The role and ultrastructure of the liver sinusoidal endothelial cell in fasting, hepatoxicity, and ageing

The majority of liver studies focus on the hepatocyte however the work of this thesis investigates the vital role of the liver sinusoidal endothelial cell (LSEC). LSECs line the liver sinusoids forming a protective barrier between the blood and hepatocytes. The LSEC cytoplasm resembles a sieve, perforated with thousands of transcellular pores of approximately 50-150 nm in diameter called fenestrations, and is underlined by a very sparse extracellular matrix. This facilitates the virtually unimpeded passage of fluid and substances smaller than fenestrations from the blood such as drugs and nutrients, and size-dependent filtration of lipoproteins, to and from hepatocytes. Fenestrations are dynamic structures, in that their size and number can be modulated by hormones, drugs, hepatotoxins, and diseases. Reduction of LSEC fenestration size and number (defenestration) is associated with ageing and pathological states, and is also a cause of hyperlipidemia and reduced drug clearance, thus changes in LSEC morphology can affect the entire organism. This thesis aims to broaden knowledge of the role and ultrastructure of the LSEC in physiological and toxicological states by investigating: whether there is fenestration modulation during fasting that could facilitate increased nutrient exchange between the blood and hepatocytes; whether changes to LSEC ultrastructure during acetaminophen hepatotoxicity are consistent with exacerbation of liver injury and/or with the facilitation of liver regeneration after severe necrosis; whether a substance that targets the LSEC could have a therapeutic benefit in acetaminophen hepatotoxicity by protecting the microvasculature from damage; whether isolation and culture of LSECs from ageing rats maintain the ageing (defenestrated) phenotype, and thus whether it is a valid method to study therapeutic substances in vitro that could reverse defenestration-related ailments associated with normal ageing

An Asymptomatic Case of Wolff-Parkinson-White Syndrome with Right-sided Free-wall Accessory Pathway and Left Ventricular Dysfunction

AbstractA 16-year-old girl with a known history of asymptomatic Wolff-Parkinson-White syndrome exhibited signs of left ventricular (LV) septal akinesia and LV dysfunction during routine follow-up. A 12-lead surface ECG showed pre-excitation, a predominantly negative delta wave in V1 and left axis deviation, which was consistent with the presence of a right free-wall accessory pathway. Radiofrequency ablation of the anterolateral right atrium around the local shortest atrium-to-ventricle interval created the accessory pathway block. An echocardiogram taken one month after the procedure revealed that LV septal wall motion had normalized and that LV ejection fraction had improved from 50% before the ablation to 64% after the ablation. Most previous reports of asymptomatic patients of WPW with LV septal dyskinesia and dysfunction have described right septal or posteroseptal accessory pathways. This patient reported here represents a rare case with right free-wall accessory pathway and LV dysfunction without tachycardia

СумДУ на сторінках преси : поточний інформаційний список, липень-серпень 2018 р.

Поточний інформаційний список містить перелік статей про Сумський державний університет з періодичних видань, які надійшли до бібліотеки за липень-серпень

Astronomical Distance Determination in the Space Age: Secondary Distance Indicators

The formal division of the distance indicators into primary and secondary leads to difficulties in description of methods which can actually be used in two ways: with, and without the support of the other methods for scaling. Thus instead of concentrating on the scaling requirement we concentrate on all methods of distance determination to extragalactic sources which are designated, at least formally, to use for individual sources. Among those, the Supernovae Ia is clearly the leader due to its enormous success in determination of the expansion rate of the Universe. However, new methods are rapidly developing, and there is also a progress in more traditional methods. We give a general overview of the methods but we mostly concentrate on the most recent developments in each field, and future expectations. © 2018, The Author(s)

DESA1002 'Nine Quarter City' - Andrew Yi Xiang Huang

Treble Clef is a music school situated in Jerusalem, specialising in classical music and catering to young adults. The school is situated on its own block of land, allowing it to provide its students the impression of complete detachment from the outside world once inside, which has been achieved through the facade of the building. The two elements of the building are complete polar opposites. The exterior of the building aims to blend in with the surroundings. Jerusalem stone wraps around the outward faces in a monolithic fashion, with only strips of weatherproof maple timber reminiscent of polished string instruments, suggesting the function of the building as a school of the musical arts. The interior element opens the pedestrian into the world of music. Approaching from the south, a fluid and lyrical steel and glass tower heralds the entering into another world, where the people are the music

Carnitine-acylcarnitine translocase deficiency, clinical, biochemical and genetic aspects.

