Mouse models of NADK2 deficiency analyzed for metabolic and gene expression changes to elucidate pathophysiology.

NADK2 encodes the mitochondrial form of nicotinamide adenine dinucleotide (NAD) kinase, which phosphorylates NAD. Rare recessive mutations in human NADK2 are associated with a syndromic neurological mitochondrial disease that includes metabolic changes, such as hyperlysinemia and 2,4 dienoyl CoA reductase (DECR) deficiency. However, the full pathophysiology resulting from NADK2 deficiency is not known. Here, we describe two chemically induced mouse mutations in Nadk2-S326L and S330P-which cause severe neuromuscular disease and shorten lifespan. The S330P allele was characterized in detail and shown to have marked denervation of neuromuscular junctions by 5 weeks of age and muscle atrophy by 11 weeks of age. Cerebellar Purkinje cells also showed progressive degeneration in this model. Transcriptome profiling on brain and muscle was performed at early and late disease stages. In addition, metabolomic profiling was performed on the brain, muscle, liver and spinal cord at the same ages and on plasma at 5 weeks. Combined transcriptomic and metabolomic analyses identified hyperlysinemia, DECR deficiency and generalized metabolic dysfunction in Nadk2 mutant mice, indicating relevance to the human disease. We compared findings from the Nadk model to equivalent RNA sequencing and metabolomic datasets from a mouse model of infantile neuroaxonal dystrophy, caused by recessive mutations in Pla2g6. This enabled us to identify disrupted biological processes that are common between these mouse models of neurological disease, as well as those processes that are gene-specific. These findings improve our understanding of the pathophysiology of neuromuscular diseases and describe mouse models that will be useful for future preclinical studies.

An evaluation of community learning disability services for children with a learning disability.

This study outlines the results of a survey carried out with parents of children with a learning disability, general practitioners and community learning disability teams as to the health service needs for this client group. Overall, 40% of parents were very dissatisfied or dissatisfied with the services they received. A number of gaps in service provision were identified. In particular, psychological and behavioural difficulties of children were of major concern to all those involved, but needs in relation to these areas were often unmet or inadequately dealt with. Of greater concern was that some families in the area studied were paying privately for child learning disability clinical psychology services because they had such difficulty in accessing NHS services. Implications for service provision are discussed.

Climatology of diurnal trends and vertical distribution of ozone in the atmospheric boundary layer in urban North Carolina.

Vertical measurements of ozone were made on a 610-m-tall tower located about 15 km southeast of Raleigh, NC, as part of an effort by the state of North Carolina to develop a state implementation plan (SIP) for ozone control in the Raleigh Metropolitan Statistical Area. During summer 1993, 1994, and 1995, ozone was monitored at ground level, 250 m, and 433 m. Boundary layer wind, temperature, and other meteorological variable profiles were determined from balloon soundings. During summer 1996 and 1997, ozone was monitored at ground level, 76 m, 128 m, and 433 m. This paper presents the analysis and discussion of the five-year data. The evolutions of the convective boundary layer during daytime and the stable nocturnal boundary layer (NBL) were found to have marked impacts on ozone concentrations. A strong diurnal pattern, with an afternoon maximum and an early morning minimum, was dominant at ground level, but it was much weaker at elevated levels and insignificant above the NBL at night. Ozone deposition velocities at night during the measurement periods were estimated to range from 0.09 to 0.64 cm/sec. We found evidence of regional transport of ozone and/or its precursors from northwest and north of the site, which may play a role in high ozone events in the Raleigh-Durham area. Ozone concentrations between the various elevated levels were well correlated, while correlations between the ground and upper levels were much weaker. However, a strong correlation was found between the nighttime and early morning ozone concentrations (CR) in the residual layer above the NBL and the maximum ground level concentration (Co max) the following afternoon. Based on this correlation, the latter may be predicted by an observational model Co max = 27.76e 0.016 CR.

An evaluation of a primary care psychological therapies clinic.

The present study evaluates a primary care psychological therapies clinic providing input one day per week to a GP practice in a rural area of Scotland. Routine data was collected over a 17 month period and a rating scale was used to evaluate treatment outcomes by both GPs and therapist. In addition GP satisfaction with the service was also evaluated. No significant differences were found between counselling and psychology cases on any of the variables examined. Treatment outcome evaluation showed an overall rate of improvement following treatment, with a mean score of 7 on a 1-10 scale, with 10 representing 'much better'. Significant agreement was found between therapist and GP on rating outcome and no significant differences were found between ratings given by psychologist and counsellor. The GPs involved also expressed high levels of satisfaction with the service.

Professional composition of community learning disability teams in Scotland: implications for service provision.

A survey of all trusts in Scotland who provided specialist services to people with learning disabilities was made with a response rate of 100%. An examination was made of the professional composition of the community learning disability teams and the population covered. A disparity was found across Scottish trusts in the professions represented in the community learning disability teams with some professions having no input. Nursing and Clinical Psychology were found to be the two professional groups with largest representation across Scotland and along with Speech and Language Therapy had representation in all of the Teams. A review of some of the factors which have impacted on the role and professional composition of these services is made and the implications discussed.

