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Focal amplification of specific regions of the genome creates high copy number and expression of oncogenes in tumors. By applying fluorescence in situ hybridization (FISH) to leukocytes of hepatitis C (HCV) patients and non-Hodgkin lymphoma (NHL) patients, we estimated gene dosage of the TERC gene at 3q26.3. Higher TERC copy numbers were found in NHL at diagnosis compared to HCV patient groups. Higher TERC copy numbers were also observed in NHL patient at diagnosis and relapse compared to patients in remission. We believe that the TERC gene amplification is involved in the process of genetic instability leading to tumor genesis such as in NHL. [ABSTRACT FROM AUTHOR]

Aseptic abscess syndrome is a rare clinical entity mainly associated with systemic inflammatory conditions, particularly inflammatory bowel disease. The syndrome is characterized by an inflammatory infiltrate predominantly consisting of neutrophils, most commonly in the liver and spleen. We present a case of a patient with symptomatic diversion colitis diagnosed with a clinical and histological presentation consistent with aseptic abscess syndrome of the liver. Treatment and resolution of the inflamed colon was associated with complete disappearance of the liver lesions and normalization of liver enzymes. To the best of our knowledge, this is the first report suggesting the unique link between diversion colitis and aseptic liver abscess., (© 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.)

Coronavirus disease (COVID-19) is highly transmissible between human beings. We examined differences in the core families with COVID-19 severity and mortality and comorbidities between Arab and Jews and explored the factors associated with COVID-19 severity and mortality to find a genetic component. A cross-sectional study was conducted among 2240 COVID-19 patients (> 18 years of age) randomly selected by online panels and questionnaires in the native language (Hebrew or Arabic) during March 2021-June 2022. Multivariable linear regression models were used to assess correlations with COVID-19 disease severity and mortality. Overall, 1549 (69%) were Arabs and 691 (31%) were Jews. The proportion of participants who died from COVID-19 was higher among Arabs compared with Jews (66% vs. 59%), P < 0.001. The mean number of deaths from COVID-19 and patients with severe COVID-19 was higher in ultra-Orthodox Jewish, non-academic core families and those who lived in the city residence compared with secular, academic core families and who live in the village residence, P < 0.001. A multivariable linear regression model showed a significant association between metabolic, kidney, cardiovascular, and respiratory diseases with COVID-19 severity (B coefficient - 0.43, B coefficient - 0.53, B coefficient - 0.53, B coefficient - 0.42, respectively) and COVID-19 mortality (B coefficient - 0.51, B coefficient - 0.64, B coefficient - 0.67, B coefficient - 0.34, respectively), P < 0.001. COVID-19 severity and mortality were highly associated with comorbidities, ethnicity, social and environmental factors. Furthermore, we believe that genetic factors also contribute to the increase in COVID-19 severity and mortality and the differences rates of these between Arabs and Jews in Israel., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Chronic kidney disease is associated with an increased risk for cardiovascular and bleeding events. Data regarding the effectiveness and risks of aspirin therapy for primary prevention in the high-risk group of patients with chronic kidney disease are scant and controversial. This retrospective study included patients with chronic kidney disease. Participants were divided according to aspirin use. Outcomes included non-fatal cardiovascular events, major bleeding events and all-cause mortality. Among 10,303 patients, 2169 met the inclusion criteria and 1818 were included after 1:1 propensity-score matching. Our final cohort included patients with mean age of 73.4 ± 11.6 years, estimated glomerular filtration rate of 31.5 ± 10.5 ml/min/1.73m 2 with follow up of 4.9 ± 1.5 years. There were no significant differences in all-cause mortality and bleeding events (odds ratio = 1.03, confidence interval [0.62, 1.84], p = .58 and odds ratio = 1.09, confidence interval [0.65, 1.72], p = .87 respectively). The incidence of cardiovascular events was higher in aspirin users versus non-users on univariate analysis (p < 0.01) and was comparable after controlling for possible risk-factors (OR = 1.05, CI [0.61, 3.14], p = .85). Chronic aspirin use for primary prevention of cardiovascular disease was not associated with lower mortality, cardiovascular events or increased bleeding among patients with chronic kidney disease. Those results were unexpected and should prompt further research in this field., (© 2022. The Author(s).)

The CHA 2 DS 2 -VASc score incorporates several comorbidities which have prognostic implications in COVID-19. We assessed whether a modified score (M-R 2 CHA 2 DS 2 -VASc), which includes pre-admission kidney function and male sex, could be used to classify mortality risk among people hospitalized with COVID-19. This retrospective study included adults admitted for COVID-19 between March and December 2020. Pre-admission glomerular filtration rate (GFR) was calculated based on serum creatinine and used for scoring M-R 2 CHA 2 DS 2 -VASc. Participants were categorized according to the M-R 2 CHA 2 DS 2 -VASc categories as 0-1 (low), 2-3 (intermediate), or ≥ 4 (high), and according to initial COVID-19 severity score. The primary outcome was 30-day mortality rates. Secondary outcomes were mortality rates over time, and rates of mechanical ventilation, hemodynamic support, and renal replacement therapy. Eight hundred hospitalizations met the study criteria. Participants were 55% males, average age was 65.2 ± 17 years. There were similar proportions of subjects across the M-R 2 CHA 2 DS 2 -VASc categories. 30-day mortality was higher in those in higher M-R 2 CHA 2 DS 2 -VASc category and with severe or critical COVID-19 at admission. Subjects in the low, intermediate, and high M-R 2 CHA 2 DS 2 -VASc categories had 30-day mortality rates of 4.7%, 17% and 31%, respectively (p < 0.001). Higher category was also associated with increased need for mechanical ventilation and renal replacement therapy. All-cause 90-day mortality remained significantly associated with M-R 2 CHA 2 DS 2 -VASc. The M-R 2 CHA 2 DS 2 -VASc score is associated with 30-day mortality rates among patients hospitalized with COVID-19, and adds predictive value when combined with initial COVID-19 severity., (© 2022. The Author(s), under exclusive licence to Società Italiana di Medicina Interna (SIMI).)

