Characteristics of 1555 childhood-onset lupus in three groups based on distinct time intervals to disease diagnosis: a Brazilian multicenter study.

Objective The objective of this study was to compare demographic data, clinical/laboratorial features and disease activity at diagnosis in three different groups with distinct time intervals between onset of signs/symptoms and disease diagnosis. Methods A multicenter study was performed in 1555 childhood-onset systemic lupus erythematosus (American College of Rheumatology criteria) patients from 27 pediatric rheumatology services. Patients were divided into three childhood-onset systemic lupus erythematosus groups: A: short time interval to diagnosis (<1 month); B: intermediate time interval (≥1 and <3 months); and C: long time interval (≥3 months). An investigator meeting was held to define the protocol. Demographic data, SLICC classification criteria and SLEDAI-2 K were evaluated. Results The number of patients in each group was: A = 60 (4%); B = 522 (33.5%); and C = 973 (62.5%). The median age at diagnosis (11.1 (4.2-17) vs. 12 (1.9-17.7) vs. 12.5 (3-18) years, P = 0.025) was significantly lower in group A compared with groups B and C. The median number of diagnostic criteria according to SLICC (7 (4-12) vs. 6 (4-13) vs. 6 (4-12), P < 0.0001) and SLEDAI-2 K (18 (6-57) vs. 16 (2-63) vs. 13 (1-49), P < 0.0001) were significantly higher in group A than the other two groups. The frequency of oral ulcers in the palate (25% vs. 15% vs. 11%, P = 0.003), pleuritis (25% vs. 24% vs. 14%, P < 0.0001), nephritis (52% vs. 47% vs. 40%, P = 0.009), neuropsychiatric manifestations (22% vs. 13% vs. 10%, P = 0.008), thrombocytopenia (32% vs. 18% vs. 19%, P = 0.037), leucopenia/lymphopenia (65% vs. 46% vs. 40%, P < 0.0001) and anti-dsDNA antibodies (79% vs. 66% vs. 61%, P = 0.01) were significantly higher in group A compared with the other groups. In contrast, group C had a less severe disease characterized by higher frequencies of synovitis (61% vs. 66% vs. 71%, P = 0.032) and lower frequencies of serositis (37% vs. 33% vs. 25%, P = 0.002), proteinuria >500 mg/day (48% vs. 45% vs. 36%, P = 0.002) and low complement levels (81% vs. 81% vs. 71%, P < 0.0001) compared with groups A or B. Conclusions Our large Brazilian multicenter study demonstrated that for most childhood-onset systemic lupus erythematosus patients, diagnosis is delayed probably due to mild disease onset. Conversely, the minority has a very short time interval to diagnosis and a presentation with a more severe and active multisystemic condition.

The effect of army vest design on the occurrence of stress fractures and overuse injuries in female military recruits.

INTRODUCTION: Stress fractures (SFs) occur when microdamage caused by repetitive mechanical load exceeds the biological load-bearing capacity of the bone. The study objective was to test whether a vest specifically designed and manufactured for female recruits, compared with the standard vest used on a regular basis by Border Police recruits, would reduce the incidence of SF in female Border Police recruits. Data based on reports of military personnel show that women are more likely to sustain SFs. METHODS: A follow-up of 240 female Border Police infantry recruits, divided into two trial groups, was conducted from 2007 to 2009. Two different vests were evaluated-the standard special unit fighting vest, which was conventionally used by both men and women during basic training, and the new fighting vest, specially design for female body shape. RESULTS: No significant difference was noted in the number of SFs between the two groups which may be attributed to increased weight of the new vest. There was a lower incidence of long bone SFs which may have been due to the superior vest design. The female Border Police Infantry recruits expressed great satisfaction with the new vest. CONCLUSIONS: Increased effort should be invested to further reduce the weight of female combat gear, alongside efforts to improve fit and comfort.

Blood Derived Amyloid Biomarkers for Alzheimer's Disease Prevention.

