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Fibrinolytic therapy is still used in patients with ST-segment elevation myocardial infarction (STEMI) when the primary percutaneous coronary intervention cannot be provided in a timely fashion. Management strategies and outcomes in transferred fibrinolytic-treated STEMI patients have not been well assessed in real-world settings. Using the Nationwide Inpatient Sample from 2008 to 2012, we identified 18 814 patients with STEMI who received fibrinolytic therapy and were transferred to a different facility within 24 hours. The primary outcome was in-hospital mortality. Secondary outcomes included gastrointestinal bleeding, bleeding requiring transfusion, intracranial hemorrhage (ICH), length of stay, and cost. The patients were divided into 3 groups: those who received medical therapy alone (n = 853; 4.5%), those who underwent coronary artery angiography without revascularization (n = 2573; 13.7%), and those who underwent coronary artery angiography with revascularization (n = 15 388; 81.8%). Rates of in-hospital mortality among the groups were 20% vs 6.6% vs 2.1%, respectively (P < 0.001); ICH was 8.5% vs 1.1% vs 0.6%, respectively (P < 0.001); and gastrointestinal bleeding was 1.1% vs 0.4% vs 0.4%, respectively (P = 0.011). Multivariate analysis identified increasing age, higher Charlson Comorbidity Index score, cardiogenic shock, cardiac arrest, and ICH as the independent predictors of not performing coronary artery angiography and/or revascularization in patients with STEMI initially treated with fibrinolytic therapy. The majority of STEMI patients transferred after receiving fibrinolytic therapy undergo coronary angiography. However, notable numbers of patients do not receive revascularization, especially patients with cardiogenic shock and following a cardiac arrest., (© 2016 Wiley Periodicals, Inc.)

Objectives: We studied the trends and predictors of drug eluting stent (DES) utilization from 2006 to 2011 to further expound the inter-hospital variability in their utilization., Background: We queried the Healthcare Cost and Utilization Project's Nationwide Inpatient Sample (NIS) between 2006 and 2011 using ICD-9-CM procedure code, 36.06 (bare metal stent) or 36.07 (drug eluting stents) for Percutaneous Coronary Intervention (PCI). Annual hospital volume was calculated using unique identification numbers and divided into quartiles for analysis., Methods and Results: We built a hierarchical two level model adjusted for multiple confounding factors, with hospital ID incorporated as random effects in the model. About 665,804 procedures (weighted n = 3,277,884) were analyzed. Safety concerns arising in 2006 reduced utilization DES from 90% of all PCIs performed in 2006 to a nadir of 69% in 2008 followed by increase (76% of all stents in 2009) and plateau (75% in 2011). Significant between-hospital variation was noted in DES utilization irrespective of patient or hospital characteristics. Independent patient level predictors of DES were (OR, 95% CI, P-value) age (0.99, 0.98-0.99, <0.001), female(1.12, 1.09-1.15, <0.001), acute myocardial infarction(0.75, 0.71-0.79, <0.001), shock (0.53, 0.49-0.58, <0.001), Charlson Co-morbidity index (0.81,0.77-0.86, <0.001), private insurance/HMO (1.27, 1.20-1.34, <0.001), and elective admission (1.16, 1.05-1.29, <0.001). Highest quartile hospital (1.64, 1.25-2.16, <0.001) volume was associated with higher DES placement., Conclusion: There is significant between-hospital variation in DES utilization and a higher annual hospital volume is associated with higher utilization rate of DES. © 2015 Wiley Periodicals, Inc., (© 2015 Wiley Periodicals, Inc.)

Objective: The aim of the study was to assess the utilization of catheter-directed thrombolysis (CDT) and its comparative effectiveness against systemic thrombolysis in acute pulmonary embolism (PE)., Background: Contemporary real world data regarding utilization and outcomes comparing systemic thrombolysis with CDT for PE is sparse., Methods: We queried the Nationwide Inpatient Sample from 2010 to 2012 using the ICD-9-CM diagnosis code 415.11, 415.13, and 415.19 for acute PE. We used propensity score analysis to compare outcomes between systemic thrombolysis and CDT. Primary outcome was in-hospital mortality. Secondary outcome was combined in-hospital mortality and intracranial hemorrhage (ICH)., Results: Out of 110,731 patients hospitalized with PE, we identified 1,521 patients treated with thrombolysis, of which 1,169 patients received systemic thrombolysis and 352 patients received CDT. After propensity-matched comparison, primary and secondary outcomes were significantly lower in the CDT group compared to systemic thrombolysis (21.81% vs. 13.36%, OR 0.55, 95% CI 0.36-0.85, P value = 0.007) and (22.89% vs. 13.36%, OR 0.52, 95% CI 0.34-0.80, P value = 0.003), respectively. The median length of stay [7 days, interquartile range (IQR) (5-9 days) vs. 7 days, IQR (5-10 days), P = 0.17] was not significant between the two groups. The CDT group had higher cost of hospitalization [$17,218, IQR ($12,272-$23,906) vs. $23,799, IQR ($17,892-$35,338), P < 0.001]. Multivariate analysis identified increasing age, saddle PE, cardiopulmonary arrest, and Medicaid insurance as independent predictors of in-hospital mortality., Conclusions: CDT was associated with lower in-hospital mortality and combined in-hospital mortality and ICH., (© 2015 Wiley Periodicals, Inc.)

Use of transcatheter endovascular stenting has been increasing in the treatment of coarctation of aorta (CoA). The present study was undertaken on adults with CoA who underwent stent placement from 2000 to 2011 to analyze the relation of hospital volumes to the outcomes of stenting in adults with CoA. It was a retrospective study based on Healthcare Cost and Utilization Project's Nationwide Inpatient Sample (NIS) database from 2000 to 2011 and identified subjects using the International Classification of Diseases, Ninth Revision, Clinical Modification procedure code of 747.10 (CoA). Annual hospital volume was calculated using unique hospital identifiers. Weights provided by the Nationwide Inpatient Sample were used to generate national estimates. A total of 105 (weighted 521) subjects were identified with International Classification of Diseases, Ninth Revision, code of 39.90 (Endovascular stent). Hospital volumes were divided into tertiles. We compared the highest tertile (≥3 procedures annually) with other tertiles (<3 procedure annually). The composite outcomes of the analysis were procedure-related complications, length of stay (LOS), and cost in relation to the hospital volume. No inhospital death was reported in either group. Hospitals with ≥3 procedures annually had significantly lower incidence of complications (9.5% vs 23.0%) compared to the hospitals with <3 procedures annually (p-value 0.002). Similar results were obtained after multivariate regression analysis in relation to hospital volume. Shorter LOS and lower cost were observed with annual hospital volume of ≥3 procedures. In conclusion, stenting adults for CoA is remarkably safe, and the outcomes of the procedure have improved in centers with annual hospital volume of ≥3 procedures. There is also decreasing trend of procedure-related complications, shorter LOS, and lower costs compared to centers with annual volume <3 procedures., (Copyright © 2015 Elsevier Inc. All rights reserved.)

