Biomarkers and subtypes of deranged lipid metabolism in non-alcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is a heterogeneous and complex disease that is imprecisely diagnosed by liver biopsy. NAFLD covers a spectrum that ranges from simple steatosis, nonalcoholic steatohepatitis (NASH) with varying degrees of fibrosis, to cirrhosis, which is a major risk factor for hepatocellular carcinoma. Lifestyle and eating habit changes during the last century have made NAFLD the most common liver disease linked to obesity, type 2 diabetes mellitus and dyslipidemia, with a global prevalence of 25%. NAFLD arises when the uptake of fatty acids (FA) and triglycerides (TG) from circulation and de novo lipogenesis saturate the rate of FA β-oxidation and very-low density lipoprotein (VLDL)-TG export. Deranged lipid metabolism is also associated with NAFLD progression from steatosis to NASH, and therefore, alterations in liver and serum lipidomic signatures are good indicators of the disease's development and progression. This review focuses on the importance of the classification of NAFLD patients into different subtypes, corresponding to the main alteration(s) in the major pathways that regulate FA homeostasis leading, in each case, to the initiation and progression of NASH. This concept also supports the targeted intervention as a key approach to maximize therapeutic efficacy and opens the door to the development of precise NASH treatments

Histopathological Changes in the Kidney following Congestive Heart Failure by Volume Overload in Rats

Background. This study investigated histopathological changes and apoptotic factors that may be involved in the renal damage caused by congestive heart failure in a rat model of infrarenal aortocaval fistula (ACF). Methods. Heart failure was induced using a modified approach of ACF in male Wistar rats. Sham-operated controls and ACF rats were characterized by their morphometric and hemodynamic parameters and investigated for their histopathological, ultrastructural, and apoptotic factor changes in the kidney. Results. ACF- induced heart failure is associated with histopathological signs of congestion and glomerular and tubular atrophy, as well as nuclear and cellular degeneration in the kidney. In parallel, overexpression of proapoptotic Bax protein, release of cytochrome C from the outer mitochondrial membrane into cell cytoplasm, and nuclear transfer of activated caspase 3 indicate apoptotic events. This was confirmed by electron microscopic findings of apoptotic signs in the kidney such as swollen mitochondria and degenerated nuclei in renal tubular cells. Conclusions. This study provides morphological evidence of renal injury during heart failure which may be due to caspase-mediated apoptosis via overexpression of proapoptotic Bax protein, subsequent mitochondrial cytochrome C release, and final nuclear transfer of activated caspase 3, supporting the notion of a cardiorenal syndrome

Cosmopolitanism in Retreat? The Crisis of Syrian Identity in Post-Arab Spring

This research project examines the following central question: what does Syrian identity mean in the eyes of contending groups in the current Syrian crisis (2011-2017)? In answering this question, the project engages in original research, shedding light on the ‘identity’ dimension of the war in Syria. It challenges primordialist and/or Orientalist approaches to identity, which shadow the cosmopolitan components of the Middle East, confining the region’s identity-politics to notions of sectarianism and conservative militant Islamism resistant to modernity. Through employing Hamid Dabashi’s critical postcolonial cosmopolitan framework of analysis, the research historicizes the crisis of Syrian identity, focusing on critical periods ranging from the 1920s, up to the contemporary crisis (2011-2017). It demonstrates that the country’s postcolonial state-imposed national identity projects have for years been exclusionary, and either have been shaped by, or have encountered, three ideological formations: those are, anti-colonial nationalism, third-world socialism, and Islamism. These formations emerged in conversation with, and in response to, European colonialism and were conveniently deployed by the ruling regimes to legitimatize their position. Through a discourse and content analysis, based on Dabashi’s analytical framework, the research argues that the 2011 Syrian Uprising was an attempt to bring an inclusive meaning to ‘Syrianism’ and to retrieve the repressed cosmopolitan worldliness. Protestors were committed to a unified Syria, as a political entity and a source of identity. They were not seeking an Islamist, a pan-‘Arabist’, a separatist, a Ba’athist socialist or a sectarian vision, but were rather united by prospects of creating a locally produced alternative that would maintain national harmony and retrieve the country’s cosmopolitanism. The research argues that the prolonging of the Syrian conflict has resulted in the deterioration of an inclusive, cosmopolitan ‘Syrianism’, as various actors have risen with conflicting ideas about national identity. Using archival primary and secondary sources, the research problematizes the identity discourse of the conflicting groups and to compare where they place ‘Syria’ in their ideologies. The research findings suggest that the ideologies of the studied combatant groups embody counter-revolutionary exclusionary notions of identity, which are not based on the cosmopolitan worldliness, but rather reinforce the suppressed, reactionary and exclusionary post-colonial ideological dichotomies

