CD93 is required for maintenance of antibody secretion and persistence of plasma cells in the bone marrow niche.

Plasma cells represent the end stage of B-cell development and play a key role in providing an efficient antibody response, but they are also involved in numerous pathologies. Here we show that CD93, a receptor expressed during early B-cell development, is reinduced during plasma-cell differentiation. High CD93/CD138 expression was restricted to antibody-secreting cells both in T-dependent and T-independent responses as naive, memory, and germinal-center B cells remained CD93-negative. CD93 was expressed on (pre)plasmablasts/plasma cells, including long-lived plasma cells that showed decreased cell cycle activity, high levels of isotype-switched Ig secretion, and modification of the transcriptional network. T-independent and T-dependent stimuli led to re-expression of CD93 via 2 pathways, either before or after CD138 or Blimp-1 expression. Strikingly, while humoral immune responses initially proceeded normally, CD93-deficient mice were unable to maintain antibody secretion and bone-marrow plasma-cell numbers, demonstrating that CD93 is important for the maintenance of plasma cells in bone marrow niches.

Cannabis and benzodiazepines as determinants of methadone trough plasma concentration variability in maintenance treatment: a transnational study.

PURPOSE: To assess tobacco, alcohol, cannabis and benzodiazepine use in methadone maintenance treatment (MMT) as potential sources of variability in methadone pharmacokinetics. METHODS: Trough plasma (R)- and (S)-methadone concentrations were measured on 77 Australian and 74 Swiss MMT patients with no additional medications other than benzodiazepines. Simple and multiple regression analyses were performed for the primary metric, plasma methadone concentration/dose. RESULTS: Cannabis and methadone dose were significantly associated with lower 24-h plasma (R)- and (S)-methadone concentrations/dose. The models containing these variables explained 14-16% and 17-25% of the variation in (R)- and (S)-methadone concentration/dose, respectively. Analysis of 61 patients using only CYP3A4 metabolised benzodiazepines showed this class to be associated with higher (R)-concentration/dose, which is consistent with a potential competitive inhibition of CYP3A4. CONCLUSION: Cannabis use and higher methadone doses in MMT could in part be a response to-or a cause of-more rapid methadone clearance. The effects of cannabis and benzodiazepines should be controlled for in future studies on methadone pharmacokinetics in MMT.

Maintenance of ancestral sex chromosomes in Palearctic tree frogs: direct evidence from Hyla orientalis.

Contrasting with the situation found in birds and mammals, sex chromosomes are generally homomorphic in poikilothermic vertebrates. This homomorphy was recently shown to result from occasional X-Y recombinations (not from turnovers) in several European species of tree frogs (Hyla arborea, H. intermedia and H. molleri). Because of recombination, however, alleles at sex-linked loci were rarely diagnostic at the population level; support for sex linkage had to rely on multilocus associations, combined with occasional sex differences in allelic frequencies. Here, we use direct evidence, obtained from anatomical and histological analyses of offspring with known pedigrees, to show that the Eastern tree frog (H. orientalis) shares the same pair of sex chromosomes, with identical patterns of male heterogamety and complete absence of X-Y recombination in males. Conservation of an ancestral pair of sex chromosomes, regularly rejuvenated via occasional X-Y recombination, seems thus a widespread pattern among Hyla species. Sibship analyses also identified discrepancies between genotypic and phenotypic sex among offspring, associated with abnormal gonadal development, suggesting a role for sexually antagonistic genes on the sex chromosomes.

When "enough" is not enough: new perspectives on optimal methadone maintenance dose.

Some methadone maintenance treatment (MMT) programs prescribe inadequate daily methadone doses. Patients complain of withdrawal symptoms and continue illicit opioid use, yet practitioners are reluctant to increase doses above certain arbitrary thresholds. Serum methadone levels (SMLs) may guide practitioners dosing decisions, especially for those patients who have low SMLs despite higher methadone doses. Such variation is due in part to the complexities of methadone metabolism. The medication itself is a racemic (50:50) mixture of 2 enantiomers: an active "R" form and an essentially inactive "S" form. Methadone is metabolized primarily in the liver, by up to five cytochrome P450 isoforms, and individual differences in enzyme activity help explain wide ranges of active R-enantiomer concentrations in patients given identical doses of racemic methadone. Most clinical research studies have used methadone doses of less than 100 mg/day [d] and have not reported corresponding SMLs. New research suggests that doses ranging from 120 mg/d to more than 700 mg/d, with correspondingly higher SMLs, may be optimal for many patients. Each patient presents a unique clinical challenge, and there is no way of prescribing a single best methadone dose to achieve a specific blood level as a "gold standard" for all patients. Clinical signs and patient-reported symptoms of abstinence syndrome, and continuing illicit opioid use, are effective indicators of dose inadequacy. There does not appear to be a maximum daily dose limit when determining what is adequately "enough" methadone in MMT.

