The Correlation Between Serum Fibroblast Growth Factor 21 and the Severity and Occurrence of Coronary Artery Disease.

BACKGROUND: The burden of cardiovascular diseases (CVDs) is increasing worldwide with CVD being one of the leading causes of death, including atherosclerosis, myocardial infarction, cardiomyopathy, and heart failure (HF). Fibroblast growth factor 21 (FGF21) is an endocrine hormone that regulates carbohydrate and lipid metabolism. It exerts direct effects on the cardiovascular system and can serve as an early indicator of CVDs. FGF21's therapeutic properties include reducing obesity, dyslipidaemia, and hyperglycemia, which can help treat metabolic disorders, autophagy, and apoptosis. Atherosclerosis is developed due to chronic inflammatory conditions, and the immune system's reaction to oxidized lipoproteins is mainly responsible for the development of atherosclerosis. FGF21's precise role in the pathogenesis of coronary artery disease (CAD) remains elusive.  Aim: This study aimed to assess the role of FGF21 in predicting the severity and magnitude of CAD in individuals diagnosed with stable angina pectoris (SAP). MATERIALS AND METHODS: A prospective cross-sectional study was conducted on 110 consecutive patients with SAP reported to the cardiology department of the Indira Gandhi Institute of Medical Sciences (IGIMS), Patna, India. They were divided into two groups based on coronary angiography findings. Control groups included patients not showing any atherosclerotic lesions and case groups with atherosclerotic lesions. The SYNTAX score is a grading system that measures the location and complexity of coronary arteries using anatomical principles. The Gensini score assessment technique was employed to determine the severity of CAD. We compared serum FGF21 levels,left ventricular ejection fraction (LVEF), and inflammatory biomarker C-reactive protein (CRP) levels between the two groups. Moreover, we examined the correlation between the serum FGF21 level and the SYNTAX and Gensini scores. The statistical analysis was done using Version 23.0 of SPSS Statistics. P-values below 0.05 were considered statistically significant. RESULTS: The study found that the case group had a higher average age and a higher proportion of male patients. The case group had considerably higher levels of FGF21 (166.59 ± 94.49791 pg/mL) compared to the control group (54.13 ± 48.467 pg/mL) (p=0.034). The LVEF exhibited a significant difference between the case and control groups, with mean values of 50.3056 ± 7.8242% and 56.078 ± 5.3987%, respectively (p=0.031). CRP levels were comparable in both groups. The case group had mean values of SYNTAX and Gensini scores of 23.19±7.43 and 50.03±27.30, respectively. We found that there was no statistically significant association between the risk assessments for CAD severity and the levels of serum FGF21 (correlation coefficient r=0.14070, p>0.05, and r=0.206415, p>0.05, respectively) Conclusions: FGF21 is gaining recognition as a prospective addition to the FGF family, potentially playing a significant role in cardiovascular disease, particularly atherosclerosis. A statistically significant difference was seen in the serum FGF21 levels between the case and control groups, indicating that it can help in the diagnosis of CAD. However, there was no apparent correlation found between the serum FGF21 levels and the SYNTAX and Gensini scores. The role of FGF21 in the development of atherosclerosis and whether FGF21 could serve as a reliable marker need to be studied further.

Prevalence of Thyroid Disorder in Gallstone Disease Patients: A Cross-Sectional Study.

