Narrative review: aspirin resistance and its clinical implications

Aspirin is currently the most cost-effective drug for the secondary prevention of cardiovascular disease, but treatment failures are relatively common. Several factors have been linked to these recurrent vascular events in patients prescribed aspirin, including smoking, drug interactions, nonadherence, comorbid conditions, and aspirin resistance. The term aspirin resistance has been used to describe not only an absence of the expected pharmacologic effects of aspirin on platelets but also poor clinical outcomes, such as recurrent vascular events, in patients treated with aspirin. Aspirin resistance is perhaps more precisely understood as the phenomenon of measurable, persisting platelet activation that occurs in patients prescribed a therapeutic dose of aspirin and may underlie an unknown proportion of aspirin treatment failures. Key challenges for future research are to standardize a definition of aspirin resistance and to compare whether different measures of platelet activation, either alone or in combination, independently predict cardiovascular events. These challenges must be met before researchers conduct studies to assess the clinical utility of testing on patient outcomes and cost-effective prescribing.     

First delivery of healthy offspring after freezing and thawing of oocytes in Switzerland

The interest in long-term storage of uninseminated oocytes through cryopreservation has seen a recent upsurge, because it provides the potential to assist young women to postpone childbirth after having overcome a malignant disease or delaying childbirth until after management of a professional career. The low fertilisation rate of frozen/thawed oocytes in earlier feasibility trials can now be improved by using intracytoplasmic sperm injection (ICSI) for assisting the penetration of the spermatozoon through the oocyte's hardened zona pellucida. Another reason for the reported low success rates of oocyte cryopreservation in earlier studies may have been the low developmental potential of spare oocytes, which were available for experimental cryopreservation. Oocytes retrieved from supernumerary follicles in women treated with gonadotropins for ovulation induction and intrauterine insemination can be used for the optimisation of cryostorage of uninseminated oocytes. We intended to investigate to what extent the well-established and successful cryopreservation protocols for pronucleate oocytes are also applicable for the cryopreservation of uninseminated oocytes. We herewith report the first successful pregnancy and delivery of frozen/thawed oocytes in Switzerland, which were inseminated with ICSI. In unbiased treatment groups the freezing and thawing of uninseminated oocytes and pronucleate oocytes give comparable results, if the additional manipulation during ICSI was taken into account.     

Protein alterations in ESCC and clinical implications: a review

Esophageal squamous cell carcinoma (ESCC) is the predominant histological subtype of esophageal cancer in Asia, characterized by high incidence and mortality rate. Although significant progress has been made in surgery and adjuvant chemoradiotherapy, the prognosis of the patients with this cancer still remains poor. Investigation into protein alterations that occurred in tumors can provide clues to discover new biomarkers for improving diagnosis and guiding targeted therapy. Hundreds of papers have appeared over the past several decades concerning protein alterations in ESCC. This review summarizes all the dysregulated proteins investigated in the disease from 187 published papers and analyzes their contributions to tumor development and progression. We document protein alterations associated with tumor metastasis and the transition from normal esophageal epithelia to dysplasia in order to reveal the most useful markers for prediction of clinical outcome, early detection, and identification of high-risk patients for targeted therapies. In particluar, we discuss the largest and most rigorous studies on prognostic implications of proteins in ESCC, in which cyclin D1, p53, E-cadherin and VEGF appeared to have the strongest evidence as independent predictors of patient outcome.     

Cardiac troponins in renal insufficiency: review and clinical implications

Patients with renal insufficiency may have increased serum troponins even in the absence of clinically suspected acute myocardial ischemia. While cardiovascular disease is the most common cause of death in patients with renal failure, we are just beginning to understand the clinical meaning of serum troponin elevations. Serum troponin T is increased more frequently than troponin I in patients with renal failure, leading clinicians to question its specificity for the diagnosis of myocardial infarction. Many large-scale trials demonstrating the utility of serum troponins in predicting adverse events and in guiding therapy and intervention in acute coronary syndromes have excluded patients with renal failure. Despite persistent uncertainty about the mechanism of elevated serum troponins in patients with reduced renal function, data from smaller groups of renal failure patients have suggested that troponin elevations are associated with added risk, including an increase in mortality. It is possible that increases in serum troponin from baseline in patients with renal insufficiency admitted to hospital with acute coronary syndrome may signify myocardial necrosis. Further studies are needed to clarify this hypothesis.     