We hypothesized that the availability of a transcatheter aortic valve implantation (TAVI) program in hospitals impacts the overall management of patients with aortic valve disease and hence may also improve postprocedural outcomes of conventional surgical aortic valve replacement (SAVR). The aim of the present study was to compare the inhospital outcomes of SAVR in centers with versus without availability of a TAVI program in an unrestricted large nationwide patient population >50 years of age. SAVRs performed on patients aged >50 years were identified from the Nationwide Inpatient Sample (NIS) for the years 2011 and 2012 using the International Classification of Diseases, Ninth Revision, Clinical Modification procedure codes. SAVR cases were divided into 2 categories: those performed at hospitals with a TAVI program (SAVR-TAVI) and those without (SAVR-non-TAVI). A total of 9,674 SAVR procedures were identified: 4,526 (46.79%) in the SAVR-TAVI group and 5,148 (53.21%) in SAVR-non-TAVI group. The mean age of the study population was 70.2 ± 0.1 years with majority (53%) of the patients aged >70 years. The mean Charlson's co-morbidity score for patients in SAVR-TAVI group was greater (greater percentage of patients were aged >80 years, had hypertension, congestive heart failure, renal failure, and peripheral arterial disease) than that of patients in SAVR-non-TAVI group (1.6 vs 1.4, p <0.001). The propensity score matching analysis showed a statistically significant lower inhospital mortality (1.25% vs 1.72%, p = 0.001) and complications rate (35.6% vs 37.3%, p = 0.004) in SAVR-TAVI group compared to SAVR-non-TAVI group. The mean length of hospital stay was similar in the 2 groups the cost of hospitalization was higher in the SAVR-TAVI group ($43,894 ± 483 vs $41,032 ± 473, p <0.0001). Having a TAVI program was a significant predictor of reduced mortality and complications rate after SAVR in multivariate analysis. In conclusion, this largest direct comparative analysis demonstrates that SAVRs performed in centers with a TAVI program are associated with significantly lower mortality and complications rates compared to those performed in centers without a TAVI program., (Copyright © 2015 Elsevier Inc. All rights reserved.)

In just over two decades, structure based protein kinase inhibitor discovery has grown from trial and error approaches, using individual target structures, to structure and data driven approaches that may aim to optimize inhibition properties across several targets. This is increasingly enabled by the growing availability of potent compounds and kinome-wide binding data. Assessing the prospects for adapting known compounds to new therapeutic uses is thus a key priority for current drug discovery efforts. Tools that can successfully link the diverse information regarding target sequence, structure, and ligand binding properties now accompany a transformation of protein kinase inhibitor research, away from single, block-buster drug models, and toward "personalized medicine" with niche applications and highly specialized research groups. Major hurdles for the transformation to data driven drug discovery include mismatches in data types, and disparities of methods and molecules used; at the core remains the problem that ligand binding energies cannot be predicted precisely from individual structures. However, there is a growing body of experimental data for increasingly successful focussing of efforts: focussed chemical libraries, drug repurposing, polypharmacological design, to name a few. Protein kinase target similarity is easily quantified by sequence, and its relevance to ligand design includes broad classification by key binding sites, evaluation of resistance mutations, and the use of surrogate proteins. Although structural evaluation offers more information, the flexibility of protein kinases, and differences between the crystal and physiological environments may make the use of crystal structures misleading when structures are considered individually. Cheminformatics may enable the "calibration" of sequence and crystal structure information, with statistical methods able to identify key correlates to activity but also here, "the devil is in the details." Examples from specific repurposing and polypharmacology applications illustrate these points. This article is part of a Special Issue entitled: Inhibitors of Protein Kinases., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Our primary objective was to study postprocedural outcomes and hospitalization costs after peripheral endovascular interventions and the multivariate predictors affecting the outcomes with emphasis on hospital volume. The study cohort was derived from Healthcare Cost and Utilization Project Nationwide Inpatient Sample database (2006 to 2011). Peripheral endovascular interventions were identified using appropriate International Classification of Diseases, Ninth Revision diagnostic and procedural codes. Annual institutional volumes were calculated using unique identification numbers and then divided into quartiles. Two-level hierarchical multivariate mixed models were created. The primary outcome was inhospital mortality; secondary outcome was a composite of inhospital mortality and postprocedural complications. Amputation rates and hospitalization costs were also assessed. Multivariate analysis (odds ratio, 95% confidence interval, p value) revealed age (1.46, 1.37 to 1.55, p <0.001), female gender (1.28, 1.12 to 1.46, p <0.001), baseline co-morbidity status as depicted by a greater Charlson co-morbidity index score (≥2: 4.32, 3.45 to 5.40, p <0.001), emergent or urgent admissions(2.48, 2.14 to 2.88, p <0.001), and weekend admissions (1.53, 1.26 to 1.86, p <0.001) to be significant predictors of primary outcome. An increasing hospital volume quartile was independently predictive of improved primary (0.65, 0.52 to 0.82, p <0.001 for the fourth quartile) and secondary (0.85, 0.73 to 0.97, 0.02 for the fourth quartile) outcomes and lower amputation rates (0.52, 0.45 to 0.61, p <0.001). A significant reduction hospitalization costs ($-3,889, -5,318 to -2,459, p <0.001) was also seen in high volume centers. In conclusion, a greater hospital procedural volume is associated with superior outcomes after peripheral endovascular interventions in terms of inhospital mortality, complications, and hospitalization costs., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Atrial fibrillation (AF) is the most prevalent arrhythmia worldwide and the most common arrhythmia leading to hospitalization. Due to a substantial increase in incidence and prevalence of AF over the past few decades, it attributes to an extensive economic and public health burden. The increasing number of hospitalizations, aging population, anticoagulation management, and increasing trend for disposition to a skilled facility are drivers of the increasing cost associated with AF. There has been significant progress in AF management with the release of new oral anticoagulants, use of left atrial catheter ablation, and novel techniques for left atrial appendage closure. In this article, we aim to review the trends in epidemiology, hospitalization, and cost of AF along with its future implications on public health., (Published by Elsevier Inc.)

