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Context: Sodium bicarbonate has been suggested as a possible strategy for prevention of contrast medium-induced nephropathy, a common cause of renal failure associated with prolonged hospitalization, increased health care costs, and substantial morbidity and mortality.Objective: To determine if sodium bicarbonate is superior to sodium chloride for preventing contrast medium-induced nephropathy in patients with moderate to severe chronic kidney dysfunction who are undergoing coronary angiography.Design, Setting, and Patients: Randomized, controlled, single-blind study conducted between January 2, 2006, and January 31, 2007, and enrolling 353 patients with stable renal disease who were undergoing coronary angiography at a single US center. Included patients were 18 years or older and had an estimated glomerular filtration rate of 60 mL/min per 1.73 m(2) or less and 1 or more of diabetes mellitus, history of congestive heart failure, hypertension, or age older than 75 years.Interventions: Patients were randomized to receive either sodium chloride (n = 178) or sodium bicarbonate (n = 175) administered at the same rate (3 mL/kg for 1 hour before coronary angiography, decreased to 1.5 mL/kg per hour during the procedure and for 4 hours after the completion of the procedure).Main Outcome Measure: The primary end point was a 25% or greater decrease in the estimated glomerular filtration rate on days 1 through 4 after contrast exposure.Results: Median patient age was 71 (interquartile range, 65-76) years, and 45% had diabetes mellitus. The groups were well matched for baseline characteristics. The primary end point was met in 13.3% of the sodium bicarbonate group and 14.6% of the sodium chloride group (relative risk, 0.94; 95% confidence interval, 0.55-1.60; P = .82). In patients randomized to receive sodium bicarbonate vs sodium chloride, the rates of death, dialysis, myocardial infarction, and cerebrovascular events did not differ significantly at 30 days (1.7% vs 1.7%, 0.6% vs 1.1%, 0.6% vs 0%, and 0% vs 2.2%, respectively) or at 30 days to 6 months (0.6% vs 2.3%, 0.6% vs 1.1%, 0.6% vs 2.3%, and 0.6% vs 1.7%, respectively) (P > .10 for all).Conclusion: The results of this study do not suggest that hydration with sodium bicarbonate is superior to hydration with sodium chloride for the prevention of contrast medium-induced nephropathy in patients with moderate to severe chronic kidney disease who are undergoing coronary angiography.Trial Registration: clinicaltrials.gov Identifier: NCT00312117. [ABSTRACT FROM AUTHOR]

Background: Access to reliable transportation is fundamental in the management of chronic disease. The purpose of this study was to investigate the association between vehicle ownership at the neighborhood-level and long-term mortality after myocardial infarction (MI)., Methods: This is a retrospective observational study evaluating adult patients admitted for MI between January 1st, 2006, and December 31st, 2016. Neighborhoods were defined by census tract and household vehicle ownership data was obtained from the American Community Survey courtesy of the University of California, Los Angeles Center for Neighborhood Knowledge. Patients were divided into 2 groups: those living in neighborhoods with higher vehicle ownership, and those living in neighborhoods with lower vehicle ownership. The cutoff of 4.34% of households reporting not owning a vehicle was used to define a neighborhood as one with "higher" vs "lower" vehicle ownership as this was the median value for the cohort. The association between vehicle ownership and all-cause mortality after MI was assessed using Cox proportional hazards regression models., Results: A total of 30,126 patients were included (age 68.1 +/- 13.5 years, 63.2% male). After adjusting for age, sex, race/ethnicity, and medical comorbidities, lower vehicle ownership was associated with increased all-cause mortality after MI (hazard ratio [HR] 1.10; 95% confidence interval [CI] 1.06-1.14; p <0.001). This finding remained significant after adjusting for median household income (HR 1.06; 95% CI 1.02-1.10; p  = 0.007). Upon comparison of White and Black patients living in neighborhoods with lower vehicle ownership; Black patients were found to have an increased all-cause mortality after MI (HR 1.21, 95% CI 1.13-1.30, p <0.001), a difference which remained significant after adjusting for income (HR 1.20; 95% CI 1.12-1.29; p <0.001). There was no significant difference in mortality between White and Black patients living in neighborhoods with higher vehicle ownership., Conclusion: Lower vehicle ownership was associated with increased mortality after MI. Black patients living in neighborhoods with lower vehicle ownership had a higher mortality after MI than White patients living in similar neighborhoods but Black patients living in neighborhoods with higher vehicle ownership had no worse mortality than their White counterparts. This study highlights the importance of transportation in determining health status after MI., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors. Published by Elsevier B.V.)

Purpose: Our objective was to calculate the positive predictive value (PPV) of the ICD-9 diagnosis code for angioedema when physicians adjudicate the events by electronic health record review. Our secondary objective was to evaluate the inter-rater reliability of physician adjudication., Methods: Patients from the Cardiovascular Research Network previously diagnosed with heart failure who were started on angiotensin-converting enzyme inhibitors (ACEI) during the study period (July 1, 2006 through September 30, 2015) were included. A team of two physicians per participating site adjudicated possible events using electronic health records for all patients coded for angioedema for a total of five sites. The PPV was calculated as the number of physician-adjudicated cases divided by all cases with the diagnosis code of angioedema (ICD-9-CM code 995.1) meeting the inclusion criteria. The inter-rater reliability of physician teams, or kappa statistic, was also calculated., Results: There were 38 061 adults with heart failure initiating ACEI in the study (21 489 patient-years). Of 114 coded events that were adjudicated by physicians, 98 angioedema events were confirmed for a PPV of 86% (95% CI: 80%, 92%). The kappa statistic based on physician inter-rater reliability was 0.65 (95% CI: 0.47, 0.82)., Conclusions: ICD-9 diagnosis code of 995.1 (angioneurotic edema, not elsewhere classified) is highly predictive of angioedema in adults with heart failure exposed to ACEI., (© 2021 John Wiley & Sons Ltd.)

Background: Characteristics and outcomes of patients with takotsubo syndrome remain to be defined. The goal of this study was to report the characteristics and long-term outcomes of patients presenting with takotsubo syndrome compared with other patients presenting with acute myocardial infarction (AMI) in a community-based population., Methods: This retrospective population-based study included patients hospitalised for AMI from 2006 to 2016. Those patients with takotsubo syndrome were compared with the patients with AMI. The primary outcome was all-cause mortality. Matching was performed to assemble a cohort of patients with similar baseline characteristics., Results: Among 26,015 patients hospitalised with an initial diagnosis of AMI, 530 (2.0%) were diagnosed with takotsubo syndrome. Patients with takotsubo syndrome were older (68.3 ± 11.3 vs 65.6 ± 12.2 years) and more likely to be women (93.4% vs 30.7%). Concomitant hypothyroidism, rheumatologic disorders, and lung disease were more prevalent in the takotsubo syndrome group, whereas diabetes and hyperlipidemia were less prevalent. Mortality was lower in the takotsubo syndrome group (1-year mortality 4.0% vs 8.9%; P < 0.001). The 530 patients with takotsubo syndrome were matched with 1,315 AMI patients with similar baseline characteristics. At a follow-up of 5.4 ± 3.3 years, patients with takotsubo syndrome had a lower risk for all-cause death than other patients who presented with AMI (hazard ratio 0.59, 95% CI 0.47-0.76)., Conclusions: Among patients presenting with AMI, patients with takotsubo syndrome were older and more likely to be women. Patients with takotsubo syndrome had better long-term outcomes compared with matched AMI patients., (Copyright © 2021 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Ovarian tissue cryopreservation (OTC) and transplantation is an innovative procedure increasingly utilized to help preserve fertility after gonadotoxic treatments especially in cancer patients. Approximately 30% of autotransplanted patients are able to achieve live birth, typically with the help of in-vitro fertilization. Numerous techniques and grafting sites have been described to continue to increase this figure. In the field of plastic surgery, tissue grafting has been successful performed for thousands of years and knowledge in this area has been significantly refined. A qualitative review of the literature using PubMed, Cochrane, SCOPUS and Medline databases was performed to look for articles relating to ovarian tissue transplantation (OTT) and comparisons made to plastic surgery tissue grafting. Many parallels were found between the principles of grafting in plastic surgery and the principles of OTT, including pre-operative patient optimization, suitable donor site selection, tissue harvest and preparation, graft site choice, immobilization of the graft and post-operative care. Consideration of the benefits and risks of using orthotopic versus heterotopic recipient sites is also highly important with regards to graft take, morbidity and ease of access of oocyte collection. We believe that ongoing discussion between disciplines can have the potential to improve knowledge, surgical techniques and patient outcomes., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/gs-21-24). WMR serves as an unpaid editorial board member of Gland Surgery from Mar 2018 to Feb 2023. The other authors have no conflicts of interest to declare., (2021 Gland Surgery. All rights reserved.)

