Alleviating spatial confounding in frailty models.

The confounding between fixed effects and (spatial) random effects in a regression setup is termed spatial confounding. This topic continues to gain attention and has been studied extensively in recent years, given that failure to account for this may lead to a suboptimal inference. To mitigate this, a variety of projection-based approaches under the class of restricted spatial models are available in the context of generalized linear mixed models. However, these projection approaches cannot be directly extended to the spatial survival context via frailty models due to dimension incompatibility between the fixed and spatial random effects. In this work, we introduce a two-step approach to handle this, which involves (i) projecting the design matrix to the dimension of the spatial effect (via dimension reduction) and (ii) assuring that the random effect is orthogonal to this new design matrix (confounding alleviation). Under a fully Bayesian paradigm, we conduct fast estimation and inference using integrated nested Laplace approximation. Both simulation studies and application to a motivating data evaluating respiratory cancer survival in the US state of California reveal the advantages of our proposal in terms of model performance and confounding alleviation, compared to alternatives.

Reassessment and Relationships of †Scutatuspinosus itapagipensis (Teleostei, Clupeomorpha, †Ellimmichthyiformes) from the Neocomian of Recôncavo Basin, Northeastern Brazil.

Clupeomorphs are found in many assemblages of the northeastern Brazil, whose ages range from the Neocomian to Paleogene. Ten species were described. Among them †Scutatuspinosus itapagipensis, a torpedo-like fish found in shales of the Marfim Formation from Bahia, remains poorly known. At first it was positioned within †Scutatuspinosinae and indicated as closely related to †Diplomystus. Diagnoses for the subfamily and genus were based on certain characters masking relationships. Recently it was placed in †Ellimmichthyiformes, but its systematic position remains controversial. We furnish additional data and restorations together with a parsimony analysis with TNT program, using 60 unordered and unweighted characters from selected species of 13 genera. Our analysis produced 12 trees with 158 steps, a consistency index (CI) of 0.44 and retention index (RI) of 0.52. Low support indices still indicate insufficient data for many taxa and uncertain status for clades. According to the majority rule consensus, †Scutatuspinosus itapagipensis is placed within a "†paraclupeine" group with †Ezkutuberezi carmenae, †Ellimma branneri, †Ellimmichthys longicostatus, and †Paraclupea chetunguensis. Its minimum age and position among †paraclupeids indicate an early history of the group older than it was thought to be, supporting a biogeographical hypothesis based on generalized track from China to northeastern Brazil during the Lower Cretaceous.

Relationships of †Codoichthys carnavalii Santos, 1994 (Teleostei, Clupeomorpha, †Ellimmichthyiformes) from the Late Aptian of São Luís-Grajaú Basin, NE Brazil.

†Codoichthys carnavalii is a clupeomorph fish only found in calcareous concretions of Codó Formation, State of Maranhão. It is known based on three specimens housed in the paleontological collection of the Museu de Ciências da Terra of Departamento Nacional da Produção Mineral, Rio de Janeiro. It was omitted in most of recent cladistic analyses about clupeomorphs. We revisited its anatomy furnishing new data and additional restorations. Furthermore we explored the relationships of †Codoichthys with the computer program TNT based on a matrix with 30 taxa and 60 unordered and unweight characters. Elops was used to root the tree. The strict consensus was obtained from three shortest trees (L=181; CI=0.387; RI=0.632). The monophyly of †Ellimmichthyiformes is supported by a sigmoid cleithrum and an uniquely derived predorsal scute series. Most of subgroups showed low support indices. †Sorbinichthyidae and †Horseshoeichthys appear in the most basal position, and not closely related to †Armigatus or †Diplomystus. A †Diplomystus clade is more advanced than †Armigatus and sister-group of remaining †ellimmichthyiforms. Within †Paraclupeidae, †Codoichthys is sister-group of remaining †paraclupeids (including †thorectichthyines and †paraclupeines). Within †Paraclupeinae, †Triplomystini includes a †Triplomystus clade, a sister group of †Rhombichthys plus †Tycheroichthys, and †Paraclupeini with †S. itapagipensis and all other †ellimmichthyiform taxa.

