Neural networks for ischemic stroke.

BACKGROUND: To have uniform criteria for evaluating populations for prevalence of transient ischemic attack (TIA)/stroke, validated instruments are necessary for objective assessment and classification. METHODS: Patient responses compatible with symptoms of TIA or ischemic stroke, obtained from participants in a substudy of the Asymptomatic Carotid Atherosclerosis Study, were used to program a neural network for each symptom. Models were designed for rapid classification into 1 of 7 outputs: no event, TIA, or stroke (in left carotid, right carotid, or vertebrobasilar). The networks were then tested by comparing decisions with a validated questionnaire used to access an independent data set of 381 patients. RESULTS: There were 144 patients who reported sudden speech change, 89 with sudden vision loss, 67 with double vision, 189 with sudden numbness, 223 with episodic dizziness, and 108 with paralysis, for a total of 820 reported symptoms among the 381 patients tested. For each category, an equal number of individuals reporting "No" to these phenomena were randomly selected and analyzed. Neural network classification correlated with the diagnoses made by specially trained stroke clinicians (e.g., all who responded "No" were correctly classified as having no neurologic event). Ten symptomatic patients were misclassified, with the most common reason being incomplete data. After adjustment of the network logic, these misclassifications did not recur. CONCLUSION: Computer networks can be trained to produce a rapid and accurate classification of TIA or stroke by vascular distribution, enabling screening of populations for assessment of their incidence and prevalence.

A temporal study of gene expression in rat lung following fixed-volume hemorrhage.

Previous studies have indicated that hemorrhage may predispose the lung to respiratory distress syndrome. Gene expression profiling with oligonucleotide microarrays was used to evaluate the genetic responses of the lung to hemorrhage. Conscious rats, chronically instrumented with a catheter and telemetry device to record blood pressure, heart rate, and temperature, had 40% of their estimated blood volume removed at a rate of 1 ml/min over 7-10 min. Groups of three or more rats were euthanized at 1, 3, 6, 16, 24, 48, or 72 h following hemorrhage. Two additional groups were unmanipulated controls and instrumented animals with sham hemorrhage. Total RNA was isolated from lung, reverse-transcribed to cDNA, fluorescently labeled, and hybridized to oligonucleotide microarrays probing 5,671 rat genes. After hemorrhage, statistically detectable alteration of expression was seen in approximately 0.8% of the genes at some time during the 72-h test period (vs. sham hemorrhage) as determined by false discovery rate statistics in the statistical analysis of microarrays program. A subset was confirmed by RT-PCR analysis. Hemorrhage influenced genes that regulate intracellular signaling and structure, growth factors, and hormonal receptors. There also appeared to be increased expression of genes that may mediate sequestration of neutrophils and mononuclear cells from the circulation. This hemorrhage model, although producing severe hemodynamic alterations, avoided mortality and histological evidence of lung damage, a feature intended to help ensure reliable evaluation of gene expression. These results indicate that gene expression profiling with microarrays provides a new tool for exploring the response of a tissue to systemic blood loss.

Lipoprotein-associated phospholipase A2: a potential therapeutic target for atherosclerosis.

Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) is an enzyme that is produced by inflammatory cells, is bound to circulating LDL, and is involved in hydrolyzing polar phospholipids, including those found in oxidized low-density lipoproteins. To date, the biological role of Lp-PLA(2) in atherogenesis has been controversial, with initial reports purporting an atheroprotective effect attributable to the degradation of platelet activating factor and similar molecules. However, more recent studies suggest a proatherogenic role for this enzyme, which is attributed to Lp-PLA(2)-mediated hydrolysis of oxidatively modified low-density lipoproteins that results in the accumulation of proinflammatory products. The liberation of lysophosphatidylcholine and oxidized nonesterified fatty acids from oxidized phospholipids by the action of Lp-PLA(2) results in diverse inflammatory effects on various cell types involved in atherogenesis. This concept is further supported by a number of recently published epidemiology studies suggesting that plasma levels of the enzyme predict future cardiovascular events independent of conventional risk factors. The development of selective inhibitors of Lp-PLA(2) that inhibit enzyme activity in the circulation as well as within human atherosclerotic lesions opens the possibility of therapeutic manipulation of vascular inflammatory processes to reduce residual cardiovascular events in high risk individuals who continue to suffer fatal and nonfatal events despite the current standard of care.

