Role of vasopressin in impaired water excretion in conscious rats with experimental cirrhosis

Role of vasopressin in impaired water excretion in conscious rats with experimental cirrhosis. The present study was undertaken to study the mechanism of impaired water excretion in experimental cirrhosis in the rat. Conscious rats in whom histologically proven cirrhosis was induced with carbon tetrachloride and phenobarbital were compared with control rats given phenobarbital alone. Impaired water excretion in experimental cirrhosis was verified by a basal hyponatremia (138 vs. 147 mEq/liter, P < 0.005) and an impaired excretion of water load (minimal urinary osmolality, 262 vs. 100 mOsm/kg; 58 vs. 102% of water load excreted, P < 0.001). To clarify the mechanism of this impaired water excretion, we measured glomerular filtration rate (GFR), renal blood flow (RBF), and vasopressin (VP) levels. In cirrhosis, GFR was normal but RBF was decreased (4.5 vs 6.8 ml/min/g, P < 0.01). VP levels were found to be higher in cirrhotic rats (1.61 vs. 0.71 pg/ml, P < 0.025). The significance of the impaired renal hemodynamics and the increase in VP was assessed by inducing cirrhosis in VP-free Brattle-boro (diabetes insipidus; DI) rats. Despite histologic, biochemical, and renal hemodynamic changes that were comparable to cirrhotic rats with an intact neurohypophysis, cirrhotic DI rats had no impairment in water excretion. To determine the cause of increased VP in experimental cirrhosis, we determined blood volume and systemic hemodynamics. Although plasma volume was greater in experimental cirrhosis (4.3 vs. 3.0 ml/100 g, P < 0.05), cirrhotic rats had a significantly lower peripheral resistance (0.37 vs. 0.42mm Hg/ml/min/kg, P < 0.05) and mean arterial pressure (104 vs. 120mm Hg, P < 0.001) than did control rats. These results document that experimental cirrhosis in the rat is associated with impaired renal water excretion in association with both abnormal renal hemodynamics and increased VP levels. The impaired water excretion, however, is solely VP mediated. The nonosmolar stimulus for VP release may be due to abnormal systemic hemodynamics.Rôle de la vasopressine dans l'altération de l'excrétion de l'eau par le rat conscient atteint de cirrhose expérimentale. Cette étude a été entreprise pour élucider le mécanisme de l'altération de l'excrétion de l'eau au cours de la cirrhose du rat. Des rats conscients chez lesquels une cirrhose prouvée histologiquement a été induite par le tétrachlorure et le phénobarbital ont été comparés à des rats contrôles recevant seulement le phénobarbital. L'altération de l'excrétion de l'eau dans la cirrhose expérimentale a été vérifiée par l'hyponatrémie basale (138 vs. 147 mEq/litre, P < 0,005) et le défaut d'excrétion d'une charge en eau (osmolalité urinaire minimale 262 vs. 100 mOsm/kg; 58 vs. 102% de la charge d'eau sont excrétés, P < 0,001). Pour élucider le mécanisme de cette altération de l'excrétion de l'eau le débit de filtration glomérulaire (GFR), le débit sanguin rénal (RBF) et les concentrations de vasopressine (VP) ont été mesurés. Dans la cirrhose GFR est normal alors que RBF est diminué (4,5 vs. 6,8 ml/min/gm, P < 0,01). VP est plus élevée chez les rats cirrhotiques (1,61 vs. 0,71 pg/ml, P < 0,025). La signification des modifications de l'hémodynamique rénale et de l'augmentation de VP a été évaluée en créant des cirrhoses chez des rats sans VP de la souche Brattleboro (DI). Malgré des modifications histologiques, biochimiques et hémodynamiques rénales qui sont comparables à celles des rats dont la neurohypophyse est intacte, les rats DI cirrhotiques n'ont pas d'altération de l'excrétion de l'eau. Pour connaître la cause de l'augmentation de VP dans la cirrhose expérimentale le volume sanguin et l'hémodynamique systémique ont été étudiés. Quoique le volume plasmatique soit augmenté dans la cirrhose expérimentale (4,3 vs. 3,0 ml/100 g, P < 0,05) les rats cirrhotiques ont des résistances périphériques inférieures (0,37 vs. 0,42mm Hg/ml/min/kg, P < 0,05) et une pression artérielle moyenne inférieure (104 vs. 120mm Hg, P < 0,001) à celles des rats contrôles. Ces résultats indiquent que la cirrhose expérimentale du rat comporte une altération de l'excrétion de l'eau associée à une hémodynamique rénale anormale et à des concentrations de VP augmentées. L'altération de l'excrétion de l'eau, cependant, a la vasopressione comme seul médiateur. Le stimulus non osmolaire de la libération de VP pourrait être l'anomalie de l'hémodynamique systémique

Predicting, Preparing for, and Creating the Future: What Will Happen to Internal Medicine?

