The role of bile acid retention and a common polymorphism in the ABCB11 gene as host factors affecting antiviral treatment response in chronic hepatitis C.

The outcome of hepatitis C virus (HCV) infection and the likelihood of a sustained virological response (SVR) to antiviral therapy depends on both viral and host characteristics. In vitro studies demonstrated that bile acids (BA) interfere with antiviral interferon effects. We investigate the influence of plasma BA concentrations and an ABCB11 polymorphism associated with lower transporter expression on viral load and SVR. Four hundred and fifty-one Caucasian HCV-patients treated with PEG-interferon and ribavirin were included in the study. ABCB11 1331T>C was genotyped, and plasma BA levels were determined. The 1331C allele was slightly overrepresented in HCV-patients compared to controls. In HCV-patients, a significant difference between patients achieving SVR vs non-SVR was observed for HCV-2/3 (5 vs 9 µm; P=0.0001), while median BA levels in HCV-1 were marginally elevated. Normal BA levels <8 µm were significantly associated with SVR (58.3%vs 36.3%; OR 2.48; P=0.0001). This difference was significant for HCV-2/3 (90.7%vs 67.6%; P=0.002) but marginal in HCV-1 (38.7%vs 27.8%; P=0.058). SVR rates were equivalent between ABCB11 genotypes for HCV-1, but increased for HCV-2/3 (TT 100%vs CC 78%; OR 2.01; P=0.043). IL28B genotype had no influence on these associations. No correlation between BA levels and HCV RNA was detected for any HCV genotype. The higher allelic frequency of ABCB11 1331C in HCV-patients compared to controls may indirectly link increased BA to HCV chronicity. Our data support a role for BA as host factor affecting therapy response in HCV-2/3 patients, whereas a weaker association was found for HCV-1.

Changes in cortical hemodynamics with the emergence of skilled motor ability in infants: An fNIRS study.

The brain activity changes during infancy that underpin the emergence of functional motor skills, such as reaching and stepping, are not well understood. The current study used functional near-infrared spectroscopy (fNIRS) to examine the hemodynamic response across the frontal, mid-coronal plane (sensorimotor cortex) and external occipital protuberance (cerebellar cortex) regions of typically developing infants (5 to 13 months) during reach-to-grasp or supported treadmill stepping behaviour. Motor ability was assessed using the third edition of the Motor Subscale of the Bayley Scales of Infant Development (BSID-III). Infants with enhanced motor ability demonstrated greater oxy-hemoglobin (HbO) concentration in the contralateral anterior mid-coronal and frontal-dorsal areas during right-handed reach-to-grasp. During bilateral reaching behavior, infants with enhanced motor ability showed greater HbO increases in right frontal-dorsal regions and lower HbO increases in left anterior mid-coronal areas. In contrast, infants' motor ability was associated with changes in de-oxyhemoglobin (HbR) concentration in the ipsilateral anterior mid-coronal, contralateral frontal and left external occipital protuberance regions during left-handed reaching behavior. These relationships between upper limb hemodynamics and infant motor ability are consistent with increased lateralization and cognitive-motor coupling as motor skills emerge. During stepping behavior, infants with enhanced motor ability demonstrated smaller increases in HbR concentration in the bilateral external occipital protuberance region consistent with an emerging efficiency as cruising and independent stepping behavior is still nascent. Together, the current results identify several distinct neural markers of functional motor ability during infancy that may be relevant to diagnostic testing and rehabilitation of developmental movement disorders.

Impaired niacin sensitivity in acute first-episode but not in multi-episode schizophrenia.