Medical follow-up of Persian Gulf War Veterans with severe medically unexplained fatigue: a preliminary study.

An important question for researchers interested in long-term consequences of military service is the health outcome of symptomatic Persian Gulf War Veterans. From an original group of 76 Gulf War Veterans who received the diagnosis of severe fatiguing illness, we attempted to get 58 veterans to return to our center for a second evaluation. Thirteen returned. Two had recovered by the time of revisit, but the rest remained ill; however, only one was so ill as to be unable to work. The data suggest that the medical consequences of serving in the Persian Gulf are not transient. The difficulty in getting veterans to return to our center suggests potential problems in the proposed nation-wide longitudinal health outcome study of Persian Gulf War Veterans.

Rationale, design, and methods for a Coreg (carvedilol) Heart Failure Registry (COHERE). COHERE Participant Physicians.

BACKGROUND: The success of beta-blocking agents in clinical trials of heart failure (HF) has led to a widespread call for their increased use, which assumes these agents will perform as well in the usual care setting. Given the traditional contraindication of the use of beta-blocking agents in HF, and their perception as difficult to use in HF, observing how they perform in the usual care setting could be critical in accelerating their widespread application. Carvedilol is the only beta-blocking agent currently approved in the United States for use in HF. METHODS: The Coreg (brand of carvedilol; SmithKline Beecham Pharmaceuticals, Philadelphia, PA) Heart Failure Registry (COHERE) is intended to collect data on outcomes and other clinical variables in a typical HF population and to observe experience with carvedilol in the hands of community practitioners. COHERE does not include any specific patient selection or exclusion criteria. The decision to use carvedilol is entirely at the discretion of the participant physician, based on evidence of HF as judged by assessments the practitioner usually uses. All patients will be followed for 1 year, with information on outcomes and other clinical variables collected and analyzed at baseline, the end of titration, and at 6 and 12 months after reaching the maximum tolerated dose. About 600 participant physicians selected to be as representative as possible of the community practice setting will enroll approximately 6,000 patients. CONCLUSIONS: COHERE will be the first and largest prospective observational experience with a new treatment, ie, carvedilol, in patients with HF managed in the usual care setting and should provide valuable information about this new treatment in this environment compared with the more rigid clinical trials setting.

Serum albumin level as a predictor of incident coronary heart disease: the Atherosclerosis Risk in Communities (ARIC) study.

Various studies have reported an inverse association between serum albumin level and incident coronary heart disease (CHD), though biologic mechanisms have not been established. The authors examined the association between serum albumin level and CHD in the Atherosclerosis Risk in Communities cohort, comprising 14,506 White and African-American middle-aged men and women. The mean albumin level in this population was 3.9 g/dl (standard deviation 0.3). During 5.2 years of follow-up, 470 incident CHD events occurred. The hazard ratio for incident CHD associated with a 1-standard deviation decrease in serum albumin level was 1.26 (95% confidence interval (CI): 1.15, 1.38) after adjustment for age, gender, and ethnicity and 1.18 (95% CI: 1.07, 1.30) after additional adjustment for covariates related to CHD. Hazard ratios were similar across gender and ethnic groups. However, there was statistically significant effect modification by smoking status, with hazard ratios of 1.01 (95% CI: 0.84, 1.22) among never smokers, 1.09 (95% CI: 0.92, 1.30) among former smokers, and 1.35 (95% CI: 1.17, 1.54) among current smokers. Further adjustment for factors related to renal disease, nutrition, platelet aggregation, inflammation, use of angiotensin-converting enzyme inhibitors, and hemostasis factors attenuated the albumin-CHD relation only slightly. In this study, serum albumin was inversely associated with incident CHD at the baseline examination in current smokers but not in never or former smokers. Albumin level may be a marker of susceptibility to the inflammatory response that results from smoking.