BACKGROUND: Reliable, widely accessible and affordable biomarkers for predicting Alzheimer's disease (AD) brain pathology status are a necessity to aid development of prevention strategies in cognitively healthy at-risk older adults, at the right timepoint. Measurements of the key neuropathological hallmark beta-amyloid (Aß) by PET neuroimaging or cerebrospinal fluid measures reflect its accumulation in the brain, yet recent methodological advancements now enable blood-based measures reflecting cerebral amyloid burden. OBJECTIVES: The current study validated the capacity of plasma Aß42/Aß40 measured using six different assays to predict amyloid positivity in a subgroup of cognitively unimpaired (CU) participants in the ADNI study and assessed its ability to discriminate CU from AD cases. We also explored economic viability of using two different plasma amyloid assays for pre-screening in AD prevention trials and as routine clinical diagnostic tool, versus amyloid PET alone. DESIGN: A cross-sectional analysis of plasma and brain amyloid data, including comparative cost analysis of the plasma biomarkers in relation to brain amyloid PET. SETTING: Alzheimer's Disease Neuroimaging Initiative (ADNI). PARTICIPANTS: ADNI participants consisting of 115 CU, mild cognitive impairment and AD cases who had plasma Aß42/Aß40 measured with six platforms. MEASUREMENTS: Plasma Aß42/Aß40 was measured via six different platforms: three immunoassays (Roche, Quanterix and ADx Neurosciences) and three mass spectrometry (MS) based assays (WashU, Shimadzu and Gothenburg). Aß-PET imaging was conducted within three months of plasma sampling using [18F]florbetapir. RESULTS: There was a weak to moderate correlation of plasma Aß42/Aß40 ratio between platforms. The MS-based WashU test had the highest capacity to discriminate between CU and AD (area under the curve, AUC = 0.734, 95% CI: 0.613-0.854; P = 0.008). Within the CU group, the WashU plasma amyloid test had the best discriminative capacity to distinguish Aß+ from Aß- (AUC = 0.753, 95% CI: 0.601-0.905; P = 0.003) closely followed by the immunoassay from Roche (AUC = 0.737, 95% CI: 0.597-0.877; P = 0.006). The exploratory economic analyses showed that the use of Roche or WashU plasma amyloid assay as a pre-screening tool prior to Aß-PET scans for clinical trial recruitment significantly reduced total screening cost (saving up to $5882 per recruited patient) expected in an AD prevention trial. CONCLUSIONS: With few available treatment strategies, dementia prevention is a global priority. CU individuals at risk for AD are the target population for dementia prevention but have been poorly studied. Our findings confirming diagnostic value of ultrasensitive immunoassays and high-performance immunoprecipitation coupled with MS for measurement of plasma Aß42/Aß40 to detect PET amyloid positivity in CU participants allude to potential clinical utility of this biomarker. Plasma Aß42/Aß40 could be optimal for pre-selecting at-risk candidates for more invasive and expensive investigations across AD prevention clinical trials and clinical care for a rapidly ageing population.

Sensitivity of the Preclinical Alzheimer's Cognitive Composite (PACC), PACC5, and Repeatable Battery for Neuropsychological Status (RBANS) to Amyloid Status in Preclinical Alzheimer's Disease -Atabecestat Phase 2b/3 EARLY Clinical Trial.

