Cardiorespiratory fitness testing and cardiovascular disease risk in male steelworkers.

BACKGROUND: The workplace has been advocated as a setting to perform cardiovascular disease (CVD) risk assessments. These risk assessments usually focus on traditional risk factors rather than cardiorespiratory fitness (CRF) despite established associations between CRF and CVD. The lack of guidance on interpreting health-related CRF values has been suggested as a barrier to utilizing CRF in practice. AIMS: To assess the merits of CRF testing in the workplace and explore whether a CRF value identified male individuals above the recommended threshold for further clinical investigation. METHODS: Cross-sectional analysis of male steelworkers from Carmarthenshire, South Wales, UK who completed a workplace-based CVD risk assessment with an added CRF protocol based on heart rate responses (Chester Step Test). Receiver operating characteristic (ROC) analysis was undertaken to explore the possibility of a CRF value to identify individuals at an increased 10-year risk of CVD (QRISK2 ≥ 10%). RESULTS: There were 81 participants. ROC analysis revealed that a CRF level of 34.5ml/kg/min identified those individuals above the ≥10% QRISK2 threshold with the best sensitivity (0.800) and specificity (0.687) to discriminate against true- and false-positive rates. Further analysis revealed that individuals with either 'Average' or 'Below Average' CRF would be five times more likely to have a 10-year CVD risk above the ≥10% QRISK2 threshold than individuals with an 'Excellent' or 'Good' level of fitness [OR 5.10 (95% CI 1.60-16.3)]. CONCLUSIONS: This study suggests CRF assessments are a useful addition to a workplace CVD assessment and could identify male individuals at increased predicted risk of the condition.

Adiposity has differing associations with incident coronary heart disease and mortality in the Scottish population: cross-sectional surveys with follow-up.

OBJECTIVE: Investigation of the association of excess adiposity with three different outcomes: all-cause mortality, coronary heart disease (CHD) mortality and incident CHD. DESIGN: Cross-sectional surveys linked to hospital admissions and death records. SUBJECTS: 19 329 adults (aged 18-86 years) from a representative sample of the Scottish population. MEASUREMENTS: Gender-stratified Cox proportional hazards models were used to estimate hazard ratios (HRs) for all-cause mortality, CHD mortality and incident CHD. Separate models incorporating the anthropometric measurements body mass index (BMI), waist circumference (WC) or waist-hip ratio (WHR) were created adjusted for age, year of survey, smoking status and alcohol consumption. RESULTS: For both genders, BMI-defined obesity (30 kg m(-2)) was not associated with either an increased risk of all-cause mortality or CHD mortality. However, there was an increased risk of incident CHD among the obese men (hazard ratio (HR)=1.78; 95% confidence interval=1.37-2.31) and obese women (HR=1.93; 95% confidence interval=1.44-2.59). There was a similar pattern for WC with regard to the three outcomes; for incident CHD, the HR=1.70 (1.35-2.14) for men and 1.71 (1.28-2.29) for women in the highest WC category (men 102 cm, women 88 cm), synonymous with abdominal obesity. For men, the highest category of WHR (1.0) was associated with an increased risk of all-cause mortality (1.29; 1.04-1.60) and incident CHD (1.55; 1.19-2.01). Among women with a high WHR (0.85) there was an increased risk of all outcomes: all-cause mortality (1.56; 1.26-1.94), CHD mortality (2.49; 1.36-4.56) and incident CHD (1.76; 1.31-2.38). CONCLUSIONS: In this study excess adiposity was associated with an increased risk of incident CHD but not necessarily death. One possibility is that modern medical intervention has contributed to improved survival of first CHD events. The future health burden of increased obesity levels may manifest as an increase in the prevalence of individuals living with CHD and its consequences.

Expression of osteonectin and matrix Gla protein in scleroderma patients with and without calcinosis.