Effects of amphotericin B and ketoconazole on mouse oocyte maturation: implications on the role of meiosis-activating sterol

Meiosis-activating sterol (MAS) has been shown to induce mouse oocytes cultured in the presence of hypoxanthine (HX) to resume meiosis. The present research was conducted to determine whether amphotericin B or ketoconazole (a promoter and an inhibitor of production of MAS), affected oocyte maturation. Mouse cumulus cell-enclosed oocytes (CEO) or denuded oocytes (DO) were cultured for 24 h in the presence of 4 mM HX with FSH or amphotericin B or ketoconazole. At the end of the culture, the frequency of germinal vesicle break down (GVBD) and polar body formation (PB) were recorded. The results demonstrated: (i) FSH (10-200 IU/l) induced dose-dependent oocytes maturation in CEO, but was without effect on DO. A maximum increase in GVBD and PB was observed with 25-50 IU/l FSH. The presence of FSH (50 IU/l) for 1 h was sufficient to induce meiotic resumption, which after 2 h reached a plateau similar to that of a continuous presence of FSH. (ii) CEO exposed to amphotericin B (0.0025-2.5 microg/l) underwent GVBD dose-dependently, whereas no effect was observed on DO. The presence of amphotericin B (0.025 microg/l) for 1 h stimulated oocyte resumption in a way similar to that of FSH. (iii) Amphotericin B (0.025 microg/l) and FSH (50 IU/l) did not show any additive effect on resumption of meiosis. (iv) Ketoconazole (10(-7)-10(-3) M) inhibited the effect of FSH on resumption of meiosis, but had no effect on oocyte spontaneous maturation. These results show that FSH and amphotericin B induce resumption of meiosis and indicate that they are likely to cause an accumulation of meiosis activating sterols in the CEO, but ketoconazole blocks the production of MAS. The present study supports the notion that MAS plays a physiological relevant role in triggering resumption of meiosis in mouse oocytes.     

Disconnected pancreatic duct syndrome: Updated review on clinical implications and management

Disconnected Pancreatic Duct Syndrome (DPDS) is an important but often overlooked complication of acute necrotising pancreatitis (ANP) that occurs due to necrosis of the main pancreatic duct (PD). This segmental necrosis leads on to disconnection between the viable upstream pancreatic parenchyma and the duodenum. The disconnected and functional segment of pancreas continues to secrete pancreatic juice that is not drained into the gastrointestinal tract and lead on to recurrent pancreatic fluid collections (PFC), refractory external pancreatic flstulae and chronic abdominal pain/recurrent pancreatitis. Because of lack of awareness of this important complication of ANP, the diagnosis of DPDS is usually delayed. The delay in diagnosis increases the morbidity of the disease as well as increase the cost of treatment and duration of hospital stay. Surgery has remained the cornerstone for management of patients with DPDS. The conventional surgical approaches have been either resection or internal drainage procedures. Surgery for DPDS in the setting of ANP is often difficult due to presence of local inflammation and extensive venous collaterals in the operative field due to splenic vein thrombosis and therefore is associated with significant morbidity. Advancement in therapeutic endoscopy, especially advent of therapeutic endoscopic ultrasound has opened an exciting new field of minimally invasive therapeutic options for management of DPDS. The present review discusses the current understanding of the clinical manifestations, imaging features and management strategies in patients with DPDS.     

Effects of progesterone on human spermatozoa: clinical implications.

Progesterone is a physiological stimulus of human sperm acrosome reaction. The effects of the steroid, which is present in high levels in the cumulus matrix that surrounds the oocyte, are mediated by an increase of intracellular calcium concentrations, tyrosine phosphorylation of proteins, efflux of chloride and stimulation of activity of phospholipases. These effects are due to activation of a nongenomic pathway. Two different types of receptors for progesterone, distinct from the genomic ones, have been identified on the surface of human spermatozoa. We demonstrated that sperm responsiveness to progesterone is impaired in subfertile patients and that is strictly correlated to the ability of fertilize the oocyte. In addition, the determination of sperm responsiveness is predictive of fertilizing ability with a positive predictive value of 90% and can be clinically useful for the preliminary assessment of the male partner to select the appropriate assisted reproductive technique.     

