Assessing angiogenesis factors as prognostic biomarkers in breast cancer patients and their association with clinicopathological factors.

INTRODUCTION: Angiogenesis is fundamental for tumor growth and metastasis across many solid malignancies. Considerable interest has focused on the molecular regulation of tumor angiogenesis as a means to predict disease outcomes and guide therapeutic decisions. METHODS: In the present study, we investigated the prognostic value of transforming growth factor beta (TGF-ß), epidermal growth factor (EGF), fibroblast growth factor (FGF), delta-like ligand 4 (DLL4), and vascular endothelial growth factor (VEGF) in the serum of 120 women diagnosed with breast cancer using ELISA as well as examined their associations with clinical parameters and the outcome of the disease. RESULTS: Our results demonstrated that the serum concentration of TGF-ß and EGF were remarkably higher in patients with higher tumor size, end stages of the disease, and positive lymph node involvement compared to patients with lower tumor size, early stages of the disease, and negative lymph node involvement. In addition, we found a significant correlation between the serum concentration of VEGF and the level of EGF, FGF, and DLL4 in patients with breast cancer. Furthermore, both univariate and multivariate analyses showed that TGF-ß and EGF can be used as end-stage predictors. DISCUSSION/CONCLUSION: Based on our findings, increasing the level of angiogenesis factors is significantly associated with higher tumor size and late stages of the disease in patients with breast cancer. Moreover, measuring the level of angiogenesis factors could lead to better prediction of disease outcomes and choosing the best treatments for patients.

The impact of intraoperative radiotherapy on breast cancer: focus on the levels of angiogenic factors.

OBJECTIVE: Angiogenesis is one of the hallmarks of cancers that is involved in tumor progression. Angiogenic factors induce the formation of new blood vessels and tumor extension, and finally reduce the survival of patients. Intraoperative radiotherapy (IORT), in which radiation is delivered to the tumor bed can kill cells and change tumor microenvironment. Here, we compared the impact of IORT on the levels of angiogenic factors in the blood and surgical wound fluids (SWF) of the breast cancer patients. PATIENTS AND METHODS: Three hundred sixty patients, who had undergone breast-conserving surgery between 2013 and 2018, were enrolled in IORT and non-IORT groups non-randomly. Blood and drained wound fluid (WF) samples were collected from the patients before and after surgery, followed by quantification of the amounts of TGF-ß, EGF, FGF, VEGF, and DLL4 in the patients using ELISA. RESULTS: Our results were indicative of significant differences between the pre-surgery and post-surgery serum levels of EGF, DLL4, and VEGF. Furthermore, ROC analyses showed that TGF-ß and DLL4 can differentiate of the early-stage from late-stage of the disease. Interestingly, the rate of the death and recurrence was reduced in IORT group. CONCLUSIONS: In summary, IORT is a safe and effective treatment that can affect angiogenic factors and improve the overall- and recurrence-free survival of breast cancer patients.

A Case of Peripartum Ventricular Tachycardia due to Arrhythmogenic Right Ventricular Dysplasia.

Arrhythmogenic right ventricular cardiomyopathy is a predominantly inherited structural disease with a heterogeneous set of implicated genetic defects. For those patients not identified by targeted population screening programs, ventricular tachycardia can be their first presentation. We report a case of a female from the genetically isolated Hutterite colonies who presented with recurrent ventricular tachycardia. She was found to be homozygous for a truncated desmocollin-2 gene, with both severe right ventricular dysfunction and left ventricular involvement. Her medical management was complicated by the finding of concomitant pre-term pregnancy. Management options for arrhythmia suppression and treatment are reviewed taking into account her decompensated biventricular dysfunction and possible fetal effects.

Molecular diagnosis of occult hepatitis C virus infection in Iranian injection drug users.