Comparative socio-economic evaluation of IBD patients with and without infliximab maintenance therapy

Background: The anti-TNFα agent Infliximab (IFX) is used for the treatment of moderate to severe inflammatory bowel disease (IBD) with insufficient response to conventional immunomodulator therapy. IFX maintenance therapy is expensive and it is unknown if indirect costs (eg. by loss of work productivity) can be reduced by this therapy. Goal: to evaluate the direct and indirect costs of an IBD patient cohort under maintenance IFX compared to a cohort under "conventional" immunomodulator therapy. Methods: Direct and indirect costs of an IBD cohort under IFX and a reference cohort (similar disease activity and location) under conventional immunomodulator therapy (Azathioprine, or 6-MP, or MTX) were retrospectively evaluated over 12 months (January to December 2008). Results: 54 IFX-patients (24f/30m, 37 CD, 10 UC, 7 IC) and 71 non-IFX-patients (38f/33m, 56 CD, 12 UC, 3 IC) were included. IFX patients were younger than non-IFX patients (36 vs. 47 years, P = 0.0003). The mean duration of inpatient stay in hospital (23 in IFX vs. 21 days for non-IFX, P = 0.909) and the hospitalization costs (7,692 in IFX vs. 4,179 SFr for non-IFX, P = 0.4540) did not differ. IFX-patients had significantly more frequently specialist outpatient consultations (8 vs. 4, P < 0.001) and outpatient-related costs (3,633 vs. 2,186 SFr, P <0.001). Total costs for all diagnostic procedures (blood work, endoscopies, radiology) were higher in the IFXcohort (2,265 vs. 1,164 SFr, P < 0.001). Sixty-five percent of IFX-patients had a 100% job employment compared to 80% in the non-IFX cohort (P = 0.001). Conclusions: The direct and indirect costs of maintenance IFX-treated IBD patients are higher compared to IBD patients under conventional immunomodulators. Care should be taken not only to judge the costs as the IFX treated population may represent a cohort with more aggressive disease phenotype, furthermore, quality of life aspects were not assessed.

The c-Jun N-terminal kinase 1 (JNK1) in spinal astrocytes is required for the maintenance of bilateral mechanical allodynia under a persistent inflammatory pain condition.

Peripheral inflammation induces persistent central sensitization characterized by mechanical allodynia and heat hyperalgesia that are mediated by distinct mechanisms. Compared to well-demonstrated mechanisms of heat hyperalgesia, mechanisms underlying the development of mechanical allodynia and contralateral pain are incompletely known. In this study, we investigated the distinct role of spinal JNK in heat hyperalgesia, mechanical allodynia, and contralateral pain in an inflammatory pain model. Intraplantar injection of complete Freund's adjuvant (CFA) induced bilateral mechanical allodynia but unilateral heat hyperalgesia. CFA also induced a bilateral activation (phosphorylation) of JNK in the spinal cord, and the phospho JNK1 (pJNK1) levels were much higher than that of pJNK2. Notably, both pJNK and JNK1 were expressed in GFAP-positive astrocytes. Intrathecal infusion of a selective peptide inhibitor of JNK, D-JNKI-1, starting before inflammation via an osmotic pump, reduced CFA-induced mechanical allodynia in the maintenance phase but had no effect on CFA-induced heat hyperalgesia. A bolus intrathecal injection of D-JNKI-1 or SP600126, a small molecule inhibitor of JNK also reversed mechanical allodynia bilaterally. In contrast, peripheral (intraplantar) administration of D-JNKI-1 reduced the induction of CFA-induced heat hyperalgesia but did not change mechanical allodynia. Finally, CFA-induced bilateral mechanical allodynia was attenuated in mice lacking JNK1 but not JNK2. Taken together, our data suggest that spinal JNK, in particular JNK1 plays an important role in the maintenance of persistent inflammatory pain. Our findings also reveal a unique role of JNK1 and astrocyte network in regulating tactile allodynia and contralateral pain.

Maintenance of remission in Crohn's disease.