Treatment of age-related visual impairment with a peptide acting on mitochondria.

Age-related visual decline and disease due to neural dysfunction are major sources of disability that have resisted effective treatment. In light of evidence that visual impairment and mitochondrial dysfunction advance with age, we characterized age-related decline of spatial visual function in mice and investigated whether treatment of aged mice with the mitochondrion-penetrating peptide elamipretide that has been reported to improve mitochondrial function, would improve it. Impaired photopic acuity measured by using a virtual optokinetic system emerged near 18 months and declined to ∼40% below normal by 34 months. Daily application of the synthetic peptide elamipretide, which has high selectivity for mitochondrial membranes that contain cardiolipin and promotes efficient electron transfer, was able to mitigate visual decline from 18 months onwards. Daily application from 24 months onwards, i.e. when acuity had reduced by ∼16%, reversed visual decline and normalized function within 2 months. Recovered function persisted for at least 3 months after treatment was withdrawn and a single treatment at 24 months delayed subsequent visual decline. Elamipretide applied daily from 32 months onwards took longer to take effect, but substantial improvement was found within 2 months. The effects of age and elamipretide treatment on contrast sensitivity were similar to those on acuity, systemic and eye drop applications of elamipretide had comparable effects, scotopic spatial visual function was largely unaffected by age or treatment, and altered function was independent of variation in optical clarity. These data indicate that elamipretide treatment adaptively alters the aging visual system. They also provide a rationale to investigate whether mitochondrial dysfunction is a treatable pathophysiology of human visual aging and age-related visual disease.

Epicardial Fat Volume Is Associated with Endothelial Dysfunction, but not with Coronary Calcification: From the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil). / Volume de Gordura Epicárdica está Associada com Disfunção Endotelial, mas Não com Calcificação Coronariana: Do ELSA-Brasil.

BACKGROUND: The increase in epicardial fat volume (EFV) is related to coronary artery disease (CAD), independent of visceral or subcutaneous fat. The mechanism underlying this association is unclear. Coronary artery calcium (CAC) score and endothelial dysfunction are related to coronary events, but whether EFV is related to these markers needs further clarification. OBJECTIVES: To evaluate the association between automatically measured EFV, cardiovascular risk factors, CAC, and endothelial function. METHODS: In 470 participants from the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil) with measures of EFV, CAC score and endothelial function, we performed multivariable models to evaluate the relation between cardiovascular risk factors and EFV (response variable), and between EFV (explanatory variable) and endothelial function variables or CAC score. Two-sided p <0.05 was considered statistically significant. RESULTS: Mean age was 55 ± 8 years, 52.3% of patients were men. Mean EFV was 111mL (IQ 86-144), and the prevalence of CAC score=0 was 55%. In the multivariable analyses, increased EFV was related to female sex, older age, waist circumference, and triglycerides (p<0.001 for all). Higher EFV was associated with worse endothelial function: as compared with the first quartile, the odds ratio for basal pulse amplitude were (q2=1.22, 95%CI 1.07-1.40; q3=1.50, 95%CI 1.30-1.74; q4=1.50, 95%CI 1.28-1.79) and for peripheral arterial tonometry ratio were (q2=0.87, 95%CI 0.81-0.95; q3=0.86, 95%CI 0.79-0.94; q4=0.80, 95%CI 0.73-0.89), but not with CAC score>0. CONCLUSION: Higher EFV was associated with impaired endothelial function, but not with CAC. The results suggest that EFV is related to the development of CAD through a pathway different from the CAC pathway, possibly through aggravation of endothelial dysfunction and microvascular disease.

