High-sensitivity electronic Stark spectrometer featuring a laser-driven light source.

We report developmental details of a high-sensitivity Stark absorption spectrometer featuring a laser-driven light source. The light source exhibits intensity fluctuations of ∼0.3% over timescales ranging from 1 min to 12 h, minimal drift (≤0.1%/h), and very little 1/f noise at frequencies greater than 200 Hz, which are comparable to or better than an arc-driven light source. Additional features of the spectrometer include balanced detection with multiplex sampling, which yielded lower noise in A, and constant wavelength or wavenumber (energy) spectral bandpass modes. We achieve noise amplitudes of ∼7 × 10-4 and ∼6 × 10-6 in measurements of single A and ΔA spectra (with 92 data points) taking ∼7 and ∼19 min, respectively.

Derivatives of a benzoquinone acyl hydrazone with activity against Toxoplasma gondii.

Toxoplasma gondii is an obligate intracellular parasite with global incidence. The acute infection, toxoplasmosis, is treatable but current regimens have poor host tolerance and no cure has been found for latent infections. This work builds upon a previous high throughput screen which identified benzoquinone acyl hydrazone (KG8) as the most promising compound; KG8 displayed potent in vitro activity against T. gondii but only marginal in vivo efficacy in a T. gondii animal model. To define the potential of this new lead compound, we now describe a baseline structure-activity relationship for this chemotype. Several derivatives displayed IC50's comparable to that of the control treatment pyrimethamine with little to no cytotoxicity. The best of these, KGW44 and KGW59, had higher metabolic stability than KG8. In an in vivo T. gondii murine model, KGW59 significantly increased survivorship. This work provides new insights for optimization of this novel chemotype.

Novel Toxoplasma gondii inhibitor chemotypes.

We profiled three novel T. gondii inhibitors identified from an antimalarial phenotypic high throughput screen (HTS) campaign: styryl 4-oxo-1,3-benzoxazin-4-one KG3, tetrahydrobenzo[b]pyran KG7, and benzoquinone hydrazone KG8. These compounds inhibit T. gondii in vitro with IC50 values ranging from 0.3 to 2µM, comparable to that of 0.25 to 1.5µM for the control drug pyrimethamine. KG3 had no measurable cytotoxicity against five mammalian cell lines, whereas KG7 and KG8 inhibited the growth of 2 of 5 cell lines with KG8 being the least selective for T. gondii. None of the compounds were mutagenic in an Ames assay. Experimental gLogD7.4 and calculated PSA values for the three compounds were well within the ranges predicted to be favorable for good ADME, even though each compound had relatively low aqueous solubility. All three compounds were metabolically unstable, especially KG3 and KG7. Multiple IP doses of 5mg/kg KG7 and KG8 increased survival in a T. gondii mouse model. Despite their liabilities, we suggest that these compounds are useful starting points for chemical prospecting, scaffold-hopping, and optimization.

Estimating gene signals from noisy microarray images.

In oligonucleotide microarray experiments, noise is a challenging problem, as biologists now are studying their organisms not in isolation but in the context of a natural environment. In low photomultiplier tube (PMT) voltage images, weak gene signals and their interactions with the background fluorescence noise are most problematic. In addition, nonspecific sequences bind to array spots intermittently causing inaccurate measurements. Conventional techniques cannot precisely separate the foreground and the background signals. In this paper, we propose analytically based estimation technique. We assume a priori spot-shape information using a circular outer periphery with an elliptical center hole. We assume Gaussian statistics for modeling both the foreground and background signals. The mean of the foreground signal quantifies the weak gene signal corresponding to the spot, and the variance gives the measure of the undesired binding that causes fluctuation in the measurement. We propose a foreground-signal and shape-estimation algorithm using the Gibbs sampling method. We compare our developed algorithm with the existing Mann-Whitney (MW)- and expectation maximization (EM)/iterated conditional modes (ICM)-based methods. Our method outperforms the existing methods with considerably smaller mean-square error (MSE) for all signal-to-noise ratios (SNRs) in computer-generated images and gives better qualitative results in low-SNR real-data images. Our method is computationally relatively slow because of its inherent sampling operation and hence only applicable to very noisy-spot images. In a realistic example using our method, we show that the gene-signal fluctuations on the estimated foreground are better observed for the input noisy images with relatively higher undesired bindings.

