In vivo imaging of brain microglial activity in antipsychotic-free and medicated schizophrenia: a [11C](R)-PK11195 positron emission tomography study.

Positron emission tomography (PET) imaging of the 18 kDa translocator protein (TSPO) has been used to investigate whether microglial activation, an indication of neuroinflammation, is evident in the brain of adults with schizophrenia. Interpretation of these studies is confounded by potential modulatory effects of antipsychotic medication on microglial activity. In the first such study in antipsychotic-free schizophrenia, we have used [11C](R)-PK11195 PET to compare TSPO availability in a predominantly antipsychotic-naive group of moderate-to-severely symptomatic unmedicated patients (n=8), similarly symptomatic medicated patients with schizophrenia taking risperidone or paliperidone by regular intramuscular injection (n=8), and healthy comparison subjects (n=16). We found no evidence for increased TSPO availability in antipsychotic-free patients compared with healthy controls (mean difference 4%, P=0.981). However, TSPO availability was significantly elevated in medicated patients (mean increase 88%, P=0.032) across prefrontal (dorsolateral, ventrolateral, orbital), anterior cingulate and parietal cortical regions. In the patients, TSPO availability was also strongly correlated with negative symptoms measured using the Positive and Negative Syndrome Scale across all the brain regions investigated (r=0.651-0.741). We conclude that the pathophysiology of schizophrenia is not associated with microglial activation in the 2-6 year period following diagnosis. The elevation in the medicated patients may be a direct effect of the antipsychotic, although this study cannot exclude treatment resistance and/or longer illness duration as potential explanations. It also remains to be determined whether it is present only in a subset of patients, represents a pro- or anti-inflammatory state, its association with primary negative symptoms, and whether there are significant differences between antipsychotics.

Bayesian latent class estimation of the incidence of chest radiograph-confirmed pneumonia in rural Thailand.

Pneumonia is a leading cause of mortality and morbidity worldwide with radiographically confirmed pneumonia a key disease burden indicator. This is usually determined by a radiology panel which is assumed to be the best available standard; however, this assumption may introduce bias into pneumonia incidence estimates. To improve estimates of radiographic pneumonia incidence, we applied Bayesian latent class modelling (BLCM) to a large database of hospitalized patients with acute lower respiratory tract illness in Sa Kaeo and Nakhon Phanom provinces, Thailand from 2005 to 2010 with chest radiographs read by both a radiology panel and a clinician. We compared these estimates to those from conventional analysis. For children aged <5 years, estimated radiographically confirmed pneumonia incidence by BLCM was 2394/100 000 person-years (95% credible interval 2185-2574) vs. 1736/100 000 person-years (95% confidence interval 1706-1766) from conventional analysis. For persons aged ⩾5 years, estimated radiographically confirmed pneumonia incidence was similar between BLCM and conventional analysis (235 vs. 215/100 000 person-years). BLCM suggests the incidence of radiographically confirmed pneumonia in young children is substantially larger than estimated from the conventional approach using radiology panels as the reference standard.

Immunity to polio, measles and rubella in women of child-bearing age and estimated congenital rubella syndrome incidence, Cambodia, 2012.

Significant gaps in immunity to polio, measles, and rubella may exist in adults in Cambodia and threaten vaccine-preventable disease (VPD) elimination and control goals, despite high childhood vaccination coverage. We conducted a nationwide serological survey during November-December 2012 of 2154 women aged 15-39 years to assess immunity to polio, measles, and rubella and to estimate congenital rubella syndrome (CRS) incidence. Measles and rubella antibodies were detected by IgG ELISA and polio antibodies by microneutralization testing. Age-structured catalytic models were fitted to rubella serological data to predict CRS cases. Overall, 29.8% of women lacked immunity to at least one poliovirus (PV); seroprevalence to PV1, PV2 and PV3 was 85.9%, 93.4% and 83.3%, respectively. Rubella and measles antibody seroprevalence was 73.3% and 95.9%, respectively. In the 15-19 years age group, 48.2% [95% confidence interval (CI) 42.4-54.1] were susceptible to either PV1 or PV3, and 40.3% (95% CI 33.0-47.5) to rubella virus. Based on rubella antibody seroprevalence, we estimate that >600 infants are born with CRS in Cambodia annually. Significant numbers of Cambodian women are still susceptible to polio and rubella, especially those aged 15-19 years, emphasizing the need to include adults in VPD surveillance and a potential role for vaccination strategies targeted at adults.

Predictive value of the test of infant motor performance and the Hammersmith infant neurological examination for cerebral palsy in infants.

