Various significant connections of the male pelvic floor muscles with special reference to the anal and urethral sphincter muscles

The male pelvic floor is a complex structure formed by several muscles. The levator ani muscle and the perineal muscles are important components of the pel     

Should IFN-γ, IL-17 and IL-2 be considered predictive biomarkers of acute rejection in liver and kidney transplant? Results of a multicentric study

Acute rejection (AR) remains a major challenge in organ transplantation, and there is a need for predictive biomarkers. In the present multicenter study, we prospectively examined a series of biomarkers in liver and kidney recipients. Intracellular expression of IFN-γ, IL-17 and IL-2 and IL-17 soluble production were evaluated both pre-transplantation and post-transplantation (1st and 2nd week, 1st, 2nd and 3rd month). 142 transplant patients (63 liver/79 kidney) were included in the study. Twenty-eight recipients (14 liver/14 kidney) developed AR. Pre- and post-transplantation intracellular expression of %IFN-γ⁺ in CD4⁺CD69⁺ and in CD8⁺CD69⁺ and soluble IL17 identified liver and kidney transplant patients at high risk of AR. Pre-transplantation, %IL-2⁺ in CD8⁺CD69⁺ also identified kidney patients at high risk. We constructed pre- and post-transplantation risk prediction models, based on a composite panel of biomarkers, which could provide the basis for future studies and will be a useful tool for the selection and adjustment of immunosuppressive treatments.     

Genetic polymorphisms of tumour necrosis factor alpha (TNF‐α) promoter gene and response to TNF‐α inhibitors in Spanish patients with inflammatory bowel disease

Tumour necrosis factor alpha (TNF‐α) has an important role in inflammatory response. Alterations in the regulation of TNF‐α have been implicated in a variety of inflammatory disorders, including Inflammatory bowel disease (IBD). Indeed, a common treatment for IBD is the use of TNF‐α inhibitors. Polymorphisms in the TNF‐α promoter region are known to affect the level of gene expression. Our aim was to investigate the influence of these single nucleotide polymorphisms (SNPs) in TNF‐α promoter gene play in the risk of IBD in a Spanish population and their individual response to anti‐TNF‐α treatment. DNA samples from patients with IBD and controls were screened for TNF‐α ?238G/A (rs361525) and ?308G/A (rs1800629) SNPs by PCR‐SSOP using a microbeads luminex assay and compared with response to TNF‐α inhibitors. There were not statistical differences in ?238G/A and ?308G/A allele and genotype frequencies between patients. However, we found an increased frequency of ?308A allele and ?308GA genotype in these nonresponders patients to TNF‐α inhibitors with respect to responders patients (Pc < 0.05). This ?308GA genotype has been classified as high producer of this cytokine. This fact could actually be interesting to explain the different response of patients with IBD with respect to TNF‐α inhibitors. TNF‐α promoter gene polymorphism does not seem to play a role in IBD susceptibility, but particular TNF‐α genotypes may be involved in the different responses to TNF‐α inhibitor treatment in Spanish patients with IBD.     

B-cell growth factor receptor expression and B-cell growth factor response of leukemic B cell precursors and B lineage lymphoid progenitor cells