Occult HCV infection (OCI) has been described as the presence of hepatitis C virus (HCV) genomic RNA in hepatocytes and/or peripheral blood mononuclear cell (PBMC) specimens and the lack of HCV genomic RNA and anti-HCV antibodies (Abs) in plasma samples. Injection drug users (IDUs) are the most important high-risk group for infection with blood-borne viruses, particularly HCV. The purpose of this study was to determine the presence of OCI in IDUs. A prospective cross-sectional study of 126 consecutive Iranian IDUs was performed from March 2017 to January 2018. PBMCs were separated from blood samples from the participants, and after extraction of the viral RNA from the plasma and PBMC specimens, HCV RNA was detected in the samples using RT-nested PCR by amplification of the 5'-NTR of HCV. HCV genotyping was carried out using restriction a fragment length polymorphism (RFLP) assay. The viral RNA was amplified using RT-nested PCR with specific primers for the NS5B gene, and the PCR products were sequenced to confirm the results obtained by HCV RNA detection and HCV genotyping. Out of the 126 IDUs studied, 105 (83.3%) were negative for anti-HCV Abs and HCV RNA in plasma samples, whereas HCV RNA was detected in the PBMC samples of six (5.7%) participants, indicating that these individuals had OCI. Moreover, HCV genomic RNA was detected in PBMC samples from five (23.8%) of the 21 IDUs studied who were positive for anti-HCV Abs and negative for HCV genomic RNA in plasma specimens. These IDUs also had OCI. The HCV genotypes in the PBMC samples from the subjects with OCI were determined. Six (54.5%) subjects were infected with HCV subtype 3a, and five (45.5%) were infected with HCV subtype 1a. This study showed that 8.7% of the Iranian IDUs had OCI, and therefore, a study focusing on the diagnosis of OCI in these individuals can be valuable and informative.

High prevalence of occult hepatitis C virus infection in injection drug users with HIV infection.

One of the pathological forms of chronic hepatitis C is occult HCV infection (OCI), in which there is no detectable HCV RNA in plasma specimens but HCV RNA is present in PBMCs and liver biopsy specimens. The aim of this study is to estimate the prevalence of OCI in HIV-positive people who are injection drug users (IDUs). From April 2015 to August 2018, 161 Iranian IDUs with HIV infection enrolled in the study. Viral RNA was extracted from plasma and PBMC samples of participants, and the presence of HCV RNA was examined using RT nested PCR with primers from two conserved regions (5´-UTR and NS5B). HCV genotyping was performed using RFLP and sequencing methods. Of the 161 patients, 134 (83.2%) were positive for anti-HCV antibodies. All 27 patients who were negative for anti-HCV were also negative for HCV RNA in plasma, but five of them (18.5%) were positive for HCV RNA in PBMCs. Importantly, 9 out of 50 patients (18.0%) who apparently had recovered from HCV infection (i.e., were anti-HCV positive and HCV RNA negative) were positive for HCV RNA in PBMCs. Overall, 18.1% of the patients who had no signs of previous HCV infection or had apparently recovered from the disease had OCI. The HCV genotypes of the cases with OCI were as follows: five patients (35.7%) were infected with subtype 1a, eight patients (57.1%) were infected with subtype 3a, and one patient (7.1%) was infected with genotype 4. Thus, it seems that the prevalence of OCI in HIV-positive IDUs is extremely significant in Iran and is likely to delay the global eradication of HCV infection until 2030.

Post-Complex Myocardial Infarct Pseudoaneurysm Rupture and Subsequent Complications.

Ventricular pseudoaneurysm is an uncommonly encountered complication of myocardial infarction (MI) in the era of percutaneous coronary intervention. Its presentation can be very non-specific, and diagnosis requires a high index of suspicion. Urgent surgical repair is generally warranted to prevent potentially catastrophic complications. We present a case of patient who presented several days after his index MI. He was ultimately diagnosed with a ruptured pseudoaneurysm, and despite best efforts had a complicated hospital course.

AngioVac System Used as an Adjunct Treatment for Intra-Cardiac Lead and Valvular Vegetations.

Infections are known complications of cardiovascular implantable electronic devices (CIEDs). We describe a case of a 62-year-old male who presented with pulseless electrical activity (PEA) cardiac arrest and respiratory failure. He had a history of cardiac resynchronization device and defibrillator (CRT-D) implantation for nonischemic cardiomyopathy. After resuscitation, he was found to have methicillin sensitive Staphylococcus aureus (MSSA) bacteremia on blood culture and large vegetations on the CRT-D lead and tricuspid valve found on echocardiography. The patient underwent extraction of the leads, but several large vegetations were present adherent to the tricuspid valve on intra-cardiac ultrasound (ICE). Due to comorbidities, the patient was not a candidate for surgical removal of these vegetations. Thus, he underwent percutaneous extraction of tricuspid and right atrial vegetations with the AngioVac device.