When remission of Crohn's disease is achieved, the next goal is to maintain long-term remission. Aminosalicylates may be recommended for maintenance remission, even though the results are less consistent than those observed in ulcerative colitis. The benefit is mainly observed in the post-surgical setting and in patients with ileitis, and with a prolonged disease duration. Corticosteroids are not effective in maintaining remission and should not be used for this indication. Azathioprine and 6-mercaptopurine are effective in maintaining remission. Maintenance benefits remain significant for patients who continued with the therapy for up to 5 years. Methotrexate has also been found to be effective in maintaining remission in Crohn's disease in patients who have responded acutely to methotrexate. Cyclosporine has not been found to be an effective maintenance agent. Mycophenolate mofetil could be considered a therapy in patients who are either allergic to azathioprine or in whom azathioprine failed to induce remission. The use of infliximab may change the future approach to maintenance therapy for Crohn's disease. Patients who responded clinically to infliximab have maintained their clinical response when receiving repeat infusions at 8-week intervals. In patients refractory to other therapies, infliximab may be effective in maintaining remission.

Safer Construction and Maintenance Safer Construction and Maintenance Practices to Minimize Potential Liability by Counties from Accidents, September 1979

Tort claims resulting from alleged highway defects have introduced an additional element in the planning, design, construction, and maintenance of highways. A survey of county governments in Iowa was undertaken in order to quantify the magnitude and determine the nature of this problem. This survey included the use of mailed questionnaires and personal interviews with County Engineers. Highway-related claims filed against counties in Iowa amounted to about $52,000,000 during the period 1973 through 1978. Over $30,000,000 in claims was pending at the end of 1978. Settlements of judgments were made at a cost of 12.2% of the amount claimed for those claims that had been disposed of, not including costs for handling claims, attorney fees, or court costs. There was no clear time trend in the amount of claims for the six-year period surveyed, although the amount claimed in 1978 was about double the average for the preceding five years. Problems that resulted in claims for damages from counties have generally related to alleged omissions in the use of traffic control devices or defects, often temporary, resulting from alleged inadequacies in highway maintenance. The absence of stop signs or warning signs often has been the central issue in a highway-related tort claim. Maintenance problems most frequently alleged have included inadequate shoulders, surface roughness, ice o? snow conditions, and loose gravel. The variation in the occurrence of tort claims among 85 counties in Iowa could not be related to any of the explanatory variables that were tested. Claims appeared to have occurred randomly. However, using data from a sub sample of 11 counties, a significant relationship was shown probably to exist between the amount of tort claims and the extensiveness of use of warning signs on the respective county road systems. Although there was no indication in any county that their use of warning signs did not conform with provisions of the Manual on Uniform Traffic Control Devices (Federal Highway Administration, Government Printing Office, Washington, D.C., 1978), many more warning signs were used in some counties than would be required to satisfy this minimum requirement. Sign vandalism reportedly is a problem in all counties. The threat of vandalism and the added costs incurred thereby have tended to inhibit more extensive use of traffic control devices. It also should be noted that there is no indication from this research of a correlation between the intensiveness of sign usage and highway safety. All highway maintenance activities introduce some extraordinary hazard for motorists. Generally effective methodologies have evolved for use on county road systems for routine maintenance activities, procedures that tend to reduce the hazard to practical and reasonably acceptable levels. Blading of loose-surfaced roads is an example of such a routine maintenance activity. Alternative patterns for blading that were investigated as part of this research offered no improvements in safety when compared with the method in current use and introduced a significant additional cost that was unacceptable, given the existing limitations in resources available for county roads.

Mutations in CTC1, encoding conserved telomere maintenance component 1, cause Coats plus.

Coats plus is a highly pleiotropic disorder particularly affecting the eye, brain, bone and gastrointestinal tract. Here, we show that Coats plus results from mutations in CTC1, encoding conserved telomere maintenance component 1, a member of the mammalian homolog of the yeast heterotrimeric CST telomeric capping complex. Consistent with the observation of shortened telomeres in an Arabidopsis CTC1 mutant and the phenotypic overlap of Coats plus with the telomeric maintenance disorders comprising dyskeratosis congenita, we observed shortened telomeres in three individuals with Coats plus and an increase in spontaneous γH2AX-positive cells in cell lines derived from two affected individuals. CTC1 is also a subunit of the α-accessory factor (AAF) complex, stimulating the activity of DNA polymerase-α primase, the only enzyme known to initiate DNA replication in eukaryotic cells. Thus, CTC1 may have a function in DNA metabolism that is necessary for but not specific to telomeric integrity.

Peroxisome proliferator-activated receptor gamma activation is required for maintenance of innate antimicrobial immunity in the colon.

