Interleukin 17 modulates the immune response to vaccinia virus infection

Interleukin 17 (IL-17) is a newly identified cytokine that has a homolog in herpesvirus saimiri. We inserted murine IL-17 into vaccinia virus to study the role of IL-17 in viral infection. Vaccinia virus expressing IL-17 (vv-IL17) and its parental control virus (vv-pRB) grew to similar titers in vitro; however, vv-IL17 was more virulent in mice with a threefold lower LD(50) than for vv-pRB, and mean time to death of 2.8 days versus 4.5 days. Mice infected with vv-IL17 had higher titers of virus in the ovaries (P < 0.02) and showed a decrease in NK cell cytotoxicity (P < 0.02) on day 3 after infection. No significant difference was found in CTL activity. In addition, a significant decrease in IgG2a (P < 0.01) and increases in IgG1, IgG3, and IgA (P < 0.03) vaccinia virus-specific antibody titers were observed in mice infected with vv-IL17 versus vv-pRB, suggesting a Th-2-like response to infection. These data indicate that IL-17 modulates the immune response during virus infection.     

The vestibulo-ocular reflex in three dimensions

The purpose of this paper is to review the kinematics and dynamics of the vestibulo-ocular reflex (VOR) in three dimensions. We give a brief, didactic tutorial on vectors and matrices and their importance as representational schemes for describing the kinematics and dynamics of the angular and linear accelerations that activate the vestibular system. We show how the vectors associated with angular and linear head accelerations are transformed by the peripheral and central vestibular systems to drive the oculomotor system to produce eye movements in three-dimensional space. We also review critical questions and controversies related to the compensatory and orientation behavior of the VOR. One such question is how the central vestibular system distinguishes tilts of the head, which generate interaural linear acceleration from translations along the interaural axis. Another question is how the velocity-position integrator is implemented centrally. The review has been placed in the context of a model that explains the behavior of the VOR in three dimensions. Model processes have been related to peripheral and central neural behavior in order to gain insight into the nature of the three-dimensional organization and the controversial questions that are addressed.     

Ocular counterrolling induced by centrifugation during orbital space flight

During the 1998 Neurolab mission (STS-90), four astronauts were exposed to interaural centripetal accelerations (Gy centrifugation) of 0.5g and 1g during rotation on a centrifuge, both on Earth and during orbital space flight. Subjects were oriented either left-ear out or right-ear out, facing or back to motion. Binocular eye movements were measured in three dimensions using a video technique. On Earth, tangential centrifugation that produces 1g of interaural linear acceleration combines with gravity to tilt the gravitoinertial acceleration (GIA) vector 45° in the roll plane relative to the head vertical, generating a summed vector of 1.4g. Before flight, this elicited mean ocular counterrolling (OCR) of 5.7°. Due to the relative absence of gravity during flight, there was no linear acceleration along the dorsoventral axis of the head. As a result, during in-flight centrifugation, gravitoinertial acceleration was strictly aligned with the centripetal acceleration along the interaural axis. There was a small but significant decrease (mean 10%) in the magnitude of OCR in space (5.1°). The magnitude of OCR during postflight 1g centrifugation was not significantly different from preflight OCR (5.9°). Findings were similar for 0.5g centrifugation, but the OCR magnitude was approximately 60% of that induced by centrifugation at 1g. OCR during pre- and postflight static tilt was not significantly different and was always less than OCR elicited by centrifugation on Earth for an equivalent interaural linear acceleration. In contrast, there was no difference between the OCR generated by in-flight centrifugation and by static tilt on Earth at equivalent interaural linear accelerations. These data support the following conclusions: (1) OCR is generated predominantly in response to interaural linear acceleration; (2) the increased OCR during centrifugation on Earth is a response to the head dorsoventral 1g linear acceleration component, which was absent in microgravity. The dorsoventral linear acceleration could have activated either the otoliths or body-tilt receptors that responded to the larger GIA magnitude (1.4g), to generate the increased OCR during centrifugation on Earth. A striking finding was that magnitude of OCR was maintained throughout and after flight. This is in contrast to most previous postflight OCR studies, which have generally registered decreases in OCR. We postulate that intermittent exposure to artificial gravity, in the form of the centripetal acceleration experienced during centrifugation, acted as a countermeasure to deconditioning of this otolith-ocular orienting reflex during the 16-day mission. Electronic Publication     

Evidence of genetic heterogeneity in the autosomal recessive adult forms of limb-girdle muscular dystrophy following linkage analysis with 15q probes in Brazilian families.

