Direct Deleterious Effect Research Articles

Bile Nephropathy in Flucloxacillin-Induced Cholestatic Liver Dysfunction.

Kidney injury in the context of cholestatic liver dysfunction is not uncommon; this has been historically referred to as cholemic nephrosis implying a direct deleterious renal effect of cholemia. However, scepticism about the exact role that bile and its constituents play in this injury has led to the disappearance of the term. We describe a case of severe AKI due to bile nephropathy with bile casts in flucloxacillin-induced liver dysfunction. We also discuss the recent literature reviving the concept of bile nephropathy.

Effect of gamma irradiation on the wear behaviour of human tooth enamel.

Radiotherapy is a frequently used treatment for oral cancer. Extensive research has been conducted to detect the mechanical properties of dental hard tissues after irradiation at the macroscale. However, little is known about the influence of irradiation on the tribological properties of enamel at the micro- or nanoscale. Therefore, this study aimed to investigate the effect of gamma irradiation on the wear behaviour of human tooth enamel in relation to prism orientation. Nanoscratch tests, surface profilometer and scanning electron microscope (SEM) analysis were used to evaluate the friction behaviour of enamel slabs before and after treatment with identical irradiation procedures. X-ray diffraction (XRD) and Fourier transform infrared spectroscopy (FTIR) were performed to analyse the changes in crystallography and chemical composition induced by irradiation. Surface microhardness (SMH) alteration was also evaluated. The results showed that irradiation resulted in different scratch morphologies, friction coefficients and remnant depth and width at different loads. An inferior nanoscratch resistance was observed independent of prism orientation. Moreover, the variation of wear behaviours was closely related to changes in the crystallography, chemical composition and SMH of the enamel. Together, these measures indicated that irradiation had a direct deleterious effect on the wear behaviour of human tooth enamel.

EPS06.2 Immune cell localization in different compartments of human end-stage CF lungs

Objectives The localization of immune cells along airways, blood vessels or in parenchyma in CF lung disease has insufficiently been established. A comprehensive quantitative immunohistochemical analysis was performed on lung tissue from CF patients and healthy controls (HC). Methods Sections (8 mm) of lung biopsies of CF patients taken during transplantation (n = 20) and control lung biopsies (n = 22) were stained for Th-lymphocytes (CD4), mast cells (tryptase) and eosinophils (EG-2). Quantification was performed by counting all single cells normalized over total area (mm 2 ) of biopsy (Th cells), or in 10 high power fields averaged per compartment (airways, blood vessels and parenchyma) per subject (mast cells and eosinophils). Results CD4+ T-lymphocyte counts were significantly increased in CF vs. HC (p = 0.001) and were present as dispersed single cells (CF & HC), or organized in follicles mainly situated in parenchyma (predominantly CF). Both total & compartmental mast cell counts were significantly increased in CF vs. HC (all p Conclusion There is an increased presence of Th lymphocytes and mast cells in the end-stage CF lung, albeit in different compartments of the lung. Inflammation was more severe in female CF patients irrespective of FEV 1 , colonization status or genotype, corroborating previous data suggesting a direct deleterious effect of female hormone on inflammation in the CF lung.

ENOS gene haplotype is indirectly associated with the recovery of cardiovascular autonomic modulation from exercise.

Polymorphisms in the endothelial nitric oxide synthase (eNOS) gene decrease expression and activation of eNOS in vitro, which is associated with lower post-exercise increase in vasodilator reactivity in vivo. However, it is unknown whether such polymorphisms are associated with other eNOS-related phenotypes during recovery from exercise. Therefore, we investigated the impact of an eNOS haplotype containing polymorphic alleles at loci -786 and 894 on the recovery of cardiovascular autonomic function from exercise. Sedentary, non-obese, healthy subjects were enrolled [n = 107, age 32 ± 1 years (mean ± SEM)]. Resting autonomic modulation (heart rate variability, systolic blood pressure variability, and spontaneous baroreflex sensitivity) and vascular reactivity (forearm hyperemic response post-ischemia) were assessed at baseline, 10, 60, and 120 min after a maximal cardiopulmonary exercise test. Besides, autonomic function was assessed by heart rate recovery (HRR) immediately after peak exercise. Haplotype analysis showed that vagal modulation (i.e., HF n.u.) was significantly higher, combined sympathetic and vagal modulation (i.e., LF/HF) was significantly lower and total blood pressure variability was significantly lower post-exercise in a haplotype containing polymorphic alleles (H2) compared to a haplotype with wild type alleles (H1). HRR was similar between groups. Corroborating previous evidence, H2 had significantly lower post-exercise increase in vasodilator reactivity than H1. In conclusion, a haplotype containing polymorphic alleles at loci -786 and 894 had enhanced recovery of autonomic modulation from exercise, along with unchanged HRR, and attenuated vasodilator reactivity. Then, these results suggest an autonomic compensatory response of a direct deleterious effect of eNOS polymorphisms on the vascular function.