Physiological functions and clinical implications of fibrinogen-like 2: A review

Fibrinogen-like 2 (FGL2) encompasses a transmembrane (mFGL2) and a soluble (sFGL2) form with differential tertiary structure and biological activities. Typically, mFGL2 functions as prothrombinase that is capable of initiating coagulation in tissue without activation of the blood clotting cascade, whereas sFGL2 largely acts as an immunosuppressor that can repress proliferation of alloreactive T lymphocytes and maturation of bone marrow dendritic cells. Protein sequences of FGL2 exhibit evolutionary conservation across wide variety of species, especially at the carboxyl terminus that contains fibrinogen related domain (FRED). The FRED of FGL2 confers specificity and complexity in the action of FGL2, including receptor recognition, calcium affiliation, and substrate binding. Constitutive expression of FGL2 during embryogenesis and in mature tissues suggests FGL2 might be physiologically important. However, excessive induction of FGL2 under certain medical conditions (e.g., pathogen invasion) could trigger complement activation, inflammatory response, cellular apoptosis, and immune dysfunctions. On the other hand, complete absence of FGL2 is also detrimental as lack of FGL2 can cause autoimmune glomerulonephritis and acute cellular rejection of xenografts. All these roles involve mFGL2, sFGL2, or their combination. Although it is not clear how mFGL2 is cleaved off its host cells and secreted into the blood, circulating sFGL2 has been found correlated with disease severity and viral loading among patients with human hepatitis B virus or hepatitis C virus infection. Further studies are warranted to understand how FGL2 expression is regulated under physiological and pathological conditions. Even more interesting is to determine whether mFGL2 can fulfill an immunoregulatory role through its FRED at carboxyl end of the molecule and, and vice versa, whether sFGL2 is procoagulant upon binding to a target cell. Knowledge in this area should shed light on development of sFGL2 as an alternative immunosuppressive agent for organ transplantation or as a biomarker for predicting disease progression, monitoring therapeutic effects, and targeting FGL2 for repression in ameliorating fulminant viral hepatitis.     

Nocturia and its clinical implications in older women

The aim of this study is to demonstrate the relationship between nocturia and geriatric syndromes, and comprehensive geriatric assessment parameters (CGA) in older women. 858 older outpatient women were included in this cross-sectional study. For the nocturia variable, the question, “Generally, during the past 30 days, how many times did you usually urinate after you have gone to sleep at night until the time you got up in the morning?’’ was used. The relationships between nocturia status and common geriatric syndromes, and CGA parameters were determined. The mean age of patients was 74.1 ± 8.0 years. The prevalence of patients who reported average of 0, ≥1, ≥2, ≥3, and ≥4 nocturnal episodes was 14.7%, 85.3%, 66.3%, 42.13%, and 24.1%, respectively. When all the covariates including age, education, Charlson Comorbidities Index score, glomerular filtration rate, antimuscarinic drugs and alpha-blockers use, diabetes mellitus, chronic obstructive pulmonary disease, and incontinence were adjusted, there were higher rates of insomnia, recurrent falls and higher scores of Timed Up-Go test in older women with ≥2 nocturia episodes (p < 0.05). There was a significant correlation between ≥3 nocturia episodes and lower Instrumental Activities of Daily Living scores and a significant correlation between ≥4 nocturnal episodes and frailty and polypharmacy (p < 0.05). Nocturia is quite common and associated with insomnia, frailty, polypharmacy, incontinence, falls, lower gait speed, and functionality in older women.Therefore, nocturia is very important for geriatric practice and ≥2 nocturia episodes can be a marker of poor health status in older women.     

Calcium metabolism in sarcoidosis and its clinical implications

OBJECTIVE.: To examine the clinical implications of disturbed calcium metabolism in sarcoidosis and how the pathophysiology affects management strategies. METHODS.: The literature concerning calcium metabolism in sarcoidosis was reviewed. RESULTS.: Dysregulated calcium metabolism is a well-recognized complication of sarcoidosis, resulting in hypercalcaemia (prevalence 5-10%), hypercalcuria (40-62%) and reduced bone density (40-55%). Extrarenal synthesis of calcitriol [1,25(OH)(2)D(3)] is central to the pathogenesis of abnormal calcium homeostasis, but alterations in parathyroid hormone (PTH) activity and the expression of PTH-related peptide have also been demonstrated. The immunosuppressive properties of calcitriol suggest that the raised levels seen in sarcoidosis could represent an adaptive response to the undefined antigen that causes sarcoidosis. CONCLUSIONS.: The mechanisms of abnormal calcium metabolism in sarcoidosis need to be understood when treating hypercalcaemia, hypercalcuria and corticosteroid-induced osteoporosis. Studies are required to determine if the currently available therapies for osteoporosis are safe and effective in sarcoidosis.     

