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Kinds of Time-points Selected AbstractsReducing sex under the influence of drugs or alcohol for patients in substance abuse treatmentADDICTION, Issue 1 2010Donald A. Calsyn ABSTRACT Aims In a previous report, the effectiveness of the Real Men Are Safe (REMAS) intervention in reducing the number of unprotected sexual occasions among male drug abuse treatment patients was demonstrated. A secondary aim of REMAS was to reduce the frequency with which men engage in sex under the influence (SUI) of drugs or alcohol. Design Men in methadone maintenance (n = 173) or out-patient psychosocial treatment (n = 104) completed assessments at baseline, 3 and 6 months post-intervention. Participants The participants were assigned randomly to attend either REMAS (five sessions containing information, motivational exercises and skills training, including one session specifically targeting reducing SUI) or human immunodeficiency virus (HIV) education (HIV-Ed; one session containing HIV prevention information). SUI during the most recent sexual event served as the primary outcome in a repeated measures logistic regression model. Findings Men assigned to the REMAS condition reporting SUI at the most recent sexual event decreased from 36.8% at baseline to 25.7% at 3 months compared to a increase from 36.9% to 38.3% in the HIV-Ed condition (tintervention = ,2.16, P = 0.032). No difference between the treatment groups was evident at 6-month follow-up. At each assessment time-point, sex with a casual partner versus a regular partner, and being in methadone maintenance versus psychosocial out-patient treatment, were associated with engaging in SUI. Conclusions Overall, a motivational and skills training HIV prevention intervention designed for men was associated with greater reduction in SUI than standard HIV education at the 3-month follow-up. [source] Glutamate transporter expression in astrocytes of the rat dentate gyrus following lesion of the entorhinal cortexEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 10 2001C. Hein Abstract The glutamate transporters GLT-1 and GLAST localized in astrocytes are essential in limiting transmitter signalling and restricting harmful receptor overstimulation. To show changes in the expression of both transporters following lesion of the entorhinal cortex (and degeneration of the glutamatergic tractus perforans), quantitative microscopic in situ hybridization (ISH) using alkaline-phosphatase-labelled oligonucleotide probes was applied to the outer molecular layer of the hippocampal dentate gyrus of rats (termination field of the tractus perforans). Four groups of rats were studied: sham-operated controls, and animals 3, 14 and 60 days following unilateral electrolytic lesion of the entorhinal cortex. The postlesional shrinkage of the terminal field of the perforant path, ipsilateral to the lesion side, was determined and considered in the evaluation of quantitative ISH data. Statistical analysis revealed that ipsilateral to the lesion side there was a significant decrease of the GLT-1 mRNA at every postlesional time-point and of the GLAST mRNA at 14 and 60 days postlesion. The maximal decrease was ,,45% for GLT-1 and ,,35% for GLAST. In the terminal field of the perforant path contralateral to the lesion side, no significant changes of ISH labelling were measured. The results were complemented by immunocytochemical data achieved using antibodies against synthetic GLT-1 and GLAST peptides. In accordance with ISH results, there was an obvious decrease of GLT-1 and GLAST immunostaining in the terminal field of the perforant path ipsilateral to the lesion side. From these data we conclude that, following a lesioning of the entorhinal cortex, the loss of glutamatergic synapses in the terminal field of the perforant path resulted in a strong downregulation of glutamate transporters in astrocytes. The decrease of synaptically released glutamate or of other neuronal factors could be involved in this downregulation. [source] Antiretroviral effects on HIV-1 RNA, CD4 cell count and progression to AIDS or death: a meta-regression analysisHIV MEDICINE, Issue 10 2008EJ Mills Objective Governments, clinicians and drug-licensing bodies have adopted changes in CD4 cell counts and HIV-1 RNA levels as evidence of effectiveness for new therapeutic interventions. We aimed to determine the strength of the association between the magnitude of the effect of changes in CD4 cell count and HIV-1 RNA and progression to AIDS or death in the highly active antiretroviral therapy (HAART) era. Methods We identified all randomized clinical trials (RCTs) evaluating the effect of HAART on both clinical and surrogate endpoints (1994 to September 2006). We performed a meta-regression and weighted linear regression. We additionally estimated potential RCT sample sizes that would be required to assess the effectiveness of new interventions in terms of clinical endpoints. Results We included data from 178 RCTs. We were unable to demonstrate a strong relationship at any time-point. Specifically, this was the case when CD4 T-cell change and clinical outcomes were examined at week 24 [coefficient ,0.01, 95% confidence interval (CI) ,0.03 to 0.001, P=0.54], week 48 (coefficient ,0.01, 95% CI ,0.02 to 0.001, P=0.83) and week 96 (coefficient 0.00, 95% CI ,0.03 to 0.04, P=0.76). This was also the case when viral load was examined as a surrogate marker. Given the small number of clinical events occurring in new interventional RCTs, any RCT aiming to evaluate clinical endpoints within these time-points would require an exceptionally large sample size. Conclusions Our findings indicate that, within short-term clinical trial settings, it is not possible to estimate the proportion of treatment effect associated with surrogate endpoints. [source] CD4 count and viral load time-courses in patients treated with highly active antiretroviral therapy and association with the CDC staging systemHIV MEDICINE, Issue 8 2006J Collazos Objectives The aim of the study was to analyse CD4 cell count and viral load dynamics in patients undergoing antiretroviral therapy and their association with the Centers for Disease Control and Prevention (CDC) classification system. Methods CD4 cell count and viral load were determined in 2982 patients who were classified according to clinical and immunological CDC stages. Measurements were carried out at baseline and at the 3rd, 6th and 12th months. Results Clear differences in the immunological and virological responses to therapy