bluuebunny/crossref_metadata_2025 huggingface dataset:
P: 22 Deficit of Short Working Memory in Rat With Thioacetamide-Induced Progressive Acute Hepatic Encephalopathy Involving Serotonin Innervation and Astroglia Dysfunctions
Authors: El Khiat A. , El Hiba O. , Aitihya Mohamed , Tamegart L. , Draoui A. , El Fari R. , Gamrani H.
Published: September 2019

BACKGROUND:

Hepatic encephalopathy (HE) is defined as the whole neurological and neuropsychiatric disorders arising from both acute and chronic liver failures. Patients with chronic HE exhibited an impairment of learning and memory abilities as well as attention. The aim of the present study is to evaluate the progression of short working memory alteration in acute HE and to delineate the glial and the neuronal alterations which may underlie such cognitive impairment.

METHODS:

The study was performed in Sprague-Dawley rats with acute liver failure induced by thioacetamide (TAA) at a dose of 300 mg/kg i.p. Different stages of acute HE was defined as: 12 h, 24 h and 36 h following administration of TAA. Working memory was assessed by the T-Maze test via the percentage of alternation behavior, as well, an immunohistochemical analysis of GFAP in the hippocampus and serotonin (5-HT) within the dorsal Raphe nucleus (DRN).

RESULTS:

Our data showed a progressive loss of the alternation behavior, which was accompanied by a time dependent and region-specific changes of GFAP-immunoreactive astrocytes within the hippocampus together with a reduced 5-HT immunoreactivity within the DRN.

CONCLUSIONS:

Our data revealed for the first time, a progressive loss of short memory function in acute HE, resulting from acute liver dysfunction which may involve a possible gliopathy as well as a 5-HTergic dysfunctions.
P: 23 Prospective Study on Mortality of Acute on Chronic Liver Failure and Its Predictors
Authors: Bhatti Rehmatullah
Published: September 2019

BACKGROUND:

Acute on chronic liver failure (ACLF) is a well recognized entity, characterized by an acute liver insult in patients with underlying chronic liver disease leading to sudden deterioration of liver function and a high mortality. We aimed to determine hospital, 28 days and 12 weeks mortality of ACLF, its predictors and precipitating factors

METHODS:

We conducted a prospective descriptive study at AIMS (Asian institute of medical sciences, Hyderabad, Pak.) from January 2018 to December 2018. We enrolled patients of ACLF as defined by Asian Pacific Association for the Study of Liver (APASL, 2014) and collected data to determine cause, precipitating acute insult, organ failure, ACLF grade MELD, and CTP scores. Patients were followed to determine hospital, 28 days and 12 weeks mortality and its predictors.

RESULTS:

Total patients were 117 with mean age of 40.9 +- 13.9 years (range 12–85). Majority were males 86 (73.5%) and 31 (26.5%) were females. Majority of patients 55 (47%) were Hepatitis B Virus (HBV) positive, among them 24 (43.6%) were with HDV co-infection. The most common precipitating acute insult was SEPSIS 65 (55.6). Others were drug induce liver injury (DILI) 8 (6.8%), HEV acute hepatitis 7 (5.9), HDV superinfection 5 (4.3%), HBV flair 4 (3.4%), alcohol binge drinking 4 (3.4%), surgery 2 (1.7%), acute PVT 2 (1.7%), Upper GI Bleed 1 (0.9%) and 20 (17.1%) were unknown. Hospital mortality was 49 (41.9%), 28 days 71 (60.7%) and 12 weeks mortality was 103 (88.0%). Organ failure (P = 0.002), ACLF grade (P = 0.002), encephalopathy (P = 0.001), MELD (P = 0.01) and AKI (P = 0.02) were found to be predictors of mortality.

CONCLUSIONS:

Acute-on-chronic liver failure (ACLF) is an acute deterioration of liver function superimposed on Chronic Liver Disease with a high mortality. In our study HBV infection was the commonest cuase of CLD, and sepsis was the commonest acute insult. We found high hospital, 28 days and 12 weeks mortality. Organ failure, ACLF grade, encephalopathy, MELD score and AKI were found to be predictors of mortality of ACLF.
P: 29 Contributors to Balance Impairment in Adults With Cirrhosis and Hepatic Encephalopathy
Authors: Murphy Susan L. , Richardson James K. , Blackwood Jennifer A. , Martinez Beanna A. , Runyan Emily J. , Park Megan L. , Louissaint Jeremy , Tapper Elliot B.
Published: September 2019

BACKGROUND:

Falls are common and associated with significant morbidity for persons with cirrhosis and hepatic encephalopathy. In order to intervene with targeted rehabilitation efforts to reduce and prevent falls, a better understanding of mechanisms underlying balance deficits is needed. To this end, unipedal stance time (UST) is a useful measure of balance as it requires the integration of sensory, neurocognitive, and muscular factors.

METHODS:

We prospectively enrolled 119 outpatients with cirrhosis and history of hepatic encephalopathy from the hepatology clinic at Michigan Medicine. The primary outcome was UST. Each patient was evaluated for demographic and clinical factors [Child Turcotte Pugh (CTP) class, MELD score], physical function (grip-strength and hip-strength using lateral plank time), neurocognitive factors [Numbers Connection Test (NCT) A and B, recognition reaction time accuracy - ability to catch or inhibit catching an instrumented stick under 'lights on' and 'lights off' conditions within 400 ms], and sensory factors (lower limb vibratory sensation and visual contrast). Falls self-efficacy, perceived ability to perform different tasks without falling, was also assessed. We evaluated bivariate Pearson correlations and developed a linear regression model to identify significant contributors to balance impairment.