Background Gallstone disease (GSD) is one of the most common disorders involving the biliary system. The three types of gallstones include pigment, cholesterol, and mixed stones. Studies have suggested a potential association between thyroid dysfunction and lipid pathogenesis, which influences bile composition. A higher prevalence of thyroid disorders may have an impact on the management of GSD patients. This study aimed to assess the prevalence of thyroid disorders and associated dyslipidemias among individuals diagnosed with GSD. Methodology This cross-sectional, observational study was conducted among 180 eligible patients with a mean age of 47.72 ± 15.29 years. This study included 56 (31%) male and 124 (69%) female patients admitted to the Department of General Surgery, Indira Gandhi Institute of Medical Sciences, in eastern India. A diagnosis of GSD was established based on a radiological investigation (ultrasonography) and was included in the study. A thyroid profile test, a liver function test, and a lipid profile test were done for all patients. Patients with a previous surgical history of thyroid disease and known cases of hypothyroidism taking thyroxin supplements for treatment, as well as uncontrolled diabetes mellitus and hypertension, were excluded from the study. Relevant data were collected and statistically analyzed. Results Among the 180 patients, 122 (67.77%) were euthyroid, 35 (19.44%) had subclinical hypothyroidism, 20 (11.11%) had clinical hypothyroidism, and three (1.66%) had hyperthyroidism. Out of a total of 55 hypothyroidism patients, 37 (67.27%) had dyslipidemias. Conclusions The prevalence of hypothyroidism in GSD was 30%, with a female predominance. Hypothyroidism is a specific risk factor for cholelithiasis, and all patients with GSD who have dyslipidemia should be evaluated for thyroid dysfunction.

Association of Thyroid Function With Lipid Profile in Patients With Metabolic Syndrome: A Prospective Cross-Sectional Study in the Indian Population.

Introduction Metabolic syndrome is a group of aberrant metabolic indicators including hypertension, dyslipidemia, impaired fasting blood glucose, and obesity. It has been reported that thyroid hormones have a strong influence on the cardiovascular system, and hypothyroidism has been linked to metabolic syndrome components. The objective of the study was to find out the association of thyroid function with lipid profile in patients with metabolic syndrome. Methods A prospective cross-sectional study was conducted in an apparently healthy adult population visiting the outpatient Department of Indira Gandhi Institute of Medical Sciences (IGIMS), Patna, Bihar, India. Metabolic syndrome was diagnosed according to the International Diabetes Federation (IDF) criteria. Fasting blood glucose, triglyceride, and HDL levels were tested using the enzymatic photometric method. Thyroid-stimulating hormone (TSH), free T4, free T3, and insulin assays were performed using chemiluminescence immunoassay (CLIA). Results Out of 197 subjects recruited, 86 (51 males and 35 females) were diagnosed with metabolic syndrome according to the IDF criteria, and the rest 111 without metabolic syndrome were considered to be the controls. The mean age of subjects with and without metabolic syndrome was 45.8±8.5 and 46.4±9.6 years, respectively. The prevalence of thyroid dysfunction in the present study was 22%. In subjects with metabolic syndrome, most of the clinical and hormonal parameters (waist circumference, waist-height ratio, fasting blood sugar, fasting insulin, triglycerides, T3, and TSH) were significantly higher (p<0.001) as compared to those without metabolic syndrome. In case of lipid profile, the triglycerides in those with metabolic syndrome (262.8±112.3 mg/dL) were significantly higher (p<0.001) than those without metabolic syndrome (137.9±19.01 mg/dL), while the serum levels of HDL were significantly higher (p<0.001) in group without metabolic syndrome (50.5±3.9 mg/dL) as compared to those with metabolic syndrome (43.4±5.2 mg/dL). Also, the TSH levels were significantly higher (p<0.001) in subjects with metabolic syndrome (5.3±3.4 µl/mL) as compared to those without metabolic syndrome (2.6±1.4 µl/mL). Among all the components of metabolic syndrome, waist circumference and HDL showed a significant strong positive correlation (r=0.51) with TSH, and systolic blood pressure (r=0.39), diastolic blood pressure (r=0.39), and fasting blood sugar levels (r=0.44) showed significantly moderate positive correlation with TSH levels. T4 (OR=8.82; 95% CI: 1.56-49.8) and TSH (OR=1.61; 95% CI: 1.19-2.18) levels were observed to have significantly higher odds as risk factors for metabolic syndrome. Conclusion There is a significant association of thyroid function with lipid profile in metabolic syndrome. It was observed that along with metabolic alterations, cardiovascular symptoms of hypothyroidism and subclinical hypothyroidism are possible. Therefore, while evaluating people with metabolic syndrome, it may be appropriate to look into how well their thyroid glands are functioning.

Short-Term Outcomes and Quality-of-Life Assessment Following Rives-Stoppa and Transversus Abdominis Release Procedures of Open Ventral Hernia Repair.