The comparative data for angioplasty and stenting for treatment of peripheral arterial disease are largely limited to technical factors such as patency rates with sparse data on clinical outcomes like mortality, postprocedural complications, and amputation. The study cohort was derived from the Healthcare Cost and Utilization Project Nationwide Inpatient Sample database from 2006 to 2011. Peripheral endovascular interventions were identified using appropriate International Classification of Diseases, Ninth Revision (ICD-9) Diagnostic and procedural codes. Two-level hierarchical multivariate mixed models were created. The primary outcome includes inhospital mortality, and secondary outcome was a composite of inhospital mortality and postprocedural complications. Amputation was a separate outcome. Hospitalization costs were also assessed. Endovascular stenting (odds ratio, 95% confidence interval, p value) was independently predictive of lower composite end point of inhospital mortality and postprocedural complications compared with angioplasty alone (0.96, 0.91 to 0.99, 0.025) and lower amputation rates (0.56, 0.53 to 0.60, <0.001) with no significant difference in terms of inhospital mortality alone. Multivariate analysis also revealed stenting to be predictive of higher hospitalization costs ($1,516, 95% confidence interval 1,082 to 1,950, p <0.001) compared with angioplasty. In conclusion, endovascular stenting is associated with a lower rate of postprocedural complications, lower amputation rates, and only minimal increase in hospitalization costs compared with angioplasty alone., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Transcatheter aortic valve implantation (TAVI) is associated with a significant learning curve. There is paucity of data regarding the effect of hospital volume on outcomes after TAVI. This is a cross-sectional study based on Healthcare Cost and Utilization Project's Nationwide Inpatient Sample database of 2012. Subjects were identified by International Classification of Diseases, Ninth Revision, Clinical Modification procedure codes, 35.05 (Trans-femoral/Trans-aortic Replacement of Aortic Valve) and 35.06 (Trans-apical Replacement of Aortic Valve). Annual hospital TAVI volumes were calculated using unique identification numbers and then divided into quartiles. Multivariate logistic regression models were created. The primary outcome was inhospital mortality; secondary outcome was a composite of inhospital mortality and periprocedural complications. Length of stay (LOS) and cost of hospitalization were assessed. The study included 1,481 TAVIs (weighted n = 7,405). Overall inhospital mortality rate was 5.1%, postprocedural complication rate was 43.4%, median LOS was 6 days, and median cost of hospitalization was $51,975. Inhospital mortality rates decreased with increasing hospital TAVI volume with a rate of 6.4% for lowest volume hospitals (first quartile), 5.9% (second quartile), 5.2% (third quartile), and 2.8% for the highest volume TAVI hospitals (fourth quartile). Complication rates were significantly higher in hospitals with the lowest volume quartile (48.5%) compared to hospitals in the second (44.2%), third (39.7%), and fourth (41.5%) quartiles (p <0.001). Increasing hospital volume was independently predictive of shorter LOS and lower hospitalization costs. In conclusion, higher annual hospital volumes are significantly predictive of reduced postprocedural mortality, complications, shorter LOS, and lower hospitalization costs after TAVI., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: Prior studies have described a negative relationship between influenza vaccination and recurrence of cardiovascular (CV) events. However, due to lack of any prior studies, we evaluated and attempted to define the relationship between non-influenza vaccines and CV mortality., Methods: We used the National Health and Nutrition Examination Survey III (NHANES III-1988-1994, n = 19,215) and Continuous NHANES (1999-2004, n > 17,000), which includes oral surveys and general examination. It was designed to assess the demographic, socioeconomic, dietary, and overall health status of a nationally representative sample in non-institutionalized patients from all 50 states in the USA. Cox proportional hazard regression modeling was used to calculate the hazard ratio of CV mortality, and multivariate models were built for the individual seropositive vaccination titers as well as after creating a combined vaccination variable., Results: A total of >35,000 subjects (>18 years old) have been identified for analysis. Multivariate analysis from NHANES III and continuous NHANES did not show any influence of individual seroprotective titers of routine vaccinations on CV mortality. The combined effect of vaccination in NHANES III data did not show any protective effect of three or more positive vaccination titers (odds ratio = 0.94, p = 0.6) or all four positive vaccination titers (odds ratio = 0.93, p = 0.6) with two or less positive vaccination titers as the referent group., Conclusion: Effect on non-influenza vaccinations in preventing CV mortality seems to be unclear.

Atrial fibrillation (AF) is the most common type of sustained arrhythmia, which is now on course to reach epidemic proportions in the elderly population. AF is a commonly encountered comorbidity in patients with cardiac and major non-cardiac diseases. Morbidity and mortality associated with AF makes it a major healthcare burden. The objective of our article is to determine the prognostic impact of AF on acute coronary syndromes, heart failure and chronic kidney disease. Multiple studies have been conducted to determine if AF has an independent role in the overall mortality of such patients. Our review suggests that AF has an independent adverse prognostic impact on the clinical outcomes of acute coronary syndromes, heart failure and chronic kidney disease.

In recent years, there has been an increased emphasis on the diagnosis and treatment of valvular heart disease and, in particular, aortic stenosis. This has been driven in part by the development of innovative therapeutic options and by an aging patient population. We hypothesized an increase in the number of hospitalizations and the economic burden associated with aortic valve disease (AVD). Using Nationwide Inpatient Sample from 2000 to 2012, AVD-related hospitalizations were identified using International Classification of Diseases, Ninth Revision, Clinical Modification, code 424.1, as the principal discharge diagnosis. Overall AVD hospitalizations increased by 59% from 2000 to 2012. This increase was most significant in patients >80 years and those with higher burden of co-morbidities. The most frequent coexisting conditions were hypertension, heart failure, renal failure, anemia, and diabetes. Overall inhospital mortality of patients hospitalized for AVD was 3.8%, which significantly decreased from 4.5% in 2000 to 3.5% in 2012 (p <0.001). The largest decrease in mortality was seen in the subgroup of patients who had heart failure (62% reduction), higher burden of co-morbidities (58% reduction), and who were >80 years (53% reduction). There was a substantial increase in the cost of hospitalization in the last decade from $31,909 to $38,172 (p <0.001). The total annual cost for AVD hospitalization in the United States increased from $1.3 billion in 2001 to $2.1 billion in 2011 and is expected to increase to nearly 3 billion by 2020. The last decade has witnessed a significant increase in hospitalizations for AVD in the United States. The associated decrease in inhospital mortality and increase in the cost of hospitalization have considerably increased the economic burden on the public health system., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Despite the valuable role of intravascular ultrasound (IVUS) guidance in percutaneous coronary interventions (PCIs), its impact on clinical outcomes remains debatable. The aim of the present study was to compare the outcomes of PCIs guided by IVUS versus angiography in the contemporary era on inhospital outcomes in an unrestricted large, nationwide patient population. Data were obtained from the Nationwide Inpatient Sample from 2008 to 2011. Hierarchical mixed-effects logistic regression models were used for categorical dependent variables like inhospital mortality, and hierarchical mixed-effects linear regression models were used for continuous dependent variables like length of hospital stay and cost of hospitalization. A total of 401,571 PCIs were identified, of which 377,096 were angiography guided and 24,475 (weighted n = 119,102) used IVUS. In a multivariate model, significant predictors of higher mortality were increasing age, female gender, higher baseline co-morbidity burden, presence of acute myocardial infarction, shock, weekend and emergent admission, or occurrence of any complication during hospitalization. Significant predictors of reduced mortality were the use of IVUS guidance (odds ratio 0.65, 95% confidence interval 0.52 to 0.83; p <0.001) for PCI and higher hospital volumes (third and fourth quartiles). The use of IVUS was also associated with reduced inhospital mortality in subgroup of patients with acute myocardial infarction and/or shock and those with a higher co-morbidity burden (Charlson's co-morbidity index ≥2). In one of the largest studies on IVUS-guided PCIs in the drug-eluting stent era, we demonstrate that IVUS guidance is associated with reduced inhospital mortality, similar length of hospital stay, and increased cost of care and vascular complications compared with conventional angiography-guided PCIs., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Contemporary data regarding percutaneous closure of atrial septal defect/patent foramen ovale (ASD/PFO) are lacking. We evaluated the current trends in utilization of ASD/PFO closure in adults and investigated the effect of annual hospital volume on in-hospital outcomes., Methods: We queried the Nationwide Inpatient Sample between the years 2001 and 2010 using the International Classification of Diseases (ICD-9-CM) procedure code for percutaneous closure of ASD/PFO with device. Hierarchical mixed effects models were generated to identify the independent multivariate predictors of outcomes., Results: A total of 7,107 percutaneous ASD/PFO closure procedures (weighted n = 34,992) were available for analysis. A 4.7-fold increase in the utilization of this procedure from 3/million in 2001 to 14/million adults in 2010 in US (P < 0.001) was noted. Overall, percutaneous ASD/PFO closure was associated with 0.5% mortality and 12% in-hospital complications. The utilization of intracardiac echocardiography (ICE) increased 15 fold (P < 0.001) during the study period. The procedures performed at the high volume hospitals [2nd (14-37 procedures/year) and 3rd (>38 procedures/year) tertile] were associated with significant reduction in complications, length of stay and cost of hospitalization when compared to those performed at lowest volume centers (<13 procedures/year). Majority (70.5%) of the studied hospitals were found to be performing <10 procedures/year hence deviating from the ACC/AHA/SCAI clinical competency guidelines., Conclusions: Low hospital volume is associated with an increased composite (mortality and procedural complications) adverse outcome following ASD/PFO closure. In the interest of patient safety, implementation of the current guidelines for minimum required annual hospital volume to improve clinical outcomes is warranted., (© 2014 Wiley Periodicals, Inc.)

