Relationship between enteric pathogens and acute gastroenteritis disease severity: a prospective cohort study.

OBJECTIVES: To evaluate the relationship between individual bacterial and viral pathogens and disease severity. METHODS: Children <18 years with three or more episodes of vomiting and/or diarrhoea were enrolled in two Canadian paediatric emergency departments between December 2014 and August 2016. Specimens were analysed employing molecular panels, and outcome data were collected 14 days after enrolment. The primary outcome was severe disease over the entire illness (symptom onset until 14-day follow-up), quantified employing the Modified Vesikari Scale (MVS) score. The score was additionally analysed in two other time periods: index (symptom onset until enrolment) and follow-up (enrolment until 14-day follow-up). RESULTS: Median participant age was 20.7 (IQR: 11.3, 44.2) months; 47.4% (518/1093) and 73.4% (802/1093) of participants had index and total MVS scores ≥11, respectively. The most commonly identified pathogens were rotavirus (289/1093; 26.4%) and norovirus (258/1093; 23.6%). In multivariable analysis, severe disease over the entire illness was associated with rotavirus (OR = 9.60; 95%CI: 5.69, 16.19), Salmonella (OR = 6.61; 95%CI: 1.50, 29.17), adenovirus (OR = 2.53; 95%CI: 1.62, 3.97), and norovirus (OR = 1.43; 95%CI: 1.01, 2.01). Pathogens associated with severe disease at the index visit were: rotavirus only (OR = 6.13; 95%CI: 4.29, 8.75), Salmonella (OR = 4.59; 95%CI: 1.71, 12.29), adenovirus only (OR = 2.06; 95%CI: 1.41, 3.00), rotavirus plus adenovirus (OR = 3.15; 95%CI: 1.35, 7.37), and norovirus (OR = 0.68; 95%CI: 0.49, 0.94). During the follow-up period, rotavirus (OR = 2.21; 95%CI: 1.50, 3.25) and adenovirus (OR = 2.10; 95%CI: 1.39, 3.18) were associated with severe disease. CONCLUSIONS: In children presenting for emergency department care with acute gastroenteritis, pathogens identified were predominantly viruses, and several of which were associated with severe disease. Salmonella was the sole bacterium independently associated with severe disease.

Adverse prognosis of incidentally detected ambulatory atrial fibrillation. A cohort study.

It was the aim of this study to determine prognosis of incidentally detected ambulatory atrial fibrillation (IA-AF) and its response to antithrombotic therapy. We performed a cohort study of 5,555 patients with IA-AF (mean age 70.9 ± 10.1, 38.4% female) and 24,705 age- and gender-matched controls without AF followed three years using UK Clinical Practice Research Datalink. We measured incidence rates of stroke, all-cause mortality, myocardial infarction, major bleeding, and effect of antithrombotic therapy. Patients with IA-AF had mean CHA2DS2VASc score 2.5 ± 1.5, 73% with score ≥2. The stroke incidence rate (IR) was 19.4 (95% confidence interval 17.1 - 21.9)/1,000 person-years vs 8.4 (7.7 - 9.1) in controls (p<0.001), mortality 40.1 (36.8 - 43.6)/1,000 person-years vs 20.9 (19.8 - 22.0) in controls (p<0.001), and myocardial infarction 9.0 (7.5 - 10.8)/1,000 person-years vs 6.5 (5.9 - 7.2) in controls (p<0.001). IRs of all endpoints increased with age. Oral anticoagulant ± antiplatelet therapy received by 51.0% in year following IA-AF was associated with adjusted hazard ratio (HR) of 0.35 (0.17 - 0.71) for stroke, and 0.56 (0.36 - 0.85) for death compared to no therapy, while antiplatelet treatment was associated with a non-significant reduction of HR: 0.81 (0.51 - 1.29) for stroke, and 0.80 (0.55 - 1.15) for death, though both carried a similar small non-significant adjusted excess IR of major bleeding. In conclusion, asymptomatic AF detected incidentally is associated with a significant adverse effect on stroke and death, with reduction in both associated with oral anticoagulant but not antiplatelet treatment. This provides justification to assess cost-effectiveness of community screening to detect unknown AF.

