Effects of the mGluR2/3 agonist LY354740 on computerized tasks of attention and working memory in marmoset monkeys

Rationale LY354740 is a recently developed metabotropic glutamatergic receptor 2 and 3 (mGluR2/3) agonist. A high density of mGluR2 has been reported in terminal fields of the perforant path in rodents and humans, suggesting its involvement in cognitive functions mediated by the temporal lobe, including memory. A small number of in vivo studies in rodents have assessed the effects of LY354740 on memory tasks, reporting the induction of impaired memory for spatial orientation in a water maze task and for delayed match and non-match to position in an operant version of these tasks.Objective In the present primate study, we used radioautography to describe the distribution and intensity of ³H-LY354740 binding in the hippocampal formation of the common marmoset monkey (Callithrix jacchus) relative to the rat. In the major, in vivo part of the study, the effects of systemic LY354740 on computerized tasks of attention and memory were investigated.Methods Adult common marmosets were trained to perform a five-choice serial reaction time (5-CSRT) task and a concurrent delayed match-to-position (CDMP) task from the Cambridge Neuropsychological Automated test Battery (CANTAB). Filter tests of LY354740 effects on motor dexterity and motivation for reward revealed high inter-individual variation in sensitivity; therefore, on the 5-CSRT, subjects were tested at a dose range of 3–10 mg/kg, and on the CDMP, subjects were tested at 1–3 or 3–10 mg/kg.Results Radioautography revealed a relatively low level of ³H-LY354740 binding in the marmoset hippocampal formation compared to the rat. Despite low binding, LY354740 reduced sustained-attention accuracy in the 5-CSRT, and reduced accuracy in two stages of the CDMP.Conclusions The current study provides novel evidence for the importance of mGluR2/3 in the regulation of primate cognitive functioning.     

Bioglue: a review of the use of this new surgical adhesive in thoracic surgery

BACKGROUND: Alveolar air leaks and broncho-pleural fistulae after thoracic surgical procedures contribute significantly to hospital morbidity and mortality. BioGlue has offered the thoracic surgeon an alternative to the products presently used to reduce the incidence of these complications. This retrospective study reviews our experience with this new adhesive. METHODS: Forty patients upon whom BioGlue was used were identified through operation records. Pre-, intra- and postoperative data were collected to establish use, indications and outcome. RESULTS: The predominant underlying pathology was malignancy. In 32 patients BioGlue was used during the primary procedure while in the remaining eight, persistent air- or lymph-leak led to a further procedure requiring the use of glue. The indications for BioGlue use were alveolar air leak (36), broncho-pleural fistula (2) and lymph leak (2). There was one death. In 35 out of 36 patients with alveolar air leak, BioGlue controlled the leak at the site of application. CONCLUSIONS: Our results in this particular patient group indicate that BioGlue is a reliable adjunct in the reduction of alveolar air leaks. Although further studies are necessary to establish the role of BioGlue in thoracic surgery in comparison to other sealants, these initial results are promising.     

Distribution and effects of polymorphic RANTES gene alleles in HIV/HCV coinfection -- a prospective cross-sectional study

AIM: Chemokines and their receptors are crucial for immune responses in HCV and HIV infection. RANTES gene polymorphisms lead to altered gene expression and influence the natural course of HIV infection. Therefore, these mutations may also affect the course of HIV/HCV coinfection. METHODS: We determined allele frequencies of RANTES-403 (G→A), RANTES-28 (C→G) and RANTES-IN1.1 (T→C) polymorphisms using real-time PCR and hybridization probes in patients with HIV (n = 85), HCV (n = 112), HIV/HCV coinfection (n = 121), and 109 healthy controls. Furthermore, HIV and HCV loads as well as CD4+ and CD8+ cell counts were compared between different RANTES genotypes. RESULTS: Frequencies of RANTES-403 A, RANTES-28 G and RANTES-IN1.1 C alleles were higher in HIV infected patients than in healthy controls (-403: 28.2% vs 15.1%, P = 0.002; -28: 5.4% vs 2.8%, not significant; IN1.1: 19.0% vs 11.0%, P = 0.038). In HIV/HCV coinfected patients, these RANTES alleles were less frequent than in patients with HIV infection alone (15.4% P = 0.002; 1.7%; P = 0.048; 12.0%; not significant). Frequencies of these alleles were not significantly different between HIV/HCV positive patients, HCV positive patients and healthy controls. CONCLUSION: All three RANTES polymorphisms showed increased frequencies of the variant allele exclusively in patients with HIV monoinfection. The finding that the frequencies of these alleles remained unaltered in HIV/HCV coinfected patients suggests that HCV coinfection interferes with selection processes associated with these alleles in HIV infection.     

