Magnetic resonance study of the influence of tissue damage and cortical reorganization on PASAT performance at the earliest stage of multiple sclerosis

We sought to determine the influence of tissue damage and the potential impact of cortical reorganization on the performance to the Paced Auditory Serial Addition Test (PASAT) in patients at the earliest stage of multiple sclerosis (MS). Magnetization transfer ratio (MTR) imaging and functional magnetic resonance imaging (fMRI) experiments using PASAT as paradigm were carried out in 18 patients with clinically isolated syndrome suggestive of MS (CISSMS) compared to 18 controls. MTR histogram analyses showed structural abnormalities in patients involving the normal-appearing white matter (NAWM) but also the gray matter (GM). Mean PASAT scores were significantly lower in the group of patients taken as a whole, and were correlated with the mean NAWM MTR value. No correlation was observed between PASAT scores and GM MTR. However, in the subgroup of patients with normal PASAT performance (n = 9), fMRI showed larger activations in bilateral Brodmann area 45 (BA45) and right BA44 compared to that in controls (n = 18). In these areas with potentially compensatory reorganization, the whole group of patients (n = 18) showed significantly greater activation than controls (n = 18). Activation in the right BA45 was inversely correlated with the mean NAWM MTR and the peak position of GM MTR histograms of patients. This study indicates that even at the earliest stage of MS, cortical reorganization is present inside the executive system of working memory and could tend to limit the determinant functional impact of NAWM injury on the execution of the PASAT.     

Human endogenous retrovirus (HERV)-W ENV and GAG proteins: Physiological expression in human brain and pathophysiological modulation in multiple sclerosis lesions

Antigen expression of a human endogenous retrovirus family, HERV-W, in normal human brain and multiple sclerosis lesions was studied by immunohistochemistry by three independent groups. The HERV-W multicopy family was identified in human DNA from the previously characterized multiple sclerosis-associated retroviral element (MSRV). A panel of antibodies against envelope (ENV) and capsid (GAG) antigens was tested. A physiological expression of GAG proteins in neuronal cells was observed in normal brain, whereas there was a striking accumulation of GAG antigen in axonal structures in demyelinated white matter from patients with MS. Prominent HERV-W GAG expression was also detected in endothelial cells of MS lesions from acute or actively demyelinating cases, a pattern not found in any control. A physiological expression of ENV proteins was detected in microglia in normal brain; however,a specific expression in macrophages was apparently restricted to early MS lesions. Thus, converging results from three groups confirm that GAG and ENV proteins encoded by the HERV-W multicopy gene family are expressed in cells of the central nervous system under normal conditions. Similar to HERV-W7q ENV (Syncitin), which is expressed in placenta and has been shown to have a physiological function in syncytio-trophoblast fusion, HERV-W GAG may thus also have a physiological function in human brain. This expression differs in MS lesions, which may either reflect differential regulation of inherited HERV-W copies, or expression of "infectious" MSRV copies. This is compatible with a pathophysiological role in MS, but also illustrates the ambivalence of such HERV antigens, which can be expressed in cell-specific patterns, under physiological or pathological conditions.     

Fecal tumor necrosis factor-alpha and calprotectin as differential diagnostic markers for severe diarrhea of small infants