Niacin (vitamin B3) flushing--a marker of altered prostaglandin signaling--is indirectly linked to the phospholipid-prostaglandin metabolism. Diminished skin flushing was repeatedly found in schizophrenia, but has not been systematically investigated at different stages of disorder as yet. We compared niacin sensitivity of 32 first-episode and 32 multi-episode patients (mainly on stable medication) with age and gender matched healthy controls. Methylnicotinate was applied in three concentrations onto the inner forearm skin. Flush response was assessed in 3 min intervals over 15 min using optical reflection spectroscopy. Whereas first-episode patients showed significantly diminished flush response as compared to controls, comparable differences were not found between multi-episode patients and controls. Comparison of niacin sensitivity at different stages of schizophrenia support the notion of altered prostaglandin signaling primarily at the onset of disorder. Longitudinal studies have to rule out possible long-term effects of neuroleptic medication.

The diethyldithiocarbamate concentration effects and interactions with other cytotoxic agents on Chinese Hamster cells (V79).

A metal chelator, diethyldithiocarbamate (DDC) perturbs the chromosome condensation processes in dividing cells. The length of the metaphase chromosomes in Chinese hamster cells (V79) treated with 17.2 micrograms/ml of DDC for 2 hr is about half of that in untreated cells. However, concentrations of 1.7 microgram or 172 micrograms/ml DDC apparently do not produce this effect. DDC at 17.2 micrograms/ml also disrupts spindle fibers. Penicillamine, EDTA, EGTA, and diamide show no effect on chromosome condensation. Bleomycin, but not mitomycin and cisplatin, added simultaneously with DDC can prevent the DDC effect on chromosomes. The cytotoxic effect of increasing concentrations of DDC to V79 cells incubated at 37 degrees C exhibits a similar biphasic response. This concentration biphasic toxic effect is not altered when the cells are treated with DDC in combination with radiation, heat, or other cytotoxic drugs. These observations suggest that the different effects of DDC concentrations on chromosome condensation should be considered as one important modification factor for DDC related toxicity.

Posttraumatic stress disorder in burn populations: a critical review of the literature.

This review of the literature examines studies concerning posttraumatic stress disorder (PTSD) in burn populations. Retrospective, cross-sectional, and prospective research and case studies are critiqued. Although the data are equivocal, several trends are clearly emerging. Though severity of burn and degree of disfigurement did not consistently predict PTSD, subjective variables were better predictors. There was a clear trend for patients who had no symptoms of PTSD while hospitalized to have PTSD develop after discharge. Finally, prevalence rates of PTSD vary greatly based on time of screening. Methodological problems with studies were related to sampling and follow-up; suggestions for future research are provided.

[Acute arterial hypotension by sodium-nitroprusside and intraocular tension (author's transl)]. / Akute arterielle Hypotonie durch Natrium-Nitroprussid und intraoculare Tension.

The relationship between intraocular pressure by short-term intravenous Sodium-Nitroprusside induced arterial hypotension in intubation-anaesthesia was studied in 19 cats. A reduction of the blood pressure from an average of 168 mm Hg to 89 mm Hg (that is 47%) was followed by a clearly reproducible reduction of intraocular pressure from an average of 22 mm Hg to 10 mm Hg (that is 55%). These findings for the "closed" eye are a prerequisite for the understanding of the effects of sodium-nitroprusside in the "open" eye.

[Bupivacaine and the humoral component of the immunlogical secondary response (author's transl)]. / Bupivacain und die humorale Komponente der immunologischen Sekundärantwort.

Using the Jerne-Plaque-Technique, as modified by Cunningham, the influence of the local anaesthetic bupivacaine (over-all dose 200 mg/kg weight) on the immunological secondary response of the mice was tested. Plasma cells producing IgM as well as those producing IgG could not be shown to be significantly susceptible to suppression by bupivacaine.

[Controlled hypotension in difficult intraocular anterior segment surgery (author's transl)]. / Kontrollierte Hypotension bei schwierigen intraokularen Eingriffen.

During anaesthesia controlled hypotension -- induced by sodium nitroprusside -- was used in 60 patients undergoing intraocular anterior segment surgery. The advantages of this procedure are that the iris-lens diaphragma and the vitreous body have a lesser tendency to protrude than with other techniques despite even more superficial anaesthesia.