Drug-induced seizures in children and adolescents presenting for emergency care: current and emerging trends.

CONTEXT: Seizures may be the presenting manifestation of acute poisoning in children. Knowledge of the etiologic agent, or likely drug-class exposure, is crucial to minimize morbidity and optimize care. OBJECTIVES: To describe the agents most commonly responsible for pediatric drug-induced seizures, whose evaluation included a medical toxicology consultation in the United States. METHODS: Using the 37 participating sites of the Toxicology Investigators Consortium (ToxIC) Case Registry, a cross-country surveillance tool, we conducted an observational study of a prospectively collected cohort. We identified all pediatric (younger than 18 years) reports originating from an Emergency Department (ED) which included a chemical or drug-induced seizure, and required a medical toxicology consultation between April 1, 2010 and March 31, 2012. Results. We identified 142 pediatric drug-induced seizure cases (56% male), which represent nearly 5% of pediatric cases requiring bedside consultation by medical toxicologists. One-hundred and seven cases (75%) occurred in children aged 13-18 years, and 86 (61%) resulted from intentional ingestions. Antidepressants were the most commonly identified agents ingested (n = 61; 42%), of which bupropion was the leading drug (n = 30; 50% of antidepressants), followed by anticholinergics/antihistamines (n = 31; 22%). All antidepressant-induced seizures in teenagers were intentional and represented self-harm behavior. Sympathomimetic agents, including street drugs, represent the most common agents in children younger than 2 years (n = 4/19). CONCLUSION: Antidepressants, and specifically bupropion, are presently the most common medications responsible for pediatric drug-induced seizures requiring medical toxicology consultation in the United States. In teenagers presenting with new-onset seizures of unknown etiology, the possibility of deliberate self-poisoning should be explored, since most drug-induced seizures in this age group resulted from intentional ingestion.

Effect of heart rate reduction by ivabradine on left ventricular remodeling in the echocardiographic substudy of BEAUTIFUL.

AIMS: Occlusive coronary artery disease (CAD) is associated with left ventricular (LV) remodeling, LV systolic dysfunction, and heart failure. The BEAUTIFUL Echo substudy aimed to evaluate the effects of heart rate reduction with ivabradine on LV size (primary end-point: change in LV end-systolic volume index [LVESVI]) and function and the cardiac biomarker N-terminal pro-brain natriuretic peptide (NT-proBNP). METHODS AND RESULTS: The substudy was carried out in 86 centers participating in the BEAUTIFUL study. 2D echocardiography was performed at baseline, and after 3 and 12 months in patients with stable CAD and LV systolic dysfunction receiving ivabradine or placebo at the same time-points. All data were read and analyzed centrally. Of 525 patients completing the study, 426 had adequate echocardiographic readings (n = 220 ivabradine; n = 206 placebo). Treatment with ivabradine was associated with a decrease in the primary end-point LVESVI (change from baseline to last value, -1.48 ± 13.00 mL/m(2)) versus an increase with placebo (1.85 ± 10.54 mL/m(2)) (P=0.018). There was an increase in LV ejection fraction with ivabradine (2.00 ± 7.02%) versus no change with placebo (0.01 ± 6.20%) (P=0.009). Reduction in LVESVI was related to the degree of heart rate reduction with ivabradine. There were no differences in any other echocardiographic parameters or NT-proBNP. Change in LVESVI was related to the log change in NT-proBNP in the ivabradine group only (r = 0.18, P = 0.006). CONCLUSIONS: Our observations suggest that ivabradine may reverse detrimental LV remodeling in patients with CAD and LV systolic dysfunction.

Four-year follow-up of the Choice of Health Options In prevention of Cardiovascular Events randomized controlled trial.