In the development and progression of hepatocellular carcinoma, tumor hypoxia plays an important role, as does activation of the Wnt pathway. The aim of this study was to characterize the expression and interrelationship between hypoxia and Wnt-pathway-associated proteins as prognostic factors for hepatocellular carcinoma. Expression of HIF-1α, CA-IX, E-cadherin, β-catenin, and Ki-67 was assessed by immunohistochemistry in 179 primary hepatocellular carcinoma cases. Univariate and multivariate analyses were performed to assess the relationship between the clinicopathological factors, protein expression, overall survival (OS), and recurrence-free survival (RFS). By univariate analysis, tumor stage, size, satellitosis, and vascular invasion were confirmed as prognostic factors for worse OS and RFS. High expression of HIF-1α, CA-IX, β-catenin, Ki-67, and E-cadherin was observed in 60, 15, 64, 8, and 64 % of tumors, respectively, and this was significantly associated with poor OS. CA-IX, HIF-1α, and E-cadherin were independent predictors of poor prognosis. We stratified 169 patients into four groups according to the expression level of hypoxia and Wnt pathway markers. The group with high expression of both hypoxia and Wnt-pathway-associated proteins showed worst OS. The poor survival of this group was also significant in patients with early stage disease and tumor size of less than 5 cm (p < 0.05). We identified a subgroup of hepatocellular carcinoma patients with high expression of both hypoxia and Wnt pathway proteins and found this predictive of poor survival. The therapeutic options for this group might need to be revisited.

Background: Transcatheter closure of coronary artery fistula has emerged as a safe and effective alternative to surgery. However, follow-up angiographic data after closure of the coronary artery fistula is extremely limited. We report our clinical and angiographic follow-up of children who underwent either transcatheter or surgical closure., Method: Clinical profile, echocardiography parameters, and closure technique were retrospectively reviewed from the hospital charts. Since 2007, 15 children have been intervened and followed up with electrocardiography, echocardiography, and angiography., Results: A total of 15 children (six girls), with mean age of 6.7±5.4 years and weighing 16.3±9.8 kg, underwent successful closure (transcatheter=13, surgical=2) without periprocedural complication. Coronary artery fistula arose from the right (n=7) and left coronary artery (n=8) and drained into the right atrium or the right ventricle. Transcatheter closure was carried out using a duct occluder. Of the patients, two underwent surgical closure of the fistula on a beating heart. At 31.8±18.7 months follow-up, all the children were asymptomatic and had no evidence of myocardial ischaemia or infarction. However, follow-up angiography revealed thrombotic occlusion of fistula with the patent parent coronary artery in those having branch coronary artery fistula, and five of seven patients with parent coronary artery fistula had near-complete occlusion of fistula extending into the native coronary artery., Conclusion: Follow-up angiography revealed a high incidence of parent artery occlusion when the fistula was arising from the native artery and not from one of its branches. Coronary artery fistula intervention of the parent coronary artery fistula always carries the potential risk of ischaemia, unless the distal-most exiting segment is the primary site of occlusion.

The use of percutaneous aortic balloon balvotomy (PABV) in high surgical risk patients has resurged because of development of less invasive endovascular therapies. We compared outcomes of concomitant PABV and percutaneous coronary intervention (PCI) with PABV alone during same hospitalization using nation's largest hospitalization database. We identified patients and determined time trends using the International Classification of Diseases, Ninth Revision, Clinical Modification, procedure code for valvulotomy from Nationwide Inpatient Sample database 1998 to 2010. Only patients >60 years with aortic stenosis were included. Primary outcome included in-hospital mortality, and secondary outcomes included procedural complications, length of stay (LOS), and cost of hospitalization. Total 2,127 PABV procedures were identified, with 247 in PABV + PCI group and 1,880 in the PABV group. Utilization rate of concomitant PABV + PCI during same hospitalization increased by 225% from 5.1% in 1998 to 1999 to 16.6% in 2009 to 2010 (p <0.001). Overall in-hospital mortality rate and complication rates in PABV + PCI group were similar to that of PABV group (10.3% vs 10.5% and 23.4% vs 24.7%, respectively). PABV + PCI group had similar LOS but higher hospitalization cost (median [interquartile range] $30,089 [$21,925 to $48,267] versus $18,421 [$11,482 to $32,215], p <0.001) in comparison with the PABV group. Unstable condition, occurrence of any complication, and weekend admission were the main predictors of increased LOS and cost of hospital admission. Concomitant PCI and PABV during the same hospitalization are not associated with change in in-hospital mortality, complications rate, or LOS compared with PABV alone; however, it increases the cost of hospitalization., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The neuro-cutaneous syndrome tuberous sclerosis is commonly associated with rhabdomyomas in various organs including the heart. We are reporting a rare case of a 7-month old male child with congenitally corrected transposition of the great arteries associated with tuberous sclerosis and cardiac rhabdomyomas. To our knowledge, this rare association has not been reported so far.

