Citations

ABSTRACT Epidemiological studies suggest that an environmental factor (possibly a virus) acquired early in life may trigger multiple sclerosis (MS). The virus may remain dormant in the central nervous system but then becomes activated in adulthood. All existing models of MS are characterized by inflammation or demyelination that follows days after virus infection or antigen inoculation. While investigating the role of CD4 + T cell responses following Theiler's virus infection in mice deficient in STAT4 or STAT6, we discovered a model in which virus infection was followed by demyelination after a very prolonged incubation period. STAT4−/− mice were resistant to demyelination for 180 days after infection, but developed severe demyelination after this time point. Inflammatory cells and up‐regulation of Class I and Class II MHC antigens characterized these lesions. Virus antigen was partially controlled during the early chronic phase of the infection even though viral RNA levels remained high throughout infection. Demyelination correlated with the appearance of virus antigen expression. Bone marrow reconstitution experiments indicated that the mechanism of the late onset demyelination was the result of the STAT4−/− immune system. Thus, virus infection of STAT4−/− mice results in a model that may allow for dissection of the immune events predisposing to late‐onset demyelination in MS.

Abstract Three-dimensional imaging of the intact lung and its vasculature is essential if the hierarchical and volumetric aspects of its structures and functions are to be quantitated. Although this is possible with clinical multislice helical CT scanners, the spatial resolution does not scale down adequately for small rodents for which cubic voxel dimensions of 50–100 μm are required. Micro-computed tomography (micro-CT) provides the necessary spatial resolution of 3D images of the intact thoracic contents. Micro-CT can provide higher resolution so that basic micro-architectural structures, such as alveoli, can be individually visualized and quantitated. Dynamic events, such as the respiratory and cardiac cycles, can be imaged at multiple time points throughout a representative cycle by coordinating the scan sequence (i.e., gating) to the cycle phase of a sequence of cycles. Fusion of the micro-CT image data with other image data, such as micro-SPECT or histology, can enhance the information content beyond the mainly structural information provided by micro-CT. Conventional attenuation-based X-ray imaging can involve significant X-ray exposures at high spatial resolutions, and this could affect the phenotype (e.g., via interstitial fibrosis) and genotype (e.g., via mutation), so its use in longitudinal studies using micro-CT may be limited in some cases. However, because of recent developments in which the phase shift or refraction of X-rays rather than attenuation is used, the X-ray exposure may be significantly reduced.

Respiration contributes importantly to short-term modulation of sympathetic nerve activity. However, the relationship between spontaneous breathing rate, chemoreflex function, and direct measures of sympathetic traffic in healthy humans has not been studied previously. We tested the hypothesis that muscle sympathetic nerve activity and chemoreflex sensitivity are linked independently to respiratory rate in normal subjects. We studied 69 normal male subjects aged 29.6±8.1 years. Subjects were subdivided according to the tertiles of respiratory rate distributions. Mean respiration rate was 10.6 breaths/min in the first tertile, 14.8 breaths/min in the second tertile, and 18.0 breaths/min in the third tertile. Subjects from the third tertile (faster respiratory rate) had greater sympathetic activity than subjects from the first tertile (slower respiratory rate; 29±3 versus 17±2 bursts/min; P <0.001). Stepwise multiple linear regression analysis revealed that only respiratory rate was linked independently to sympathetic activity ( r =0.42; P <0.001). In comparison to subjects with slow respiratory rate, subjects with fast respiratory rate had greater increases in minute ventilation during both hypercapnia (7.3±0.8 versus 3.2±1.0 L/min; P =0.005) and hypoxia (5.7±0.8 versus 2.4±0.7 L/min; P =0.007). Muscle sympathetic nerve activity and chemoreflex sensitivity are linked to spontaneous respiratory rate in normal humans. Faster respiratory rate is associated with higher levels of sympathetic traffic and potentiated responses to hypoxia and hypercapnia. Spontaneous breathing frequency, central sympathetic outflow, and chemoreflex sensitivity exhibit significant and hitherto unrecognized interactions in the modulation of neural circulatory control.