FUNDAMENTO: O aumento no volume de gordura epicárdica (VGE) está relacionado com doença arterial coronariana (DAC), independentemente de gordura visceral ou subcutânea. O mecanismo dessa associação não é claro. O escore de cálcio coronariano (CC) e a disfunção endotelial estão relacionados com eventos coronarianos, mas não está bem esclarecido se o VGE está relacionado com esses marcadores. OBJETIVOS: Avaliar a associação entre VGE medido por método automatizado, fatores de risco cardiovasculares, escore de CC, e função endotelial. Métodos: Em 470 participantes do Estudo Longitudinal de Saúde do Adulto LSA-Brasil com medidas de VGE, escore de CC e função endotelial, realizamos modelos multivariados para avaliar a relação entre fatore de risco cardiovascular e VGE (variável resposta), e entre VGE (variável explicativa), e função endotelial ou escore de CC. Valor de p<0,05 bilateral foi considerado estatisticamente significativo. RESULTADOS: A idade média foi 55 ± 8 anos, e 52,3% dos pacientes eram homens. O VGE médio foi 111mL (86-144), e a prevalência de escore de CC igual a zero foi 55%. Nas análises multivariadas, um VGE mais alto relacionou-se com sexo feminino, idade mais avançada, circunferência da cintura, e triglicerídeos (p<0,001 para todos). Um VGE mais alto foi associado com pior função endotelial: em comparação ao primeiro quartil, os valores de odds ratio para a amplitude de pulso basal foram (q2=1,22; IC95% 1,07-1,40; q3=1,50, IC95% 1,30-1,74; q4=1,50, IC95% 1,28-1,79) e para a razão de tonometria arterial periférica foram (q2=0,87; IC95% 0,81-0,95; q3=0,86, IC95% 0,79-0,94; q4=0,80, IC95% 0,73-0,89), mas não com escore de CC maior que zero. CONCLUSÃO: Um VGE mais alto associou-se com comprometimento da função endotelial, mas não com escore de CC. Os resultados sugerem que o VGE esteja relacionado ao desenvolvimento de DAC por uma via diferente da via do CC, possivelmente pela piora da disfunção endotelial e doença microvascular.

Estimating hidden populations by transferring knowledge from geographically misaligned levels.

The estimation of hidden sub-populations is a hard task that appears in many fields. For example, public health planning in Brazil depends crucially of the number of people who holds a private health insurance plan and hence rarely uses the public services. Different sources of information about these sub-populations may be available at different geographical levels. The available information can be transferred between these different geographic levels to improve the estimation of the hidden population size. In this study, we propose a model that use individual level information to learn about the dependence between the response variable and explanatory variables by proposing a family of link functions with asymptotes that are flexible enough to represent the real aspects of the data and robust to departures from the model. We use the fitted model to estimate the size of the sub-population at any desired level. We illustrate our methodology estimating the sub-population that uses the public health system in each neighborhood of large cities in Brazil.

Assessing spatial confounding in cancer disease mapping using R.

BACKGROUND: Exploring spatial patterns in the context of cancer disease mapping (DM) is a decisive approach to bring evidence of geographical tendencies in assessing disease status and progression. However, this framework is not insulated from spatial confounding, a topic of significant interest in cancer epidemiology, where the latent correlation between the spatial random effects and fixed effects (such as covariates), often lead to misleading interpretation. AIMS: To introduce three popular approaches (RHZ, HH and SPOCK; details in paper) often employed to tackle spatial confounding, and illustrate their implementation in cancer research via the popular statistical software R. METHODS: As a solution to alleviate spatial confounding, restricted spatial regressions are constructed by either projecting the latent effect onto the orthogonal space of covariates, or by displacing the spatial locations. Popular parametric count data models, such as the Poisson, generalized Poisson and negative binomial, were considered for the areal count responses, while the spatial association is quantified via the conditional autoregressive (CAR) model. Our method of inference in Bayesian, sometimes aided by the integrated nested Laplace approximation (INLA) to accelerate computing. The methods are implemented in the R package RASCO available from the first author's GitHub page. RESULTS: The results reveal that all three methods perform well in alleviating the bias and variance inflation present in the spatial models. The effects of spatial confounding were also explored, which, if ignored in practice, may lead to wrong conclusions. CONCLUSION: Spatial confounding continues to remain a critical bottleneck in deriving precise inference from spatial DM models. Hence, its effects must be investigated, and mitigated. Several approaches are available in the literature, and they produce trustworthy results. The central contribution of this paper is providing the practitioners the R package RASCO, capable of fitting a large number of spatial models, as well as their restricted versions.