Background:  Microsurgical free tissue transfer has become a reliable technique with success rates around 99% and around 5% requiring exploration for vascular compromise. Protocols for flap monitoring between plastic surgery units vary. We aimed to elucidate the time period when monitoring is crucial for flap salvage., Methods:  A systematic search of literature was performed in PubMed, Cochrane Library, Medline, and Scopus databases from 1966 to July 2018 according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, identifying 3,844 studies with mention of free flap and monitoring or timing or salvage or compromise. Studies were screened for relevance according to predetermined inclusion criteria. Data was extracted from included studies relating to flap type, monitoring, timing and reason for failure, and success of salvage intervention., Results:  A total of 109 studies featuring 44,031 free flaps were included. A total of 2,549 (5.8%) flaps required return to theater for compromise; 926 (2.1%) were lost and 1,654 (3.7%) were salvaged. In the first 24 hours postoperatively 93.8% of explored flaps are successfully salvaged, by day 2: 83.33%, day 3: 12.1%, and beyond day 4: none were successful. Of the 355 flaps where the cause of failure was reported, 59.5% was venous, 27.9% was arterial, 2.3% was a combination of both, and 10.2% was hematoma or infection. The proportion of flap failures at various recipient sites was highest in the trunk/viscera (7%, 95% confidence interval [CI] 0.00, 0.36), followed by limbs (5%, 95% CI 0.02, 0.08), head and neck (3%, 95% CI 0.02, 0.04), and breast (<1%; 95% CI 0.00, 0.02)., Conclusion:  Close flap monitoring is of most value in the first 48 hours postoperatively, facilitating rapid detection of vascular compromise, early salvage, and better outcomes. The location of the flap has implications on its success and certain recipient sites may need particular attention to improve chances of success., Competing Interests: None declared., (Thieme. All rights reserved.)

Background: Heart failure is an uncommon diagnosis among pregnant women with limited data on this condition. We sought to describe the characteristics and outcomes of pregnant women with heart failure stratified by etiologies of cardiomyopathy., Methods: This is a retrospective population-based cohort study across medical centers in Southern California in the United States. Pregnant women with heart failure were identified using ICD-9 codes and adjudicated by manual review of the medical records. Obstetric complications, fetal birthweight, and maternal mortality outcomes were evaluated., Results: Between 2003 and 2014, there were 488 pregnancies (0.1% of all pregnancies) complicated by heart failure, of which 333 (68.2%) were due to peripartum cardiomyopathy (PPCM) and 155 (31.8%) were due to other etiologies (non-PPCM). Compared to patients with non-PPCM, patients with PPCM were more likely to be Black Americans (26.7% vs 15.5%) or Asian Americans (16.8% vs 7.1%). A high proportion of PPCM patients had preeclampsia (11.1% vs 5.2%, p = 0.04). Infants born to mothers with non-PPCM were more likely to be small for gestational age (SGA) (SGA <3% 4.1% vs 9.7%, p < 0.001; SGA <10% 20% vs 8.8%, p = 0.001). No significant difference in maternal mortality was observed between PPCM and non-PPCM patients., Conclusions: PPCM is the most common etiology of HF during pregnancy. Infants born to mothers with PPCM were likely to be small for gestational age., Competing Interests: Declaration of competing interest None for all authors., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: There is limited information on the risks and benefits of anticoagulation in patients with atrial fibrillation receiving peritoneal dialysis., Objective: The aim was to determine the risk of mortality, ischemic stroke, and bleeding associated with warfarin use in patients with atrial fibrillation receiving peritoneal dialysis., Patients and Methods: This is a retrospective observational study of a multi-ethnic cohort of patients with atrial fibrillation receiving peritoneal dialysis in the United States. Using a dialysis registry, we identified 476 patients with atrial fibrillation receiving peritoneal dialysis. Among these patients, 115 (24%) were treated with warfarin. Cox proportional hazard models were used to compare risks of mortality, ischemic stroke and bleeding between the groups., Results: Compared to untreated patients, patients receiving warfarin were older (67.3 ± 10.8 vs 62.9 ± 13.3 years) and more likely to be white (42% vs 31%). Prevalence of comorbidities including hypertension, hyperlipidemia, diabetes, heart failure, and prior ischemic stroke were similar between the two groups. All cause mortality rates were 19.9 per 100 person-years in the warfarin group and 21.0 per 100 person-years in the untreated group. There was no difference between groups in the risk of mortality [hazard ratio (HR) 0.8, 95% confidence interval (CI) 0.53-1.2, p = 0.28], ischemic stroke (HR 2.3, 95% CI 0.94-5.4, p = 0.07), hemorrhagic stroke (HR 2.0, 95% CI 0.32-12.8, p = 0.46), gastrointestinal bleeding (HR 0.92, 95% CI 0.39-2.2, p = 0.86), or any bleeding (HR 1.2, 95% 0.60-2.3, p = 0.65). Even in the subgroup of patients with > 70% time in therapeutic range, no association was seen between warfarin treatment and mortality., Conclusion: There is no significant association between warfarin treatment with risks of mortality, ischemic stroke or bleeding in patients with atrial fibrillation receiving peritoneal dialysis.

Background The goal of this study is to report the characteristics and long-term clinical outcomes of patients with spontaneous coronary artery dissection (SCAD) and to identify factors associated with recurrent SCAD . Methods and Results This is a retrospective cohort study that included patients who underwent coronary angiography for evaluation of acute myocardial infarction between 2006 and 2016. Among 26 598 patients hospitalized with a principal diagnosis of acute myocardial infarction, 208 (0.78%) were diagnosed with SCAD . Patients with SCAD were younger (49.0±11.6 versus 65.6±12.2 years) and more likely to be women (88.9% versus 31.6%). Atherosclerotic risk factors, such as hypertension, hyperlipidemia, obesity, and diabetes mellitus, were less prevalent. Median follow-up was 4.7 years. Mortality was lower in patients with SCAD (1-year mortality: 2.4% versus 8.8%; P<0.001). After using propensity score matching to control for differences in age, sex, and comorbidities, the difference in mortality was no longer present, suggesting that lower mortality in patients with SCAD is attributed primarily to their baseline characteristics. Recurrent SCAD occurred in 22 patients (10.6%). Multivariate Cox regression modeling showed concomitant fibromuscular dysplasia (hazard ratio, 5.1; 95% CI , 1.6-15.8; P=0.005) and migraine headaches (hazard ratio, 3.4; 95% CI , 1.4-8.4; P=0.008) to be associated with increased risk of recurrent SCAD . Conclusions Among patients with acute myocardial infarction, patients with SCAD have a lower risk of mortality, which is attributed primarily to their younger age, female sex, and low prevalence of atherosclerotic risk factors. Risk of recurrent SCAD persists years after the initial presentation. Patients with fibromuscular dysplasia and migraine are at higher risk for recurrent SCAD .

Background: Chloramphenicol ointment is often used in plastic and dermatologic surgery as a topical antibiotic for surgical wounds, but evidence regarding its efficacy and side effects is lacking. In addition, anecdotal fear of aplastic anaemia exists from the oral use of this drug. We performed a systematic review of the literature to assess the efficacy and side effect profile of topical chloramphenicol ointment on non-ocular surgical wounds., Methods: A systematic search of MEDLINE, EMBASE and the Cochrane Library from inception until 4 September 2017 was undertaken. Clinical studies of topical chloramphenicol ointment use on surgical wounds were included. Studies looking only at ocular use or those not available in full text or English were excluded. The review was conducted adhering to PRISMA guidelines., Results: After full-text review, five articles were included. Two were randomized controlled trials, one was retrospective case control and two were case studies. There was evidence that chloramphenicol ointment use on surgical wounds produced a non-statistically significant reduction in infection rates. Delayed hypersensitivity and acute oesophagitis were noted as potential side effects of non-ocular topical use. Aplastic anaemia was not reported., Conclusion: There is a paucity of clinical data regarding the use of topical chloramphenicol ointment on surgical wounds. Further randomized controlled trials may be beneficial in order to support or refute its use in this setting., (© 2018 Royal Australasian College of Surgeons.)

