Urethral blood circulation during cardiopulmonary bypass

The haemodynamic changes induced by extracorporeal circulation (ECC) are thought to be important in the induction of urethral strictures in open heart surgery when indwelling latex catheters are used. In the present study, 6 piglets were cannulated and connected to extracorporeal perfusion apparatus. Pump flows correlated with human ECC values with non-haemic prime were used. The mucosal and submucosal blood circulation in the urethra reduced by 66% during ECC (P less than 0.05). The brain and hepatic arterial flows increased. A significant reduction was seen in renal blood circulation. The changes in the urethral blood circulation during ECC correlated with previous findings. The reduced wash out levels of chemicals leaching from the indwelling latex catheters as a result of reduced local blood circulation are the main trigger for the induction of urethral strictures during ECC and in other shock-like circulatory disturbances in the human body.     

A comparison of remifentanil and alfentanil for use with propofol in patients undergoing minimally invasive coronary artery bypass surgery

Most patients undergoing minimally invasive direct coronary artery bypass surgery can be awakened and tracheally extubated in the operating room. We have compared two techniques of total IV anesthesia in this patient population: 30 patients (aged 44 to 74 yr; 24 male) premedicated with temazepam were randomly assigned to receive either remifentanil-propofol or alfentanil-propofol. Anesthesia was induced with remifentanil 2 microg/kg or with alfentanil 40 microg/kg, with propofol, and maintained with remifentanil at 0.25 or 0.5 microg x kg(-1) x min(-1) or alfentanil at 0.5 or 1 microg x kg(-1) x min(-1). The stable maintenance infusion rate of propofol was adjusted for age. Times to awakening and tracheal extubation were recorded. Postoperatively, IV morphine provided by patient-controlled analgesia was used for 48 h. Times to awakening and tracheal extubation (mean +/- SD) were shorter (P < 0. 01) in patients receiving remifentanil, and interpatient variations in times to awakening and tracheal extubation smaller (awakening 25 +/- 7 vs 74 +/- 32 min, and extubation 27 +/- 7 vs 77 +/- 32 min). Analysis of variance revealed that postoperative consumption of morphine was dependent on both the intraoperative opioid and the time elapsed after surgery (P < 0.05): patient-controlled analgesia morphine use during the first 3 h after awakening was more in patients receiving remifentanil (P < 0.01). Implications: Recovery of patients undergoing Minimally Invasive Direct Coronary Artery Bypass Surgery is significantly shorter and more predictable after total IV anesthesia with remifentanil-propofol than with alfentanil-propofol, which may be important if the goal is that patients will be awakened and tracheally extubated in the operating room.     

Factors associated with higher oxytocin requirements in labor

Objective: To identify clinical characteristics associated with high maximum oxytocin doses in women who achieve complete cervical dilation.

Methods: A retrospective nested case-control study was performed within a cohort of all term women at a single center between 2004 and 2008 who reached the second stage of labor. Cases were defined as women who had a maximum oxytocin dose during labor >20?mu/min, while women in the control group had a maximum oxytocin dose during labor of ≤20?mu/min. Exclusion criteria included no oxytocin administration during labor, multiple gestations, major fetal anomalies, nonvertex presentation, and prior cesarean delivery. Multiple maternal, fetal, and labor factors were evaluated with univariable analysis and multivariable logistic regression.

Results: Maximum oxytocin doses >20?mu/min were administered to 108 women (3.6%), while 2864 women received doses ≤20?mu/min. Factors associated with higher maximum oxytocin dose after adjusting for relevant confounders included maternal diabetes, birthweight >4000?g, intrapartum fever, administration of magnesium, and induction of labor.

Conclusions: Few women who achieve complete cervical dilation require high doses of oxytocin. We identified maternal, fetal and labor factors that characterize this group of parturients.     

Functional genomics bridges the gap between quantitative genetics and molecular biology

