Non-alcoholic fatty liver disease in a young multiracial Asian population: a worrying ethnic predilection in Malay and Indian males

Purpose

Previous studies on multiracial Malaysian populations found inordinately high prevalence of NAFLD among Malays and Indians. Whether the prevalence of NAFLD is different among young adults of different ethnic origins is not known. We aimed to determine racial differences in NAFLD in a young multiracial Malaysian population and associated factors.

Methods

This was a cross-sectional study on medical students from the University of Malaya. Diagnosis of NAFLD was by transabdominal ultrasonography and following exclusion of significant alcohol intake and other causes of chronic liver disease.

Results

Data of 469 subjects were analyzed (mean age 23.2 ± 2.4 years, 40.3 % male). The racial distribution was: Chinese 53.9 %, Malay 30.5 % and Indian 15.6 %. The overall prevalence of NAFLD was 7.9 %. Subjects with NAFLD were older, had greater BMI and WC, higher SBP and DBP, higher FBS, serum TG and LDL levels, and lower serum HDL level. The prevalence of NAFLD was higher among males compared to females (17.9 % vs. 3.3 %, p < 0.001). The highest prevalence of NAFLD was seen among Indian and Malay males at 33.3 and 25.5 %, respectively, compared to Chinese males at 6.8 % (p < 0.001). No significant difference was seen among females of different races. Independent factors associated with NAFLD were male gender, obesity and hypertriglyceridemia.

Conclusions

The difference in prevalence of NAFLD among the different ethnic groups can be observed as early as young adulthood. An inordinately high prevalence of NAFLD was observed among Malay and Indian males consistent with the higher prevalence of obesity in these groups.     

Confusing untypical intestinal Behcet's disease:Skip ulcers with severe lower gastrointestinal hemorrhage

Behcet's disease(BD) is a rare and life-long disorder characterized by inflammation of blood vessels throughout the body. BD was originally described in 1937 as a syndrome involving oral and genital ulceration in addition to ocular inflammation. Intestinal BD refers to colonic ulcerative lesions documented by objective measures in patients with BD. Many studies have shown that over 40% of BD patients have gastrointestinal complaints. Symptoms include abdominal pain, diarrhea, nausea, anorexia and abdominal distension. Although gastrointestinal symptoms are common, the demonstration of gastrointestinal ulcers is rare. This so-called intestinal BD accounts for approximately 1% of cases. There is no specific test for BD, and the diagnosis is based on clinical criteria. The manifestations of intestinal BD are similar to those of other colitis conditions such as Crohn's disease or intestinal tuberculosis, thus, it is challenging for gastroenterologists to accurately diagnose intestinal BD in patients with ileocolonic ulcers. However, giant ulcers distributed in the esophagus and ileocecal junction with gastrointestinal hemorrhage are rare in intestinal BD. Here, we present a case of untypical intestinal BD. The patient had recurrent aphthous ulceration of the oral mucosa, and esophageal and ileo-colonic ulceration, but no typical extra-intestinal symptoms. During examination, the patient had massive acute lower gastrointestinal bleeding. The patient underwent ileostomy after an emergency right hemicolectomy and partial ileectomy, and was subsequently diagnosed with incomplete-type intestinal BD by pathology. The literature on the evaluation and management of this condition is reviewed.     

Association between serum adipocytokine levels and microangiopathies in patients with type 2 diabetes mellitus

Aims/Introduction

It is thought that adipocytokines contribute to the increased risk of vascular complications in type 2 diabetes. However, there is still limited information on the relationship between microangiopathies and adipocytokines, such as adiponectin, leptin and tumor necrosis factor‐α (TNF‐α) in patients with type 2 diabetes.

Materials and Methods

The present study examined the relationship between fasting serum adiponectin, leptin, and TNF‐α levels and microangiopathies in Korean type 2 diabetes. A total of 153 patients were recruited and evaluated for diabetic nephropathy, retinopathy and neuropathy. Serum adiponectin, TNF‐α and leptin levels were measured.