Recurrent Ischemic Stroke: A Manifestation of a Sinus of Valsalva Pseudoaneurysm.

An 83-year-old female presented to the emergency department with bilateral eye pain, dizziness, and acute shortness of breath. Her blood pressure (BP) at presentation was 184/93 mmHg. She was admitted for hypertensive emergency and her symptoms improved with BP control. However, during hospitalization, she developed left-sided paresthesia which on investigation was found to be secondary to ischemic stroke. She had two previous aortic mechanical valve replacements for aortic stenosis. Transthoracic echocardiogram revealed a large pseudoaneurysm of the non-coronary sinus of Valsalva that we believe was the cause of her recurrent stroke. A sinus of Valsalva pseudoaneurysm is an uncommon complication of aortic valve replacement surgery which in turn has been associated with aortic rupture, myocardial infarction, and stroke. Our case identifies a situation where sinus of Valsalva pseudoaneurysm predisposed our patient to recurrent ischemic strokes and this should be kept in mind when evaluating a patient with ischemic stroke.

Patient-Centered Home Model of Care and the Role of Patient Care Teams in the Treatment and Management of Chronic Disease.

Patient-centered medical home (PCMH) is a concept of a team of providers caring for a panel of patients with the goals to improve the quality of care while simultaneously decreasing the cost of that care. The clinical evidence that the PCMH approach achieves either goal is mixed. More studies are in progress that will provide more data.

The Prediction of DLL4 as a Prognostic Biomarker in Patients with Gastric Cancer Using Anti-DLL4 Nanobody.

BACKGROUND: Angiogenesis and cancer metastasis depend on the DLL4/Notch signaling pathway. A new approach to treating angiogenesis could inhibit or block this pathway. In the present study, we investigated DLL4 expression as a biomarker capable of predicting survival outcomes in gastric cancer patients using a novel anti-DLL4 Nanobody. PATIENTS AND METHODS: By using a recently developed anti-DLL4 Nanobody, the expression of DLL4 was evaluated in tissue samples from 135 gastric cancer patients. It was evaluated whether DLL4 expression is related to clinicopathological factors, overall survival (OS), and recurrence-free survival (RFS). RESULTS: Sixty-five (48%) gastric cancer patients had a positive expression of DLL4 within the tumor tissue. Based on both the univariate and multivariate regression analyses, the expression of DLL4 was strongly associated with RFS (HR, 1.94; p = 0.008) and OS (HR, 2.06; p = 0.004). Moreover, the survival analysis demonstrated that DLL4 expression was a significant independent factor of unfavorable OS (HR, 2.7; p = 0.01) and RFS (HR, 2.3; p = 0.02) in gastric cancer patients. CONCLUSION: DLL4 expression in gastric cancer patients may predict poor prognosis and survival. Furthermore, the current data demonstrate the potential of Nanobody for detecting DLL4, and it may lead to develop novel therapies and diagnostics for tumors.

Single-Field Fundus Photography for Screening of Diabetic Retinopathy: The Prevalence and Associated Factors in a Population-Based Study.

INTRODUCTION: We aimed to determine the prevalence and risk factors for diabetic retinopathy (DR) in a multi-primary healthcare facilities-based DR screening project by analyzing single-field fundus photographs among patients with diabetes in Rafsanjan City, Iran, based on the Rafsanjan Cohort Study, as a part of the prospective epidemiological research studies in IrAN (PERSIAN). METHODS: Of all participants in the Rafsanjan Cohort Study (performed in four primary healthcare facilities across Rafsanjan City from August 2015 to December 2017), patients with diabetes were recruited in this study. All participants underwent a standardized interview and clinical and paraclinical examinations for demographic characteristics, and medical conditions according to the PERSIAN's protocols. In addition, digital fovea-centered and single-field fundus photography was performed for DR identification and grading. For assessment of agreement, a subgroup of participants underwent fundus examination, randomly. DR was graded as nonproliferative (NPDR) or proliferative (PDR). RESULTS: Of 8414 screened participants, 1889 had diabetes. The total prevalence of DR was 6.93% [131 individuals including 110 (5.82%) with NPDR, and 21 (1.11%) with PDR] based on single-field fundus photographs, with almost perfect agreement with fundus examinations (κ = 0.82). On adjusted multivariate analysis, duration of diabetes (OR 1.16, 95% CI 1.13-1.19), positive family history for diabetes (OR 1.73, 95% CI 1.09-2.75), fasting plasma glucose (FPG) ≥ 126 mg/dL (OR 1.98, 95% CI 1.16-3.39), and serum creatinine level (OR 1.79, 95% CI 1.08-2.98) were associated with DR. Factors including age, education level, physical activity, body mass index, hypertension, and cardiovascular and renal diseases did not have association with DR on adjusted multivariate analysis. CONCLUSIONS: Single-field fundus photography can be used for screening of DR in primary healthcare facilities. In individuals with diabetes, duration of diabetes, positive family history for diabetes, FPG ≥ 126 mg/dL, and serum creatinine level may be associated with DR.