RESULTS:

Participants were 50% female, aged 62.9 + 7.3 years, 80% CTP A, 18% CTP B, 2% CTP C, with MELD 11 + 5. The mean UST was 12.7 + 9.9 seconds (median = 9.42 seconds, IQR = 19.26). In bivariate analyses, UST was most highly correlated with lateral plank time (r = 0.61), followed by recognition reaction time accuracy [total, percent correct in lights on, and in lights off conditions (r = 0.47, r = .36, r = .33)] and NCT A and B tests (each r = 0.27). In multivariable regression, 54% of variance in UST was explained by significant factors of plank time, recognition reaction time accuracy, falls self-efficacy, age, and CTP. Based on standardized beta coefficients, plank time, CTP of B or C, and recognition reaction time accuracy were the strongest predictors. For every second increase of plank time, UST increases by 0.26 seconds on average. If classified by CTP of B or C, UST decreases by 5.8 seconds. For each additional percent correct on recognition reaction time accuracy, UST increases by 0.12 seconds.

CONCLUSIONS:

The strongest factors associated with diminished balance, as indicated by UST, in this high fall-risk cirrhosis population are hip strength, clinical disease severity, and neurocognitive capacity. These findings support a rehabilitation approach that targets strengthening as well as neurocognitive training to address balance impairment.
P: 38 Rifaximin Reduces the Incidence of Spontaneous Bacterial Peritonitis, Variceal Bleeding and All-cause Admissions in Patients on the Liver Transplant Waiting List
Authors: Tranah Thomas , Salehi Shayon , Heaton Nigel , Heneghan Michael , Aluvihare Varuna , Patel Vishal , Shawcross Debbie
Published: September 2019

BACKGROUND:

Rifaximin reduces the risk of overt hepatic encephalopathy (HE) in patients with advanced chronic liver disease (ACLD) and is associated with significant reductions in hospitalisations and 30‐day readmissions. This study examined clinical outcomes of patients listed for liver transplantation with a diagnosis of HE on rifaximin compared to those naïve to the drug.

METHODS:

Patient records of those listed for liver transplantation over a 2-year period were retrospectively reviewed. Patients were included if they had at least two episodes of overt HE resulting in hospitalisation or were encephalopathic at the time of assessment. Information collected included patient demographics, aetiology of liver disease, disease severity scoring at transplant listing, concomitant medications and medical co-morbidities. Emergency admissions whilst on the waiting list for complications of ACLD in addition to requirement for prioritisation (UKELD score ≥63), duration on the waiting list (days) and mortality on the waiting list were recorded. Univariate and multivariate regression analyses were performed on acute admission and complication data (related to sepsis, acute variceal bleeding (AVB), HE and complications of ascites) with rifaximin use as the independent variable.

RESULTS:

Of the 622 patients listed for transplantation, 101 were listed with HE. 66 patients were treated with rifaximin and 35 were naïve at listing. Median MELD score was similar (15 [14–16)] rifaximin-treated and 16 [14–18] rifaximin-naïve). The use of lactulose was not significantly different between groups. Patients on the waiting list treated with rifaximin had an independent association with reduced all-cause admissions (P = 0.037), episodes of spontaneous bacterial peritonitis (P = 0.008) and AVB (P = 0.026). Mean length of hospital stay was 9 (95% CI 6–12) in the rifaximin-treated group vs 14 days (95% CI 7–21) in the rifaximin-naïve group. Multivariate regression analysis demonstrated that rifaximin was independently associated with an increase in days to readmission (adjusted effect estimate 71, 95% CI 3–140 days, P = 0.037) and reduced likelihood of requirement for prioritisation on the waiting list (odds ratio 0.29; 95% CI 0.89–0.93, P = 0.037).

CONCLUSION:

Rifaximin prescribed for HE in patients listed for liver transplantation improved outcomes on the waiting list with a significant reduction in admissions related to spontaneous bacterial peritonitis, ascites and AVB and indicating potential beneficial impacts of rifaximin beyond HE in ACLD.
P: 39 Modulation of the Urea Cycle Function by Toll-like Receptor 4 Signaling: A Potential Novel Therapeutic Target for Hyperammonemia and Hepatic Encephalopathy
Authors: Kerbert Annarein J. C. , Sharifi Yalda , Sheikh Mohammed , Engelmann Cornelius , Andreola Fausto , Jalan Rajiv
Published: September 2019

BACKGROUND:

Lipopolysaccharide (LPS) and ammonia act synergistically in mediating the severity of hepatic encephalopathy (HE) in cirrhosis. Although LPS results in neuroinflammation, it is not clear whether it induces hyperammonemia (HA) contributing to HE. This study addressed the following questions: 1) Does LPS worsen HA in cirrhosis? 2) Does treatment with an antagonist (TAK242) of the LPS receptor, toll-like receptor 4 (TLR4), prevent HA? 3) Is a TLR4 knock-out (TLR4-/-) animal protected from HA? 4) If so, what is the underlying mechanism? Do they have a more effective urea cycle?

METHODS:

Study 1: Sprague Dawley rats were treated with LPS (0.025 mg/kg, ip.) 4 weeks after bile duct ligation (BDL). 4 groups of rats were studied: sham (n = 4), BDL (n = 4), BDL+LPS (n = 6) and BDL+TAK242 (10 mg/kg ip.) 3 hours before LPS injection (n = 7). Study 2: 4 groups of mice were studied: wild type control (WTC, n = 7), WT with HA (WTH, n = 10), TLR4-/- control (TLR4-/-C, n = 10) and TLR4-/- with HA (TLR4-/-H, n = 10). HA was induced by adding 0.28M ammonium chloride to drinking water for 3 days. For both studies, plasma ammonia and liver gene expression (qPCR, data shown as 2^-ΔΔCT compared to sham/WT) of the 5 urea cycle enzymes (UCEs) were assessed. For study 2, protein expression of the key, rate-limiting enzyme carbamoyl phosphate synthetase 1 (CPS1) was also assessed (Western Blot, immunohistochemistry).