Curcumin attenuates fructose-induced vascular dysfunction of isolated rat thoracic aorta rings

Context: Consumption of high fructose is associated with metabolic abnormalities, insulin resistance, and hypertension. It is not known whether this hypertensive effect of fructose is related to metabolic abnormalities or due to the direct effect of fructose on blood vessels.Objective: Here, we investigated the direct effect of fructose on rat isolated aorta and the possible protective effect of curcumin.Materials and methods: The isolated rat thoracic aorta rings were used to measure the contractile responses to different concentrations of both phenylephrine and KCl, and the relaxant response to acetylcholine (Ach). The effect of curcumin (1 µM) alone or in combination with tempol (1 mM), a superoxide dismutase mimetic agent, and N-{[3(amino-methyl)-phenyl]-methyl} ethanimidamide dihydrochloride (1400 W), a specific inducible nitric oxide synthase (iNOS) inhibitor, (1 µM) on fructose-treated aorta was compared. The aortic rings were incubated with different treatments for 60 min before starting the experiment. Changes in the intracellular calcium in response to KCl and nitric oxide levels were also measured.Results and discussion: Fructose strongly increased the contractile response of aortic rings to both phenylephrine and KCl (Emax was increased by 147.3% and 150.5%, respectively) but it did not affect the relaxant response to Ach. Curcumin significantly decreased the hyper responsiveness of arterial rings to both vasopressors (for phenylephrine, Emax decreased from 147.3% in fructose incubated aorta to 81%, and for KCl, Emax decreased from 150.5% in fructose-incubated aorta to 77.24% respectively). Curcumin also reduces the intracellular calcium level (85% reduction in intracellular calcium). A 1400 W was the only agent that potentiates the effect of curcumin.Conclusion: Fructose has a direct deleterious effect on aortic vascular reactivity. Curcumin can partially protect against fructose-induced impairment in vascular contractility via an antioxidant effect and reduction of elevated intracellular calcium.

Nerve injury and recovery after lateral lumbar interbody fusion with and without bone morphogenetic protein-2 augmentation: a cohort-controlled study

