Effect of test position on pelvic floor muscle assessment

The aims of this study were to analyse the effect of different body positions on pelvic floor muscle (PFM) assessment using digital muscle testing, manometry and transabdominal ultrasound. In addition, subject acceptance of each testing position was recorded. Subjects were 20 women's health physiotherapists. The testing protocol included the best of three maximum voluntary contractions tested in each of four positions (crook lying, supine, sitting and standing). Significant differences in muscle strength and subject acceptance between positions were found with each tool, most often between lying and upright positions. Digital muscle testing and vaginal squeeze-pressure scores were highest in the lying position, and vaginal resting pressure and transabdominal ultrasound scores were highest in the standing position. Subjects preferred the lying positions for internal examinations. The clinical significance of these differences and the reasons for these variations require further investigation.     

Abnormally High and Heterogeneous Bone Matrix Mineralization After Childhood Solid Organ Transplantation: A Complex Pathology of Low Bone Turnover and Local Defects in Mineralization

Chronic renal, liver, and heart failure in children associates with multiple skeletal complications. Increased fracture incidence often persists after transplantation and could be related to alterations in bone material properties. In the present cohort study we evaluated bone mineralization density distribution (BMDD) by quantitative backscattered electron imaging (qBEI) in 23 pediatric solid organ allograft recipients with suspected osteoporosis. We measured BMDD in the entire cross‐sectional area of transiliac bone biopsies obtained from kidney (n = 9), liver (n = 9), and heart (n = 5) transplant recipients (aged 7.6 to 19.7 years; 6.0 ± 5.6 years posttransplantation, patients with a history of clinical fractures: n = 14). The BMDD findings were compared with age‐appropriate references and with a previously presented cohort of children with chronic kidney disease on dialysis (CKD5D, n = 18). Furthermore, we related the BMDD parameters with patients’ clinical and bone histomorphometric outcomes. Compared to healthy children, qBEI results for cancellous and cortical bone in transplant recipients revealed an increase in the most frequently occurring calcium concentration (+2.9%, p = 0.001; +3.5%, p = 0.014), in the portion of fully mineralized bone (fivefold; 10‐fold, both p < 0.0001) and in heterogeneity of mineralization (+26,5% and +27.8%, both p < 0.0001), respectively. Moreover, the BMDD parameters were nonsignificantly distinct from CKD5D cohort except that the heterogeneity in mineralization was higher posttransplantation. There was a strong inverse correlation between the average calcium content of the bone matrix and patients’ biochemical ALP levels, histomorphometric indices of bone formation and resorption. The abnormally high bone matrix mineralization in transplant recipients, consistent with serum and histomorphometric outcomes, suggests a history of low bone turnover with accumulation of fully mineralized bone packets. Additionally, the increased heterogeneity of mineralization suggests local alterations in mineralization kinetics, which may be linked to dysfunctional osteocytes that were recently shown to accumulate within the bone matrix during organ failure and concomitant glucocorticoid and immunosuppressive medication. © 2017 American Society for Bone and Mineral Research.     

Clinical Utility of Using Lumbar Spine Trabecular Bone Score to Adjust Fracture Probability: The Manitoba BMD Cohort

Decreased lumbar spine trabecular bone score (TBS), a dual‐energy X‐ray absorptiometry (DXA)‐derived image texture measurement, is a risk factor for major osteoporotic fracture (MOF) and hip fracture (HF) independent of 10‐year fracture probability estimated using FRAX. We determined how often applying the TBS adjustment to fracture probability altered treatment qualification. Using a population‐based registry containing all clinical DXA results for Manitoba, Canada, we identified 34,316 women with baseline spine and hip DXA, FRAX‐based fracture probability measurements (computed with femoral neck bone mineral density), lumbar spine TBS, and minimum 5 years of observation (mean 8.7 years). Population‐based health services data were used to identify incident non‐traumatic MOF and HF in 3503 and 945 women, respectively. Baseline MOF and HF probabilities were estimated using FRAX before and after applying the TBS adjustment. Risk recategorization was assessed using net reclassification improvement (NRI) for individual FRAX‐based intervention criteria and three national clinical practice guidelines (CPGs) (US National Osteoporosis Foundation, Osteoporosis Canada, and UK National Osteoporosis Guideline Group). Overall, proportions of women reclassified with the TBS adjustment to FRAX were small (less than 5%) with more than 90% of the reclassification occurring close to the intervention threshold. For women close to an intervention cut‐off reclassification, rates ranged from 9.0% to 17.9% and were <1% otherwise. There was a small but significant improvement in overall NRI for all individual FRAX‐based intervention criteria (range 0.007 to 0.018) and all three national CPGs (range 0.008 to 0.011). NRI was larger in women below age 65 years (up to 0.056 for hip fracture). In summary, a small but significant improvement in MOF and HF risk assessment was found by using lumbar spine TBS to adjust FRAX probability. An improvement in risk reclassification was observed for CPGs from three different countries, with almost all of the benefit found in individuals close to an intervention threshold. © 2017 American Society for Bone and Mineral Research. © 2017 American Society for Bone and Mineral Research.     