Deep characterization of molecular function of genetic variants in the human genome is becoming increasingly important for understanding genetic associations to disease and for learning to read the regulatory code of the genome. In this paper, I discuss how recent advances in both quantitative genetics and molecular biology have contributed to understanding functional effects of genetic variants, lessons learned from eQTL studies, and future challenges in this field.Most of human genetics research falls under two main questions: What are the genetic origins of variation in human disease and other traits? How does the blueprint of the human genome function to give rise to a living individual? These questions have different historical roots—in quantitative or medical genetics and molecular biology, respectively—as well as different molecular and statistical methods, and thus for decades they have been largely distinct areas of research. However, a question of increasing importance for understanding the human genome lies at their intersection: What are the functional effects of genetic variants across the human genome?The study of the evolutionary origins of human genetic variation and its contribution to human disease and traits has its origins in quantitative, statistical, and population genetics. Advances in high-throughput genotyping and sequencing technologies during the past 10 years have led to tremendous progress in this field, with the HapMap and 1000 Genomes projects (The International HapMap Consortium et al. 2007; The 1000 Genomes Project Consortium 2012) creating the foundation for hundreds of genome-wide association studies (GWAS) and now also rare variant analyses in the context of both common and rare diseases (Bamshad et al. 2011; Lee et al. 2014). However, these maps of genetic associations to disease do not give us direct information of the function of these variants: how they perturb the biology of the genome, the cell, and eventually the organism to affect disease risk—or from a population genetics perspective, to affect different selective pressures. Without such understanding, the information from genetic association studies will yield little benefit to human health.On the other side, understanding the mechanistic function of the human genome—as well as genomes of other species—has always been one of the fundamental questions of molecular biology. During the past five years, the approach has become genome-wide via the development of diverse high-throughput sequencing assays, applied to multiple cell types. Projects such as ENCODE (The ENCODE Project Consortium 2012), the Epigenomics Roadmap (Roadmap Epigenomics Consortium 2015), and FANTOM (The FANTOM Consortium and the RIKEN PMI and CLST (DGT) 2014) have produced large catalogs of functional elements in the genome—or more accurately, some genomes, since naturally, there is no archetype of the human genome. These studies do not typically capture variation in genome function among individuals, and the contribution of genetic differences in variation between samples is often ignored in study design. Thus, while these resources are used to annotate the putative regulatory function of genetic variants, this is done via indirect inference rather than direct measurement of genetic contribution to human phenotype diversity at the cellular level.The need to bridge conventional quantitative genetics and functional or molecular genetics has now become widely acknowledged (Fig. 1). The concept is not new—medical genetics has a long history of characterizing cellular effects of disease-causing mutations. However, the development of genome-wide methods now allows systematic high-throughput analysis, which is eventually more cost-efficient and informative of generalizable patterns than laborious locus-specific characterization. High-throughput analysis, with scalable and robust molecular assays, careful statistical analysis, and deep biological interpretation, are essential to achieve the future goal of being able to accurately read the genetic code, i.e., predict functional and phenotypic effects of genetic variants.Open in a separate windowFigure 1.Intersections of fields analyzing genetic variation, molecular biology, and medicine. GWAS and EWAS stand for genome-wide and epigenome-wide association studies, respectively, and eQTL is an abbreviation of expression quantitative trait loci.     

Suppression of pro-inflammatory cytokine release by selective inhibition of inducible nitric oxide synthase in mucosal explants from patients with ulcerative colitis

BACKGROUND: In ulcerative colitis (UC), inflammatory damage is associated with increased production of pro-inflammatory cytokines and nitric oxide through the inducible nitric oxide synthase (iNOS) pathway. In an animal model of acute experimental colitis we have previously shown amelioration of inflammation with the highly selective iNOS inhibitor 1400W. The aim of the present study was to investigate the effects of selective iNOS inhibition on the production of pro-inflammatory cytokines by the colon mucosa in UC. METHODS: Inflamed and uninflamed mucosa from patients with severe UC were incubated with a highly selective iNOS inhibitor N-[3-(aminomethyl)benzyl]acetamidine (1400W), with a relatively selective cNOS inhibitor N(G)-nitro-L-arginine-methyl-esther (L-NAME), or with an NO-donor, S-nitroso-acetylpenicillamine (SNAP). Cytokine concentrations in the incubation medium were quantitated with ELISA. RESULTS: Compared to uninflamed mucosa there was an increase in iNOS protein and nitrotyrosine levels in inflamed mucosal samples. Immunolocalization of iNOS and nitrotyrosine showed their expression in inflammatory cells in the lamina propria. Expression of iNOS was also found in the epithelial brush border. Selective inhibition of iNOS suppressed the release of tumour necrosis factor alpha (TNF-alpha, by 66%) and interleukin-6 (IL-6, by 27%). The NO-donor, SNAP, augmented the secretion of TNF-alpha, IL-6 and IL-1-beta (by 62%, 52% and 175%, respectively) and decreased the release of IL-1 receptor antagonist (IL-1Ra, by 34%) by the inflamed mucosa. Moreover, in uninflamed samples, 1400W suppressed the production of TNF-alpha (by 69%) and incubation with SNAP decreased IL-6 concentrations by 48%. The cNOS over iNOS selective inhibitor L-NAME had no significant effects on the accumulation of cytokines. CONCLUSION: Selective inhibition of iNOS suppresses mucosal TNF-alpha and IL-6 release in active UC, whereas NO seems to exacerbate the inflammatory response. These results suggest that selective iNOS inhibition may have therapeutic promise in the treatment of UC.     

Changed gait pattern in patients with total knee arthroplasty but minimal influence of tibial insert design

Introduction Previous radiostereometric studies have revealed abnormal anterior-posterior translation of the femur in patients operated with AMK (DePuy, Johnson and Johnson, Leeds, UK) total knee arthroplasty (TKA). Based on these observations, we hypothesized that patients with TKA have an abnormal gait pattern, and that there are differences in kinematics depending on the design of the tibial joint area.

Method We used a gait analysis system to evaluate the influence of joint area design on the kinematics of the hip and knee during level walking. 39 TKA patients (42 knees) and 18 healthy age-matched controls were studied. Patients with 5° varus/valgus alignment or less were randomized to receive either a relatively flat or a concave tibial insert with retention of the posterior cruciate ligament. Patients who had more than 5° varus-valgus alignment and/or extension defect of 10° or more were randomized to receive the concave or a posterior-stabilized tibial component with resection of the posterior cruciate ligament.