INTRODUCTION: Ventral hernia is one of the common surgical conditions that can significantly impact a patient's quality of life (QoL). Open ventral hernia repair using the Rives-Stoppa (RS) and Transversus Abdominis Release (TAR) procedures has gained recognition for its effectiveness in achieving hernia repair and reducing the risk of further recurrence. However, limited research has been performed to explore the short-term outcomes and QoL assessment following these two surgical techniques. The aim of this study was to know the result after RS and TAR methods of hernia repair in terms of short-term recurrences, pain, postoperative complications, and QoL. METHODS: This was a prospective, interventional study, which included 30 patients fulfilling the inclusion criteria. The study group was subjected to posterior component separation (PCS)-TAR and RS repair as per surgical indication (RS if defect size 4-10cm; PCS-TAR if defect size >10cm and

Urinary Neutrophil Gelatinase Associated Lipocalin: A Novel Biomarker Determining Steroid Responsiveness in Nephrotic Syndrome.

BACKGROUND: Urinary Neutrophil Gelatinase Associated Lipocalin (uNGAL) has been demonstrated to be a powerful marker of progression in chronic kidney disease. The present study was done to find out the ability of uNGAL as a biomarker to differentiate steroid-sensitive nephrotic syndrome (SSNS), steroid-dependent nephrotic syndrome (SDNS), and steroid-resistant nephrotic syndrome (SRNS) from each other. METHOD: The cross-sectional study included 45 patients with Idiopathic Nephrotic Syndrome (INS) (15 each of SSNS, SDNS, and SRNS). uNGAL was measured by ELISA. Demographic profile of patients with INS, lab parameters including Serum albumin, cholesterol, urinary albumin, creatinine, etc., were estimated using standard laboratory methods. Various statistical methods were used to assay the usefulness of NGAL as a diagnostic marker. RESULTS: Among the three groups, the median value of uNGAL was 8.68 ng/ml in SSNS, higher in SDNS (32.8 ng/ml), and highest in the SRNS group (50 ng/ml). The receiver operating curve (ROC) was generated for uNGAL to differentiate between SDNS and SSNS. Cut-off 13.26 ng/ml had a sensitivity of 86.7% and specificity of 97.4%, PPV 92.9%, and NPV 87.5 % with an area under the curve (AUC) of 0.958. Another ROC was generated for uNGAL to differentiate between SRNS and SDNS, and cut-off 40.02 ng/ml had a sensitivity of 80% and specificity of 86.7% with an AUC of 0.907. A similar result was observed when ROC was generated to differentiate SRNS from SSNS and SDNS combined. CONCLUSION: uNGAL can distinguish between SSNS, SDNS, and SRNS.

Assessment of Serum Cortisol Levels in Hypothyroidism Patients: A Cross-Sectional Study.

BACKGROUND: Hypothyroidism, characterized by insufficient thyroid hormone production, affects a significant global population, particularly women and the elderly. Recent research has emphasized the interaction between hypothyroidism and the hypothalamic-pituitary-adrenal (HPA) axis, highlighting cortisol's crucial role in the disease's physiological manifestations. OBJECTIVE: This study aims to evaluate serum cortisol levels in hypothyroid patients, examining the intricate relationship between these two endocrine systems. By exploring the potential impact of altered cortisol levels on hypothyroidism's clinical presentation and progression, the study seeks to contribute valuable insights to enhance diagnostic approaches and develop more effective treatment strategies. METHODS: A cross-sectional observational study was conducted at the Indira Gandhi Institute of Medical Sciences, assessing 65 hypothyroid cases and 65 age-matched euthyroid controls. Demographic data, medical history, and blood samples were collected, and serum cortisol, thyroid-stimulating hormone (TSH), triiodothyronine (T3), and thyroxine (T4) levels were measured. The study adhered to ethical considerations and received institutional approval. RESULTS: The study included 65 hypothyroid cases (56 females, 9 males) and 65 euthyroid controls. Serum cortisol showed a significant correlation with TSH and T4 levels. Linear regression revealed a negative correlation between serum T4 and T3 levels and serum cortisol in hypothyroidism. A positive correlation was observed between TSH and cortisol. These findings align with previous studies, suggesting potential regulatory mechanisms and compensatory responses in hypothyroid patients. DISCUSSION: The study's results emphasize the complex interaction between cortisol and thyroid function, suggesting a direct relationship between serum cortisol and TSH levels in hypothyroidism. Patients with severe hypothyroidism exhibited elevated cortisol concentrations, indicating a potential compensatory mechanism initiated by the HPA axis. Integrating serum cortisol assessment with conventional thyroid function tests could offer comprehensive insights into hypothyroidism severity and progression, providing a more holistic approach to patient care. CONCLUSIONS: This study contributes to understanding the complex relationship between serum cortisol levels and hypothyroidism, emphasizing the need for further research to uncover underlying mechanisms and therapeutic implications. A comprehensive understanding holds the potential for more tailored and effective treatment strategies for individuals with hypothyroidism.