Occurrence of liver cirrhosis in England, a cohort study, 1998-2009: a comparison with cancer

OBJECTIVES: There is no routine registration of the occurrence of newly diagnosed cases of cirrhosis in the United Kingdom. This study seeks to determine precise estimates and trends of the incidence of cirrhosis in England, and directly compare these figures with those for the 20 most commonly diagnosed cancers in the United Kingdom. METHODS: We used the Clinical Practice Research Datalink and linked English Hospital Episode Statistics to perform a population-based cohort study. Adult incident cases with a diagnosis of cirrhosis between January 1998 and December 2009 were identified. We described trends in incidence by sex and etiology. We performed a direct standardization to estimate the number of people being newly diagnosed with cirrhosis in 2009, and calculated the change in incidence between 1998 and 2009. RESULTS: A total of 5,118 incident cases of cirrhosis were identified, 57.9% were male. Over the 12-year period, crude incidence increased by 50.6%. Incidence increased for both men and women and all etiology types. We estimated approximately 17,000 people were newly diagnosed with cirrhosis in 2009 in the United Kingdom, greater than that of the fifth most common cancer non-Hodgkin's lymphoma. The percentage change in incidence of cirrhosis between 1998 and 2009 for both men (52.4%) and women (38.3%) was greater than that seen for the top four most commonly diagnosed cancers in the United Kingdom (breast, lung, bowel, and prostate). CONCLUSIONS: The occurrence of cirrhosis increased more than that of the top four cancers during 1998 to 2009 in England. Strategies to monitor and reduce the incidence of this disease are urgently needed

IL28B genotype is associated with cirrhosis or transition to cirrhosis in treatment-naive patients with chronic HCV genotype 1 infection: the international observational Gen-C study

Background and purpose: Contradictory data exist on the association between host interleukin-28B (IL28B) rs12979860 genotype and liver fibrosis in patients with chronic hepatitis C (CHC). This large, international, observational study (NCT01675427/MV25600) investigated relationships between IL28B rs12979860 genotype and liver fibrosis stage in CHC patients. Methods: A total of 3003 adult, treatment-naive CHC patients were enrolled into the study. Patients made one study visit to provide a blood sample for genotyping; other data were obtained from medical records. Results: 2916 patients comprised the analysis population; the majority were enrolled in Europe (n = 2119), were Caucasian (n = 2582) and had hepatitis C virus (HCV) genotype (G) 1 infection (n = 1702) (G2 = 323, G3 = 574, G4 = 260). Distribution of IL28B genotypes varied according to region of enrolment, patient ethnicity and HCV genotype. A significant association was observed between increasing number of IL28B T alleles and the prevalence of cirrhosis/transition to cirrhosis (based on biopsy or non-invasive assessments) in G1-infected patients (CC = 22.2% [111/499], CT = 27.5% [255/928], TT = 32.3% [87/269]; p = 0.0018). The association was significant in the large subgroup of European Caucasian G1 patients (n = 1245) but not in the smaller Asian (n = 25), Latin American (n = 137) or Middle Eastern (n = 289) G1 subgroups. IL28B genotype was not associated with liver fibrosis stage in patients with HCV G2, G3 or G4 infection. Conclusion: This large, international study found that IL28B rs12979860 genotype is significantly associated with liver fibrosis stage in CHC patients with HCV G1 infection. This association was evident in European Caucasians but not in G1-infected patients from Asia, Latin America or the Middle EastF. Hoffmann-La Roche Ltd, Basel, Switzerlan

Metabolomic-Based Noninvasive Serum Test to Diagnose Nonalcoholic Steatohepatitis: Results From Discovery and Validation Cohorts