Pulmonary embolism (PE) is a relatively common life-threatening cardiovascular condition associated with significant morbidity and mortality. We present the efficacy and safety data of weight-adjusted tenecteplase in 30 consecutive patients of acute PE. 30 patients (22 male, 8 female) with acute PE were included in the study and divided into three groups: (1) Acute PE complicated by shock stage and/or persistent hypotension (12 patients). (2) RV dilatation and/or dysfunction without hypotension (14 patients). (3) Severe hypoxemia without hypotension and RV dysfunction (4 patients). Predominant symptoms were dyspnoea, cough, chest pain, syncope and haemoptysis, noted in 100% (30), 40% (12), 54% (16), 32% (9) and 10% (3) of patients respectively. RV dilatation and dyskinesia were present in 86%, septal paradoxical movement in 73% and inferior venacava collapse absent in 53% of patients respectively. 12 patients presented with acute PE and cardiogenic shock, 14 patients showed RV dilatation and dysfunction with systolic BP >90 mmHg and four patients were having RV dilation without dysfunction but severe hypoxemia. There was significant reduction in right ventricular systolic pressure and improvement in right ventricular dysfunction. Our study shows that tenecteplase is very effective and safe in the treatment of PE with minimal risk of bleeding in high risk group and intermediate risk and even in selective low risk category group of patients. However, in view of small number of patients in study group, a large multicentre randomized study would be required to draw a firm conclusion regarding the thrombolysis in low risk category patient.

Chondroma of the mandibular condyle is a rare benign tumor, with just a handful of cases reported in the literature. Chondromas are rare in the maxillofacial region, but are quite common in the bones of the hands and feet. So far only eight cases of true chondroma have been reported. Here, we present a case of true chondroma of the mandibular condyle of the right side, for which condylectomy was done. No signs of recurrence are noted at 2 years follow-up.

Context: Early-life adversity, defined as physical, emotional, or sexual abuse and neglect before 18 years of age, is associated with metabolic syndrome, obesity, and type 2 diabetes mellitus in adult life. However, the underlying mechanism is not fully understood, and whether adipomyokines are associated with early-life adversity independent of other factors such as body mass index, psychosocial risks, and health behaviors is not known., Objectives: The objective of the study was to evaluate the association between early-life adversity and circulating the levels of the adipomyokines such as leptin, adiponectin, and irisin and the inflammatory marker, C-reactive protein (CRP). DESIGN/SUBJECTS/SETTING: This study was a cross-sectional study of 95 adults at a university-based research center. We collected venous blood from participants and analyzed serum for leptin, adiponectin, irisin, and CRP., Results: Circulating leptin, irisin, and CRP levels were significantly higher in the highest adversity tertile group compared with low and middle tertile groups (P < .001 for leptin, P = .01 for irisin, and P = .02 for CRP). Adiponectin levels were lower in the highest tertile group compared with the low and middle tertile groups (P = .03). After adjusting for demographic variables, physical activity, diet, current mental health, and body mass index, the associations between early-life adversity leptin, irisin, and did not change. However, adiponectin and CRP levels were no longer significantly related to early life adversity., Conclusion: Early-life adversity is directly associated with elevated circulating leptin and irisin, and indirectly associated with elevated CRP and decreased adiponectin. These findings suggest that these adipomyokines may play a role in the pathogenesis of metabolic abnormality in a population with significant early life adversity.

Objective: Fetuin-A may mediate cross-talk between the liver and adipose tissue. We studied the physiologic regulation of fetuin-A and explored its potential regulation by leptin., Design and Methods: Fetuin-A levels were measured in three interventional studies as well as in in vitro experiments. Study 1: 15 lean subjects received placebo or physiologic replacement-dose recombinant human leptin (metreleptin) following short term complete caloric deprivation to induce severe hypoleptinemia; Study 2: 7 women with relative leptin deficiency due to strenuous exercise or low weight received 3 months of metreleptin; Study 3: 17 women with relative leptin deficiency were randomized to receive metreleptin or placebo over 9 months. In study 4 human hepatoma Hep G2 cells were treated with leptin. Fetuin-A mRNA expression and secretion were measured., Results: Complete caloric deprivation significantly decreased leptin but had no effect on fetuin-A levels. Normalizing leptin levels with metreleptin in hypoleptinemic subjects had no effect on circulating fetuin-A levels. Leptin treatment had no effect on fetuin-A mRNA expression and secretion in vitro., Conclusions: Circulating fetuin-A levels are not affected by short and long-term energy deprivation. Furthermore, both in vivo and in vitro experiments confirm that fetuin-A is not regulated by leptin., (Published by Elsevier Inc.)

Objective: To study the clinical profile of patients with long QT syndrome presenting as seizures., Methods: Retrospective analysis of six pediatric patients admitted at authors' institute between October 2008 and January 2013 with seizures and a presumptive diagnosis of long QT syndrome (LQTS) was done. The diagnosis was made on the basis of updated Schwartz diagnostic criteria. Clinical data, investigation profile and follow up of patients was recorded in a standard format and analysed., Results: All the 6 patients in the study were boys with a mean age of 10.3 ± 2.8 y at the time of diagnosis. The lag period between symptom onset and diagnosis was 5.6 ± 3.14 y. All patients had history of seizures with a history of precipitating event in 4 patients. Average baseline QTc interval was 556 ± 41.31 ms. Mean Schwartz score was 6.66 ± 1.16. Polymorphic VT was documented in 4 patients. After initiating standard treatment with betablockers, nicorandil, spironolactone or pacemaker, all the six patients were asymptomatic at a mean follow up period of 17.5 mo, with no recurrence of seizures., Conclusions: LQTS can cause seizures due to prolonged ventricular arrhythmias in high risk subgroup. Children, who present with LQTS and seizures, generally have a precipitating event causing seizures, and they respond well to drug therapy.

Inhibition of the phosphatidylinositol-3-kinase (PI3K) signaling pathway is a cancer treatment strategy that has entered into clinical trials. We performed a meta-analysis on the frequency of prominent genetic (PIK3CA mutation, PIK3CA amplification and PTEN deletion) and protein expression (high PI3K, PTEN loss and high pAkt) aberrations in the PI3K pathway in gastric cancer (GC) and colorectal cancer (CRC). We also performed laboratory analysis to investigate the co-occurrence of these aberrations. The meta-analysis indicated that East Asian and Caucasian GC patients differ significantly for the frequencies of PIK3CA Exon 9 and 20 mutations (7% vs. 15%, respectively), PTEN deletion (21% vs. 4%) and PTEN loss (47% vs. 78%), while CRC patients differed for PTEN loss (57% vs. 26%). High study heterogeneity (I(2) > 80) was observed for all aberrations except PIK3CA mutations. Laboratory analysis of tumors from East Asian patients revealed significant differences between GC (n = 79) and CRC (n = 116) for the frequencies of PIK3CA amplification (46% vs. 4%) and PTEN loss (54% vs. 78%). The incidence of GC cases with 0, 1, 2 and 3 concurrent aberrations was 14%, 52%, 27% and 8%, respectively, while for CRC it was 10%, 60%, 25% and 4%, respectively. Our study consolidates knowledge on the frequency, co-occurrence and clinical relevance of PI3K pathway aberrations in GC and CRC. Up to 86% of GC and 90% of CRC have at least one aberration in the PI3K pathway, and there are significant differences in the frequencies of these aberrations according to cancer type and ethnicity., (© 2013 UICC.)