Carnitine-acylcarnitine translocase deficiency, clinical, biochemical and genetic aspects. Rubio-Gozalbo ME, Bakker JA, Waterham HR, Wanders RJ. Department of Pediatrics, University Hospital Maastricht, Maastricht, The Netherlands. [email protected] The carnitine-acylcarnitine translocase (CACT) is one of the components of the carnitine cycle. The carnitine cycle is necessary to shuttle long-chain fatty acids from the cytosol into the intramitochondrial space where mitochondrial beta-oxidation of fatty acids takes place. The oxidation of fatty acids yields acetyl-coenzyme A (CoA) units, which may either be degraded to CO(2) and H(2)O in the citric acid cycle to produce ATP or converted into ketone bodies which occurs in liver and kidneys. Metabolic consequences of a defective CACT are hypoketotic hypoglycaemia under fasting conditions, hyperammonemia, elevated creatine kinase and transaminases, dicarboxylic aciduria, very low free carnitine and an abnormal acylcarnitine profile with marked elevation of the long-chain acylcarnitines. Clinical signs and symptoms in CACT deficient patients, are a combination of energy depletion and endogenous toxicity. The predominantly affected organs are brain, heart and skeletal muscle, and liver, leading to neurological abnormalities, cardiomyopathy and arrythmias, skeletal muscle damage and liver dysfunction. Most patients become symptomatic in the neonatal period with a rapidly progressive deterioration and a high mortality rate. However, presentations at a later age with a milder phenotype have also been reported. The therapeutic approach is the same as in other long-chain fatty acid disorders and includes intravenous glucose (+/- insulin) administration to maximally inhibit lipolysis and subsequent fatty acid oxidation during the acute deterioration, along with other measures such as ammonia detoxification, depending on the clinical features. Long-term strategy consists of avoidance of fasting with frequent meals and a special diet with restriction of long-chain fatty acids. Due to the extremely low free carnitine concentrations, carnitine supplementation is often needed. Acylcarnitine profiling in plasma is the assay of choice for the diagnosis at a metabolite level. However, since the acylcarnitine profile observed in CACT-deficient patients is identical to that in CPT2-deficient patients, definitive identification of CACT-deficiency in a certain patient requires determination of the activity of CACT. Subsequently, mutational analysis of the CACT gene can be performed. So far, 9 different mutations have been identified in the CACT gene

Galactose-1-phosphate uridyl transferase deficiency is not associated with Mullerian aplasia in Dutch patients.

Contains fulltext : 80664.pdf (publisher's version ) (Closed access)STUDY OBJECTIVE: To study whether a deficiency in galactose-1-phosphate uridyl transferase (GALT) activity of mothers was an explanation for the occurrence of Mullerian aplasia of their daughters. DESIGN: A case control study. SETTING: The patients were selected from the outpatient clinic of the University Medical Center Nijmegen, and compared with the general population in The Netherlands. PARTICIPANTS: Patients (n=9) diagnosed with the syndrome of Mullerian aplasia and their mothers were included. INTERVENTIONS: A questionnaire for medical and family history was taken, and a venous blood sample and urine were collected. MAIN OUTCOME MEASURES: GALT activity (in blood), galactose and galactilol (in urine) were measured. Measured values were analyzed by Student's paired t-test. RESULTS: All patients and their mothers had normal GALT activities> or =20 micromol/h/g Hb. The mean value did not differ from the mean of the normal Dutch population, which was 31.6 (SD=5.0) mumol/h/g Hb. CONCLUSION: GALT deficiency is not an explanation for Mullerian aplasia, at least in the Dutch population

Novel metabolic and molecular findings in hepatic carnitine palmitoyltransferase I deficiency

Detection of hepatic carnitine palmitoyltransferase I (CPT IA) deficiency by metabolite screening may be problematic. The urine organic acid profile is generally said to be normal and no abnormal or increased acylcarnitine species are evident on bloodspot tandem MS examination. We diagnosed CPT IA deficiency presenting with acute encephalopathy +/- hypoglycemia and hepatomegaly in one Bukharan Jewish and two Palestinian Arab infants from consanguineous families. CPT1A mutation analysis identified two novel nonsense mutations, c.1737C>A (Y579X) and c.1600delC (L534fsX), extending the known genetic heterogeneity in this disorder. A distinctive organic aciduria was observed in all three patients, even several days after initiation of treatment and resolution of symptoms. Abnormal findings included a hypoketotic dicarboxylic aciduria with prominence of the C12 dicarboxylic (dodecanedioic) acid. This C12 dicarboxylic aciduria suggests that CPT I may play a role in uptake of long-chain dicarboxylic acids by mitochondria after their initial shortening by beta-oxidation in peroxisomes. In addition, increased excretion of 3-hydroxyglutaric acid was detected in all three patients, a finding previously observed only in glutaric aciduria type 1, ketosis, and short-chain hydroxyacyl-CoA dehydrogenase deficiency. Examination of urine organic acids with awareness of these metabolic findings may lead to improved diagnosis of this seemingly rare disorde

Molecular basis of Sjögren-Larsson syndrome: frequency of the 1297-1298 del GA and 943C>T mutation in 29 patients

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Phytanic acid impairs mitochondrial respiration through protonophoric action.

Item does not contain fulltextRefsum disease is a rare, inherited neurodegenerative disorder characterized by accumulation of the dietary branched-chain fatty acid phytanic acid in plasma and tissues caused by a defect in the alphaoxidation pathway. The accumulation of phytanic acid is believed to be the main pathophysiological cause of the disease. However, the exact mechanism(s) by which phytanic acid exerts its toxicity have not been resolved. In this study, the effect of phytanic acid on mitochondrial respiration was investigated. The results show that in digitonin-permeabilized fibroblasts, phytanic acid decreases ATP synthesis, whereas substrate oxidation per se is not affected. Importantly, studies in intact fibroblasts revealed that phytanic acid decreases both the mitochondrial membrane potential and NAD(P)H autofluorescence. Taken together, the results described here show that unesterified phytanic acid exerts its toxic effect mainly through its protonophoric action, at least in human skin fibroblasts