It is the year 2025. During the past 20 years, internal medicine as a discipline continued to become less prestigious, less respected, and more fragmented. As fewer medical students chose internal medicine as a career, residency programs began to close. Those that remained open filled with fewer graduates of US medical schools but filled with more US citizens who graduated from international medical schools, more graduates of osteopathic medical schools, and more foreign graduates of international medical schools. Due to lack of adequate remuneration and a shift of primary care provision from generalist physicians to nurse practitioners and physician assistants, training in general internal medicine as a patient care specialty ceased. Generalist internal medicine careers have been replaced by tracks designed to foster health services research or academic careers; internal medicine training graduates subspecialty physicians. Although the projected collapse of Medicare in 2019 was avoided, severe cuts in federal funding for undergraduate and graduate medical education programs forced medical schools and residency programs to compete for federal funds. As a result, medical school tuition became prohibitive, for-profit health care systems viewed medical education as a significant cost center and chose to limit the size of their residency programs, and community-based training programs could not withstand the financial pressures and closed. The result was a reduced supply of internists. Furthermore, compliance with the regulatory burden imposed by accrediting organizations—such as the Accreditation Council for Graduate Medical Education—drove individuals from sustained careers in education, further impacting the viability of training programs

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

Surgical site infection after gastrointestinal surgery in high-income, middle-income, and low-income countries: a prospective, international, multicentre cohort study

Background: Surgical site infection (SSI) is one of the most common infections associated with health care, but its importance as a global health priority is not fully understood. We quantified the burden of SSI after gastrointestinal surgery in countries in all parts of the world. Methods: This international, prospective, multicentre cohort study included consecutive patients undergoing elective or emergency gastrointestinal resection within 2-week time periods at any health-care facility in any country. Countries with participating centres were stratified into high-income, middle-income, and low-income groups according to the UN's Human Development Index (HDI). Data variables from the GlobalSurg 1 study and other studies that have been found to affect the likelihood of SSI were entered into risk adjustment models. The primary outcome measure was the 30-day SSI incidence (defined by US Centers for Disease Control and Prevention criteria for superficial and deep incisional SSI). Relationships with explanatory variables were examined using Bayesian multilevel logistic regression models. This trial is registered with ClinicalTrials.gov, number NCT02662231. Findings: Between Jan 4, 2016, and July 31, 2016, 13 265 records were submitted for analysis. 12 539 patients from 343 hospitals in 66 countries were included. 7339 (58·5%) patient were from high-HDI countries (193 hospitals in 30 countries), 3918 (31·2%) patients were from middle-HDI countries (82 hospitals in 18 countries), and 1282 (10·2%) patients were from low-HDI countries (68 hospitals in 18 countries). In total, 1538 (12·3%) patients had SSI within 30 days of surgery. The incidence of SSI varied between countries with high (691 [9·4%] of 7339 patients), middle (549 [14·0%] of 3918 patients), and low (298 [23·2%] of 1282) HDI (p < 0·001). The highest SSI incidence in each HDI group was after dirty surgery (102 [17·8%] of 574 patients in high-HDI countries; 74 [31·4%] of 236 patients in middle-HDI countries; 72 [39·8%] of 181 patients in low-HDI countries). Following risk factor adjustment, patients in low-HDI countries were at greatest risk of SSI (adjusted odds ratio 1·60, 95% credible interval 1·05–2·37; p=0·030). 132 (21·6%) of 610 patients with an SSI and a microbiology culture result had an infection that was resistant to the prophylactic antibiotic used. Resistant infections were detected in 49 (16·6%) of 295 patients in high-HDI countries, in 37 (19·8%) of 187 patients in middle-HDI countries, and in 46 (35·9%) of 128 patients in low-HDI countries (p < 0·001). Interpretation: Countries with a low HDI carry a disproportionately greater burden of SSI than countries with a middle or high HDI and might have higher rates of antibiotic resistance. In view of WHO recommendations on SSI prevention that highlight the absence of high-quality interventional research, urgent, pragmatic, randomised trials based in LMICs are needed to assess measures aiming to reduce this preventable complication

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Are Two Better Than One? Angiotensin-Converting Enzyme Inhibitors Plus Angiotensin Receptor Blockers for Reducing Blood Pressure and Proteinuria in Kidney Disease

Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers each reduce proteinuria and blood pressure. Several studies have compared the antiproteinuric and antihypertensive effects of combination therapy with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers with those of therapy with either drug class alone. This article reviews those trials as well as evidence suggesting a mechanism for the benefits observed with combination therapy

Evidence for involvement of 3'-untranslated region in determining angiotensin II receptor coupling specificity to G-protein.

