Oral ganciclovir for patients with cytomegalovirus retinitis treated with a ganciclovir implant. Roche Ganciclovir Study Group

BACKGROUND: The intraocular ganciclovir implant is effective for local treatment of cytomegalovirus retinitis in patients with the acquired immunodeficiency syndrome (AIDS), but it does not treat or prevent other systemic manifestations of cytomegalovirus infection. METHODS: Three hundred seventy-seven patients with AIDS and unilateral cytomegalovirus retinitis were randomly assigned to one of three treatments: a ganciclovir implant plus oral ganciclovir (4.5 g daily), a ganciclovir implant plus oral placebo, or intravenous ganciclovir alone. The primary outcome measure was the development of new cytomegalovirus disease, either contralateral retinitis or biopsy-proved extraocular disease. RESULTS: The incidence of new cytomegalovirus disease at six months was 44.3 percent in the group assigned to the ganciclovir implant plus placebo, as compared with 24.3 percent in the group assigned to the ganciclovir implant plus oral ganciclovir (P=0.002) and 19.6 percent in the group assigned to intravenous ganciclovir alone (P<0.001). As compared with placebo, oral ganciclovir reduced the overall risk of new cytomegalovirus disease by 37.6 percent over the one-year period of the study (P=0.02). However, in the subgroup of 103 patients who took protease inhibitors, the rates of new cytomegalovirus disease were low and of similar magnitude, regardless of treatment assignment. Progression of retinitis in the eye that initially received an implant was delayed by the addition of oral ganciclovir, as compared with placebo (P=0.03). Treatment with oral or intravenous ganciclovir reduced the risk of Kaposi's sarcoma by 75 percent (P=0.008) and 93 percent (P<0.001), respectively, as compared with placebo. CONCLUSIONS: In patients with AIDS and cytomegalovirus retinitis, oral ganciclovir in conjunction with a ganciclovir implant reduces the incidence of new cytomegalovirus disease and delays progression of the retinitis. Treatment with oral or intravenous ganciclovir also reduces the risk of Kaposi's sarcoma.     

Cloning and functional characterization of a novel connexin expressed in somites of Xenopus laevis.

Connexin-containing gap junctions play an essential role in vertebrate development. More than 20 connexin isoforms have been identified in mammals. However, the number identified in Xenopus trails with only six isoforms described. Here, identification of a new connexin isoform from Xenopus laevis is described. Connexin40.4 was found by screening expressed sequence tag databases and carrying out polymerase chain reaction on genomic DNA. This new connexin has limited amino acid identity with mammalian (<50%) connexins, but conservation is higher (approximately 62%) with fish. During Xenopus laevis development, connexin40.4 was first expressed after the mid-blastula transition. There was prominent expression in the presomitic paraxial mesoderm and later in the developing somites. In adult frogs, expression was detected in kidney and stomach as well as in brain, heart, and skeletal muscle. Ectopic expression of connexin40.4 in HEK293 cells, resulted in formation of gap junction like structures at the cell interfaces. Similar ectopic expression in neural N2A cells resulted in functional electrical coupling, displaying mild, asymmetric voltage dependence. We thus cloned a novel connexin from Xenopus laevis, strongly expressed in developing somites, with no apparent orthologue in mammals.     

The inversion effect on gaze perception reflects processing of component information

When faces are turned upside-down they are much more difficult to recognize than other objects. This "face inversion effect" has often been explained in terms of configural processing, which is impaired when faces are rotated away from the upright. Here we report a "gaze inversion effect" and discuss whether it is related to configural face processing of the whole face. Observers reported the gaze locations of photographed upright or inverted faces. When whole faces were presented, we found an inversion effect both for constant errors and observer sensitivity. These results were closely replicated when only the eyes were visible. Together, our findings suggest that gaze processing is largely based on component-based information from the eye region. Processing this information is orientation-sensitive and does not seem to rely on configural processing of the whole face.     

Cross-reactivity between IgE-binding proteins from Anisakis German cockroach, and chironomids

Pascual CY, Crespo JF, San Martin S, Ornia N, Ortega N, Caballero T, Munoz-Pereira M, Martin-Estaban M. Cross-reactivity between IgE-binding proteins from Anisakis German cockroach, and chironomids. Anisakis simplex larvae parasitize animals used as seafood and can produce a specific immune response in man. The ingestion of seafood contaminated with stage three of A. simplex larvae can induce a specific IgE response with clinical symptoms, usually urticaria, even if the fish is cooked before ingestion and the invasive infestation power destroyed by heating. Our preliminary studies showed a strong association of A. simplex sensitization with Ascaris lumbricoides, Daphnia chironomid spp., Atlantic shrimp ‘Pandalus borealis’ and German cockroach ‘Blattella germanica’. We conducted the cross-reactivity study with cockroach, a ubiquitous insect, and Chironomidae ‘red mosquito larvae’, a work-related allergen, without any possibility of Anisakis contamination. Serum samples were collected from 60 pediatric patients, with serum specific IgE to A. simplex. Both specific-IgE and immunoblot-inhibition studies, with a serum pool from 18 patients, were performed to determine whether the association of sensitizations to nematodes and arthropods was due to immunologic cross-reactivity. In addition, serum samples from 21 of 60 patients who showed also sensitization to German cockroach were used for individual immunoblot studies. In the serum pool, dose-dependent inhibition of B. germanica and Chironomus spp. was observed after preincubation with the A. simplex extract. Immunoblot of Anisakis inhibited with Chironomus and German cockroach, yielded a partial blot inhibition but mainly on bands below 41 kDa. Blot inhibition of German cockroach and Chironomus with Anisakis was dose related. The band patterns in individual blots were heterogeneous, but most of them had bands of 30–43 kDa. None of these sera recognized allergens in the 14–kDa area. In our study, CAP-inhibition and immunoblot-inhibition analysis of Anisakis showed that several IgE-binding components could be shared by the three allergens.     