Association between C reactive protein and all-cause mortality in the ELSA-Brasil cohort.

BACKGROUND: High-sensitivity C reactive protein (hsCRP) has been proposed as a marker of incident cardiovascular disease and vascular mortality, and may also be a marker of non-vascular mortality. However, most evidence comes from either North American or European cohorts. The present proposal aims to investigate the association of hsCRP with the risk of all-cause mortality in a multiethnic Brazilian population. METHODS: Baseline data (2008-2010) of a cohort of 14 238 subjects participating in the Brazilian Longitudinal Study of Adult Health were used. hsCRP was assayed with immunochemistry. The association of baseline covariates with all-cause mortality was calculated by Cox regression for univariate model and adjusted for different confounders after a mean follow-up of 8.0±1.1 years. The final model was adjusted for age, sex, self-rated race/ethnicity, schooling, health behaviours and prevalent chronic disease. RESULTS: The risk of death increased steadily by quartiles of hsCRP, from 1.45 (95% CI 1.05 to 2.01) in quartile 2 to 1.95 (95% CI 1.42 to 2.69) in quartile 4, compared with quartile 1. Furthermore, the persistence of a significant graded association after the exclusion of deaths in the first year of follow-up suggests that these results are unlikely to be due to reverse causality. Finally, the HR was unaffected by the exclusion of participants who had self-reported medical history of diabetes, cancer and chronic obstructive pulmonary disease. CONCLUSIONS: Our study shows that hsCRP level is associated with mortality in a highly admixed population, independent of a large set of lifestyle and clinical variables.

Circadian rhythm of synaptic excitability in rat and monkey central nervous system.

Synaptic responses in hippocampal granule cells to stimulation of their afferent fibers from the entorhinal cortex fluctuate with a 24-hour period. The phase of this cycle for rats and monkeys depends on whether the animal is naturally nocturnal or diurnal. In a rat blinded by enucleation, the rhythm persists but drifts out of phase with the rhythm of sighted controls.

The sodium-activated potassium channel Slack is modulated by hypercapnia and acidosis.

Slack (Slo 2.2), a member of the Slo potassium channel family, is activated by both voltage and cytosolic factors, such as Na(+) ([Na(+)](i)) and Cl(-) ([Cl(-)](i)). Since the Slo family is known to play a role in hypoxia, and since hypoxia/ischemia is associated with an increase in H(+) and CO(2) intracellularly, we hypothesized that the Slack channel may be affected by changes in intracellular concentrations of CO(2) and H(+). To examine this, we expressed the Slack channel in Xenopus oocytes and the Slo 2.2 protein was allowed to be inserted into the plasma membrane. Inside-out patch recordings were performed to examine the response of Slack to different CO(2) concentrations (0.038%, 5%, 12%) and to different pH levels (6.3, 6.8, 7.3, 7.8, 8.3). In the presence of low [Na(+)](i) (5 mM), the Slack channel open probability decreased when exposed to decreased pH or increased CO(2) in a dose-dependent fashion (from 0.28+/-0.03, n=3, at pH 7.3 to 0.006+/-0.005, n=3, P=0.0004, at pH 6.8; and from 0.65+/-0.17, n=3, at 0.038% CO(2) to 0.22+/-0.07, n=3, P=0.04 at 12% CO(2)). In the presence of high [Na(+)](i) (45 mM), Slack open probability increased (from 0.03+/-0.01 at 5 mM [Na(+)](i), n=3, to 0.11+/-0.01, n=3, P=0.01) even in the presence of decreased pH (6.3). Since Slack activity increases significantly when exposed to increased [Na(+)](i), even in presence of increased H(+), we propose that Slack may play an important role in pathological conditions during which there is an increase in the intracellular concentrations of both acid and Na(+), such as in ischemia/hypoxia.