OBJECTIVES: Our aim was to evaluate (i) whether the bone matrix proteins osteonectin and matrix gamma-carboxyglutamic acid protein (MGP) are up-regulated in skin biopsies from patients with systemic sclerosis (SSc) and (ii) whether there is differential expression between patients with and without dermal calcinosis, a distressing and debilitating complication of SSc. METHODS: Skin punch biopsies were taken from the forearms of 38 SSc patients with the limited cutaneous subtype of SSc [17 without calcinosis (lcSSc) and 21 with calcinosis (lcSScCal)] and from 11 healthy control subjects. Immunohistochemistry was performed with antibodies to osteonectin and MGP. Staining was assessed semiquantitatively in the microvascular endothelium and in dermal fibroblasts. The Kruskal-Wallis one-way ANOVA was used to compare the data between patient groups. RESULTS: Both lcSSc and lcSScCal groups showed a statistically significant increase in the percentage of microvessels with osteonectin-positive endothelial cells (EC) (especially the lcSScCal group), whereas lcSScCal alone showed an increase in the percentage of microvessels with MGP-positive EC when compared with controls. In both SSc groups, the percentage of osteonectin and MGP-stained fibroblasts was increased in the reticular dermis (for osteonectin this was more marked in the lcSScCal group). In the papillary dermis, the percentage of osteonectin-stained fibroblasts was increased in both SSc groups but the lcSScCal group alone had a higher percentage of MGP-stained fibroblasts. CONCLUSIONS: When compared with controls, protein expression of osteonectin and MGP was greater in SSc patients generally, and osteonectin expression was significantly higher in EC and fibroblasts of the lcSScCal patients than the lcSSc patients without calcinosis.

The glial cell response to a viral vector in the aged brain.

The normal aged brain undergoes pro-inflammatory changes. We investigated the effect of injecting a potential inflammatory stimulus, an adenoviral vector, on the response of microglia and astroglia in the aged brain. Groups of young (4 months) and old (31 months) male C57BL/Icrfat mice received a unilateral injection into the striatum of adenoviral vector encoding the LacZ gene. After 48 h, the mice were killed and the brains analysed for numbers of activated microglia and macrophages using the biotinylated lectin Griffonia simplicifolia as a marker; astroglia were identified by immunohistochemistry for glial fibrillary acidic protein (GFAP). The cell counts were analysed using two-way analysis of variance (anova). Transgene expression was assessed by beta-galactosidase histochemistry. The numbers of activated microglia in the striatum increased in response to the adenovirus in both young [contralateral 19.5 (3.7), ipsilateral 36 (3.0)] and old [contralateral 23.1 (9.6), ipsilateral 40.8 (6.9)] mice (two-way anova; P < 0.0001), but there was no significant difference between the two age groups. There was a significant age-related increase in the number of GFAP-positive astroglia in the uninjected, contralateral striatum [4 months, 2.5 (1.4); 31 months, 29.7 (9.3)] (two-way anova; P < 0.0001). However, there was no difference in response to the adenovirus in both young [contralateral 2.5 (1.4), ipsilateral 3.2 (1.2)] and old [contralateral 29.7 (9.3), ipsilateral 28.9 (8.2)] mice. We conclude that even though it has been argued that the aged brain is in a pro-inflammatory state, under the experimental conditions used in this study, there was no difference in the nature of the immune response between young and old mice of this strain to an adenoviral load.

Characterization of the radical product formed from the reaction of nitric oxide with the spin trap 3,5-dibromo-4-nitrosobenzene sulfonate.

Previously, 3,5-dibromo-4-nitrosobenzene sulfonate (DBNBS) has been used in combination with electron paramagnetic resonance (EPR) spectrometry to trap nitric oxide (NO(*)). The reaction between DBNBS and NO(*) yields a radical product which gives rise to an EPR signal consisting of three lines with an A(N) = 0.96 mT, but the structure of this product is unknown. A two-stage high-performance liquid chromatography fractionation was performed to isolate the radical product from the other components in the DBNBS/NO(*) reaction mixture. The fractions containing the radical product were identified by the presence of the three-line EPR signal, and then these fractions were analyzed by negative ion fast atom bombardment-mass spectrometry (FAB-MS). Collectively, the FAB-MS data suggested that the radical product is the monosodium electrostatic complex with the dianion, bis(2,6-dibromo-4-sulfophenyl) nitroxyl. Analysis of the Gaussian and Lorentzian linewidths of the EPR signal suggested that bis(2,6-dibromo-4-sulfophenyl) nitroxyl molecules may group together to form micelles. Further studies also indicated that significant amounts of nitrogen and nitrate were produced during the reaction between DBNBS and NO(*). A reaction scheme consistent with these results is presented.

Oedema and glial cell involvement in the aged mouse brain after permanent focal ischaemia.