Background contextDespite common use of intraoperative electrophysiologic neuromonitoring, injuries to the lumbar plexus during lateral lumbar interbody fusion (LLIF) have been reported. Emerging data suggest that recombinant human bone morphogenetic protein-2 (rhBMP-2) use during an anterior or transforaminal lumbar interbody fusion may be associated with an increased risk of neurological deficit. Clinical data on the sequelae of rhBMP-2 implantation in close proximity to the lumbosacral plexus during LLIF remains to be understood. PurposeThe purpose of this study was to compare the incidence of neurologic deficits and pain in patients undergoing LLIF with and without rhBMP-2. Study design/settingRetrospective outcome analysis in controlled cohorts undergoing the lateral exposure technique for LLIF with and without rhBMP-2. MethodsThe electronic medical records of patients undergoing LLIF with and without supplemental posterior fusion for degenerative spinal conditions were retrospectively reviewed over a 6-year period. Patients with previous lumbar spine surgery or follow-up of less than 6 months were excluded. Patients were divided into 2 groups, Group 1 (rhBMP-2 use; n=72) and Group 2 (autograft/allograft use; n=72), and were matched according to the age at the time of surgery, gender, weight, body mass index, side of approach, total number of treated spinal segments, use of supplemental posterior fusion, and length of follow-up. ResultsImmediately after surgery, a sensory deficit was recorded in 33 patients in Group 1 and 35 patients in Group 2 (odds ratio [OR] 0.895; 90% confidence interval [CI] 0.516–1.550; p=.739). At last follow-up, a persistent sensory deficit was identified in 29 patients whose LLIF procedure was supplemented by rhBMP-2 and 20 patients in whom autograft/allograft was used (OR 1.754; 90% CI 0.976–3.151; p=.115). A motor deficit was recorded in 37 patients immediately after the rhBMP-2 procedure and 28 patients treated with autograft/allograft (OR 1.661; 90% CI 0.953–2.895; p=.133). A persistent motor deficit was recorded in 35 and 17 patients in Groups 1 and 2, respectively, at last follow-up (OR 3.060; 90% CI 1.681–5.571; p=.002). During the first postoperative examination, 37 patients in Group 1 and 25 patients in Group 2 complained of anterior thigh or groin pain (OR 1.987; 90% CI 1.133–3.488; p=.045). At last follow-up, there was a significantly higher number of patients in Group 1 who complained of persistent anterior thigh or groin pain than Group 2 (8 vs. 0 patients) (OR 16.470; 90% CI 1.477–183.700; p=.006). ConclusionsOur results provide evidence of an increased rate of postoperative neurologic deficit and anterior thigh/groin pain after LLIF using rhBMP-2, when compared with matched controls without rhBMP-2 exposure. This study suggests a potential direct deleterious effect of rhBMP-2 on the lumbosacral plexus.

Cord Blood Allograft Rejection Mediated By Coordinated Donor-Specific Cellular and Humoral Immune Processes

Recent statistical analyses of the clinical outcome have revealed that the presence of donor-specific anti-HLA antibodies (DSAs) in pre-transplant recipient is correlated with increased risk for graft rejection after allogeneic hematopoietic stem cell (HSC) transplantation. However, while cytotoxic T lymphocytes (CTLs) recognizing mismatched HLA molecule of the donor have been shown to be involved in graft rejection, there has been no biological evidence in humans that graft rejection is mediated by DSAs. In the present study, we demonstrate a case of cord blood allograft rejection in which DSAs acted to mediate graft rejection. Interestingly, CTL clones specific for donor HLA molecule were also isolated, suggesting that humoral and cellular immune responses were together responsible for allograft rejection. A patient with graft rejection after HLA-mismatched cord blood transplantation was studied. The white blood cell count increased transiently, subsequently decreased to undetectable level, and finally graft rejection was diagnosed on day 34. Screening for pre-transplant anti-HLA antibodies was not routinely performed at that time. We initially presumed that DSA would be responsible for graft rejection. The patient serum on day 36 were screened for HLA antibodies and further evaluated to determine HLA specificities using a LABScreen Single Antigen Kit. An antibody against HLA-B* 54:01, which was expressed in donor cells but not in patient cells, was detected. To test the effect of the DSA against HLA-B* 54:01 on HSC engraftment, antibody-dependent cellular cytotoxicity (ADCC) activity was assessed using unrelated HLA-B* 54:01-positive bone marrow mononuclear cells (BMMNCs) pre-cultured with patient serum and pre-transplant NK cells. The patient serum clearly showed an inhibitory effect on colony formation. Complement-dependent cytotoxicity activity of the DSA could not be detected. These data suggest that the DSA impaired the cord blood engraftment through ADCC activities. We next determined if cellular immunity was also responsible for allograft rejection. Two independent CTL clones, CD4-CD8+ and CD4+CD8-, were isolated from the patient blood at the time of graft rejection by limiting dilution. Both CTL clones were of patient origin by using short tandem repeat analysis and showed cytotoxicity against donor cells but not patient cells in Cr release assay. A CTL stimulation assay using COS cells transfected with various mismatched donor HLA cDNA constructs demonstrated that CD8+ and CD4+CTL clones recognized HLA-B* 54:01 and -DRB1* 15:02 molecules, respectively, both of which were expressed in donor cells but not in patient cells. To test the effect of the CTL clones on engraftment, a colony forming assay using either HLA-B* 54:01 or -DRB1* 15:02-positive unrelated BMMNCs pre-cultured with the corresponding CTL clones was performed. Each of these CTL clones inhibited colony formation from unrelated BMMNCs sharing target HLA in a dose-dependent manner. These data suggest that the CTLs also impaired the cord blood engraftment. Furthermore, anti-HLA-B* 54:01 antibody was detected in cryopreserved pre-transplant patient serum, and in nested PCR assays specific for the HLA-B* 54:01-specific CTL clone’s uniquely rearranged T cell receptor V beta chain, PCR product was detected by amplification of cDNA from pre-transplant patient peripheral blood mononuclear cells. Thus, both HLA-B* 54:01-specific antibody and CTL clone developed in the patient prior to transplantation. The present data provide the first direct evidence showing that humoral and cellular immune responses were involved in the graft rejection. Of note is the recognition of the same mismatched HLA-B* 54:01 molecule by the DSA and CTL, suggesting that humoral and cellular immune processes acted together to mediate allograft rejection. Given the difficulty in detecting HLA-specific CTLs in pre-transplant patient blood in contrast to the easiness in screening for DSAs, the presence of DSA not only means a direct deleterious effect on donor cells but it may also reflect the presence of CTLs that causes allograft rejection. Further studies are warranted to clarify whether the present observation can be duplicated in other patients with DSA. We are conducting the study to clarify whether patients with anti-HLA antibodies have CTLs that recognize the same HLA molecules before transplantation. Disclosures: No relevant conflicts of interest to declare.