Heart failure after myocardial infarction: clinical implications and treatment

Heart failure is a frequent complication of myocardial infarction. Several factors, such as recurrent myocardial ischemia, infarct size, ventricular remodeling, stunned myocardium, mechanical complications, and hibernating myocardium influence the appearance of left ventricular systolic dysfunction after myocardial infarction. Importantly, its presence increases the risk of death by at least 3‐ to 4‐fold. The knowledge of the mechanisms and clinical features are essential for the diagnosis and treatment of left ventricular dysfunction and heart failure after myocardial infarction. Therefore, this review will focus on the clinical implications and treatment of heart failure after myocardial infarction. © 2011 Wiley Periodicals, Inc. The authors have no funding, financial relationships, or conflicts of interest to disclose.     

Postprocedure chest pain after coronary stenting: implications on clinical restenosis

OBJECTIVES: The goal of this study was to analyze the incidence and predictors of postprocedure chest pain (PPCP) after percutaneous coronary intervention (PCI) and its correlation with clinical restenosis. BACKGROUND: Chest pain after PCI occurs frequently even in the absence of procedural events and is considered to be due to vasospasm or coronary artery stretch. The short- and long-term significance of PPCP after otherwise successful stenting is not clear. METHODS: We analyzed 1,362 patients undergoing coronary stenting for PPCP, procedural and in-hospital events, 30-day major adverse cardiac events, and target vessel revascularization (TVR) at 6 to 9 months. RESULTS: There were 488 patients with PPCP and, of these, 312 patients were excluded due to procedural events. The remaining 176 patients with PPCP were compared with 874 patients without PPCP. Creatine kinase-MB isoenzyme elevation occurred in 25.6% of the PPCP group versus 9.6% of the no PPCP group (p < 0.001). Despite similar reference vessel diameter, the PPCP group had larger postprocedure minimum lumen diameter, higher stent-to-vessel ratio, and higher inflation pressure versus the no PPCP group (p < 0.01). At 30 days, the emergency room visits and repeat catheterization (16% vs. 2.7%; p < 0.001) were higher in the PPCP group versus the no PPCP group, but repeat intervention was similar. At 6- to 9-month follow-up, the TVR was significantly higher in the PPCP group compared with the no PPCP group (29.5% vs. 16.6%; p < 0.01). CONCLUSIONS: Our analysis suggests micromyonecrosis and vessel stretch as causes of PPCP. Postprocedure chest pain is associated with similar short-term outcome as no PPCP, but has higher restenosis, perhaps mediated by deep vessel wall injury. Therefore, PPCP may identify patients at high risk for restenosis.     

Effects of insulin resistance on endothelial function: possible mechanisms and clinical implications

Insulin resistance (IR) is defined as a reduced responsiveness of peripheral tissues to the effects of the hormone, referring to abated ability of insulin in stimulating glucose uptake in peripheral tissues and in inhibiting hepatic glucose output. Insulin has both a vasodilatory effect, which is largely endothelium dependent through the release of nitric oxide, and a vasoconstrictory effect through the stimulation of the sympathetic nervous system and the release of endothelin-1. IR and endothelial dysfunction (ED) are not only linked by common pathogenetic mechanisms, involving deranged insulin signalling pathways, but also by other, indirect to the hormone's actions, mechanisms. Different treatment modalities have been proposed to affect positively both the metabolic effects of insulin and ED. Weight loss has been shown to improve sensitivity to insulin as a result of either altered diet or exercise. Exercise has favourable effects on endothelial function in normal states and in states of disease, in men and women, and throughout the age spectrum and, hence, in IR states. Metformin improves sensitivity to insulin and most likely affects positively ED. Studies have shown that inhibitors of the renin-angiotensin system alter IR favourably, while Angiotensin converting enzyme (ACE) inhibitors and Angiotensin receptor type II (ATII) inhibitors improve ED. Ongoing studies are expected to shed more light on the issue of whether treatment with the thiazolidinediones results in improvement of endothelial function, along with the accepted function of improving insulin sensitivity. Finally, improved endothelial function by such treatments is not in itself proof of reduced risk for atherosclerosis; this remains to be directly tested in clinical trials.     

上海部分医院细菌耐药性监测及其临床意义

为了解医院细菌耐药性，要用１６种抗菌药纸片、Ｋｉｒｂｙ－Ｂａｕｅｒ琼脂扩散法监测了上海６家医院临床分离细菌的耐药性，结果共２０５０株细菌中５４０株革兰阳性球菌，７７株革兰阴性球菌，１４３３株革兰阴性杆菌。