This study examines the effect of age on oedema and brain swelling, and associated glial cell involvement on the size of the lesion in two models of permanent, focal cerebral ischaemia. Ischaemia was induced in male C57BL/Icrfat mice (4-6 and 26-31-month-old) by middle cerebral artery (MCA) occlusion using either electrocoagulation after craniotomy (MCA/craniotomy), or by an intraluminal filament through the carotid artery (MCA/icf). Twenty-four hours after inducing ischaemia, brain swelling and lesion size were measured in young and aged mice, and cerebral oedema by wet/dry brain weights. Histopathology and immunocytochemistry were performed on a separate set of perfusion fixed brains. The MCA/icf technique produced a significantly larger lesion than MCA/craniotomy in both age groups. The percentage of water taken into the brain was significantly greater after MCA/icf, with aged mice showing the greatest increase. When lesion size was corrected for brain swelling there was no age-related increase in the size of the lesion. The numbers of microglia and astroglia increased significantly in the parietal cortex of aged control animals, and there were qualitative differences in the glial response between the two stroke models. This study emphasizes the importance of age in models of permanent focal ischaemia, with oedema clearly being a significant factor. Differ-ences in the responsiveness of the glial cell population with age may be of fundamental importance in the progress of ischaemic brain damage.

Simultaneous analysis of nitrite, nitrate and the nicotinamide nucleotides by capillary electrophoresis: application to biochemical studies and human extracellular fluids.

A simple but rapid capillary electrophoresis method was developed for the measurement of nitrite and nitrate in human extracellular fluids and other aqueous solutions. The capabilities of the method were demonstrated by the measurement of endogenous nitrite and nitrate in plasma and serum samples from healthy volunteers, and serum and synovial fluid samples from rheumatoid arthritis patients. Furthermore, this method was used to simultaneously measure nicotinamide adenine dinucleotide, reduced (NADH), nicotinamide adenine dinucleotide (NAD+), nitrite, and nitrate, when studying the nitrite reductase activity of xanthine oxidase. The stability of nitrite was also investigated and it was found that when whole blood was spiked with nitrite and then processed, the nitrite was more stable in the plasma than in the serum. Our findings may help to explain the variations in basal nitrite concentrations reported in the literature.

The progression and topographic distribution of interleukin-1beta expression after permanent middle cerebral artery occlusion in the rat.

The cytokine interleukin-1 (IL-1) has been implicated in the exacerbation of ischemic damage in the brains of rodents. This study has ascertained the cellular localization and chronologic and topographic distribution of pro/mature interleukin-1beta (IL-1beta) protein 0.5, 1, 2, 6, 24, and 48 hours after ischemia by subjecting rats to permanent unilateral occlusion of the middle cerebral artery. Interleukin-1beta was localized immunocytochemically in vibratome sections of perfusion-fixed brains. The cells that expressed IL-1beta had the morphologic features of microglia and macrophages. Interleukin-1beta was first detected 1 hour after occlusion in ipsilateral meningeal macrophage-like cells. By 6 hours, pro/mature IL-1beta-immunoreactive (IL-1(beta)ir) putative microglia were present in the ischemic cerebral cortex, corpus callosum, caudoputamen, and surrounding tissue. By 24 and 48 hours after ischemia, the number and spread of IL-1(beta)ir cells increased greatly, including those resembling activated microglia and macrophages, as the core of the infarct became infiltrated. Interleukin-1(beta)ir cells also were present in apparently undamaged tissue, adjacent to the lesion ipsilaterally, and contralaterally in the cerebral cortex, dorsal corpus callosum, dorsal caudoputamen, and hippocampus. These results support the functional role of IL-1 in ischemic brain damage and reveal a distinct temporal and spatial expression of IL-1beta protein in cells believed to be microglia and macrophages.

Inspiratory muscle function and body composition in cystic fibrosis.