The mRNA 3'-untranslated region (3'-UTR) of many genes has been identified as an important regulator of the mRNA transcript itself as well as the translated product. Previously, we demonstrated that Chinese-hamster ovary-K1 cells stably expressing angiotensin receptor subtypes (AT(1A)) with and without 3'-UTR differed in AT(1A) mRNA content and its coupling with intracellular signalling pathways. Moreover, RNA mobility-shift assay and UV cross-linking studies using the AT(1A) 3'-UTR probe identified a major mRNA-binding protein complex of 55 kDa in Chinese-hamster ovary-K1 cells. In the present study, we have determined the functional significance of the native AT(1A) receptor 3'-UTR in rat liver epithelial (WB) cell lines by co-expressing the AT(1A) 3'-UTR sequence 'decoy' to compete with the native receptor 3'-UTR for its mRNA-binding proteins. PCR analysis using specific primers for the AT(1A) receptor and [(125)I]angiotensin II (AngII)-binding studies demonstrated the expression of the native AT(1A) receptors in WB (B(max)=2.7 pmol/mg of protein, K(d)=0.56 nM). Northern-blot analysis showed a significant increase in native receptor mRNA expression in 3'-UTR decoy-expressing cells, confirming the role of 3'-UTR in mRNA destabilization. Compared with vehicle control, AngII induced DNA and protein synthesis in wild-type WB as measured by [(3)H]thymidine and [(3)H]leucine incorporation respectively. Activation of [(3)H]thymidine and [(3)H]leucine correlated with a significant increase in cell number (cellular hyperplasia). In these cells, AngII stimulated GTPase activity by AT(1) receptor coupling with G-protein alpha i. We also delineated that functional coupling of AT(1A) receptor with G-protein alpha i is an essential mechanism for AngII-mediated cellular hyperplasia in WB by specifically blocking G-protein alpha i activation. In contrast with wild-type cells, stable expression of the 3'-UTR 'decoy' produced AngII-stimulated protein synthesis and cellular hypertrophy as demonstrated by a significant increase in [(3)H]leucine incorporation and no increase in [(3)H]thymidine incorporation and cell number. Furthermore, [(125)I]AngII cross-linking and immunoprecipitation studies using specific G-protein alpha antibodies showed that in wild-type cells, the AT(1A) receptor coupled with G-protein alpha i, whereas in cells expressing the 3'-UTR 'decoy', the AT(1A) receptor coupled with G-protein alpha q. These findings indicate that the 3'-UTR-mediated changes in receptor function may be mediated in part by a switch from G-protein alpha i to G-protein alpha q coupling of the receptor. Our results suggest that the 3'-UTR-mediated post-transcriptional modification of the AT(1A) receptor is critical for regulating tissue-specific receptor functions

Mechanism of decreased vascular response to angiotensin II in renal vascular hypertension

Mechanism of decreased vascular response to angiotensin II in renal vascular hypertension. Compared to many forms of hypertension, vascular reactivity to angiotensin II (AII) is decreased in the early phase of two–kidney, one clip (2-K, 1C) renovascular hypertension (RVH). To determine the role of the AII receptor, we examined vascular responsiveness and 125I-AII binding to mesenteric artery membrane fractions after three weeks of 2-K, 1C RVH. Systolic blood pressure was 165 ± 8 in RVH and 105 ± 4mm Hg in controls, P < 0.001. Plasma renin activity was 4.2 ± 0.6 in RVH and 1.4 ± 0.5ng AI/ml/hr in controls, P < .001. The pressor response to exogenous AII was reduced by 40% in RVH. Since administration of a single dose of converting enzyme inhibitor (CEI) did not normalize the response to exogenous AII, the decreased reactivity was not caused by receptor occupancy. 125I-AH binding to mesenteric arteries was equal to or greater in RVH than controls at all concentrations of AIL Scatchard analysis revealed an increase in the total number of binding sites (BMAX): 140.8 ± 6.3 in RVH versus 91.7 ± 6.5 fmol/mg in controls, P < 0.01, while the apparent dissociation constant was unchanged. To determine if the increase in circulating AII caused these binding alterations, rats were either 1) treated with CEI for three days; or 2) unilaterally nephrecto-mized. Both of these manipulations reversed the decrease in vascular responsiveness as well as the increase in receptor number (BMAX = 136 ± 13.4 in RVH vs. 94 ± 9.4 fmol/mg in RVH + nephrectomy, P < 0.05). We conclude that a post-receptor defect induced by increased circulating AII mediated the decreased vascular response to AII in early 2-K, 1C RVH