OBJECTIVE: The etiology of early-onset diarrhea of neonates and small infants that persists despite bowel rest is heterogeneous. Two different categories of disorders presenting with diarrhea in the first weeks of life can be distinguished: constitutive intestinal epithelial disorders (microvillus atrophy [MVA] or epithelial dysplasia [ED]) and immune-inflammatory disorders, (autoimmune enteropathy [AIE] or inflammatory colitis [IC]). We aimed to evaluate in a prospective manner the use of fecal inflammatory markers in the differential diagnosis of severe persistent diarrhea. MATERIAL AND PATIENTS: Twenty-five patients (17 males) were enrolled in this study (median age 8 months). Fourteen children had a constitutive enterocyte disorder (group 1: MVA = 8, ED = 6), and 11 patients had an immuno-inflammatory disease (group 2: AIE = 5, IC = 6). Stool samples were collected at the time of diagnosis and stored at -80 degrees until tumor necrosis factor (TNF)-alpha and calprotectin were measured by enzyme-linked immunoadsorbent assay. RESULTS: No significant differences in age at onset of diarrhea or in stool volumes were observed between both groups. In group 1, fecal TNF-alpha was undetectable/normal in 14 of 14 children, whereas group 2 showed dramatically elevated TNF-alpha levels (mean 3,104, range 237-18,078 pg/g) in 8 of 11 patients. Similarly, calprotectin levels were undetectable/normal in 14 of 14 patients in group 1 and highly raised in 11 of 11 patients in group 2 (median 1,145, range 375-3,095 mug/g), P < 0.01. Under therapy, these inflammatory parameters normalized. CONCLUSIONS: Determination of fecal inflammatory markers is a simple method helping to distinguish constitutive from immuno-inflammatory etiologies of severe persistent diarrhea. These data also suggest that constitutive enterocyte disorders are not accompanied by an inflammatory mucosal reaction.     

Diet, metabolism and lifespan in Drosophila

Dietary restriction (DR) by dilution of the food medium can extend lifespan in Drosophila. DR results in a state that is characterized by reduced fecundity, increased starvation resistance and higher total lipid levels. In the past, each of these correlated phenotypes has been proposed to play a causal role in the lifespan-extending effects of food reduction. However, more recent data show that each phenotype can be uncoupled from the long-lived state to varying extents. In this mini-review, we summarize the principal findings of the effects of DR on Drosophila in order to address what these phenotypes can tell us about the physiological remodeling required for Drosophila to be long-lived. Current data indicate lifespan-extension by DR is likely to involve both enhancement of various defense and detoxification mechanisms and a complex range of metabolic alterations that make energy available for these processes.     

Left ventricular assist device implantation in a patient with congenitally corrected transposition of the great arteries

Congenitally corrected transposition of the great arteries (ccTGA) is a rare anomaly characterized by atrioventricular and ventriculo-arterial discordance and several other malformations that eventually lead to heart failure. We describe the case of a 53-year-old woman with ccTGA and aortic insufficiency who was a candidate for heart transplantation due to end-stage congestive heart failure. Her condition deteriorated before a suitable donor heart could be found; therefore, we placed a left ventricular assist device in the right (systemic) ventricle. Concomitantly, we removed the aortic (systemic) valve, closed the aortic annulus with a bovine pericardial patch, and repaired the mitral valve. The patient recovered uneventfully and was discharged from the hospital 2 months postoperatively. She underwent cardiac transplantation approximately 6 months later and continued to do well after 18 months.     

Unifying the spatial population dynamics and molecular evolution of epidemic rabies virus

Infectious disease emergence is under the simultaneous influence of both genetic and ecological factors. Yet, we lack a general framework for linking ecological dynamics of infectious disease with underlying molecular and evolutionary change. As a model, we illustrate the linkage between ecological and evolutionary dynamics in rabies virus during its epidemic expansion into eastern and southern Ontario. We characterized the phylogeographic relationships among 83 isolates of fox rabies virus variant using nucleotide sequences from the glycoprotein-encoding glycoprotein gene. The fox rabies virus variant descended as an irregular wave with two arms invading from northern Ontario into southern Ontario over the 1980s and 1990s. Correlations between genetic and geographic distance suggest an isolation by distance population structure for the virus. The divergence among viral lineages since the most recent common ancestor correlates with position along the advancing wave front with more divergent lineages near the origin of the epidemic. Based on divergence from the most recent common ancestor, the regional population can be partitioned into two subpopulations, each corresponding to an arm of the advancing wave. Subpopulation A (southern Ontario) showed reduced isolation by distance relative to subpopulation B (eastern Ontario). The temporal dynamics of subpopulation A suggests that the subregional viral population may have undergone several smaller waves that reduced isolation by distance. The use of integrated approaches, such as the geographical analysis of sequence variants, coupled with information on spatial dynamics will become indispensable aids in understanding patterns of disease emergence.     