Assessment of tumor markers CA 19-9, CEA, CA 125, and CA 242 for the early diagnosis and prognosis prediction of gallbladder cancer.

BACKGROUND: Gallbladder cancer (GBC) is one of the leading and aggressive cancers in this region of India. It is very difficult to diagnose in the early stage, as it lacks typical early signs and symptoms; thus, the diagnosis is often in the advanced stage, which ultimately leads to a poor 5-year survival outcome. Tumor markers including carbohydrate antigen 19-9 (CA 19-9), carcinoembryonic antigen (CEA), CA 125, CA 242, and alpha fetoprotein are used as indicators in the diagnosis and prognosis of GBC. AIM: To compare tumor marker levels between GBC and benign GB diseases (GBDs) and to assess the combined use of tumor markers to increase the diagnostic accuracy for GBC. METHODS: Patients of either sex aged ≥ 18 years, with suspected GBC (GB polyp, irregular thick GB wall, GB mass, porcelain GB) on the basis of radiological imaging were included in this study. GB wall thickness using ultrasonography and tumor markers CEA, CA 125, CA 19-9, and CA 242 in all patients were recorded. All cases after surgical intervention were divided into two groups, GBC and benign GBD, according to histopathological examination findings. The cases were followed up and clinical findings, radiological findings, and levels of tumor markers were assessed. RESULTS: A total of 200 patients were included in this study, of whom 80 patients had GBC and 120 patients had benign GBD. The median (interquartile range) age was 52.0 (41.0-60.0) years and the majority of patients (132, 66.0%) were women. Tumor markers including CA 19-9, CA 125, CEA, and CA 242 were significantly elevated in patients with GBC (P < 0.001). There was a significant reduction in tumor markers at 3 and 6 mo from baseline (P < 0.001). The mean survival of patients with normal and elevated levels of tumor markers CA 125, CA 19-9, and CEA was comparable; however lymph node metastasis and CA 242 expression level were independent prognostic factors. CONCLUSION: Serum levels of tumor markers including CA 19-9, CA 125, CEA, and CA 242 were significantly associated with GBC. However, no significant association was observed between the presence of elevated levels of any tumor marker with respect to survival. Tumor marker assessment during follow-up may represent a treatment response.

Long-term clinical outcomes with use of an angiotensin-converting enzyme inhibitor early after heart transplantation.

BACKGROUND: The safety and efficacy of angiotensin converting enzyme inhibition (ACEI) after heart transplantation (HT) is unknown. This study examined long-term clinical outcomes after ACEI in HT recipients. METHODS: The ACEI after HT study was a prospective, randomized trial that tested the efficacy of ACEI with ramipril after HT. In this study, long-term clinical outcomes were assessed in 91 patients randomized to either ramipril or placebo (median, 5.8 years). The primary endpoint was a composite of death, retransplantation, hospitalization for rejection or heart failure, and coronary revascularization. RESULTS: The primary endpoint occurred in 10 of 45 patients (22.2%) in the ramipril group and in 14 of 46 patients (30.4%) in the placebo group (Hazard ratio (HR), 0.68; 95% CI, 0.29-1.51; P = .34). When the analysis was restricted to comparing patients who remained on a renin-angiotensin system inhibitor beyond 1 year with those who did not, there was a trend to improved outcomes (HR, 0.54; 95% CI, 0.22-1.28, P = .16). There was no significant difference in creatinine, blood urea nitrogen, and potassium at 3 years after randomization. The cumulative incidence of the primary endpoint was significantly higher in patients in whom the index of microcirculatory resistance increased from baseline to 1 year compared with those in whom it did not (39.1 vs 17.4%, HR: 3.36; 95% CI, 1.07-12.7; P = .037). CONCLUSION: The use of ramipril after HT safely lowers blood pressure and is associated with favorable long-term clinical outcomes. Clinical Trial Registration-URL: https://www.clinicaltrials.gov. Unique identifier: NCT01078363.