were observed depending on the CDC stage, with better results associated with less advanced stages. There was a marked parallelism in the CD4 cell count curves of the different CDC stages over the year of follow up, in both naïve and experienced patients, indicating that the increase in CD4 cell count at each time-point was similar for all clinical and immunological CDC stages. However, as the baseline values were closely associated with CDC stage, the CD4 cell counts finally reached were clearly dependent on CDC stage. The highest virological responses were observed during the initial 3 months, particularly in naïve patients, but whereas naïve patients showed additional increases up to the 6th month experienced patients reached a plateau at the 3rd month. The CD4 increases were also higher during the initial 3 months but persisted during the year of follow-up. Conclusion Both clinical and immunological CDC stages at baseline are highly predictive of the immunological and virological response to therapy, a finding that could have clinical implications. [source] Protective role of osteopontin in endodontic infectionIMMUNOLOGY, Issue 1 2010Susan R. Rittling Summary Endodontic infections are polymicrobial infections resulting in bone destruction and tooth loss. The host response to these infections is complex, including both innate and adaptive mechanisms. Osteopontin (OPN), a secreted, integrin-binding protein, functions in the regulation of immune responses and enhancement of leucocyte migration. We have assessed the role of OPN in the host response to endodontic infection using a well-characterized mouse model. Periapical bone loss associated with endodontic infection was significantly more severe in OPN-deficient mice compared with wild-type 3 weeks after infection, and was associated with increased areas of inflammation. Expression of cytokines associated with bone loss, interleukin-1, (IL-1,) and RANKL, was increased 3 days after infection. There was little effect of OPN deficiency on the adaptive immune response to these infections, as there was no effect of genotype on the ratio of bacteria-specific immunoglobulin G1 and G2a in the serum of infected mice. Furthermore, there was no difference in the expression of cytokines associated with T helper type 1/type2 balance: IL-12, IL-10 and interferon-,. In infected tissues, neutrophil infiltration into the lesion area was slightly increased in OPN-deficient animals 3 days after infection: this was confirmed by a significant increase in expression of neutrophil elastase in OPN-deficient samples at this time-point. We conclude that OPN has a protective effect on polymicrobial infection, at least partially because of alterations in phagocyte recruitment and/or persistence at the sites of infection, and that this molecule has a potential therapeutic role in polymicrobial infections. [source] Periapical radiographs overestimate root canal wall thickness during post space preparationINTERNATIONAL ENDODONTIC JOURNAL, Issue 8 2008E. M. Souza Abstract Aim, To evaluate differences between anatomic and radiographic measurements of root canal wall thickness (RCWT) after each root canal preparation stage during post placement. Methodology, Twenty mandibular premolars with a single canal were decoronated and the roots embedded in resin using a teflon muffle. Roots were sectioned horizontally at a pre-established level and canals were prepared for post placement. Endodontic hand files were used for root canal preparation, followed by Gates Glidden drills and Peeso reamers. Standardized radiographs and photographs at pre-established measurement levels were taken before preparation, after root canal instrumentation, after Gates Glidden preparation and after Peeso enlargement. All images were digitized and RCWT at the mesial and distal walls measured (imagetool 3.0). Differences between radiographic and anatomic measurements were analysed with paired t- tests. anova was used to compare the percentages of radiographic distortions. Results, Regardless of the time-point evaluated, RCWT determined by radiographs were greater than the respective anatomic measurements (P < 0.05). The difference detected at each stage was similar and constant (P > 0.05). Conclusions, Throughout preparation for post placement, radiographic images overestimated the RCWT by approximately 25%, regardless of the clinical stage evaluated. [source] Temporal expression changes during differentiation of neural stem cells derived from mouse embryonic stem cellJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 3 2004Joon-Ik Ahn Abstract Temporal analysis in gene expression during differentiation of neural stem cells (NSCs) was performed by using in-house microarrays composed of 10,368 genes. The changes in mRNA level were measured during differentiation day 1, 2, 3, 6, 12, and 15. Out of 10,368 genes analyzed, 259 genes were up-regulated or down-regulated by 2-fold or more at least at one time-point during differentiation, and were classified into six clusters based on their expression patterns by K-means clustering. Clusters characterized by gradual increase have large numbers of genes involved in transport and cell adhesion; those which showed gradual decrease have much of genes in nucleic acid metabolism, cell cycle, transcription factor, and RNA processing. In situ hybridization (ISH) validated microarray data and it also showed that Fox M1, cyclin D2, and CDK4 were highly expressed in CNS germinal zones and ectonucleotide pyrophosphatase/phosphodiesterase 2 (Enpp2) was highly expressed in choroid plexus where stem/progenitor cells are possibly located. Together, this clustering analysis of expression patterns of functionally classified genes may give insight into understanding of CNS development and mechanisms of NSCs proliferation and differentiation. © 2004 Wiley-Liss, Inc. [source] An aging Interventions Testing Program: study design and interim reportAGING CELL, Issue 4 2007Richard A. Miller Summary The National Institute on Aging's Interventions Testing Program (ITP) has developed a plan to evaluate agents that are considered plausible candidates for delaying rates of aging. Key features include: (i) use of genetically heterogeneous mice (a standardized four-way cross), (ii) replication at three test sites (the Jackson Laboratory, TJL; University of Michigan, UM; and University of Texas, UT), (iii) sufficient statistical power to detect 10% changes in lifespan, (iv) tests for age-dependent changes in T cell subsets and physical activity, and (v) an annual