Introduction: While there is evidence of the presence of the coronavirus in the kidneys and resultant acute kidney injury (AKI), information on the effect of chronic kidney disease (CKD) on COVID-19 outcomes and its pathogenesis is currently lacking., Methods: This retrospective, observational study evaluated the outcomes of all consecutive patients hospitalized during COVID-19 outbreaks in Meir Medical Center. Serum creatinine level was assessed before hospitalization ("baseline serum creatinine") and at admission, as well as minimum and maximum serum creatinine levels during hospitalization., Results: Among 658 patients, 152 had eGFR < 60 ml/min (termed the CKD group), 506 patients served as controls. Patients in the CKD group were older, with higher prevalence of hypertension, diabetes mellitus and atherosclerosis. Disease severity and clinical presentation of CKD group were comparable to that of control group. Odds ratio for AKI was 5.8 (95%CI 3.8-8.7; p < 0.001) in CKD group vs. control group and 3.4 (95%CI 1.1-10.8) for renal replacement therapy (p < 0.026). Among the CKD group, 32.2% died after COVID-19 infection versus 14.8% of the controls (p < 0.001). Mortality increased as CKD stage increased (14.8% in controls, 29.6% in CKD stage 3, and 39.3% in CKD stages 4 and 5, p < 0.001)., Conclusion: Despite comparable disease severity at presentation, patients with CKD had significantly more AKI events and required more renal replacement therapy during hospitalization than control patients did. Mortality increased as CKD stage increased., (© 2022. The Author(s), under exclusive licence to The Japanese Society of Nephrology.)

Background: Chest-pain patients with no evidence of acute coronary syndrome might still be at risk for adverse outcomes. Adding renal function to the classic scoring of CHADS and CHA 2 DS 2 VASC may improve risk stratification of chest-pain patients discharged from internal medicine wards after acute coronary syndrome (ACS) rule-out., Methods: We accessed medical records of patients admitted to internal medicine wards during 2010-2016 and discharged following ACS rule-out. A R 2 CHA 2 DS 2 -VASc score model that included higher scores as kidney function deteriorated was calculated and compared to CHADS and CHA 2 DS 2 VASC scores. The primary endpoint was the composite of 30-day ACS and mortality. One-year ACS and 1-year mortality were the secondary endpoints. The study included 12,449 patients, stratified into three risk groups according to their R 2 CHA 2 DS 2 -VASc score., Results: Participants were stratified into 3 groups according to R 2 CHA 2 DS 2 -VASc score. R 2 CHA 2 DS 2 -VASc score predicted better the composite outcome of ACS and 30-day and 1-year mortality after discharge (OR: 4, 95%, CI 2.3-7, p < 0.01 and OR: 13.3, 95% CI 7.8-22.7, p < 0.01, respectively). Receiver operating characteristic curve analysis showed better risk stratification of the R 2 CHA 2 DS 2 -VASc compared with both CHADS and CHA 2 DS 2 VASC score., Conclusions: The R 2 CHA 2 DS 2 -VASc score is a better predictor of short- and long-term cardiovascular morbidity and mortality after hospital discharge., (Copyright © 2020. Published by Elsevier Ltd.)

Background: Calcium deposits on heart valves are considered a local manifestation of atherosclerosis and are associated with poor cardiovascular outcomes. The clinical significance of cardiac calcifications among heart failure (HF) patients, as assessed by echocardiography, is unknown. This study evaluated associations of cardiac calcifications with mortality and hospital admissions in this specific population., Methods: Medical records of all patients who initiated ambulatory surveillance at our HF clinic during 2011-2018 were reviewed. Calcifications in the aortic valve, aortic root, or the mitral valve were evaluated. Patients with moderate to severe regurgitation or stenosis of the aortic or mitral valves were excluded. The primary endpoint was the composite of long-term all-cause mortality and HF hospitalizations. Secondary endpoints were long-term all-cause mortality and more than one hospitalization due to HF., Results: This retrospective study included 814 patients (mean age 70.9 ± 13 years, 63.2% male). Of the total cohort, 350 (43%) had no cardiac calcifications and 464 (57%) had at least 1 calcified site. Considering the patients with no calcification as the reference group yielded a higher adjusted odds ratios for the composite endpoint, all-cause death, and recurrent HF hospitalizations, among patients with any cardiac calcification (OR = 1.68, 95%CI = 1.1-2.5, p = 0.01, OR=1.61, 95%CI = 1.1-2.3, p < 0.01, and OR = 1.50, 95%CI = 1.1-2.2, p < 0.01, respectively)., Conclusions: We found an independent association between cardiac calcifications and the risk of death and HF hospitalizations among ambulatory HF patients. Cardiac calcifications evaluated during routine echocardiography may contribute to the risk stratification of patients with HF., (Copyright © 2020. Published by Elsevier Ltd.)