Chronic fatigue syndrome beginning suddenly occurs seasonally over the year.

The fact that many patients with chronic fatigue syndrome (CFS) have an infectious like sudden onset to their illness has led to the hypothesis that CFS is a medical illness. If CFS were, on the other hand, a psychiatric disorder related to symptom amplification, one would expect illness onset to occur randomly over the calendar year. This study tested that hypothesis with 69 CFS patients whose illness was on the more severe side of the illness spectrum; all patients reported sudden illness onset with the full syndrome of sore throat, fatigue/malaise, and diffuse achiness developing over no longer than a 2-day period. Date of illness onset was distinctly nonrandom. It peaked from November through January and was at its lowest from April through May. These data support the hypothesis that an infectious illness can trigger the onset of CFS.

Heritability of BDNF alleles and their effect on brain morphology in schizophrenia.

Accumulating evidence suggests that disturbed brain development may play a role in the etiology of schizophrenia, and that the illness is, to a significant degree, heritable. We therefore investigated brain derived neurotrophic factor (BDNF), a neurotrophin expressed in fetal brain, as a candidate disease gene for schizophrenia. We also investigated the effect of BDNF on adult brain morphology. All subjects were diagnosed by DSM-IIIR or DSM-IV criteria with schizophrenia spectrum disorders. Association of a BDNF polymorphism was examined in 48 proband-parent trios using the haplotype based haplotype relative risk method of case control. In a related group of 63 subjects, relationships between the presence or absence of allele 1 and the volumes of the major cerebral lobes, the ventricles, and the cerebellum were assessed using logistic regression. No association was found between this polymorphism and schizophrenia. Subjects who had at least one copy of allele 1, however, had larger parietal lobes than those who did not when controlling for overall cortical volume and age at the time of magnetic resonance. We did not find support for BDNF as a disease gene for schizophrenia. Allelic variability of the gene may, however, influence brain morphology in these same subjects. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 88:724-728, 1999.

Recurrent carotid stenosis : results of the asymptomatic carotid atherosclerosis study.

BACKGROUND AND PURPOSE: We sought to determine the incidence of recurrent carotid stenosis in patients in the Asymptomatic Carotid Atherosclerosis Study (ACAS) who had undergone carotid endarterectomy and were prospectively followed with Doppler ultrasound for up to 5 years. METHODS: The ACAS database was interrogated to determine the rate of recurrent carotid stenosis (>/=60%) based up angiogram-validated Doppler data, with a 90% and a 95% positive predictive value, as well as information concerning the technologists' interpretation of percent stenosis. These 3 parameters are reported for each of 3 time intervals: within 3 months of operation (residual disease), between 3 and 18 months (early restenoses), and between 18 and 60 months (late restenosis). RESULTS: Of the 825 patients randomized to the surgical arm of the study, 720 actually underwent carotid endarterectomy, and 645 had complete ultrasound data. The aggregate incidence of residual and recurrent carotid stenosis for all time intervals ranged from 12.7% to 20.4%, depending on the positive predictive value confidence level desired. Residual disease occurred in 4.1% to 6.5%; true, early restenosis was found in 7.6% to 11.4%; and late restenosis occurred in 1.9% to 4.9%. None of the traditional risk factors showed a statistically significant effect on recurrent stenosis. The use of patch angioplasty closure reduced overall risk of restenosis from 21.2% to 7.1%, from 16.7% to 4.6%, and from 27.4% to 8.2%, depending on the PPV confidence level desired (P<0.001). Of the 136 patients judged to have recurrent stenosis, only 8 (5.9%) underwent reoperation (only 1 for symptoms). There was no correlation between late stroke and recurrent stenosis. CONCLUSIONS: Carotid endarterectomy is a durable procedure with a low rate of true restenosis, particularly when patch angioplasty is used to close the arteriotomy.

The delay in reporting symptoms of carotid artery stenosis in an at-risk population. The Asymptomatic Carotid Atherosclerosis Study experience: a statement of concern regarding watchful waiting.