Tissue factor produced by the endocrine cells of the islets of Langerhans is associated with a negative outcome of clinical islet transplantation

There are strong indications that only a small fraction of grafts successfully engraft in clinical islet transplantation. One explanation may be the instant blood-mediated inflammatory reaction (IBMIR) elicited by tissue factor, which is produced by the endocrine cells. In the present study, we show that islets intended for islet transplantation produce tissue factor in both the transmembrane and the alternatively spliced form and that the membrane-bound form is released as microparticles often associated with both insulin and glucagon granules. A low-molecular mass factor VIIa (FVIIa) inhibitor that indirectly blocks both forms of tissue factor was shown in vitro to be a promising drug to eliminate the IBMIR. Thrombin-antithrombin complex (TAT) and FVIIa-antithrombin complex (FVIIa-AT) were measured in nine patients who together received 20 infusions of isolated human islets. Both the TAT and FVIIa-AT complexes increased rapidly within 15-60 min after infusion. When the initial TAT and FVIIa-AT levels were plotted against the increase in C-peptide concentration after 7 days, patients with an initially strong IBMIR showed no significant increase in insulin synthesis after 7 days. In conclusion, tissue factor present in both the islets and the culture medium and elicits IBMIR, which affects the function of the transplanted islets.     

Soluble CD30 and HLA antibodies as potential risk factors for kidney transplant rejection

Recent literary data suggest that high pre- and post-transplant serum levels of the soluble CD30 (sCD30) molecule may be a risk factor for acute rejection and worse prognosis of the transplanted kidney. The aim of our study was to correlate the concentrations of sCD30 and the presence of HLA antibodies as defined by flow cytometry and ELISA with the clinical course and graft prognosis after transplantation. One hundred and seventeen kidney transplant patients were included into the study. The incidence of rejection episodes, graft function and graft survival for up to 1 year post-transplant were evaluated. Soluble CD30 levels before transplantation were virtually the same in patients who experienced rejection and in non-rejecting patients. In both patient groups, a significant decrease of sCD30 was detected 2 weeks after transplantation (104.4 U/ml before vs. 37.0 U/ml post-transplant, P < 0.001). However, there was a substantial difference in the level of decrease of sCD30 between rejecting and non-rejecting patients. Patients without rejection had lower sCD30 values (31.2 U/ml post-transplant) compared to patients who experienced rejection episodes (62.9 U/ml), P < 0.04. Multifactorial analysis showed that antibodies to HLA class II antigens and elevated concentrations of sCD30 shortly after transplantation were associated with increased risk for acute rejection in the first post-transplant year. Measurement of soluble CD30 after transplantation, taken into consideration with the presence of HLA class II antibodies, might be helpful for evaluating the potential risk for acute rejection.     

Genetic analysis of polymorphisms in biologically relevant candidate genes in patients with abdominal aortic aneurysms

BACKGROUND: Abdominal aortic aneurysms (AAAs) are characterized by histologic signs of chronic inflammation, destructive remodeling of extracellular matrix, and depletion of vascular smooth muscle cells. We investigated the process of extracellular matrix remodeling by performing a genetic association study with polymorphisms in the genes for matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs), and structural extracellular matrix molecules in AAA. Our hypothesis was that genetic variations in one or more of these genes contribute to greater or lesser activity of these gene products, and thereby contribute to susceptibility for developing AAAs. METHODS: DNA samples from 812 unrelated white subject (AAA, n = 387; controls, n = 425) were genotyped for 14 polymorphisms in 13 different candidate genes: MMP1(nt-1607), MMP2(nt-955), MMP3(nt-1612), MMP9(nt-1562), MMP10(nt+180), MMP12(nt-82), MMP13(nt-77), TIMP1(nt+434), TIMP1(rs2070584), TIMP2(rs2009196), TIMP3(nt-1296), TGFB1(nt-509), ELN(nt+422), and COL3A1(nt+581). Odds ratios and P values adjusted for gender and country of origin using logistic regression and stratified by family history of AAA were calculated to test for association between genotype and disease status. Haplotype analysis was carried out for the two TIMP1 polymorphisms in male subjects. RESULTS: Analyses with one polymorphism per test without interactions showed an association with the two TIMP1 gene polymorphisms (nt+434, P = .0047; rs2070584, P = .015) in male subjects without a family history of AAA. The association remained significant when analyzing TIMP1 haplotypes (chi 2 P = .014 and empirical P = .009). In addition, we found a significant interaction between the polymorphism and gender for MMP10 ( P = .037) in cases without a family history of AAA, as well as between the polymorphism and country of origin for ELN ( P = .0169) and TIMP3 ( P = .0023) in cases with a family history of AAA. CONCLUSIONS: These findings suggest that genetic variations in TIMP1, TIMP3, MMP10, and ELN genes may contribute to the pathogenesis of AAAs. Further work is needed to confirm the findings in an independent set of samples and to study the functional role of these variants in AAA. It is noteworthy that contrary to a previous study, we did not find an association between the MMP9 (nt-1562) polymorphism and AAA, suggesting genetic heterogeneity of the disease. CLINICAL RELEVANCE: Abdominal aortic aneurysms (AAAs) are an important cardiovascular disease, but the genetic and environmental risk factors, which contribute to individual's risk to develop an aneurysm, are poorly understood. Histologically, AAAs are characterized by signs of chronic inflammation, destructive remodeling of the extracellular matrix, and depletion of vascular smooth muscle cells. We hypothesized that genes involved in these events could harbor changes that make individuals more susceptible to developing aneurysms. This study identified significant genetic associations between DNA sequence changes in tissue inhibitor of metalloproteinase 1 (TIMP1), TIMP3, matrix metalloproteinase 10 (MMP10) and elastin (ELN) genes, and AAA. The results will require confirmation using an independent set of samples. After replication it is possible that these sequence changes in combination with other risk factors could be used in the future to identify individuals who are at increased risk for developing an AAA.     