Background: Hyponatremia is the most common electrolyte abnormality observed in clinical practice. Among patients with acute coronary syndrome (ACS), serum sodium levels are inversely associated with mortality risk. We assessed associations of serum sodium level with ACS and mortality in patients with chest pain., Methods: This retrospective cohort study used clinical data from a large, academic hospital. All adults admitted with chest pain and without hypernatremia and discharged after ACS rule-out from January 2010 through June 2016 were included. The primary endpoint was the composite of 30-day ACS and mortality. Secondary endpoints were a hospital admission due to ACS and mortality in the first year following discharge., Results: Included were 12 315 patients (mean age 58.2 ± 13 years, 60% male). Patients were classified according to the serum sodium (Na) level: hyponatremia, defined as less than 135 mEq/L (n = 289, 2.3%); 140 > Na ≥ 135 mEq/L (n = 8066, 65.5%), and 145 > Na ≥ 140 mEq/L (n = 3960, 32.2%). Patients with serum sodium more than 145 mEq/L were excluded. Among patients with hyponatremia, low-normal, and high-normal levels, rates of the composite outcome of unadjusted 30-day all-cause mortality and ACS admission were 4.5, 1.0, and 0.7%, respectively (P < 0.001). Unadjusted one-year ACS rates were 3.8, 1.5, and 1.4%, respectively (P < 0.01)., Conclusion: Hyponatremia is associated with higher mortality and ACS risk among patients with chest pain who were discharged from internal medicine wards following ACS-rule-out. Sodium level may be included in the risk stratification of patients with chest pain.

Background: Red blood cell distribution width (RDW) is a measure of the degree of heterogeneity of erythrocyte volume. Higher RDW levels are associated with increased mortality among patients with acute coronary syndrome (ACS), heart failure and other cardiovascular diseases. The association between RDW levels and clinical outcomes in patients admitted for further evaluation of chest pain is not known. Methods: A retrospective analysis of patients hospitalised with chest pain 2010-2016 was conducted. Patients diagnosed with ACS in the emergency department (ED) were excluded. Patients were divided into tertiles according to baseline ED RDW levels (≤13.1%, 13.1%13.9%). Study endpoints were diagnosis of ACS during the index hospitalisation and ACS and all-cause mortality during a median follow-up of 3.3 ± 1.9 years. Results: Included were 13,018 patients (mean age 58 ± 13 years, 61% male). Increased RDW levels were associated with higher rates of ACS in the index hospitalisation (6.1%, 6.6% and 8.1% for 1st, 2nd and 3rd tertiles, respectively, p  < .01), ACS during follow-up (8.6%, 10.1% and 13.4%, respectively, p  < .01), and with all-cause mortality during follow-up (2.5%, 4.6% and 15.4%, respectively, p  < .01). In multivariate analysis, RDW levels >13.9% (vs. ≤13.1%) were associated with ACS in the index hospitalisation (adjusted OR 1.25, 95% CI 1.04-1.51, p  = .02), ACS during follow-up (adjusted OR 1.35, 95% CI 1.05-1.73, p  = .02) and with all-cause mortality (adjusted HR 2.41, 95% CI 1.94-2.99, p  < .01). Conclusion: In this retrospective study of patients hospitalised with chest pain, higher RDW levels were associated with future ACS and long-term mortality.

Background: Currently, there are no clinical scores for risk stratification of low-risk patients with chest pain. We aimed to examine the association between mean platelet volume (MPV) and risk for adverse clinical outcomes in patients with chest pain discharged from internal medicine wards following acute coronary syndrome (ACS) rule-out., Patients and Methods: Included were patients who were admitted to internal medicine wards and were discharged following an ACS-rule-out during 2010-2016. The primary endpoint was the composite of all-cause mortality and hospital admission due to ACS at 30-days following hospital discharge., Results: Included in the study were12 440 patients who were divided into three groups according to MPV. The composite endpoint of 30-day all-cause mortality and hospital admission for ACS occurred more frequently among patients with high MPV. Each one-point increase in MPV was associated with an 18% increase in the risk for the composite endpoint (P = 0.02). Considering patients with MPV less than 7.8 fl as the reference group yielded adjusted hazard ratios for the composite endpoint that was significantly higher in patients in the high MPV tertile ( > 8.8 fl) (hazard ratio 1.6; 95% confidence interval = 1.1-2.5; P = 0.04). Each one-point increase in MPV was associated with an 11% increase in the risk for 1-year all-cause mortality (P = 0.01) and a 10% increase in the risk for 1-year ACS (P = 0.04)., Conclusion: We found an independent association between high MPV and the risk of death and ACS among patients with chest pain who were discharged from internal medicine wards following an ACS-rule-out. MPV may be combined in the risk stratification of patients with chest pain.

Background: Iodinated contrast media (ICM) allergy may entail severe adverse events in patients who undergo percutaneous coronary intervention (PCI). Premedication protocols and low-osmolality contrast media have been thought to improve the outcomes of these individuals., Objective: The objective of this study was to assess the prevalence and severity of allergic reactions during PCI in patients admitted for investigation of chest pain., Methods: This is a retrospective analysis of 13,652 patients who were hospitalized with chest pain during the years 2010-2016, at the Department of Internal Medicine, Meir Medical Center. Patient records were screened for diagnosis of prior ICM allergy. Primary outcomes were: (1) records of previous allergy to ICM, (2) administration of antiallergic premedication, and (3) allergic reactions to the ICM during the procedure., Results: Nine hundred thirty-one individuals without prior ICM allergy were referred for PCI, of whom 2 had minor allergic reactions. Previously diagnosed ICM allergy was recorded for 216 subjects (mean age 65.5 ± 10 years, 42% males). Of these, 32 were referred to in-hospital PCI. Premedication was administered in 10 cases only with no documented rationale for not treating the other 22. Only one of the pretreated patients experienced a reaction attributed to allergy, showing no statistical advantage for premedication. No mortality was documented in the 30 days after PCI among the patients with known ICM allergy., Conclusions: PCI did not induce substantial allergic reactions to ICM in patients with a previously diagnosed allergy. This study did not demonstrate an advantage for premedication., (Copyright © 2018 American Academy of Allergy, Asthma & Immunology. All rights reserved.)