Carotid intimal-medial thickness is related to cardiovascular risk factors measured from childhood through middle age: The Muscatine Study.

BACKGROUND: Higher carotid intimal-medial thickness (IMT) is associated with cardiovascular risk factors and is predictive of coronary artery disease and stroke in older adults. Carotid IMT was measured in young and middle-aged adults to determine its relationship with risk factors measured (1) in childhood, (2) currently, and (3) as a "load" from childhood to adulthood. METHODS AND RESULTS: Carotid ultrasound studies were performed in 346 men and 379 women aged 33 to 42 years who were representative of a cohort followed since childhood and who live in Muscatine, Iowa. The mean of the measurements of maximal carotid IMT at 12 locations was determined for each subject. A medical questionnaire was completed, and measurements of anthropometric characteristics and risk factors were obtained. The mean maximum carotid IMT was 0.79+/-0.12 mm for men and 0.72+/-0.10 mm for women. On the basis of multivariable analysis, the significant current predictors of IMT were age and LDL cholesterol in both sexes and diastolic blood pressure in women. Total cholesterol was a significant childhood predictor in both sexes, while childhood body mass index was significant only in women. For men, LDL cholesterol, HDL cholesterol, and diastolic blood pressure were predictive of carotid IMT in a risk factor load model, whereas in women, LDL cholesterol, body mass index, and triglycerides were predictive. CONCLUSIONS: Higher carotid IMT in young and middle-aged adults is associated with childhood and current cardiovascular risk factors, as well as risk factor load.

Predictors of bacteremia in febrile children 3 to 36 months of age.

PURPOSE: To develop an improved model for the prediction of bacteremia in young febrile children. METHODS: A retrospective review was performed on patients 3 to 36 months of age seen in a children's hospital emergency department between December 1995 and September 1997 who had a complete blood count and blood culture ordered as part of their regular care. Exclusion criteria included current use of antibiotics or any immunodeficient state. Clinical and laboratory parameters reviewed included age, gender, race, weight, temperature, presence of focal bacterial infection, white blood cell count (WBC), polymorphonuclear cell count (PMN), band count, and absolute neutrophil count (ANC). Logistic regression analyses were used to identify factors associated with bacteremia, defined as growth of a pathogen in a blood culture. The model that was developed was then validated on a second dataset consisting of febrile patients 3 to 36 months of age collected from a second children's hospital (validation set). RESULTS: There were 633 patients in the derivation set (46 bacteremic) and 9465 patients in the validation set (149 bacteremic). The mean age of patients in the derivation and validation sets were 15.8 months (95% confidence interval [CI]: 15.2-16.5) and 16.6 months (95% CI: 16.5-16.8), respectively; the mean temperatures were 39.1 degrees C (95% CI: 39. 0-39.2) and 39.8 degrees C (95% CI: 39.7-39.8); 56% were male in the derivation set and 55% male in the validation set. Predictors of bacteremia identified by logistic regression included ANC, WBC, PMN, temperature, and gender. Receiver operator characteristic (ROC) analysis showed similar performance of ANC and WBC as predictors of bacteremia. When placed into a multivariate logistic regression model, band count was not significantly associated with bacteremia. Information regarding focal infection was available for 572 patients in the derivation set. The percentage of patients diagnosed with bacteremia with a focal bacterial infection was not significantly different from the percentage who had bacteremia without a focal bacterial infection (16/200 vs 30/372). Based on this dataset, a logistic regression formula was developed that could be used to develop a unique risk value for each patient based on temperature, gender, and ANC. When the final model was applied to the validation set, the area under the ROC curve (AUC) constructed from these data indicated that the model retained good predictive value (AUC for the derivation vs validation data =.8348 vs 0.8221, respectively). CONCLUSIONS: Use of the formulas derived here allows the clinician to estimate a child's risk for bacteremia based on temperature, ANC, and gender. This approach offers a useful alternative to predictions based on fever and WBC alone.bacteremia, detection, white blood cell.

Pediatric emergency department nurses' perspectives on fever in children.