solicitation for collaborators who wish to suggest new interventions for evaluation. Mice in the first cohort were exposed to one of four agents: aspirin, nitroflurbiprofen (NFP), 4-OH-,-phenyl-N-tert-butyl nitrone (4-OH-PBN), or nordihydroguiaretic acid (NDGA). An interim analysis was conducted using survival data available on the date at which at least 50% of the male control mice had died at each test site. Survival of control males was significantly higher, at the interim time-point, at UM than at UT or TJL; all three sites had similar survival of control females. Males in the NDGA group had significantly improved survival (P = 0.0004), with significant effects noted at TJL (P < 0.01) and UT (P < 0.04). None of the other agents altered survival, although there was a suggestion (P = 0.07) of a beneficial effect of aspirin in males. More data will be needed to determine if any of these compounds can extend maximal lifespan, but the current data show that NDGA reduces early life mortality risks in genetically heterogeneous mice at multiple test sites. [source] Region-selective alterations of glucose oxidation and amino acid synthesis in the thiamine-deficient rat brain: a re-evaluation using 1H/13C nuclear magnetic resonance spectroscopyJOURNAL OF NEUROCHEMISTRY, Issue 2 2008Darren Navarro Abstract Thiamine deficiency provides an effective model of selective neuronal cell death. 1H and 13C-NMR was used to investigate the effects of thiamine deficiency on the synthesis of amino acids derived from [1- 13C]glucose in vulnerable (medial thalamus; MT) compared to non-vulnerable (frontal cortex; FC) brain regions. Following 11 days of thiamine deficiency, a time-point associated with the absence of significant neuronal cell death, regional concentrations of glutamate, glutamine and GABA remained unaffected in FC and MT; however, decreased levels of aspartate in MT at this time-point were a predictor of regional vulnerability. De novo synthesis of glutamate and GABA were unaffected at 11 days of thiamine deficiency, while synthesis of [2- 13C]aspartate was significantly impaired. Glucose loading, which has been shown to exacerbate symptoms in patients with thiamine deficiency, resulted in further decreases of TCA cycle flux and reduced de novo synthesis of glutamate, aspartate and GABA in thiamine-deficient (TD) rats. Isotopomer analysis revealed that impaired TCA cycle flux and decreased aspartate synthesis due to thiamine deficiency occurred principally in neurons. Glucose loading deteriorated TD-related decreases in TCA cycle flux, and concomitantly reduced synthesis of aspartate and glutamate in MT. [source] Efficient gene transfer from innervated muscle into rat peripheral and central nervous systems using a non-viral haemagglutinating virus of Japan (HVJ)-liposome methodJOURNAL OF NEUROCHEMISTRY, Issue 3 2003Naoki Kato Abstract We evaluated the feasibility of gene delivery into the peripheral and central nervous systems via retrograde axonal transport following injection of a haemagglutinating virus of Japan (HVJ)-liposome-DNA complex vector into an innervated muscle. Transfection efficiency was assessed by measuring luciferase activity, and was compared statistically with that achieved using a liposome-DNA control vector. High luciferase activity was observed in the injected muscle, the ipsilateral sciatic nerve, and the ipsilateral dorsal root ganglia on day 1 after gene transfer. The spinal cord also showed luciferase activity, although this was lower than in the other tissues. However, no activity was observed in the contralateral sciatic nerve or the contralateral dorsal root ganglia. In addition, we performed gene transfer twice, with a 1-week interval, to evaluate the feasibility of repeated therapeutic gene delivery. Again, a high transfection efficiency was observed immediately, even after the second gene transfer, and transfection efficiency was significantly higher at each defined time-point using the HVJ-liposome complex vector than using a control vector. These results indicate that this method could be used for repeated therapeutic gene delivery into muscle, nerve, dorsal root ganglia, and possibly spinal cord, without the need for a surgical approach, making it well suited to clinical applications. [source] Use of a collagen-platelet rich plasma scaffold to stimulate healing of a central defect in the canine ACLJOURNAL OF ORTHOPAEDIC RESEARCH, Issue 4 2006Martha M. Murray Abstract The anterior cruciate ligament (ACL) of the knee fails to heal after primary repair. Here we hypothesize that a beneficial biologic repair response can be induced by placing a collagen-platelet rich plasma (collagen-PRP) material into a central ACL defect. A collagen-PRP scaffold was used to treat a central ACL defect in vivo. In the first experiment, the histologic response in treated and untreated defects was evaluated at 3 (n,=,5) and 6 weeks (n,=,5). In the second experiment, biomechanical testing of the treated ligaments (n,=,8) was performed at 6 weeks and compared with the results of biomechanical testing of untreated defects at the same time-point (n,=,6). The percentage filling of the defects in the treated ACLs was significantly higher at both the 3- and 6-week time-points when compared with the untreated contralateral control defects (50,±,21% vs. 2,±,2% at 3 weeks, and 43,±,11% vs. 23,±,11 at 6 weeks; all values mean,±,SEM. Biomechanically, the treated ACL defects had a 40% increase in strength at 6 weeks, which was significantly higher than the 14% increase in strength previously reported for untreated defects (p,<,0.02). Placement of a collagen-PRP bridging scaffold in a central ACL defect can stimulate healing of the ACL histologically and biomechanically. © 2006 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 24:820,830, 2006 [source] The Impact of Chronic Cigarette Smoking on Recovery From Cortical Gray Matter Perfusion Deficits in Alcohol Dependence: Longitudinal Arterial Spin Labeling MRIALCOHOLISM, Issue 8 2009Anderson Mon Background:, Neuroimaging studies reported cerebral perfusion abnormalities in individuals with alcohol use disorders. However, no longitudinal magnetic resonance imaging (MRI) studies of cerebral perfusion changes during abstinence from alcohol have been reported. Methods:, Arterial spin labeling MRI was used to evaluate cortical gray matter perfusion changes in short-term abstinent alcohol dependent individuals in treatment and to assess the impact of chronic cigarette smoking on perfusion changes during abstinence. Seventy-six