Evaluation by monte carlo simulation of the pharmacokinetics of two doses of meropenem administered intermittently or as a continuous infusion in healthy volunteers

Meropenem is a broad-spectrum carbapenem antibacterial agent. In order to optimize levels in plasma relative to the MICs, the ideal dose level and dosage regimen need to be determined. The pharmacokinetics of meropenem were studied in two groups, each comprising eight healthy volunteers who received the following doses: 500 mg as an intravenous infusion over 30 min three times a day (t.i.d.) versus a 250-mg loading dose followed by a 1,500 mg continuous infusion over 24 h for group A and 1,000 mg as an intravenous infusion over 30 min t.i.d. versus a 500-mg loading dose followed by a 3,000-mg continuous infusion over 24 h for group B. Meropenem concentrations in plasma and urine were determined by liquid chromatography-mass spectrometry/mass spectrometry and high-performance liquid chromatography with UV detection, respectively. Pharmacokinetic calculations were done by use of a two-compartment open model, and the data were extrapolated by Monte Carlo simulations for 10,000 simulated subjects for pharmacodynamic evaluation. There were no significant differences in total clearance and renal clearance between group A and group B or between the intermittent treatment and the continuous infusion. The analyses of the probability of target attainment by MIC for the high- and low-dose continuous infusions were robust up to MICs of 4 mg/liter and 2 mg/liter, respectively. The corresponding values for intermittent infusions were only 0.5 mg/liter and 0.25 mg/liter. When these observations were correlated with MICs obtained from the MYSTIC database, intermittent infusion results in adequate activity against two of the most common nosocomially acquired pathogens, Klebsiella pneumoniae and Enterobacter cloacae. However, against Pseudomonas aeruginosa, the evaluation shows a clear advantage of high-dose therapy administered as a continuous infusion. We believe that in the empirical therapy situation, the continuous-infusion mode of administration is most worth the extra efforts. We conclude that clinical trials for evaluation of the continuous infusions of meropenem in critically ill patients are warranted.     

The potential for Toll-like receptors to collaborate with other innate immune receptors

Cells of the innate immune system express a large repertoire of germ-line encoded cell-surface glycoprotein receptors including Toll-like receptors (TLRs). TLRs recognize conserved motifs on microbes and induce inflammatory signals. Evidence suggests that individual members of the TLR family or other non-TLR surface antigens either physically or functionally interact with each other and cumulative effects of these interactions instruct the nature and outcome of the immune response to a particular pathogen.     

Cultures of ovarian surface epithelium from women with and without a hereditary predisposition to develop female adnexal carcinoma

AIM: Conflicting evidence exists on whether in vivo morphological characteristics can distinguish Ovarian Surface Epithelium (OSE) of ovaries obtained from women with and without a predisposition to develop female adnexal (ovarian and fallopian tube) carcinoma. This study aims to detect differences in growth potential and morphology that are maintained or specifically expressed in vitro. STUDY DESIGN: Ovarian surfaces were scraped to retrieve OSE cells from 56 women at hereditary high risk for female adnexal carcinoma, of whom 33 are BRCA1 and four are BRCA2 mutation carriers (Predisposed OSE, POSE) and from 26 women without such risk (Non Predisposed OSE, NPOSE). Number of passages and total cell yield until last passage, as well as morphology was compared between both groups. To confirm morphology, the expression of epithelial, mesothelial, and fibroblast markers was assessed. RESULTS: Both POSE and NPOSE cultures displayed similar growth potential and morphology. The expression of epithelial markers cyto-keratins 7 and 8 was similar between both groups. Only in cultures in which cells did not uniformly exhibit these markers, the percentage of cells expressing these markers was significantly lower at last passage when compared to the initial culture. In these latter cultures, cells that were morphologically indistinguishable from fibroblasts were observed. Mesothelial marker calretinin was expressed in 75% of cells of both POSE and NPOSE cultures and correlates with cyto-keratins 7 and 8 expression. CA 125 expression was equally low in POSE and NPOSE cultures (4.3%). Fibroblast markers FSM and vimentin were expressed in 100% and collagen IV was expressed in 16% of cells in all cultures. CONCLUSION: OSE cells derived from women with a hereditary predisposition to develop female adnexal cancer possess similar in vitro characteristics as OSE from women without this predisposition. On basis of our results, it seems advisable to study only 100% cyto-keratins 7 and 8 positive OSE cultures, since contamination of fibroblasts in some primary OSE cultures cannot be ruled out.     