Dose‐dependent inhibitory effects of proton pump inhibitors on human osteoclastic and osteoblastic cell activity

Proton pump inhibitors (PPIs), a class of molecules that are used to decrease gastric acid production, might have adverse effects on bone metabolism. The aim of this study was to characterize the concentration-dependent and time-dependent effects of three PPIs (omeprazole, esomeprazole, and lansoprazole) on human osteoclast precursor cells isolated from peripheral blood, and on human mesenchymal stem cells (osteoblast precursors). Cell cultures were characterized for total protein content, apoptosis, and several osteoclastic/osteoblastic features, and also for the involvement of some intracellular signaling pathways. PPIs caused a dose-dependent decrease in cellular density, which correlated with an increase in the apoptosis rate, effects that became statistically significant at concentrations ≥ 10(-5) m. They also inhibited phenotype-related gene expression and functional parameters. For both cell types, cellular function, i.e. osteoclastic resorption and the formation of mineralized deposits by osteoblastic cells, was more affected than proliferation-related parameters. The three PPIs showed similar qualitative and quantitative effects, but displayed some differences in the underlying intracellular signaling pathways. These results suggest that PPIs might have a direct deleterious effect on bone cells, with the possibility of decreased bone turnover.

P34 Mechanisms underlying the protective effect of H2S donors against carrageenan-induced knee joint synovitis and nociception

Controversy exists as to whether H 2 S has a direct protective or deleterious effect on arthritis. Although we have evidence from our previous study that exogenous H 2 S delivered to the knee joint can produce a significant anti-inflammatory and anti-nociceptive effect against carrageenan-induced joint synovitis [1] , the mechanisms involved are unknown. To investigate this, synovitis was induced in Wistar rats (previously treated with Lawesson reagent [LR], a classical H 2 S donor) by intra-articular injection of carrageenan into the knee joint in the presence or absence of treatment with glibenclamide (antagonist at the sulfonylurea receptor 1 (SUR1) regulatory sub-unit of ATP-sensitive K + (K ATP ) channels), capsazepine (transient receptor potential vanilloid 1 antagonist TRPV1), and verapamil (L-type Ca 2+ channel blocker). Both nociceptive and inflammatory parameters were assessed 4 h later. Animal procedures were approved by the local Ethics Committee and injections were performed under isoflurane anaesthesia. As expected, LR significantly attenuated the carrageenan (CGN)-induced nociceptive response of the ipsilateral hindpaw (impaired gait and secondary tactile allodynia) and related inflammatory process. Suppression of CGN-induced synovitis formation by H 2 S donor was not reversed by the blockade of K + (K ATP ), TRPV1 or L-type Ca 2+ channels. However, CGN-induced knee oedema and associated nociception was suppressed by glibenclamide, capsazepine or verapamil alone to the same extent as by LR. Compared with control group, determinants of oxidative stress (e.g. glutathione S-transferase (GST) and glutathione reductase (GR)) in the synovial membrane of rats with synovitis showed no differences among groups. These findings demonstrate that exogenous administration of H 2 S donor Lawesson reagent-induced protective effect against CGN-mediated synovitis and referred allodynia does not seem to require activation of both K ATP channels and L-type Ca 2+ or TRPV1 receptors in rats. Thus, the full details of the mechanisms of action of H 2 S donors in CGN-induced synovitis remain to be elucidated. Financial support : CAPES, CNPq, FAPESP.

