Brain damage and cortical compensation in foreign accent syndrome

Foreign Accent Syndrome (FAS) is a well-known neurological deficit whose underlying cause has remained obscure despite almost a century of study. Combining structural and functional imaging, our studies suggest that FAS represents a compensatory response to impaired motor regulation of speech. We describe a patient who acquired FAS as a result of an ischemic stroke in the left basal ganglia. In addition to this case being exceptionally clean, we were able to confirm a specific lesion location as well as provide strong evidence that impaired motor speech regulation resulted in compensation by other areas of the cortical motor speech network.     

The epidemiology of bipolar disorder: sociodemographic, disability and service utilization data from the Australian National Study of Low Prevalence (Psychotic) Disorders

OBJECTIVES: Data from the Australian National Study of Low Prevalence (Psychotic) Disorders were used to describe the clinical and sociodemographic profile of individuals with bipolar disorder, their levels of impairment and disability, and use of medication and treatment services. METHODS: A 1-month census of contacts with mental health services, private psychiatric and general practices, as well as contact points in marginalized settings, was conducted in a national catchment of 1.1 million adults. The census yielded 3,800 individuals who screened positive for psychosis, of whom a random sample of 980 were administered a comprehensive semi-structured interview schedule. Results are presented on 112 persons with an ICD-10 diagnosis of bipolar disorder. RESULTS: Overall, 69.6% of the 112 persons who met the ICD-10 criteria for bipolar disorder reported a recurrent episodic illness, 25.0% had a chronic course without clear remissions, and 5.4% had a single episode of mania. Assessed on a lifetime basis, suicidal ideation was common (78.6%) and levels of drug and alcohol abuse/dependence were high (32.1%). The majority (84.8%) had had at least one contact with inpatient, outpatient or emergency services in the previous year. Those with serious impairment had levels of service utilization similar to the rest of the sample, but were more likely to report a poorer quality of life and unmet service needs. While the percentage experiencing social and occupational dysfunction was substantial and similar for both sexes, women appeared to be better integrated socially than men. Comparisons with schizophrenia patients within the same survey sample highlighted less chronic impairment but equal or greater utilization of services by bipolar patients. CONCLUSIONS: Despite low levels of chronicity, the burden of social disablement associated with bipolar disorder is high. The data suggest a number of important gaps in the provision of services for this predominantly treated population.     

Evaluation of the pattern of treatment, level of anticoagulation control, and outcome of treatment with warfarin in patients with non-valvar atrial fibrillation: a record linkage study in a large British population

Objective: To evaluate how well patients with non-valvar atrial fibrillation (NVAF) were maintained within the recommended international normalised ratio (INR) target of 2.0–3.0 and to explore the relation between achieved INR control and clinical outcomes.

Design: Record linkage study of routine activity records and INR measurements.

Setting: Cardiff and the Vale of Glamorgan, South Wales, UK.

Participants: 2223 patients with NVAF, no history of heart valve replacement, and with at least five INR measurements.

Main outcome measures: Mortality, ischaemic stroke, all thromboembolic events, bleeding events, hospitalisation, and patterns of INR monitoring.

Results: Patients treated with warfarin were outside the INR target range 32.1% of the time, with 15.4% INR values > 3.0 and 16.7% INR values < 2.0. However, the quartile with worst control spent 71.6% of their time out of target range compared with only 16.3% out of range in the best controlled quartile. The median period between INR tests was 16 days. Time spent outside the target range decreased as the duration of INR monitoring increased, from 52% in the first three months of monitoring to 30% after two years. A multivariate logistic regression model showed that a 10% increase in time out of range was associated with an increased risk of mortality (odds ratio (OR) 1.29, p < 0.001) and of an ischaemic stroke (OR 1.10, p = 0.006) and other thromboembolic events (OR 1.12, p < 0.001). The rate of hospitalisation was higher when INR was outside the target range.

Conclusions: Suboptimal anticoagulation was associated with poor clinical outcomes, even in a well controlled population. However, good control was difficult to achieve and maintain. New measures are needed to improve maintenance anticoagulation in patients with NVAF.

