The toxicity of methotrexate in male fertility and paternal teratogenicity

Introduction: There is a high prevalence of methotrexate (MTX) use in males of reproductive age. The scope of this paper reviews what is known regarding risks to fertility and partners’ pregnancy outcomes with regard to MTX use in men.

Areas covered: This paper reviews the evidence for current recommendations for MTX use and male fertility and aims to educate professionals regarding MTX use in reproducing males so that patients may be counseled appropriately. A literature search included peer-reviewed sources from PubMed searches and the literature referenced within.

Expert opinion: There is a lack of evidence regarding effects of MTX on male fertility. The recommendation to stop MTX three months prior to conception is safe, but is not evidenced by an understanding of the impact of MTX on spermatogenesis or paternal-mediated teratogenicity but rather the timeframe of spermatogenesis. Given the unclear evidence, patients treated with MTX must be counseled on the likelihood of adverse effects of MTX and role of sperm cryopreservation. Future studies are needed to help elucidate the unclear evidence of MTX effects on male fertility and pregnancy outcomes.     

Btk regulates multiple stages in the development and survival of B-1 cells

B-1 cells are important players in the first line of defense against pathogens. According to current models for the origin of B-1 cells, they either represent a separate lineage from conventional B-2 cells or differentiate from conventional B-2 cells via an intermediate, B-1(int), in response to positive selection by antigen. Here we show that Btk, a Tec family kinase that mediates B cell antigen receptor (BCR) signaling, is required at multiple stages of B-1 cell development. VH12 anti-phosphatidylcholine (PtC) IgH transgenic mice provide a model for the induced differentiation of B-1 cells. This transgene selects for PtC-reactive cells and induces them to adopt a B-1 phenotype. Both processes have been shown to depend on Btk. To determine whether this is secondary to a requirement for Btk in the development of mature B-2 cells, we crossed VH12 transgenic mice to mice expressing low levels of Btk. B-2 cell development occurs normally in Btk(lo) mice despite reduced responsiveness to BCR crosslinking. Analysis of VH12.Btk(lo) mice reveals that Btk regulates the B-1(int) to B-1 transition and/or the survival of splenic B-1 cells, in part via a mechanism independent of its role in BCR signaling. We also show that Btk mediates the survival of, and expression of IL-10 by, those B-1 cells that do develop and migrate to the peritoneum. Multiple roles for Btk in B-1 cell development and maintenance may explain the particular sensitivity of this population to mutations in components of Btk signaling pathways.     

First Epidemiologic Study in Argentina of the Prevalence of BK Viruria in Kidney Transplant Patients

BackgroundThe worldwide seroprevalence of human BK polyomavirus (BKV) in adults is 80%. About 10%–60% of renal transplant recipients experience BKV infection, nephropathy of the graft may occur in 5% of the cases, and up to 45% lose the graft. The aim of this work was to describe the prevalence of BK viruria during the 1st year after transplantation.MethodsAn epidemiologic multicenter cross-sectional study was carried out in consecutive patients at each site with kidney transplantation from August 2011 to July 2012. Clinically significant viruria was defined as >10⁷ copies/mL. Viral DNA was extracted with the use of silica columns. Quantification was performed with the use of real-time polymerase chain reaction with primers that amplify a fragment of the large T-antigen gene and with a specific Taqman-MGB probe for BKV. For each assay, a standard curve with a quantified plasmid was included.ResultsOf 402 renal transplant recipients at 18 renal transplant sites, we analyzed 382; median age was 46.33 years, and 46.40% were female. The median of the temporal distribution for urine samples was 153 days. BK virus was detected in 50/382 samples (13%), 18 with values >10⁷ copies/mL (4.7%). The median of the distribution of positive values was 123 days and the highest frequency of positive values was in months 3–7. The conditions of recipient older than 34 years and donor older than 41 years were the only ones that showed statistically significant association with BK viruria. No association with any specific immunosuppressive drug was observed.ConclusionsThis is the first multicenter study conducted in Argentina to determine the prevalence of BK viruria in renal transplant recipients. Because of the growing number of the population susceptible to this infection, it is important to register and describe data about its epidemiology and associated risk factors.     