Activity study of a hydroxynaphthoquinone fraction from Arnebia euchroma in experimental arthritis

Although various drugs for the treatment of rheumatoid arthritis (RA) have been used in clinics, RA is not completely curable to date. Thus, to seek new drugs for the treatment of RA has been a hotspot. Hydroxynaphthoquinones are the major anti-inflammatory active constituents in Arnebia euchroma (Royle) Johnst. The present study aims to evaluate the anti-arthritic activity of a hydroxynaphthoquinone mixture (HM) of A. euchroma (Royle) Johnst, including its anti-inflammatory and analgesic effects. The anti-arthritic efficacy of HM was examined using complete Freund's adjuvant- and bovine type II collagen-induced arthritic models. The paw edema, polyarthritis index and histopathological change were evaluated. The analgesic effect was assessed using the chemical and thermal models of nociception. Results found that HM administered prophylactically and curatively showed marked anti-arthritic activity by suppressing the paw swelling and development of inflammation, lowering the levels of TNF-α and IL-1β and protecting cartilage and bone from damage. The protection of HM was superior to that of reference drugs such as prednisone acetate or etanercept, and showed no direct deleterious effect. Similarly, HM showed significant analgesic effects. In summary, HM possessed potent anti-arthritic activity. It could relieve inflammatory symptoms and protect against joint destruction. These findings indicate that HM would be a potential therapeutic agent for arthritic disease, which provide pharmacological evidence for its clinical application.

Oxidative Stress and Reproductive Capacity in Iron Overload Thalassemia Major Women