Loss of body mass, which occurs in the later stages of cystic fibrosis (CF), probably affects all body compartments. We hypothesized that loss of skeletal muscle mass would include inspiratory muscles and impair their function. To test this, we determined the effect of body mass index (BMI) and lean body mass (LBM) depletion on handgrip (HG) force and inspiratory muscle function (IMF). The maximum inspiratory pressure (MIP) and the sustained maximum inspiratory pressure (SMIP) were measured with a computerized system. The relationship of IMF and reduced BMI to survival was studied in 49 patients, and a further 25 patients were studied to define the link between IMF and LBM. LBM was assessed by anthropometry. In the survival study a BMI < 20 kg/m2 was associated with a low SMIP (p < 0.001) and reduced survival, whereas MIP was relatively preserved. In the cross-sectional study SMIP (p < 0.001), MIP (p < 0.01), and HG (p < 0.01) were all reduced in the low LBM group, but not when related to total LBM. C-reactive protein and LBM were inversely related (r = -0.71, p < 0.01). Impaired IMF was chiefly a loss of sustained muscle contraction secondary to a reduced skeletal muscle mass, which may be related to pulmonary inflammation.

An integrated analysis of the progression of cell responses induced by permanent focal middle cerebral artery occlusion in the rat.

Defining the chronology and severity of cell damage in an evolving lesion after ischemia is important for understanding the underlying mechanisms in the development of therapeutic intervention. In the present study, we used a combination of histological and immunocytochemical methods to evaluate cell responses from 30 min to 48 h after permanent occlusion of the middle cerebral artery (MCAO) in the rat. Specific immunocytochemical markers clearly revealed acute early responses in neurons (neurofilament protein 200), astrocytes (glial fibrillary acidic protein), and microglia/macrophages (OX-42 and ED-1) such as enlarged, convoluted neuronal processes, and disintegration of glia. Progressive topographic changes in the developing lesion, pinpointed by immunolabeling, indicated the severity and extension of the cell damage. Proliferation and hypertrophy of astrocytes and microglia around the infarct, and contralaterally, occurred 24-48 h after MCAO and coincided with mass necrosis and infiltration of neutrophils and macrophages into the core. These observations corroborate the suggestion that the inflammatory process is involved in the progression of the infarct.

Nutrition in adults with cystic fibrosis.

Improved survival has been associated with better nutritional status in patients with cystic fibrosis (CF). In this study we examined the relationship between nutritional state and other measures of clinical severity in adult patients with CF, attending a regional centre. Eighty-one patients (median age 21 years) were studied. Patients with CF were significantly under weight, compared to healthy individuals but were of similar height. Measurements of lung function, FEV1 and FVC were significantly related to body mass index. Lung function was poorer in patients with chronic pseudomonal infection but body weight and body mass index were not significantly different compared to those without such infection. In 53 patients who were alive 4 years later, FEV1 had declined by -10.5 (2.1)% (P < 0.001) but there was no significant change in body weight 1.5 (6.5) kgs. In 23 patients who died or had lung transplantation the change from 1994 to the date of death or transplantation the FEV1 was reduced by -7.9 (11.2)% (P = 0.004) and body weight -2.8 (4.4) kgs (P < 0.01). In 12 patients who had supplemental enteral feeding, the median increase in body weight was 7|kgs over a period of 12 months. This study confirms that young adult patients with CF are significantly under weight and declining health is associated with significant weight loss. In patients with severe malnutrition significant improvement can be achieved by enteral feeding.

Information for management--the extent of information management in the acute care hospital sector.

The article explores the contributions of information and information technology to health care management by means of a study into current information use in a small acute care hospital and the preparations for new general practitioner purchasing systems. The findings highlight the interdependency between manual and computer systems and key departments in the hospital. With increased emphasis on primary health care, there is a greater need for information sharing between the hospital and general practitioners. Provision of information itself becomes a factor in determining service quality. Information systems are therefore emerging as an element in gaining competitive advantage in hospitals in the United Kingdom.

A prodigious information systems failure.

The article reports a case study in the conception and implementation of a regional information systems project in a Regional Health Authority in England in the 1980s. The project was technically ambitious and involved far-reaching organizational changes throughout the region. The project failed, after considerable expenditure, because support in the region dwindled. With reference to the context of changing management practice in the National Health Service in the 1980s, the project is assessed in the light of its technocratic focus and its effects on the organization, including implicit changes in power relationships.

Is the "preamyloid" of diffuse plaques in Alzheimer's disease really nonfibrillar?