BACKGROUND: Fever is the most common complaint of children seen in a Pediatric Emergency Department (PED). Since pediatric emergency nurses commonly educate parents on fever management, this study sought to examine their knowledge base regarding fever in children. METHODS: Through convenience sampling, pediatric emergency registered nurses working at one of four PEDs were surveyed using a self-administered questionnaire containing 10 open-ended questions pertaining to fever in children. RESULTS: Eighty-eight pediatric emergency registered nurses (median experience 8.0 years, range 3 months to 28 years) were surveyed. The median temperature considered by pediatric emergency nurses to be a fever was 38.0 degrees C (100.4 degrees F) with a range of 37.2 degrees C (99.0 degrees F) to 38.9 degrees C (102.0 degrees F), while the median temperature considered to be dangerous to a child was 40.6 degrees C (105.0 degrees F) with a range of 38.0 degrees C (100.4 degrees F) to 41.8 degrees C (107.0 degrees F). Eleven percent was not sure what temperature constituted a fever while 31% was not sure what temperature would be dangerous to a child. Fifty-seven percent considered seizures the primary danger to a febrile child while 29% stated permanent brain injury or death could occur from a high fever. Sixty percent chose acetaminophen as first line treatment while 7% stated alcohol or tepid water baths were also acceptable treatment options. Thirty-eight percent stated that a different medication should be added if a child was still febrile 1 hour after initial treatment while 31% would not use additional medication. Eighteen percent stated it was dangerous for a child to leave the PED if still febrile. CONCLUSION: Fever phobia and inconsistent treatment approaches occur among experienced pediatric emergency registered nurses. These phobias and inconsistencies subsequently could be conveyed to parents. In order to assure accurate parental education, PEDs should educate their medical team regarding the management of fever in children.

Increased carotid intimal-medial thickness and coronary calcification are related in young and middle-aged adults. The Muscatine study.

BACKGROUND: Increased carotid intimal-medial thickness (IMT) and coronary artery calcification (CAC) are used as 2 markers of early atherosclerosis. Our objectives were to assess whether increased IMT and CAC are related and to determine the relationship between cardiovascular risk factors and carotid IMT in young adults. METHODS AND RESULTS: A sample of 182 men and 136 women aged 33 to 42 years living in Muscatine, Iowa, underwent B-mode carotid ultrasound to determine the mean of 12 measurements of maximal carotid IMT. CAC was defined as calcification in the proximal coronary arteries in >/=3 contiguous pixels with a density of >/=130 HU. The mean IMT was 0.788 mm (SD 0.127) for men and 0.720 mm (SD 0.105) for women. CAC was present in 27% of men and 14% of women and was significantly associated with IMT in men (P<0.025) and women (P<0.005). With multivariate analysis, after adjustment for age, significant risk factors for carotid IMT were LDL cholesterol (P<0.001) and pack-years of smoking (P<0.05) in men and LDL cholesterol (P<0.001) and systolic blood pressure (P<0.01) in women. These risk factors remained significant after CAC was included in the multivariate model. CONCLUSIONS: There is an association between increased carotid IMT and CAC and between cardiovascular risk factors and increased IMT in young adults. Carotid IMT may provide information in addition to CAC that can be used to identify young adults with premature atherosclerosis.

Antithrombotic treatment of ischemic stroke among patients with occlusion or severe stenosis of the internal carotid artery: A report of the Trial of Org 10172 in Acute Stroke Treatment (TOAST).

OBJECTIVE: To examine the responses to early IV administration of an anticoagulant or placebo started within 24 hours of stroke among persons with an ipsilateral occlusion or severe stenosis of the internal carotid artery (ICA) identified by carotid duplex imaging. BACKGROUND: Patients with ischemic stroke of the cerebral hemisphere secondary to an ipsilateral occlusion or severe stenosis of the ICA generally have a poor prognosis. Early, accurate identification of these patients might permit improved treatment. METHODS: Exploratory analysis of outcomes at 7 days and 3 months was performed among patients enrolled in the Trial of Org 10172 in Acute Stroke Treatment (TOAST) who had an ischemic stroke in the cerebral hemisphere ipsilateral to an occlusion or a stenosis >50% of the ICA identified by carotid duplex imaging. RESULTS: Regardless of treatment, patients with duplex evidence of an occlusion of the ICA had more severe strokes and poorer outcomes at 7 days and 3 months than patients who had a stenosis. Favorable outcomes at 7 days were noted in 64 of 119 patients given danaparoid (53.8%) and 41 of 108 patients treated with placebo (38.0%; p = 0.023). By 3 months, favorable outcomes were noted in 82 patients given danaparoid (68.3%) and 58 patients administered placebo (53.2%; p = 0.021). CONCLUSIONS: Early identification by duplex imaging of an occlusion or severe stenosis of the ICA ipsilateral to a hemispheric ischemic stroke might improve selection of patients who could be treated with emergent anticoagulation. Further testing of this approach is needed.