OBJECTIVE: To determine if the improved risk factor profile at 1 year attributed to the Choice of Health Options In prevention of Cardiovascular Events (CHOICE) program was maintained at 4 years. DESIGN: Single-blind randomized controlled trial with post-hoc 476 months follow-up (76% complete). SETTING: Australian tertiary referral hospital. PATIENTS: Two hundred and eight acute coronary syndrome survivors. INTERVENTIONS: Acute coronary syndrome survivors not accessing cardiac rehabilitation (CR) were randomized to control (n=72) or CHOICE (n=72) comprising the tailored risk factor reduction packaged as a clinic visit and 3 months phone support. A contemporary CR reference group were also recruited (n=64). Blinded risk assessment occurred at baseline, 1 and 4 years. MAIN OUTCOME MEASURES: Total cholesterol, systolic blood pressure, smoking status, physical activity. RESULTS: One year improvements in all the modifiable risk factors achieved in CHOICE were maintained at 4 years. CHOICE and control were well-matched at baseline. At 4 years, there was a trend towards lower total cholesterol in CHOICE compared with controls (mean 4.0±0.1 vs. 4.2±0.1 mmol/l, P=0.05), significantly better systolic blood pressure (mean 132.2±2.1 vs. 136.8±2.0 mmHg, P=0.01), physical activity scores (1200±209 vs. 968±196 metabolic equivalent min/week, P=0.02) and proportion with three or more risk factors above national targets (20 vs. 42%,P=0.02). Participants in CHOICE were at higher baseline risk than CR but at 4 years they had similar risk factor profiles. CONCLUSION: Participants in CHOICE maintained favorable changes in coronary risk profile at 4 years compared with control, indicating that CHOICE is an effective long-term intervention among those not accessing facility-based CR.

Impact of medical consultation frequency on modifiable risk factors and medications at 12 months after acute coronary syndrome in the CHOICE randomised controlled trial.

BACKGROUND: We aimed to determine whether the frequency of General Practitioner and Cardiologist consultations impacted on improvements in risk factors in Choice of Health Options in Reducing Cardiovascular Events (CHOICE) randomised controlled trial. METHODS: Retrospective subgroup analysis of single-blind randomised controlled trial. We included acute coronary syndrome survivors not accessing cardiac rehabilitation in the CHOICE trial whose General Practitioner or Cardiologist returned a visit frequency survey. The CHOICE group participated in tailored risk factor reduction packaged as clinic visit plus 3 months telephone support. Controls participated in physician-directed usual medical care. We compared total cholesterol, systolic blood pressure, smoking status, physical activity, number of modifiable risk factors and medications with frequency of medical consultations at baseline and 12 months. RESULTS: Most control and CHOICE patients saw their General Practitioner≥5 times (85% vs 90%) and Cardiologist at least once (65% vs 57%). CHOICE patients had a significantly better modifiable risk profile (factor levels and multiples) and more patients were on evidence-based medications at 12 months compared to controls. In CHOICE, the significant reduction in total cholesterol was unrelated to medical visits but lower systolic blood pressure was significant in patients who saw their General Practitioner≥5 compared with ≤4 times. In controls, frequency of medical visits was not associated with any changes in risk profile. CONCLUSIONS: Acute coronary syndrome survivors receiving frequent medical follow-up without packaged secondary prevention had no improvement in multiple risk factors over 12 months. CHOICE patients who saw their doctors frequently were more likely to have significantly reduced systolic blood pressure and be on evidence-based medications.

Choice of secondary prevention improves risk factors after acute coronary syndrome: 1-year follow-up of the CHOICE (Choice of Health Options In prevention of Cardiovascular Events) randomised controlled trial.