Nonalcoholic fatty liver disease (NAFLD) is the most common type of chronic liver disease worldwide and includes a broad spectrum of histologic phenotypes, ranging from simple hepatic steatosis or nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH). While liver biopsy is the reference gold standard for NAFLD diagnosis and staging, it has limitations due to its sampling variability, invasive nature, and high cost. Thus, there is a need for noninvasive biomarkers that are robust, reliable, and cost effective. In this study, we measured 540 lipids and amino acids in serum samples from biopsy-proven subjects with normal liver (NL), NAFL, and NASH. Using logistic regression analysis, we identified two panels of triglycerides that could first discriminate between NAFLD and NL and second between NASH and NAFL. These noninvasive tests were compared to blinded histology as a reference standard. We performed these tests in an original cohort of 467 patients with NAFLD (90 NL, 246 NAFL, and 131 NASH) that was subsequently validated in a separate cohort of 192 patients (7 NL, 109 NAFL, 76 NASH). The diagnostic performances of the validated tests showed an area under the receiver operating characteristic curve, sensitivity, and specificity of 0.88 +/- 0.05, 0.94, and 0.57, respectively, for the discrimination between NAFLD and NL and 0.79 +/- 0.04, 0.70, and 0.81, respectively, for the discrimination between NASH and NAFL. When the analysis was performed excluding patients with glucose levels >136 mg/dL, the area under the receiver operating characteristic curve for the discrimination between NASH and NAFL increased to 0.81 +/- 0.04 with sensitivity and specificity of 0.73 and 0.80, respectively. Conclusion: The assessed noninvasive lipidomic serum tests distinguish between NAFLD and NL and between NASH and NAFL with high accuracy.Supported by the National Institutes of Health Blueprint for Neuroscience Research (R01AT001576 to S.C.L., J.M.M.), Agencia Estatal de Investigacion of the Ministerio de Economia, Industria y Competitividad (SAF2014-52097R to J.M.M.), CIBER Hepatic and Digestive Diseases and Instituto de Salud Carlos III (PIE14/0003 to J.M.M.), Etorgai 2015-Gobierno Vasco (ER-2015/00015 to R.M., I.M.A., C.A., A.C.), Plan de Promocion de la Innovacion 2015-Diputacion Foral de Bizkaia (6/12/IN/2015/00131 to A.C., C.A.), National Institute of Diabetes and Digestive and Kidney Diseases (RO1DK81410 to A.J.S.), and Czech Ministry of Health (RVO VFN64165 to L.V.)

Intravitreal triamcinolone acetonide: Pattern of secondary intraocular pressure rise and possible risk factors

Ziad F Bashshur1, Abdallah M Terro1, Christelle P El Haibi1, Akaber M Halawi1, Alexandre Schakal2, Baha’ N Noureddin11The Department of Ophthalmology, American University of Beirut, Lebanon; 2The Department of Ophthalmology, Hotel Dieu de France (St. Joseph University), LebanonPurpose: To determine the pattern of increase in intraocular pressure (IOP) following intravitreal triamcinolone acetonide (IVTA) and identify possible risk factors associated with this rise in IOP.Methods: We carried out a retrospective review of records for 185 patients (226 eyes) who received 4 mg of IVTA at the American University of Beirut Medical Center and Hotel Dieu de France eye clinics between 2003 and 2005.Results: Mean follow-up was 8.17 months (range 6 to 24 months). The mean number of IVTA injections per eye was 1.31 ± 0.69. The mean IOP increased after the first IVTA injection from 15.04 ± 3.18 mmHg at baseline to a mean maximum of 17.20 ± 5.75 mmHg (p < 0.0001, paired t-test) at month 3 of follow-up with a return to mean baseline IOP (15.49 ± 4.79 mmHg) at month 12. Fifty nine of 226 eyes showed IOP higher than 21 mmHg during follow-up. Nine eyes started to have IOP greater than 21 mmHg, 6 to 12 months after a single injection. Intraocular pressure lowering medications were started when IOP exceeded 25 mmHg in 15 of the 226 eyes studied. No risk factors have been found to predict this IOP rise.Conclusions: IOP elevation can occur in a significant number of eyes receiving 4 mg of IVTA. This phenomenon seems to be transient and a small number of eyes required treatment during this period. Eyes that received IVTA need to be monitored for IOP changes especially during the first 3 months, but the IOP may still rise 6 months and even 12 months after a single injection. This study did not show any risk factor that may predict this IOP rise.Keywords: intravitreal triamcinolone acetonide, intraocular pressure elevation, diabetic macular edema, choroidal neovascular membrane due to age-related macular degeneration, central retinal vein occlusion, Branch retinal vein occlusion, Uveiti

