syndrome and the use of coloured filters: a long-term placebo-controlled study of reading strategies using analysis of miscue.

This study investigated the long-term effects of using coloured filters on the frequency and type of errors in oral reading. A double-masked, placebo-controlled crossover experimental design was used, with subjects being assessed over a period of 20 months. There were three experimental groups (Placebo tints, Blue tints, and Diagnosed tints) involving 113 subjects with reading difficulties, ranging in age from 9.2 yr. to 13.1 yr. The 35 controls (ranging in age from 9.4 yr. to 12.9 yr.) had reading difficulties but did not require coloured filters. There was a significant improvement for all groups in the accuracy of miscues over the period, although experimental groups over-all did not improve at a significantly different rate than the control group. The failure to find significantly greater improvement for the experimental groups over the control group for the total period, despite subjects' reports of improved print clarity, may be partly related to the lack of effective letter-sound analysis and synthesis skills and to the use of a word-identification strategy of guessing based on partial visual analysis.

Effect of a long-term nerve growth factor treatment on body weight, blood pressure, and serum corticosterone in rats.

Nerve growth factor is a well-characterized neurotrophin essential for the development and maintenance of certain central and peripheral neurons. As many neurons affected by aging depend for their survival on a constant supply of neurotrophins, nerve growth factor has been proposed as a possible treatment to prevent aging-associated neurodegeneration. There is evidence that nerve growth factor also plays a role in the immune system and modulates certain aspects of endocrine function. Here we have determined the effects of prolonged peripheral (intraperitoneal) treatment with nerve growth factor on body weight, blood pressure, and serum corticosterone levels in the rat. Our data indicate that intraperitoneally-injected nerve growth factor can affect body weight gain in rats. This effect may not be mediated by nerve growth factor-induced increases in serum corticosterone levels, as exogenous administration of corticosterone did not result in a similar body weight loss. These results show that, as previously reported for intracerebroventricular treatment with nerve growth factor, intraperitoneally-injected nerve growth factor also reduces body weight gain in rats. The data also suggest that exogenous delivery of nerve growth factor as part of therapeutic regimens is likely to have several effects.

The familial incidence of symptoms of Scotopic Sensitivity/Irlen syndrome.

The familial incidence of Scotopic Sensitivity/Irlen Syndrome was investigated using parents of 751 children identified with symptoms. Children were identified by methods independent of their parents' symptoms or lack of symptoms. For these children, there was an 84% chance of either one or both parents showing similar symptoms, with similar numbers of mothers identified with symptoms as fathers. The data suggest that Scotopic Sensitivity/Irlen Syndrome may be a genetically based deficit in visual processing, but the simplest genetic models do not appear to fit.

Effects of acetyl-L-carnitine treatment and stress exposure on the nerve growth factor receptor (p75NGFR) mRNA level in the central nervous system of aged rats.

1. There is growing evidence that the nerve growth factor protein (NGF), a neurotrophic factor for peripheral and central nervous system (CNS) neurons, may play a role in the modulation of the hypothalamo-pituitary-adrenocortical axis (HPAA). While NGF binding is decreased in rodent CNS after stress exposure, this reduction is prevented by treatment with Acetyl-L-Carnitine (ALCAR), a chemical substance able to prevent some degenerative events associated with aging. 2. The authors studied the effect of cold stress on the low-affinity NGF receptor (p75NGFR) mRNA levels in the basal forebrain and cerebellum of aged rats chronically treated with ALCAR. 3. The present results show that ALCAR abolished the age-associated reduction of p75NGFR mRNA levels in the basal forebrain of old animals, but did not affect the response to stress stimuli. 4. Also, treatment with ALCAR maintained p75NGFR mRNA levels in the cerebellum of old animals at levels almost identical to those observed in young control animals. 5. These results suggest a neuroprotective effect for ALCAR on central cholinergic neurons exerted at the level of transcription of p75NGFR. The restoration of p75NGFR levels could increase trophic support by NGF of these CNS cholinergic neurons which are implicated in degenerative events associated with aging.

Nerve growth factor and p75NGFR factor receptor mRNA change in rodent CNS following stress activation of the hypothalamo-pituitary-adrenocortical axis.

The synthesis of nerve growth factor (NGF) by the hippocampus raises the possibility that NGF may play a role in the regulation of the hypothalamic-pituitary-adrenal axis (HPAA). Subchronic cold stress has been shown to activate the HPAA in a mild noninvasive manner, to stimulate serum glucocorticoid levels, and to perturb NGF binding in hippocampus and basal forebrain. One or repeated episodes of cold stress increased NGF mRNA levels in the hippocampus and p75NGFR mRNA levels in the basal forebrain. These changes were not due to elevated serum glucocorticoid levels since treatment with exogenous corticosterone had no effect on NGF and p75NGFR mRNA levels. Adrenalectomy did not prevent the stress induced increases in NGF and p75NGFR mRNA.

Paediatric management practices in Down syndrome: a follow-up survey.

In a follow-up survey to a 1984 study, 339 paediatricians in Australia were invited to complete a brief questionnaire in 1990, in which they indicated their usual recommendations, practices and advice when managing children with Down syndrome. The response rate was 67%. The results indicated that the most frequent paediatrician-initiated referrals were for early intervention and for discussion with other parents; these options were selected more frequently in 1990 than in 1984. While referral to a social worker was the next most frequent choice, it occurred less in 1990 than in 1984. Other increases in referrals were for physiotherapy and speech therapy. Paediatricians were more likely to support referral to a geneticist, speech therapist or cosmetic surgeon in response to a specific parental enquiry, and less likely to support referral to a social worker or to full-time care. There had been significant increases since 1984 in the likelihood that paediatricians would order audiology and investigation of thyroid and cardiac function. There was less opposition to the use of sedatives, and virtual cessation of the use of tryptophan. Paediatricians were more optimistic about the likelihood of persons with Down syndrome living independently, caring for their own finances, and marrying, but not about other developmental areas.