OBJECTIVE: To examine whether patients in the Asymptomatic Carotid Atherosclerosis Study reported symptoms of cerebral and retinal ischemia promptly to the investigating team. DESIGN: Cohort study within the Asymptomatic Carotid Atherosclerosis Study, a prospective, randomized, multicenter clinical trial, with a median follow-up time of 2.7 years. SETTING: Thirty-nine clinical sites across the United States and Canada. PATIENTS: Patients with asymptomatic carotid artery stenosis (> or = 60% reduction in diameter) who experienced either a transient ischemic attack (TIA) (n = 115) or stroke (n = 127) during the follow-up period, as verified by an external committee. MAIN OUTCOME MEASURE: Proportion of patients who reported cerebrovascular symptoms to a study nurse or physician within 3 days of occurrence. RESULTS: Thirty-seven patients (32.2%) experiencing TIA and 57 (44.9%) experiencing stroke reported symptoms to the study staff within 3 days of onset. For TIA, there was a statistically significant inverse association between prompt reporting and the amount of time a patient was enrolled in the study before the event occurred (48% with TIA occurring within 6 months vs 9% with TIA after year 3; P = .04). For stroke, there was a statistically significant association between prompt reporting and treatment arm (56% for the surgical vs 38% for the medical group; P = .05). For either TIA or stroke, none of the other factors examined were significantly associated with prompt reporting. CONCLUSIONS: Despite extensive education and reinforcement, fewer than 40% of all first events were reported within 3 days and fewer than 25% were reported in less than 24 hours. Frequent outpatient evaluation of high-risk patients and careful review of symptoms is necessary to determine when asymptomatic carotid artery stenosis has become symptomatic to offer appropriate forms of therapy.

Fluoride release of restorative materials exposed to a fluoridated dentifrice.

The purpose of this study was to examine the effect that brushing with a fluoridated dentifrice (Crest--Procter and Gamble) has on the fluoride release of restorative materials. Thirty standardized discs were fabricated; 10 were P-50 (3M) nonfluoridated composite resin (control), ten were Heliomolar Radiopaque (Ivoclar/Vivadent) fluoride releasing composite resin, and ten were Ketac Fil (ESPE) glass ionomer cement. Specimens were placed into separate containers of 10 mL deionized water. Half the specimens from each group were brushed with fluoridated dentifrice for two minutes twice per day and rinsed. The fluoride level of each specimen was evaluated for thirty days, using a fluoride specific ion analyzer. An analysis of variance (ANOVA) and Duncan's test (p < 0.05) indicated significant differences in fluoride release. The brushed glass ionomer was significantly higher than all other groups and the glass ionomer not brushed was significantly higher than all composite groups. Glass Ionomer Cement-brushed > Glass Ionomer Cement > Fluoridated Composite Resin-brushed = Fluoridated Composite Resin = Composite Resin-brushed = Composite Resin. Brushed glass ionomer appears to release the highest fluoride level, acting as a fluoride reservoir from the dentifrice for subsequent fluoride release.

Validation of the ACAS TIA/stroke algorithm.

BACKGROUND AND PURPOSE: An easily administered questionnaire and algorithm classifying transient ischemic attacks (TIAs) or strokes, and also their distribution, could be invaluable for identifying endpoints in epidemiologic studies or clinical trials of prevention and therapy of cerebral ischemia. The Asymptomatic Carotid Atherosclerosis Study (ACAS) devised a symptom-based questionnaire and algorithm for detecting events in the trial. The purpose of this study was to determine sensitivity, specificity, and agreement rates of the questionnaire and algorithm against diagnoses of a panel of cerebrovascular disease authorities. METHODS: Three hundred eighty-one men and women at eight medical centers reported symptoms of stroke, TIA, or other neurologic illness. The questionnaire was administered by trained interviewers and the responses were analyzed using the algorithm. A standardized neurologic examination was performed by a neurologist. Data were submitted to two or more external reviewers. Sensitivity, specificity, and the kappa statistic (kappa) were used to evaluate the relationship between the algorithm and the external reviewers' diagnosis. RESULTS: Of the 381 reviews, 196 were diagnosed as TIA or stroke by the external panel. The algorithm's agreement with the diagnosis of TIA or stroke was 80.1%, and kappa was 0.60. Sensitivity was 87.8%, and specificity was 71.9%. CONCLUSION: While statistical agreement rates depend on the method of sample selection, the algorithm has a high agreement with an external panel of experts and is a sensitive tool for event detection. The lower specificity indicates that careful neurologic evaluation may be required to confirm or refute events identified by the screening algorithm.