Influenza Vaccine Booster Stimulates Antibody Response in Beta Thalassemia Major Patients.

The aim of this study was to evaluate antibody response against influenza vaccine in beta thalassemia major patients from Iran. Thirty beta thalassemia major patients were enrolled and divided into three groups: single dose (group 1), double dose (group 2), and control (group 3). Seroconversion, seroprotection, and geometric mean titer (GMT) assays were performed through hemagglutination inhibition (HI) on days 0, 14, and 60. Based on the results, the level of antibody titer was increased in group 2. Two weeks after vaccination, seroconversion rate was about 20% and 30% in groups 1 and 2. Sixty days after vaccination, the seroconversion rate was around 70% and GMT showed a more than 2-fold increase in group 2. Based on the results, the immunogenicity of double dose vaccination against influenza infection appears to be higher than the single dose vaccine in beta thalassemia major patients, and thus it is recommended to use two doses of vaccine, especially in splenectomized patients who are more sensitive than others.

Immunomodulatory Effects of Human Adipose Tissue-derived Mesenchymal Stem Cells on T Cell Subsets in Patients with Rheumatoid Arthritis.

Adipose-derived mesenchymal stem cells (Ad-MSCs) have been reported to suppress the effector T cell responses and have beneficial effects on various immune disorders, like rheumatoid arthritis (RA). This study was designed to investigate the effects of co-cultured Ad-MSCs on peripheral blood mononuclear cells (PBMCs) of RA patients and healthy individuals, through assessing transcription factors of T cell subsets. PBMCs from RA patients and healthy donors were co-cultured with Ad-MSCs with or without Phytohaemagglutinin (PHA). The quantitative real-time polymerase chain reaction (qRT-PCR) was used to measure the expression of T-box 21 (T-bet), GATA-binding protein-3 (GATA3), retinoid-related orphan receptor Î³t (ROR-γt) and forkhead box P3 (Foxp3). Based on the results, Ad-MSCs greatly upregulated Th2 and Treg cell transcription factors, i.e., GATA3 and Foxp3 (p<0.05), and downregulated Th1 and Th17 transcription factors, i.e., T-bet and RORγt (p<0.05). These results demonstrate that Ad-MSCs can result in an immunosuppressive environment through inhibition of pro-inflammatory T cells and induction of T cells with a regulatory phenotype. Therefore, they might have important clinical implications for inflammatory and autoimmune diseases such as RA.

The Association between the Pulmonary Arterial Obstruction Index and Atrial Size in Patients with Acute Pulmonary Embolism.

PURPOSE: Pulmonary embolism (PE) is a common and potentially fatal form of venous thromboembolism. The aim of this study is to investigate the association between the pulmonary arterial obstruction index and atrial size in patients with acute pulmonary embolism. BASIC PROCEDURE: The study consisted of 86 patients with clinical symptoms of PE. Out of 86 individuals, 50 patients were diagnosed with PE and considered as the patient group. The others were considered as the control group. All patients were scanned by a multidetector CT scanner. Using the radiology workstation, an expert radiologist calculated the left atrium (LA) and right atrium (RA) areas from planimetric measurements obtained from free-hand delineation of the atrial boarders using an electronic pen. Quantitative volumetric measurements of LA and RA were obtained from original axial images. MAIN FINDINGS: There were 25 males and 25 females with PE, who had a mean age of 58 years. There was not a significant difference in the positive history of diabetes mellitus, hypertension, asthma, chronic obstructive pulmonary diseases, ischemic heart disease, and smoking between patients and control group. There was a significant negative correlation between almost all LA measurements and the PAOI. RA area and volume had the highest area under the curves for recognizing larger clot burden. PRINCIPAL CONCLUSIONS: A higher clot load is associated with a smaller LA size and increased RA/LA ratios, measured with CTPA. Atrial measurements are correlated with POAI, and they could be used as sensitive parameters in predicting heart failure in patients with PE.