Experimental animal model and RNA interference: a promising association for bladder cancer research

Animal models are at the centre of laboratory bladder cancer (BC) research and at the same time, the bridge to the clinic. A new and very promising therapeutical approach is to silence abnormally up-regulated genes in cancer, through small interfering RNA (siRNA) molecules. Therapeutic use and success of siRNAs will largely depend on their efficient and safe in vivo delivery and on avoiding accidental off-target effects. Intravesical siRNA is a strategy which may be the best deliver option to surperficial BC like intravesical immunotherapy. Its direct action might allow a continuous intracellular exposure to effective siRNA concentrations. While the procedure of transurethral siRNA administration is promising for BC research allowing detection of new targets in BC therapy, the optimal intravesical carrier and the best target(s) to siRNA are to be determined.     

FSH and bFGF stimulate the production of glutathione in cultured rat Sertoli cells

Migration of developing germ cells from the basal to the adluminal compartment of the seminiferous epithelium requires extensive tissue restructuring, resulting in the production of reactive oxygen species. Sertoli cells are involved in this process. Glutathione (GSH), produced by Sertoli cells, has an essential role in cell protection against oxidative stress. Intracellular GSH content is maintained by de novo synthesis, involving glutamate-cysteine ligase catalytic (GCLC) and modulatory (GCLM) subunits, and by recycling from oxidized GSH, catalysed by glutathione reductase (GR). To assess whether follicle-stimulating hormone (FSH) and basic fibroblast growth factor (bFGF) modulate GSH production in Sertoli cells by regulating the expression of GCLC, GCLM and/or GR, we performed in vitro studies using rat Sertoli cells in primary culture. FSH and bFGF stimulation increased Sertoli cell GSH levels after 24 h incubation. The simultaneous addition of FSH and bFGF did not produce any further effect. GCLM expression was upregulated by FSH and bFGF 6 h. At 24 h, only the FSH-mediated effect was still observed. FSH and bFGF also upregulated GR expression. In conclusion, our results show that FSH and bFGF increase GSH levels in Sertoli cells through stimulation of the de novo synthesis and recycling by upregulating GCLM and GR expression respectively. Therefore, protection of germ cells against oxidative stress seems to be regulated by hormones and germ cell-released growth factors capable of influencing the production of Sertoli cell GSH.     

High revision rates after laparoscopic vertical banded gastroplasty

BACKGROUND: To evaluate, in a surgical department at a university hospital in Stockholm, Sweden, the long-term results after laparoscopic vertical banded gastroplasty (VBG), with special emphasis on revisional surgery. Few studies are available with long-term results after laparoscopic VBG. Some short-term studies have shown results similar to gastric banding. METHODS: All consecutive patients who underwent attempted laparoscopic VBG between 1995 and 2005 were followed up regarding weight loss and the need for revisional surgery. Follow-up was from the date of surgery to the end of the observational period (December 2006). RESULTS: In 486 patients, laparoscopic VBG was attempted. Of the 486 cases, 64 were converted to open surgery. Conversions were common in the first patients, with a conversion rate of 4% during the last 100 patients. The mean body mass index at surgery was 42.4 kg/m2. The median follow-up was 3 years (range 0-11). All patients lost weight. A total of 104 patients (21%) required revisional surgery 114 times during the follow-up period, with food intolerance/vomiting and insufficient weight loss the most common reasons. Of the 104 patients, 31 underwent repeat VBG, of whom 10 needed a secondary revisional procedure, and 49 required conversion to gastric bypass, of whom none have required additional revisional surgery. CONCLUSION: Laparoscopic VBG is associated with high revisional rates. In the case of failed VBG, repeat VBG seems to be a poor option and conversion to gastric bypass yields better results. We have abandoned VBG as a surgical option in the treatment of obesity.