Abstract 2155Despite progress in chelation regimens, excess iron still results in deleterious effect on the reproductive system of thalassemia major (TM) patients; subsequently compromised fertility is common in TM men and women. We have recently assessed the reproductive potential and its relation to iron overload in TM women as measured by the current methods for ovarian reserve testing (ORT) demonstrating a reduced ovarian antral follicle count (AFC) and corresponding low anti mullerian hormone (AMH) levels (Blood PMID 21757620). In the current study we further explored a possible link between iron overload and oxidative stress on fertility potential in thalassemia. Increase in reactive oxygen species (ROS) production and decrease in antioxidant defense mechanisms are thought to be major causes for accelerated follicle aging over time. Excess redox active non-protein bound iron acts as potent catalyst for highly deleterious ROS, causing oxidative damage to plasma lipids, DNA and proteins, and is therefore likely to further accelerate follicle aging and loss of reproductive potential. However, such an effect in TM women has not been demonstrated. Extensive oxidation of intracellular Glutathione (GSH) affects the structural integrity of cells. The ratio of GSH to its oxidized disulfide (GSH/GSSG) has been shown to be a sensitive measure of oxidative stress in biological systems and was noted to be compromised in thalassemia.We studied 26 TM women (median age 28y); obtaining total non-transferrin bound iron (NTBI) and its low-molecular component, labile plasma iron (LPI). Liver iron concentration (LIC) was measured by superconducting quantum interference device (SQUID) biosusceptometer system. Fourteen women had a trans-vaginal ultrasound (TVUS) for assessment of AFC and for ovarian volume measurements. Plasma GSH, GSSG and GSH precursors were obtained from the TM women and from 12 age-matched healthy non-smoking women, all fasting, were assayed by liquid chromatography–electrospray positive ionization–tandem mass spectrometry (LC-MS/MS) as previously described.GSH concentration was ∼25% lower in TM compared to normal controls, mostly due to low concentration of free GSH; 3.88±2.8 (median 2.9) and 5.74±1.4 (median 5.86), respectively. This resulted in a plasma GSH/GSSG ratio drop by 45% from the control ratio of 79.8 to a ratio of 43.4 in the thalassemia cohort (p=0.04). Plasma GSSG levels remained similar in both groups; 0.1±0.07μM in controls and 0.15±0.1μM in thalassemia women. TM women had an increase in precursors of GSH compare to controls (Table 1), suggesting that key metabolic pathways to augment synthesis of GSH may be up-regulated as a compensatory response to increased oxidative stress. GSH/GSSG, an oxidative measure, significantly correlated with AFC and with ovarian volume (R=0.57, p<0.05 and R=0.77, p=0.003, respectively). LIC (mean 14.5±11mg/gr dry wt, range 3.2–42) and GSH levels inversely correlated (R= −0.47 p<0.05). NTBI and LPI were elevated in the TM (as previously shown) but have not correlated with GSH/GSSG ratio. However, AFC (median 6.5, range 0–20) showed a trend of reverse correlation with NTBI and LPI (R=−0.21 and − 0.34, respectively).Although the current finding of lower levels of GSH and GSH/GSSG ratio in TM women does not provide a direct cause-and-effect relationship between GSH redox and fertility in thalassemia, impaired GSH redox homeostasis in the context of iron overload may be a key precipitating factor involved in accelerated follicular aging experienced by female thalassemia patients. Ovarian tissue in TM women is likely vulnerable to the iron-induced oxidative damage and the low antioxidant protection; a direct deleterious effect beyond the ovarian quiescence due to low gonadotropine stimulation. Oxidative stress may have a major effect on the maturation and growth of oocytes, resulting in further shrinking of ovarian tissue. This data suggests a potential role for antioxidants and improved nutritional supplementation as a therapeutic approach for TM women in particular during their reproductive years.Altered Glutathione (GSH) Precursors in Plasma of Thalassemia Patients Compared with Healthy ControlsGSH precursors (mM)Controls (n=15)Thalassemia women (n=23)pGlutamine297 ± 67440 ± 1760.005Cysteine7.4 ± 3.510 ± 3.80.03Cystathionine0.67 ± 0.20.82 ± 0.8ns [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Molecular Diagnosis of Analbuminemia: A New Case Caused by a Nonsense Mutation in the Albumin Gene

Analbuminemia is a rare autosomal recessive disorder manifested by the absence, or severe reduction, of circulating serum albumin (ALB). We report here a new case diagnosed in a 45 years old man of Southwestern Asian origin, living in Switzerland, on the basis of his low ALB concentration (0.9 g/L) in the absence of renal or gastrointestinal protein loss, or liver dysfunction. The clinical diagnosis was confirmed by a mutational analysis of the albumin (ALB) gene, carried out by single-strand conformational polymorphism (SSCP), heteroduplex analysis (HA), and DNA sequencing. This screening of the ALB gene revealed that the proband is homozygous for two mutations: the insertion of a T in a stretch of eight Ts spanning positions c.1289 + 23–c.1289 + 30 of intron 10 and a c.802 G > T transversion in exon 7. Whereas the presence of an additional T in the poly-T tract has no direct deleterious effect, the latter nonsense mutation changes the codon GAA for Glu244 to the stop codon TAA, resulting in a premature termination of the polypeptide chain. The putative protein product would have a length of only 243 amino acid residues instead of the normal 585 found in the mature serum albumin, but no evidence for the presence in serum of such a truncated polypeptide chain could be obtained by two dimensional electrophoresis and western blotting analysis.

Risque parodontal chez le patient obèse

Many epidemiological studies indicate a positive association between body mass index and chronic periodontitis. Periodontitis are multifactorial inflammatory diseases with a bacterial etiology, and are immune response dependent. Without treatment, these diseases lead to tooth loss through destruction of the gingival attachment system and the supporting bone. The chronic periodontitis susceptibility of the obese patients might involve the direct deleterious effect of inflammatory factors secreted by adipose tissue (adipokines), oxidative stress, or indirect mechanisms related to obesity-associated diseases (type 2 diabetes, hypertension, dyslipidemia). On the other hand, periodontitis may indirectly contribute to obesity by inducing chewing disorders due to an overall increase in teeth mobility and loss. Thus, a routine periodontal and dental examination of the obese patients should allow early diagnosis and treatment improving their chewing ability and oral health.