patients were scanned at least once. Data from 19 non-smoking (17 males, 2 females) and 22 smoking (21 males, 1 female) patients scanned at 1 and 5 weeks of abstinence were used to assess perfusion changes over time. Twenty-eight age-equated healthy controls (25 males, 3 females) were scanned for cross-sectional comparison, 13 of them were scanned twice. Given the age range of the cohort (28 to 68 years), age was used as a covariate in the analyses. Mean perfusion was measured in voxels of at least 80% gray matter in the frontal and parietal lobes and related to neurocognitive and substance use measures. Results:, At 1 week of abstinence, frontal and parietal gray matter perfusion in smoking alcoholics was not significantly different from that in non-smoking alcoholics, but each group's perfusion values were significantly lower than in controls. After 5 weeks of abstinence, perfusion of frontal and parietal gray matter in non-smoking alcoholics was significantly higher than that at baseline. However, in smoking alcoholics, perfusion was not significantly different between the time-points in either region. The total number of cigarettes smoked per day was negatively correlated with frontal gray matter perfusion measured at 5 weeks of abstinence. Lobar perfusion measures did not correlate significantly with drinking severity or cognitive domain measures at either time-point. Conclusion:, Although cerebral perfusion in alcohol dependent individuals shows improvement with abstinence from alcohol, cigarette smoking appears to hinder perfusion improvement. [source] Effects of low-level laser therapy on collagen expression and neutrophil infiltrate in 5-fluorouracil-induced oral mucositis in hamstersLASERS IN SURGERY AND MEDICINE, Issue 6 2010Nilza Nelly Fontana Lopes DDS Abstract Background and Objectives Several studies have suggested that low-level laser therapy (LLLT) can ameliorate oral mucositis; however, the mechanisms involved are not well understood. The aim of this study was to investigate the mechanisms of action of LLLT on chemotherapy-induced oral mucositis, as related to effects on collagen expression and inflammation. Materials and Methods A hamster cheek pouch model of oral mucositis was used with all animals receiving intraperitoneal 5-fluorouracil, followed by surface irritation. Animals were randomly allocated into three groups, and treated with an InGaAIP diode laser at a wavelength of 660,nm and output power of 35 or 100,mW laser, or no laser. Clinical severity of mucositis was assessed at four time-points by a blinded examiner. Buccal pouch tissue was harvested from a subgroup of animals in each group at four time-points. Collagen was qualitatively and quantitatively evaluated after picrosirius staining. The density of the neutrophil infiltrate was also scored. Results Peak clinical severity of mucositis was reduced in the 35,mW laser group as compared to the 100,mW and control groups. The reduced peak clinical severity of mucositis in the 35,mW laser group was accompanied by a decrease in the number of neutrophils and an increase in the proportion of mature collagen as compared to the other two groups. The total quantity of collagen was significantly higher in the control (no laser) group at the day 11 time-point, as compared to the 35,mW laser group, consistent with a more prolonged inflammatory response in the control group. Conclusion This study supports two mechanisms of action for LLLT in reducing mucositis severity. The increase in collagen organization in response to the 35,mW laser indicates that LLLT promotes wound healing. In addition, LLLT also appears to have an anti-inflammatory effect, as evidenced by the reduction in neutrophil infiltrate. Lasers Surg. Med. 42:546,552, 2010. © 2010 Wiley,Liss, Inc. [source] Host serological response to Helicobacter pylori after successful eradication: long-term follow-up in patients with cured and persistent infectionALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 2006J. TANAKA Summary Aim To systematically determine the usefulness of Helicobacter pylori IgG antibody titer decline as a predictor of treatment success after H. pylori eradication in large patient samples. Patients and Methods Serum samples from 258 H. pylori positive patients (52.8 yrs, 65% males) were retrospectively collected from five medical centers, and H. pylori titers were quantitatively determined by ELISA. Serial serum samples were collected at baseline and for up to 4.9 years after treatment. 169 patients underwent successful eradication while 89 remained infected. The median total observation period was 635 days (range, 51 to 1,800 days). Chronological changes in H. pylori titers were analyzed and compared between cured and infection persistent subjects. Results The proportion of infection persistent patients who developed negative H. pylori IgG antibody titers was below 5%. A receiver operating characteristic (ROC) curve for the confirmation of successful eradication according to the percent decline over baseline at each time-point showed that a 60% decline at 1 year or more after eradication treatment strongly correlated with successful eradication (sensitivity = 90% and specificity = 87%). Conclusion A 60% decline in H. pylori IgG titers (HEL-p kit) from baseline to one year or greater is a reliable predictor of successful H. pylori eradication. [source] An open-labelled study of granulocyte colony-stimulating factor in the treatment of active Crohn's diseaseALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 4 2005J. R. Korzenik Summary Background :,Immunodeficiency syndromes associated with a Crohn's-like illness suggest innate immune defects may lead to Crohn's disease. Anecdotal cases using haemopoietic colony-stimulating factors report improvement in intestinal disease associated with these syndromes. Aim :,To test the safety and efficacy of recombinant human granulocyte colony-stimulating factor in active Crohn's disease. Methods :,In an open-labelled 12-week trial, patients with a Crohn's Disease Activity Index between 220 and 450 were treated with recombinant human granulocyte colony-stimulating factor (filgrastim, Neupogen). Concomitant immunosuppressants were prohibited except prednisone ,20 mg/day. Patient's received recombinant human granulocyte colony-stimulating factor 300 mcg daily subcutaneously adjusted to achieve an absolute neutrophil count between 25 and 35 × 109/L. Results :,Twenty patients were enrolled with a mean initial Crohn's Disease Activity Index of 307 (range: 234,428). Fifteen patients (75%) completed 8 weeks; 13 patients (65%) completed 12 weeks with the mean Crohn's Disease Activity Index for patients continuing through those times of 196 (range: 36,343) and 162 (range: 20,308), respectively. At week 12, 11 patients (55%) demonstrated a decrease of at least 70 points; five (25%) achieved a sustained remission. The mean decrease was statistically significant at each assessment time-point. Three of four patients with fistulae had a positive response. Adverse effects included bone pain, mostly mild resolving with continued treatment. One patient was hospitalized with a viral-like syndrome but it is uncertain if this was treatment related. Conclusion :,Recombinant human granulocyte colony-stimulating factor is safe and potentially effective therapy for active Crohn's disease. [source] Renal arterial resistance index and computerized quantification of fibrosis as a combined predictive tool in chronic allograft nephropathyPEDIATRIC TRANSPLANTATION, Issue 6 2004Lars Pape Abstract:, The renal arterial resistance index (RI) and the PicroSiriusRed stained cortical fractional interstitial fibrosis volume (VintFib) proved to be two independent methods that are reliable predictive factors of poor renal allograft outcome. No data have been published, which define the correlation between ultrasound assessment and quantitative morphologic changes. Renal biopsies were performed in 56 children according to increases in s-creatinine >10%. VintFib was calculated by computerized image analysis. RI was determined in two segmental arteries, 1 yr after transplantation and at the time-point of biopsy. RIs 1 yr after transplantation correlated significantly with RIs at time of biopsy (r = 0.58, p < 0.001). VintFib was higher in children with a RI = 80 than in children with a RI < 80 (mean VintFib = 9.5 ± 3.2% vs. 5.2 ± 5.1%, p = 0.004). In children with VintFib > 10%, the mean RI was 77 ± 5 compared with 69 ± 6 in patients with VintFib < 10% (p = 0.0002). The highest positive predictive value to detect the risk of decline of GFR at 2 yr after biopsy was 98% when an RI = 80% was associated with a VintFib > 10%. For VintFib > 10% or RI = 80 alone, it was 87% or 67%, respectively. The combined measurement of RI and VintFib is a reliable predictive tool for the risk of developing long-term graft dysfunction after kidney transplantation. [source] Accommodation in ABO-Incompatible Kidney Allografts, a Novel Mechanism of Self-Protection Against Antibody-Mediated InjuryAMERICAN JOURNAL OF TRANSPLANTATION, Issue 8 2003Walter D. Park To elucidate the mechanism of self-protection against anti-donor blood-group antibody known as accommodation, we studied 16 human ABO-incompatible living-donor kidney transplant recipients at 3 and 12 months post transplantation. Both circulating anti-blood-group antibody and the target blood-group antigen in the graft were demonstrable in all patients after transplantation. Thirteen of 16 grafts had normal renal function and histology, while three grafts with prior humoral rejection demonstrated significant glomerulopathy and thus did not meet the criterion for accommodation. Using microarrays, we compared five 1-year protocol ABO-compatible renal graft biopsies to four accommodated ABO-incompatible graft biopsies. Significant alterations in gene expression in 440 probe sets, including SMADs, protein tyrosine kinases, TNF-, and Mucin 1 were identified. We verified these changes in gene expression using RT-PCR and immunohistochemistry. Heme oxygenase-1, Bcl-2 and Bcl-xl were not increased in ABO-incompatible grafts at any time-point. We conclude that accommodation is always present in well-functioning, long-surviving ABO-incompatible kidney transplants. This self-protection against antibody-mediated damage may involve several novel mechanisms including the disruption of normal signal transduction, attenuation of cellular adhesion and the prevention of apoptosis. [source] Clinical Pathology Alterations in Pregnant and Non-Pregnant Rats following Scorpion EnvenomationBASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 4 2009Hmed Ben Nasr Existing diagnostic criteria are not sufficiently specific to allow antivenin administration in the absence of a confirmed scorpion sting. This study was performed to evaluate conventional haematological and serum chemical measurements as potential indices of scorpion envenomation. Adult, cycling nulliparous and near-term primiparous, white Wistar rats received a single subcutaneous injection of crude venom (600 µg/kg) from the Buthidae scorpion (Buthus occitanus tunetanus). All envenomed rats were observed for external signs and symptoms of toxicity until necropsy, which entailed terminal blood collection at either 0.5, 1, 2, or 4 hr after venom administration (n = 6 per reproductive state per time-point) for evaluation of selected clinical chemistry and haematological analytes. Control cohorts (matched for age and reproductive state) received saline injections subcutaneously and were necropsied at 0.5 hr. Almost all envenomed rats but no control animals displayed physical symptoms of intoxication, including agitation, mastication with hypersalivation, and/or vocalizing. Reproducible alterations in clinical pathology parameters were lacking in venom-treated rats regardless of reproductive status, although modest but significant Rho correlations suggested that mild haemoconcentration, haemolysis, renal function deficits and possibly coagulation difficulties developed over time. [source] Probing the active site of MIO-dependent aminomutases, key catalysts in the biosynthesis of ,-amino acids incorporated in secondary metabolitesBIOPOLYMERS, Issue 9 2010Heather A. Cooke Abstract The tyrosine aminomutase SgTAM produces (S)-ß-tyrosine from L -tyrosine in the biosynthesis of the enediyne antitumor antibiotic C-1027. This conversion is promoted by the methylideneimidazole-5-one (MIO) prosthetic group. MIO was first identified in the homologous family of ammonia lyases, which deaminate aromatic amino acids to form ,,ß-unsaturated carboxylates. Studies of substrate specificity have been described for lyases but there have been limited reports in altering the substrate specificity of aminomutases. Furthermore, it remains unclear as to what structural properties are responsible for catalyzing the presumed readdition of the amino group into the ,,ß-unsaturated intermediates to form ß-amino acids. Attempts to elucidate specificity and mechanistic determinants of SgTAM have also proved to be difficult as it is recalcitrant to