RESULTS:

Study 1: There was a stepwise increase in plasma ammonia throughout sham, BDL and BDL+LPS groups (P < 0.001). Pre-treatment with TAK242 prior to LPS injection in BDL rats was associated with a reduction in plasma ammonia (P < 0.01, Figure 1a) and a higher coma-free survival rate (100% vs. 15%). Gene expression of all UCEs showed a stepwise decrease throughout sham, BDL and BDL+LPS (all P < 0.05), which was prevented by TAK242 (all P < 0.05). This was most pronounced for CPS1, for which expression levels in the TAK242-treated group were restored to that of the sham animals (Figure 1b). Study 2: In TLR4-/- mice, the increase in plasma ammonia was less compared to WT mice (P < 0.001). Although no significant changes were found for gene expression of UCEs between groups, protein expression of CPS1 was significantly higher in TLR4-/- mice as compared to WT mice, as shown by both Western Blot and immunohistochemistry.

CONCLUSIONS:

These data suggest that TLR4 signaling contributes to the development of hyperammonemia by modulating the urea cycle function. Inhibition of TLR4 with TAK242 offers a potential novel therapy for HA and HE in cirrhosis.
P: 41 Precipitants of Hepatic Encephalopathy, In-hospital Mortality and Its Predictors
Authors: Ali Mashooque , Hassan Adil , Iqbal Javed , Bughio Ubedullah , Bhatti Rehmatullah , Ali Mohsin , Sadik Muhammad
Published: September 2019

BACKGROUND:

Hepatic encephalopathy (HE) is a common complication of liver dysfunction, including acute liver failure and liver cirrhosis. HE presents as a spectrum of neuropsychiatric symptoms ranging from subtle fluctuating cognitive impairment to coma. It is a significant contributor of morbidity in patients with liver disease. Common culprits include gastrointestinal bleeding, infection, constipation, hypokalemia, hyponatremia, and medications such as opiates and benzodiazepines. This study aim to evaluate the change in common precipitants of HE, in-hospital mortality and its predictors.

METHODS:

This descriptive study was conducted in Hepatology division of Asian Institute of Medical Sciences, Hyderabad, Pakistan from October 2018 to April 2019. A total of 82 cirrhotic patients with HE were included in the study. Frequency of precipitating factors were determined and in-hospital mortality was evaluated.

RESULTS:

A total of 82 cirrhotic patients with mean age 52.31 years, with males 62.2%. Common etiology for cirrhosis was HCV 64.63%, 56.09% were CTP B, 36.58% patients had MELD in between 11-15. According to West Haven criteria most common grades were Grade II 52.43%, Grade III 17% and Grade IV 16%. Most common precipitants were hyponatremia 18%, constipation 12%, hypokalemia 5%, infections 10%, variceal upper GI bleeding 4%, 24% had mixed precipitants and in 27% patients no precipitant found. 42.7% had Acute Kidney Injury (AKI) mostly associated with electrolyte imbalance. 70.7% were improved and discharged, 11% were expired, 18.3% discharged on request. AKI, SBP and Shock were associated with high mortality.

CONCLUSIONS:

Electrolyte imbalance, constipation and infections were leading causes of HE. AKI was independent predictor of HE and in-hospital mortality along with SBP and shock.
P: 56 Evaluation of Cognitive Dysfunction in Animal Models and Relatability to Human Disease
Authors: Cabrera-Pastor Andrea , Llansola Marta , Montoliu Carmina , Felipo Vicente
Published: September 2019

Animal models are essential to investigate the mechanisms responsible for the cognitive and motor alterations in minimal or clinical hepatic encephalopathy (HE). The characterization of these mechanisms allows identifying new therapeutic targets which modulation may improve neurological function in patients. Animal models also allow testing if treatments directed to modulate these targets improve cognitive and motor function. These studies require evaluation of cognitive and motor function in animal models. It is important to understand which tests can be performed in rodents, which cognitive and motor aspects are evaluated by the tests and how they can be related to cognitive and motor dysfunction in the patients. The earliest alterations in patients with minimal HE (MHE) include attention deficits, psychomotor slowing, impairment of visuo-motor and bimanual coordination, of working memory, spatial memory, long-term memory, spatial orientation, verbal learning, concentration, balance and equilibrium, associated with increased falls. To understand the mechanisms involved in each type of cognitive and motor alteration in MHE the behavioral tests in animal models should be designed to evaluate these neurological alterations by procedures that maximize the translatability to the human situation and the utility to evaluate treatments to improve cognitive and motor impairment. Many functions are evaluated in humans using pencil or computerized tests such as number connection tests, repetition of series of words or numbers, naming colors, and other actions which can't be reproduced exactly in animal models. Functions such as verbal learning can't be evaluated in animal models. However, a good number of cognitive and motor processes impaired in patients with MHE may be evaluated in rodents using appropriate behavioral tests. For example, a combination of properly designed tests in the radial maze, Morris water maze, object recognition and object location allows evaluating with high sensitivity working memory, reference memory and distinguishing the spatial and non-spatial components of working and reference memory. These components are altered in rats with MHE and different mechanisms are involved in the impairment of different components. Also, there are pharmacological treatments that restore selectively working or reference memory and spatial or non-spatial learning and memory in rats with MHE. There are also appropriate test to assess some motor alterations: hypokinesia, fine motor coordination or balance. Studies based on proper use of animal models will accelerate the advance in understanding the mechanisms involved in MHE and will open new therapeutic approaches to improve quality of life and life span of the patients.
P: 58 Prediction of Overt Hepatic Encephalopathy by the Continuous Reaction Time Method and the Portosystemic Encephalopathy Syndrome Test in Patients With Cirrhosis
Authors: Wernberg Charlotte , de Muckadell O. Schaffalitzky , Vilstrup Hendrik , Lauridsen Mette Munk
Published: September 2019