[Controlled hypotension by sodium-nitroprusside in general anaesthesia for difficult intraocular surgery (preliminary report) (author's transl)]. / Kontrollierte Hypotension durch Natrium-Nitroprussid bei der Allgemeinnarkose für schwierige intraokulare Eingriffe (Vorläufige Mitteilung).

General anaesthesia was performed in 75 patients with difficult intraocular procedures in which the standard relaxation and hyperventilation was supplemented by controlled short-term hypotension by sodium-nitroprusside. This resulted in a significant decrease of the "vis a tergo"--e.g. the threatening prolaps of intraocular tissue. Preliminary experience revealed that intraoperative complications in these difficult situations are reduced. As this facilitates also the task of the anaesthesist this broadens our indications for complex intraocular surgery particularly in younger patients.

Autoreactive T cells from MRL-lpr/lpr mice secrete multiple lymphokines and induce the production of IgG anti-DNA antibodies.

The study of T cells in individuals with systemic lupus erythematosus has been limited because a specific marker for the disease has not been identified. To approach this issue, we isolated autoreactive T cell clones from lupus-prone MRL mice, a strain that develops an accelerated form of lupus. These CD4+ T cell clones grew spontaneously from unimmunized mice, and were maintained in culture by intermittent stimulation with syngeneic antigen presenting cells in the absence of exogenous antigen. One autoreactive T cell clone, termed ARTC-1, previously reported to have atypical MHC requirements for activation (both I-Ak and I-Ek were required) and to stimulate B cell proliferation and Ig production in vitro, was found to have an unrestricted pattern of lymphokine secretion. Following stimulation, it produced IL-4, IFN-gamma and IL-2. ARTC-1 induced B cell proliferation both by cell contact and through secretion of soluble lymphokines. B cell proliferation by cell-cell contact was MHC restricted in a manner analogous to ARTC-1 activation by APCs; the B cell response was inhibited by both anti-I-Ak and anti-I-Ek antibodies. The ARTC-1 B cell interaction was also found to result in the production of IgG autoantibodies. These observations suggest that cells such as ARTC-1, if unregulated, could lead to B cell stimulation and autoantibody production in vivo, in the absence of exogenous stimulation. Furthermore, IFN-gamma production by ARTC-1 could also result in enhanced class II expression, leading both to additional T-B cell interactions and to T cell interactions with endogenous cells capable of expressing class II antigens in other organs.

Autoreactive T cells with atypical MHC restriction from MRL-lpr/lpr mice: forbidden clones revisited.

MRL-lpr/lpr mice spontaneously develop a lethal form of systemic lupus erythematosus associated with massive lymphadenopathy, polyclonal B-cell activity, autoantibody production and antibody-dependent tissue injury. The sequence of events leading to B-cell proliferation and pathogenic autoantibody production are not clearly defined--abnormalities of both B and T cells have been observed. Isolation of individual T-cell clones would facilitate analysis of the cellular events involving both B and T cells that lead to autoantibody production. For this purpose, an autoreactive T-cell line (ARTC-1) was derived from the splenocytes of an unimmunized MRL-lpr/lpr mouse and maintained in culture by stimulation with syngeneic antigen presenting cells, without exogenous antigens. By T-cell receptor analysis it was demonstrated that ARTC-1 cells developed as a clone even through no attempt was made to clone them in vitro: Southern blot analysis of ARTC-1 revealed a single rearrangement of the TcR beta chain locus with the other TcR beta chain gene remaining in the germline configuration. Northern blot analysis confirmed these findings and demonstrated that ARTC-1 utilized C beta 1 J beta 1.3 exclusively. ARTC-1 had atypical MHC requirements for activation: antigen-presenting cells bearing both I-Ak and I-Ek major histocompatibility complex class II antigens were required for maximal proliferation of the ARTC-l clone. Activated ARTC-l secreted soluble factors that induced B-cell proliferation, immunoglobulin secretion, and anti-DNA antibody production. Unregulated cells of the AR-TC1 type could, therefore, lead to polyclonal B-cell activation and autoantibody production in vivo in the absence of exogenous antigenic stimulation.