BACKGROUND: Current recommendations for early detection tools for cerebral palsy (CP) include assessments that vary in feasibility and resource requirements. The predictive value of less resource-intensive tools has not been fully explored. AIMS: To determine the predictive value of the Test of Infant Motor Performance (TIMP) at 3-4 months corrected age (CA) for CP, and whether administration of both the TIMP and the Hammersmith Infant Neurological Exam (HINE) improves early CP detection. STUDY DESIGN: Five-year retrospective observational study of infants who received the TIMP and the HINE at 3-4 months CA in a high-risk follow-up clinic. TIMP and HINE cut-off scores (alone and in combination) were compared for CP discriminatory ability. SUBJECTS: Of patients with HINE scores (n = 1389; 676 [48.7 %] female; median gestational age at birth 31 weeks [interquartile range 29-34 weeks]), 1343 had concurrent TIMP scores available. OUTCOME MEASURES: Clinical diagnosis of CP. RESULTS: HINE total score <57 had optimal CP predictive value (AUC = 0.815; 77 % sensitivity; 91 % specificity) compared to optimal TIMP cut-off (1 SD below the mean, AUC = 0.71; 52 % sensitivity; 94 % specificity) and all tested TIMP and HINE combinations (all p < 0.001). CONCLUSIONS: HINE total score <57 at 3-4 months CA had the best CP predictive value, confirming its value absent first-line detection tools. Concurrent administration of TIMP did not improve predictive value.

Effects on patients with asthma of eradicating visible indoor mould: a randomised controlled trial.

BACKGROUND: It is not clear whether associations between respiratory symptoms and indoor mould are causal. A randomised controlled trial was conducted to see whether asthma improves when indoor mould is removed. METHODS: Houses of patients with asthma were randomly allocated into two groups. In one group, indoor mould was removed, fungicide was applied and a fan was installed in the loft. In the control group, intervention was delayed for 12 months. Questionnaires were administered and peak expiratory flow rate was measured at baseline, 6 months and 12 months. RESULTS: Eighty-one houses were allocated to the intervention group and 83 to the control group; 95 participants in 68 intervention houses and 87 in 63 control houses supplied follow-up information. Peak expiratory flow rate variability declined in both groups, with no significant differences between them. At 6 months, significantly more of the intervention group showed a net improvement in wheeze affecting activities (difference between groups 25%, 95% CI 3% to 47%; p = 0.028), perceived improvement of breathing (52%, 95% CI 30% to 74%; p<0.0001) and perceived reduction in medication (59%, 95% CI 35% to 81%; p<0.0001). By 12 months the intervention group showed significantly greater reductions than the controls in preventer and reliever use, and more improvement in rhinitis (24%, 95% CI 9% to 39%; p = 0.001) and rhinoconjunctivitis (20%, 95% CI 5% to 36%; p = 0.009). CONCLUSIONS: Although there was no objective evidence of benefit, symptoms of asthma and rhinitis improved and medication use declined following removal of indoor mould. It is unlikely that this was entirely a placebo effect.

Erythropoietin sensitivity as a differentiation marker in the hemopoietic system: studies of three erythropoietic colony responses in culture.

A time course study of the sequential appearance of erythropoietin-dependent colonies and bursts (derived from CFU-E and BFU-E, respectively) was performed on mouse hemopoietic cells cultured in methyl cellulose containing 2-mercaptoethanol. A new type of small, short-lived burst was found to be apparent by the third day in culture. By the sixth day most of these bursts had lysed. At the same time, differentiating erythroblasts began to be detectable in the large, late appearing bursts described previously. These two types of burst, differing from each other and from CFU-E derived colonies both in their ultimate size and morphology, as well as in their time course of appearance and lysis, were compared in other ways. It was found that early burst formation required about 100 times more erythropoietin than that needed to stimulate CFU-E. On the other hand, early burst formation required less than one-quarter of the amount of erythropoietin needed to obtain the large, late appearing bursts. Comparison of the distribution of early burst progenitors relative to pluripotent stem cells (CFU-S) in individual spleen colonies gave a correlation coefficient that was also intermediate between that obtained comparing CFU-S with CFU-E and that obtained comparing CFU-S with the progenitors of late bursts. These results suggest that decreasing proliferative capacity is associated with progressively increasing erythropoietin responsiveness as primitive erythropoietic progenitors move from a position close to pluripotent stem cells through several differentiation steps to reach a stage just prior to the onset of detectable hemoglobin synthesis.

Three stages of erythropoietic progenitor cell differentiation distinguished by a number of physical and biologic properties.

Previous studies have shown that erythroid precursors at sequential stages of differentiation along the red cell pathway can be distinguished by differences in the size and maturation kinetics of the colonies to which they give rise in vitro. Using criteria based on these two parameters, it is thus possible to identify three distinct erythroid progenitor cell populations in the mouse, known as day 8 BFU-E, day 3 BFU-E, and CFU-E. These cell types have now been shown to differ in a number of other respects, including progenitor cell size, sensitivity to cycle-active agents, response to plethora, and effects of the W/Wv genotype. In addition, a comparison of the differences found between day 8 BFU-E and day 3 BFU-E on one hand and those distinguishing day 3 BFU-E and CFU-E on the other provides support for the view that early erythropoietic cell differentiation involves a series of changes that take place long before competence to synthesize hemoglobin becomes manifest.