The autosomal recessive limb-girdle muscular dystrophies (LGMD) represent a heterogeneous group of diseases which may be characterised by one or more autosomal loci. A gene at 15q has recently been found to be responsible for a mild form of LGMD in a group of families from the isolated island of Réunion, now classified as LGMD2. Based on results of eight out of 11 large Brazilian LGMD families of different racial background (which were informative for the closest available probe to the LGMD2 gene), we confirmed linkage to the LGMD2 gene at 15q in two of these families and exclusion in six others. These data provide the first evidence of genetic heterogeneity for the autosomal recessive limb-girdle muscular dystrophies.     

Autoimmune hepatitis associated with the use of black cohosh: a case study

Herbal remedies generate more than 1.8 billion dollars in annual sales in the United States. Herbal products have been associated with a wide spectrum of hepatic toxicities. With the recent Women's Health Initiative Study demonstrating increased risk of breast cancer and cardiovascular events associated with hormone therapy, many women may resort to herbal remedies for persistent menopause symptoms. We report a case of autoimmune hepatitis likely triggered by the use of black cohosh (Actaea racemosa), an agent marketed to treat menopause symptoms. Given this case report, we recommend close monitoring of women using this herbal preparation.     

Angiogenic and lymphangiogenic microvessel density in breast carcinoma: correlation with clinicopathologic parameters and VEGF-family gene expression.

Angiogenesis and lymphangiogenesis are essential for breast cancer progression and are regulated by vascular endothelial growth factors (VEGF). To determine clinical and molecular correlates of these processes, we measured blood and lymphatic vascular microvessel density in 29 invasive carcinomas (22 ductal, six lobular, one papillary), using the vascular marker CD31 and the novel lymphatic marker D2-40. Microvessel density was assessed microscopically and by image cytometry, and was compared with tumor histology, grade, stage, lymph node metastasis, hormone receptors, HER2/neu status, and expression of VEGF, VEGF-C and VEGF-D by immunohistochemistry or quantitative RT-PCR. Strong correlation was observed between visual and image cytometric microvessel density using D2-40 but not CD31 (P=0.016 and 0.1521, respectively). Image cytometric CD31 microvessel density correlated with tumor size, grade, stage and lymph node metastasis (P=0.0001, 0.0107, 0.0035 and 0.0395, respectively). D2-40 microvessel density correlated with tumor stage (P=0.0123 by image cytometry) and lymph node metastasis (P=0.0558 by microscopy). Immunohistochemical VEGF signal in peritumoral blood vessels correlated with image cytometric CD31 and D2-40 microvessel density (P=0.022 and 0.0012, respectively), consistent with the role of VEGF in blood and lymphatic vascular growth. Intratumoral VEGF-C and VEGF-D expression by quantitative RT-PCR correlated with D2-40 (P=0.0291 by image cytometry) but not with CD31 microvessel density, which could suggest a selective role of VEGF-C and VEGF-D in lymphangiogenesis. CD31 and D2-40 microvessel density correlated significantly with several prognostic factors, including lymph node metastasis. Thus, measurements of angiogenesis and lymphangiogenesis may have utility for breast cancer pathology, particularly for estimation of metastatic risk.     

Induction of the anti-ergotypic response

The injection of syngeneic activated T cells into rodents caninduce a T cell response against activation markers of the Tcells, ergotopes. The responding antl-ergotypic T cells havebeen shown to suppress experimental autoimmune encephalomyelitis(EAE). This paper reports the characteristics of the antl-ergotypicresponse. It was found that irradiated activated T cells wereas good as untreated living activated T cells in inducing anti-ergotypiccells in vivo. Glutardialdehyde-fixed (0.3%) cells were poorstimulators in vivo and non-stimulatory in vitro. Dilution ofglutardialdehyde to 0.003% before fixation preserved the stimulatorycapacity in vitro. Fixation or irradiation of T cells at differenttimes after activation showed that the stimulatory ergotopeappears only after more than 12 h of activation. This ergotopeis not secreted by activated T cells, but is a structural componentof the activated T cell. Injection of solubilized proteins fromactivated T cells, but not of supernatants from activated Tcells, was able to induce an anti-ergotypic response in vivo.In vitro supernatants from activated T cells also were not stimulatoryto anti-ergotypic T cells. The anti-ergotypic response couldbe measured in draining lymph nodes 3 days after injection,reached a maximum after 7–10 days and subsided thereafter.It was earlier and stronger than the anti-ldiotypic response.Induction of the response was dose dependent. As few as 100cells were able to induce a marked anti-ergotypic response.The ease of the induction and the strength of the anti-ergotypicresponse suggest a physiological role in immunoregulatlon.