A novel and innovative hair test to determine glucocorticoid levels in racing camels for use in assessment of doping, health, and disease.

The aim of this project was to develop and validate a new test for the analysis of glucocorticoids in camel hair and to use the new test to analyse hair samples from a variety of camel breeds in sports and racing applications. These findings could be of importance when evaluating racing camels for suspected doping offenses or for injury and disease control. Camel hair samples were collected from 30 non-racing dromedary camels along with 3 racing camels in Al Ain, UAE and were decontaminated, pulverised, sonicated, and extracted prior to analysis. A liquid chromatographic-mass spectrometric method was employed to determine the levels of glucocorticoids in the hair samples. The 4 drugs of interest, namely hydrocortisone, dexamethasone, flumethasone and methylprednisolone, and an internal standard were quantified in camel hair samples. All 4 of the glucocorticoids were detected in camel hair samples with concentrations ranging between 31 and 935 pg/mg for hydrocortisone, 8-59 pg/mg for dexamethasone, 0.7-1034 pg/mg for flumethasone and 5-66 pg/mg for methylprednisolone in non-racing camels. One of the racing camels displayed high concentrations of hydrocortisone (1130 pg/mg), flumethasone (2576 pg/mg), methylprednisone (1156 pg/mg) and dexamethasone (29 pg/mg). The authors believe this is the first report of a test for corticosteroids in camel hair. The new test has been validated according to Food and Drug Administration (FDA) guidelines. This new hair test could be useful for further studies in doping control, toxicological studies, pharmacological studies and other clinical applications in camel health, injury, and disease.

Meta-Analysis Comparing Catheter-Guided Ablation Versus Conventional Medical Therapy for Patients With Atrial Fibrillation and Heart Failure With Reduced Ejection Fraction.

The prognostic benefit of catheter ablation (CA) for atrial fibrillation in the setting of heart failure (HF) with reduced ejection fraction (EF) is unclear. A systematic search of medical literature was limited to randomized controlled trials. The primary outcome was all-cause mortality, and secondary outcomes were HF hospitalizations, stroke, left ventricular EF improvement, change in 6-minute walk test, and change in Minnesota living with HF questionnaire (Δ MLHFQ). Random effects risk ratios (RR) were calculated for categorical outcomes and standardized mean differences (SMD) for continuous ones, using Der-Simonian and Liard model. A total of 775 ambulatory patients from 6 trials were included. The mean EF was 31% with a mean New York Heart Association classification class 2.5. At a mean follow-up of 26 months, CA was associated with lower incidences of all-cause mortality (RR 0.50, 95% confidence intervals [CI] 0.34 to 0.74, I2 = 0%, p <0.0001), and HF hospitalizations (RR 0.58, 95% CI 0.41 to 0.81, p = 0.002, I2 = 0%), with similar incidences of stroke. Left ventricular EF improvement (SMD = 2.58, 95% CI 0.88 to 4.27), and change in Minnesota living with heart failure HF questionnaire (SMD = -0.40, 95% CI -0.65 to -0.14) were also in favor of CA, with no difference noted in change in 6-minute walk test. The incidence of all reported procedural complications (including major and minor) was 7.3%. In conclusion, CA of atrial fibrillation appears to be associated with improved survival and HF hospitalizations compared with medical therapy, with evidence of low ablation-related complications.

The "Chimney Sweep Technique" and Recurrent Coronary Artery Dissections.

We are reporting a case of a 65-year-old female who experienced three ST elevation myocardial infarctions (STEMI) during the course of 3 weeks. The first infarct was related to intramural coronary hematoma that propagated proximally after stenting, the second involved progression of this hematoma with obstruction of the vessel lumen, and the third caused subacute stent thrombosis that required "stent cleaning" using the inflated balloon technique.