Results

Serum adiponectin levels were significantly lower in patients with nephropathy than in those without nephropathy (P = 0.017), and were significantly higher in patients with retinopathy or neuropathy than those without retinopathy or neuropathy (P = 0.01 and P = 0.002, respectively). The mean levels of leptin were significantly higher in patients with neuropathy than in those without neuropathy (P = 0.002). The mean levels of TNF‐α were not significantly different according to any of the three microangiopathies. Multivariate logistic regression analysis showed that the odds ratio for the presence of neuropathy in the highest tertile of adiponectin was 4.3 (95% confidence interval 1.59–11.62), as compared with the patients in the lowest tertile of adiponectin level.

Conclusions

Levels of adipocytokines were significantly different according to the presence of each microangiopathy. In particular, higher serum adiponectin was independently associated with increased odds for the presence of neuropathy. Future prospective studies with larger numbers of patients are required to establish a direct relationship between plasma adipocytokine concentrations and the development or severity of diabetic microangiopathies.     

Pivotal role for the ubiquitin Y59-E51 loop in lysine 48 polyubiquitination

Lysine 48 (K48)-polyubiquitination is the predominant mechanism for mediating selective protein degradation, but the underlying molecular basis of selecting ubiquitin (Ub) K48 for linkage-specific chain synthesis remains elusive. Here, we present biochemical, structural, and cell-based evidence demonstrating a pivotal role for the Ub Y59-E51 loop in supporting K48-polyubiquitination. This loop is established by a hydrogen bond between Ub Y59’s hydroxyl group and the backbone amide of Ub E51, as substantiated by NMR spectroscopic analysis. Loop residues Y59 and R54 are specifically required for the receptor activity enabling K48 to attack the donor Ub-E2 thiol ester in reconstituted ubiquitination catalyzed by Skp1-Cullin1-F-box (SCF)^βTrCP E3 ligase and Cdc34 E2-conjugating enzyme. When introduced into mammalian cells, loop-disruptive mutant Ub^R54A/Y59A diminished the production of K48-polyubiquitin chains. Importantly, conditional replacement of human endogenous Ub by Ub^R54A/Y59A or Ub^K48R yielded profound apoptosis at a similar extent, underscoring the global impact of the Ub Y59-E51 loop in cellular K48-polyubiquitination. Finally, disulfide cross-linking revealed interactions between the donor Ub-bound Cdc34 acidic loop and the Ub K48 site, as well as residues within the Y59-E51 loop, suggesting a mechanism in which the Ub Y59-E51 loop helps recruit the E2 acidic loop that aligns the receptor Ub K48 to the donor Ub for catalysis.Central to selective protein turnover by the 26S proteasome is the formation of homotypic lysine 48 (K48)-linked ubiquitin (Ub) chains that tag substrate proteins for degradation (1). Among the most extensively studied systems that produce K48-linked Ub chains is the SCF (Skp1-Cullin1-F-box) E3-directed ubiquitination. SCF is a member of the multisubunit Cullin-RING E3 Ub ligase (CRL) family, the largest of all E3s (2). CRL contains a tandem of a large scaffold protein [Cullin (CUL)] and a RING domain-containing protein (ROC1/Rbx1) that typically associates with an adaptor protein (such as Skp1) in complex with a substrate recognition protein (such as F-box protein). As such, the organization of CRL subunits positions the substrate receptor (such as the F-box protein) within the proximity of ROC1, which recruits an E2-conjugating enzyme that catalyzes the transfer of Ub to a bound substrate. In the SCF reconstitution system, K48-linked polyubiquitin chains on a substrate such as IκBα and β-catenin are produced in a two-step reaction. The E2 UbcH5c deposits the first Ub moiety, forming a substrate–Ub linkage, which is followed by repeated discharge of subsequent Ubs by E2 Cdc34 to form K48-specific Ub chains (3). Human Cdc34 contains a highly conserved charged acidic loop (residues 102–113) that participates in the elongation of K48 chains (4, 5). The current work addresses whether there are determinants on the Ub itself that dictate K48 linkage specificity and, moreover, how Cdc34 might recognize Ub K48.     