Dual reporter system to dissect cis- and trans-effects influencing the mutation rate in a hypermutating cell line

Activation induced cytidine deaminase (AID) plays a key role in the induction of somatic hypermutation and class switching in the immunoglobulin genes of B-lymphocytes. AID expression by itself is sufficient to induce a GC-basepair biased mutator phenotype in lymphoid and non-lymphoid cell lines. Nevertheless a network of cis-regulatory elements and additional trans-factor proteins seems to govern the molecular mechanism of somatic hypermutation. To address the nature of mutation rate changes observed in the hypermutating pre-B cell line 18–81, we extended our previously described green fluorescent protein (GFP) reversion-system. Introducing an additional mutation reporter transgene enables us to discriminate between cis- and trans-factor caused alterations in the mutator phenotype. We show here that in cell line 18–81 the mutation rate declines upon prolonged periods of cell culture. The gradual loss of the mutator phenotype in cell line 18–81 is due to the downregulation of endogenous AID expression and can be reconstituted by overexpression of human AID protein. A correlation between AID mRNA levels and mutation rates is evident and even small changes in AID expression levels cause a significant effect on the mutability of the reporter transgenes.     

Virtual reality and haptics as a training device for movement rehabilitation after stroke: a single-case study

OBJECTIVE: To investigate whether training in a virtual environment with a haptic device will improve motor function in the left hemiparetic arm of a stroke subject. DESIGN: Single case, A-B-A design. SETTING: University hospital research laboratory. PARTICIPANT: A man in his late fifties (right handed), with a right-hemisphere lesion that caused a deficit in the left upper extremity. INTERVENTION: The subject trained with a 3-dimensional computer game during a 4-week period that consisted of twelve 90-minute sessions. MAIN OUTCOME MEASURES: Three tests (Purdue pegboard test, dynamometer hand-grip strength, upper-extremity test) and a subjective interview were used to evaluate motor performance. RESULTS: Improvements were found in fine manual dexterity, grip force, and motor control of the affected upper extremity. The subject reported that there was a change in his day-to-day use of the upper extremity and that he was able to use it in activities that were previously impossible for him. CONCLUSIONS: Training with virtual reality and haptics can promote motor rehabilitation.     

Bimanual coordination involving homologous and heterologous joint combinations: when lower stability is associated with higher flexibility

Variability in behavior is often put in an unfavorable light as a marker of lack of skill. Here, we provide evidence that increased variability during preferred patterns of coordination is associated with higher flexibility in adopting new patterns. Twelve right-handed subjects performed cyclical bimanual flexion and extension patterns with four homologous and six heterologous joint combinations involving shoulder, elbow, wrist, and finger movements. Preferred (isofrequency) as well as less preferred (multifrequency) coordination patterns were studied. The findings revealed less accurate and less stable 1:1 coordination patterns during heterologous as compared to homologous limb segment combinations. Conversely, coordination patterns with a 2:1 frequency ratio were performed more accurately and more consistently during heterologous as compared to homologous conditions. Accordingly, a lower degree of coupling between effectors during performance of preferred coordination patterns was associated with more successful performance of less familiar patterns. This suggests that variability may promote the creative exploration of new performance modes.