Prostaglandin transporter expression in mouse brain during development and in response to hypoxia.

Prostaglandins (PGs) are bioactive lipid mediators released following brain hypoxic-ischemic injury. Clearance and re-uptake of these prostaglandins occur via a transmembrane prostaglandin transporter (PGT), which exchanges PG for lactate. We used Western blot analyses to examine the PGT developmental profile and its regional distribution as well as changes in transporter expression during chronic hypoxia in the neonatal mouse brain. Microsomal preparations from four brain regions (cortex, hippocampus, cerebellum and brainstem/diencephalon) showed gradual increases in prostaglandin transporter expression in all brain regions examined from postnatal day 1 till day 30. There was a significant regional heterogeneity in the prostaglandin transporter expression with highest expression in the cortex, followed by cerebellum and hippocampus, and least expressed in the brainstem/diencephalon. To further delineate the pattern of prostaglandin transporter expression, separate astrocytic and neuronal microsomal preparations were also examined. In contrast to neurons, which had a robust expression of prostaglandin transporters, astrocytes had very little PGT expression under basal conditions. In response to chronic hypoxia, there was a significant decline in PGT expression in vivo and in neurons in vitro, whereas cultured astrocytes increased their PGT expression. This is the first report on PGT expression in the CNS and our studies suggest that PGTs have 1) a widespread distribution in the CNS; 2) a gradual increase and a differential expression in various regions during brain development; and 3) striking contrast in expression between glia and neurons, especially in response to hypoxia. Since PGTs play a role as prostaglandin-lactate exchangers, we hypothesize that PGTs are important in the CNS during stress such as hypoxia.

Vitamin C for preventing and treating the common cold.

BACKGROUND: The role of vitamin C (ascorbic acid) in the prevention and treatment of the common cold has been a subject of controversy for 60 years, but is widely sold and used as both a preventive and therapeutic agent. OBJECTIVES: To discover whether oral doses of 0.2 g or more daily of vitamin C reduces the incidence, duration or severity of the common cold when used either as continuous prophylaxis or after the onset of symptoms. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 4, 2006); MEDLINE (1966 to December 2006); and EMBASE (1990 to December 2006). SELECTION CRITERIA: Papers were excluded if a dose less than 0.2 g per day of vitamin C was used, or if there was no placebo comparison. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed trial quality. 'Incidence' of colds during prophylaxis was assessed as the proportion of participants experiencing one or more colds during the study period. 'Duration' was the mean days of illness of cold episodes. MAIN RESULTS: Thirty trial comparisons involving 11,350 study participants contributed to the meta-analysis on the relative risk (RR) of developing a cold whilst taking prophylactic vitamin C. The pooled RR was 0.96 (95% confidence intervals (CI) 0.92 to 1.00). A subgroup of six trials involving a total of 642 marathon runners, skiers, and soldiers on sub-arctic exercises reported a pooled RR of 0.50 (95% CI 0.38 to 0.66). Thirty comparisons involving 9676 respiratory episodes contributed to a meta-analysis on common cold duration during prophylaxis. A consistent benefit was observed, representing a reduction in cold duration of 8% (95% CI 3% to 13%) for adults and 13.6% (95% CI 5% to 22%) for children. Seven trial comparisons involving 3294 respiratory episodes contributed to the meta-analysis of cold duration during therapy with vitamin C initiated after the onset of symptoms. No significant differences from placebo were seen. Four trial comparisons involving 2753 respiratory episodes contributed to the meta-analysis of cold severity during therapy and no significant differences from placebo were seen. AUTHORS' CONCLUSIONS: The failure of vitamin C supplementation to reduce the incidence of colds in the normal population indicates that routine mega-dose prophylaxis is not rationally justified for community use. But evidence suggests that it could be justified in people exposed to brief periods of severe physical exercise or cold environments.

