Characterization of the Effects of Ligands on Bonding and σ-Aromaticity of Small Pt Nanoclusters.

Nanoclusters, particularly gold nanoclusters, have attracted the attention of researchers due to their potential applications in the medicine and energy fields. Other noble-metal nanoclusters, including Pt, have also been studied, but in lesser detail. Pt is known for its excellent catalytic properties and is a promising candidate for applications in catalysis and biomedicine. In this study, we used density functional theory to elucidate the molecular and electronic structures of small phosphine-ligated Pt nanoclusters. This study is directed at identifying highly stable platinum clusters. Our results show that phosphine-ligated platinum nanoclusters with σ-aromaticity have high stability. In addition, we were able to predict the most stable clusters using an electron counting equation.

Position statement on the use of albumin in liver cirrhosis.

Cirrhosis is characterised by a prolonged asymptomatic period in which the inflammation persists, increasing as the disease progresses. Characteristic of this is the increase in pro-inflammatory cytokines and pro-oxidant molecules which are determining factors in the development of multiple organ dysfunction. In the early development of cirrhosis, splanchnic arterial vasodilation, activation of vasoconstrictor systems (renin-angiotensin-aldosterone) and the sympathetic nervous system (noradrenaline) bring about bacterial translocation and systemic dissemination via portal circulation of bacterial products, and molecular patterns associated with damage, which exacerbate the systemic inflammation present in the patient with cirrhosis. Albumin is a molecule that undergoes structural and functional changes as liver damage progresses, affecting its antioxidant, immunomodulatory, oncotic and endothelial stabilising properties. Our knowledge of the properties of albumin reveals a molecule with multiple treatment options in patients with cirrhosis, from the compensated then decompensated phases to multiple organ dysfunction. Its recognised uses in spontaneous bacterial peritonitis, post-paracentesis circulatory dysfunction, acute kidney injury and hepatorenal syndrome are fully validated, and a treatment option has opened up in decompensated cirrhosis and in acute-on-chronic liver disease.

Role of sterics in phosphine-ligated gold clusters.

This study examined the solution-phase exchange reactions of triphenylphosphine (PPh3) ligands on Au8L72+ (L = PPh3) gold clusters with three different tolyl ligands using electrospray ionization mass spectrometry to provide insight into how steric differences in the phosphines influence the extent of ligand exchange and the stability of the resulting mixed-phosphine clusters. The size distributions of tolyl-exchanged gold clusters were found to depend on the position of the methyl group in the tri(tolyl)phosphine ligands (-ortho, -meta, and -para). Due to different sterics, the tri(m-tolyl)phosphine (TMTP) and tri(p-tolyl)phosphine (TPTP) ligands exchanged efficiently onto the Au8L72+ (L = PPh3) clusters while the tri(o-tolyl)phosphine ligands did not exchange. In addition, while TPTP fully exchanged with all seven PPh3 on the Au8L72+ cluster, TMTP exchanged with only six PPh3 ligands. Employing collision-induced dissociation, the tolyl-exchanged mixed-ligand clusters were demonstrated to fragment through loss of neutral ligands and AuL2+. Comparison of the relative fragmentation yields of PPh3vs. TMTP and TPTP from the mixed-ligand clusters indicated that these tolyl ligands are more strongly bonded to the Au82+ gold core than PPh3. To provide molecular-level insight into the experimental results we also performed complementary electronic structure calculations using density functional theory at the B3LYP-D3/SDD level of theory on representative model systems. These computations revealed that steric interactions of the CH3 group on the tri(o-tolyl)phosphine ligand are responsible for the lack of ligand exchange in solution with PPh3. Our joint experimental and theoretical findings demonstrate the subtle interplay of steric and electronic factors that determine the size distribution, stability, and dissociation pathways of phosphine ligated gold clusters.

A Frameshift in CSF2RB Predominant Among Ashkenazi Jews Increases Risk for Crohn's Disease and Reduces Monocyte Signaling via GM-CSF.