Quantitative assessment of mRNA TGF-beta1 in liver tissue in connection with serum mean daily level of TGF-1 in chronic hepatitis B patient

Monitoring of fibrosis process with the use of histopathologic studies on liver's bioptates is limited, so it is attempted to find reliable, obtained with less invasive methods, sensitive and reflecting fibrosis dynamics markers of this process. The aim of the study was simultaneously to assess liver's expression as well as circadian and mean daily TGF-betal concentration in serum of patients with chronic hepatitis type B in comparison to control group. Studies were performed on 50 patients (9 women, 41 men) aged 45.9 +/- 2.3 years with chronic hepatitis type B. Control group consisted of 20 patients (mean age 38.6 +/- 3.7 years), in which so called minimal changes without fibrosis were observed in histophatologic bioptate of liver. Blood for studies was collected every 4 houres during the day. Serum concentration of TGF-betal was assessed with the use of ELISA method, and expression of mRNA TGF-betal in liver with QRT-PCR method. No significant difference between circadian as well as mean daily serum TGF-betal concentration beetwen control group and the group with chronic hepatitis type B was shown. Increased expression of mRNA, TGF-betal in bioptate of liver of patients with chronic hepatitis type B in comparison to control group was noted. In "minimal changes" control group presence of significant positive correlation between expression of mRNA TGF-beta1 in liver and concentration of this cytokine in serum was shown, in the group of patients with chronic hepatitis B this connection was not noted.     

Selective impairment of subcategories of long-term memory in mice with hippocampal lesions accessed by the olfactory tubing maze

A new apparatus, the olfactory tubing maze for mice, was developed recently to study learning and memory processes in mice in regard to their ethological abilities. As in humans, BALB/c mice with selective bilateral lesions of the hippocampal formation showed selective impairment of subcategories of long-term memory when tested with the olfactory tubing maze. After three learning sessions, control mice reached a high percentage of correct responses. They consistently made the olfactory-reward associations, but antero-dorsal and postero-ventral hippocampal-lesioned mice did not. However, all lesioned mice learned the paradigm and the timing of the task as fast and as well as control mice. These data suggest that the olfactory tubing maze can be used to study subcategories of memory, such as declarative and non-declarative memory, which are similar in some respects to those observed in humans. Consequently, possible memory effects of classical approaches (i.e., pharmacological or lesion studies) or genetic modifications in transgenic or gene-targeting mice can be effectively analyzed using this new apparatus.     

Effect of ethnicity and gender on the incidence of venous thromboembolism in a diverse population in California in 1996

There have been very few studies that have describe the epidemiology of first-time venous thromboembolism (VTE) in a large, ethnically diverse population. The California Discharge Data Set was used to identify a cohort of cases with incidentVTE in 1996. Cases associated with traditional provoking risk factors were identified and the remaining cases were labeled as idiopathicVTE. Direct standardization using census information was performed to compare incidence rates across races, gender, and gender within race. There were 21,002 cases with incident VTE in 1996, a crude incidence of 90 events per 100,000 adults. Thirty percent of all VTE events were pulmonary embolism. The directly standardized incidence per 100,000 California adults was 93+/-1.7 (+/-95% CI) in women, 85+/-1.7 in men, 103+/-2.1 in Caucasians, 138+/-6.5 in African- Americans, 61+/-2.8 in Hispanics and 29 +/- 2.4 in Asian-Pacific Islanders (p<0.001 for all inter-group comparisons). After adjusting for misclassification of race, the incidence of VTE per 100,000 was 104 in Caucasians, 141 in African-Americans, 55 in Hispanics, and 21 in Asian/Pacific-Islanders. The incidence of idiopathic VTE was significantly lower among both Hispanics and Asian/Pacific-Islanders (p<0.001) than Caucasians or African-Americans. African-Americans were more likely, and Hispanics less likely, to be diagnosed with idiopathic pulmonary embolism compared to Caucasians. The 28 day case-fatality rate among cases with idiopathic VTE was 2%, and it was significantly higher among African-Americans (4.1%) compared to Caucasians (1.8%, p<0.001). There are important differences in the incidence of total and idiopathicVTE and in the proportion of events diagnosed as pulmonary embolism among each of the major racial/ethnic groups in California. Further research is needed to explain these observed differences among the different racial/ethnic groups.