Background: Magnesium is an essential intracellular cation. Magnesium deficiency is common in the general population and its prevalence among patients with cirrhosis is even higher. Correlation between serum levels and total body content is poor because most magnesium is intracellular. Minimal hepatic encephalopathy is a subclinical phase of hepatic encephalopathy with no overt symptoms. Cognitive exams can reveal minor changes in coordination, attention, and visuomotor function, whereas language and verbal intelligence are usually relatively spared., Objectives: To assess the correlation between intracellular and serum magnesium levels and minimal hepatic encephalopathy., Methods: Outpatients with a diagnosis of compensated liver cirrhosis were enrolled in this randomized, double-blinded study. Patients were recruited for the study from November 2013 to January 2014, and were randomly assigned to a control (placebo) or an interventional (treated with magnesium oxide) group. Serum and intracellular magnesium levels were measured at enrollment and at the end of the study. Cognitive function was assessed by a specialized occupational therapist., Results: Forty-two patients met the inclusion criteria, 29 of whom were included in this study. Among these, 83% had abnormal cognitive exam results compatible with minimal hepatic encephalopathy. While only 10% had hypomagnesemia, 33.3% had low levels of intracellular magnesium. Initial intracellular and serum magnesium levels positively correlated with cognitive performance., Conclusions: Magnesium deficiency is common among patients with compensated liver cirrhosis. We found an association between magnesium deficiency and impairment in several cognitive function tests. This finding suggests involvement of magnesium in the pathophysiology of minimal hepatic encephalopathy.

Background: Assessment of chest pain is one of the most common reasons for hospital admissions in internal medicine wards. However, little is known regarding predictors for poor prognosis in patients discharged from internal medicine wards after acute coronary syndrome (ACS) rule-out., Objective: To assess the association of kidney function with mortality and hospital admissions due to ACS in patients with chest pain who were discharged from internal medicine wards following ACS rule-out., Methods: Included were patients admitted to an internal medicine ward who were subsequently discharged following an ACSrule-out during 2010-2016. The primary endpoint was the composite of all-cause mortality and hospital admission due to ACS at 30-days following hospital discharge., Results: Included in the study were12,337 patients who were divided into 3 groups according to renal function. Considering patients with an eGFR ≥ 60 ml/min/1.73m 2 as the reference group yielded adjusted hazard ratios for the composite of 30-day all-cause mortality and hospital admission for ACS that increased with reduced eGFR (HR = 2, 95%CI = 1.3-3.3, HR = 4.8, 95%CI = 3-7.6, for patients with eGFR of 45 to 59.9 or <45 ml/min/1.73m 2 , respectively, p < 0.001). Similarly, reduced renal function was associated with increased 1-year all-cause mortality (HR = 1.6, 95%CI = 1.2-2.2, HR = 4.5, 95%CI = 3.4-5.9, for patients with eGFR of 45-59.9 or <45 ml/min/1.73m 2 , respectively, p < 0.001)., Conclusion: We found an independent graded association between lower eGFR and the risk of death and ACS among patients with chest pain who were discharged from internal medicine wards following an ACS rule-out. The eGFR may be combined in the risk stratification of patients with chest pain., (Copyright © 2018. Published by Elsevier B.V.)

Background: Shortened telomeres were found in patients with cirrhosis, probably reflecting chronic liver injury, continuous regeneration, and destruction of hepatic nodules., Objectives: To test whether telomere shortening is a general marker of cirrhosis, independent of disease etiology., Methods: We evaluated telomere length in patients with cryptogenic cirrhosis (largely a late sequela of steatohepatitis) compared to patients with cirrhosis caused by chronic hepatitis B and C (HBV/HCV). We also evaluated telomere aggregates, a sensitive parameter of telomere dysfunction and genetic instability. We analyzed peripheral lymphocytes from 25 patients with cryptogenic cirrhosis, 15 patients with cirrhosis due to chronic viral hepatitis, and 20 age-matched controls. Telomere length was analyzed using quantitative fluorescence in situ hybridization. Aggregate size was divided into three fusion groups of 2-5, 6-10, and 11-15 telomeres, relative to the size of a single telomere., Results: Shorter telomere length was found in patients with cirrhosis from all three etiologies (mean 121.3 ± 24.1) compared to controls (mean 63.5 ± 23.5). In contrast, there was significantly more fusion of > 5 telomeres only in the HBV/HCV cirrhosis group compared to healthy controls (P = 0.023), but not in the cryptogenic cirrhosis group., Conclusions: While shortened telomeres in peripheral lymphocytes are a general marker of liver cirrhosis, telomere aggregates may signify a more sensitive genetic instability parameter for the diverse, etiology-based malignant potential of cirrhosis. This finding is in agreement with the well-known higher tendency toward developing hepatocellular carcinoma with cirrhosis caused by chronic hepatitis relative to steatohepatitis.

Background: Chest-pain patients deemed safe for discharge from internal medicine wards might still be at risk for adverse outcomes., Hypothesis: CHA 2 DS 2 -VASc score improves risk stratification of low-risk chest-pain patients discharged after acute coronary syndrome (ACS) rule-out., Methods: We accessed medical records of patients who were admitted to internal medicine wards at a single medical center during 2010-2016 and discharged following an ACS rule-out. Patients were classified according to CHA 2 DS 2 -VASc score: 0-1 (low), 2-3 (intermediate), >3 (high). Primary endpoint was occurrence of ACS at 1 year; 30-day and 1-year all-cause mortality (ACM) were secondary outcomes., Results: Of 12 449 patients, 7057 (57%) had low, 3781 (30%) intermediate, and 1611 (13%) high CHA 2 DS 2 -VASc scores. Compared with a low score, intermediate and high scores were associated with significantly increased risk for 1-year ACS during the first year (OR: 2.89, 95% CI: 1.91-4.37, P < 0.01 and OR: 4.84, 95% CI: 3.02-7.74, P < 0.01, respectively). Each 1-point increase in CHA 2 DS 2 -VASc was associated with a 37% increased risk for 1-year ACS. A higher CHA 2 DS 2 -VASc score was associated with significantly higher 30-day ACM. Hazard ratios for 30-day ACM were 1.9 (95% CI: 1.1-3.4, P = 0.03) and 4.4 (95% CI: 2.4-7.9, P < 0.01) for intermediate and high CHA 2 DS 2 -VASc scores, respectively, compared with a low score. Each 1-point increase in CHA 2 DS 2 -VASc score was associated with 43% increased risk for 30-day mortality., Conclusions: High CHA 2 DS 2 -VASc score (>3) was associated with adverse outcomes among chest-pain patients discharged from internal medicine wards following ACS rule-out., (© 2018 Wiley Periodicals, Inc.)