Impact of Asymmetric Dimethylarginine on Coronary Physiology Early After Heart Transplantation.

Cardiac allograft vasculopathy is a major cause of long-term graft failure following heart transplantation. Asymmetric dimethylarginine (ADMA), a marker of endothelial dysfunction, has been mechanistically implicated in the development of cardiac allograft vasculopathy, but its impact on coronary physiology early after transplantation is unknown. Invasive indices of coronary physiology, namely, fractional flow reserve (FFR), the index of microcirculatory resistance, and coronary flow reserve, were measured with a coronary pressure wire in the left anterior descending artery within 8 weeks (baseline) and 1 year after transplant. Plasma levels of ADMA were concurrently assayed using high-performance liquid chromatography. In 46 heart transplant recipients, there was a statistically significant correlation between elevated ADMA levels and lower FFR values at baseline (r = -0.33; p = 0.024); this modest association persisted 1 year after transplant (r = -0.39; p = 0.0085). Patients with a baseline FFR <0.90 (a prognostically validated cutoff) had significantly higher baseline ADMA levels (0.63 ± 0.16 vs 0.54 ± 0.12 µM; p = 0.034). Baseline ADMA (odds ratio 1.80 per 0.1 µM; 95% confidence interval 1.07 to 3.03; p = 0.027) independently predicted a baseline FFR <0.90 after multivariable adjustment. Even after dichotomizing ADMA (≥0.60 µM, provides greatest diagnostic accuracy by receiver operating characteristic curve), this association remained significant (odds ratio 7.52, 95% confidence interval 1.74 to 32.49; p = 0.006). No significant relationship between ADMA and index of microcirculatory resistance or coronary flow reserve was detected. In conclusion, baseline ADMA was a strong independent predictor of FFR <0.90, suggesting that elevated ADMA levels are associated with abnormal epicardial function soon after heart transplantation.

The Path of Most Resistance: Transdifferentiation Underlies Exceptional Nonresponses to Androgen Receptor Pathway Inhibition in Prostate Cancer.

In this issue of Cancer Discovery, Zou and colleagues describe a mechanism involving cellular transdifferentiation that promotes exceptional resistance to antiandrogen therapy in prostate cancer. A background of coinactivation of Trp53 and Pten increased the frequency of the transdifferentiated neuroendocrine phenotype. These findings have implications for developing approaches to repress cellular plasticity and overcome treatment resistance. Cancer Discov; 7(7); 673-4. ©2017 AACRSee related article by Zou et al., p. 736.

Angiotensin-Converting Enzyme Inhibition Early After Heart Transplantation.