The purpose of this study was to analyze the expression of B cell growth factor (BCGF) receptors and to elucidate the biologic effects of biochemically purified natural BCGF at the B cell precursor stage of human B lineage lymphoid differentiation. The specific binding of radioiodinated high-mol-wt BCGF (125I-HMW-BCGF) and low-molecular-wt BCGF (125I-LMW-BCGF) to fresh marrow blasts from B cell precursor acute lymphoblastic leukemia (ALL) patients was initially investigated. The estimated number of radioiodinated BCGF molecules bound per blast ranged from undetectable to 24.3 X 10(3) for HMW-BCGF, and from 11.5 X 10(3) to 457.8 X 10(3) for LMW-BCGF. In 3H-TdR incorporation assays, 75% of cases showed a significant response to LMW-BCGF with a median stimulation index of 9.3. By comparison, only 33% of cases showed a significant response to HMW-BCGF with a median stimulation index of 2.4. Subsequently, B cell precursor colony assays were performed to assess and compare the biologic effects of BCGF on leukemic B lineage lymphoid progenitor cells. Among 28 cases studied, 57% responded to both HMW-BCGF and LMW-BCGF, 21% responded only to LMW-BCGF, and the remaining cases showed no proliferative response to either growth factor. The response patterns of virtually pure populations of FACS- sorted leukemic B cell precursors were essentially identical to the proliferative responses of unsorted leukemic B-cell precursors. Synergistic effects between HMW-BCGF and LMW-BCGF were observed in 80% of the cases that responded to both. The numbers of cell-bound radioiodinated BCGF molecules, the stimulation indices, as well as the number of B cell precursor colonies in BCGF-stimulated cultures showed a marked interpatient variation. Patients with structural chromosomal abnormalities (SCAs) involving 12p11-13 or patients with a Philadelphia chromosome showed a greater HMW-BCGF response at the level of leukemic progenitor cells than did other patients (P = .02). The LMW-BCGF response was significantly greater for patients with SCA than for patients without SCA (P = .04). The response of leukemic progenitor cells to HMW-BCGF or LMW-BCGF did not correlate with sex, age, disease status, FAB morphology, WBC at diagnosis, or immunophenotype. To our knowledge, this study represents the first detailed analyses of BCGF receptor expression and BCGF effects in B cell precursor ALL. The data presented provide direct evidence for the expression of functional receptors for both HMW-BCGF and LMW-BCGF in B cell precursor ALL.     

Effects of oral morphine on breathlessness and exercise tolerance in patients with chronic obstructive pulmonary disease

Previous studies have shown that opiates increase the maximal external work performed at exhaustion in patients with chronic obstructive pulmonary disease (COPD). The mechanism responsible for this improvement in exercise tolerance is unknown. The purpose of this study was to determine the effects of an oral morphine solution (0.8 mg/kg) on the exercise tolerance, perception of dyspnea, and arterial blood gases of patients with COPD. Thirteen eucapnic patients with stable COPD (FEV1 = 0.99 +/- 0.48) underwent duplicate incremental cycle ergometer tests to exhaustion (Emax) after the ingestion of placebo and after the ingestion of morphine. After the ingestion of morphine, the maximal workload increased by 18% (p less than 0.001) and the VO2 increased by 19.3% (p less than 0.001). Ten of the 13 patients had a higher ventilation at Emax after morphine ingestion. Despite the higher ventilation at Emax after morphine, the mean Borg score was not significantly higher. At Emax after morphine ingestion, the PaO2 (65.8 +/- 11.6 mm Hg) was significantly lower and the PaCO2 (43.5 +/- 8.3 mm Hg) was significantly higher than at Emax after placebo (71.9 +/- 15.5 and 38.3 +/- 8.5, respectively). When data at the highest equivalent workload were analyzed, the ventilation and the Borg scores were significantly lower, whereas the VO2 and VCO2 were comparable. From this study, we conclude that the administration of opiates can substantially increase the exercise capacity of patients with COPD. The improved exercise tolerance appears to be related to both a higher PaCO2 resulting in lowered ventilation requirements for a given workload and also to a reduced perception of breathlessness for a given level of ventilation.     

The natural history of a genetic subtype of arrhythmogenic right ventricular cardiomyopathy caused by a p.S358L mutation in TMEM43

To determine the phenotype and natural history of a founder genetic subtype of autosomal dominant arrhythmogenic right ventricular cardiomyopathy (ARVC) caused by a p.S358L mutation in TMEM43. The age of onset of cardiac symptoms, clinical events and test abnormalities were studied in 412 subjects (258 affected and 154 unaffected), all of which occurred in affected males significantly earlier and more often than unaffected males. Affected males were hospitalized four times more often than affected females (p ≤ 0.0001) and died younger (p ≤ 0.001). The temporal sequence from symptoms onset to death was prolonged in affected females by 1–2 decades. The most prevalent electrocardiogram (ECG) manifestation was poor R wave progression (PRWP), with affected males twice as likely to develop PRWP as affected females (p ≤ 0.05). Left ventricular enlargement (LVE) occurred in 43% of affected subjects, with 11% fulfilling criteria for dilated cardiomyopathy. Ventricular ectopy on Holter monitor was common and occurred early: the most diagnostically useful clinical test. No symptom or test could rule out diagnosis. This ARVC subtype is a sex‐influenced lethal arrhythmogenic cardiomyopathy, with a unique ECG finding, LV dilatation, heart failure and early death, where molecular pre‐symptomatic diagnosis has the greatest clinical utility.