The objective of this study was to assess methodological and reporting quality of systematic reviews in hand and wrist pathology. MEDLINE, EMBASE and Cochrane Library were searched from inception to November 2016 for relevant studies. Reporting quality was evaluated using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and methodological quality using a measurement tool to assess systematic reviews, the Assessment of Multiple Systematic Reviews (AMSTAR). Descriptive statistics and linear regression were used to identify features associated with improved methodological quality. A total of 91 studies were included in the analysis. Most reviews inadequately reported PRISMA items regarding study protocol, search strategy and bias and AMSTAR items regarding protocol, publication bias and funding. Systematic reviews published in a plastics journal, or which included more authors, were associated with higher AMSTAR scores. A large proportion of systematic reviews within hand and wrist pathology literature score poorly with validated methodological assessment tools, which may affect the reliability of their conclusions., Level of Evidence: I.

Background: The optimal management of stroke prophylaxis in hemodialysis patients with atrial fibrillation is controversial., Objective: The purpose of this study was to determine the risk of mortality, stroke, and bleeding associated with the use of warfarin in hemodialysis patients with atrial fibrillation., Methods: This was a retrospective, population-based study of hemodialysis patients with atrial fibrillation between January 1, 2006, and September 30, 2015. Association of warfarin use with mortality, stroke, and bleeding was determined by propensity score-matched, Cox proportional hazard models., Results: Among the 4286 patients with atrial fibrillation on hemodialysis, 989 (23%) were prescribed warfarin. Propensity score matching was used to identify 888 matched pairs with similar baseline characteristics. Warfarin use was associated with lower risk of all-cause death (hazard ratio [HR] 0.76, 95% confidence interval [CI] 0.69-0.84) and lower risk of ischemic stroke (HR 0.68, 95% CI 0.52-0.91). Warfarin use was not associated with a higher risk of hemorrhagic stroke (HR 1.2, 95% CI 0.6-2.2) or gastrointestinal bleeding (HR 0.97, 95% CI 0.77-1.2). The treatment effect was largest in the group with the best international normalized ratio control as measured by time in therapeutic range. Subgroup analyses showed warfarin use was associated with survival benefit in most subgroups. The 2 subgroups that did not benefit were patients with a history of hemorrhagic stroke and patients with concurrent aspirin use., Conclusion: Warfarin use is associated with lower all-cause mortality and ischemic stroke, without significantly increasing the risk of bleeding in hemodialysis patients with atrial fibrillation., (Copyright © 2017 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Pain associated with appendiceal endometriosis can mimic other intra-abdominal pathology. The diagnosis is usually obvious during gross inspection of the appendix; however, the absence of classical macroscopic appearances may lead to missed cases in which the patient's pain is misdiagnosed and inappropriately managed., Case: A 34-year-old woman presented with cyclical right iliac fossa pain and an elevated serum C-reactive protein of 13 mg/L (normal < 5 mg/L). Diagnostic laparoscopy showed an isolated appendiceal mass with no pelvic endometriosis, and an appendectomy was performed. Histopathology demonstrated appendiceal endometriosis without macroscopic involvement of other pelvic organs., Conclusion: This case gives insight into the pathophysiology of endometriosis. We advocate routine appendectomy in women with unexplained recurrent abdominal pain because a diagnostic laparoscopy may miss isolated endometriosis of the appendix, and we now have evidence that this may have no external features suggesting the diagnosis. Additionally, endometriosis can involve the gastrointestinal tract without involvement of the reproductive organs. This is important information in the further progression of theories underlying the pathophysiology of endometriosis., (Copyright © 2016 The Society of Obstetricians and Gynaecologists of Canada/La Société des obstétriciens et gynécologues du Canada. Published by Elsevier Inc. All rights reserved.)

Background: The goal of this study was to determine the prevalence of atrial fibrillation and atrial flutter (AF) in pregnant women and to examine the impact of AF on maternal and fetal outcomes., Methods and Results: Between January 1, 2003 and December 31, 2013, there were 264 730 qualifying pregnancies (in 210 356 women) in the Kaiser Permanente Southern California hospitals, among whom AF was noted in 157 pregnancies (129 women; 61.3 per 100 000 women, or 59.3 per 100 000 pregnancies). Prevalence of AF (per 100 000 women) in white, black, Asian, and Hispanic women was 111.6, 101.7, 45.0, and 34.3, respectively. Older age was associated with higher odds of having AF. Compared to women <25 years of age, the odds ratio (OR) of AF was 4.1 in women age 30 to 34 years, 4.9 in women age 35 to 39 years, and 5.2 in women age ≥40. Odds of AF episodes were higher during the third trimester compared to the first trimester (OR, 3.2; 95% CI: 1.5-7.7). Among AF patients, adverse maternal cardiac events were rare-2 women developed heart failure and there were no strokes or systemic embolic events and no maternal death. There were 156 live births (99.4% of all pregnancies). Compared to women without AF, fetal birth weights were similar, but rate for neonates' admission to the neonatal intensive care unit was higher (10.8% vs 5.1%; P=0.003)., Conclusions: AF is rare in pregnant women. Certain factors such as increased maternal age and white race increase the odds of having AF. Major maternal and fetal complications are infrequent, albeit a source of concern., (© 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

Objectives: This study aimed to conduct a methodological assessment of paper-based systematic reviews (SR) published in oral health using a validated checklist. A secondary objective was to explore temporal trends on methodological quality., Material and Methods: Two electronic databases (OVID Medline and OVID EMBASE) were searched for paper-based SR of interventions published in oral health from inception to October 2014. Manual searches of the reference lists of paper-based SR were also conducted. Methodological quality of included paper-based SR was assessed using an 11-item questionnaire, Assessment of Multiple Systematic Reviews (AMSTAR) checklist. Methodological quality was summarized using the median and inter-quartile range (IQR) of the AMSTAR score over different categories and time periods., Results: A total of 643 paper-based SR were included. The overall median AMSTAR score was 4 (IQR 2-6). The highest median score (5) was found in the pain dentistry and periodontology fields, while the lowest median score (3) was found in implant dentistry, restorative dentistry, oral medicine, and prosthodontics. The number of paper-based SR per year and the median AMSTAR score increased over time (median score in 1990s was 2 (IQR 2-3), 2000s was 4 (IQR 2-5), and 2010 onwards was 5 (IQR 3-6))., Conclusion: Although the methodological quality of paper-based SR published in oral health has improved in the last few years, there is still scope for improving quality in most evaluated dental specialties., Clinical Relevance: Large-scale assessment of methodological quality of dental SR highlights areas of methodological strengths and weaknesses that can be targeted in future publications to encourage better quality review methodology.

Purpose: The purpose of this study was to examine radiographic and clinical outcomes in the treatment of adult degenerative scoliosis using a minimally invasive (MI) lateral approach for anterior lumbar interbody fusion (IBF)., Methods: A prospective study of 24 consecutive degenerative scoliosis patients treated with MI, 90° lateral, transpsoas approach for anterior IBF was conducted. Twenty-one patients (88 %) were available for at least 12 months follow-up (mean 24 months)., Results: Mean operating time, estimated blood loss, and length of stay was 218 min, 68 mL, and 2.2 days, respectively. Complications occurred in one (5 %) case, a postoperative foot drop. At the last follow-up, disability improved by 50 % from 48.4 to 24.4. Back pain improved by 59 % from 7.0 to 2.9. Leg pain improved by 41 % from 5.6 to 3.3. In patients with a baseline score greater than 2.0, leg pain decreased by 42 % from 6.6 to 3.8. SF-36 physical component score improved by 41 % from 28.0 to 39.6, while mental component score increased by 18 % from 42.2 to 49.8. All changes were statistically significant, p < 0.05. Cobb angle was corrected from 27.7° to 16.6° and lumbar lordosis increased 39 % from -31.8° to -44.0°. Disc height increased from 5.7 to 11.6 mm, segmental lordosis increased by 48 % from 11.6° to 17.2°, and foraminal height increased from 16.4 to 21.7 mm. At the last follow-up, 100 % of patients were satisfied with their outcome, and 86 % would undergo the same procedure again. No revisions occurred., Conclusions: MI lateral IBF in the treatment of degenerative scoliosis results in lower complication rates and clinical and radiographic outcomes equivalent to reports in the literature of conventional approaches.