Human marrow cells capable of erythropoietic differentiation in vitro: definition of three erythroid colony responses.

A systematic study has been undertaken to analyze the spectrum of erythropoietic colonies obtained in cultures of human marrow cells plated in methyl cellulose. Colonies were identified as erythropoietic on the basis of the appearance in them of hemoglobin-containing erythroblasts. As found previously in mouse marrow cultures, three sequentially appearing types of colonies which differed in their ultimate cluster content could be readily distinguished. Small erythroid colonies containing 1-2 clusters reached a peak after 7-8 days; small bursts containing 3-8 clusters reached a peak after 10-12 days; and large bursts containing greater than 16 clusters reached a peak after 17-20 days. The previously reported enhancing effect of human leukocyte conditioned medium on burst formation seen in cultures of human nonadherent cells was found to be due largely to an effect on the formation of the largest, late appearing type of burst. By analogy with the mouse, the progenitors of such bursts would represent a primitive cell type which has a close relationship with pluripotent stem cells, as well as a second and independent close relationship to the progenitors of granulopoietic colonies.

A study of the immunosuppressive activity of methylene dimethane sulphonate (MDMS) in relation to its effectiveness as an anti-tumour agent.

The anti-tumour action of methylene dimethane sulphonate (MDMS) has been further investigated in relation to its immunosuppressive properties. Following a dose of 10 mg/kg, the proportion of permanent regressions of Yoshida lymphosarcoma transplants is lower in animals treated during the first 5 days of tumour growth. Re-implants on day 28 to those animals in which regression of the tumour had occurred indicated that the immune response to the tumour increases during the first 7 days of tumour growth.Studies of the effect of MDMS on the primary antibody-forming cell response of mice to sheep red cell antigens showed this drug to be an immunosuppressant comparable in strength to x-radiation. MDMS given to rats prior to tumour transplantation also acted as an immunosuppressant in this system resulting in an increased rate of tumour growth. For both responses the maximum immunosuppressive effect was obtained when the interval between drug administration and antigenic challenge was minimal.

The cellular basis for the defect in haemopoiesis in flexed-tailed mice. III. Restriction of the defect to erythropoietic progenitors capable of transient colony formation in vivo.

Three assays for erythropoietic progenitor cells have been applied to mice of genotype f/f and to nearly congenic +/+ controls. When f/f mice were tested for their ability to generate transient endogenous erythroid spleen colonies 4-6 days after 800 rads and 10 units of erythropoietin, the numbers of such colonies detected were greatly reduced, although normal numbers of spleen colonies appeared at later times (9-12 days) postirradiation. In contrast, cells capable of erythropoietic colony formation in culture (CFU-E) were present within the normal range in both f/f spleen and marrow and their sensitivity to erythropoietin in culture was the same as that found previously for CFU-E in the marrow and spleen of +/+ mice. Transfusion-induced plethora reduced the number of CFU-E in marrow to a similar extent in both f/f and +/+ mice; likewise, subsequent administration of 10 units of erythropoietin induced a rapid return in the number of marrow CFU-E in both genotypes. In the spleen, CFU-E numbers were approximately three-fold lower in f/f mice in each group. These results support the view that the 5 day assay for transient endogenous spleen colonies detects cells (TE-CFU) that are different from both CFU-E and pluripotent stem cells (CFU-S), although possibly overlapping to some extent with the immediate progenitors of CFU-E. The results also indicate that the generation or maturation of TE-CFU represents a primary site of expression of the f/f defect.

Transient erythropoietic spleen colonies: effects of erythropoietin in normal and genetically anemic W/Wv mice.

Properties of the cells (TE-CFU) that give rise within four to six days to transient endogenous erythropoietic spleen colonies in irradiated mice have been investigated. The results obtained indicate that (1) erythropoietic maturation within such colonies is highly erythropoietin-dependent, (2) the population size of TE-CFU is not erythropoietin-dependent, (3) initial exposure to a high dose of erythropoietin followed by continuing exposure to lower doses is required for maximal efficiency of colony formation by TE-CFU, (4) successful transplantation of TE-CFU has not been achieved, but they appear among the progeny of transplanted hemopoietic cells, (5) TE-CFU are defective in mice of genotype W/Wv. These findings are consistent with the view that the TE-CFU assay detects a class of early erythropoietin-sensitive progenitor cells committed to erythropoietic diffferentiation, rather than "abortive" colony formation by pluripotent stem cells.