BACKGROUND & AIMS: Crohn's disease (CD) has the highest prevalence in Ashkenazi Jewish populations. We sought to identify rare, CD-associated frameshift variants of high functional and statistical effects. METHODS: We performed exome sequencing and array-based genotype analyses of 1477 Ashkenazi Jewish individuals with CD and 2614 Ashkenazi Jewish individuals without CD (controls). To validate our findings, we performed genotype analyses of an additional 1515 CD cases and 7052 controls for frameshift mutations in the colony-stimulating factor 2-receptor ß common subunit gene (CSF2RB). Intestinal tissues and blood samples were collected from patients with CD; lamina propria leukocytes were isolated and expression of CSF2RB and granulocyte-macrophage colony-stimulating factor-responsive cells were defined by adenomatous polyposis coli (APC) time-of-flight mass cytometry (CyTOF analysis). Variants of CSF2RB were transfected into HEK293 cells and the expression and functions of gene products were compared. RESULTS: In the discovery cohort, we associated CD with a frameshift mutation in CSF2RB (P = 8.52 × 10(-4)); the finding was validated in the replication cohort (combined P = 3.42 × 10(-6)). Incubation of intestinal lamina propria leukocytes with granulocyte-macrophage colony-stimulating factor resulted in high levels of phosphorylation of signal transducer and activator of transcription (STAT5) and lesser increases in phosphorylation of extracellular signal-regulated kinase and AK straining transforming (AKT). Cells co-transfected with full-length and mutant forms of CSF2RB had reduced pSTAT5 after stimulation with granulocyte-macrophage colony-stimulating factor, compared with cells transfected with control CSF2RB, indicating a dominant-negative effect of the mutant gene. Monocytes from patients with CD who were heterozygous for the frameshift mutation (6% of CD cases analyzed) had reduced responses to granulocyte-macrophage colony-stimulating factor and markedly decreased activity of aldehyde dehydrogenase; activity of this enzyme has been associated with immune tolerance. CONCLUSIONS: In a genetic analysis of Ashkenazi Jewish individuals, we associated CD with a frameshift mutation in CSF2RB. Intestinal monocytes from carriers of this mutation had reduced responses to granulocyte-macrophage colony-stimulating factor, providing an additional mechanism for alterations to the innate immune response in individuals with CD.

The product of triglycerides and glucose as biomarker for screening simple steatosis and NASH in asymptomatic women.

UNLABELLED:  Introduction and aim. Given that early identification of non-alcoholic fatty liver disease (NAFLD) is an important issue for primary prevention of hepatic disease, the objectives of this study were to evaluate the efficacy of the product of triglyceride and glucose levels (TyG) for screening simple steatosis and non-alcoholic steatohepatitis (NASH) in asymptomatic women, and to compare its efficacy vs. other biomarkers for recognizing NAFLD. MATERIAL AND METHODS: Asymptomatic women aged 20 to 65 years were enrolled into a cross-sectional study. The optimal values of TyG, for screening simple steatosis and NASH were established on a Receiver Operating Characteristic scatter plot; the sensitivity, specificity, and likelihood ratios of TyG index were estimated versus liver biopsy. According sensitivity and specificity, the efficacy of TyG was compared versus the well-known clinical biomarkers for recognizing NAFLD. RESULTS: A total of 50 asymptomatic women were enrolled. The best cutoff point of TyG for screening simple steatosis was 4.58 (sensitivity 0.94, specificity 0.69); in addition, the best cutoff point of TyG index for screening NASH was 4.59 (sensitivity 0.87, specificity 0.69). The positive and negative likelihood ratios were 3.03 and 0.08 for simple steatosis, and 2.80 and 0.18 for NASH. As compared versus SteatoTest, NashTest, Fatty liver index, and Algorithm, the TyG showed to be the best test for screening. CONCLUSIONS: TyG has high sensitivity and low negative likelihood ratio; as compared with other clinical biomarkers, the TyG showed to be the best test for screening simple steatosis and NASH.

Cooperativity of c-MYC with Krüppel-Like Factor 6 Splice Variant 1 induces phenotypic plasticity and promotes prostate cancer progression and metastasis.