The Effect of Emergency Department Crowding on Education: Blessing or Curse?

Emergency department (ED) crowding is a national crisis that contributes to medical error and system inefficiencies. There is a natural concern that crowding may also adversely affect undergraduate and graduate emergency medicine (EM) education. ED crowding stems from a myriad of factors, and individually these factors can present both challenges and opportunities for education. Review of the medical literature demonstrates a small body of evidence that education can flourish in difficult clinical environments where faculty have a high clinical load and to date does not support a direct deleterious effect of crowding on education. To provide a theoretical framework for discussing the impact of crowding on education, the authors present a conceptual model of the effect of ED crowding on education and review possible positive and negative effects on each of the six recognized Accreditation Council for Graduate Medical Education (ACGME) core competencies.

Muscle performance enhancement in some non-orthopedic conditions: Evidence based on modified randomized controlled trials

Muscle performance relates to a set of parameters that reflect the capacity of muscles to provide the necessary means for accomplishing a specific task. While these tasks may depend on strength or endurance, parameters such as power or impulse may frequently be the most representative entity. To enhance muscle performance, intervention in the form of training or reconditioning is necessary. A wide scientific background covers the theory of such interventions which often relate to either normal healthy subjects and athletes or to patients presenting with musculo-skeletal disorder. However muscular insufficiency is encountered in a significant number of other pathologies that are not related to orthopedic dysfunction. Interventions targeting some of these pathologies are at the center of this paper. In order to scientifically vindicate the benefit of muscle reconditioning (MR) programs the most rigorous way is by employing a randomized controlled trial (RCT) design. An RCT typically relates to a patient group (entered randomly or consecutively) which is further randomly divided into at least 3 groups: experimental, placebo and control but may often include more than one experimental group. RCT studies constitute the classical approach in pharmacological studies where experimental drugs are administered along with placebo. The effects of both are then compared to another group which either uses another drug or is not treated during the course of the experiment. Moreover, the tests are carried out using a double blind design. With respect to the effect of MR, the implementation of an RCT approach is almost impossible to realize for the following reasons. First while prescribing a placebo drug is recognized to have no effect, it is difficult to ‘prescribe’ a physical exercise that may not have any effect. Thus when comparing e.g. high intensity exercise with any other form of exercise, the latter should not be perceived as placebo. Second MR requires strict adherence to the protocol which normally takes up weeks to complete. Hence, intervention studies relating to training are much prolonged in comparison with other modalities. In addition, unlike pharmacotherapy which from the patient’s point of view is relatively easy to follow, training, in most cases means physical presence in designated places and dedication of time and physical effort. Third, in case where a ‘notreatment’ group is to be included, RCT studies relating to musculoskeletal conditions cannot be undertaken as prescribing no activity will put the patient in an immediate risk, particularly following surgical intervention. However, this may not be the immediate situation with non-orthopedic conditions. As a result RCT relating to MR has almost exclusively been applied where no direct and immediate deleterious effect could be expected. Even then, the design was not strictly based on including a placebo group, for the reason explained above, but generally consisted of comparing different protocols. As such the term used for the studies described in this paper is modified RCT, although the text will refer to RCT. The following sections will describe the use of RCT studies for assessing the benefit of MR programs in

Cardiovascular Safety of Gadoterate Meglumine (Gd-DOTA)

Gadolinium complexes are not considered to be a drug class at high risk for prolonging cardiac repolarization, which can lead to potentially life-threatening arrhythmias such as torsade de pointes. However, only limited robust data are available on these compounds despite their extensive use as contrast enhancers in magnetic resonance imaging. We present an overview of recent cardiovascular safety data obtained on gadoterate meglumine (Gd-DOTA). Cardiovascular safety was evaluated by "state-of-the-art" nonclinical ex vitro (dog Purkinje fibers) and in vivo studies in both normal (dogs) and sensitized animal models (rabbits) and in patients with various diseases in a specific clinical trial. In all of these studies, Gd-DOTA did not show any direct deleterious effect on cardiac electrophysiology and especially on ventricular repolarization. These results confirmed the good safety profile of Gd-DOTA derived from postmarketing evaluations. Nonspecific gadolinium complexes used for magnetic resonance contrast enhancement do not constitute a class-at-risk for drug-related arrhythmias.