Purpose: To examine an association between red blood cell distribution width (RDW) and the prognosis of influenza patients., Methods: We conducted a retrospective analysis of patients hospitalized with influenza during 2012-2015 in the internal medicine wards of one medical center. RDW measurements during hospitalization were analyzed. Primary outcome was complicated hospitalization (defined as at least one of: length of stay ≥7days, need for mechanical ventilation, septic shock, transfer to intensive-care, or 30-day mortality). Secondary outcome was 30-day mortality., Results: 153 patients were included, mean age: 62.5±1, 82 (54%) male; 84 (55%) had a high RDW value (>14.5%) during hospitalization. Patients with high and low RDW (≤14.5%) had similar age and comorbidity profiles, but those with high RDW had lower hemoglobin and higher creatinine levels. Patients with high RDW had a higher rate of complicated hospitalization (32.5% vs. 10.3%, p<0.01) and a trend for increased 30-day mortality. In a multivariate regression model, high RDW was a predictor of complicated hospitalization (OR 5.03, 95% CI 1.81-13.93, p<0.01). Each 1-point increase in RDW was associated with a 29% increase in the risk for the primary outcome., Conclusion: RDW>14.5% was a predictor of severe hospital complications in patients with influenza., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: The CHA2DS2-VASc score has been recommended for the assessment of thromboembolic risk in patients with atrial fibrillation. Data regarding the association between the pre-admission CHA2DS2-VASc score and the outcome of patients with stroke and TIA are scarce. We aimed to assess the predictive value of pre-admission CHA2DS2-VASc score for early risk stratification of patients with acute cerebrovascular event., Methods: The study group consisted of 8309 patients (53% males, mean age of 70±13.3years) with acute stroke and TIA included in the prospective National Acute Stroke Israeli (NASIS) registry. The two-primary end-points were in-hospital mortality and severe disability at discharge. We divided the study population into 4 groups according to their pre-admission CHA2DS2-VASc score (0-1, 2-3, 4-5, >5)., Results: Following a multivariate analysis odds ratios (OR) for all-cause mortality increased for CHA2DS2-VASc score >1 (OR=2.1 95% CI=1.2-3.6, OR=1.8 95% CI=1.1-3.2, OR=1.8 95% CI 1.1-3.3, for patients with CHA2DS2-VASc score of 2-3, 4-5 and >5, respectively, p<0.001). OR for severe disability (mRS 4-5) at discharge increased significantly in direct association with the CHA2DS2-VASc score (OR=1.55 95% CI=1.14-2.12, OR=2.42 95% CI=1.8-3.3, OR=3 95% CI 2.19-4.27, for patients with CHA2DS2-VASc score of 2-3, 4-5 and >5, respectively as compared with 0-1, p<0.001). Each 1-point increase in the CHA2DS2-VASc score was associated with a 21% increase in the risk for severe disability., Conclusions: High-risk pre-admission CHA2DS2-VASc score among patients with acute cerebrovascular events is associated with higher in-hospital mortality and severe disability at discharge., (Copyright © 2017. Published by Elsevier B.V.)

Competing Interests: Conflict of Interest: The authors declared no conflicts of interest with respect to the authorship and/or publication of this article.

Background: Direct-acting antiviral (DAA) treatment regimens and response rates of patients with HCV genotype-1 (GT1) are currently considered subtype-dependent. Identification of clinically relevant resistance-associated substitutions (RASs) in the NS3 and NS5A proteins at baseline and in DAA failures, may also impact clinical decisions., Methods: In a multicentre cohort study (n=308), NS3 or NS5B sequencing (n=248) was used to discriminate between GT1 subtypes. The correlation between baseline NS3 and NS5A RASs on the 12-week sustained virological response (SVR12) rates of 160 of the patients treated with second-generation DAAs was also assessed. Post-treatment resistance analysis was performed on samples from 58 patients exhibiting DAA virological failure., Results: GT1a, GT1b and GT1d subtypes were identified in 23.0%, 75.4% and 1.2% of tested samples. GT1b was most prevalent (97.7%, 128/131) among patients born in the former Soviet Union. The Q80K NS3 RAS was identified in 17.5% (10/57) of the GT1a carriers, most of whom were Israeli-born. NS3 and NS5A baseline RASs showed a negligible correlation with SVR12 rates. Treatment-emergent RASs were observed among 8.9% (4/45) and 76.9% (10/13) of first- and second-generation DAA failures, respectively, with D168V/E (NS3), Y93H and L31M (NS5A) being the most prevalent mutations., Conclusions: NS3 sequencing analysis can successfully discriminate between GT1 subtypes and identify NS3 amino acid substitutions. While pre-treatment NS3 and NS5A RASs marginally affect second-generation DAA SVR12 rates, post-treatment resistance analysis should be considered prior to re-therapy.