Influence of exercise training soon after myocardial infarction on regional myocardial perfusion and resting left ventricular function.

There is scant information regarding the effect of exercise training begun soon after hospital discharge for myocardial infarction (MI) with respect to subsequent improvement in exercise tolerance, enhancement of regional myocardial perfusion, or left ventricular function. Accordingly, 19 post-MI patients (mean age 53 +/- 7 years) underwent treadmill exercise quantitative thallium-201 (Tl-201) scintigraphy and rest radionuclide angiography (RNA) prior to and after 12 weeks of thrice-weekly exercise training which was targeted to 70-85% of maximum exercise heart rate achieved. Training was begun at 25 +/- 3 days after hospital discharge. Eight Tl-201 scan segments were each scored from 1-6 points based upon uptake and washout criteria with 6 being the most severe defect (greater than 50% reduction in Tl-201 events with no delayed redistribution). When matched to the pretraining peak workload on exercise testing, 12 weeks of training significantly lessened heart rate (120 +/- 4 to 97 +/- 4, p less than 0.001), peak systolic blood pressure (142 +/- 6 to 129 +/- 5 mmHg, p less than 0.01), and significantly reduced double product [17.2 +/- 10.8 to 12.7 +/- 9 (x10(3), p less than 0.001]. Training was associated with a reduction of exercise-induced ST depression or angina (42 to 16%) which was not statistically significant. The mean resting by RNA ejection fraction was 50 +/- 3% prior to training and 51 +/- 3% after training. There was no significant change in overall Tl-201 defect score or the number of defect regions per patient scan comparing pre- and post-training scintigrams.(ABSTRACT TRUNCATED AT 250 WORDS)

Double-blind, placebo-controlled trial of propranolol given once, twice and four times daily in stable angina pectoris: a multicenter study using serial exercise testing.

To determine if propranolol given twice daily (b.i.d.) or once daily (q.d.) was as effective as 4 times daily (q.i.d.) for treatment of stable angina pectoris, 78 patients with exercise-induced ST depression of 1.5 mm were randomized to q.i.d., b.i.d., q.d. and placebo groups. All patients received 5 tablets per day, and propranolol groups received 80, 160 and 320 mg/day on successive weeks. At weekly visits, patients underwent treadmill exercise testing before the 8:00 AM dose and at 2 and 9 hours afterward. Exercise duration (seconds) was significantly improved at the final visit compared with baseline by b.i.d. (120 +/- 36 [mean +/-] standard error of the mean p less than 0.001 n = 18) and q.i.d. (100 +/- 37, p less than 0.01; n = 17) regimens, but not by the q.d. (30 +/- 33; n = 18) and placebo regimens (27 +/- 37; n = 17). There was a significant decrease from baseline in the magnitude of ST depression at the final visit, measured at maximal common exercise duration in b.i.d. (-0.96 +/- 0.20 mm, p less than 0.001), q.i.d. (-0.84 +/- 0.20 mm, p less than 0.01) and q.d. (-0.58 +/- 0.18 mm, p less than 0.05) groups, but not in the placebo group (0.03 +/- 0.2 mm). Hourly heart rate by Holter was reduced in all 3 propranolol groups; however, the mean serum propranolol level was significantly lower just before the first dose with q.d. group (56 +/- 20 ng/ml) compared with b.i.d. and q.i.d. groups (146 +/- 22 and 119 +/- 28 ng/ml) with 320 mg/day (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

The FDA report on intraocular lenses.

Clinical studies of intraocular lenses (IOLs) as investigational devices have been regulated in the United States by the Food and Drug Administration (FDA) since 9 February 1978. As of August 1982, data have been collected on more than one million IOLs implanted. During the last 12 months of the study, 409 000 IOLs were implanted. Visual acuity of 20/40 or better at one year after surgery was present in 85% of over 45 000 cases reviewed. Increasing patient age, surgical problems, postoperative complications, and adverse reactions were factors that reduced the visual acuity. The current trend in the USA is for implantation of posterior chamber and anterior chamber IOLs.

Trends in cataract surgery and intraocular lenses in the United States.

Cataracts are the second leading cause of blindness in the United States. The rate of cataract surgery has greatly increased in the past several years, in part because of the extensive use of intraocular lenses for aphakic correction. It is estimated that more than 600,000 cataract operations were done in 1982. During a similar period, an estimated 496,000 intraocular lenses were implanted. Thus, more than 70% of all cataract operations in the United States involved intraocular lens implantation. Although iris fixation lenses accounted for 52% of all intraocular lenses implanted in 1978, during the six-month period from July 1982 through January 1983 57% of all implanted intraocular lenses were posterior chamber lenses and 40% were anterior chamber lenses.