     

Persistence of group C anticapsular antibodies two to three years after immunization with an investigational quadrivalent Neisseria meningitidis-diphtheria toxoid conjugate vaccine

BACKGROUND: An investigational quadrivalent (A, C, Y and W-135) meningococcal conjugate (MC-4) vaccine was reported to be more immunogenic in 2-year-olds than the currently licensed meningococcal polysaccharide vaccine, but persistence of serum antibody beyond 6 months after conjugate vaccination is unknown. OBJECTIVE: Determine persistence and the immunologic basis of protective activity of group C anticapsular antibodies in sera obtained 2-3 years after MC-4 vaccination. DESIGN: Group C antibody concentrations, bactericidal activity and passive protective activity were measured in sera from 48 children, ages 4-5 years, who had been immunized 2-3 years earlier with an MC-4 vaccine and from 47 children who had not been previously vaccinated. RESULTS: Serum antibody concentrations were higher in the vaccinated than the unvaccinated children (geometric means, 0.30 and 0.09 mug/mL, respectively, P < 0.0001). Bactericidal titers > or =1/4 (considered protective) were infrequent in both vaccinated and unvaccinated children (14.6 and 6.4%, respectively, P = 0.3). Passive protective activity against bacteremia in the infant rat model was more frequent in sera from vaccinated (37.5%) than sera from unvaccinated children (12.5%, P < 0.02). The proportion of sera with passive protective activity increased with increasing anticapsular antibody concentrations (P < 0.0001). INTERPRETATION: Serum group C antibody concentrations remained elevated for 2-3 years after MC-4 vaccination, and passive protective activity was more frequent in vaccinated than unvaccinated children. However, serum antibody concentrations in many vaccinated children were no longer sufficient to activate complement-mediated bacteriolysis in vitro or to confer passive protection against experimental group C disease.     

Mass of the postsynaptic density and enumeration of three key molecules

The total molecular mass of individual postsynaptic densities (PSDs) isolated from rat forebrain was measured by scanning transmission EM. PSDs had a mean diameter of 360 nm and molecular mass of 1.10 +/- 0.36 GDa. Because the mass represents the sum of the molecular masses of all of the molecules comprising a PSD, it becomes possible to derive the number of copies of each protein, once its relative mass contribution is known. Mass contributions of PSD-95, synapse-associated protein (SAP)97, and alpha-Ca2+/calmodulin-dependent protein kinase II (CaMKII) were determined by quantitative gel electrophoresis of PSD fractions. The number of PSD-95 molecules per average PSD, contributing 2.3% of the mass of the PSD, was calculated to be 300, whereas the number of SAP97 molecules, contributing 0.9% of the mass of the PSD, was 90. The alpha-CaMKII holoenzymes, which contribute 6% of the mass when brains are homogenized within 2 min of interrupting blood flow, have 80 holoenzymes associated with a typical PSD. When blood flow is interrupted 15 min before homogenization, the average mass of PSDs increases by approximately 40%. The additional alpha-CaMKII associated with PSDs accounts for up to 20% of this mass increase, representing the addition of 100-200 alpha-CaMKII holoenzymes.     

Motherhood mitigates aging-related decrements in learning and memory and positively affects brain aging in the rat

The current work examined spatial learning and memory (i.e., latencies to find a baited food well) in age-matched nulliparous, primiparous and multiparous (NULL, PRIM and MULT, zero, one or two pregnancies and lactations, respectively). We tested at 6, 12, 18 and 24 months of age in a dry land version of the Morris water maze (Main task), and at 12, 18 and 24 months in the same task in which the original location of the baited well was changed (Reversal task). We show that PRIM/MULT rats, compared to the age-matched NULL females, learned the spatial tasks significantly better and exhibited attenuated memory decline, up to 24 months of age. Furthermore, at the conclusion of behavioral testing, we investigated levels of these animals' hippocampal (CA1 and dentate gyrus) immunoreactive amyloid precursor protein (APP), a marker of neurodegeneration and age-related cognitive loss. MULTs had significantly reduced APP in both CA1 and DG, relative to PRIMs and NULLs, and PRIMs had a trend (p<0.06) toward a reduction in APP compared to NULLs in DG. Further, level of APP was negatively correlated with performance in the two tasks (viz., more APP, worse maze performance). Reproduction, therefore, with its attendant natural endocrine and postpartum sensory experiences, may facilitate lifelong learning and memory, and may mitigate markers of neural aging, in the rat. Combining natural hormonal exposure with subsequent substantial experience with stimuli from the offspring may preserve the aged parous female brain relative to that of NULL females.     