BACKGROUND: Cardiac allograft vasculopathy (CAV) remains a leading cause of mortality after heart transplantation (HT). Angiotensin-converting enzyme inhibitors (ACEIs) may retard the development of CAV but have not been well studied after HT. OBJECTIVES: This study tested the safety and efficacy of the ACEI ramipril on the development of CAV early after HT. METHODS: In this prospective, multicenter, randomized, double-blind, placebo-controlled trial, 96 HT recipients were randomized to undergo ramipril or placebo therapy. They underwent coronary angiography, endothelial function testing; measurements of fractional flow reserve (FFR) and coronary flow reserve (CFR) and the index of microcirculatory resistance (IMR); and intravascular ultrasonography (IVUS) of the left anterior descending coronary artery, within 8 weeks of HT. At 1 year, the invasive assessment was repeated. Circulating endothelial progenitor cells (EPCs) were quantified at baseline and 1 year. RESULTS: Plaque volumes at 1 year were similar between the ramipril and placebo groups (162.1 ± 70.5 mm3 vs. 177.3 ± 94.3 mm3, respectively; p = 0.73). Patients receiving ramipril had improvement in microvascular function as shown by a significant decrease in IMR (21.4 ± 14.7 to 14.4 ± 6.3; p = 0.001) and increase in CFR (3.8 ± 1.7 to 4.8 ± 1.5; p = 0.017), from baseline to 1 year. This did not occur with IMR (17.4 ± 8.4 to 21.5 ± 20.0; p = 0.72) or CFR (4.1 ± 1.8 to 4.1 ± 2.2; p = 0.60) in the placebo-treated patients. EPCs decreased significantly at 1 year in the placebo group but not in the ramipril group. CONCLUSIONS: Ramipril does not slow development of epicardial plaque volume but does stabilize levels of endothelial progenitor cells and improve microvascular function, which have been associated with improved long-term survival after HT. (Angiotensin Converting Enzyme [ACE] Inhibition and Cardiac Allograft Vasculopathy; NCT01078363).

Cortactin promotes exosome secretion by controlling branched actin dynamics.

Exosomes are extracellular vesicles that influence cellular behavior and enhance cancer aggressiveness by carrying bioactive molecules. The mechanisms that regulate exosome secretion are poorly understood. Here, we show that the actin cytoskeletal regulatory protein cortactin promotes exosome secretion. Knockdown or overexpression of cortactin in cancer cells leads to a respective decrease or increase in exosome secretion, without altering exosome cargo content. Live-cell imaging revealed that cortactin controls both trafficking and plasma membrane docking of multivesicular late endosomes (MVEs). Regulation of exosome secretion by cortactin requires binding to the branched actin nucleating Arp2/3 complex and to actin filaments. Furthermore, cortactin, Rab27a, and coronin 1b coordinately control stability of cortical actin MVE docking sites and exosome secretion. Functionally, the addition of purified exosomes to cortactin-knockdown cells rescued defects of those cells in serum-independent growth and invasion. These data suggest a model in which cortactin promotes exosome secretion by stabilizing cortical actin-rich MVE docking sites.

Exosome secretion is enhanced by invadopodia and drives invasive behavior.

Unconventional secretion of exosome vesicles from multivesicular endosomes (MVEs) occurs across a broad set of systems and is reported to be upregulated in cancer, where it promotes aggressive behavior. However, regulatory control of exosome secretion is poorly understood. Using cancer cells, we identified specialized invasive actin structures called invadopodia as specific and critical docking and secretion sites for CD63- and Rab27a-positive MVEs. Thus, inhibition of invadopodia formation greatly reduced exosome secretion into conditioned media. Functionally, addition of purified exosomes or inhibition of exosome biogenesis or secretion greatly affected multiple invadopodia life cycle steps, including invadopodia formation, stabilization, and exocytosis of proteinases, indicating a key role for exosome cargoes in promoting invasive activity and providing in situ signaling feedback. Exosome secretion also controlled cellular invasion through three-dimensional matrix. These data identify a synergistic interaction between invadopodia biogenesis and exosome secretion and reveal a fundamental role for exosomes in promoting cancer cell invasiveness.

Alterations in replication timing of cancer-related genes in malignant human breast cancer cells.