Dexamethasone blocks nerve growth factor induction of nerve growth factor receptor mRNA in PC12 cells.

Glucocorticoids and nerve growth factor (NGF) have been shown to have antagonistic effects on chromaffin cells in vivo. Here we determined the effect of the synthetic glucocorticoid, dexamethasone, on levels of mRNA for the nerve growth factor receptor (NGFR) in rat PC12 pheochromocytoma cells. Following administration of dexamethasone (1 microM) there is a decline in NGFR mRNA expression. More importantly, administration of dexamethasone appears to block the NGF-mediated induction of NGFR when both agents are administered simultaneously. These data support the hypothesis that glucocorticoids and NGF act in opposition in determination of the phenotype of chromaffin cells.

Nerve growth factor modulates the activation of the hypothalamo-pituitary-adrenocortical axis during the stress response.

In the present study, we have investigated the functional relationship between the nerve growth factor protein (NGF) and the hypothalamus-pituitary-adrenocortical axis (HPAA). We have found that while iv injected NGF is able to stimulate the HPAA activity in rats, NGF is not able to stimulate the axis after a block of the hypothalamus produced by chlorpromazine-morphine-Nembutal treatment. Also, the stress activation of the HPAA is significantly reduced by pretreatment of the rats with anti-NGF immunoglobulin G. These results suggest that the stimulatory action of NGF on HPAA activity requires the release of ACTH secretagogues from the hypothalamus and that NGF may modulate the HPAA response to stress stimuli.

125I-beta-nerve growth factor binding is reduced in rat brain after stress exposure.

In the central nervous system (CNS), the presence of nerve growth factor (NGF) and its receptor, NGFR, in cholinergic neurons has been demonstrated. In this study we report that, after exposure to stress, there was a reduction in total binding of NGF in the hippocampus and basal forebrain of 3.5-month-old rats without significant changes in the frontal cortex or cerebellum. Chronic treatment with acetyl-l-carnitine (ALCAR), that prevents some age-related impairments of CNS, for 1.5 months, decreased NGF binding in hippocampus and basal forebrain but abolished the stress-related reduction of NGF binding observed in the hippocampus of untreated rats.

Nerve growth factor and neuronal cell death.

The regulation of neuronal cell death by the neuronotrophic factor, nerve growth factor (NGF), has been described during neural development and following injury to the nervous system. Also, reduced NGF activity has been reported for the aged NGF-responsive neurons of the sympathetic nervous system and cholinergic regions of the central nervous system (CNS) in aged rodents and man. Although there is some knowledge of the molecular structure of the NGF and its receptor, less is known as to the mechanism of action of NGF. Here, a possible role for NGF in the regulation of oxidant--antioxidant balance is discussed as part of a molecular explanation for the known effects of NGF on neuronal survival during development, after injury, and in the aged CNS.

Cardiovascular response to speaking in schizophrenics.

Cardiovascular responses to speaking are compared in schizophrenic and nonschizophrenic psychiatric patients. Schizophrenics show a significantly smaller mean arterial pressure (MAP) response to speaking than nonschizophrenics, and a trend toward significantly smaller heart rate (HR) and diastolic blood pressure (DBP) responses. Previous studies found that normal individuals consistently increase MAP when they speak. Nonschizophrenic psychiatric patients resemble normals, but a significant number of schizophrenics do not increase MAP when they speak. This difference is not explained by baseline differences between the two groups (Law of Initial Value effects). Effects of neuroleptic use cannot be excluded entirely, but the pattern of response is not consistent with a neuroleptic-induced attenuation of response.

An evaluation of cell therapy in Down syndrome.

A group of children with Down syndrome who were being treated with cell therapy was matched for age and sex with an untreated control group. Comparisons were made between the groups with respect to a number of developmental and physical variables which have been reported to be influenced by cell therapy. Of 55 comparisons made between treated and control groups, two differences were statistically significant. This study failed to show sufficient significant results for the treatment to be regarded as effective.

A survey of paediatric management practices in Down's syndrome.

Paediatricians throughout Australia and New Zealand completed a questionnaire in which they indicated the type of advice they normally give to parents of children with Down's syndrome. Results indicated strong support for early intervention, discussion with other parents of children with Down's syndrome, and conventional therapy services. Cosmetic surgery appears to be receiving increasing support. Megavitamin therapy, cell therapy and the Doman programme are unsupported. A tendency was noted for paediatricians to underestimate the developmental potential of children with Down's syndrome.

Blood pressure increases while signing in a deaf population.

Recent technologic advances have permitted the observation of rapid and significant increases in blood pressure (BP) during verbal communication. The magnitude of the increase in BP is influenced by rate of speech, audience size, status, affective content, environmental setting, and resting BP. The current study evaluates the effect of communicating without vocalizing in 38 deaf adults. Similar to speaking individuals, deaf individuals exhibited significant increases in BP and heart rate (HR) while signing, and the magnitude of the increases were related to resting BP levels. These findings suggest that communication, independent of vocalization, has significant effects on the cardiovascular system. Further studies are needed to explore other dimensions of cardiovascular-communication relationships in deaf populations.