BACKGROUND:

Predicting overt hepatic encephalopathy (OHE) is of major importance because the condition is unpleasant, requires hospitalization, and partly preventable. The risk is related to pre-existing discrete cognitive defects, and a number of psychometric tests are validated for detection of such defects. For clinical practice it is recommended to apply two different tests. We used the Continuous Reaction Time test (CRT) and the Porto Systemic Encephalopathy Test (PSE), and examined their single and combined value for prediction of OHE in cirrhosis patients.

METHODS:

We studied 130 mentally unimpaired cirrhosis patients by the two tests and followed them up for on average 38.5 months. The CRT measures velocity and stability in motor reaction times to 150 repeated auditory. The PSE is a paper-and-pencil test measuring the duration of completing 5 tasks. We collected data on episodes of OHE during follow-up. The clinical course was analysed in patient groups according to the outcome of each test and of both tests together. No anti-HE treatment was initiated except for OHE.

RESULTS:

We observed 74 OHE events. The PHES was abnormal in 47 and predicted 31 OHE episodes among 14 patients (PPV = 29%, NPV of 75%, sens. 40%, spec. 65%). The CRT test was abnormal in 74/130 and predicted 54 OHE episodes among 23 patients (PPV = 31%, NPV = 78%, sens. 65%, spec. 46%). One or both tests were abnormal in 87/130 and predicted 60 OHE episodes among 27 patients (PPV = 31%, NPV = 81%, sens. 77%, spec. 40%). 43/130 had two normal tests but 8 experienced OHE and had 14 OHE-admissions.

CONCLUSIONS:

The combined use of PSE and CRT test identified 77% of patients who later experienced OHE while ruling out future OHE with an NPV of 81%.
P: 61 Attenuation of Neurological Symptoms of Type C Hepatic Encephalopathy by Selective Ablation of Neuronal FXR Expression
Authors: Grant Stephanie , Williams Elaina , Petrescu Anca , McMillin Matthew , Frampton Gabriel , DeMorrow Sharon
Published: September 2019

BACKGROUND:

Hepatic encephalopathy (HE) describes the neurological deficits that result from liver impairment. Liver disease is associated with an increase of circulating bile acids that can cross the blood brain barrier and activate FXR receptors in neurons. We have previously demonstrated that aberrant bile acid signaling via activation of neuronal FXR contributes to HE pathogenesis in rodent models of acute liver failure. However, a role for FXR-mediated bile acid signaling in HE due to chronic liver cirrhosis is undefined.

METHODS:

Neuron-specific FXR knockout mice were generated by crossing Floxed FXR mice (FXRfl) with SNAP-25 cre recombinase mice. The resulting mice were designated FXRΔneu. C57Bl/6 (WT), FXRfl, and FXRΔneu were treated with carbon tetrachloride (CCl4; 1 ml/kg) by oral gavage twice per week for 12 weeks. Neurobehavioral indices and neuromuscular deficits were assessed by open field test, rotarod, grip strength test and gait analysis. After 12 weeks, tissue was collected and liver damage was assessed by serum chemistry and H&E staining. Total bile acid content was assessed in the cortex and cerebellum using colorimetric assays. The expression of ASBT, FXR, and its downstream effector SHP was assessed by qPCR and immunofluorescence. Microglia activation was assessed by Iba1 immunofluorescence. The expression of proinflammatory cytokines were assessed by qPCR and EIA. In parallel, total bile acids, ASBT and FXR expression were assessed in brain tissue from cirrhotic patients with HE, compared to cirrhotics without HE and age- and gender-matched controls that had been collected and banked by the Australian Brain Bank Network.

RESULTS:

Total bile acid content was elevated in the cortex and cerebellum in CCl4-treated WT mice and in cirrhotic patients with HE, compared to cirrhotics without HE and non-liver impaired controls. Furthermore, ASBT, FXR and SHP expression were increased in the frontal cortex of mice and humans with HE, but not in non-HE control samples. WT and FXRfl mice treated with CCl4 had significant deficits observed in every neurobehavioral and neuromuscular test performed, as well as marked microglia activation and increased proinflammatory cytokine expression compared to vehicle-treated mice. These neurological deficits and neuroinflammation were attenuated in FXRΔneu mice after CCl4 treatment, even though liver damage was comparable in all genotypes of mice used.

CONCLUSIONS:

These data indicate that neuronal expression of FXR plays an important role in the development of HE. Specific targeting of FXR activation in the brain may be a potential therapeutic target for the management of HE.
P: 63 Animal Naming Test Is Highly Accurate and Reliable for Diagnosis of Minimal Hepatic Encephalopathy in Outpatients With Cirrhosis
Authors: Taneja Sunil , Agarwal Ankit , Chopra Madhu , Duseja Ajay , Dhiman Radha K.
Published: September 2019

BACKGROUND:

Background and Aims: Minimal hepatic encephalopathy (MHE) is the mildest form in the spectrum of hepatic encephalopathy that impairs health-related quality of life. PHES remains the gold standard for the diagnosis of this condition. Animal naming test (ANT) is reliable and sensitive tool for diagnosis of MHE and can also predict overt episodes of HE. We compared usefulness of PHES and ANT for the diagnosis of MHE and for the prediction of the development of overt episodes of HE.