The replication timing of nine genes commonly involved in cancer was investigated in the MCF10 cell lines for human breast cancer progression. Six of these nine genes are part of a constellation of tumor suppressor genes that play a major role in familial human breast cancer (TP53, ATM, PTEN, CHK2, BRCA1, and BRCA2). Three other genes are involved in a large number of human cancers including breast as either tumor suppressors (RB1 and RAD51) or as an oncogene (cMYC). Five of these nine genes (TP53, RAD51, ATM, PTEN, and cMYC) show significant differences (P < 0.05) in replication timing between MCF10A normal human breast cells and the corresponding malignant MCF10CA1a cells. These differences are specific to the malignant state of the MCF10CA1a cells since there were no significant differences in the replication timing of these genes between normal MCF10A cells and the non-malignant cancer MCF10AT1 cells. Microarray analysis further demonstrated that three of these five genes (TP53, RAD51, and cMYC) showed significant changes in gene expression (≥2-fold) between normal and malignant cells. Our findings demonstrate an alteration in the replication timing of a small subset of cancer-related genes in malignant breast cancer cells. These alterations partially correlate with the major transcriptional changes characteristic of the malignant state in these cells.

Transvaginal repair of complex and complicated vesicovaginal fistulae.

OBJECTIVE: To document the experience at a tertiary referral hospital in India with managing complex and complicated vesicovaginal fistulae (VVF) by the transvaginal route, and to document the complications and the long-term outcome of the patients. METHODS: The medical records of 102 patients with complex or complicated VVF who underwent transvaginal surgical repair during 2000-2009 were reviewed retrospectively. RESULTS: The mean age of the patients was 24 years and the mean duration of urinary incontinence was 3 years (range 6 months to 12 years). The patients were followed up for a median of 48 months. In total, 78 patients had obstetric fistulae, 20 patients had surgical (gynecologic) fistulae, and 4 patients had postradiation fistulae. The overall success rate for the transvaginal approach was 86.3%. Fourteen patients remained incontinent despite the surgical repair. Early failure of the repair was observed in 11.8% of the patients and delayed failure in 2.0%. Postoperative complications included stress urinary incontinence (9.8%), urge urinary incontinence (7.8%), dyspareunia (5.9%), and chronic labial pain (2.0%). CONCLUSION: The transvaginal approach to the repair of complex and complicated VVF gives good long-term results with low complication rates.

Cortactin: a multifunctional regulator of cellular invasiveness.

Branched actin assembly is critical for a variety of cellular processes that underlie cell motility and invasion, including cellular protrusion formation and membrane trafficking. Activation of branched actin assembly occurs at various subcellular locations via site-specific activation of distinct WASp family proteins and the Arp2/3 complex. A key branched actin regulator that promotes cell motility and links signaling, cytoskeletal and membrane trafficking proteins is the Src kinase substrate and Arp2/3 binding protein cortactin. Due to its frequent overexpression in advanced, invasive cancers and its general role in regulating branched actin assembly at multiple cellular locations, cortactin has been the subject of intense study. Recent studies suggest that cortactin has a complex role in cellular migration and invasion, promoting both on-site actin polymerization and modulation of autocrine secretion. Diverse cellular activities may derive from the interaction of cortactin with site-specific binding partners.

Reconstructive surgery for tuberculous contracted bladder: experience of a center in northern India.

OBJECTIVE: To document the management of tuberculous cicatrized urinary bladder by incorporating bowel segment and the long-term follow-up after the reconstructive surgery. MATERIALS AND METHODS: Twenty-three patients (out of 28) were managed by augmentation cystoplasty (AC) and 5 by orthotopic neobladder (OTN) reconstruction. Sigmoidocystoplasty was performed in 11 cases, ileocystoplasty in 10 patients and ileocecocystoplasty in 2 patients. Ileal neobladder reconstruction was done in 2 patients, ileocecal neobladder reconstruction in 1 patient and sigmoid neobladder reconstruction in 2 patients, respectively. The patients were followed according to standard follow-up protocols. RESULT: The mean age of patients who underwent AC was 32.5 years and of those who underwent OTN reconstruction was 31 years. The mean pre-operative bladder capacity in patients with AC was 70 ml (range 40-100 ml) and of patients with OTN reconstruction was 14 ml (range 10-20 ml). The mean postoperative bladder capacity at 3 months following AC was 427 ml (range 450-500 ml) and following OTN reconstruction it was 430 ml (range 350-450 ml). The mean follow-up in patients who underwent AC was 43.3 months (range 12-90 months) and in those who underwent OTN reconstruction it was 35.6 months (16-60 months). None of the patients had upper urinary tract deterioration following the reconstructive surgery. CONCLUSION: Urinary bladder rehabilitation either by AC or OTN reconstruction increases the bladder capacity and storage time and also preserves the upper tracts.