Background: The administration of intravenous fluid remains the cornerstone treatment for the prevention of contrast-induced acute kidney injury. However, no well-defined protocols exist to guide fluid administration in this treatment. We aimed to establish the efficacy of a new fluid protocol to prevent contrast-induced acute kidney injury., Methods: In this randomised, parallel-group, comparator-controlled, single-blind phase 3 trial, we assessed the efficacy of a new fluid protocol based on the left ventricular end-diastolic pressure for the prevention of contrast-induced acute kidney injury in patients undergoing cardiac catheterisation. The primary outcome was the occurrence of contrast-induced acute kidney injury, which was defined as a greater than 25% or greater than 0·5 mg/dL increase in serum creatinine concentration. Between Oct 10, 2010, and July 17, 2012, 396 patients aged 18 years or older undergoing cardiac catheterisation with an estimated glomerular filtration rate of 60 mL/min per 1·73 m(2) or less and one or more of several risk factors (diabetes mellitus, history of congestive heart failure, hypertension, or age older than 75 years) were randomly allocated in a 1:1 ratio to left ventricular end-diastolic pressure-guided volume expansion (n=196) or the control group (n=200) who received a standard fluid administration protocol. Four computer-generated concealed randomisation schedules, each with permuted block sizes of 4, were used for randomisation, and participants were allocated to the next sequential randomisation number by sealed opaque envelopes. Patients and laboratory personnel were masked to treatment assignment, but the physicians who did the procedures were not masked. Both groups received intravenous 0·9% sodium chloride at 3 mL/kg for 1 h before cardiac catheterisation. Analyses were by intention to treat. Adverse events were assessed at 30 days and 6 months and all such events were classified by staff who were masked to treatment assignment. This trial is registered with ClinicalTrials.gov, number NCT01218828., Findings: Contrast-induced acute kidney injury occurred less frequently in patients in the left ventricular end-diastolic pressure-guided group (6·7% [12/178]) than in the control group (16·3% [28/172]; relative risk 0·41, 95% CI 0·22-0·79; p=0·005). Hydration treatment was terminated prematurely because of shortness of breath in three patients in each group., Interpretation: Left ventricular end-diastolic pressure-guided fluid administration seems to be safe and effective in preventing contrast-induced acute kidney injury in patients undergoing cardiac catheterisation., Funding: Kaiser Permanente Southern California regional research committee grant., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Therapeutic monoclonal antibodies (mAb) are often produced in Chinese hamster ovary (CHO) cells. Three commonly used CHO host cells for generating stable cell lines to produce therapeutic proteins are dihydrofolate reductase (DHFR) positive CHOK1, DHFR-deficient DG44, and DUXB11-based DHFR deficient CHO. Current Genentech commercial full-length antibody products have all been produced in the DUXB11-derived DHFR-deficient CHO host. However, it has been challenging to develop stable cell lines producing an appreciable amount of antibody proteins in the DUXB11-derived DHFR-deficient CHO host for some antibody molecules and the CHOK1 host has been explored as an alternative approach. In this work, stable cell lines were developed for three antibody molecules in both DUXB11-based and CHOK1 hosts. Results have shown that the best CHOK1 clones produce about 1 g/l for an antibody mAb1 and about 4 g/l for an antibody mAb2 in 14-day fed batch cultures in shake flasks. In contrast, the DUXB11-based host produced ∼0.1 g/l for both antibodies in the same 14-day fed batch shake flask production experiments. For an antibody mAb3, both CHOK1 and DUXB11 host cells can generate stable cell lines with the best clone in each host producing ∼2.5 g/l. Additionally, studies have shown that the CHOK1 host cell has a larger endoplasmic reticulum and higher mitochondrial mass., (© 2013 American Institute of Chemical Engineers.)

Objectives: This study sought to examine the pattern of death and myocardial infarction (MI) after clopidogrel cessation in patients undergoing percutaneous coronary intervention (PCI) of the saphenous vein graft (SVG)., Background: The timing and incidence of adverse events by different durations of clopidogrel therapy after SVG PCI remain unknown., Methods: This is a cohort study of patients undergoing SVG PCI between 2000 and 2009, followed for all-cause mortality or MI after stopping clopidogrel. Incidence rates were calculated across different time periods after clopidogrel cessation. Adjusted incidence rate ratios (IRR) were calculated with multivariable regression (piecewise exponential and Poisson)., Results: There were 603 patients who underwent SVG PCI, of which 411 were event-free at the time of clopidogrel cessation. The incidence rate (95% confidence interval: [CI])/1,000 person-days of death or MI after stopping clopidogrel in the time intervals of 0 to 90 days, 91 to 365 days, and 1 to 2 years were 1.26 (95% CI: 0.93 to 1.70), 0.41 (95% CI: 0.30 to 0.56), and 0.41 (95% CI: 0.30 to 0.55), respectively. In multivariable analyses, the overall IRR (95% CI) for death or MI in the 0- to 90-day interval after stopping clopidogrel compared with the 91- to 365-day interval was 2.58 (95% CI: 1.64 to 4.07). Similar results were observed over a broad range of clopidogrel treatment durations (<6 months, 6 months to 1 year, 1 to 2 years, or >2 years). The results were also consistent across subgroups, including sex, stent type, stent diameter, PCI period, and diabetes status. When death alone was evaluated, there remained a significant increase in the event rate in the 0- to 90-day interval compared with the 91- to 365-day interval (IRR: 2.33; 95% CI: 1.32 to 4.11)., Conclusions: A clustering of events was observed in the initial 0 to 90 days after clopidogrel cessation in all treatment durations of clopidogrel investigated after SVG PCI. These results might have important implications in high-risk cohorts undergoing PCI. Additional studies are needed to elucidate the mechanisms underlying the early clustering of events after clopidogrel cessation., (Copyright © 2012 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

OBJECTIVE To assess whether patients with psoriasis treated with tumor necrosis factor (TNF) inhibitors have a decreased risk of myocardial infarction (MI) compared with those not treated with TNF inhibitors. DESIGN Retrospective cohort study. SETTING Kaiser Permanente Southern California health plan. PATIENTS Patients with at least 3 International Classification of Diseases, Ninth Revision, Clinical Modification, codes for psoriasis (696.1) or psoriatic arthritis (696.0) (without antecedent MI) between January 1, 2004, and November 30, 2010. MAIN OUTCOME MEASURE Incident MI. RESULTS Of 8845 patients included, 1673 received a TNF inhibitor for at least 2 months (TNF inhibitor cohort), 2097 were TNF inhibitor naive and received other systemic agents or phototherapy (oral/phototherapy cohort), and 5075 were not treated with TNF inhibitors, other systemic therapies, or phototherapy (topical cohort). The median duration of follow-up was 4.3 years (interquartile range, 2.9, 5.5 years), and the median duration of TNF inhibitor therapy was 685 days (interquartile range, 215, 1312 days). After adjusting for MI risk factors, the TNF inhibitor cohort had a significantly lower hazard of MI compared with the topical cohort (adjusted hazard ratio, 0.50; 95% CI, 0.32-0.79). The incidence of MI in the TNF inhibitor, oral/phototherapy, and topical cohorts were 3.05, 3.85, and 6.73 per 1000 patient-years, respectively. CONCLUSIONS Use of TNF inhibitors for psoriasis was associated with a significant reduction in MI risk and incident rate compared with treatment with topical agents. Use of TNF inhibitors for psoriasis was associated with a non-statistically significant lower MI incident rate compared with treatment with oral agents/phototherapy.