The current study attempts to clarify the multi‐faceted nature of impulsivity through the use of the four‐factor UPPS Impulsive Behaviour scale. In order to build the nomological network surrounding this scale, the UPPS was administered to individuals with borderline personality disorder (BPD), pathological gamblers (PG), alcohol abusers (divided into two groups based on the presence of antisocial features), and a control group. Several of the UPPS scales (e.g. Urgency, lack of Premeditation, and Sensation Seeking) differentiated the BPD, PG, and alcohol abusers with antisocial features from a group of non‐antisocial alcohol abusers and a control group. Overall, the UPPS scales accounted for between 7% (pathological gambling) and 64% (borderline personality disorder features) of the overall variance in the psychopathology measures. Individual UPPS scales also made unique contributions to several of these disorders, which may provide insight into which of these personality traits may predispose individuals to behave in maladaptive or problematic ways. The results provide support for the differentiation of impulsivity‐related constructs into the current four‐factor model. Copyright © 2005 John Wiley & Sons, Ltd.

Detection of calcifications in breast is an important problem in the diagnosis of breast cancer. Vibro-acoustography is a recently developed method that uses the radiation force of ultrasound to create images of the mechanical response of an object at a low frequency using the magnitude or phase of the response. Small spheres are used to explore the use of the phase of vibration as a contrast modality for use in detection and identification of calcifications in breast tissue. An experiment is presented to measure the magnitude and phase of vibration at different frequencies. The theoretical and experimental results are compared for spheres of two different sizes. Phase images are shown in which five spheres of different density can be clearly distinguished from each other. With phase measurements and images, it is demonstrated that predictable image contrast exists for spheres of different density embedded in a viscoelastic medium.

Background and Purpose— This review considers the current state of knowledge of genetic factors underlying vascular cognitive impairment (VCI). Summary of Review— We argue here that genes conferring susceptibility to VCI must be of 2 nonmutually exclusive classes: (1) genes that confer susceptibility to cerebrovascular disease, and (2) genes that determine brain tissue responses to cerebrovascular disease (ie, render parenchymal tissue more or less susceptible to injury or able to repair itself after injury). Although some progress has been made in identifying genes of the first class, little has been done to explore genes of the second class. Evidence for the existence of such genes is presented. We discuss the advantages and disadvantages of different forms of cerebrovascular disease for studying these genes, and different study designs that might be used. Conclusion— The most critical challenge for genetic studies of VCI is to identify quantifiable phenotypes that can be reliably and effectively determined in large samples of subjects.

AbstractDetection of circulating myeloma cells (CMCs) by flow cytometry in patients with multiple myeloma (MM) indicates active disease. We hypothesized that detection of CMCs at the time of stem-cell collection prior to autologous stem-cell transplantation (ASCT) identifies patients at high risk of rapid progression. A cohort of patients undergoing ASCT was identified. CMCs were determined by gating on CD38+/CD45- cells using flow cytometry. The impact of CMCs on overall survival (OS) and time to progression (TTP) was evaluated in univariate and multivariate analyses. Of 246 patients undergoing ASCT, 95 had CMCs. Complete response (CR) rates after transplantation were 32% and 36% for patients with and without CMCs, respectively (P = .50). OSs were 33.2 and 58.6 months (P = .01) whereas TTPs were 14.1 and 22 months, respectively (P = .001). On multivariate analysis, CMCs remained independent of cytogenetics and disease status at time of transplantation (P = .03). CMCs and cytogenetics were combined in a new scoring system. Patients with neither, one, or both parameters had a median OS of 55, 48, and 21.5 months and a median TTP of 22, 15.4, and 6.5 months, respectively. CMCs at the time of ASCT is an independent prognostic factor and in combination with cytogenetics provides a powerful scoring system that stratifies patients and guides management.