Background/aims: Non-alcoholic fatty liver disease (NAFLD) and cryptogenic cirrhosis (CC), which is largely a late sequela of NAFLD, are considered pre-neoplastic conditions that might progress to hepatocellular carcinoma. Aneuploidy, telomere aggregates and synchronization of replication were evaluated as markers of genetic instability in these patients., Methodology: Peripheral blood lymphocytes from 22 patients with NAFLD, 20 patients with CC and 20 age-matched healthy controls were analyzed. To determine random aneuploidy, we used the fluorescence in situ hybridization (FISH) with probes for chromosomes 9 and 18. The rate of aneuploidy was inferred from the fraction of cells revealing one, three or more hybridization signals per cell. Aggregate size was divided into three fusion groups of 2-5, 6-10 and 11-15 telomeres, relative to the size of a single telomere. The replication pattern was determined by FISH in two pairs of alleles, 15qter and 13qter. Asynchrony was determined by the presence of one single and one set of double dots in the same cell., Results: Significantly higher random aneuploidy rate was found in the CC patients than in the control group, and to a lesser degree in NAFLD patients. Telomere aggregates were insignificantly higher in both groups. Only patients with CC showed significantly higher rate of asynchronous replication with proportionately more cells with two single dots among the normal cells (p<0.001)., Conclusions: These results likely reflect changes in gene replication and cell cycle progression in these conditions, possibly correlating with their malignant potential., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Nonalcoholic fatty liver disease (NAFLD) and cryptogenic cirrhosis (CC) are considered preneoplastic conditions that might progress to hepatocellular carcinoma. We evaluated parameters of telomere dysfunction in these patient groups to study the correlation between telomere length and the progression of NAFLD. We analyzed peripheral lymphocytes from 22 patients with NAFLD, 20 patients with CC, and 20 healthy, age-matched controls. Telomere length was analyzed using quantitative fluorescence in situ hybridization, and cellular senescence was evaluated by the percentage of cells with senescence-associated heterochromatin foci. The expression of telomerase reverse transcriptase (hTERT) mRNA was measured using polymerase chain reaction, and telomere capture (TC) was assessed with 2 Cytocell probes, 15qter and 13qter. Shorter telomere length and increased cellular senescence was demonstrated in patients with NAFLD, compared to the CC patients and healthy controls. While hTERT mRNA was significantly decreased, TC was increased in CC patients, compared to the NAFLD group and healthy individuals. Thus, there is a correlation between hTERT mRNA expression and telomere length in patients with NAFLD, which might be related to associated metabolic disorders and the risk of malignant transformation. Patients with CC, on the contrary, elongate their telomeres through the TC mechanism., (© 2016 S. Karger AG, Basel.)

Background and Aims: Primary sclerosing cholangitis and inflammatory bowel disease are two associated, chronic inflammatory, pre-malignant conditions. We hypothesized that patients with these disorders may harbour telomere dysfunction as a marker of chromosomal instability. The aim of our study was to compare parameters of the telomere-telomerase system in these cohorts., Methods: In this prospective study, peripheral blood was withdrawn from patients with primary sclerosing cholangitis (N=20), inflammatory bowel disease (N=20) and healthy controls (N=20), and lymphocytes were isolated. Telomere length was quantified as a function of the signal intensity and telomere number. Random aneuploidy and telomere capture were determined by fluorescence in situ hybridization technique with specific probes., Results: Patients with inflammatory bowel disease had higher measures of intestinal disease activity than patients with primary sclerosing cholangitis. Despite this, shorter telomere length and telomere aggregates, especially the fusion of 2-5 telomeres, were observed at significantly higher rate in patients with primary sclerosing cholangitis relative to inflammatory bowel disease or healthy controls. Rates of aneuploidy and telomere capture were higher in the two probes in both diseases compared to controls (p<0.001)., Conclusion: Dysfunction of telomeres was demonstrated in primary sclerosing cholangitis patients more than inflammatory bowel disease and healthy controls patients, which attests to genetic instability and immunosenescence., Trial Registration Number: NCT02247622., (Copyright © 2015 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD) are associated chronic inflammatory diseases with malignant potential. Loss of replication synchrony during the S-phase of the cell cycle has been shown to be linked to several malignant and premalignant states. This study evaluated temporal differences in replication timing between these diseases. The replication pattern of peripheral blood lymphocytes obtained from patients with PSC and IBD and healthy individuals was analyzed by fluorescence in situ hybridization (FISH) in 2 pairs of alleles, in 15qter and 13qter. Asynchrony was determined by the presence of 1 single and 1 set of double dots in the same cell. Samples from subjects with PSC showed significantly greater temporal differences in replication timing, in contrast to the high level of synchrony observed in samples from healthy individuals (p = 0.045). Samples from IBD patients exhibited a nonsignificant increase in replication asynchrony. We believe that these results reflect impairment in the replication control of structural homologous loci in PSC, and that this phenomenon may be correlated with the inflammation-induced malignant potential of this condition., (© 2015 S. Karger AG, Basel.)

Objective: Primary sclerosing cholangitis (PSC) is a chronic cholestatic disorder that involves inflammatory and fibrotic changes in the bile ducts. Up to 80% of patients have concomitant inflammatory bowel disease (IBD) with colitis. PSC patients are predisposed to develop hepatobiliary, colonic and other extrahepatic malignancies, probably related to inflammatory processes that might promote carcinogenesis. Telomerase is an enzyme complex that lengthens telomeres and has enhanced expression in numerous malignancies. In this study, we evaluated the TERC gene copy number, the proportion of cells in senescence and the amount of fragmentation in the senescent state., Methods: Fluorescence in situ hybridization (FISH) for the TERC gene was applied to lymphocytes retrieved from PSC (N=19), colitis (N=20) and healthy control patients (N=20) to determine the TERC copy number. On the same FISH slides, cells stained with DAPI were also analyzed for senescence-associated heterochromatin foci (SAHF) status, including the number of cells with fragments and the number of SAHF fragments in each cell., Results: A higher TERC gene copy number was observed in cells from PSC patients compared to colitis and control group patients. It was also higher in the colitis than in the control group. Significantly more cells in the senescent state and more fragmentation in each cell were observed in the PSC group compared to colitis and control groups., Conclusion: The TERC gene copy number and the number of cells in the senescent state were increased in PSC patients compared to the colitis and control groups. These findings are probably related to the genetic instability parameters that reflect the higher tendency of this patient group to develop malignancies., (© 2013.)