BACKGROUND: Cognitive composites commonly serve as primary outcomes in Alzheimer's disease (AD) secondary prevention trials. OBJECTIVE: To evaluate the association between amyloid (Aß) burden level (+/-) and performance on three separate composite endpoints: Preclinical Alzheimer's Cognitive Composite (PACC), PACC+Semantic Fluency (PACC5), and Repeatable Battery for Neuropsychological Status (RBANS). DESIGN: Screening data from the randomized, double-blind, placebo-controlled, phase 2b/3 atabecestat EARLY study in preclinical AD participants were used in this analysis. SETTING: The EARLY study was conducted at 143 centers across 14 countries. PARTICIPANTS: 3,569 cognitively unimpaired older adults (Clinical Dementia Rating of 0; aged 60-85 years) screened for inclusion in the EARLY study with Aß status and at least PACC or RBANS at screening were included. Participants were categorized as those with non-pathological Aß levels (Aß-, n=2,824) and those with pathological Aß levels (Aß+, n=745) based on florbetapir uptake or levels of cerebrospinal fluid Aß1-42. MEASUREMENTS: Analysis of Covariance models controlling for age, sex, and education were used to examine the difference in PACC, PACC5, and RBANS between Aß groups. Nonparametric bootstrap was used to compare sensitivity of composites to differentiate between Aß status. RESULTS: Of 3,569 participants, 2,116 were women (59%); 3,006 were Caucasian (84%); mean (SD) age was 68.98 (5.28) years. Aß+ participants performed worse versus Aß- participants on all cognitive composites though the magnitude of the Aß effect was generally small. The Aß+/- effect size for the PACC (Cohen's d=-0.15) was significantly greater than the RBANS (d=-0.097) while the PACC5 effect size (d=-0.139) was numerically larger than the RBANS. When examining subscores from the composites, memory tests (i.e., Free and Cued Selective Reminding Test, Figure Recall) and speed of processing (i.e., Digit-Symbol/Coding on the PACC/RBANS) exhibited the largest Aß+/- effect sizes. CONCLUSIONS: Cross-sectional relationships between Aß and cognition among clinically unimpaired older adults are detectable on multi-domain cognitive composites but are relatively small in magnitude. The Aß+/- group effect was statistically larger for PACC and marginally larger for PACC5 versus RBANS. However, interpretation of composite sensitivity to Aß status cross-sectionally cannot be generalized to sensitivity to change over time.

Lost and found dark matter in elliptical galaxies.

There is strong evidence that the mass of the Universe is dominated by dark matter, which exerts gravitational attraction but whose exact nature is unknown. In particular, all galaxies are believed to be embedded in massive haloes of dark matter. This view has recently been challenged by the observation of surprisingly low random stellar velocities in the outskirts of ordinary elliptical galaxies, which has been interpreted as indicating a lack of dark matter. Here we show that the low velocities are in fact compatible with galaxy formation in dark-matter haloes. Using numerical simulations of disk-galaxy mergers, we find that the stellar orbits in the outer regions of the resulting ellipticals are very elongated. These stars were torn by tidal forces from their original galaxies during the first close passage and put on outgoing trajectories. The elongated orbits, combined with the steeply falling density profile of the observed tracers, explain the observed low velocities even in the presence of large amounts of dark matter. Projection effects when viewing a triaxial elliptical can lead to even lower observed velocities along certain lines of sight.

Detection of early FXTAS motor symptoms using the CATSYS computerised neuromotor test battery.

BACKGROUND: Carriers of the FMR1 premutation allele are at a significantly increased risk for a late-onset neurodegenerative disorder, fragile X-associated tremor/ataxia syndrome (FXTAS). This disorder is distinct from fragile X syndrome (FXS) in its molecular aetiology and clinical presentation. The primary features of FXTAS are late-onset intention tremor and gait ataxia. Associated features include parkinsonism, neuropsychological dysfunction, autonomic dysfunction and peripheral neuropathy. AIM: To investigate the usefulness of a quantitative neurological test battery implemented through the CATSYS instrument to identify preclinical symptoms of FXTAS. METHODS: Both premutation carriers with 70-199 repeats (62 men) and their low-repeat allele carrier siblings (27 men), identified through families with an individual affected with FXS, were tested. RESULTS: As expected, because of its sensitivity, use of the instrument allowed identification of tremor in 23% of men who had not self-reported tremor, and ataxia in 30% of men who had not self-reported ataxia. Among subjects with self-reported tremor and ataxia, we found significant concordance between measures of the CATSYS system and the self-report. CONCLUSION: Rates of these traits among premutation carriers and low-repeat allele carrier siblings could be identified, and are presented in this paper, along with the minimum estimates of age-related prevalence.

Prospective Evaluation of Cognitive Health and Related Factors in Elderly at Risk for Developing Alzheimer's Dementia: A Longitudinal Cohort Study.