Objective: Undercarboxylated osteocalcin (ucOC) is a bone marker with potent metabolic effects. Leptin regulates Esp gene expression and osteocalcin carboxylation in animal models. We aim to elucidate day/night patterns of ucOC levels, whether short-term and/or chronic energy deprivation alters ucOC levels, and whether leptin may mediate these changes in humans., Design and Methods: Twelve healthy males and females were studied for 72 h in the fed state to study day/night pattern of ucOC. The six female subjects were also studied in a crossover interventional study in the fasting state for 72 h with administration of either placebo or metreleptin in physiological doses. Blood samples were obtained hourly from 0800 a.m. on day 3 until 0800 a.m. on day 4. In a separate study, eleven obese subjects who underwent bariatric surgery were followed for 24 weeks to examine the effects of postsurgery weight loss on ucOC levels., Results: Males have higher ucOC levels compared to females. There is no day/night variation pattern of circulating ucOC in humans. Short-term and chronic energy deprivation or leptin administrations do not alter ucOC levels., Conclusions: The hypothesis that ucOC plays a role in energy homeostasis or of leptin in regulating ucOC in humans is not supported., (Copyright © 2013 The Obesity Society.)

Context: Irisin, a recently identified hormone, has been proposed to regulate energy homeostasis and obesity in mice. Whether irisin levels are associated with risk of the metabolic syndrome (MetS), cardiometabolic variables, and cardiovascular disease (CVD) risk in humans remains unknown., Objective: Our objective was to assess the associations between baseline serum irisin levels and MetS, cardiometabolic variables, and CVD risk., Design, Setting, and Subjects: We conducted a comparative cross-sectional evaluation of baseline circulating levels of the novel hormone irisin and the established adipokine adiponectin with MetS, cardiometabolic variables, and CVD risk in a sample of 151 subjects., Results: Baseline irisin levels were significantly higher in subjects with MetS than in subjects without MetS. Irisin was associated negatively with adiponectin (r = -0.4, P < .001) and positively with body mass index (r = 0.22, P = .008), systolic (r = 0.17, P = .04) and diastolic (r = 0.27, P = .001) blood pressure, fasting glucose (r = 0.25, P = .002), triglycerides (r = 0.25, P = .003), and homeostasis model assessment for insulin resistance (r = 0.33, P < .001). After adjustment for potential confounders, including body mass index, subjects in the highest tertile of irisin levels were more likely to have MetS (odds ratio [OR] = 9.44, 95% confidence interval [CI] = 2.66-33.44), elevated fasting blood glucose (OR = 5.80, 95% CI = 1.72-19.60), high triglycerides (OR = 3.89, 95% CI = 1.16-13.03), and low high-density lipoprotein cholesterol (OR = 3.30, 95% CI = 1.18-9.20). Irisin was independently associated with homeostasis model assessment for insulin resistance and general Framingham risk profile in multiple linear regression analyses after adjustment for confounders. Adiponectin demonstrated the expected associations with outcomes., Conclusions: Irisin is associated with increased risk of MetS, cardiometabolic variables, and CVD in humans, indicating either increased secretion by adipose/muscle tissue and/or a compensatory increase of irisin to overcome an underlying irisin resistance in these subjects.

Amelogenesis Imperfecta (AI) represents a group of developmental conditions, genomic in origin, which affect the structure and clinical appearance of enamel of all or nearly all the teeth in a more or less equal manner. AI is a serious problem that reduces oral health-related quality of life and causes some physiological problems. We presented here four case reports of AI (Hypoplastic and Hypomaturation) which we diagnosed on the basis of classical clinical and radiographic features.

Single coronary artery is an uncommon variation of the coronary circulation. After transposition of great arteries, coronary artery fistulas are the most common associated cardiac anomalies in these patients. Transcatheter closure of coronary artery fistula (CAF) involving single coronary artery is a challenging intervention. In the absence of contralateral coronary artery, a complex anatomy of the CAF and a large myocardial perfusion territory of the dominant circulation pose an additional risk during interventional procedure. We report our experience of a successful transcatheter closure of a coronary artery fistula in a patient with single coronary artery., (Copyright © 2013 Wiley Periodicals, Inc.)

Introduction: Accumulating evidence suggests that patients with type 2 diabetes mellitus (T2DM) and hyperinsulinemia are at increased risk for developing malignancies. It remains to be fully elucidated whether use of metformin, an insulin sensitizer, and/or sulfonylureas, insulin secretagogues, affect cancer incidence in subjects with T2DM., Material & Methods: We performed a meta-analysis using PubMed, of randomized control trials (RCTs), cohorts, and case-control studies published through July 2012 that assess effects of metformin and/or sulfonylurea sulfonylureas on cancer risk at any site, in subjects with T2DM. Fixed and random effects meta-analysis models were used, and the effect size was summarized as relative risk (RR) for RCTs/cohorts and as odds ratio (OR) for the case-control studies., Results: Analysis of 24 metformin studies in subjects with T2DM showed that metformin use is associated with reduced risk for the development of cancer, in both cohort (RR=0.70 [95% CI=0.67-0.73]) and case-control studies (OR=0.90 [95% CI=0.84-0.98]), but this finding was not supported by RCTs (RR=1.01[95% CI=0.81-1.26]). Data from 18 sulfonylurea studies in subjects with T2DM showed that sulfonylurea use is associated with an increase in all-cancer risk, in cohort studies (RR=1.55 [95% CI=1.48 -1.63]), though data from RCTs (RR=1.17 [95% CI=0.95-1.45]) and case-control studies (OR=1.02 [95% CI=0.93-1.13]) failed to demonstrate a statistically significant effect., Conclusions: This analysis using pooled primary data demonstrates that metformin use reduces, while sulfonylurea use may be associated with an increased cancer risk in subjects with T2DM. These findings need to be confirmed in large-scale RCTs before they are translated into clinical practice., (Published by Elsevier Inc.)

Recurrent or residual right ventricular outflow tract obstruction after early surgical repair of congenital heart disease is one of the most frequent indications for either surgical or transcatheter reintervention. Transcatheter stent implantation across the stenotic right ventricular outflow tract or conduit is a safe and effective alternative to surgical reintervention. However, chronic deleterious effects of pulmonary regurgitation can potentially counterbalance the early improvement in clinical and hemodynamic parameters, sometimes necessitating further intervention. While there are several studies documenting safe and effective palliation by transcatheter right ventricular outflow tract stenting in infants with tetralogy of Fallot, literature on isolated infundibular stent implantation sparing the normal pulmonary valve in postoperative infundibular restenosis is very scant. We report our experience of safety and feasibility of transcatheter right ventricular outflow tract stent implantation while preserving the native pulmonary valve function in two children with infundibular stenosis after surgical repair of congenital heart disease.