Ketamine (KT), a dissociative anesthetic, is known to induce schizophrenia-like psychosis. The percentage of KT abuse has recently grown fast despite KT being a controlled drug. The mechanism of KT actions is related to the inhibition of NMDA receptors. Whether KT produces other effects on ion currents in hippocampal neurons remains unclear. In this study, we attempted to evaluate the possible effects of KT and other related compounds on ion currents in hippocampal neuron-derived H19-7 cells. This drug exerted an inhibitory effect on Ca(2+)-activated K(+) current (IK(Ca)) in these cells with an IC(50) value of 274 μM. Pimaric acid (30 μM) or abietic acid (30 μM), known to stimulate large-conductance Ca(2+)-activated K(+) channels, reversed KT-induced inhibition of I(K)(Ca). In HEK293T cells expressing a-humans low poke, KT-induced inhibition of I(K)(Ca) still existed. Dehydronorketamine (300 μM) had little or no effect on the IK(Ca) amplitude, while norketamine (300 μM) slightly but significantly suppressed it. In inside–out configuration, KT applied to the intracellular face of the membrane did not alter single channel conductance of large-conductance Ca(2+)-activated K(+) (BKCa) channels; however, it did significantly reduce the probability of channel openings. Addition of KT was effective in depressing the peak amplitude of voltage-gated Na(+) current. Moreover, the presence of KT was noted to enhance the amplitude of membrane electroporation-induced inward currents (IMEP) in differentiated H19-7 cells. KT-stimulated IMEP was reversed by further application of LaCl(3) (100 μM), but not by NMDA (30 μM). The modulations by this compound of ion channels may contribute to the underlying mechanisms through which KT and its metabolites influence the electrical behavior of hippocampal neurons if similar findings occur in vivo.

Introduction: The pulmonary embolism severity index (PESI) and the recently derived simplified PESI prognostic model have been developed to estimate the risk of 30-day mortality in patients with acute PE. We sought to assess if the PESI and simplified PESI prognostic models can accurately identify adverse events and to determine the rates of events in patients treated as outpatients., Methods: A retrospective cohort study of patients with acute pulmonary embolism (PE) presenting at the Ottawa Hospital (Canada) was conducted between 1 January 2007 and 31 December 2008., Results: Two hundred and forty three patients were included. A total of 118 (48.6%) and 81 (33.3%) were classified as low risk patients using the original and simplified PESI prognostic models respectively. None of the low risk patients died within the 3months of follow-up. One hundred and fifteen (47.3%) patients were safely treated as outpatients with no deaths or bleeding episodes and only 1 recurrent event within the first 14days or after 30days of follow-up. Thirty four (29.6%) of these outpatients were classified as high risk patients according to the original PESI and 54 (47.0%) to the simplified PESI prognostic model., Conclusion: Both PESI strategies accurately identify patients with acute PE who are at low risk and high risk for short-term adverse events. However, 30 to 47% of patients with acute PE and a high risk PESI score were safely managed as outpatients. Future research should be directed at developing tools that predict which patients would benefit from inpatient management., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Protein glycation is a non-enzymatic glycosylation that can occur to proteins in the human body, and it is implicated in the pathogenesis of multiple chronic diseases. Glycation can also occur to recombinant antibodies during cell culture, which generates structural heterogeneity in the product. In a previous study, we discovered unusually high levels of glycation (>50%) in a recombinant monoclonal antibody (rhuMAb) produced by CHO cells. Prior to that discovery, we had not encountered such high levels of glycation in other in-house therapeutic antibodies. Our goal here is to develop cell culture strategies to decrease rhuMAb glycation in a reliable, reproducible, and scalable manner. Because glycation is a post-translational chemical reaction between a reducing sugar and a protein amine group, we hypothesized that lowering the concentration of glucose--the only source of reducing sugar in our fed-batch cultures--would lower the extent of rhuMAb glycation. When we decreased the supply of glucose to bioreactors from bolus nutrient and glucose feeds, rhuMAb glycation decreased to below 20% at both 2-L and 400-L scales. When we maintained glucose concentrations at lower levels in bioreactors with continuous feeds, we could further decrease rhuMAb glycation levels to below 10%. These results show that we can control glycation of secreted proteins by controlling the glucose concentration in the cell culture. In addition, our data suggest that rhuMAb glycation occurring during the cell culture process may be approximated as a second-order chemical reaction that is first order with respect to both glucose and non-glycated rhuMAb. The basic principles of this glycation model should apply to other recombinant proteins secreted during cell culture., (Copyright © 2011 Wiley Periodicals, Inc.)

The effects of chemical injury with oxidizing agents on voltage-gated Na+ current (I(Na)) in differentiated NG108-15 neuronal cells were investigated in this study. In whole-cell patch-clamp recordings, the challenge of these cells with t-butyl hydroperoxide (t-BHP; 1 mM) decreased the peak amplitude of I(Na) with no modification in the current-voltage relationship. It caused a slowing of current inactivation, although there was no alteration in the activation time course of I(Na). Cell exposure to t-BHP also increased a non-inactivating I(Na) (I(Na(NI)) elicited by long-lasting ramp pulses. The t-BHP-induced increase of I(Na(NI)) was reversed by a further application of riluzole (10 microM) or oxcarbazepine (10 microM). When I(Na) was elicited by simulated waveforms of action potentials (APs), during exposure to t-BHP, the amplitude of this inward current was diminished, accompanied by a reduction in inactivation/deactivation rate and an increase in current fluctuations. Under current-clamp recordings, addition of t-BHP (0.3 mM) enhanced AP firing in combination with clustering-like activity and sub-threshold membrane oscillations. In the simulation study, when the fraction of non-inactivating Na(v) channels was elevated, the simulated window component of I(Na) in response to a long-lasting ramp pulse was reduced; however, the persistent I(Na) was markedly enhanced. Moreover, when simulated firing of APs was generated from a modeled neuron, changes of AP firing caused by the increased fraction of non-inactivating Na(v) channels used to mimic the t-BHP actions were similar to the experimental observations. Taken together, it is anticipated that the effects of oxidizing agents on I(Na(NI)) could be an important mechanism underlying their neurotoxic actions in neurons or neuroendocrine cells occurring in vivo.

Methadone (Mtd) is a widely used opioid drug associated with the side effect of hyperprolactinemia. The mechanism of how Mtd induces prolactin secretion remains unclear. The effects of Mtd and its two main metabolites (EDDP: (±)-2-ethyl-1,5-dimethyl-3,3-diphenylpyrrolinium percholarate and EMDP: 2-ethyl-5-methyl-3,3-dipnehyl-1-pyrroline) on ion currents were investigated in GH₃ pituitary tumor cells. Hyperpolarization-elicited K+ currents in GH₃ cells bathed in a high-K(+), Ca(2+)-free solution were studied to evaluate the effects of Mtd and other related compounds on the ether-à-go-go-related-gene (erg) K(+) current (I(K(erg))). Mtd suppressed the amplitude of I(K(erg)) in a concentration-dependent manner with an IC(50) value of 10.4 μM. With the aid of a minimal binding scheme, the inhibitory action of Mtd on I(K(erg)) was estimated with a dissociation constant of 8.2 μM. Mtd tended to increase the rate of I(K(erg)) deactivation in a voltage-dependent fashion. EDDP (10 μM) had no effect on I(K(erg)), while EMDP (10μM) slightly suppressed it. In GH₃ cells incubated with naloxone (30 μM), the Mtd-induced inhibition of I(K(erg)) remained unaltered. Under cell-attached voltage-clamp recordings, Mtd increased the frequency of spontaneous action currents with no change in current amplitude. Similarly, Mtd can suppress I(K(erg)) in differentiated NG108-15 cells; dynorphin A(1-13) did not reverse Mtd-induced inhibition of I(K(erg)). This study shows that Mtd has a depressant effect on I(K(erg)), and suggests its ability to affect membrane excitability and prolactin secretion. The cyclization of Mtd, in which EDDP and EMDP are formed, tends to be critical in removal of the Mtd binding to erg K+ channel., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Introduction: Data regarding outpatient treatment of pulmonary embolism (PE) is scarce. This study evaluates the safety of outpatient management of acute PE., Methods: This is a retrospective cohort study of consecutive patients presenting at the Ottawa Hospital with acute PE diagnosed between 1 January 2007 and 31 December 2008. PE was defined as an arterial filling defect on CTPA or a high probability V/Q scan. Patients were managed as outpatients if they were hemodynamically stable, did not require supplemental oxygenation and did not have contraindications to low-molecular-weight heparin therapy., Results: In this cohort of 473 patients with acute PE, 260 (55.0%) were treated as outpatients and 213 (45.0%) were admitted to the hospital. The majority of the patients were admitted because of severe comorbidities (45.5%) or hypoxia (22.1%). No outpatient died of fatal PE during the 3-month follow-up period. At the end of follow-up, the overall mortality was 5.0% (95% CI, 2.7-8.4%). The rates of recurrent venous thromboembolism (VTE) in outpatients were 0.4% (95% CI, 0.0-2.1%) and 3.8% (95% CI, 1.9-7.0%) within 14 days and 3 months, respectively. The rates of major bleeding episodes were 0% (95% CI, 0-1.4%) and 1.5% (95% CI, 0.4-3.9%) within 14 days and 3 months, respectively. Four (1.5%) outpatients were admitted to the hospital within 14 days., Conclusions: A majority of patients with acute PE can be managed as outpatients with a low risk of mortality, recurrent VTE and major bleeding episodes., (© 2010 International Society on Thrombosis and Haemostasis.)