Baseline NIH Stroke Scale score strongly predicts outcome after stroke: A report of the Trial of Org 10172 in Acute Stroke Treatment (TOAST).

OBJECTIVE: To compare the baseline National Institutes of Health Stroke Scale (NIHSS) score and the Trial of Org 10172 in Acute Stroke Treatment (TOAST) stroke subtype as predictors of outcomes at 7 days and 3 months after ischemic stroke. METHODS: Using data collected from 1,281 patients enrolled in a clinical trial, subtype of stroke was categorized using the TOAST classification, and neurologic impairment at baseline was quantified using the NIHSS. Outcomes were assessed at 7 days and 3 months using the Barthel Index (BI) and the Glasgow Outcome Scale (GOS). An outcome was rated as excellent if the GOS score was 1 and the BI was 19 or 20 (scale of 0 to 20). Analyses were adjusted for age, sex, race, and history of previous stroke. RESULTS: The baseline NIHSS score strongly predicted outcome, with one additional point on the NIHSS decreasing the likelihood of excellent outcomes at 7 days by 24% and at 3 months by 17%. At 3 months, excellent outcomes were noted in 46% of patients with NIHSS scores of 7 to 10 and in 23% of patients with scores of 11 to 15. After multivariate adjustment, lacunar stroke had an odds ratio of 3.1 (95% CI, 1.5 to 6.4) for an excellent outcome at 3 months. CONCLUSIONS: The NIHSS score strongly predicts the likelihood of a patient's recovery after stroke. A score of > or =16 forecasts a high probability of death or severe disability whereas a score of < or =6 forecasts a good recovery. Only the TOAST subtype of lacunar stroke predicts outcomes independent of the NIHSS score.

A case of late-onset MELAS.

We describe a 60-year-old man with MELAS syndrome (mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes) and discuss the mitochondrial DNA point mutation 3243. A diagnosis of MELAS should be considered in the appropriate clinical setting at any age.

Design of the Trial of Org 10172 in Acute Stroke Treatment (TOAST).

TOAST is a multicenter, randomized, placebo-controlled clinical trial testing the usefulness of a new antithrombotic drug in improving the outcome of persons with acute ischemic stroke. Until recently, no clinical trial testing a treatment for ischemic stroke had demonstrated efficacy in outcome. Design problems of previously conducted trials with inconclusive results may partly explain their failures. During the design of TOAST, the investigators addressed several issues so the trial could test the treatment accurately. We report the strategies used in designing, implementing, and coordinating the trial.

Characteristics of medical students by level of interest in family practice.

BACKGROUND AND OBJECTIVES: This study provides information on student factors associated with a career choice in family practice. METHODS: Information was used from multiple surveys completed by medical students, including the Premedical Questionnaire, the Matriculating Student Questionnaire, and the Graduation Questionnaire, as well as information from residency directors about residents in the Graduate Medical Education Tracking Census. These questionnaires are all a part of the Student and Applicant Information Management System of the Association of American Medical Colleges. Participants were 30,789 students graduating from US medical schools in 1991 and 1992. Comparisons were made between longitudinal student responses on the surveys to four types of outcomes. RESULTS: A total of 1,029 (3.3%) students were in the "Maintained" group (students who originally planned to enter family practice and were in a family practice residency at postgraduate year 1; 1,958 (6.4%) were "Gained" (originally chose a specialty other than family practice but entered a family practice residency); 1,950 (6.3%) were "Lost Interest" (originally identified family practice but entered another residency-two thirds of whom selected non-primary care specialties); 21,573 (70.1%) were "Never Interested" (did not express an early interest nor select a family practice residency); and the remainder (13.9%) had incomplete specialty data. Of those originally interested in family practice, 34.5% entered family practice residencies. Only 8.3% of those not originally interested entered family practice residencies. The four groups of students differed on many demographic, attitudinal, and experiential characteristics. Prestige, income, opportunities for research, and faculty status were more important to future specialists, while emphasis on primary care and prevention and practice in smaller communities were more important to the future family physicians. CONCLUSIONS: Medical schools could potentially increase the number of students selecting family practice residencies through both admissions policies and medical school experiences. These data provide some specifics on how to recruit students and prevent loss of those originally interested in family practice.