Background/aims: Shortened telomeres reflect genetic instability that might lead to increased aneuploidy and malignant transformations. Chronic hepatitis C (HCV) viral infection is considered a pre-neoplastic condition that might progress to hepatocellular carcinoma. We evaluated telomere length and elongation, in patients with different stages of HCV to study the correlation between telomere length and the progression of HCV., Methodology: We analyzed peripheral lymphocytes from 10 patients with chronic active HCV, 10 patients with HCV infection in a remission stage, and 10 healthy, age-matched patients, as controls. The expression of hTERT mRNA, which is correlated with elongation of telomeres was measured using RT-PCR and telomere length was analyzed using Q-FISH and a novel computerized technique., Results: hTERT mRNA was significantly decreased in patients with active HCV and slightly decreased in patients who were in remission, compared to healthy individuals. Telomere length was shorter in patients with chronic active HCV and in patients in remission, compared to the healthy controls., Conclusions: There is a correlation between telomerase reverse transcriptase mRNA expression and telomere length in patients with different stages of HCV infection that might be related to the risk of malignant transformation.

Thiopurine drugs, azathioprine (Imuran) and 6-mercaptopurine (6-MP), are immunomodulators that have been shown to be effective at inducing and maintaining remission in inflammatory bowel disease. Although usually well-tolerated, the occurrence of side effects, typically myelotoxicity and hepatotoxicity, is a major drawback. The side effects can be classified as dose-dependent and independent. Both cholestatic hepatitis and endothelial injury, leading to vascular congestion and nodular regenerative hyperplasia, have been described during therapy with thiopurines, which can end up with portal hypertension. These injuries are potentially mediated by different metabolites. In this article we present a case of hyperammonaemic encephalopathy during therapy with 6-MP, possibly the first recorded in the literature, which probably resulted from the combination of thiopurine-induced liver injury with portal hypertension and the presence of spontaneous portosystemic venous shunts.

A 48 years old patient was admitted to the Internal Medicine ward due to progressive weakness and abnormal liver function tests. During three months of hospitalization she developed opportunistic infections with Cryptococcus and Pneumocystic jiroveci pneumonia. The CD4+ T-cell lymphocyte count was very low with no evidence of infection with human immunodeficiency virus. Liver disease deteriorated with the appearance of profound jaundice and severe hepatitis. The patient's laboratory and clinical presentation were compatible with the diagnosis of idiopathic CD4 + T-cell lymphocytopenia--ICL. The authors reviewed the literature on ICL and discuss the rare hepatic presentation of this uncommon syndrome.

Objective: Individuals with chromosomal aneuploidies tend to develop malignancies. Telomerase is an enzyme complex that lengthens telomeres and has enhanced expression in numerous malignancies; one of its components is encoded by the TERC gene. In this study, we evaluated the TERC gene copy number in amniocytes from fetuses with aneuploidy, other than trisomy-21., Methods: In this prospective, basic research study, fluorescence in situ hybridization (FISH) for the TERC gene (3q26) was applied to amniocytes retrieved from 14 fetuses with various aneuploidies and from a control group of 6 fetuses with a normal karyotype, to determine the TERC gene copy number., Results: The percentage of cells with more than two copies of the TERC gene was lowest in the control group (x3=1.2 ± 0.4%; x4=0 ± 0%), higher in the sex chromosome aneuploidies (x3=4 ± 3%; x4=0.7 ± 0.95%) and even higher in trisomy 18 (x3=10.6 ± 2.3; x4=4.6 ± 1.8). The differences were statistically significant (P<0.05)., Conclusion: The TERC gene copy number is increased in aneuploid amniocytes, which demonstrates their genetic instability and is presumably related to their tendency to develop malignancies., (Copyright © 2012. Published by Elsevier B.V.)