Background: Atrial fibrillation affects 4% to 8% of individuals over 60 years of age based on studies of predominantly white populations, whether this is true among nonwhite individuals is not clear. This study was undertaken to define racial/ethnic differences in atrial fibrillation prevalence among a large community cohort., Methods: This is a cross-sectional study. In 2008, there were 430,317 members aged 60 years or older in a large California health maintenance organization. By searching International Classification of Diseases, Ninth Revision codes and electronic electrocardiographic archives, we identified all members in this age group with primary, nonvalvular atrial fibrillation. Race/ethnicity data were assigned using health plan enrollment, service utilization, Asian/Hispanic surname and geocoding methods, and was available for 80.5% of members (79.8% of non-atrial fibrillation and 92% of atrial fibrillation), 99% of which were white, black, Asian, or Hispanic. We assessed the age- and gender-specific atrial fibrillation prevalence rates for each racial/ethnic group. The effect of race/ethnicity on atrial fibrillation was analyzed with logistic regression methods adjusting for potential confounders., Results: The overall atrial fibrillation prevalence was 5.3%. Among members with assigned race/ethnicity data, the prevalence among whites, blacks, Asians, and Hispanics was 8.0%, 3.8%, 3.9%, and 3.6%, respectively. The adjusted odds ratios (95% confidence intervals) of atrial fibrillation among blacks, Asians, and Hispanics with whites as referent were 0.49 (0.47-0.52), 0.68 (0.64-0.72), and 0.58 (0.55-0.61), respectively., Conclusions: Atrial fibrillation is less prevalent in older nonwhite individuals than whites. White race/ethnicity is associated with significantly greater odds for atrial fibrillation compared to blacks, Asians, and Hispanics, after adjusting for comorbidities associated with the development of atrial fibrillation.

Animal cell culture technology has advanced significantly over the last few decades and is now generally considered a reliable, robust and relatively mature technology. A range of biotherapeutics are currently synthesized using cell culture methods in large scale manufacturing facilities that produce products for both commercial use and clinical studies. The robust implementation of this technology requires optimization of a number of variables, including 1) cell lines capable of synthesizing the required molecules at high productivities that ensure low operating cost; 2) culture media and bioreactor culture conditions that achieve both the requisite productivity and meet product quality specifications; 3) appropriate on-line and off-line sensors capable of providing information that enhances process knowledge; and 4) good understanding of culture performance at different scales to ensure smooth scale-up. Successful implementation also requires appropriate strategies for process development, scale-up and process characterization and validation that enable robust operation that is compliant with current regulations. This review provides an overview of the state-of-the art technology in key aspects of cell culture, e.g., engineering of highly productive cell lines and optimization of cell culture process conditions. We also summarize the current thinking on appropriate process development strategies and process advances that might affect process development.

In this study, an attempt was made to elucidate the effects of thymol, a monocyclic phenolic compound, on Ca2+ mobilization and ion currents in pituitary GH3 cells with the aid of fura-2 fluorimetry and the whole-cell voltage-clamp technique. Thymol increased intracellular Ca2+ concentrations ([Ca2+]i) in GH3 cells loaded with Ca2+-sensitive dye fura-2. Removing extracellular Ca2+ reduced the thymol-induced [Ca2+]i rise. In Ca2+ -free solution, thymol-evoked [Ca2+]i rise was unchanged by depleting the Ca2+ store with thapsigargin (1 microM), while the thapsigargin-induced [Ca2+]i rise was reduced by pretreatment with thymol. These results imply that the Ca2+ stores depleted by thymol comprise thapsigargin-sensitive and thapsigargin-insensitive pools. In addition, after depletion of the internal Ca2+ store with 100 microM thymol in Ca2+ -free solution, a subsequent application of Ca2+ greatly induced a [Ca2+]i increase. The results indicate that, similar to thapsigargin, 100 microM thymol may activate the capacitative calcium entry (CCE) channel. However, thymol (100 microM) had a slight depressant action in L-type calcium current (I(CaL)). The stimulatory actions of thymol on Ca2+ signaling may partly be responsible for the underlying cellular mechanisms through which it affects neuroendocrine functions.

Background and Purpose: Warfarin reduces stroke risk in studies of predominantly white patients with atrial fibrillation (AF). Whether nonwhites also have lower rates of stroke while treated with warfarin is unclear., Methods: A multiethnic stroke-free cohort hospitalized with nonrheumatic AF was identified in a large health maintenance organization. Stroke risk factors (advanced age, diabetes, hypertension, and heart failure), warfarin use, and anticoagulation intensity were assessed. Crude ischemic stroke rates were calculated by Poisson regression for each group while using and not using warfarin. Cox proportional hazard models were constructed to assess the independent effect of race/ethnicity on ischemic stroke., Results: Between 1995 and 2000, we identified 18867 AF hospitalizations (78.5% white, 8% black, 9.5% Hispanic, and 3.9% Asian). Over the course of 63204 person-years follow-up (median, 3.3 years), 1226 ischemic strokes were identified. The percent-time on warfarin did not differ by race/ethnicity. The median percent-time on warfarin that international normalized ratio was 2 to 3 was 54.5% overall, but it was lower in blacks at 47.8%, whereas the other groups had a rate of approximately 54%. The rate ratios (95% CI) of ischemic stroke with warfarin compared to without warfarin for whites, blacks, Hispanics, and Asians were 0.79 (0.68 to 0.90), 0.92 (0.65 to 1.30), 0.71 (0.48 to 1.05), and 0.65 (0.34 to 1.23), respectively., Conclusions: In this cohort, we did not observe a statistically significant lower rate of stroke with warfarin therapy among nonwhites (in particular blacks) with previous AF hospitalizations. The relatively small numbers of nonwhites renders our estimates less than precise and should be interpreted with caution.

Objectives: The purpose of this study was to determine whether long-term clinical outcomes differed between bare-metal stents (BMS) and drug-eluting stents (DES) by duration of clopidogrel use among diabetic patients., Background: There is concern that DES are associated with late adverse events such as death and myocardial infarction (MI) secondary to stent thrombosis. However, data on outcomes in diabetic patients remain limited., Methods: We identified 749 patients with diabetes mellitus who underwent stent implantation with either BMS (n = 251) or DES (n = 498) from October 2002 to December 2004. We performed survival analysis on the full cohort and on those event-free from death, MI, or repeat revascularization at 6 months (n = 671)., Results: By clopidogrel duration, the event rate for death or MI was 3.2% in the >9-month group, 9.4% in the 6- to 9-month group, and 16.5% in the <6-month group, p < 0.001. For death alone, the event rate was 0.5% in the >9-month group, 4.3% in the 6- to 9-month group, and 10.0% in the <6-month group, p < 0.001. When taking BMS clopidogrel non-users as a referent in the multivariate analysis, the hazard ratio (95% confidence interval [CI]) for death and nonfatal MI for DES clopidogrel users, DES clopidogrel nonusers, and BMS clopidogrel users were: HR 0.22 (95% CI 0.08 to 0.62, p = 0.005), HR 0.39 (95% CI 0.13 to 1.13, p = 0.08), and HR 0.25 (95% CI 0.08 to 0.81, p = 0.02), respectively., Conclusions: Longer duration of clopidogrel use was associated with a lower incidence of death or MI in both the BMS and DES groups. Among clopidogrel nonusers, the incidence of death/MI or death did not differ by stent type.