Volume de Gordura Epicárdica está Associada com Disfunção Endotelial, mas Não com Calcificação Coronariana: Do ELSA-Brasil / Epicardial Fat Volume Is Associated with Endothelial Dysfunction, but not with Coronary Calcification: From the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil)

Resumo Fundamento O aumento no volume de gordura epicárdica (VGE) está relacionado com doença arterial coronariana (DAC), independentemente de gordura visceral ou subcutânea. O mecanismo dessa associação não é claro. O escore de cálcio coronariano (CC) e a disfunção endotelial estão relacionados com eventos coronarianos, mas não está bem esclarecido se o VGE está relacionado com esses marcadores. Objetivos Avaliar a associação entre VGE medido por método automatizado, fatores de risco cardiovasculares, escore de CC, e função endotelial. Métodos: Em 470 participantes do Estudo Longitudinal de Saúde do Adulto LSA-Brasil com medidas de VGE, escore de CC e função endotelial, realizamos modelos multivariados para avaliar a relação entre fatore de risco cardiovascular e VGE (variável resposta), e entre VGE (variável explicativa), e função endotelial ou escore de CC. Valor de p<0,05 bilateral foi considerado estatisticamente significativo. Resultados A idade média foi 55 ± 8 anos, e 52,3% dos pacientes eram homens. O VGE médio foi 111mL (86-144), e a prevalência de escore de CC igual a zero foi 55%. Nas análises multivariadas, um VGE mais alto relacionou-se com sexo feminino, idade mais avançada, circunferência da cintura, e triglicerídeos (p<0,001 para todos). Um VGE mais alto foi associado com pior função endotelial: em comparação ao primeiro quartil, os valores de odds ratio para a amplitude de pulso basal foram (q2=1,22; IC95% 1,07-1,40; q3=1,50, IC95% 1,30-1,74; q4=1,50, IC95% 1,28-1,79) e para a razão de tonometria arterial periférica foram (q2=0,87; IC95% 0,81-0,95; q3=0,86, IC95% 0,79-0,94; q4=0,80, IC95% 0,73-0,89), mas não com escore de CC maior que zero. Conclusão Um VGE mais alto associou-se com comprometimento da função endotelial, mas não com escore de CC. Os resultados sugerem que o VGE esteja relacionado ao desenvolvimento de DAC por uma via diferente da via do CC, possivelmente pela piora da disfunção endotelial e doença microvascular.

Abstract Background The increase in epicardial fat volume (EFV) is related to coronary artery disease (CAD), independent of visceral or subcutaneous fat. The mechanism underlying this association is unclear. Coronary artery calcium (CAC) score and endothelial dysfunction are related to coronary events, but whether EFV is related to these markers needs further clarification. Objectives To evaluate the association between automatically measured EFV, cardiovascular risk factors, CAC, and endothelial function. Methods In 470 participants from the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil) with measures of EFV, CAC score and endothelial function, we performed multivariable models to evaluate the relation between cardiovascular risk factors and EFV (response variable), and between EFV (explanatory variable) and endothelial function variables or CAC score. Two-sided p <0.05 was considered statistically significant. Results Mean age was 55 ± 8 years, 52.3% of patients were men. Mean EFV was 111mL (IQ 86-144), and the prevalence of CAC score=0 was 55%. In the multivariable analyses, increased EFV was related to female sex, older age, waist circumference, and triglycerides (p<0.001 for all). Higher EFV was associated with worse endothelial function: as compared with the first quartile, the odds ratio for basal pulse amplitude were (q2=1.22, 95%CI 1.07-1.40; q3=1.50, 95%CI 1.30-1.74; q4=1.50, 95%CI 1.28-1.79) and for peripheral arterial tonometry ratio were (q2=0.87, 95%CI 0.81-0.95; q3=0.86, 95%CI 0.79-0.94; q4=0.80, 95%CI 0.73-0.89), but not with CAC score>0. Conclusion Higher EFV was associated with impaired endothelial function, but not with CAC. The results suggest that EFV is related to the development of CAD through a pathway different from the CAC pathway, possibly through aggravation of endothelial dysfunction and microvascular disease.