OBJECTIVE: To determine the effect of a new CHOICE (Choice of Health Options In prevention of Cardiovascular Events) programme on cardiovascular risk factors in acute coronary syndrome (ACS) survivors. DESIGN: Single-blind randomised controlled trial. SETTING: Tertiary referral hospital in Sydney Australia. PATIENTS: 144 ACS survivors who were not accessing standard cardiac rehabilitation. Data were also collected on a further 64 ACS survivors attending standard cardiac rehabilitation. INTERVENTION: The CHOICE group (n = 72) participated in a brief, patient-centred, modular programme comprising a clinic visit plus telephone support, encompassing mandatory cholesterol lowering and tailored preferential risk modification. The control group (n = 72) participated in continuing conventional care but no centrally coordinated secondary prevention. MAIN OUTCOME MEASURES: Values for total cholesterol, systolic blood pressure, smoking status and physical activity. RESULTS: CHOICE and control groups were well matched at baseline. At 12 months, the CHOICE group (n = 67) had significantly better risk factor levels than controls (n = 69) for total cholesterol (TC) (mean (SEM) 4.0 (0.1) vs 4.7 (0.1) mmol/l, p<0.001), systolic blood pressure (131.6 (1.8) vs 143.9 (2.3) mm Hg, p<0.001), body mass index (28.9 (0.7) vs 31.2 (0.7) kg/m(2), p = 0.025) and physical activity (1369.1 (167.2) vs 715.1 (103.5) METS/kg/min, p = 0.001) as well as a better knowledge of risk factor targets. Also at 1 year, fewer CHOICE participants (21%) had three or more risk factors above widely recommended levels then controls (72%) (p<0.001). CONCLUSIONS: Participation in a brief CHOICE programme significantly improved the modifiable risk profiles and risk factor knowledge of ACS survivors over 12 months. CHOICE is an effective alternative for dealing with the widespread underuse of existing secondary prevention programmes. TRIAL REGISTRATION NUMBER: ISRCTN42984084.

The CHOICE (Choice of Health Options In prevention of Cardiovascular Events) replication trial: study protocol.

BACKGROUND: Although morbidity and mortality from coronary heart disease (CHD) are high, only a minority of acute coronary syndrome (ACS) survivors accesses an effective secondary prevention program. We aim to determine whether the previously proven CHOICE program can be replicated at multiple sites and whether ongoing reinforcement further improves risk factor modification. METHODS/DESIGN: Participants eligible for but not accessing standard cardiac rehabilitation will be randomly allocated to either a previously tested 3-month CHOICE program or a 30-month CHOICE program (CHOICE-plus). Both groups will participate in individualised risk factor modules of differing duration that involve choice, goal setting and telephone follow-up for three months. CHOICE-plus will also receive additional face-to-face and telephone reinforcement between three and 30 months. At one site we will recruit a randomised control group, receiving conventional care. Primary outcomes are lipid levels, blood pressure, physical activity levels and smoking rates. Secondary outcomes include readmission rates, death, the number of risk factors, other modifiable risk factors, quality of life and process evaluation measures over three years. DISCUSSION: We present the rationale and design of a multi-centre, replication study testing a modular approach for the secondary prevention of CHD following an ACS. TRIAL REGISTRATION: [Clinical Trial Registration Number, ACTRN12608000182392].

Polymorphonuclear leukocyte phagocytic function increases in plasminogen knockout mice.

BACKGROUND: Mice lacking plasminogen (PG-/-) require alternative pathways of fibrinolysis for survival. This may depend on polymorphonuclear leukocytes (PMN) that can clear soluble and insoluble fibrin(ogen) through PG-independent processes. Our objective was to demonstrate that PMNs from PG-/- mice exhibit increased Mac-1 dependent phagocytic activity, which may explain their increased fibrin(ogen)lytic activity compared with wild type (PG+/+) mice. METHODS: Phagocytic activity of PMNs from PG-/- and PG+/+ mice was compared following exposure to Staphylococcus aureus (S. aureus) particles and the expression of Mac-1 was assessed in parallel by flow cytometric analysis. Resistance to phorbol-12-myristate-13-acetate (PMA)-induced cell death was compared between PMNs from the different genotypes. RESULTS: Stimulation of PG-/- PMNs by opsonized S. aureus diluted in PG-/- plasma significantly increased phagocytosis (15-fold) compared with stimulation of PG+/+ PMNs in PG+/+ plasma. Incubation of PG-/- PMNs with PG+/+ plasma (control) or PG-/- plasma supplemented with human PG inhibited this increased phagocytic activity. Mac-1 cell surface density increased 6.2+/-1.0-fold in PG-/- PMNs versus 2.9+/-0.6-fold in PG+/+ PMNs (P < 0.01) indicating that Mac-1 may be associated with increased phagocytic activity. Supporting this, treatment of PG-/- PMNs with an anti-Mac-1 antibody in PG-/- plasma inhibited phagocytic activity. In addition, physiologic PG blocked Mac-1 accessibility at the surface of PMNs. Addition of PMA resulted in 33% death of PMNs from PG-/- mice versus 68% in PG+/+ controls (P < 0.001). CONCLUSIONS: PMNs from PG-/- mice exhibit a Mac-1 dependent increase in phagocytic activity that is suppressed with human PG, an anti-Mac-1 antibody or the plasma from PG+/+ mice. The propensity for PMNs from PG-/- mice to be activated in response to PMA together with their relative resistance to PMA-toxicity may contribute to increased PMN half-life and enhanced fibrin(ogen) clearance in the setting of PG deficiency.