BACKGROUND: The CHARIOT PRO Main study is a prospective, non-interventional study evaluating cognitive trajectories in participants at the preclinical stage of Alzheimer's disease (AD) classified by risk levels for developing mild cognitive impairment due to AD (MCI-AD). OBJECTIVES: The study aimed to characterize factors and markers influencing cognitive and functional progression among individuals at-risk for developing MCI-AD, and examine data for more precise predictors of cognitive change, particularly in relation to APOE ε4 subgroup. DESIGN: This single-site study was conducted at the Imperial College London (ICL) in the United Kingdom. Participants 60 to 85 years of age were classified as high, medium (amnestic or non-amnestic) or low risk for developing MCI-AD based on RBANS z-scores. A series of clinical outcome assessments (COAs) on factors influencing baseline cognitive changes were collected in each of the instrument categories of cognition, lifestyle exposure, mood, and sleep. Data collection was planned to occur every 6 months for 48 months, however the median follow-up time was 18.1 months due to early termination of study by the sponsor. RESULTS: 987 participants were screened, among them 690 participants were actively followed-up post baseline, of whom 165 (23.9%) were APOE ε4 carriers; with at least one copy of the allele. The mean age was 68.73 years, 94.6% were white, 57.4% were female, and 34.8% had a Family History of Dementia with a somewhat larger percentage in the APOE ε4 carrier group (42.4%) compared to the non-carrier group (32.4%). Over half of the participants were married and 53% had a Bachelor's or higher degree. Most frequently, safety events typical for this population consisted of upper respiratory tract infection (10.4%), falls (5.2%), hypertension (3.5%) and back pain (3.0%). Conclusion (clinical relevance): AD-related measures collected during the CHARIOT PRO Main study will allow identification and evaluation of AD risk factors and markers associated with cognitive performance from the pre-clinical stage. Evaluating the psycho-biological characteristics of these pre-symptomatic individuals in relation to their natural neurocognitive trajectories will enhance current understanding on determinants of the initial signs of cognitive changes linked to AD.

Review article: dose optimisation of infliximab for acute severe ulcerative colitis.

BACKGROUND: Although optimal medical management of acute severe ulcerative colitis (UC) is ill-defined, infliximab has become a standard of care. Accumulating evidence suggests an increased rate of infliximab clearance in patients with acute severe UC and a reduced colectomy rate with an intensified infliximab induction regimen. AIM: To assess the strength of the current evidence for the relationship between infliximab pharmacokinetics, dosing strategies and disease behaviour in patients with acute severe UC. METHODS: We systematically searched MEDLINE and conference proceedings from 2000 to 2016 for relevant articles describing the pharmacokinetics of infliximab in acute severe UC and/or infliximab dose intensification strategies in acute severe UC. Eligible articles described randomised controlled trials, and cohort, cross-sectional, and case-controlled studies. RESULTS: Of 400 citations identified, 76 studies were eligible. Increased infliximab clearance occurs in patients with acute severe UC, and is driven by the total inflammatory burden and leakage of drug into the colonic lumen. Several cohort studies suggest that infliximab dose intensification is beneficial to at least 50% of acute severe UC patients and the results of case-controlled studies indicate that an intensified infliximab dosing regimen with 1-2 additional infusions in the first 3 weeks of treatment could reduce the early (3-month) colectomy rate by up to 80%, although these data require prospective validation. CONCLUSIONS: Uncontrolled studies suggest a benefit for infliximab dose optimisation in patients with acute severe UC. A randomised controlled trial in acute severe UC patients comparing a personalised infliximab dose-optimisation strategy with conventional dosing is a research priority.

A Randomized, Double-Blind, Phase 2 Study of the Effects of the Vaccine Vanutide Cridificar with QS-21 Adjuvant on Immunogenicity, Safety and Amyloid Imaging in Patients with Mild to Moderate Alzheimer's Disease.