Obesity and Male Reproductive Potential

Obesity and Male Reproductive Potential

Glycemia in acute coronary syndromes

Diabetes is an established major factor of poor prognostis after an acute coronary syndrome. Recent studies have addressed the impact of abnormal glucose metabolism at the acute phase in patients without known diabetes. It has been found that abnormal glycemia regulation is more common than normal regulation in patients presenting with acute coronary syndrome, whatever the method used to evaluate blood glucose metabolism. High blood glucose at admission, whether fasting or not, are associated with worse outcome after an acute coronary syndrome, i.e. by increased mortality and development of severe heart failure. The prognosistic value of glycemia is valuable for both short and long term outcomes. Admission glycemia measurement allows therapeutic strategies at the acute phase. Fasting glycemia and oral glucose tolerance test performed during the hospital stay discloses valuable diagnostic information and provide useful tools for secondary prevention. Moreover, fasting glycemia is a more powerful predictor for short term outcome after myocardial infarction than admission glycemia. The mechanisms by which hyperglycemia deteriorates the cardiovascular prognosis, in particular for left ventricular dysfunction, are not fully understood. Stress hyperglycemia may be a marker of extensive cardiac damage, reflecting a surge of stress hormones such as catecholamines and cortisol that participate to insulinresistance and affect fatty acid and glucose homeostasis. Recent findings also argue for a direct deleterious effect of hyperglycemia on myocardium.

Suppressor of cytokine signaling 1 expression protects oligodendrocytes from the deleterious effects of interferon-gamma.

Interferon-gamma (IFN-gamma) is a pleiotropic cytokine produced by T cells and natural killer cells that has been implicated as a deleterious factor in the immune-mediated demyelinating disorder multiple sclerosis. In vitro, purified developing and mature oligodendrocytes have been shown to die in the presence of IFN-gamma by apoptosis and necrosis, respectively. Moreover, transgenic expression of IFN-gamma in the CNS of mice during development results in tremor, hypomyelination, and oligodendrocyte cell loss, and IFN-gamma expression in adult animals after demyelinating insults inhibits remyelination. To examine the molecular mechanisms of IFN-gamma-induced oligodendrocyte injury, we generated a transgenic mouse line [PLP/SOCS1 (proteolipid protein/suppressor of cytokine signaling 1)] that exhibits diminished oligodendrocyte responsiveness to IFN-gamma attributable to the targeted expression of SOCS1 in these cells. We demonstrate that oligodendrocytes in the PLP/SOCS1 transgenic mice are protected against the injurious effect of IFN-gamma. Our data indicate that IFN-gamma exerts a direct deleterious effect on developing oligodendrocytes. The capacity of SOCS1 to inhibit the effects of IFN-gamma suggests a therapeutic approach toward protection of myelinating oligodendrocytes against the harmful effects of inflammation.

Lung metastases after liver resection or cryotherapy for hepatic metastasis from colorectal cancer–there is a difference!

Background. The most common site of colorectal extra‐abdominal metastases is the lung. The relative risk of lung metastases after resection and cryotherapy has not previously been compared. Methods. All patients underwent an extensive preoperative staging including clinical examination, abdominal computed tomography (CT) and abdominal angio‐CT to assess their hepatic disease. Two groups of patients were compared in this study (hepatic resection alone and hepatic cryotherapy with or without resection). A retrospective analysis of prospectively collected data was performed to assess the incidence and disease‐free interval of pulmonary metastasis after surgical treatment of colorectal liver metastasis. Results. This paper clearly shows two differences regarding pulmonary metastases between patients treated with resection only and cryotherapy with or without resection. Among the 10 clinical variables, cryotherapy had the greatest correlation with pulmonary metastases (p=0.004). A patient who undergoes hepatic resection only has a probability of 35% for developing pulmonary recurrence, compared with 51% following cryotherapy. Cryotherapy was also independently associated with shorter pulmonary disease‐free interval (p=0.036). Conclusion. There clearly is a higher risk of pulmonary metastasis after cryotherapy than after resection, whether this is related to selection of patients or a direct deleterious procedural effect requires more study.