Metastasis remains a major cause of morbidity and mortality in men with prostate cancer, and the functional impact of the genetic alterations, alone or in combination, driving metastatic disease remains incompletely understood. The proto-oncogene c-MYC, commonly deregulated in prostate cancer. Transgenic expression of c-MYC is sufficient to drive the progression to prostatic intraepithelial neoplasia and ultimately to moderately differentiated localized primary tumors, however, c-MYC-driven tumors are unable to progress through the metastatic cascade, suggesting that a "second-hit" is necessary in the milieu of aberrant c-MYC-driven signaling. Here, we identified cooperativity between c-MYC and KLF6-SV1, an oncogenic splice variant of the KLF6 gene. Transgenic mice that co-expressed KLF6-SV1 and c-MYC developed progressive and metastatic prostate cancer with a histological and molecular phenotype like human prostate cancer. Silencing c-MYC expression significantly reduced tumor burden in these mice supporting the necessity for c-MYC in tumor maintenance. Unbiased global proteomic analysis of tumors from these mice revealed significantly enriched vimentin, a dedifferentiation and pro-metastatic marker, induced by KLF6-SV1. c-MYC-positive tumors were also significantly enriched for KLF6-SV1 in human prostate cancer specimens. Our findings provide evidence that KLF6-SV1 is an enhancer of c-MYC-driven prostate cancer progression and metastasis, and a correlated genetic event in human prostate cancer with potential translational significance.

The triglycerides and glucose index is highly associated with non-alcoholic fatty liver disease in overweight and obese women.

BACKGROUND: Although some previous studies have indicated that the triglycerides and glucose (TyG) index is associated with an increased risk of non-alcoholic fatty liver disease (NAFLD), there are still few studies in this field. AIMS: The goal of this study was to assess whether the TyG index is associated with the presence of non-alcoholic fatty liver disease NAFLD in overweight and obese women. METHODS: Overweight and obese women aged 20 to 65 years were enrolled in a cross-sectional study and allocated into the groups with and without NAFLD. Alcohol consumption, pregnancy, normal-weight, positive markers of viral or autoimmune hepatitis, acute or chronic liver disease, renal disease, cardiovascular disease, neoplasia, and intake of hepatotoxic drugs were exclusion criteria. The diagnosis of NAFLD was established by liver ultrasound and the TyG index was calculated as the Ln [fasting triglycerides (mg/dL) × fasting glucose (mg/dL)]/2. RESULTS: A total of 420 participants were enrolled and allocated into the groups with (n = 212) and without (n = 208) NAFLD. In the overall population, the frequency of NAFLD was 50.4%. The logistic regression analysis adjusted by body mass index, waist circumference, and total body fat showed that total cholesterol (OR = 1.004; 95% CI: 1.000-1.007), triglycerides (OR = 1.002; 95% CI: 1.000-1.004), AST (OR = 1.19; 95% CI: 1.15-1.23), ALT (OR = 1.20; 95% CI: 1.15-1.25), and TyG index (OR = 3.15; 95% CI: 1.64-6.06) are significantly associated with NAFLD. CONCLUSIONS: The results show that the TyG index is highly associated with the presence of NAFLD in women with overweight and obesity.

Decrease of aminotransferase levels in obese women is related to body weight reduction, irrespective of type of diet.

OBJECTIVE: To evaluate the efficacy of low carbohydrate diet (LCD) as compared with low fat diet (LFD) to decrease aminotransferase levels in obese women with nonalcoholic fatty liver disease. MATERIAL AND METHODS: A total of 59 women were randomly enrolled in a non-controlled clinical intervention study to receive either LCD or LFD during six months. Apparently healthy non-pregnant obese women aged 20 to 65 years were eligible to participate. Previous diagnosis of hepatic disease, serum creatinine level ≥ 1.5 mg/dL, severe life-limiting medical illness, pregnancy, active participation in other dietary program, use of weight loss drugs, or alcohol consumption ≥ 30 g per day were exclusion criteria. RESULTS: A total of 31 obese women who received LCD were compared with 28 women allocated in the LFD group. There were 3 (LCD group) and 2 (LFD group) women with lost of follow-up. No differences in the proportion of type 2 diabetes, hypertension and hyperlipidemia were noted between women in the LCD and LFD groups. At end of follow-up, there were not significant statistical differences in the anthropometric and biochemical characteristics between women in both groups. The weight loss was 5.7 and 5.5% for women in the LCD LFD groups. Although the decrease of AST (31.7 and 22.4%) and ALT (41 and 33.3%) levels was more elevated in the women of LCD group, as compared with the LFD group, there were not significant statistical differences. CONCLUSIONS: Our results show that weight loss, irrespective of the type of diet, reduces aminotransferase levels in obese women with NAFLD.

ESI-MS Identification of the Cationic Phosphine-Ligated Gold Clusters Au1-22: Insight into the Gold-Ligand Ratio and Abundance of Larger Clusters.