Results Patients with TKA tended to have less hip and knee extension and decreased knee and hip extension moment than controls. They also tended to walk more slowly. TKA altered the gait pattern, but choice of implant design had little influence.

Interpretation In patients with a similar degree of degenerative joint disease and within the limits of the constraints offered by the prostheses under study, the choice of joint area constraint has little influence on the gait pattern.     

Long-term efficacy and urological toxicity of low-dose-rate brachytherapy (LDR-BT) as monotherapy in localized prostate cancer

PurposeThe purpose of this study was to evaluate the incidence of late severe (≥Grade 3) urinary toxicity and the long-term efficacy after low-dose-rate brachytherapy (LDR-BT) in patients with localized prostate cancer (PCa).Methods and MaterialsDuring the years 1999–2008, 241 patients with PCa who underwent LDR-BT with I¹²⁵ and were followed up in Kuopio University Hospital were included to this analysis. The incidence of late severe (Grade 3) urinary toxicity and the long-term efficacy results were analyzed.ResultsAll D'Amico risk groups were represented, as 58.9%, 35.3%, and 5.8% of the patients were classified as low-, intermediate-, and high-risk patients, respectively. With a median followup of 11.4 years after implantation, the incidence of severe urinary toxicity increased throughout the followup period. The risk of Grade 3 urinary toxicity was highest among patients with higher Gleason scores (p = 0.016) and higher initial urine residual volumes (p = 0.017) and the cumulative incidence of severe urinary toxicity was 10.0%. The crude rate for transurethral prostatic resection was 5.8%. The relapse-free survival, the cause-specific survival, and the overall survival were 79.3%, 95.0%, and 66.4%, respectively.ConclusionsThe treatment was well tolerated as 90% of patients avoided any Grade 3 urinary toxicity. LDR-BT for localized PCa achieved high and durable efficacy. These results support the role of LDR-BT monotherapy as one of the valid primary treatment options for low-risk and favorable intermediate-risk patients.     

Intracellular energetic units in healthy and diseased hearts

BACKGROUND:

The present review examines the role of intra-cellular compartmentation of energy metabolism in vivo.

OBJECTIVE:

To compare the kinetics of the activation of mitochondrial respiration in skinned cardiac fibres by exogenous and endogenous adenine nucleotides in dependence of the modulation of cellular structure and contraction.

METHODS:

Saponin-permeabilized cardiac fibres or cells were analyzed using oxygraphy and confocal microscopy.

RESULTS:

Mitochondria respiration in fibres or cells was upregulated by cumulative additions of ADP to the medium with an apparent K_m of 200 μM to 300 μM. When respiration was stimulated by endogenous ADP produced by intracellular ATPases, a near maximum respiration rate was achieved at an ADP concentration of less than 20 μM in the medium. A powerful ADP-consuming system, consisting of pyruvate kinase and phosphoenolpyruvate, that totally suppressed the activation of respiration by exogenous ADP, failed to abolish the stimulation of respiration by endogenous ADP, but did inhibit respiration after the cells were treated with trypsin. The addition of up to 4 μM of free Ca²⁺ to the actively respiring fibres resulted in reversible hypercontraction associated with a decreased apparent K_m for exogenous ADP. These changes were fully abolished in fibres after the removal of myosin by KCl treatment.

CONCLUSIONS:

Mitochondria and ATPases, together with cytoskeletal proteins that establish the structural links between mitochondria and sarcomeres, form complexes – intracellular energetic units (ICEUs) – in cardiac cells. Within the ICEUs, the mitochondria and ATPases interact via specialized energy transfer systems, such as the creatine kinase- and adenylate kinase-phosphotransfer networks, and direct ATP channelling. Disintegration of the structure and function of ICEUs results in dyscompartmentation of adenine nucleotides and may represent a basis for cardiac diseases.     

Altered mitochondrial metabolism in the insulin‐resistant heart

Obesity‐induced insulin resistance and type 2 diabetes mellitus can ultimately result in various complications, including diabetic cardiomyopathy. In this case, cardiac dysfunction is characterized by metabolic disturbances such as impaired glucose oxidation and an increased reliance on fatty acid (FA) oxidation. Mitochondrial dysfunction has often been associated with the altered metabolic function in the diabetic heart, and may result from FA‐induced lipotoxicity and uncoupling of oxidative phosphorylation. In this review, we address the metabolic changes in the diabetic heart, focusing on the loss of metabolic flexibility and cardiac mitochondrial function. We consider the alterations observed in mitochondrial substrate utilization, bioenergetics and dynamics, and highlight new areas of research which may improve our understanding of the cause and effect of cardiac mitochondrial dysfunction in diabetes. Finally, we explore how lifestyle (nutrition and exercise) and pharmacological interventions can prevent and treat metabolic and mitochondrial dysfunction in diabetes.