METHODS:

Between July 2017 to June 2018, one hundred and three consecutive patients with liver cirrhosis without overt HE were subjected to PHES and ANT evaluation. MHE was diagnosed when the PHES was ≤−5. Receiver-operating characteristic (ROC) curve was used to determine the optimum cut-off of ANT value for the diagnosis of MHE. The best sensitivity and specificity was found at <14. Patients were followed-up every 3-6 months till October 2018.

RESULTS:

Thirty-seven (35.9%) patients had MHE as assessed by altered PHES. ANT (<14) was present in 36 (34.95%) patients with MHE with sensitivity of 89.19% and specificity of 95.7%, PPV of 91.67%, NPV of 94.03% and diagnostic accuracy of 93.20%. The area under the curve for diagnosis of MHE was 0.978 (95% CI 0.954–1.0). MHE patients had significantly lower ANT as compared to non MHE patients and controls (10.81 ± 0.324 vs 15.27 ± 0.147 vs 15.78 ± 0.192, respectively, P = 0.01). MHE patients had lower hand grip strength compared to non-MHE patients and the control group (Males: 26 vs 30 vs 38, Females 25 vs 28 vs 28, P > 0.05). PHES significantly correlated with Child-Pugh (r = −0.421, P = 0.001) and model for end-stage liver disease (MELD) (r = −0.345, P = 0.001) scores. ANT correlated with PHES (r = 0.752, P = 0.001) and also with Child-Pugh (r = −0.408, P = 0.001) and MELD (r = −0.318, P = 0.001) scores. During follow-up, 14 patients in MHE group and 4 in non-MHE group developed overt episodes of HE (P = 0.001). Out of 37 patients with abnormal PHES 14 patients developed overt HE on follow up and out of 36 patients with abnormal ANT 14 patients developed overt HE on follow up. 33 patients had both PHES and ANT abnormal. 4 patients had PHES abnormal and ANT normal. 3 patients had PHES normal and ANT abnormal.

CONCLUSIONS:

ANT is a highly accurate and reliable test for the diagnosis of MHE and prediction of overt episodes of HE in outpatients of cirrhosis as compared to PHES and correlates well with the Child-Pugh and MELD scores.
P: 71 Faecal Cytokine Profiling Provides Novel Insights Into Intestinal Barrier Disruption and Bacterial Translocation in Acute Decompensation of Cirrhosis
Authors: Gray Elizabeth H. , Riva Dr Antonio , Azarian Sarah , Williams Roger , Chokshi Shilpa , Patel Vishal C. , Edwards Lindsey A.
Published: September 2019

BACKGROUND:

Intestinal dysbiosis with gut barrier impairment (GBI) and bacterial translocation (BT) are recognised as central features of acutely decompensated cirrhosis (AD) and propagating hepatic encephalopathy (HE). Gut mucosal function is technically challenging to investigate, with a difficulty in obtaining representative tissue in cirrhotics and a paucity of non-invasive techniques. A novel assay we developed was to quantify faecal cytokines (FC) as surrogate makers of intestinal inflammation, compared to GBI markers and systemic cytokines.

METHODS:

Protein was extracted from faeces of patients with stable cirrhosis (SC; n = 16), AD (n = 48), and healthy participants (HC; n = 31). A multiplex panel of 13 cytokines were quantified by electrochemiluminescence or ELISA in paired faecal lysates and plasma. Intestinal epithelium-associated fatty acid binding protein 2 (FABP2) and intestinal-microbiota metabolite D-lactate, as markers of intestinal barrier disruption, were quantified by ELISA and colorimetric enzymatic assay, respectively.

RESULTS:

Median ages and MELD scores of AD vs SC patients were 61 (53–68) vs 55 (44–59) years and 18 (13–26) vs 8 (7.0–8.5), respectively. Male gender predominated (AD: 65%; SC: 75%) The causes of cirrhosis were alcohol, NAFLD and treated hepatitis C. Median venous ammonia levels were significantly higher in AD vs SC (51 [38–74] vs 36 [26–59], P = 0.027). Faecal IL-1β, IFN-γ, TNF-α, IL-21, IL-17A/F and IL-22 were significantly different in AD vs SC on univariate comparison (q < 0.01 all comparisons). Along with IL-1β, faecal IL-23 was significantly elevated in AD vs HC (P = 0.0007), important in promoting deleterious Th17 cell effector function. Faecal FABP2 and D-lactate (P < 0.0001 for both) and plasma FABP2 and D-lactate (P = 0.0004; P = 0.011) were significantly elevated in AD vs SC and AD vs HC, respectively, consistent with GBI. FABP2 was the faecal marker that correlated most strongly with disease scores (Spearman's rho: Child-Pugh 0.466, P < 0.0001; MELD 0.488, P < 0.0001). With the exception of IL-8, IL-12 & IL-23, faecal cytokines and D-lactate were more discriminant than circulating equivalent molecules in discriminating AD from SC by Principal Component Analysis (Figure 1).