Triphenylphosphine (PPh3)-ligated gold nanoclusters are valuable for a number of potential applications due to their relative ease of synthesis and usefulness in forming advanced cluster architectures. While previous studies have reported cationic PPh3-ligated gold clusters with core sizes of Au1-4, Au6-11, and Au13-14, there has not been definitive identification by mass spectrometry of many larger clusters in the Au12-25 range. Herein, we survey a polydisperse solution of cationic PPh3-ligated gold clusters using high-mass-resolution (M/ΔM = 60,000) electrospray ionization mass spectrometry (ESI-MS). To improve the sensitivity and mass resolution of larger clusters for unambiguous identification, we increased the number of scan averages and reduced the range of mass collection windows to 200 m/z, thereby mitigating potential mass and ion abundance bias resulting from smaller "building block" gold clusters that are present in much higher abundance in solution. In addition to the previously reported clusters, we identify several new species including Au5(PPh3)5+, Au12(PPh3)9HCl2+, Au15(PPh3)9Cl2+, Au16(PPh3)10Cl22+, Au17(PPh3)113+, Au18(PPh3)102+, Au19(PPh3)10Cl2+, Au20(PPh3)12H33+, Au21(PPh3)10Cl2+, and Au22(PPh3)10Cl22+, indicating that a full range of clusters between Au1-22 may be observed in a single polydisperse solution. Considering all of the clusters observed, our findings provide evidence that the Au12-14 size range is a critical transition point in cluster nucleation. While smaller clusters exhibit a 1:1 gold-to-ligand ratio, larger clusters (beginning Au12-14) feature additional gold atoms without an equal number of accompanying ligands. Our results support previous evidence in the literature indicating that the "magic number" icosahedral Au13 geometry is the smallest cluster size where a ligand-less central gold atom is coordinated by a complete shell of 12 surrounding ligated gold atoms, thereby creating a stable "one-shell" cluster. Furthermore, our findings reinforce growing evidence that ligands may be used to actively direct gold cluster size and abundance during synthesis. While for PPh3-ligated systems the most abundant species are Au6-9 clusters, we find that for related methyldiphenylphosphine (PPh2Me) and dimethylphenylphosphine (PPhMe2)-ligated systems the most abundant cluster sizes are Au10-11 and Au12-14, respectively. Together, we demonstrate that reducing the range of m/z collection windows and increasing the number of scan averages dramatically improves instrument sensitivity for cationic gold clusters, enabling thorough characterization of polydisperse solutions that is not possible using conventional techniques.

Ion Mobility Spectrometry Characterization of the Intermediate Hydrogen-Containing Gold Cluster Au7(PPh3)7H52.

We employ ion mobility spectrometry and density functional theory to determine the structure of Au7(PPh3)7H52+ (PPh3 = triphenylphosphine), which was recently identified by high mass resolution mass spectrometry. Experimental ion-neutral collision cross sections represent the momentum transfer between the ionic clusters and gas molecules averaged over the relative thermal velocities of the colliding pair, thereby providing structural insights. Theoretical calculations indicate the geometry of Au7(PPh3)7H52+ is similar to Au7(PPh3)7+, with three hydrogen atoms bridging two gold atoms and two hydrogen atoms forming single Au-H bonds. Collision-induced dissociation products observed during IMS experiments reveal that smaller hydrogen-containing clusters may be produced through fragmentation of Au7(PPh3)7H52+. Our findings indicate that hydrogen-containing species like Au7(PPh3)7H52+ act as intermediates in the formation of larger phosphine ligated gold clusters. These results advance the understanding and ability to control the mechanisms of size-selective cluster formation, which is necessary for scalable synthesis of clusters with tailored properties.

Nonalcoholic fatty liver disease in asymptomatic obese women.