Context: Nonspecific changes (nonspecific chronic inflammation) in patients with chronic diarrhea represent the commonest diagnosis in colorectal biopsy interpretation, but these changes are of little clinical significance., Objective: To find, within this group, histologic and immunohistologic diagnostic criteria to predict the duration and resolution of diarrhea., Design: Detailed clinical features and histologic findings were analyzed in a cohort of 47 patients with chronic diarrhea, with near-normal histology and no clear-cut known etiologic agent. Immunohistochemistry to mast cells (CD117) and Treg cells (FOXP3) was also assessed in 39 patients., Results: Increased number of lymphoid follicles and aggregates, increased number of mast cells, and paucity of Treg were the statistically significant key findings (P  =  .003, P  =  .008, and P  =  .04, respectively). The duration of diarrhea was correlated with the number of large lymphoid follicles and aggregates (P  =  .001, r  =  .48), number of total lymphoid follicles and aggregates (P  =  .003, r  =  .43), density of lymphoid follicles and aggregates (P  =  .009, r  =  .38), and total lymphoid follicles and aggregates per biopsy (P  =  .004, r  =  .42) and the number of mast cells (P  =  .001, r  =  .52). The number of mast cells and Treg cells showed significant difference between resolved and unresolved cases (P  =  .001 and P  =  .01 respectively)., Conclusions: Lymphocytic follicles and aggregates colitis, previously regarded as of negligible diagnostic significance, allows the prediction of the behavior of chronic diarrhea in a subset of patients with nonspecific changes on colonic biopsy. The increased number of mast cells and paucity of Treg cells further helps to identify such unresolved cases.

Objectives: To evaluate prospective single centre experience of mid-term safety and efficacy of perventricular device closure of isolated large muscular ventricular septal defect (mVSD) in high-risk infants., Background: Surgical closures of large mVSD in infants represent a challenge with significant morbidity., Methods: Between August 2008-2010, perventricular closure was attempted in 24 infants of 6.01 ± 2.37 months age and 4.27 ± 0.56 kg weight under TEE guidance., Results: The device was successfully deployed in 21/24 infants. Size of mVSD was 8.42 ± 1.46 mm (6.1-12 mm). Mean procedure time was 28.8 ± 11.7 min. The closure rate was 84% immediately and 100% at 6 months. Four patients suffered major complications: 2-died, 1-esophageal perforation, 1-persistent CHB. At 26.23 ± 6.63 months follow-up two patients were symptomatic: 1-required device retrieval, 1-died of severe gastroenteritis., Conclusion: Perventricular device closure of isolated mVSD appears feasible option at mid-term follow-up and may either substitute or complement the conventional surgical technique in selected cases depending on institutional paediatric cardiac surgery performance., (Copyright © 2012 Cardiological Society of India. Published by Elsevier B.V. All rights reserved.)

RUNX3 aberrations play a pivotal role in the oncogenesis of breast, gastric, colon, skin and lung tissues. The aim of this study was to characterize further the expression of RUNX3 in lung cancers. To achieve this, a lung cancer tissue microarray (TMA), frozen lung cancer tissues and lung cell lines were examined for RUNX3 expression by immunohistochemistry, while the TMA was also examined for EGFR and p53 expression. RUNX3 promoter methylation status, and EGFR and KRAS mutation status were also investigated. Inactivation of RUNX3 was observed in 70% of the adenocarcinoma samples, and this was associated with promoter hypermethylation but not biased to EGFR/KRAS mutations. Our results suggest a central role of RUNX3 downregulation in pulmonary adenocarcinoma, which may not be dependent of other established cancer-causing pathways and may have important diagnostic and screening implications.

Understanding the determinants of resistance of 5-fluorouracil (5FU) is of significant value to optimising administration of the drug, and introducing novel agents and treatment strategies. Here, the expression of 92 genes involved in 5FU transport, metabolism, co-factor (folate) metabolism and downstream effects was measured by real-time PCR low density arrays in 14 patient-derived colorectal cancer xenografts characterised for 5FU resistance. Candidate gene function was tested by siRNA and uridine modulation, and immunoblotting, apoptosis and cell cycle analysis. Predictive significance was tested by immunohistochemistry of tumours from 125 stage III colorectal cancer patients treated with and without 5FU. Of 8 genes significantly differentially expressed between 5FU sensitive and resistant xenograft tumours, CTPS2 was the gene with the highest probability of differential expression (p=0.008). Reduction of CTPS2 expression by siRNA increased the resistance of colorectal cancer cell lines DLD1 and LS174T to 5FU and its analogue, FUDR. CTPS2 siRNA significantly reduced cell S-phase accumulation and apoptosis following 5FU treatment. Exposure of cells to uridine, a precursor to the CTPS2 substrate uridine triphosphate, also increased 5FU resistance. Patients with low CTPS2 did not gain a survival benefit from 5FU treatment (p=0.072), while those with high expression did (p=0.003). Low CTPS2 expression may be a rationally-based determinant of 5FU resistance.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is characterised by progressive fibro-fatty replacement of right ventricular myocardium. Earlier studies described ARVC as non-inflammatory, non-coronary disorder associated with arrhythmias, heart failure and sudden death due to functional exclusion of the right ventricle. Molecular genetic studies have identified nine different loci associated with ARVC; accordingly each locus is implicated for each type of ARVC (ARVC1-ARVC9). So far five genes have been identified as containing pathogenic mutations for ARVC. Though mutations in each of the gene/s indicate disruption of different pathways leading to the condition, the exact pathogenesis of the condition is still obscure. This review tries to understand the pathogenesis of the condition by examining the individual proteins implicated and relate them to the pathways that could play a role in the aetiology of the condition. Cardiac ryanodine receptor (RYR-2), which regulates intra-cellular Ca(2+) concentration by releasing Ca(2+) reserves from the sarcoplasmic reticulum (SR), was the first gene for ARVC. The mutation in this gene is believed to disrupt coupled gating of RYR-2, causing after-depolarisation, leading to arrhythmias followed by structural changes due to altered intra-cellular Ca(2+) levels. Three other genes implicated for ARVC, plakoglobin (Naxos disease), desmoplakin (ARVC8) and plakophilin (ARVC9) have prompted the speculation that ARVC is primarily a disease of desmosomes. But identification of TGFbeta-3 for ARVC1 and the role of all these three genes (plakoglobin, desmoplakin and plakophilin) in cardiac morphogenesis indicate some kind of signal-transducing pathway disruption in the condition. The finding that ARVC as a milder form of Uhl's anomaly indicates similar ontogeny for the condition. Further, discovery of apoptotic cells in the autopsy of the right ventricular myocardium of ARVC patients does indicate a common pathway for different types of ARVCs, which is more specific for the right ventricular myocardium involving desmosomal plaque proteins, growth factors and Ca(2+) receptors.