CONCLUSIONS:

FC profiling represents a novel targeted approach to localised measurement of the intestinal cytokine milieu in cirrhosis, and in conjunction with D-lactate, demonstrates that progression to AD from SC may be a intestinally initiated and mediated process. The AD gut micro-environment may skew T cell priming away from restorative Tregs and towards inflammatory Th1/Th17 profiles, promoting epithelial barrier damage and preventing repair. These data provide insights into intestinal mucosal injury and GBI, as a novel pathobiology in AD and HE.
Tumor-induced osteomalacia: a clinical case report
Authors: Grebennikova Tatiana A. , Umiarova Diliara Sh. , Slashchuk Konstantin Y. , Degtyarev Mikhail V. , Rodionova Svetlana S. , Rumyantsev Pavel O. , Belaya Zhanna E.
Published: September 2019

Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome usually caused by small-sized tumors. Tumors secrete fibroblast growth factor 23 (FGF23), which has a phosphaturic effect. The clinical signs of TIO are non-specific, and include fatigue, bone pain and muscle weakness, which makes timely diagnosis of the disease difficult and treatment is often delayed.
Well-timed diagnosis is essential and combined with complete tumor resection it leads to complete relief of symptoms and good postoperative prognosis. In cases of undetected tumors, medical treatment with phosphate supplements and active vitamin D medications is usually successful, however, treatment is associated with numerous complications and side effects can be burdensome for the patients. Due to the risk of recurrence or metastasis, patients with TIO require long-term management and follow-up.
In this article, we present a clinical case of successful diagnosis and treatment of TIO in a young patient with type 1 diabetes mellitus.
Pilot study of 10-year absolute fracture risk assessment tool (FRAX®) introduction into the structure of undegraduate practical training "physician assistant” course
Authors: Popov Artem A. , Teplyakova Olga V. , Vorontsova Anna V. , Sarapulova Anastasia V. , Bogoslovskaya Larisa V.
Published: September 2019

Background: high fracture rates throughout the Eastern Europe and Central Asia region have been reported. Major fractures rate increasing, primary care physicians need to be aware of risk assessment and prevention tools.
Aims: The aim of this pilot study was to assess main issues of FRAX tool introduction into undergraduate medical education.
Material and methods: Russian version of the IOF approved presentation on FRAX application procedure, results assessment and interpretation as well as Russian Association for Osteoporosis clinical guidelines and reference to www.osteoporoz.ru site have been provided to 248 undergraduate medical students. To increase osteoporosis related issues study motivation the students were asked to apply the Russian version of on-line FRAX calculator to assess risk fracture in their close relatives of appropriate age. Also the students were asked to create a FRAX assessment based patient management program.
Results: 207 FRAX assessment reports were received as feedback. Derived intervention threshold was reached in 41 cases (19.8%), while in 45 reports (21.7%) body mass index (BMI) value was mistaken for a 10-year fracture risk. There were 123 cases of the students’ parents assessments. These subjects appeared to be quite young (median 48, range 42 – 62) and relatively healthy to report no fracture risk factors. The students’ grandparents or great-grandparents (68 cases) were assessed on rare occasions due to lack of information or absence of personal contacts between students and their relatives. The students reported appreciable difficulties in decision making. Lifestyle and diet modification were not included in 165 of recommendations, while calcium and vitamin D prescriptions were severely biased by TV advertising. The students reported that it was quite difficult for them to give the patients recommendations regarding the choice of drug and administration timeframe.
Conclusion: pilot study of FRAX introduction into undergraduate medical education helped to ascertain several gaps in teaching of osteoporosis diagnosis, prevention and treatment to be covered during undergraduate medical education
Desde la ficha de protección social al registro social de hogares, el nuevo instrumento de focalización en Chile. Una perspectiva desde los actores locales
Authors: Contreras Álvarez Jaime , Figueroa Aillañir Katherine
Published: September 2019

La presente investigación busca ahondar desde la perspectiva de los actores municipales, en la implementación del nuevo Registro Social de Hogares, como mecanismo de selección de beneficiarios, en las categorías de comportamiento de los usuarios y principales cambios del sistema. Se utilizaron encuestas a equipos comunales de las regiones de Biobío y Ñuble y entrevistas a actores claves. Se concluye que las familias continúan entregando información tergiversada al sistema, y una mayor incidencia del patrimonio en los criterios de focalización del instrumento, no obstante, es valorado positivamente por los actores locales.
Ketunggalan Titik Tetap Pada Pemetaan Kontraksi θ-ϕ di Ruang Metrik Parsial
Authors: Malahayati Malahayati
Published: September 2019

Paper ini mempelajari kontraksi θ-ϕ dan kontraksi tipe Kannan θ-ϕ serta beberapa teorema ketunggalan titik tetap  pada ruang metrik parsial. Selanjutnya membandingkan Teorema serupa yang telah dikemukakan oleh peneliti sebelumnya dan membahas contoh sebagai ilustrasi dari teorema yang dibahas.