OBJECTIVE: To determine the clinical characteristics of NAFLD in asymptomatic obese women. METHODS: A total of 457 asymptomatic obese women were enrolled in a cross-sectional study and allocated into groups with and without NAFLD. Irrespective of ALT levels, diagnosis of NAFLD was established by ultrasonographic findings; irrespective of fibrosis, NASH was defined by hepatic histological changes. RESULTS: One hundred ninety five (42.7%) women had elevated ALT levels. Diagnosis of NAFLD was established in 228 (49.9%) women; among women with NAFLD, 34 (14.9%) have ALT levels within the normal range. On the other hand, based on the healthy range for ALT levels (19 UI/L), 336 (73.5%) women had elevated ALT, but only 2 (0.9%) women with NAFLD exhibited ALT levels within normal healthy values. Furthermore, 93 (41%) women who had AST/ALT levels (3) 1 underwent liver biopsy; of these, 90 (96.8%) had diagnosis of NASH and 3 (3.2%) of hepatic cirrhosis. Women with NAFLD were more obese and have higher fasting plasma glucose, triglycerides, ALT, and AST levels than obese women without NAFLD. Seventy six (16.6%) women had diagnosis of diabetes; of these 47 (61.8) in the NAFLD group. CONCLUSIONS: Results of this study support the statement that women with NAFLD have an adverse metabolic profile. Furthermore, our results show that hyperglycemia, hypertriglyceridemia and markers of liver injury such as AST/ALT > or = 1 may be useful for early recognition of NAFLD.

Dyslipidemia as a risk factor for liver fibrosis progression in a multicentric population with non-alcoholic steatohepatitis.

Background: Nonalcoholic fatty liver disease (NAFLD) is a serious worldwide health problem, with an estimated global prevalence of 24%; it has a notable relationship with other metabolic disorders, like obesity and type 2 diabetes mellitus (T2DM). Nonalcoholic steatohepatitis (NASH) is one of the most important clinical entities of NAFLD, which is associated with an increased risk of progression to liver cirrhosis and hepatocellular carcinoma (HCC). Mexico is one of the countries with the highest prevalence of metabolic diseases; therefore, we sought to investigate the impact that these clinical entities have in the progression to advanced fibrosis in Mexican patients with NASH. Methods: We performed a multicenter retrospective cross-sectional study, from January 2012 to December 2017. A total of 215 patients with biopsy-proven NASH and fibrosis were enrolled. NASH was diagnosed according NAS score and liver fibrosis was staged by the Kleiner scoring system. For comparing the risk of liver fibrosis progression, we divided our sample into two groups. Those patients with stage F0-F2 liver fibrosis were included in the group with non-significant liver fibrosis (n=178) and those individuals with F3-F4 fibrosis were included in the significant fibrosis group (n=37). We carried out a multivariate analysis to find risk factors associated with liver fibrosis progression. Results: From the 215 patients included, 37 had significant liver fibrosis (F3-4). After logistic regression analysis T2DM (p=0.044), systemic arterial hypertension (p=0.014), cholesterol (p=0.041) and triglycerides (p=0.015) were the main predictor of advanced liver fibrosis. Conclusions: In a Mexican population, dyslipidemia was the most important risk factor associated with advanced liver fibrosis and cirrhosis.

Adding cognitive behavioural treatment to either low-carbohydrate or low-fat diets: differential short-term effects.

To evaluate the efficacy of adding cognitive behavioural treatment (CBT) to either a low-carbohydrate (LC) diet or a low-fat (LF) diet in the treatment of weight loss of obese women, a randomised clinical intervention study was performed. A total of 105 healthy non-pregnant obese women (average age and BMI of 45.4 (sd 10.4) years and 36 (sd 4.3) kg/m2) were randomly allocated to the CBT or control (C) groups; within each group, women were randomly selected to receive either the LC or LF diet during 6 months. The pre-planned primary trial end-point was the weight loss. Differences between the groups were assessed using one-way ANOVA. There were three women (2.8 %) who dropped out, all of them in the CBT group. No differences in the anthropometric and laboratory characteristics at baseline were noted between women in the CBT (n 52) and control groups (n 50). Intention-to-treat analysis showed that weight loss in the CBT-LC (90 (sd 12.3) to 82.1 (sd 12.1) kg) and C-LC (89.4 (sd 10.0) to 85.8 (sd 9.8) kg) groups reached 8.7 and 4.0 %, respectively (P < 0.0001), and in the CBT-LF (87.9 (sd 11.4) to 79.4 (sd 11.8) kg) and C-LF (88.8 (sd 14.5) to 85.3 (sd 14.3) kg) groups it was 9.7 and 3.9 %, respectively (P < 0.05). Weight loss was higher in the CBT-LF group than in the CBT-LC groups (P = 0.049). The present results showed that adding CBT to either the LF or LC diet produced significantly greater short-term weight loss in obese women compared with diet alone. These finding support the efficacy of CBT in breaking previous dietary patterns and in developing healthier attitudes that reinforce a healthier lifestyle.