Coping and Management Techniques Used by Chronic Low Back Pain Patients Receiving Treatment From Chiropractors

ObjectivesThe purpose of this study was to describe coping strategies (eg, mechanisms, including self-treatment) that a person uses to reduce pain and its impact on functioning as reported by patients with chronic low back pain who were seen by doctors of chiropractic and how these coping strategies vary by patient characteristics.MethodsData were collected from a national sample of US chiropractic patients recruited from chiropractic practices in 6 states from major geographical regions of the United States using a multistage stratified sampling strategy. Reports of coping behaviors used to manage pain during the past 6 months were used to create counts across 6 domains: cognitive, self-care, environmental, medical care, social activities, and work. Exploratory analyses examined counts in domains and frequencies of individual items by levels of patient characteristics.ResultsA total of 1677 respondents with chronic low back pain reported using an average of 9 coping behaviors in the prior 6 months. Use of more types of behaviors were reported among those with more severe back pain, who rated their health as fair or poor and who had daily occurrences of pain. Exercise was more frequent among the healthy and those with less pain. Female respondents tended to report using more coping behaviors than men, and Hispanics more than non-Hispanics.ConclusionPersons with chronic back pain were proactive in their coping strategies and frequently used self-care coping strategies like those provided by chiropractors in patient education. In alignment with patients’ beliefs that their condition was chronic and lifelong, many patients attempted a wide range of coping strategies to relieve their pain.     

Decrease in sulphated glycosaminoglycans in aortic dissection--possible role in the pathogenesis.

STUDY OBJECTIVE--The aim was to investigate alterations in sulphated glycosaminoglycans in aortic dissection. DESIGN--Aortic fragments were taken from 10 patients within the first 3 d after onset of symptoms of aortic dissection and from nine age matched patients with no aortic disease. Sulphated glycosaminoglycans were analysed and quantified by agarose gel electrophoresis and densitometry after degradation with specific enzymes. MEASUREMENTS AND MAIN RESULTS--The amount of chondroitin sulphate was similar (7.14 v 7.60 mg.g-1 of dry tissue, n = 10, p greater than 0.5) in patients with dissection and in the control group. Total sulphated glycosaminoglycan content was decreased (11.51 v 14.26 mg.g-1 of dry tissue, n = 10, p less than 0.001). This difference was due to heparan sulphate (1.79 v 2.48 mg.g-1 of dry tissue, n = 10, p less than 0.05) and mainly to dermatan sulphate (2.58 v 4.18 mg.g-1 of dry tissue, n = 10, p less than 0.001). The ratio of 6-/4-sulphated disaccharides after chondroitinase ABC digestion was increased in the affected group. No correlation between these biochemical results and a histological evaluation of mucoid content was found. On the other hand, a significant increase in chondroitin sulphate could be observed related to aging. CONCLUSIONS--The diminution in sulphated glycosaminoglycans and its possible relationship with fat, collagen, and other extracellular matrix molecules could lead to a weakness in the aortic wall related to the dissection.     

Life Support Courses: Are They Effective?

Study objective: To determine the effectiveness of life support courses for health care providers on the basis of one of three outcomes: (1) patient mortality and morbidity, (2) retention of knowledge or skills, and (3) change in practice behavior. Methods: English-language articles from 1975 to 1992 were identified through MEDLINE and ERIC searches, bibliographies of articles, and current abstracts. Studies were considered relevant if they included a study population of life support providers, an intervention of any of the identified life support courses, and assessment of at least one of the three listed outcomes. Relevant studies were selected and validity scores were assigned to them by agreement of two independent reviewers, using a structured form to assess validity. Data on setting, methods, participants, intervention, and outcomes were then abstracted and verified. Results: Seventeen of 67 identified studies pertaining to life support courses met the inclusion criteria. (1) All three mortality and morbidity studies indicated a positive impact, with an overall odds ratio of .28 (95% confidence interval [CI], .22 to .37). (2) No net increase in scores was found in 5 of 8 studies of retention of knowledge and in 8 of 9 studies of skills retention. Two of three studies reporting refresher activities yielded positive effects on knowledge retention. Outcomes were not significantly different between groups taught with modular or didactic techniques. (3) Studies assessing behavioral outcome were methodologically weak. Conclusion: Among providers, retention of knowledge and skills acquired by participation in support courses is poor. However, refresher activities increase knowledge retention. Modular courses are as good as lectures for learning course material. There is evidence that use of the Advanced Trauma Life Support course has decreased mortality and morbidity. Further studies of patient outcome and provider behaviors are warranted. [Jabbour M, Osmond MH, Klassen TP: Life support courses: Are they effective? Ann Emerg Med December 1996;28:690-698.]     