[In this paper, we study the notions of θ-ϕ contraction and θ-ϕ Kannan Type contraction, and some fixed point theorem on partial metric spaces. The results presented in the paper study and consederation some previously results, we also give an example to illustrate our results.]
Aseksual Reproduction of Black Sea Cucumber from Jepara Waters
Authors: Hartati Retno , Zainuri Muhammad , Ambariyanto Ambariyanto , Redjeki Sri , Riniatsih Ita , Azizah Ria , Endrawati Hadi
Published: September 2019

Black sea cucumber or Lollyfish are trade name for Holothuria atra, one species of family Holothuriidae abundance in Jepara waters, especially in Panjang Island.  They inhabit on the seabed, in shallow waters on reefs and sand flats or in Seagrass meadows. Beside reproduce sexually, H. atra also do fission (biology), i.e. able to reproduce asexually by transverse fission. Monthly survey has been conducted for three months to determine frequency of fission among H. atra population in Panjang Island waters. In total 891 individu of H. atra inhabit in seagrass meadow mixed with rubble were examimed. In fissiparous sea cucumber, transverse fission are followed by regeneration and in this research identified from external observations. The fission state was divided into three category, i.e. closed wound (Category 1), little regeneration either posterior or anterior part (category 2), moderate regeneration either posterior or anterior part (category 3).   The result showed that the fission frequency was highest during end of rainy season in April (13,21%) and decreased during May (4,61%) and June (4,86%). Body regeneration seem happened fast, since the new individu sea cucumber at category 1 was low but high as category 3. The regeneration were related with the condition of environment.
Source Identification, Bioavailability, and Risk Assessment based on Geochemical Fractionation of Heavy Metals Pb, Cu, and Zn in Surface Sediments of Kelabat Bay, Bangka Island
Authors: Nugraha Mohammad Agung , Hudatwi Mu’alimah , Sari Fajar Indah Puspita Puspita
Published: September 2019

Although concentrations of many heavy metals has been measured totally, they may not give a good indicator for environmentally hazard to organism. The purpose of this study is to identify sources, determine bioavailability, and assess risk based on the geochemical fractionation of heavy metals Pb, Cu and Zn on the surface sediments of Kelabat Bay, Bangka Island. Fractionation of heavy metals was analyzed by sequential extraction. The concentrations of heavy metals Pb, Cu, and Zn in sediments ranged from 8.86-29.21 mg.kg-1 (average 16.85 mg /kg), 0.16-9.54 mg.kg-1 (average 4.39 mg.kg-1), and 25.58-237.24 mg.kg-1 (average 71.99 mg.kg-1). Pb and Zn in Kelabat Bay are more bound to non-residual fractions (F1+F2+F3) or non-resistant with a range of 60.63-89.87% and 47.98-84.66% that are mainly come from anthropogenic activities. Cu tend to be stored or bound to the residual fraction (F4) with a proportion of 97.7-100% meaning that it comes from natural sources. Based on the Risk Assessment Code (RAC), Pb have a low to moderate risk in the environment and Zn heavy metals are not at risk to low. These conditions indicate the potential for biological availability (bioavailability) of Pb and Zn in the inner bay waters. For heavy metals Cu is not at risk in the environment.
Fragile X syndrome, the search for a targeted treatment
Authors: Zeidler Shimriet , Willemsen Rob
Published: September 2019

Fragile X syndrome (FXS), the most common monogenetic cause of intellectual disability and autism spectrum disorders, is characterized by behavioral and physical problems. There is currently no adequate treatment available. While animal model studies seemed extremely promising, no success has been achieved in the larger clinical trials with human FXS patients. This short review describes the steps that have been taken in the development of a targeted treatment for FXS. Possible reasons for the lack of translation between animal models and human FXS patients are being explored and solutions are being proposed. The FXS story illustrates pitfalls and possibilities in translational research, that might especially be applicable for other neurodevelopmental disorders as well.
On unbounded commuting Jacobi operators and some related issues
Authors: Osipov Andrey
Published: September 2019

We consider the situations, when two unbounded operators generated by infinite Jacobi matrices, are self-adjoint and commute. It is found that if two Jacobi matrices formally commute, then two corresponding operators are either self-adjoint and commute, or admit a commuting self-adjoint extensions. In the latter case such extensions are explicitly described. Also, some necessary and sufficient conditions for self-adjointness of Jacobi operators are studied.
Sex differences in infant body composition emerge in the first 5 months of life
Authors: Davis Shanlee M. , Kaar Jill L. , Ringham Brandy M. , Hockett Christine W. , Glueck Deborah H. , Dabelea Dana
Published: September 2019

Background

Sex differences in body composition are appreciated throughout the lifespan with probable contributions from sex steroids: testosterone and estrogen. The purpose of this longitudinal observational study was to determine if sex differences in body composition emerge during the first months of life in healthy infants, corresponding to the age at which male infants produce endogenous testosterone.

Methods

Linear growth and body composition parameters using air displacement plethysmography were obtained from 602 healthy infants after birth and again at 5 months of age. Rate of change in body composition parameters were compared between sexes.

Results

Sex differences in length, total mass, fat free mass (FFM), and percent fat mass (%FM) were present both at birth and at 5 months (p < 0.001 for all), with males having greater total mass and FFM but lower %FM. Gain in %FM over the first 5 months was significantly lower in males (p = 0.0004). This difference was secondary to a gain of 17 g/week more in FFM in males compared to females.

Conclusions

Sex differences in body composition emerge in the first months of life, with lower adiposity accumulation in males. Endogenous testosterone production in males ~1–4 months of age may account for findings and may have lifelong implications for sex differences in body composition.
Screening of monogenic autoimmune diabetes among children with type 1 diabetes and multiple autoimmune diseases: is it worth doing?
Authors: Strakova Veronika , Elblova Lenka , Johnson Matthew B. , Dusatkova Petra , Obermannova Barbora , Petruzelkova Lenka , Kolouskova Stanislava , Snajderova Marta , Fronkova Eva , Svaton Michael , Lebl Jan , Hattersley Andrew T. , Sumnik Zdenek , Pruhova Stepanka
Published: September 2019

Background

Paediatric type 1 diabetes (T1D) and rare syndromes of monogenic multi-organ autoimmunity share basic features such as full insulin dependency and the presence of circulating beta-cell autoantibodies. However, the aetiopathogenesis, natural course and treatment of these conditions differ; therefore, monogenic multi-organ autoimmunity requires early recognition. We aimed to search for these monogenic conditions among a large cohort of children with T1D.