HL-A8: a genetic link with thyrotoxicosis.

The incidence of HL-A8 was significantly increased in 64 Caucasian patients with thyrotoxicosis compared with 700 Australian blood donors (42% versus 24%). No significant correlation was observed between HL-A8 and autoantibodies to thyroid components in thyrotoxic patients; thus the association of HL-A8 must be either with the disease itself, or possibly with immune responses not tested for this study.     

KCNE1 reverses the response of the human K+ channel KCNQ1 to cytosolic pH changes and alters its pharmacology and sensitivity to temperature

Previous studies have shown that heteromultimeric KCNQ1/KCNE1 (KvLQT1/minK) channels and homomultimeric KCNQ1 (KvLQT1) channels exhibit different current properties, e.g. distinct kinetics and different sensitivities to drugs. In this study we report on the divergent responses to internal pH changes and further characterize some of the current properties of the human isoforms of KCNQ1 and KCNE1 expressed in Chinese hamster ovary (CHO) cells or Xenopus laevis oocytes. Decreasing the bath temperature from 37 degrees C to 20 degrees C increased the half-activation time by a factor of 5 for KCNQ1/KCNE1 currents (IKs) but by only twofold (not significant) for KCNQ1 currents (IK) in CHO cells. Acidification of cytosolic pH (pHi) increased IKs but decreased 1K whereas intracellular alkalinization decreased I(Ks) but increased IK. pHi-induced changes in intracellular Ca2+ activity ([Ca2+]i) did not correlate with the current responses. At 20 degrees C mefenamic acid (0.1 mM) significantly augmented IKs but slightly decreased IK. It changed the slow activation kinetics of I(Ks) to an instantaneous onset. The form of the current/voltage (I/V) curve changed from sigmoidal to almost linear. In contrast, at 37 degrees C, mefenamic acid also increased I(Ks) but slowed the activation kinetics and shifted the voltage activation to more hyperpolarized values without markedly affecting the sigmoidal shape of the I/V curve. The potassium channel blockers clotrimazole and tetrapentylammonium (TPeA) inhibited I(Ks) with a lower potency than I(K). These results show that coexpression of KCNE1 reversed pH regulation of KCNQ1 from inhibition to activation by acidic pHi. In addition, KCNE1 altered the pharmacological properties and sensitivity to temperature of KCNQ1. The pH-dependence of I(Ks) might be of clinical and pathophysiological relevance in the pathogenesis of ischaemic cardiac arrhythmias.     

Consistency of remission and outcome in bipolar and unipolar mood disorders: a 10-year prospective follow-up

BACKGROUND: Previous studies of the natural course of bipolar disorder have suggested that relapse and psychosocial impairment are more common than many would expect during treatment under routine conditions. The present research sought to identify patterns of consistency in longitudinal recovery after an index manic or depressive episode in patients formerly hospitalized for major affective disorders. The data extend prior findings from the Chicago Follow-up Study involving four successive assessments of course and outcome for bipolar and unipolar patients over a 10-year follow-up interval. METHODS: Thirty-four RDC bipolar I manic, 17 psychotic unipolar depressed, and 72 nonpsychotic unipolar depressed patients were assessed at index hospitalization and prospectively followed-up at 2, 4.5, 7.5 and 10 years. Psychosocial functioning, rehospitalization, and overall outcome were rated by standardized instruments. Patterns of consistent remission or impairment in functioning were compared across follow-up periods. RESULTS: Consistently good functioning was observed more often among patients with unipolar nonpsychotic depression than bipolar disorder or unipolar psychotic depression. Psychosis at index hospitalization was not associated with poorer outcomes for either the bipolar or unipolar groups, although it significantly predicted psychosis at follow-up more robustly for unipolar than bipolar patients. Less than half of the bipolar cohort had good work performance at each follow-up, while unipolar nonpsychotic depressed patients had consistently better work functioning. Rehospitalization was more common for the bipolar than unipolar patients at the 4.5- and 7.5-year assessments. Sustained remission across follow-ups was associated with remission at subsequent follow-ups regardless of diagnostic polarity at index hospitalization. LIMITATIONS: The observational design, small sample size, and naturalistic treatment of subjects in this protocol prompts caution when interpreting treatment outcome findings. The availability of a bipolar cohort with relatively low attrition over a 10-year period may limit the generalizability of the current findings to patients who remain engaged in sustained contact with a long-term research program. CONCLUSIONS: Over a 10-year follow-up period, about half of bipolar patients show sustained remissions or patterns of improvement, while 30-40% experience some functional decline. The degree of consistency in remission patterns over time may hold greater prognostic significance than the polarity of an index affective episode in anticipating subsequent levels of psychosocial adjustment in severe mood disorders.     

Antigen-specific suppression of a primed immune response by dendritic cells mediated by regulatory T cells secreting interleukin-10

Antigen-specific suppression of a previously primed immune response is a major challenge for immunotherapy of autoimmune disease. RelB activation is required for myeloid DC differentiation. Here, we show that antigen-exposed DCs in which RelB function is inhibited lack cell surface CD40, prevent priming of immunity, and suppress previously primed immune responses. DCs generated from CD40-deficient mice similarly confer suppression. Regulatory CD4+ T cells induced by the DCs transfer antigen-specific "infectious" tolerance to primed recipients in an interleukin-10-dependent fashion. Thus CD40, regulated by RelB activity, determines the consequences of antigen presentation by myeloid DCs. These observations have significance for autoimmune immunotherapy and suggest a mechanism by which peripheral tolerance might be constitutively maintained by RelB(-) CD40(-) DCs.