Filariae of raccoons from southeast Georgia.

The prevalence of filariae in wild raccoons trapped in southeast Georgia was determined. Examination of blood samples revealed that 74 of 113 raccoons (66%) trapped in 6 southeastern Georgia counties were infected. Seventy-three of these raccoons (65%) were infected with Mansonella llewellyni and this parasite was observed in raccoons from every location examined. Dirofilaria tenuis was found in 22 raccoons (20%) and was observed in only 3 of the 6 counties surveyed. An adult specimen of Acanthocheilonema procyonis was found in the subcutaneous tissues of 1 of 5 necropsied raccoons. This is the first record of filariae in raccoons from Georgia. In addition, Dirofilaria-like larvae were found in Aedes taeniorhyncus mosquitoes collected in Liberty County.

Lifetime cost of stroke in the United States.

BACKGROUND AND PURPOSE: Stroke imposes a substantial economic burden on individuals and society. This study estimates the lifetime direct and indirect costs associated with the three major types of stroke: subarachnoid hemorrhage (SAH), intracerebral hemorrhage (ICH), and ischemic stroke (ISC). METHODS: We developed a model of the lifetime cost of incident strokes occurring in 1990. An epidemiological model of stroke incidence, survival, and recurrence was developed based on a review of the literature. Data on direct cost of treating stroke were obtained from Medicare claims data, the 1987 National Medical Expenditure Survey (NMES), and insurance claims data representing a group of large, self-insured employers. Indirect costs (the value of foregone market and nonmarket production) associated with premature morbidity and mortality were estimated based on data from the US Bureau of Economic Analysis and the 1987 NMES. RESULTS: The lifetime cost per person of first strokes occurring in 1990 is estimated to be $228,030 for SAH, $123,565 for ICH, $90,981 for ISC, and $103,576 averaged across all stroke sub-types. Indirect costs accounted for 58.0% of lifetime costs. Aggregate lifetime cost associated with an estimated 392,344 first strokes in 1990 was $40.6 billion: $5.6 billion for SAH, $6.0 billion for ICH, and $29.0 billion for ISC. Acute-care costs incurred in the 2 years following a first stroke accounted for 45.0%, long-term ambulatory care accounted for 35.0%, and nursing home costs accounted for 17.5% of aggregate lifetime costs of stroke. CONCLUSIONS: The lifetime cost of stroke varies considerably by type of stroke and entails considerable costs beyond the first 2 years after a stroke.

Silent cerebral infarction in patients enrolled in the TOAST Study.

To determine the frequency, location, size, and risk factors for silent cerebral infarctions (SCIs) on brain CT, we identified 629 patients without a history of previous stroke who were enrolled in a multicenter clinical trial of therapy for acute ischemic stroke. On the baseline CT, 143 patients (22.7%) had SCIs; 34.3% of the lesions were in the right hemisphere, 38.5% in the left hemisphere, and 27.3% were bilateral. The lesion size was < 1 cm in 65.7%, and the most common site was the basal ganglia (48.3%). Patients with SCI were compared with controls without SCI to determine the odds ratios (ORs) for each risk factor. On univariate analysis, race (black versus white) had an OR of 1.80 (95% confidence interval [CI], 1.14 to 2.85), male sex an OR of 1.68 (95% CI, 1.12 to 2.51), and congestive heart failure an OR of 1.88 (95% CI, 1.07 to 3.31). Significant risk factors on multivariate analysis include age (OR 1.03 per year, p = 0.0070), male sex (OR 1.78, p = 0.0094), and race (OR 2.43, p = 0.0004). After including interaction terms with age and hypertension and age, sex, and race, hypertension was also a significant risk factor.