Methods

Of 519 children with T1D followed-up in a single centre, 18 had multiple additional autoimmune conditions – either autoimmune thyroid disease (AITD) and coeliac disease (CD) or at least one additional organ-specific autoimmune condition in addition to AITD or CD. These 18 children were tested by direct Sanger sequencing (four patients with a suggestive phenotype of immune dysregulation, polyendocrinopathy, enteropathy, X-linked [IPEX] or signal transducer and activator of transcription 3 [STAT3]- and cytotoxic T-lymphocyte protein 4 [CTLA4]-associated syndromes) or by whole-exome sequencing (WES) focused on autoimmune regulator (AIRE), forkhead box protein 3 (FOXP3), CTLA4, STAT3, signal transducer and activator of transcription 1 (STAT1), lipopolysaccharide-responsive and beige-like anchor protein (LRBA) and interleukin-2 receptor subunit α (IL2RA) genes. In addition, we assessed their T1D genetic risk score (T1D-GRS).

Results

We identified novel variants in FOXP3, STAT3 and CTLA4 in four cases. All patients had a severe phenotype suggestive of a single gene defect. No variants were identified in the remaining 14 patients. T1D-GRS varied among the entire cohort; four patients had scores below the 25th centile including two genetically confirmed cases.

Conclusions

A monogenic cause of autoimmune diabetes was confirmed only in four patients. Genetic screening for monogenic autoimmunity in children with a milder phenotype and a combination of AITD and CD is unlikely to identify a monogenic cause. In addition, the T1D-GRS varied among individual T1D patients.
Modeling Working Memory to Identify Computational Correlates of Consciousness
Authors: Reggia James A. , Katz Garrett E. , Davis Gregory P.
Published: September 2019

Recent advances in philosophical thinking about consciousness, such as cognitive phenomenology and mereological analysis, provide a framework that facilitates using computational models to explore issues surrounding the nature of consciousness. Here we suggest that, in particular, studying the computational mechanisms of working memory and its cognitive control is highly likely to identify computational correlates of consciousness and thereby lead to a deeper understanding of the nature of consciousness. We describe our recent computational models of human working memory and propose that three computational correlates of consciousness follow from the results of this work: itinerant attractor sequences, top-down gating, and very fast weight changes. Our current investigation is focused on evaluating whether these three correlates are sufficient to create more complex working memory models that encompass compositionality and basic causal inference. We conclude that computational models of working memory are likely to be a fruitful approach to advancing our understanding of consciousness in general and in determining the long-term potential for development of an artificial consciousness specifically.
Fundamental physical and chemical concepts behind “drug-likeness” and “natural product-likeness”
Authors: Athar Mohd , Sona Alfred Ndeme , Bekono Boris Davy , Ntie-Kang Fidele
Published: September 2019

The discovery of a drug is known to be quite cumbersome, both in terms of the microscopic fundamental research behind it and the industrial scale manufacturing process. A major concern in drug discovery is the acceleration of the process and cost reduction. The fact that clinical trials cannot be accelerated, therefore, emphasizes the need to accelerate the strategies for identifying lead compounds at an early stage. We, herein, focus on the definition of what would be regarded as a “drug-like” molecule and a “lead-like” one. In particular, “drug-likeness” is referred to as resemblance to existing drugs, whereas “lead-likeness” is characterized by the similarity with structural and physicochemical properties of a “lead”compound, i.e. a reference compound or a starting point for further drug development. It is now well known that a huge proportion of the drug discovery is inspired or derived from natural products (NPs), which have larger complexity as well as size when compared with synthetic compounds. Therefore, similar definitions of “drug-likeness” and “lead-likeness” cannot be applied for the NP-likeness. Rather, there is the dire need to define and explain NP-likeness in regard to chemical structure. An attempt has been made here to give an overview of the general concepts associated with NP discovery, and to provide the foundational basis for defining a molecule as a “drug”, a “lead” or a “natural compound.”
Modified Calculations of Lateral Displacement and Soil Pressure of Pile Considering Pile–Soil Interaction under Cyclic Loads
Authors: Luo Xiaoye , Huang Fuyun , Zhuang Yizhou , Wu Suiwen , Qian Haimin
Published: September 2019

A reciprocating low-cycle pseudostatic loading test on four prestress high-strength concrete (PHC) pipe piles was performed to study their failure modes and seismic behaviors. The distributions of lateral deformation and soil pressure along the piles as well as their analysis methods were studied. The test results show that with an increase in the embedded depth of pile, the soil pressure around the piles initially increased up to the maximum and then decreased or even reversed slightly at a certain depth. The pressure at shallower soil increased rapidly, up to nearly the ultimate passive earth pressure, while the pressure at the deeper soil increased relatively slowly. The results further indicate that the strain transformation method and m method were only appropriate for calculating the lateral displacements of piles under linear and small deformation but not suitable to calculate lateral displacement of piles under large deformation. Moreover, although the p–y curve method took into account the nonlinearity of soil, the calculated lateral displacement and soil pressure of pile still showed a significant difference with the test results, especially under large deformation. Furthermore, modified calculations of lateral displacement and soil pressure of pile were proposed based on regression analysis on the test results and existing p–y curve methods, respectively, and calculated results showed a good agreement with the test results in terms of lateral displacements and soil pressures. Therefore, they were recommended for analyzing the soil–pile interaction for pile foundations in integral abutments jointless bridges (IAJBs).