The calcium-sensitive large-conductance potassium channel (BK/MAXI K) is present in the inner mitochondrial membrane of rat brain.

Large-conductance voltage- and calcium-sensitive channels are known to be expressed in the plasmalemma of central neurons; however, recent data suggest that large-conductance voltage- and calcium-sensitive channels may also be present in mitochondrial membranes. To determine the subcellular localization and distribution of large-conductance voltage- and calcium-sensitive channels, rat brain fractions obtained by Ficoll-sucrose density gradient centrifugation were examined by Western blotting, immunocytochemistry and immuno-gold electron microscopy. Immunoblotting studies demonstrated the presence of a consistent signal for the alpha subunit of the large-conductance voltage- and calcium-sensitive channel in the mitochondrial fraction. Double-labeling immunofluorescence also demonstrated that large-conductance voltage- and calcium-sensitive channels are present in mitochondria and co-localize with mitochondrial-specific proteins such as the translocase of the inner membrane 23, adenine nucleotide translocator, cytochrome c oxidase or complex IV-subunit 1 and the inner mitochondrial membrane protein but do not co-localize with calnexin, an endoplasmic reticulum marker. Western blotting of discrete subcellular fractions demonstrated that cytochrome c oxidase or complex IV-subunit 1 was only expressed in the mitochondrial fraction whereas actin, acetylcholinesterase, cadherins, calnexin, 58 kDa Golgi protein, lactate dehydrogenase and microtubule-associated protein 1 were not, demonstrating the purity of the mitochondrial fraction. Electron microscopic examination of the mitochondrial pellet demonstrated gold particle labeling within mitochondria, indicative of the presence of large-conductance voltage- and calcium-sensitive channels in the inner mitochondrial membrane. These studies provide concrete morphological evidence for the existence of large-conductance voltage- and calcium-sensitive channels in mitochondria: our findings corroborate the recent electrophysiological evidence of mitochondrial large-conductance voltage- and calcium-sensitive channels in glioma and cardiac cells.

Perception of visual motion coherence by rats and mice.

The coherence thresholds to discriminate the direction of motion in random-dot kinematograms were measured in rats and mice. Performance was best in the rats when dot displacement from frame-to-frame was about 2 degrees, and frame duration was less than 100 ms. Mice had coherence thresholds similar to those of rats when tested at the same step size and frame duration. Although the lowest thresholds in the rats and mice occasionally reached human levels, average rodent values ( approximately 25%) were 2-3 times higher than those of humans. These data indicate that the rodent and primate visual systems are similar in that both have local motion detectors and a system for extracting global motion from a noisy signal.

HIV prevalence and risk behaviours for HIV transmission in South Australian prisons.

During the latter half of 1989, HIV prevalence in South Australian prisoners was 1.4%. The prevalence of HIV infection across the prison system did not change significantly during 1989 but there was clustering of HIV-infected prisoners in some prisons. Almost half the prisoners from all of the South Australian prisons agreed to participate in our studies, from which we estimate that about 42% of prisoners engage in risk behaviours at least once while incarcerated. Prisoners estimated that 36% of all prisoners inject drugs intravenously at some stage during their stay and that 12% engage in anal intercourse at least once. Interviews with former prisoners who had a history of intravenous drug use revealed that about half had injected themselves while in prison, 60% shared needles and most did not clean shared needles adequately. Most of these prisoners injected themselves once a month or less frequently. The conditions for spread of HIV within the prison system exist but at the current prevalence of infection, transmission can be expected to be infrequent. The opportunity exists now to improve and expand preventive measures.