Background: This study examined trends and outcomes for breast cancer surgery performed at Department of Veterans Affairs (VA) hospitals., Study Design: We examined breast cancer operations performed in VA hospitals from October 1991 to September 1997. Data from the VA National Surgical Quality Improvement Program, surgical pathology reports, discharge data, and outpatient data were used. Surgical outcomes included postoperative length of stay, 30-day morbidity rates, 1-year surgery-related readmission rates, and mortality. An expert panel of breast cancer clinicians identified surgery-related hospital readmissions. Hierarchical regression analysis was used to identify patient, provider, and hospital characteristics associated with postoperative length of stay, and 30-day morbidity., Results: From October 1991 to September 1997 1,333 breast operations were performed, ranging from 1 to 38 on average per hospital; 478 operations were for breast cancer. Among breast cancer surgery patients, 25% were men. Thirty-day morbidity rates, 1-year hospital readmission rates, and mortality were very low for both men and women. Postoperative length of stay averaged 6.8 days. Lower income, longer operation times, and older age increased the likelihood of 30-day morbidity. Lower functional status, older age, longer operation time, and lower average annual volume of procedures increased postoperative length of stay. Documentation of the extent of disease and surgical margin in pathology reports was poor in medical records., Conclusions: Hospital stays were longer, and morbidity and readmission rates for patients having breast cancer operations at VA hospitals were comparable to those reported for private sector hospitals.

Background: Information regarding survival and prognostic factors in children with metachronous bilateral Wilms' tumor is limited., Methods: A literature search of English language articles from 1950-1996 was performed. A total of 108 of 123 children with metachronous bilateral Wilms' tumor from 30 studies were evaluable for analysis. The children were classified according to the time interval to the development of a contralateral Wilms' tumor (< 18 months vs. > or = 18 months)., Results: Kaplan-Meier analysis rates of overall survival for metachronous bilateral Wilms' tumor were 49.1% and 47.2% at 5 and 10 years, respectively. The median time interval to the development of a second tumor was 23.1 months. Of 106 children, 102 (96.2%) had a metachronous presentation of Wilms' tumor by 5 years. In children ages < 2 years and children ages 2-5 years, 95.2% and 93.9%, respectively, of contralateral tumors appeared within 60 months. For children ages > or = 5 years, all contralateral kidney tumors appeared by 54 months. Analysis of overall survival of patients with a time interval of < 18 months and > or = 18 months showed a 10-year survival of 39.6% and 55.2%, respectively (P = 0.024, log rank test)., Conclusions: Children with a metachronous bilateral Wilms' tumor who developed a contralateral tumor > or = 18 months from the initial diagnosis of Wilms' tumor had a better overall survival than children with a time interval of < 18 months. Children ages < 2 years at the initial diagnosis of Wilms' tumor did not have a longer period of risk for developing a contralateral kidney tumor than those ages > or = 2 years. Screening by abdominal ultrasound of the contralateral kidney for > 5 years after initial diagnosis of Wilms' tumor may not be necessary because > 95% of children had a time interval to the development of a second tumor of < or = 60 months.

The synthesis, antihyperlipaemic evaluation and quantitative structure-activity relationships (QSAR) of two series of thieno[3,2-d]pyrimidin-4-one derivatives are reported. While most of the compounds in these series were found to exhibit antihyperlipaemic activity, the QSAR study of these two series indicated a positive influence of only the electronic nature of the 2-substitutents on the biological activity. The lipophilic and the steric parameters did not appear to be significant.

The anorectic compound fenfluramine hydrochloride was injected into young Holtzman strain rats (from days 6 to 40 of life), at the dose of 75 mg/kg body weight. Intralysosomal lamellar bodies (LBs) were seen in the endothelial cells, pericytes, the perivascular astrocyte processes and occasionally in the lumen. The pathology of myelinated fibres varied from thinning of myelin to complete demyelination and, at times, presence of dense bodies in the axons, the changes perhaps being a result of the oligodendroglia damage. A small group of adult mice was administered three oral doses each of Ponderax equivalent to 5 mg of fenfluramine. The brain stem and cerebellar neurons of these mice showed abnormal dark cytoplasm, without lamellar bodies. Even in this short-term experiment, there was formation of a few LBs in the neuropil, the prominence of dark glial cells, probably oligodendroglia, and some perivascular intracytoplasmic oedema. The earliest detection of dense bodies in the undistended astrocyte processes before they were observed in the cell perikarya, both in the younger rats and the adult mice, suggested the perivascular astrocyte to be the first CNS constituent to come in contact with the toxic agent as it passes the blood-brain barrier. On the basis of our observations, it also appears that the 'myelinosomes' or lamellar phagolysosomes developing due to failure of degradation of drug-phospholipid interaction product, accumulate in different cells of the CNS.

Type C virus produced by dog thymus cells (A7573) that were infected with virus (HL-23V), isolated from cultured leukocytes of an acute myelogenous leukemia patient, transformed marmoset and horse cells in vitro and induced virus-producing fibromas in marmosets. The tumors and transformed foci were indistinguishable morphologically from those induced by simian sarcoma virus, type 1 (SSV-1/SSAV-1). HL-23V was indistinguishable from SSV-1/SSAV-1 by immunofluorescence and neutralization tests, and the nontransforming virus associated with HL-23V completely inhibited SSV-1 focus induction in interference tests. Cell cultures established from a marmoset fibroma produced transforming and nontransforming virus biologically and antigenically indistinguishable from HL-23V and SSV-1/SSAV-1.

Two strains of feline fibrosarcoma virus (ST-FeSV and GA-FeSV) were found to induce tumors in cats and marmosets, and to transform feline and marmoset cells in vitro after primary inoculation. A third strain (SM-FeSV) failed to induce tumors or transform marmoset cells after primary inoculation; however, when SM-FeSV-injected marmoset cultures were passed 26 times in vitro, the cell cultures released infectious virus which transformed marmoset fibroblasts but still failed to induce tumors in marmosets. ST-FeSV induced mainly round-cell type transformation (r foci), GA-FeSV induced predominantly mixed round-fusiform cell type transformation (fr foci), and SM-FeSV induced r and fr type foci with a higher proportion of fusiform cells in the fr foci than seen with GA-FeSV. Transforming virus was obtained from r or mixed r/fr foci of ST-FeSV but not from fr foci; heat treatment changed the virus from producing almost exclusively r type foci to inducing an increased number of fr foci. Passage of FeSV in cat cells yielded viruses with a higher ratio of infectivity for feline vs marmoset cells, while passage of FeSV in marmoset cells yielded virus with a relatively higher infectivity ratio for marmoset cells; the three strains differed in the degree of change in the infectivity ratio. Despite the alteration of host range of SM-FeSV propagated in marmoset fibroblasts, the virus retained feline P-30 antigen by CF and FA assays. Neutralization tests did not indicate but also did not exclude an alteration of the surface antigens of ST-FeSV or SM-FeSV propagated in marmoset fibroblasts. The alteration of the relative infectivity of FeSV during passage in marmoset cells may be due to: (1) the selection of a variant present in the original heterogenous uncloned population; (2) mutation; or (3) recombination with some marmoset genetic material, possibly an as yet unidentified endogenous marmoset virus.