Pregnancy, delivery, and neonatal complications in a population cohort of women with schizophrenia and major affective disorders

OBJECTIVE: This study ascertained the incidence of complications during pregnancy, labor, and delivery and the neonatal characteristics of infants born to women with schizophrenia, bipolar disorder, or major depression in a population-based cohort. METHOD: Based on records linkage across a psychiatric case register and prospectively recorded obstetric data, the study comprised women with schizophrenia or major affective disorders who had given birth to 3,174 children during 1980-1992 in Western Australia. A comparison sample of 3,129 births to women without a psychiatric diagnosis was randomly selected from women giving birth during 1980-1992. Complications were scored with the McNeil-Sj?str?m Scale. Odds ratios were calculated for specific reproductive events. RESULTS: Both schizophrenic and affective disorder patients had increased risks of pregnancy, birth, and neonatal complications, including placental abnormalities, antepartum hemorrhages, and fetal distress. Women with schizophrenia were significantly more likely to have placental abruption, to give birth to infants in the lowest weight/growth population decile, and to have children with cardiovascular congenital anomalies. Neonatal complications were significantly more likely to occur in winter; low birth weight peaked in spring. Complications other than low birth weight and congenital anomalies were higher in pregnancies after psychiatric illness than in pregnancies preceding the diagnosis. CONCLUSIONS: While genetic liability and gene-environment interactions may account for some outcomes, maternal risk factors and biological and behavioral concomitants of severe mental illness appear to be major determinants of increases in reproductive pathology in this cohort. Risk reduction in these vulnerable groups may be achievable through antenatal and postnatal interventions.     

Antinociceptive tolerance to morphine from repeated nociceptive testing in the rat

Repeated morphine administration has been shown to produce tolerance to the antinociceptive effects of morphine. However, the degree to which repeated morphine administration decreases antinociception is exaggerated by repeated behavioral testing, a phenomenon known as behavioral tolerance. An important question is whether behavioral tolerance can be overcome by direct administration of morphine into the ventrolateral periaqueductal gray (vPAG), a key structure contributing to morphine antinociception. Rats were injected with morphine or saline into the vPAG (Experiment 1) or subcutaneously (Experiment 2) followed 20 min later with hot-plate testing. The control groups received the same drug administration, but no nociceptive testing. Repeated nociceptive testing or repeated morphine administration produced antinociceptive tolerance regardless of whether morphine was injected into the vPAG or systemically. Administration of a high dose of morphine (20 mg/kg, s.c.) was able to overcome the development of behavioral tolerance, but not pharmacological tolerance revealing separate mechanisms for these two types of tolerance. These data indicate that behavioral tolerance is independent of the route of morphine administration.     

A novel somatic mutation of the 3beta-hydroxysteroid dehydrogenase gene in sporadic cutaneous verruciform xanthoma

OBJECTIVE: To analyze the 3beta-hydroxysteroid dehydrogenase (NSDHL) gene in verruciform xanthoma (VX) to elucidate its potential role in the histogenesis of this lesion. DESIGN: DNA was extracted from paraffin-embedded tissue, followed by polymerase chain reaction amplification of exons 4 and 6 of the NSDHL gene. The polymerase chain reaction products were then directly sequenced and analyzed for the presence of somatic mutations. PATIENTS: Nine lesions of VX from 8 patients and 3 unrelated normal controls were evaluated. RESULTS: Two of 9 VXs (22%) demonstrated a novel somatic missense mutation in exon 6 of the NSDHL gene. The mutation was not present in the remaining 7 lesions of VX, nonlesional internal controls, and 3 unrelated normal controls. No mutation of exon 4 was found in any case. Mutations of exons 4 and 6 previously identified in CHILD syndrome were not seen in our cases. CONCLUSIONS: (1) A novel missense mutation (R199H) in exon 6 of the NSDHL gene was identified in a small subset of sporadic VXs. (2) Known CHILD syndrome mutations in exons 4 and 6 of the NSDHL gene do not contribute to the histogenesis of sporadic VXs.     

Dynamic complexity of the microglial activation response in transgenic models of amyloid deposition: implications for Alzheimer therapeutics

The presence of activated microglia in postmortem Alzheimer disease specimens is used to support the argument that inflammation contributes to Alzheimer pathogenesis. Transgenic mice overexpressing the amyloid precursor protein (APP) gene form amyloid plaques that are accompanied by local activation of microglia/macrophages in a manner similar to the human disease. Many markers of microglial activation and inflammation increase in an age-dependent manner in these mice. However, manipulation of these inflammatory reactions can lead to unexpected outcomes with several instances of reduced pathology when microglia/macrophages are activated further. In particular, anti-Abeta immunotherapy in amyloid-depositing transgenic mice causes a complex series of changes in microglial markers, negating the implicit belief that such activation is monotonic and represented equally well by any of several "activation" markers. A survey of the peripheral macrophage literature identifies at least 2 distinct activation states of macrophages with different consequences for the surrounding tissue. These different activation states can often be distinguished by the markers that are expressed. Several markers are identified from studies outside the brain that neuroscientists might consider evaluating when attempting to more definitively describe the activation state of the monocyte-derived cells in the brain.