Modular prevention of heart disease following acute coronary syndrome (ACS) [ISRCTN42984084].

BACKGROUND: Coronary heart disease (CHD) is a major cause of morbidity and mortality in Australia and it is recommended that all persons with unstable angina (UA) or myocardial infarction (MI) participate in secondary prevention as offered in cardiac rehabilitation (CR) programs. However, the majority of patients do not access standard CR and have higher baseline coronary risk and poorer knowledge of CHD than those persons due to commence CR. The objective of this study is to investigate whether a modular guided self-choice approach to secondary prevention improves coronary risk profile and knowledge in patients who do not access standard CR. METHODS/DESIGN: This randomised controlled trial with one year follow-up will be conducted at a tertiary referral hospital. Participants eligible for but not accessing standard CR will be randomly allocated to either a modular or conventional care group. Modular care will involve participation in individualised modules that involve choice, goal-setting and coaching. Conventional care will involve ongoing heart disease management as directed by the participant's doctors. Both modular and conventional groups will be compared with a contemporary reference group of patients attending CR. Outcomes include measured modifiable risk factors, relative heart disease risk and knowledge of risk factors. DISCUSSION: We present the rationale and design of a randomised controlled trial testing a modular approach for the secondary prevention of coronary heart disease following acute coronary syndrome.

C-reactive protein contributes to the hypercoagulable state in coronary artery disease.

OBJECTIVES: Elevated plasma C-reactive protein (CRP) levels predict coronary events, but it is unclear whether CRP plays a role in thrombosis associated with these events. We investigated tissue factor (TF) induction by CRP on peripheral blood mononuclear cells (PBMC) from patients with coronary disease. PATIENTS AND METHODS: PBMC from 35 patients with stable angina (SA) in study 1, 10 male patients with SA, 10 with unstable angina (UA) and 10 matched controls in study 2, and 25 patients with inflammatory disorders (ID) and 24 normal controls in study 3 were stimulated with CRP, interferon-gamma (IFN) or lipopolysaccharide (LPS), or their combination. PBMC from additional normal donors were also stimulated with CRP in adherent and non-adherent conditions, and TF activity, antigen and mRNA expression detected. RESULTS: CRP (5-25 microg mL(-1)) dose dependently induced more TF on PBMC from SA patients than 42 contemporary controls (P = 0.001, study 1). Compared with controls, patients with SA or UA had higher basal, and much higher CRP- or CRP/LPS-induced monocyte TF activity although serum CRP levels were similar (study 2). IFN induced monocyte TF activity in patients with angina, but not in controls. Basal or CRP-induced TF levels did not differ between controls and ID, even though ID patients had much higher serum CRP levels (study 3). CRP-induced monocyte TF activity correlated with serum CRP levels in controls (P = 0.005) and ID (P = 0.007) in study 3, but not in patients with angina (P =0.84) in study 2. CRP induced more TF activity, protein and mRNA under adherent than non-adherent conditions implying that it may mainly target macrophages in lymphocyte-rich lesions. CONCLUSIONS: Our results indicate that monocytes from patients with angina are preactivated and express TF but CRP is unlikely to be a major priming factor in vivo. IFN and CRP further increase TF levels that may contribute to the hypercoagulable state in coronary disease.

Suppression of acute experimental allergic encephalomyelitis with a small molecule inhibitor of alpha4 integrin.