Background: Gut flora is related to the major complications of liver cirrhosis including hepatic encephalopathy, spontaneous bacterial peritonitis, and variceal bleeding. Prior studies have reported a beneficial effect of gut flora modification with probiotic bacteria in patients with minimal hepatic encephalopathy. We aimed to study the effect of probiotics on clinical and laboratory parameters of patients with compensated cirrhosis., Methods: A double-blind placebo-controlled study that included patients with liver cirrhosis and at least one major complication of cirrhosis in the past, clinical evidence of portal hypertension, or decreased hepatic synthetic function. Participants were randomly assigned to receive probiotic capsules containing Lactobacillus acidophilus, Lactobacillus bulgaricus, Bifidobacterium lactis, and Streptococcus thermophiles or placebo for a period of 6 mo., Results: A total of 36 patients were available for final analysis (distributed equally between the probiotic and placebo groups). The administration of probiotics was not associated with significant differences in either clinical or laboratory parameters between the two groups. Because the lack of a beneficial effect may be related to the compensated liver disease of patients, we conducted a subanalysis of patients with baseline ammonia levels > 50 mmol/L. In this subgroup, the administration of probiotics appeared to significantly reduce the ammonia levels starting after 1 mo of treatment. However, this effect diminished and lost its significance following comparison to the placebo group., Conclusions: Our study did not show a significant beneficial effect of probiotic supplementation in patients with compensated liver cirrhosis. Nevertheless, it points toward a possible positive effect of probiotics in patients with above normal baseline ammonia levels. This issue requires further investigation in larger cohorts., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Telomeres are specific repetitive DNA sequences that cap and stabilize the ends of chromosomes. Functional telomeres are essential for the normal segregation and maintenance of chromosomes during mitotic and meiotic division. Pre-eclampsia, a pregnancy-specific syndrome of increased blood pressure accompanied by proteinuria, is often associated with growth deficiency in the fetus. Oxidative stress is a major component in the pathophysiology of pre-eclampsia. In contrast to the nonoverlapping nature of telomeres in normal nuclei, telomeres of tumor nuclei tend to form aggregates (TAs) in various numbers and sizes. The formation of TAs represents a stress-related process and is independent of telomere length and telomerase activity. The aim of this study was to evaluate TA formation in paraffin-embedded placentas from pregnancies complicated with pre-eclampsia (study group), compared with placentas from normal pregnancies (control group). There were significantly more TAs in the study group (mean, 8.00 TAs per case) than in the control group (mean, 2.36 TAs per case) (P < 0.01). Pre-eclampsia-related stress may accelerate apoptosis and cell death and lead to placental dysfunction. TAs formation, which has been linked to stress and tumorgenesis is increased in placentas of pre-eclamptic patients.

Telomeres of tumor nuclei tend to form aggregates (TA). The aim of this study was to estimate the TA formation in leukocytes of patients with chronic hepatitis C (HCV) which is considered to be premalignant disease, in patients of HCV who eradicated the virus. PNA Telomere kit (Dako) was used to evaluate the TA formation with the utilization of 2D fluorescence microscopy. A higher rate of TA was found in both HCV groups as compared to controls. Our results indicate that HCV patients have some of the components that create the cascade of events leading to malignancies.

Broken chromosomes can acquire new telomeres by "telomere capture" (TC), and it has become possible to investigate the terminus in cytogenetically visible telomere rearrangements. The TC phenomenon was observed in malignant conditions. We evaluated the TC rate in hepatitis C virus (HCV) patients compared to non-Hodgkin's lymphoma patients, as well as relative to a control group. For this purpose, we used two Cytocell probes, 15qter and 13qter. Higher TC rates were found in the three study groups relative to the control group. Our results showed that HCV patients have some of the components that can initiate the cascade of events leading to malignancies.

Background: Hepatitis C virus (HCV) consists of a single positive RNA molecule. In the present study we investigated the possibility that HCV may undergo integration into the genomic DNA of infected cells., Materials and Methods: HCV(+) patients (n = 51) and 21 HCV(-) controls were investigated for HCV integration. RNase treated DNA samples of mononuclear cells (MNC) and liver biopsies of the patients were screened by PCR and seminested PCR processes for detection of integration. Positive results were further investigated by means of Southern analysis of patient's DNA as well as sequencing of PCR products of patient's DNA., Results: Positive PCR results were detected in 4/51 of the HCV(+) patients and in none of the control group. Southern analysis showed the presence of HCV sequence in a 23 kbp band of the patient which is much larger than the viral genome itself (9.646 kbp). Sequencing of cloned PCR products showed an identity of over 95.0% to HCV., Conclusions: As much as we are aware this is the first demonstration of the possible integration of HCV sequences into the DNA of HCV(+) patients.

Hepatitis C virus (HCV) has been recently recognized as a potential cause of B-cell lymphoma. Both chronic hepatitis B and C with or without cirrhosis represent major preneoplastic conditions, and the majority of hepatocellular carcinomas arise in these pathological settings. According to the aneuploidy-cancer theory, carcinogenesis is initiated by random aneuploidy, which is either induced by carcinogens or arises spontaneously. The aim of this study was to evaluate random aneuploidy rate in HCV patients during chronic infection and remission (past infection eradicated), compared with non-Hodgkin lymphoma (NHL) patients and healthy controls. To determine random aneuploidy, we applied the FISH technique with probes for chromosomes 9 and 18. Significantly higher random aneuploidy rate was found in the HCV-infected and lymphoma patients than in the control group; the past HCV group in remission had intermediate rates, between those of the control group and the chronically infected patients. Patients who have eradicated HCV infection may nonetheless carry higher risk for future malignancy and therefore need long-term follow-up.

The aim of this study is to report the extrarenal computerized tomography (CT) findings in patients with acute pyelonephritis (APN). Twenty-one CT examinations of 20 patients [19 women and one man, with ages ranging from 18 to 57 years (mean -35.2 years)], presenting either with a clinical diagnosis of APN (n=17) or with a suspected acute appendicitis, fever of unknown origin, and adult respiratory distress syndrome, one in each, were retrospectively reviewed. None had a known preexisting systemic disease. Results showed that renal abnormalities were seen on CT in all patients. In addition, ascites was detected in all women patients associated with subcutaneous edema in five of them. A thickened gallbladder wall was found in 19 cases, all were women, and periportal tracking and a dilated inferior vena cava in 17 CTs. Pleural effusion and thickened interlobular septa were present in 16 and 15 studies, respectively. Relevant laboratory findings included hypoalbuminemia in 14, elevated liver enzymes in 11, hypocholesterolemia in nine, and elevated LDH levels in six cases. In conclusion, radiologists should be familiar with the extrarenal imaging features of APN that may be seen on CT, and on ultrasonography as well, and should look for renal abnormalities to diagnose a clinically unsuspected APN. Alternatively, APN should be included in the differential diagnosis of systemic diseases that cause gallbladder wall thickening to avoid misdiagnosing it as acute cholecystitis.