Complex, humanitarian emergencies: III. Measures of effectiveness.

Complex humanitarian emergencies lack a mechanism to coordinate, communicate, assess, and evaluate response and outcome for the major participants (United Nations, International Committee of the Red Cross, non-governmental organizations and military forces). Success in these emergencies will depend on the ability to accomplish agreed upon measures of effectiveness (MOEs). A recent civil-military humanitarian exercise demonstrated the ability of participants to develop consensus-driven MOEs. These MOEs combined security measures utilized by the military with humanitarian indicators recognized by relief organizations. Measures of effectiveness have the potential to be a unifying disaster management tool and a partial solution to the communication and coordination problems inherent in these complex emergencies.

Dietary and other correlates of changes in total and low density lipoprotein cholesterol in hypercholesterolemic men: the lipid research clinics coronary primary prevention trial.

Correlates of changes in total (TOTAL-C) and low density lipoprotein cholesterol (LDL-C) were examined in the 3806 hypercholesterolemic men of the Lipid Research Clinics Coronary Primary Prevention Trial. These correlates included changes in weight, dietary and alcohol intake, plasma glucose and thyroxine, cigarette smoking, packet count, lipid-lowering drugs other than cholestyramine, and antihypertensive drugs. In both placebo plus diet and cholestyramine plus diet treatment groups, decreases in Quetelet index and in saturated fat and cholesterol intake and increases in polyunsaturated fat intake were consistently associated with reductions in TOTAL-C and in LDL-C. In the cholestyramine group, plasma glucose and smoking were predictors of increased TOTAL-C and LDL-C; age and packet count were predictors of decreased TOTAL-C and LDL-C. Diuretic use was associated with increases in TOTAL-C in both groups and with increases in LDL-C in the cholestyramine group.

Quantitation of o- and p-sulfamoylbenzoic acids in commerical saccharin by high-performance liquid chromatography.

Quantitation of o- and p-sulfamoylbenzoic acid residues in saccharin and its sodium salt is achieved by a method comprising methanolic extraction and high-performance ion exchange chromatography. A commercially available anion exchange column was employed with an aqueous buffered (pH 9.2) mobile phase. As little as 80 ppm of the ortho-isomer and 25 ppm of the para-isomer can be accurately determined. The levels of detectability (2 times noise) are estimated as 8 ppm (0.16 mug on column) and 2.5 ppm (0.05 mug on column), respectively. Recoveries from saccharin ranged from 92.7 to 96.5% (ortho) and from 92.2 to 103.3% (para). Recoveries from the sodium salt ranged from 93.1 to 104.4% (ortho) and from 93.5 to 97.8% (para). Of 9 other potential saccharin impurities tested separately, only one was found to interfere slightly in the chromatographic part of the procedure.

Nuclear magnetic resonance analysis of pharmaceuticals-VII Determination of aminophylline in tablets.

An NMR procedure is described by which theophylline and ethylenediamine are simultaneously determined in aminophylline tablets. t-Butyl alcohol was chosen as the internal standard and 4% ammonia-0.3% potassium cyanide in deuterium oxide was the solvent. The solvent system was selected to deal with the problems of solubility of the theophylline, overlapping of the components' resonance signals, and potential interference from metal impurities. Known standard and commercial preparations were determined and the results compared with those obtained by alternative procedures. The technique, when applied to the determination of aminophylline in tablets, is rapid, simple and specific and has an error of 1-2%.