Cardiac rehabilitation following coronary artery bypass surgery.

Early expectations of coronary revascularization prolonging life and reducing coronary events have been modified by 15 years' experience to mostly initial palliation of ischemic symptoms. Bypass surgery represents only a single therapeutic aspect for coronary atherosclerosis. Technically successful operations often fail miserably without overall risk factor alteration and functional capacity optimization which progressive exercise initiates during the postoperative period. Regular activity program participation improves physical conditioning, raises the symptom-limited exertional level, lessens post surgical musculoskeletal discomfort, and improves morale. Yet exercise alone without comprehensive secondary prevention and risk factor modification will be no more successful at arresting atherosclerosis than any other single measure. Both operative intervention and vigorous exertion are valuable components of coronary artery disease therapy, but must be part of an all-embracing effort. Whether regular exertion combined with overall risk factor modification will prolong life and reduce future cardiac events or beneficially alter the process of atherogenesis remain areas of avid investigation.

The FDA report on intraocular lenses.

Clinical studies of intraocular lenses (IOLs) as investigational devices have been regulated in the United States by the Food and Drug Administration (FDA) since February 9, 1978. As of August 1982, data have been collected on more than one million IOLs implanted. During the last 12 months of the study, 409,000 IOLs were implanted. Visual acuity of 20/40 or better at one year after surgery was present in 85% of over 45,000 cases reviewed. Increasing patient age, surgical problems, postoperative complications, and adverse reactions were factors that reduced the visual acuity. The current trend in the USA is for implantation of the posterior chamber and anterior chamber IOLs.

Cervical fracture complicating ankylosing spondylitis: a report of eight cases and review of the literature.

Fracture of the cervical spine is a serious and often fatal complication of ankylosing spondylitis. An evaluation of eight patients and a review of 75 additional cases from the literature are presented. Although this complication is relatively uncommon, it is clear that people with advanced disease and complete ankylosis of the cervical spine are at increased risk of sustaining cervical fracture. When fracture occurs it usually stems from minor trauma resulting most commonly in disruption of the lower cervical segments (fifth through the seventh cervical vertebrae). Fracture is most likely the result of a hyperextension type injury, occurs through what was formerly an intervertebral space, and is unstable. Severe neurologic sequelae occur in 57 percent of the cases and the mortality rate (35 percent) is twice that observed with similar fracture involving normal spines. The majority of patients are best treated with closed reduction with halo traction together with body cast or jacket. Laminectomy is rarely indicted except in the event of an advancing neurologic deficit. With appropriate understanding and execution of management principles, the outcome in these patients can be favorable. Unfortunately, recognition of cervical fracture in patients with ankylosing spondylitis is often needlessly delayed. Distortion of normal anatomy in spondylitics, predominant fracture location in lower cervical spine segments and lack of obvious displacement make identification difficult. Thus, management is often inappropriate resulting in excessive neurologic injury and mortality.

Distribution of HLA antigens in a Mexican--American population and a comparison with two similar populations from different geographical locales.

The frequencies of 32 HLA antigens of the A and B series were determined in a previously unstudied population of Mexican-Americans in South Texas. The phenotype and gene frequencies for this group are presented and are contrasted with those determined in studies of Mexican/Mexican--American populations from two different locales. The statistically significant differences observed emphasize the need for indigenous controls when evaluating racially heterogeneous populations for disease-associated HLA antigens.

A novel rapid scanning microspectrophotometer and its use in measuring rhodopsin photoproduct pathways and kinetics in frog retinas.

A novel rapid scanning microspectrophotometer is described which utilizes a cathode ray tube as a measuring light source. Spectral scanning is accomplished electronically with a sampling time of 600 mus for each waveband. The cathode ray tube emission is chopped electronically into two separate beams, 180 degrees out of phase, resulting in a dual-beam configuration. A lock-in amplifier functions as a coherent detector to recover separately the signals from the two beams. The instrument generates separate voltage outputs, one proportional to the transmittance of a single sample and the other to the difference between two samples. A computer calculates both absorption and difference spectra directly from voltage measurements. A demonstration of the instrument's use to study kinetics of visual pigment photoproducts is presented. Two models of photoproduct sequence and kinetics were examined to determine which better represents the experimental data. The experiments show that environmental factors, such as pH, metabolic and respiratory state, interact in complex ways to determine the pathways and kinetics of photoproducts of rhodopsin in intact vertebrate eyes.

A study of HLA antigens in adults with acute rheumatic fever.

By use of a microlymphocytotoxic assay to detect 32 HLA antigens of the A and B series, we examined 49 Mexican-American adults with acute rheumatic fever and contrasted the findings with 100 ethnically identical controls. Eighty-nine percent of the total possible antigens were identified. Strong associations between HLA antigens from either locus and acute rheumatic fever were not detected. These findings serve to emphasize the importance of nongenetic factors in the pathogenesis of acute rheumatic fever and help clarify the role of HLA antigens in rheumatic diseases.