Multimorbidity and Evidence Generation

Most people with a chronic disease actually have more than one, a condition known as multimorbidity. Despite this, the evidence base to prevent adverse disease outcomes has taken a disease-specific approach. Drawing on a conference, Improving Guidelines for Multimorbid Patients, the goal of this paper is to identify challenges to the generation of evidence to support the care of people with multimorbidity and to make recommendations for improvement. We identified three broad categories of challenges: 1) challenges to defining and measuring multimorbidity; 2) challenges related to the effects of multimorbidity on study design, implementation and analysis; and 3) challenges inherent in studying heterogeneity of treatment effects in patients with differing comorbid conditions. We propose a set of recommendations for consideration by investigators and others (reviewers, editors, funding agencies, policymaking organizations) involved in the creation of evidence for this common type of person that address each of these challenges. The recommendations reflect a general approach that emphasizes broader inclusion (recruitment and retention) of patients with multimorbidity, coupled with more rigorous efforts to measure comorbidity and comorbidity burden and the influence of multimorbidity on outcomes and the effects of therapy. More rigorous examination of heterogeneity of treatment effects requires careful attention to prioritizing the most important comorbid-related questions, and also requires studies that provide greater statistical power than conventional trials have provided. Relatively modest changes in the orientation of current research along these lines can be helpful in pointing to and partially addressing selected knowledge gaps. However, producing a robust evidence base to support patient-centered decision making in complex individuals with multimorbidity, exposed to many different combinations of potentially interacting factors that can modify the risks and benefits of therapies, is likely to require a clinical research enterprise fundamentally restructured to be more fully integrated with routine clinical practice.     

Benefits of Residual Aluminum Oxide for Sand Blasting Titanium Dental Implants: Osseointegration and Bactericidal Effects

Objectives. The purpose of this work was to determine the influence of residual alumina after sand blasting treatment in titanium dental implants. This paper studied the effect of alumina on physico-chemical surface properties, such as: surface wettability, surface energy. Osseointegration and bacteria adhesion were determined in order to determine the effect of the abrasive particles. Materials and Methods. Three surfaces were studied: (1) as-received, (2) rough surface with residual alumina from sand blasting on the surface and (3) with the same roughness but without residual alumina. Roughness was determined by white light interferometer microscopy. Surface wettability was evaluated with a contact angle video-based system and the surface free energy by means of Owens and Wendt equation. Scanning electron microscopy equipped with microanalysis was used to study the morphology and determine the chemical composition of the surfaces. Bacteria (Lactobacillus salivarius and Streptococcus sanguinis) were cultured in each surface. In total, 110 dental implants were placed into the bone of eight minipigs in order to compare the osseointegration. The percentage of bone-to-implant contact was determined after 4 and 6 weeks of implantation with histometric analysis. Results. The surfaces with residual alumina presented a lower surface free energy than clean surfaces. The in vivo studies demonstrated that the residual alumina accelerated bone tissue growth at different implantation times, in relation to clean dental implants. In addition, residual alumina showed a bactericidal effect by decreasing the quantity of bacteria adhering to the titanium. Conclusions. It is possible to verify the benefits that the alumina (percentages around 8% in weight) produces on the surface of titanium dental implants. Clinical relevance. Clinicians should be aware of the benefits of sand-blasted alumina due to the physico-chemical surface changes demonstrated in in vivo tests.