Atrial fibrillation (AF) is the most common sustained arrhythmia seen in clinical practice. It affects approximately 6% of persons over 65 years of age and is independently associated with a 4- to 5-fold higher risk of ischaemic stroke and a 2-fold higher risk of death. Randomized controlled trials have shown that treatment with adjusted-dose oral vitamin K antagonists (primarily warfarin with a target international normalized ratio [INR] of 2.0-3.0) reduces the relative risk of ischaemic stroke by two-thirds (an approximately 3% reduction in annual absolute risk), but is associated with a 0.2% excess annual absolute risk of intracranial haemorrhage (ICH). However, in 'real world' studies, the risk reductions in ischaemic stroke with warfarin have been significantly lower (25-50% relative risk reduction) than in selected trial samples. Moreover, more than 90% of patients enrolled in the sentinel trials were White/European. This raises the question of whether the beneficial results of warfarin can be extrapolated to persons of colour. Important differences in stroke risk profile and responsiveness to warfarin exist across racial/ethnic groups, such that one cannot assume a priori that there is a net benefit of warfarin therapy for AF patients of all racial/ethnic groups.Among patients with ischaemic stroke, AF is more likely to be implicated as the cause of stroke in the White population than in other racial/ethnic groups. Furthermore, AF may be a stronger predictor of ischaemic stroke among the White population than in Black or Hispanic/Latino populations. Approximately one-third of strokes in AF patients are noncardioembolic. Warfarin has been shown to be ineffective in preventing recurrent noncardioembolic strokes. Many persons of colour with AF have other risk factors that predispose them to noncardioembolic stroke, which may partially explain why warfarin has been reported to be less efficacious in preventing strokes in non-White patients with AF, even after adjustment for co-morbidities and anticoagulation monitoring. Notably, the background incidence of ICH is higher in Black, Hispanic and Asian patients than in White patients. Any greater than expected increases in bleeding secondary to anticoagulation may potentially offset any benefit gained from cardioembolic stroke reduction, although this has not been fully resolved.Finally, there are racial/ethnic differences in the prevalence of certain polymorphisms in genes that influence warfarin pharmacokinetics and pharmacodynamics (e.g. cytochrome P450 2C9 and vitamin K epoxide reductase). The Asian population generally appear to require the lowest daily dose of warfarin to maintain a given INR target, with the White population requiring an intermediate daily dose and the Black population requiring the highest daily dose. These differences must be taken into account when administering warfarin in order to minimize the risk of under- or over-anticoagulation.In summary, warfarin is highly effective in preventing ischaemic strokes in White patients with AF at a modestly higher risk of ICH. Whether the same net clinical benefit extends to persons of colour is unproven. Given the rapidly changing demographic nationally and internationally, additional research is needed to resolve this important question.

Objectives: This study was designed to study racial/ethnic differences in the risk for intracranial hemorrhage (ICH) and the effect of warfarin on ICH risk among patients with atrial fibrillation (AF)., Background: Nonwhites are at greater risk for ICH than whites in the general population. Whether this applies to patients with AF and whether warfarin therapy is associated with comparable risk of ICH in nonwhites are unknown., Methods: We retrospectively identified a multiethnic stroke-free cohort hospitalized with nonrheumatic AF. Warfarin use and anticoagulation intensity were assessed by searching pharmacy and laboratory records. Crude ICH event rates were calculated by Poisson regression. Cox proportional hazard models were constructed to assess the independent effect of race/ethnicity on ICH after adjusting for age, gender, hypertension, diabetes, heart failure, and warfarin exposure., Results: Between 1995 and 2000, we identified 18,867 qualifying AF hospitalizations (78.5% white, 8% black, 9.5% Hispanic, and 3.9% Asian) and 173 qualifying ICH events over 3.3 years follow-up. Achieved anticoagulation intensity was lower among blacks but not different between the other groups. Warfarin was associated with increased ICH risk in all races, but the magnitude of risk was greater among nonwhites. There were no gender differences. The hazard ratio for ICH with whites as referent was 4.06 for Asians (95% confidence interval [CI] 2.47 to 6.65), 2.06 for Hispanics (95% CI 1.31 to 3.24), and 2.04 (95% CI 1.25 to 3.35) for blacks., Conclusions: Nonwhites with AF were at greater risk for warfarin-related ICH. Blacks, Hispanics, and Asians were at successively greater ICH risk than whites.

There are no large population-based studies on the incidence and prognosis of peripartum cardiomyopathy (PC). Between 1996 and 2005, there were 241,497 deliveries within the Southern California Kaiser healthcare system. Among these, we identified 60 cases of PC by searching for an International Classification of Diseases, Ninth Edition diagnosis of heart failure (HF) and detailed chart review. PC was confirmed if all of the following criteria were satisfied: (1) left ventricular ejection fraction <0.50, (2) met the Framingham criteria for HF, (3) new symptoms of HF or initial echocardiographic diagnosis of left ventricular dysfunction occurred in the month before or in the 5 months after delivery, and (4) no alternative cause of HF could be identified. The overall incidence of PC was 1 in 4,025 deliveries. The incidence in whites, African-Americans, Hispanics, and Asians was 1 of 4,075, 1 of 1,421, 1 of 9,861, and 1 of 2,675 deliveries, respectively. The incidence of PC was greatest in African-Americans, which was 2.9-fold higher compared with whites (p = 0.03) and 7-fold that of Hispanics (p <0.001). With a mean follow-up of 4.7 years, the freedom from all-cause death was 96.7% by the Kaplan-Meier method. In conclusion, this large population-based study highlights important racial differences in the incidence of PC. We observed the lowest incidence of PC in Hispanics and the highest in African-Americans. Our findings also suggest that the current mortality associated with PC may be less than reported in older series, perhaps because of the high utilization of modern HF therapy.

The ionic mechanisms and cytoprotective activities of 4-piperidinomethyl-2-isopropyl-5-methylphenol (THPI), an analogue of thymol, were investigated in HL-60 granulocytes and in human erythrocytes, respectively. THPI inhibited K+ outward current (I(K)) in a concentration-dependent manner in HL-60 leukocytes, with an IC50 value of 4 microM. Neither iberiotoxin (200 nM) nor paxilline (1 microM) suppressed the amplitude of I(K), whereas clotrimazole (5 microM) significantly inhibited it. In the inside-out configuration of single channel recordings, application of THPI (5 microM) into the bath medium did not alter the single-channel conductance of intermediate-conductance Ca2+-activated K+ (IK(Ca)) channels (i.e K(Ca)3.1 channels), but it suppressed the channel activity significantly. THPI-induced inhibition of IK(Ca) channels was reversed by a further application of 1-ethyl-2-benzimidazolinone (10 microM). THPI-induced reduction in IK(Ca)-channel activity in these cells was primarily due to a decrease in mean open time. These results provide direct evidence that THPI is capable of suppressing the activity of IK(Ca) channels in HL-60 cells. The antioxidant action of THPI also revealed a beneficial cytoprotective effect against mitomycin C-mediated haemolytic effect in human erythrocytes. The results of this study suggest that blockade of IK(Ca) channels and the membrane-protecting activity of THPI would combine to have beneficial effects in lessening the severity of haemolytic crisis and reducing anaemia in sickle cell disease.

Heart failure and kidney disease are two important emerging epidemics. The importance of pre-end stage kidney disease was introduced in the 2002 publication of the National Kidney Foundation's Chronic Kidney Disease Guidelines. One in nine US adults has some degree of kidney disease, many of whom also have heart failure. Among all patients with heart failure, approximately half have significant kidney disease. The distribution of etiologies of these conditions varies among races; blacks tend to have heart and kidney disease predominantly due to hypertension, while whites tend to be affected by ischemic heart disease and Hispanics by diabetic kidney disease. The burden of disease is disproportionately borne by minorities, the cause of which remains to be fully elucidated. The bulk of knowledge of these diseases is based on studies involving predominantly white subjects. Recent studies have suggested that there are racial differences in patients' responsiveness to various classes of drugs. Designs of future studies should take into account these differences.