PURPOSE: To determine the efficacy of a small molecule inhibitor of alpha4 integrin (CT301) at reversing the clinical, pathological and MR-detectable deficits associated with the acute phase of experimental allergic encephalomyelitis (EAE). MATERIALS AND METHODS: EAE was induced in 36 female Hartley guinea pigs, and the treatment period was from day 11 to day 17 post-immunization. Animals received either saline (n = 12), anti-alpha4 integrin antibody (AN100226m; n = 12) or CT301 (n = 12). T2-weighted fast spin echo and T1-weighted pre- and post-contrast scans were performed at the beginning (day 11) and end (day 18) of the treatment period, and scored for cerebral inflammation and gadolinium enhancement. T1-weighted images were further analyzed to quantify this enhancement as a measure of blood-brain barrier integrity. Dissected CNS was evaluated for inflammation and demyelination. RESULTS: CT301 successfully reversed two clinical indicators of disease over the course of the treatment period. These animals showed decreased T2-weighted abnormalities, as well as a reduction in gadolinium leakage on T1-weighted images. Meningeal and perivascular inflammation was decreased by anti-alpha4 integrin treatments. CONCLUSION: CT301 effectively reverses the clinical, pathological and MR-detectable deficits of acute EAE, and may therefore be a promising therapeutic agent in multiple sclerosis (MS).

Spontaneous remyelination following prolonged inhibition of alpha4 integrin in chronic EAE.

Inhibition of alpha(4)beta(1) integrin blocks immune cell influx into the CNS providing benefit to patients with multiple sclerosis and in animal model systems. We have used this mechanism to examine whether the presence of inflammatory cells suppresses spontaneous myelin repair in experimental autoimmune encephalomyelitis. We observed (1) 87% of plaques showed remyelination after 40 days of treatment; (2) myelin repair occurred in half of the total lesion area; (3) half of the animals regained motor function. There was no significant repair or gain of motor function in vehicle-treated animals. Therefore, prolonged inhibition of CNS inflammation, in the absence of targeted myelin repair, facilitates mechanisms of spontaneous remyelination.

Elevated circulating levels of matrix metalloproteinase-9 and -2 in patients with symptomatic coronary artery disease.

BACKGROUND: Matrix metalloproteinases (MMP-9 and MMP-2) have been implicated in development of atherosclerosis and plaque rupture in acute coronary syndromes (ACS). AIM: To determine the relationship between circulating MMPs and symptomatic coronary artery disease. METHODS: Plasma levels of MMP-9 and MMP-2 were measured in patients with ACS, stable angina (SA) and in controls, using a quantitative gelatin zymography. These measurements were correlated with markers of systemic inflammation (hs-CRP) in all subjects and myocardial injury (troponin T) in patients with ACS. RESULTS: Plasma MMP-9 in ACS was greater than in SA, and was greater in SA than in controls (P < 0.01 ACS vs SA and controls, P < 0.01 SA vs control). Plasma MMP-2 was significantly greater in ACS than SA or controls (P < 0.01 vs SA and controls). There was strong overall relationship between hs-CRP and MMP-9 (r = 0.65, P < 0.0001) driven by a significant relationship in ACS patients (r = 0.58, P = 0.02), as there was no significant association in SA or controls. A weaker overall correlation was found between hs-CRP and MMP-2 (r = 0.39, P = 0.02), but no significant relationship was present for either of the two patient subgroups or controls. There was no correlation between levels of troponin T and MMP-9, MMP-2 or hs-CRP in ACS patients. CONCLUSION: Quantitative gelatin zymography identifies increased circulating levels of MMP-9 and MMP-2 in patients with symptomatic coronary disease. MMP-9 and MMP-2 are higher in ACS than SA patients and might have use as markers of plaque rupture or instability. The strong relationship between MMP-9 and hs-CRP in ACS patients suggests MMP-9 might be an additional marker and/or consequence of the inflammatory component in ACS.

Prolonged reversal of chronic experimental allergic encephalomyelitis using a small molecule inhibitor of alpha4 integrin.