[Risk factors associated with upper gastrointestinal bleeding and with mortality]. / Factores de riesgo asociados a hemorragia del tubo digestivo alto y su mortalidad.

OBJECTIVE: to determine the associated risk factors with upper gastrointestinal bleeding (UGIB) and mortality in subjects with peptic ulcer. METHODS: a total of 345 subjects with peptic ulcer, < 60 years of age, were enrolled in a cross-sectional study. Subjects were allocated into one of two groups in accordance with the presence of UGIB. A logistic regression model, adjusted by age and sex, was used to compute the relationship between the risk factors and both UGIB and mortality. RESULTS: smoking (OR = 2.6, CI 95 % = 1.2-8.7), alcohol consumption (OR = 4.8, CI 95 % = 1.4-10.5), and previous history of UGIB (OR = 1.8, CI 95 % = 1.1-9.7) were strongly and independently associated with UGIB; chronic obstructive pulmonary disease (OR = 1.9, CI 95 % = 1.2-11.4), and high blood pressure (OR = 1.4, CI 95 % = 1.1- 7.5) were associated with mortality in UGIB. CONCLUSIONS: the associated risk factors with UGIB in patients with peptic ulcer were: age lower than 60 years; smoking; history of UGIB; and alcohol consumption. The chronic obstructive pulmonary disease and high blood pressure were associated with mortality in UGIB.

Risk factors associated with nonalcoholic fatty liver disease and its relationship with the hepatic histological changes.

OBJECTIVE: The objective of this study is to determine the association between risk factors and nonalcoholic fatty liver disease (NAFLD), and to establish the relationship between risk factors and hepatic histological changes in obese women. METHODS: A case-control design study. Women with NAFLD (cases) were compared with a control group of obese women without NAFLD matched by age, body mass index, waist circumference, and body fat. Irrespective of serum aminotransferases levels, diagnosis of NAFLD was established by the presence of type II diabetes, hypertriglyceridemia, and ultrasonographic changes of hepatic steatosis. Diagnosis of nonalcoholic steatohepatitis was performed by a liver biopsy. Women with an aspartate aminotransferase/alanine aminotransferase (ALT) ratio of at least 1 underwent liver biopsy. Alcohol consumption, hepatitis, and drugs that promote cholestasis or liver injury were the exclusion criteria. Multiple regression analysis was used to compute the association between the risk factors and NAFLD, and Spearman's analysis was used to examine its relationship with histological hepatic changes. RESULTS: A total of 108 obese women were enrolled. The frequency of high blood pressure, hypertriglyceridemia, and diabetes was similar between the groups. ALT (54.4+/-33.3 and 39.8+/-29.8, P=0.03) but not aspartate aminotransferase (45.4+/-23.1 and 36.7+/-21.2, P=0.06) was significantly higher in the women with NAFLD. The multivariate regression analysis showed a significant association of ALT (odds ratio 2.7; 95% confidence interval, 1.3-10.4), but not other variables with NAFLD. Type II diabetes was strongly correlated with ballooning and inflammation, and ALT with inflammation and fibrosis. CONCLUSION: Obese women with similar metabolic alterations exhibit different hepatic outcomes. Elevation of ALT, but not other risk factors, was associated with NAFLD. Diabetes and ALT correlate with histological hepatic changes.

Order type dataset analysis for fiducial markers.

Order Type (OT) describes a point set avoiding the use of metric information. We show that OT is a descriptor which is invariant to Euclidean geometric transformations, change of scale and perspective projection. In this paper we provide the data related to the application of Order Type with sets of 5, 6, 7, and 8 points to build fiducial markers. The OT is represented through a λ -matrix. We provide the set of points which are suitable to solve directly the point matching, because these have a unique associated λ -matrix. We provide maximal perturbation data for all set of points, maximal perturbation is the radius of the circle, centered in each point in the set, inside which each point can be moved without changing its associated OT. Also we provide the scripts to validate the use of OT in fiducial markers.

Current trends of liver cirrhosis in Mexico: Similitudes and differences with other world regions.