Drugs that influence the opening of potassium (K(+)) channels and as a consequence cause hyperpolarization of cell membrane possess clinical potential. The large conductance Ca(2+)-activated K(+) (BK) channel is highly selective for K(+). Activation of this channel is Ca(2+)- and voltage-dependent. We have investigated the effects of thymol, a natural product, on ion currents in pituitary GH(3) cells. The patch-clamp technique was used to investigate the effect of thymol (100 microM) in these cells. Thymol reversibly stimulated the Ca(2+)-activated K(+) current with an EC (50) value of 75 microM. In a cell-attached configuration, application of thymol to the bath increased the activity of BK channels. BAPTA (1 mM) attenuated thymol-stimulated channel activity. In an experiment using the inside-out configuration, thymol exposed to the intracellular face of excised patches did not modify the single-channel conductance of these channels whereas it enhanced the channel activity. Neither menthol (100 microM) nor zingerone (100 microM) had an effect on BK-channel activity while AAPH (100 microM) suppressed it significantly. The stimulatory actions of thymol on Ca(2+)-activated K(+) currents may be associated with the underlying cellular mechanisms through which it affects neuronal or neuroendocrine functions.

4-Piperidinomethyl-2-isopropyl-5-methylphenol (THPI) was synthesized by reaction of thymol with piperidine and formaldehyde. The biological effect of THPI on superoxide anion scavenging activity, antiplatelet activity and calcium current inhibition were investigated. THPI (50 microM) was shown to be a scavenger of superoxide radicals in human neutrophils stimulated with N-formyl-Met-Leu-Phe (66% inhibition). Since superoxide anions are essential for platelet aggregation and L-type Ca2+-channel activity, we further found that THPI inhibited platelet aggregation induced by arachidonic acid (IC50 46.80+/-6.88 microM). The effect of THPI on Ca2+ current in NG108-15 cells was investigated using the whole-cell voltage-clamp technique. THPI inhibited voltage-dependent L-type Ca2+ current (ICa, L). The IC50 value of THPI-induced inhibition of ICa, L was 3.60+/-0.81 microM. THPI caused no change in the overall shape of the current-voltage relationship of ICa, L. This indicates that THPI is an inhibitor of ICa, L in NG108-15 cells. Therefore, the channel-blocking properties of THPI may contribute to the underlying mechanism by which it affects neuronal or neuroendocrine function. Furthermore, no significant cytotoxic effects of THPI (0.3-50 microM) were observed in NG108-15 cells. The results indicate that THPI is a potential reactive oxygen species scavenger and may prevent platelet aggregation or inhibit L-type Ca2+-channel activity, possibly by scavenging reactive oxygen species.

Dang-Gui-Shao-Yao-San (DGSYS) is a mixture of medicinal herbs, which has long been used in traditional Chinese medicine for treating anemia and ovulary disorders. Its preparation comprises Angelicae sinensis (Oliv.) Diels, Ligustucum chuanxiong Hort, Paeonia lactiflora pall, Poria cocos (Schw.) Wolf, Atractylodis macrocephala Koidz and Alisma orientalis (Sam.) Juzep. The present study examined the anti-superoxide formation, free radical scavenging and anti-lipid peroxidation activities of DGSYS by xanthine oxidase inhibition, cytochrome C system with superoxide anion released by the fMLP or PMA activating pathway in human neutrophils, and FeCl2 ascorbic acid-induced lipid peroxidation effects on lipids in rat liver homogenate, respectively. DGSYS showed anti-superoxide formation and free radical scavenging activity in a concentration-dependent manner. It also inhibited PMA- but not fMLP-induced superoxide anion released from human neutrophils. These antioxidant actions of DGSYS showed beneficial cytoprotective effects against lipid peroxidation in rat liver homogenate, human platelet aggregation induced by arachidonic acid (AA) and adenosine diphosphate (ADP) and mitomycin C-mediated hemolytic in human erythrocytes.

Among 1,138 patients in our congestive heart failure care management database, 37 (3.2%) met guideline criteria for cardiac resynchronization therapy. Advancing age was a predictor of prolonged QRS duration in this population, but gender, ejection fraction (EF) and cause of heart failure were not. There was a trend toward an inverse correlation between QRS duration and EF among patients with EF < or = 35%., (Copyright 2004 Excerpta Medica, Inc.)

The effects of quercetin, a natural polyphenolic compound, on voltage-dependent L-type Ca(2+) current (I(Ca,L)) in rat pituitary GH(3) cells were investigated with the aid of the whole-cell voltage-camp technique. Quercetin (0.5-200 microM) stimulated I(Ca,L) in a concentration-dependent manner. The current-voltage (I-V) relationship of I(Ca,L) was slightly shifted to more negative potentials in the presence of quercetin. The EC(50) value of the quercetin-induced stimulation of I(Ca,L) was about 7 microM. The presence of quercetin (5 microM) shifted the steady state inactivation curve of I(Ca,L) to a more negative potential by approximately -10 mV. Although quercetin might increase intracellular cyclic AMP, sp-cAMPS did not affect I(Ca,L). In addition, neither flavone nor wortmannin had any effect on the amplitude of I(Ca,L), while epicatechin and genistein slightly suppressed it. Quercetin (50 microM) decreased the amplitude of tetrodotoxin-sensitive Na(+) current in GH(3) cells. Under current-clamp configuration, quercetin could increase the firing frequency of actions potentials. Conversely, in NG108-15 neuronal cells, quercetin suppressed the amplitude of I(Ca,L). The quercetin-induced inhibition of I(Ca,L) was abolished in NG108-15 cells preincubated with t-butyl hydroperoxide (1 mM). Quercetin-mediated stimulation of I(Ca,L) in GH(3) cells was presumably not associated with the level of intracellular cyclic AMP, or with the activity of tyrosine or phosphoinositide 3-kinases. Therefore, the effects of quercetin on ion currents may, at least in part, contribute to the underlying mechanisms through which it affects neuronal or neuroendocrine function., (Copyright 2003 Wiley-Liss, Inc.)

Quinones have been shown to possess antineoplastic activity; however, their effects on ionic currents remain unclear. The effects of 2-mercaptophenyl-1,4-naphthoquinone (2-MPNQ), menadione (MD) and 1,4-naphthoquinone (1,4 NQ) on cell proliferation and ionic currents in pituitary GH3 lactotrophs were investigated in this study. 2-MPNQ was more potent than menadione or 1,4-naphthoquinone in inhibiting the growth of GH3 cells. 2-MPNQ decreased cell proliferation in a concentration-dependent manner with an IC50 value of 3 microM. In whole-cell recording experiments, 2-MPNQ reversibly caused an inhibition of Ca2+-activated K+ current (I(K(Ca)) in a concentration-dependent manner. The IC50 value for 2-MPNQ-induced inhibition of I(K(Ca)) was 7 microM. In the inside-out configuration of single channel recording, 2-MPNQ (30 microM) applied intracellularly suppressed the activity of large-conductance Ca2+-activated K+ (BK(Ca)) channels but did not modify single channel conductance. Menadione (30 microM) had no effect on the channel activity, whereas 1,4-naphthoquinone (30 microM) suppressed it by about 26%. Both 2-MPNQ and thimerosal suppressed the dithiothreitol-stimulated channel activity. 2-MPNQ also blocked voltage-dependent K+ currents, but it produced a slight reduction of L-type Ca2+ inward current. However, unlike E-4031, 2-MPNQ (30 microM) did not suppress inwardly rectifying K+ current present in GH3 cells. Under the current clamp configuration, the presence of 2-MPNQ (30 microM) depolarized the cells, and increased the frequency and duration of spontaneous action potentials. The 2-MPNQ-mediated inhibition of K+ currents would affect hormone secretion and cell excitability. The blockade of these ionic channels by 2-MPNQ may partly explain its inhibitory effect on the proliferation of GH3 cells.