BACKGROUND: Vanutide Cridificar (ACC-001), a novel investigational immunotherapeutic vaccine designed to elicit antibodies against the N-terminal peptide 1-7 of the amyloid-beta peptide, believed to be important in the pathogenesis of Alzheimer's disease (AD). OBJECTIVES: To evaluate the immunogenicity, safety and impact of ACC-001 with Quillaja saponaria (QS-21) adjuvant on the reduction of brain fibrillar amyloid burden, assayed by positron emission tomography (PET) imaging, in patients with mild to moderate AD. DESIGN: Randomized, phase 2, interventional study. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01284387. PARTICIPANTS: Individuals with mild to moderate Alzheimer's disease (Mini-Mental State Examination scores 18-26; measurable amyloid burden in the expected range, on the screening 18F-florbetapir PET scan; and a Rosen modified Hachinski ischemic score ≤4). INTERVENTION: Participants were randomized to 3 µg or 10 µg ACC-001 (each in combination with 50 µg QS-21) or placebo (without QS-21). MEASUREMENTS: Primary endpoint was the change from baseline to week 104 in cerebral amyloid burden as measured by the global cortical average (GCA) standard value uptake ratio (SUVR) based on the brain 18F-florbetapir PET composite cortical SUVR between each ACC-001+QS-21 dose compared with placebo. Secondary endpoints included safety, immunogenicity and pharmacodynamics. Exploratory endpoints included cognitive and functional efficacy, and health outcome measures. RESULTS: Of 126 randomized patients (placebo: 40; ACC-001 3 µg+QS-21: 43; and ACC-001 10 µg+QS-21: 43), 125 received study treatment; 92 (73%) completed the study. Change in 18F-florbetapir PET GCA SUVR, was not significantly different between either of the two ACC-001+QS-21 treatment groups and placebo (3 µg +QS-21 vs. placebo diff=-0.03, p=0.54; 10 µg +QS-21 vs. placebo diff=-0.08, p=0.07), but the trend was numerically consistent with a dose response. The geometric mean peak anti-Aß IgG titers were slightly higher in the 10 µg than the 3 µg group. The proportion of responders was similar in both dose groups of ACC-001+QS-21. The cerebrospinal fluid (CSF) p-tau changes from baseline in both active treatment groups were not statistically different from placebo, but were numerically consistent with a dose response (3 µg +QS-21 vs. placebo diff=-3.2, p=0.57; 10 µg +QS-21 vs. placebo diff=-7.0, p=0.19). The vMRI showed statistically significant faster treatment-related decrease in brain volume in the 10 µg group but was not significant in the 3 µg group, compared with placebo (3 µg diff =-1.3 mL/year, p=0.50; 10 µg diff=-4.2 mL/year, p=0.02). Measured plasma Aß levels increased in parallel with peak anti-Aß titers after each injection. Amyloid-related imaging abnormalities with edema/effusion (ARIA-E) were more frequent in patients who received ACC-001+QS-21 than placebo (6% vs. 0%) but none were symptomatic. The most common treatment-emergent adverse events in the active groups were injection reactions, and occurred more frequently in the ACC-001+QS-21 groups than the placebo (48% vs 8%), the majority of which were mild and transient. CONCLUSIONS: Primary biomarker efficacy endpoints were not statistically significant in either dose group. The numerical decreases in 18F-florbetapir PET GCA SUVR suggests a dose-related trend for greater reductions in fibrillar amyloid burden in the ACC-001+QS-21 10 µg group compared with placebo. Likewise, while not significant, there was a numerical trend of decreased CSF p-tau levels with ACC-001, possibly consistent with a downstream effect in the ACC-001+QS-21 group. Insufficient antibody titers or quality, insufficient power to detect a difference, or too short duration of follow up may be reasons why a statistically significant response was not observed. Brain volume measures showed faster volume loss in the 10 µg treatment group, similar to the effect seen in few earlier AD immunotherapy trials which may suggest removal of amyloid and resultant decrease in inflammation. No new, unexpected safety signals were detected.

Effects of clozapine on auditory event-related potentials in schizophrenia.

BACKGROUND: Schizophrenia is associated with cognitive deficits that are an intrinsic component of the disorder. Clozapine is an atypical antipsychotic that is superior to typical agents in the treatment of positive symptoms. The degree to which clozapine ameliorates cognitive deficits, however, is still controversial. Mismatch negativity (MMN), N200 (N2), and P300 (P3) are cognitive event-related potentials (ERPs) that index preattentive (MMN) and attention-dependent information processing (N2, P3) and provide a measure of cognitive deficits associated with schizophrenia. In schizophrenic patients deficient generation of MMN, N2, and P3 has been observed, suggesting impairments of discrete stages of information processing. METHODS: This study investigates the effects of clozapine treatment on MMN, N2, and P3 generation. Patients were recruited from a haloperidol-controlled, double-blind treatment study of clozapine in chronic schizophrenia. ERPs were obtained at the beginning of the study and after 9 weeks (4 patients) and 16 weeks (13 patients) of treatment. RESULTS: Clozapine treatment was associated with a significant increase of P3 amplitude, which was not observed in the haloperidol group; however, clozapine treatment did not affect deficits in MMN and N2. CONCLUSIONS: These findings suggest that clozapine--in contrast to conventional antipsychotics--improves electrophysiological measures of attention-dependent information processing, but does not ameliorate preattentive deficits.