CNS leukocytic invasion in experimental allergic encephalomyelitis (EAE) depends on alpha4beta1 integrin/vascular cell adhesion molecule-1 (VCAM-1) interactions. A small molecule inhibitor of alpha4beta1 integrin (CT301) was administered to guinea pigs in the chronic phase (>d40) of EAE for 10, 20, 30 or 40 days. CT301 elicited a rapid, significant improvement in the clinical and pathological scores that was maintained throughout the treatment period. A progressive loss of cells in the spinal cord of treated animals confirmed the resolution of inflammation associated with clinical recovery. Therefore, prolonged inhibition of alpha4beta1 integrin caused a sustained reversal of disease pathology in chronic EAE and may be similarly useful in MS.

Predictors of bacterial meningitis in the era after Haemophilus influenzae.

OBJECTIVE: To determine if, in the era after Haemophilus influenzae type b, the cerebrospinal fluid (CSF) white blood cell (WBC) count can be safely used to stratify children suspected of having bacterial meningitis into low- and high-risk groups. DESIGN: Retrospective analysis of CSF samples. SETTING: Tertiary care pediatric center in Toronto, Ontario, between January 1, 1992, and October 1, 1996. PATIENTS: All CSF samples collected on children aged 2 months to 17 years were included. The final database consisted of 1617 atraumatic samples from children without prior neurologic or immunologic disease who underwent a lumbar puncture to assess the possibility of community-acquired bacterial meningitis. MAIN OUTCOME MEASURES: The predictive values of CSF WBC count, differential, protein, and glucose. RESULTS: There were 44 cases of bacterial meningitis. Five had 3 CSF WBCs per microliter or less, and 6 had 4 to 30 CSF WBCs per microliter. The negative predictive value of CSF specimens with 30 WBCs per microliter or less for bacterial meningitis was 99.3%. Cerebrospinal fluid samples with greater than 30 WBCs per microliter had a likelihood ratio for bacterial meningitis of 10.3 (95% confidence interval, 8.0-13.1) and a positive predictive value of 22.3%. Other significant predictors of bacterial meningitis included age, CSF glucose, protein, gram stain, CSF-serum glucose ratio, and peripheral blood band count. CONCLUSIONS: Given the occurrence of bacterial meningitis in children in the absence of CSF pleocytosis, other factors should be considered when managing children with suspected bacterial meningitis. Children older than 6 months with 30 CSF WBCs per microliter or less are at low risk for bacterial meningitis. If clinically stable and without other laboratory markers of bacterial meningitis, hospital admission and empiric antibiotic therapy may be unwarranted.

BACE knockout mice are healthy despite lacking the primary beta-secretase activity in brain: implications for Alzheimer's disease therapeutics.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by accumulation of amyloid plaques and neurofibrillary tangles in the brain. The major components of plaque, beta-amyloid peptides (Abetas), are produced from amyloid precursor protein (APP) by the activity of beta- and gamma-secretases. beta-secretase activity cleaves APP to define the N-terminus of the Abeta1-x peptides and, therefore, has been a long- sought therapeutic target for treatment of AD. The gene encoding a beta-secretase for beta-site APP cleaving enzyme (BACE) was identified recently. However, it was not known whether BACE was the primary beta-secretase in mammalian brain nor whether inhibition of beta-secretase might have effects in mammals that would preclude its utility as a therapeutic target. In the work described herein, we generated two lines of BACE knockout mice and characterized them for pathology, beta-secretase activity and Abeta production. These mice appeared to develop normally and showed no consistent phenotypic differences from their wild-type littermates, including overall normal tissue morphology and brain histochemistry, normal blood and urine chemistries, normal blood-cell composition, and no overt behavioral and neuromuscular effects. Brain and primary cortical cultures from BACE knockout mice showed no detectable beta-secretase activity, and primary cortical cultures from BACE knockout mice produced much less Abeta from APP. The findings that BACE is the primary beta-secretase activity in brain and that loss of beta-secretase activity produces no profound phenotypic defects with a concomitant reduction in beta-amyloid peptide clearly indicate that BACE is an excellent therapeutic target for treatment of AD.