Copper is an endogenous modulator of neural circuit spontaneous activity

For reasons that remain insufficiently understood, the brain requires among the highest levels of metals in the body for normal function. The traditional paradigm for this organ and others is that fluxes of alkali and alkaline earth metals are required for signaling, but transition metals are maintained in static, tightly bound reservoirs for metabolism and protection against oxidative stress. Here we show that copper is an endogenous modulator of spontaneous activity, a property of functional neural circuitry. Using Copper Fluor-3 (CF3), a new fluorescent Cu⁺ sensor for one- and two-photon imaging, we show that neurons and neural tissue maintain basal stores of loosely bound copper that can be attenuated by chelation, which define a labile copper pool. Targeted disruption of these labile copper stores by acute chelation or genetic knockdown of the CTR1 (copper transporter 1) copper channel alters the spatiotemporal properties of spontaneous activity in developing hippocampal and retinal circuits. The data identify an essential role for copper neuronal function and suggest broader contributions of this transition metal to cell signaling.The foundation of cellular signal transduction relies on intricate chemical messenger systems that operate through the dynamic spatial and temporal regulation of elements, ions, and molecules. Nowhere is this concept better illustrated than in the brain, which extensively regulates fluxes of alkali and alkaline earth metals such as sodium, potassium, and calcium for a diverse array of signaling processes. Interestingly, the brain also accumulates among the highest levels of transition metals in the body (1–3), including redox-active copper. This high-redox metal load, in combination with the brain''s disproportionately active oxygen metabolism (4), makes this organ particularly susceptible to oxidative stress (4–6). As such, copper has been historically regarded as a tightly sequestered cofactor that must be buried within protein active sites to protect against reactive oxygen species generation and subsequent free radical damage chemistry. Indeed, elegant work continues to identify molecular players that maintain copper homeostasis in the brain (7, 8) and related organs (9–11), and loss of this strict regulation is implicated in neurotoxic stress (12–14) and a variety of neurodegenerative and neurodevelopmental disorders including Menkes (15, 16) and Wilson''s (17) diseases, familial amyotrophic lateral sclerosis (18, 19), Alzheimer''s (6, 14, 20–22) and Huntington''s (23, 24) diseases, and prion-mediated encephalopathies (14, 25, 26).Despite this long-held paradigm, emerging data also link pools of labile copper (defined as dynamic and loosely bound stores that undergo facile ligand exchange relative to static, tightly bound pools buried within protein active sites) to neurophysiology. Included are observations of ⁶⁴Cu efflux from stimulated neurons (12, 27), reversible trafficking of ATP7A from the perinuclear trans-Golgi to neuronal processes by NMDA receptor activation (12), effects of copper chelation on olfactory response to thiol odorants (28), and direct X-ray fluorescence imaging of copper translocation in neurons from somatic cell bodies to peripheral processes upon depolarization (29). Against this backdrop, we have initiated a program aimed at exploring the potential contributions of loosely bound forms of redox-active metals like copper in cell signaling. In this report, we identify a role for copper in the brain as a modulator of spontaneous activity, a fundamental property of developing neural circuits. The design and synthesis of Copper Fluor-3 (CF3), a fluorescent copper sensor based on a hydrophilic and tunable rhodol scaffold, along with Control Copper Fluor-3 (Ctrl-CF3), a matched control dye based on an identical fluorophore but lacking responsiveness to copper, enabled the visualization of loosely bound Cu⁺ in dissociated neurons and neural tissue by one- and two-photon microscopy. Disruption of Cu⁺ stores by acute application of a copper chelator or genetic knockdown of the copper ion channel CTR1 altered the spatiotemporal properties of spontaneous activity. In dissociated hippocampal cultures, these manipulations increased the correlation of spontaneous calcium transients, whereas in retina, both cell participation and frequency of correlated calcium transients increased.     

Impact of a Spatial Repellent on Malaria Incidence in Two Villages in Sumba,Indonesia

A randomized, double-blinded, placebo-controlled study was conducted to examine the effect of spatial repellent (SR) in households at risk of malaria in Indonesia. Following presumptive radical cure for malaria in 180 adult men representing sentinels of new infection in four clusters within two villages, all households were given either metofluthrin or placebo mosquito coils. Weekly blood smear screening and human-landing mosquito catches were done throughout the 6 months intervention. Malaria infections occurred in 61 subjects living in placebo households and 31 subjects living in SR coil households, suggesting a 52% protective effect of SR. Likewise, anopheles indoor human landing rates were 32% lower in homes receiving SR coils. Differences in the malaria attack rate between SR- and placebo-treated homes was significant when not accounting for the effects of clustering. When the analysis was adjusted for intra-cluster correlation, the differences between SR- and placebo-treated homes were not statistically significant. The findings provide evidence of SR public health benefit and support a larger trial statistically powered to detect those effects.