Commissural inhibition and facilitation of granule cell discharge in fascia dentata.

Stimulation of the contralateral hippocampus in the hilar region had a marked effect on granule cell excitability in the fascia dentata. The primary effect was to block the population spike that otherwise occurred in response to perforant path stimulation. In contrast, the size the excitatory post-synaptic potential component of the perforant path-evoked field potential was only slightly reduced. The population spike diminution began at short latency (3.5 msec), beginning at about 1.0 msec after the onset of the slow component of the potential evoked by the contralateral stimulus. The completeness and duration of this population spike diminution depended on the contralateral stimulus intensity. The maximum duration was less than 40 msec in unanesthetized rats and more than 100 msec in rats under pentobarbital anaesthesia. Bicuculline did not diminish the field potential evoked by the contralateral stimulus but it did prevent the stimulus from blocking the perforant path population spike and, instead, permitted a weak facilitation of the population spike. The normal reduction of the population spike was not mediated by recurrent inhibition, secondary to granule cell activation, since it occurred whether or not the granule cells were inhibited at the time of contralateral stimulation. These results imply that the initial main effect on fascia dentata granule cells of activity in the contralateral hilus is a gamma-aminobutyric-acid-mediated inhibition. This effect most probably involves commissural excitation of local inhibitory interneurons. The direct excitatory action of commissural fibers on granule cells, by comparison, is very weak.

A radioimmunoassay for immunologic phenomena in pneumococcal disease and for the antibody response to pneumococcal vaccines. I. Method for the radioimmunoassay of anticapsular antibodies and comparison with other techniques.

A radioimmunossay is described which uses a 14C biosynthetically internally labeled antigen. This modified Farr technique has been standardized by quantitative precipitation and compared with hemagglutination and mouse protection. Specificity was established by use of heterologous hyperimmune sera and by use of unlabeled pneumococcal polysaccharides for inhibition. Reproducibility has been evaluated for different preparations of antigens and varying storage conditions of sera. The system has been applied to a wide variety of studies requiring analysis of human and animal sera.

Conservative surgery, patient selection, and chemoradiation as organ-preserving treatment for muscle-invading bladder cancer.

Multimodality organ-sparing treatment has, during the last decade, become the standard of care for many common malignancies. In appropriately selected patients with muscle-invading bladder cancer, bladder-preserving treatment combining surgical transurethral resection (TUR) with chemoradiation therapy offers a chance for long-term cure and survival equal to cystectomy, while also affording a 60% to 70% chance of maintaining a normally functioning bladder. Selection criteria helpful in determining appropriate patients for bladder preservation include such variables as small tumor size, that a visibly complete TUR is possible, the absence of hydronephrosis and that a complete response (CR) to induction chemoradiotherapy was achieved. Selecting patients based on response to induction therapy allows for prompt cystectomy if residual disease is found or for prompt consolidation chemoradiotherapy if a CR with induction therapy is achieved. Bladder-preserving treatment usually results in a normally functioning bladder without incontinence or hematuria for stage T2 and T3a patients. Stage T3b-T4 patients are locally controlled less frequently using these techniques. However, no data exist to suggest that patients with more advanced disease are in any way disadvantaged by preoperative chemoradiotherapy as an attempt at bladder conservation. Patients require close urological surveillance as do any patients with superficial bladder cancer who are being treated conservatively. As studies addressing the possibility of organ preservation continue to show positive results, more patients will become informed about and will be offered selective bladder-sparing approaches as one-treatment option.