AIM: To investigate the main current etiologies of cirrhosis in Mexico. METHODS: We performed a cross-sectional retrospective multicenter study that included eight hospitals in different areas of Mexico. These hospitals provide health care to people of diverse social classes. The inclusion criteria were a histological, clinical, biochemical, endoscopic, or imaging diagnosis of liver cirrhosis. Data were obtained during a 5-year period (January 2012-December 2017). RESULTS: A total of 1210 patients were included. The mean age was 62.5 years (SD = 12.1), and the percentages of men and women were similar (52.0% vs 48.0%). The most frequent causes of liver cirrhosis were hepatitis C virus (HCV) (36.2%), alcoholic liver disease (ALD) (31.2%), and nonalcoholic steatohepatitis (23.2%), and the least frequent were hepatitis B virus (1.1%), autoimmune disorders (7.3%), and other conditions (1.0%). CONCLUSION: HCV and ALD are the most frequent causes of cirrhosis in Mexico. However, we note that non-alcoholic fatty liver disease (NAFLD) as an etiology of cirrhosis increased by 100% compared with the rate noted previously. We conclude that NAFLD will soon become one of the most frequent etiologies of liver cirrhosis in Mexico.

Functional variants in the LRRK2 gene confer shared effects on risk for Crohn's disease and Parkinson's disease.

Crohn's disease (CD), a form of inflammatory bowel disease, has a higher prevalence in Ashkenazi Jewish than in non-Jewish European populations. To define the role of nonsynonymous mutations, we performed exome sequencing of Ashkenazi Jewish patients with CD, followed by array-based genotyping and association analysis in 2066 CD cases and 3633 healthy controls. We detected association signals in the LRRK2 gene that conferred risk for CD (N2081D variant, P = 9.5 × 10-10) or protection from CD (N551K variant, tagging R1398H-associated haplotype, P = 3.3 × 10-8). These variants affected CD age of onset, disease location, LRRK2 activity, and autophagy. Bayesian network analysis of CD patient intestinal tissue further implicated LRRK2 in CD pathogenesis. Analysis of the extended LRRK2 locus in 24,570 CD cases, patients with Parkinson's disease (PD), and healthy controls revealed extensive pleiotropy, with shared genetic effects between CD and PD in both Ashkenazi Jewish and non-Jewish cohorts. The LRRK2 N2081D CD risk allele is located in the same kinase domain as G2019S, a mutation that is the major genetic cause of familial and sporadic PD. Like the G2019S mutation, the N2081D variant was associated with increased kinase activity, whereas neither N551K nor R1398H variants on the protective haplotype altered kinase activity. We also confirmed that R1398H, but not N551K, increased guanosine triphosphate binding and hydrolyzing enzyme (GTPase) activity, thereby deactivating LRRK2. The presence of shared LRRK2 alleles in CD and PD provides refined insight into disease mechanisms and may have major implications for the treatment of these two seemingly unrelated diseases.

Insulin resistance is associated with elevated transaminases and low aspartate aminotransferase/alanine aminotransferase ratio in young adults with normal weight.

OBJECTIVE: The aim of this study is to determine whether insulin resistance is associated with elevation of transaminases levels and aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ratio in normal-weight healthy young adults. PARTICIPANTS AND METHODS: Apparently healthy nonpregnant women and men, aged 18-23 years, were enrolled in a cross-sectional study. According to the homeostasis model assessment of insulin resistance, the participants were allocated into groups of patients with (>2.5) and without (≤2.5) insulin resistance. Normal weight was defined by BMI of at least 18.5 and less than 25.0 kg/m. A multiple logistic regression analysis was carried out to determine the association between insulin resistance and elevated transaminases and AST/ALT ratio of 1 or less. RESULTS: A total of 1732 young adults were enrolled and allocated into groups with (n=287) and without (n=1445) insulin resistance. The prevalence of insulin resistance was 16.6% in the overall population. The multivariate logistic regression analysis adjusted by age, sex, waist circumference, and BMI indicated that the odds ratio (OR) between insulin resistance and elevated ALT concentrations is 1.65 [95% confidence interval (CI): 1.04-2.62, P=0.03], for AST/ALT ratio lower than 1 OR is 1.69 (95% CI: 1.27-2.26, P<0.001), and for elevated AST levels OR is 1.31 (95% CI: 0.71-2.43, P=0.377). CONCLUSION: The results of the present study suggest that insulin resistance is significantly associated with elevated ALT levels and AST/ALT ratio of lower than 1, but not with elevated AST levels.