perturbations to the active site via mutagenesis. An X-ray cocrystal structure of the SgTAM mutant of the catalytic base with L -tyrosine verified important substrate binding residues as well as the enzymatic base. Further mutagenesis revealed that removal of these crucial interactions renders the enzyme inactive. Proposed structural determinants for mutase activity probed via mutagenesis, time-point assays and X-ray crystallography revealed a complicated role for these residues in maintaining key quaternary structure properties that aid in catalysis. © 2010 Wiley Periodicals, Inc. Biopolymers 93: 802,810, 2010. [source] Evaluation of vitreous levels of gatifloxacin after systemic administration in inflamed and non-inflamed eyesACTA OPHTHALMOLOGICA, Issue 6 2009Rajpal Abstract. Purpose:, This study aimed to evaluate the human vitreous penetration of gatifloxacin in inflamed and non-inflamed eyes after oral administration. Methods:, Vitreous penetration of single-dose (400 mg) oral gatifloxacin was evaluated in patients (n = 33) undergoing vitreous tap during the standard procedure for intravitreal antibiotic injection for acute postoperative endophthalmitis at various time-points. Vitreous penetration of 400 mg oral gatifloxacin was evaluated in the non-inflamed eyes of patients (n = 33) undergoing pars plana vitrectomy at similar time-points. The study was extended to evaluate the vitreous penetration of single-dose oral (800 mg) gatifloxacin at a single time-point in inflamed (n = 10) and non-inflamed (n = 11) eyes. Results:, After 400 mg oral gatifloxacin, inflamed eyes showed mean vitreous concentrations of 0.58±0.19,g/ml, 1.33±0.33 ,g/ml and 1.30 ± 0.23 ,g/ml at 2, 4 and 6 hours, respectively. The levels reached at 2 and 4 hours were found to be significantly increased compared with those in non-inflamed eyes. At the 800-mg dose, 4-hour vitreous levels in inflamed and non-inflamed eyes were 1.57 ± 0.3 ,g/ml and 1.42 ± 0.24 ,g/ml, respectively. Although the increased dose of gatifloxacin elevated plasma concentration, it failed to raise vitreous levels significantly higher than the 400-mg dose at the 4-hour time-point. Conclusions:, Orally administered gatifloxacin achieves therapeutic levels in both inflamed and non-inflamed human eyes with a spectrum covering the bacterial species most frequently involved in the various causes of endophthalmitis. However, the levels achieved were below the MIC90 for Pseudomonas aureginosa and Enterococcus. [source] Effects of repeated injection of intravitreal triamcinolone on macular oedema in central retinal vein occlusionACTA OPHTHALMOLOGICA, Issue 3 2009Lili Wang Abstract. Purpose:, To investigate the effectiveness of repeated injections of intravitreal triamcinolone acetonide (IVTA) in the treatment of macular oedema caused by central retinal vein occlusion (CRVO). Methods:, Seventeen pseudophakic or aphakic eyes of 17 patients (10 male, seven female) with macular oedema caused by CRVO received a repeat injection of 4 mg IVTA, 16 weeks after the first injection of the same dose. The examination included measurements of best-corrected visual acuity (BCVA) for distance and central foveal thickness (CFT) by optical coherence tomography (OCT), preoperatively and 1, 2, 3 and 4 months postoperatively. The values were compared by paired- t test. Side-effects were monitored. Results:, BCVA and CFT were not significantly different before initial and repeat injections. Transient improvements of BCVA and CFT were achieved after both injections. At the end of follow-up, BCVA and CFT were significantly different compared to pre-injection values in the same group (P = 0.032, 0.049 in the initial-injection group and P = 0.001, 0.008 in the repeat-injection group, respectively). However, compared to the initial injection, BCVA measurements were significantly worse at each time-point (P = 0.043, 0.011, 0.010 and 0.012, respectively) after the repeat injection, as were CFT at 1, 2 and 3 months post-injection (P = 0.040, 0.015 and 0.025, respectively). The achieved maximum mean intraocular pressures were 20.00 [standard deviation (SD) 2.06] mmHg and 18.56 (SD 3.65) mmHg after the first and repeat injections, respectively. These values were not significantly different (P = 0.467). No other significant adverse events were noted during the study. Conclusion:, A repeat injection of 4 mg IVTA may not be as effective as an initial injection for the treatment of macular oedema caused by CRVO. [source] Intraocular pressure control over 24 hours using travoprost and timolol fixed combination administered in the morning or evening in primary open-angle and exfoliative glaucomaACTA OPHTHALMOLOGICA, Issue 1 2009Anastasios G. P. Konstas Abstract. Purpose:, To evaluate intraocular pressure (IOP) control over 24 hours using travoprost and timolol fixed combination (TTFC) administered in the morning or evening in primary open-angle and exfoliative glaucoma. Methods:, Patients were randomized to TTFC administered in either the morning or evening for 8 weeks. Previously treated patients underwent an untreated washout period of 4,6 weeks, after which baseline IOP was required to be > 25 mm Hg and < 38 mmHg (in two readings taken at 10.00 ± 1 hours). During the treatment period, IOP was measured at 10.00, 14.00, 18.00, 22.00, 02.00 and 06.00 hours. Patients were then treated with the opposite dosing regimen for 8 weeks and IOP measurements were repeated. Results:, In 32 subjects who completed the study, the untreated baseline IOP following washout was 27.7 ± 3.5 mmHg. Both dosing regimens reduced IOP from baseline at each time-point and throughout the 24-hour diurnal curve (p < 0.0001). When treatments were compared directly, evening dosing (18.4 ± 3.3 mmHg) provided a statistically significant lower 24-hour curve than morning dosing (19.2 ± 3.5 mmHg; p = 0.001). Evening dosing also resulted in a lower 24-hour IOP fluctuation (3.8 ± 1.6 mmHg) than morning dosing (5.1 ± 1.6 mmHg; p = 0.0002) and lower peak IOP (p = 0.0003). Conclusions:, Both morning and evening administration of TTFC provide effective 24-hour IOP reduction, but evening dosing demonstrates better 24-hour pressure control. [source] The action of pro-inflammatory cytokines on retinal endothelial cell barrier permeability: protective effect of corticosteroidsACTA OPHTHALMOLOGICA, Issue 2008AF AMBROSIO Purpose The pro-inflammatory cytokines interleukin-1, (IL-1,) and tumor necrosis factor-alpha (TNF-,) were found to be increased in the vitreous of diabetic patients and in diabetic rat retinas, and increased