Class III obesity is a risk factor for the development of acute on chronic liver failure in patients with decompensated cirrhosis

BACKGROUND AND AIMS: Acute on chronic liver failure (ACLF) is a syndrome of systemic inflammation and organ failures. Obesity, also characterized by chronic inflammation, is a risk factor among patients with cirrhosis for decompensation, infection, and mortality. Our aim was to test the hypothesis that obesity predisposes to ACLF development in patients with decompensated cirrhosis. METHODS: We examined the United Network for Organ Sharing (UNOS) database, from 2005-2016, characterizing patients at wait-listing as non-obese (BMI < 30), obese class I-II (BMI 30-39.9) and obese class III (BMI≥40). ACLF was determined based on the CANONIC study definition. We used Cox proportional hazards regression to assess the association between obesity and ACLF development at liver transplantation (LT). We confirmed our findings using the Nationwide Inpatient Sample (NIS), years 2009-2013, using validated diagnostic coding algorithms to identify obesity, hepatic decompensation and ACLF. Logistic regression evaluated the association between obesity and ACLF occurrence. RESULTS: Among 387,884 with decompensated cirrhosis, 116,704 patients (30.1%) were identified as having ACLF in both databases. Multivariable modeling from the UNOS database revealed class III obesity to be an independent risk factor for ACLF at LT (HR=1.24, 95% CI 1.09-1.41, p<0.001). This finding was confirmed using the NIS (OR=1.30, 95% CI 1.25-1.35, p<0.001). Regarding specific organ failures, analysis of both registries demonstrated patients with class I-II and class III obesity had greater prevalence of renal failure. CONCLUSION: Class III obesity is a newly identified risk factor for ACLF development in patients with decompensated cirrhosis. Obese patients have a particularly higher prevalence of renal failure as a component of ACLF. These findings have important implications regarding stratifying risk and preventing the occurrence of ACLF. LAY SUMMARY: In this study, we identify that among patients with decompensated cirrhosis, class III obesity is a modifiable risk factor for the development of acute on chronic liver failure (ACLF). We further demonstrate that regarding the specific organ failures associated with ACLF, renal failure is significantly more prevalent among obese patients, particularly class III obesity. These findings underscore the importance of weight management in cirrhosis, to reduce the risk of ACLF. Patients with class III obesity should be monitored closely for the development of renal failure

Change in lumbar lordosis during prone lying knee flexion test in subjects with and without low back pain

BACKGROUND: Prone lying knee flexion (PLKF) is one of the clinical tests used for assessment of the lumbo-pelvic movement pattern. Considerable increase in lumbar lordosis during this test has been considered as impairment of movement patterns in lumbar-pelvic region. However, no study has directly evaluated the change in lordosis during active PLKF test in subjects with low back pain (LBP). The purpose of this study was to investigate the change of lumbar lordosis in PLKF test in subjects with and without LBP. METHODS: A convenience sample of 80 subjects participated in the study. Subjects were categorized into two groups: those with chronic non-specific LBP (N = 40, mean age: 40.84 ± 17.59) and with no history of LBP (N = 40, mean age: 23.57 ± 10.61). Lumbar lordosis was measured with flexible ruler, first in prone position and then on active PKF test in both subjects with and without LBP. Data was analyzed by using statistical methods such as, independent t-test and paired t-test. RESULTS: There were statistically significant differences in lumbar lordosis between prone position and after active PLKF in both subjects with and without LBP (P < 0.0001). The amount of change in lordosis during PLKF test was not significant between the two groups (P = 0.65). However these changes were greater among patients with LBP. CONCLUSION: Increase in lumbar lordosis during this test may be due to excessive flexibility of movement of the lumbar spine in the direction of extension and abnormal movement patterns in the individuals with LBP