Crohn's disease (CD), a major form of human inflammatory bowel disease, is characterized by primary immunodeficiencies. The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma) is essential for intestinal homeostasis in response to both dietary- and microbiota-derived signals. Its role in host defense remains unknown, however. We show that PPARgamma functions as an antimicrobial factor by maintaining constitutive epithelial expression of a subset of beta-defensin in the colon, which includes mDefB10 in mice and DEFB1 in humans. Colonic mucosa of Ppargamma mutant animals shows defective killing of several major components of the intestinal microbiota, including Candida albicans, Bacteroides fragilis, Enterococcus faecalis, and Escherichia coli. Neutralization of the colicidal activity using an anti-mDefB10 blocking antibody was effective in a PPARgamma-dependent manner. A functional promoter variant that is required for DEFB1 expression confers strong protection against Crohn's colitis and ileocolitis (odds ratio, 0.559; P = 0.018). Consistently, colonic involvement in CD is specifically linked to reduced expression of DEFB1 independent of inflammation. These findings support the development of PPARgamma-targeting therapeutic and/or nutritional approaches to prevent colonic inflammation by restoring antimicrobial immunity in CD.

Lenalidomide maintenance after stem-cell transplantation for multiple myeloma.

BACKGROUND: High-dose chemotherapy with autologous stem-cell transplantation is a standard treatment for young patients with multiple myeloma. Residual disease is almost always present after transplantation and is responsible for relapse. This phase 3, placebo-controlled trial investigated the efficacy of lenalidomide maintenance therapy after transplantation. METHODS: We randomly assigned 614 patients younger than 65 years of age who had nonprogressive disease after first-line transplantation to maintenance treatment with either lenalidomide (10 mg per day for the first 3 months, increased to 15 mg if tolerated) or placebo until relapse. The primary end point was progression-free survival. RESULTS: Lenalidomide maintenance therapy improved median progression-free survival (41 months, vs. 23 months with placebo; hazard ratio, 0.50; P<0.001). This benefit was observed across all patient subgroups, including those based on the β(2)-microglobulin level, cytogenetic profile, and response after transplantation. With a median follow-up period of 45 months, more than 70% of patients in both groups were alive at 4 years. The rates of grade 3 or 4 peripheral neuropathy were similar in the two groups. The incidence of second primary cancers was 3.1 per 100 patient-years in the lenalidomide group versus 1.2 per 100 patient-years in the placebo group (P=0.002). Median event-free survival (with events that included second primary cancers) was significantly improved with lenalidomide (40 months, vs. 23 months with placebo; P<0.001). CONCLUSIONS: Lenalidomide maintenance after transplantation significantly prolonged progression-free and event-free survival among patients with multiple myeloma. Four years after randomization, overall survival was similar in the two study groups. (Funded by the Programme Hospitalier de Recherche Clinique and others; ClinicalTrials.gov number, NCT00430365.).

Highway Maintenance Concept Vehicle, June 2002

This report documents Phase IV of the Highway Maintenance Concept Vehicle (HMCV) project, a pooled fund study sponsored by the Departments of Transportation of Iowa, Pennsylvania, and Wisconsin. This report provides the background, including a brief history of the earlier phases of the project, a systems overview, and descriptions of the research conducted in Phase IV. Finally, the report provides conclusions and recommendations for future research. Background The goal of the Highway Maintenance Concept Vehicle Pooled Fund Study is to provide travelers with the level of service defined by policy during the winter season at the least cost to taxpayers. This goal is to be accomplished by using information regarding actual road conditions to facilitate and adjust snow and ice control activities. The approach used in this study was to bring technology applications from other industries to the highway maintenance vehicle. This approach is evolutionary in that as emerging technologies and applications are found to be acceptable to the pooled fund states and as they appear that to have potential for supporting the study goals they become candidates for our research. The objective of Phase IV is to: Conduct limited deployment of selected technologies from Phase III by equipping a vehicle with proven advanced technologies and creating a mobile test laboratory for collecting road weather data. The research quickly pointed out that investments in winter storm maintenance assets must be based on benefit/cost analysis and related to improving level of service. For example, Iowa has estimated the average cost of fighting a winter storm to be about $60,000 to $70,000 per hour typically. The maintenance concept vehicle will have advanced technology equipment capable of applying precisely the correct amount of material, accurately tailored to the existing and predicted pavement conditions. Hence, a state using advanced technology could expect to have a noticeable impact on the average time taken to establish the winter driving service level. If the concept vehicle and data produced by the vehicle are used to support decision-making leading to reducing material usage and the average time by one hour, a reasonable benefit/cost will result. Data from the friction meter can be used to monitor and adjust snow and ice control activities and inform travelers of pavement surface conditions. Therefore, final selection of successfully performing technologies will be based on the foundation statements and criteria developed by the study team.