cytokine levels were correlated with elevated retinal vascular permeability. In this work, we investigated the mechanisms underlying IL-1,- and TNF-,-induced retinal endothelial cell permeability and evaluated the ability of a glucocorticoid, dexamethasone (DEX), to prevent changes in permeability. Methods Primary cultures of bovine retinal endothelial cells (BRECs) were grown on transwell filters and exposed to IL-1, and TNF-,. BRECs permeability to 70 kDa RITC-dextran was measured. The content and localization of tight junction proteins was assessed by Western blotting and immunocytochemistry. Results IL-1, and TNF-, increased retinal endothelial cell permeability in a concentration- and time-dependent manner, but TNF-, was more effective (increased permeability at a lower dose and shorter time-point). The increase in permeability was not due to changes in cell viability. IL-1, and TNF-, altered ZO-1 and claudin-5 content. TNF-, also decreased ZO-1 staining at the cell border. Pre-treatment with DEX prevented TNF-,-induced cell permeability, and the protective effect of DEX was partially abolished by the glucocorticoid receptor antagonist RU486. Conclusion These data demonstrate that TNF-, and IL-1, potently induce endothelial cell permeability through alterations in tight junctions. Also, the study supports the potential therapeutic use of glucocorticoids to reduce retinal vascular permeability. Support: FCT (Portugal), NIH, JDRF and Allergan [source] Influences of optic edge design on posterior capsule opacification and anterior capsule contractionACTA OPHTHALMOLOGICA, Issue 1 2007Kazunori Miyata Abstract. Purpose:, To investigate the influence of optic edge design on posterior capsule opacification (PCO) and anterior capsule contraction (ACC). Methods:, A total of 43 eyes of 43 patients scheduled to undergo cataract surgery were included in this study. Patients received either a Sensor® AR40 intraocular lens (IOL) or a Sensor® AR40e IOL. The area of the anterior capsule opening (ACO) was determined by diaphanoscopy using the anterior eye segment analysis system EAS-1000 at 1 day, 1 week and 1, 3, 6 and 12 months postoperatively. Posterior capsule opacification was evaluated objectively in two ways, using either the EAS-1000 or POCOman. Results:, There was no significant difference between the two groups in either ACO area or percentage reduction of ACO area at any time-point after surgery. The difference in the degree of PCO 1 year after surgery was not significant when measured by either the EAS-1000 or POCOman. Conclusions:, A sharp IOL edge is required to prevent PCO. Sharp-edged IOLs do not appear to be a risk factor for ACC. [source] Efficacy and safety of timolol maleate/latanoprost fixed combination versus timolol maleate and brimonidine given twice dailyACTA OPHTHALMOLOGICA, Issue 3 2003William C. Stewart Abstract. Purpose:, To evaluate the efficacy and safety of the timolol maleate/latanoprost fixed combination (TLFC) given once each evening versus brimonidine and timolol solution given twice daily as concomitant therapy in primary open-angle glaucoma or ocular hypertension patients. Methods:, Qualified subjects were begun on timolol alone twice daily for 1 month and then randomized to either TLFC or brimonidine and timolol concomitant therapy for 6 weeks. Patients were then switched to the other treatment regimen. Intraocular pressures (IOPs) were measured every 2 hours between 08 : 00 and 20 : 00 hours at baseline and at the end of periods 1 and 2. Results:, This study found that in 32 subjects the IOP diurnal curve on timolol alone (20.9 ± 2.8 mmHg) decreased to 17.9 ± 3.2 mmHg when patients were treated with TLFC and to 19.0 ± 2.4 mmHg when patients were treated with brimonidine and timolol (p = 0.02). Intraocular pressures at individual time-points were statistically similar between the groups at the 08 : 00 trough and 2 and 4 hours after dosing. However, beyond 4 hours after dosing, TLFC-treated subjects demonstrated a trend towards lower IOPs at each 2-hour time-point that was not statistically significant after a Bonferroni correction (p , 0.05). The incidence of both solicited and unsolicited side-effects was similar between groups. Conclusion:, This study suggests that TLFC given in the evening reduces the mean daytime diurnal IOP more than brimonidine and timolol given concomitantly twice daily. [source] Longitudinal validity and responsiveness of the Food Allergy Quality of Life Questionnaire , Parent Form in children 0,12 years following positive and negative food challengesCLINICAL & EXPERIMENTAL ALLERGY, Issue 3 2010A. DunnGalvin Summary Background There are no published studies of longitudinal health-related quality of life (HRQL) assessments of food-allergic children using a disease-specific measure. Objective This study assessed the longitudinal measurement properties of the Food Allergy Quality of Life Questionnaire , Parent Form (FAQLQ-PF) in a sample of children undergoing food challenge. Methods Parents of children 0,12 years completed the FAQLQ-PF and the Food Allergy Independent Measure (FAIM) pre-challenge and at 2 and 6 months post food challenge. In order to evaluate longitudinal validity, differences between Group A (positive challenge) and Group B (negative challenge) were expected over time. We computed correlation coefficients between change scores in the FAQLQ-PF and change scores in the FAIM. To determine the minimally important difference (MID), we used distributional criterion and effect size approaches. A logistic regression model profiled those children falling below this point. Results Eighty-two children underwent a challenge (42 positive; 40 negative). Domains and total score improved significantly at pos-challenge time-points for both groups (all P<0.05). Sensitivity was demonstrated by significant differences between positive and negative groups at 6 months [F(2, 59)=6.221, P<0.003] and by differing improvement on relevant subscales (P<0.05). MID was 0.45 on a seven-point response scale. Poorer quality of life at baseline increased the odds by over 2.0 of no improvement in HRQL scores 6-month time-point. General maternal health (OR 1.252), number of foods avoided (OR 1.369) and children >9 years (OR 1.173) were also predictors. The model correctly identified 84% of cases below MID. Conclusion The FAQLQ-PF is sensitive to change, and has excellent longitudinal reliability and validity in a food-allergic patient population. The standard error of measurement value of 0.5 points as a threshold for meaningful change in