ISG20L1 is a p53 family target gene that modulates genotoxic stress-induced autophagy.

BACKGROUND: Autophagy is characterized by the sequestration of cytoplasm and organelles into multimembrane vesicles and subsequent degradation by the cell's lysosomal system. It is linked to many physiological functions in human cells including stress response, protein degradation, organelle turnover, caspase-independent cell death and tumor suppression. Malignant transformation is frequently associated with deregulation of autophagy and several tumor suppressors can modulate autophagic processes. The tumor suppressor p53 can induce autophagy after metabolic or genotoxic stress through transcriptionally-dependent and -independent mechanisms. In this study we expand on the former mechanism by functionally characterizing a p53 family target gene, ISG20L1 under conditions of genotoxic stress. RESULTS: We identified a p53 target gene, ISG20L1, and show that transcription of the gene can be regulated by all three p53 family members (p53, p63, and p73). We generated an antibody to ISG20L1 and found that it localizes to the nucleolar and perinucleolar regions of the nucleus and its protein levels increase in a p53- and p73-dependent manner after various forms of genotoxic stress. When ectopically expressed in epithelial cancer-derived cell lines, ISG20L1 expression decreased clonogenic survival without a concomitant elevation in apoptosis and this effect was partially rescued in cells that were ATG5 deficient. Knockdown of ISG20L1 did not alter 5-FU induced apoptosis as assessed by PARP and caspase-3 cleavage, sub-G1 content, and DNA laddering. Thus, we investigated the role of ISG20L1 in autophagy, a process commonly associated with type II cell death, and found that ISG20L1 knockdown decreased levels of autophagic vacuoles and LC3-II after genotoxic stress as assessed by electron microscopy, biochemical, and immunohistochemical measurements of LC3-II. CONCLUSIONS: Our identification of ISG20L1 as a p53 family target and discovery that modulation of this target can regulate autophagic processes further strengthens the connection between p53 signaling and autophagy. Given the keen interest in targeting autophagy as an anticancer therapeutic approach in tumor cells that are defective in apoptosis, investigation of genes and signaling pathways involved in cell death associated with autophagy is critical.

Effect of rapamycin therapy on coronary artery physiology early after cardiac transplantation.

BACKGROUND: Rapamycin has been shown to reduce anatomical evidence of cardiac allograft vasculopathy, but its effect on coronary artery physiology is unknown. METHODS: Twenty-seven patients without angiographic evidence of coronary artery disease underwent measurement of fractional flow reserve (FFR), coronary flow reserve (CFR), and the index of microcirculatory resistance (IMR) within 8 weeks and then 1 year after transplantation using a pressure sensor/thermistor-tipped guidewire. Measurements were compared between consecutive patients who were on rapamycin for at least 3 months during the first year after transplantation (rapamycin group, n = 9) and a comparable group on mycophenolate mofetil (MMF) instead (MMF group, n = 18). RESULTS: At baseline, there was no significant difference in FFR, CFR, or IMR between the 2 groups. At 1 year, FFR declined significantly in the MMF group (0.87 +/- 0.06 to 0.82 +/- 0.06, P = .009) but did not change in the rapamycin group (0.91 +/- 0.05 to 0.89 +/- 0.04, P = .33). Coronary flow reserve and IMR did not change significantly in the MMF group (3.1 +/- 1.7 to 3.2 +/- 1.0, P = .76; and 27.5 +/- 18.1 to 19.1 +/- 7.6, P = .10, respectively) but improved significantly in the rapamycin group (2.3 +/- 0.8 to 3.8 +/- 1.4, P < .03; and 27.0 +/- 11.5 to 17.6 +/- 7.5, P < .03, respectively). Multivariate regression analysis revealed that rapamycin therapy was an independent predictor of CFR and FFR at 1 year after transplantation. CONCLUSION: Early after cardiac transplantation, rapamycin therapy is associated with improved coronary artery physiology involving both the epicardial vessel and the microvasculature.