Chromogenic in situ Hybridization Compared with Real time Quantitative Polymerase Chain Reaction to Evaluate HER2/neu Status in Breast Cancer.

BACKGROUND AND OBJECTIVE: The assessment of human epidermal growth factor receptor 2 (HER2) status has become of great importance in the diagnosis of breast cancer. The aim of this study was to investigate the diagnostic value of quantitative Polymerase Chain Reaction (qPCR) and Chromogenic In Situ Hybridization (CISH) to assess HER2 status of biopsy specimens. METHODS: To elucidate the status of HER2 gene amplification, biopsies of breast carcinoma from 120 patients with 2+ IHC status were analyzed by qPCR and CISH. RESULTS: The results of the two experiments were compared, and it was depicted that the concordance rate between CISH and qPCR assays was 88.1%.The quantification of HER2 gene with CISH and qPCR showed that there was a significant correlation (p value= 0.0001 and r= 0.808). CONCLUSION: The results of this research support the idea that qPCR is a precise and reproducible technique, which can be employed as a supplementary method to evaluate HER2 status.

Prevalence of Post-Traumatic Stress Disorder Due to Community Violence Among University Students in the World's Most Dangerous Megacity: A Cross-Sectional Study From Pakistan.

Community violence among the youth can lead to a number of adverse psychiatric outcomes including post-traumatic stress disorder (PTSD). However, little research has been conducted in non-Western countries to assess this problem. This study aims to fill the void by assessing the lifetime exposure to traumatic events and burden of probable PTSD among university students in Karachi, Pakistan. A cross-sectional study was conducted at four private institutions in Karachi. Self-administered questionnaires were filled out by 320 students. Lifetime exposure and symptoms of PTSD were assessed using modified Composite International Diagnostic Interview (CIDI) and Post-Traumatic Stress Disorder Checklist-Civilian Version (PCL-C) questionnaires, respectively. A PCL-C score of 44 or above was used as cutoff for probable PTSD. Pearson chi-square test was used to assess the association between PTSD and different variables at a level of significance of 5%. Ninety-three percent of the respondents reported having lifetime exposure to at least one traumatic event with sudden unexpected death of a loved one (n = 187) and assaultive violence (n = 169) being the commonest reported traumatic events. Positive association for PTSD was seen with enduring physical attacks and motor vehicle accidents. Over a quarter of the students screened positive for probable PTSD, among them almost one third were male and 17% were female. Our results indicate a high exposure to violent events and elevated rates of lifetime PTSD among urban youth. Reduction in violence and better access to mental health facilities is warranted to decrease the health burden of PTSD in Pakistan.

Outcome of coronary artery bypass grafting in a tertiary-care center in Pakistan.

BACKGROUND: Coronary artery bypass grafting and percutaneous coronary intervention are revascularization options for significant coronary artery disease. While international data support the use of coronary artery bypass in high-risk groups, regional data on outcomes in these groups are rare. We conducted a retrospective study to determine the outcomes of patients undergoing coronary artery bypass for left main and multivessel disease. METHODS: Two thousand eight hundred and fifty-one patients undergoing coronary artery bypass at the Aga Khan University Hospital from 2006 to 2013 were included; patients undergoing redo surgery were excluded. Demographic data, comorbidities, angiography findings, in-hospital complications, one-month and one-year follow-up were analyzed. RESULTS: Of the 2851 patients, 568 had left main disease (group 1) and 2283 (group 2) had multivessel disease (≥2 vessels excluding the left main). Group 1 had significantly more chronic lung disease, cardiogenic shock, and congestive heart failure than group 2 (p < 0.001); 50.6% of patients were diabetic and 71.8% were hypertensive. Mortality was 5.1% and 2.2% during hospital stay, 6.5% and 2.6% at 30 days, and 6.7% and 2.7% at 1 year in groups 1 and 2, respectively. CONCLUSION: Our comparable results and international data advocate revision of the current practice of using percutaneous coronary intervention over coronary artery bypass in the developing world. Institutional results are essential to determine the outcome of coronary artery bypass in high-risk populations with a high burden of diabetes and hypertension. We noted increased complications and mortality in patients with left main rather than multivessel disease.