Several papers have described an 'amorphous' component of the amyloid in diffuse plaques and it has been suggested that this is 'preamyloid,' which is not organized into fibrils. Because most of the studies have been performed on autopsy tissue it was the purpose of this study to compare the ultrastructure of diffuse amyloid deposits in well preserved Alzheimer's disease biopsy specimens with autopsy tissues from patients with Alzheimer's disease and Down's syndrome. A postembedding immunogold technique with anti-beta/A4 protein demonstrated gold particles exclusively on extracellular amyloid fibrils in both biopsy and autopsy brains. We have presented evidence that suggests the claim for the existence of an amorphous component within the beta/A4 protein-positive material is unconvincing.

A quantitative assessment of somatostatin-like and neuropeptide Y-like immunostained cells in the frontal and temporal cortex of patients with Alzheimer's disease.

Immunocytochemical studies utilizing radioimmunoassay and morphological techniques have provided conflicting evidence for the involvement of somatostatin and neuropeptide Y in Alzheimer's disease (AD). However, previous investigators have not considered the effects of cortical atrophy in AD tissue on their findings. This study reports the numbers of somatostatin-like (SLI) and neuropeptide Y-like immunoreactive (NPYLI) neuronal perikarya and the length of SLI and NPYLI immunoreactive fibres, with appropriate corrections for atrophy in 6 control and 6 AD cases. There were significantly fewer SLI neurones in AD in layers II + III combined from the temporal cortex, and fewer NPYLI neurones in layers V + VI in both frontal and temporal cortices. Using a randomized method to quantify immunostained fibre length in the neuropil, an analysis of variance revealed no significant differences in the mean SLI or NPYLI fibre length per cortical strip between control and AD groups in frontal or temporal cortex. However, using a second measure of fibre length by tracing the fibres attached to consecutive immunostained perikarya, there were significant reductions in the AD brains in the mean fibre length per cell in layers V + VI for SLI in the temporal cortex, and for NPYLI in the frontal cortex. This reduction in fibre length per individual cell was presumably masked by the large variation in the fibre length found between cases using the randomized approach. It was concluded that in order to evaluate the involvement of these neuropeptides in AD from any measurements of concentration, it is essential to include some compensation for the extent of cortical atrophy that occurs with the disease.

Reversal of midazolam sedation with flumazenil following conservative dentistry.

The purpose of this double-blind randomized study was to assess recovery of mental function following reversal of midazolam-induced sedation with the specific antagonist flumazenil (R015-1788) or placebo following conservative dental procedures. Recovery was assessed using choice reaction time and critical flicker fusion threshold, both objective tests of psychomotor function; linear analogue sedation scores and simple memory tests. Assessments were repeated up to 3 h after administration of flumazenil or placebo to discover whether recovery was sustained or whether resedation occurred due to the short duration of action of flumazenil. Flumazenil in doses from 0.5 to 1.0 mg rapidly reversed the sedative and amnesic effects of a mean dose of 8.2 mg of midazolam without apparent evidence of subsequent resedation. Since recovery of mental function in the control group had ordinarily occurred 45 min after administration of placebo, routine reversal of midazolam sedation with flumazenil cannot be justified. Nevertheless, in cases of undue sedation persisting after dental treatment, flumazenil may be used with minimal risk of resedation occurring.

A morphological analysis of senile plaques in the brains of non-demented persons of different ages using silver, immunocytochemical and lectin histochemical staining techniques.

The prevalence and severity of senile plaque (SP) formation was investigated in the cerebral cortex, hippocampus and amygdala of 60 non-demented individuals of age range 6-84 years, using immunocytochemical (anti-A4 amyloid, anti-PHF protein), lectin histochemical (Con A binding) and silver (Methenamine (MS) and Palmgren), staining methods. By at least one of these methods, 18 patients showed the presence of SP within one or more of these brain regions; 15 of these patients were over 60 years of age. Comparisons between each staining method showed that, in the hippocampus and amygdala all five methods detected the presence and number of SP equally well, whereas, in the cerebral cortex, MS and anti-A4 staining demonstrated more SP in a greater number of patients than did either Con A or Palmgren silver and anti-PHF staining. The additional SP detected by these former two staining methods contained diffuse deposits of amyloid (A4) protein, and sometimes also large clumps of Con A positive material, but no neurites as detected by Palmgren or anti-PHF staining. Such SP closely resemble those seen in the cerebral cortex of young patients with Down's syndrome, and which are thought to be an early form of SP. The relationship between the pathological changes in these non-demented patients and a possible diagnosis of early Alzheimer's disease is discussed.