HRQL questionnaires was confirmed. The FAQLQ-PF may be used to identify problems in children, to assess the effectiveness of clinical trials or interventions, and to guide the development of regulatory policies. Cite this as: A. DunnGalvin, C. Cullinane, D. A. Daly, B. M. J. Flokstra-de Blok, A. E. J. Dubois and J. O'B. Hourihane, Clinical & Experimental Allergy, 2010 (40) 476,485. [source] Neurotoxic effects of venoms from seven species of australasian black snakes (Pseudechis): Efficacy of black and tiger snake antivenomsCLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 1-2 2005Sharmaine Ramasamy SUMMARY 1.,Pseudechis species (black snakes) are among the most widespread venomous snakes in Australia. Despite this, very little is known about the potency of their venoms or the efficacy of the antivenoms used to treat systemic envenomation by these snakes. The present study investigated the in vitro neurotoxicity of venoms from seven Australasian Pseudechis species and determined the efficacy of black and tiger snake antivenoms against this activity. 2.,All venoms (10 µg/mL) significantly inhibited indirect twitches of the chick biventer cervicis nerve,muscle preparation and responses to exogenous acetylcholine (ACh; 1 mmol/L), but not to KCl (40 mmol/L), indicating activity at post-synaptic nicotinic receptors on the skeletal muscle. 3.,Prior administration of either black or tiger snake antivenom (5 U/mL) prevented the inhibitory effects of all Pseudechis venoms. 4.,Black snake antivenom (5 U/mL) added at t90 (i.e. the time-point at which the original twitch height was reduced by 90%) significantly reversed the effects of P. butleri (28 ± 5%), P. guttatus (25 ± 8%) and P. porphyriacus (28 ± 10%) venoms. Tiger snake antivenom (5 U/mL) added at the t90 time-point significantly reversed the neurotoxic effects of P. guttatus (51 ± 4%), P. papuanus (47 ± 5%) and P. porphyriacus (20 ± 7%) venoms. 5.,We show, for the first time, the presence of neurotoxins in the venom of these related snake species and that this activity is differentially affected by either black snake or tiger snake antivenoms. [source] Emollients in a propanol-based hand rub can significantly decrease irritant contact dermatitisCONTACT DERMATITIS, Issue 6 2005Günter Kampf The objective of this study is to determine the effect of emollients in a propanol-based hand rub on skin dryness and erythema. In this prospective, randomized, controlled, double-blind trial, 35 subjects participated; of them approximately half were atopic (modified Erlanger atopy score ,8). 2 propanol-based formulations were tested in a repeated open application test, 1 contained a mixture of emollients (0.81%, w/w). 2 aliquots of 0.7 ml of each formulation were applied twice per day over 2 weeks to the cubital fossa of each subject after random assignment of the preparations. Treatment areas were assessed before each application and 3 days postfinal application by visual inspection for erythema and dryness according to a standard scale. The sum score over all assessment time-points served as primary parameter. The mean sum score for erythema and dryness was significantly lower for the hand rub with emollients (0.8 ± 2.4) in comparison with that for the hand rub without emollients (1.5 ± 3.5; P = 0.022; Wilcoxon signed rank test). A comparison of the atopic and non-atopic subjects revealed no significant difference for any of the products (P > 0.05; Mann,Whitney U -test). It is concluded that the addition of emollients to a propanol-based hand rub can significantly decrease irritant contact dermatitis under frequent-use conditions. [source] Factors regulating renal angiotensin-converting enzyme activity in the ratACTA PHYSIOLOGICA, Issue 1 2000Changes in angiotensin-converting enzyme (ACE) activity appear to be important in mediating the natriuresis which ensues after administration of an oral or gastric sodium load. In this study, we sought to determine the time course of the changes in ACE activity in the kidney which occur after sodium ingestion. In addition, we sought to investigate mechanisms which might underlie these changes. Angiotensin-converting enzyme activity was measured by generation of histidyl-leucine in homogenates of kidneys harvested at varying time-points after gastric sodium administration. The effects of intravenous sodium loading, solution osmolality and of changes in renal nerve activity were also investigated. Intragastric instillation of both the sodium-containing solution and its iso-osmotic urea control solution resulted in significant increases in renal ACE activity (NaCl: P < 0.0005; Urea: P < 0.01). The increase in renal ACE activity after gastric sodium loading was more prolonged than after the urea control (P < 0.025, NaCl vs. urea at 90 min). This prolonged increase in renal ACE activity appeared to reflect a response to absorbed sodium as intravenous sodium administration caused a significant increase in renal ACE activity at 90 min (P < 0.0005). In contrast to these stimuli which increased renal ACE activity, renal denervation caused a significant decrease in ACE activity in the kidney (P < 0.05). We conclude that gastric sodium loading increases renal ACE activity. This effect appears to be due initially to a response to an increase in gastric lumenal osmolality and later to absorbed sodium. These changes in renal ACE activity are not mediated by a decrease in renal nerve activity. [source] High cortisol awakening response is associated with an impairment of the effect of bright light therapyACTA PSYCHIATRICA SCANDINAVICA, Issue 3 2009K. Martiny Objective:, We investigated the predictive validity of the cortisol awakening response (CAR) in patients with non-seasonal major depression. Method:, Patients were treated with sertraline in combination with bright or dim light therapy for a 5-week period. Saliva cortisol levels were measured in 63 patients, as an awakening profile, before medication and light therapy started. The CAR was calculated by using three time-points: awakening and 20 and 60 min after awakening. Results:, Patients with low CAR had a very substantial effect of bright light therapy compared with dim light therapy, whereas patients with a high CAR had no effect of bright light therapy compared with dim light therapy. Conclusion:, High CAR was associated with an impairment of the effect of bright light therapy. This result raises the question of whether bright light acts through a mechanism different from that of antidepressants. [source] | ||||||||||||||||||||||||||||||||||||||||