Neuroradiological manifestations of focal polymorphic delta activity in children.

To examine the neuroradiological and clinical correlations of focal continuous polymorphic delta activity (PDA) in children, we reviewed the records of patients with continuous PDA that was either focal or lateralized to one hemisphere. Of 2571 electroencephalograms (EEGs) performed between July 1, 1988, and December 31, 1990, a total of 125 records from 87 patients revealed continuous PDA. Eighty of these patients had neuroimaging performed either by computed tomographic scan (n = 59) or by magnetic resonance imaging (n = 38) within 8 weeks of the EEG. Twenty-two patients (28%) showed no abnormalities on neuroimaging, 16 patients (20%) showed diffuse abnormalities, and 42 patients (52%) showed focal abnormalities that correlated with the EEG findings. Most (18 of 22) patients with no neuroradiological abnormalities presented to the hospital with seizures from various causes. The presence of focal spikes or additional focal EEG abnormalities did not differ significantly among the three imaging groups. Generalized EEG abnormalities and multifocal spikes were significantly more common among the patients who had generalized abnormalities on neuroimaging. Focal continuous PDA without correlated changes on neuroimaging occurred in 48% of patients, which is much higher than what has been reported in adults.

Risk factors for status epilepticus in children with symptomatic epilepsy.

The purpose of this study was to determine risk factors for status epilepticus (SE) in children with symptomatic epilepsy through a retrospective case-control study. Patients (44 children with a prior diagnosis of symptomatic epilepsy experiencing one or more episodes of SE between January 1, 1991, and June 1, 1995) were matched for age at follow-up to controls (88 children with symptomatic epilepsy without SE during that interval) and medical records were reviewed. Patients and controls did not differ in etiology or in age at epilepsy onset (1 year 5 months [SD, 2 years 3 months] versus 1 year 3 months [SD, 1 year 5 months]). Univariate analysis revealed significant associations between SE and several factors, including history of a first seizure as SE, partial epilepsy, partial seizures with secondary generalization, focal paroxysmal abnormalities and focal background abnormalities on EEG, and generalized abnormalities on neuroimaging. Groups did not differ in the proportion of patients on polypharmacy or with subtherapeutic serum antiepileptic drug levels, but there was a trend for greater use of phenobarbital in patients (57% versus 38%, odds ratio (OR) = 2.6, p = 0.057). With multiple logistic regression, four factors emerged as independent predictors of SE risk: focal background EEG abnormalities (OR = 6.51, p = 0.0005), partial seizures with secondary generalization (OR = 4.61, p = 0.0021), first seizure as SE (OR = 3.99, p = 0.034), and generalized abnormalities on neuroimaging (OR = 2.85, p = 0.034). These four factors are indicators of a higher risk of SE in children with symptomatic epilepsy.

Status epilepticus in children with epilepsy: the role of antiepileptic drug levels in prevention.

OBJECTIVES: To determine the association between subtherapeutic antiepileptic drug (AED) levels or AED withdrawal and status epilepticus (SE) in children with epilepsy. METHODS: We studied the AED levels at the time of SE in 51 consecutive children with epilepsy. Information about prior AED levels, possible etiology of seizures, and acute precipitants was extracted from medical records. RESULTS: The mean age at the time of SE was 5.7 years (range, 3 months through 18 years). Forty-three patients had history of remote insult, five had history of progressive encephalopathy, and three patients were classified as idiopathic. At the time of SE all AED levels were therapeutic in 34 (66%) patients and at least one level was therapeutic in 42 (82%) patients. All levels were subtherapeutic in 9 (18%) patients. Four patients had their AED reduced or discontinued less than 1 week before SE. Twelve patients with therapeutic AED levels on their most recent clinic visit had at least one subtherapeutic level at the time of SE. Eight (16%) patients were febrile and one was hyponatremic. Of the 51 patients, 31 (61%) had no obvious explanation for the development of SE, as all known AEDs were therapeutic and there were no known acute insults. CONCLUSIONS: Neurologically abnormal children with preexisting epilepsy are at high risk for development of SE despite having therapeutic AED levels at that time. Acute precipitants of SE, such as fever or AED withdrawal, may play a role in inducing SE only in a minority of patients.

Early-onset Haemophilus sepsis in newborn infants: clinical, roentgenographic, and pathologic features.

Nine infants with early-onset Haemophilus sepsis were seen between January 1973 and July 1977. Of the five isolated strains that were typed, only one was type B. All infants had respiratory distress, metabolic acidosis, and large alveolar-arterial oxygen tension difference gradients. Eight infants weighed less than 1,500 gm and died; one infant weighed 1,701 gm and survived. Roentgenograms in six of eight showed hyaline membrane disease. Pulmonary pathologic specimens in eight infants revealed hyaline membranes in six and polymorphonuclear leukocytes in the alveolar spaces in four. In two infants, small Gram-negative bacilli were noted within proteinaceous exudates in alveolar ducts. The route and time of infection in these infants with early-onset Haemophilus sepsis are unclear. However, the possibility that the infection occurs before birth and that these infants represent septically aborted prematures is suggested by the high incidence of prematurity in infants with early-onset Haemophilus sepsis and early detection of bacteremia in three infants.

Schizophrenia: elevated mRNA for calcium-calmodulin-dependent protein kinase IIbeta in frontal cortex.

Because amphetamine releases two to three times more dopamine in schizophrenia patients than in control subjects, and because calcium-calmodulin-dependent protein kinase II has a key role in the enhanced action of amphetamine-induced dopamine release in rats, the synaptic content of calcium-calmodulin-dependent protein kinase IIbeta mRNA was measured (by quantitative competitive RT-PCR; reverse transcriptase-polymerase chain reaction) in seven frontal cerebral cortices of post-mortem brains from patients who had schizophrenia and in seven control tissues. The results indicate that the mRNA of this kinase is elevated in the schizophrenia frontal cortex.

Schizophrenia and Nogo: elevated mRNA in cortex, and high prevalence of a homozygous CAA insert.

Schizophrenia is a major psychiatric disorder which is hypothesized to result from abnormal neurodevelopment or neural changes in adulthood and possibly associated with altered gene expression. To search for genes overexpressed in schizophrenia, cDNA library subtractive hybridization experiments between post-mortem human frontal cerebral cortices from schizophrenia individuals and neurological controls were carried out. One of the genes over-expressed in schizophrenia was identified as Nogo (also known as reticulon 4, RTN4, NI 250, or RTN-X), a myelin-associated protein which inhibits the outgrowth of neurites and nerve terminals. The elevated expression of Nogo mRNA in schizophrenia was confirmed by quantitative reverse transcription-polymerase chain reaction studies: 16.5 pg Nogo cDNA/microg total RNA in schizophrenia, and 10.2 pg Nogo cDNA/microg total RNA in controls (n=7; P=0.01, t-test for n<30). To identify possible polymorphisms in this gene, the Nogo nucleotide sequence was determined in a series of schizophrenia and control samples. The Nogo mRNA was found to contain a CAA insert polymorphism in the 3'-untranslated region. The prevalence of individuals homozygous for this CAA insert was significantly higher in schizophrenia compared to controls in genomic DNA samples extracted from post-mortem brain and blood samples: 17/81 or 21% in schizophrenia and 2/61 or 3% in controls (P=0.0022, chi(2)- and Fisher's exact-tests). Because the 3'-untranslated regions of eukaryotic genes are known to regulate gene expression, the increased frequency of the Nogo CAA insert in schizophrenia may contribute to abnormal regulation of Nogo gene expression, and may indicate a role for Nogo in disturbed neurodevelopment in schizophrenia.

Schizophrenia: elevated mRNA for dopamine D2(Longer) receptors in frontal cortex.

Because dopamine D2 receptors are the primary targets for antipsychotic drugs, including clozapine and quetiapine, and because some studies have found D2 receptors to be elevated in schizophrenia, we examined the mRNA of three forms of the D2 receptor, particularly the new form of the dopamine D2 receptor, D2(Longer), in post-mortem brains from patients who died with schizophrenia. Using quantitative competitive RT-PCR (reverse transcriptase-polymerase chain reaction), the D2(Longer) mRNA was higher in the frontal cortex, compared to control tissues. The mRNA concentration of D2(Long) and D2(Short) was also higher in the frontal cortex, compared to control tissues. Although most of the schizophrenia patients had received different antipsychotic drugs for varying periods of time, the mRNA of D2(Longer), as well as that for D2(Long) and D2(Short), in such medicated tissues was similar to that in a frontal cortex tissue from a patient who had reliably never received antipsychotic drugs. It is possible, therefore, that the elevation of the mRNAs for D2(Longer), D2(Long) and D2(Short) in the frontal cortex may be related to the disease of schizophrenia itself.

Rhinorrhea, ventricular radiopharmaceutical stasis and communicating hydrocephalus: evaluation by serial cisternography.

Spontaneous cerebrospinal fluid rhinorrhea has been known to occur in association with hydrocephalus. The specific pathophysiology which results in a potential communication between the cerebrospinal fluid space (subarachnoid space) and the nasopharynx is unknown. The relationship of CSF movement and rhinorrhea was evaluated in ten random source mongrel dogs. These data suggest that spontaneous CSF rhinorrhea may occur during the early developmental phase of communicating hydrocephalus in dogs. At this time radiopharmaceutical movement showed ventricular entry and clearing. When the lateral ventricles enlarged, ventricular radiopharmaceutical stasis was seen and the rhinorrhea disappeared. This suggests that CSF rkinorrhea may act as a compensatory mechanism which partially protects the CSF compartment to withstand the extra CSF during the early development of communicating hydrocephalus.

Natural history of autologous blood clot embolization in swine.

Previous studies of the natural history of embolized clots in dogs have demonstrated rapid lysis, presumably because the canine fibrinolytic system is very active. The fibrinolytic activity in swine, however, is similar to humans, and for this reason the pig was chosen for our study. The gluteal branches of the external iliac artery in nine domestic swine were embolized with either unmodified or modified (heat-formed, Amicar) autologous clot. In addition, three pigs were embolized with unmodified autologous clot to branches of the gastrosplenic artery. The lysis of clot emboli in both groups was followed by serial angiography at 48 hours and 14 days. Clot lysis as assessed by euglobulin lysis and plasmin generation was not activated by the experimental technique. Necropsy was performed on the animals in the second group. Partial or total obstruction of all arteries was present 48 hours after embolization and only 50% of arteries were recanalized at 14 days. At necropsy, organized partially occluding clot was demonstrated in the splenic artery of all 3 embolized swine. It is concluded that: 1)swine provide an excellent animal model for studying the natural history of arterial embolization; 2)Amicar or heat-formed clot shows no advantage over simple autologous clot in retarding intra-arterial clot lysis, and 3)simple autologous clot is an effective material for temporary intra-arterial occlusion.

Early changes in experimental hydrocephalus.

In acute obstruction of the cerebral spinal fluid (CSF) absorption pathways, fluid is produced more rapidly than it is absorbed, and the ventricles enlarge proximal to the obstructions. Communicating hydrocephalus results from a difference between the rates of production and absorption of cerebrospinal fluid. In animals with chronic communicating hydrocephalus, the initial pathologic changes appear to involve the periventricular tissue near the angles of the lateral ventricles. The present investigation was designed to identify the various changes associated with the production of communicating hydrocephalus in acutely hydrocephalic preparations and to relate these findings to those found in experimental animals with chronic communicating hydrocephalus. The results of this study seem to confirm that the changes noted in the chronically hydrocephalic animals occur as early as 12 hours after the restriction of the normal flow of CSF.