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1.  The clinical course of alcoholic cirrhosis: effects of hepatic metabolic capacity, alcohol consumption, and hyponatremia – a historical cohort study 
BMC Research Notes  2012;5:509.
Background
The cirrhosis complications hepatic encephalopathy, ascites, and variceal bleeding increase mortality but develop in random sequence. Therefore prognoses based on the presence or absence of these clinical complications are inherently inaccurate, and other determinants of the clinical course should be identified. Here we present our study of patho-etiological factors that may be causally involved in the development of specific complications to alcoholic cirrhosis; it was based on a model of cirrhosis pathophysiology encompassing hepatic metabolic capacity, continued alcohol consumption, and circulatory dysfunction.
Methods
We followed a Danish community-based cohort of 466 patients with alcoholic cirrhosis. Stratified Cox regression was used to examine the effects of GEC (a measure of hepatic metabolic capacity), alcohol consumption, and plasma sodium concentration (a measure of circulatory dysfunction) on the hazard rates of first-time hepatic encephalopathy, first-time ascites, first-time variceal bleeding, and mortality. We adjusted for confounding by comorbidity, gender, and age. Data on risk factors and confounders were updated during follow-up.
Results
A low GEC increased the risk of first-time hepatic encephalopathy (hazard ratio [HR] 1.21 per 0.1 mmol/min GEC loss, 95% CI 1.11-1.31), but was unassociated with other adverse events. Alcohol consumption increased the risk of first-time ascites (HR 3.18, 95% CI 1.19-8.47), first-time variceal bleeding (HR 2.78, 95% CI 1.59-4.87), and mortality (HR 2.45, 95% CI 1.63-3.66), but not the risk of first-time hepatic encephalopathy. Hyponatremia increased the risk of all adverse events.
Conclusions
Reduced hepatic metabolic capacity, alcohol consumption, and hyponatremia were causally involved in the development of specific complications to alcoholic cirrhosis.
doi:10.1186/1756-0500-5-509
PMCID: PMC3494654  PMID: 22988833
Alcoholic liver disease; Hepatic encephalopathy; Ascites; Variceal bleeding; Prognosis
2.  Clinical presentation and mutations in Danish patients with Wilson disease 
This study describes the clinical presentation and diagnosis in all Danish patients (49, 41 unrelated) with Wilson disease (WND). On the basis of the number of diagnosed patients from 1990–2008, the prevalence was estimated to be 1:49 500. Among routinely used diagnostic tests, none were consistently indicative of WND, with the exception of the 24-h urine-Cu test, which is always outside the normal range. Mutations were identified in 100% of the screened ATP7B alleles (70 unrelated), including five novel mutations: p.1021K; p.G1158V; p.L1304F; IVS20-2A>G; Ex5_6del. In all, 70% of mutations were found in exons 8, 14, 17, 18, and 20. The most frequent mutation, p.H1069Q, comprised 18%. We propose a new and simple model that correlates genotype and age of onset. By assuming that the milder of two mutations is ‘functionally dominant' and determines the age of onset, we classified 25/27 mutations as either severe (age of onset <20 years) or moderate (age of onset >20 years), and correctly predicted the age of onset in 37/39 patients. This method should be tested in other Wilson populations.
doi:10.1038/ejhg.2011.80
PMCID: PMC3179371  PMID: 21610751
Wilson disease; ATP7B; mutations; genotype/phenotype; age of onset; Denmark
3.  [N-Methyl-11C]Cholylsarcosine, a Novel Bile Acid Tracer for PET/CT of Hepatic Excretory Function: Radiosynthesis and Proof-of-Concept Studies in Pigs 
Journal of Nuclear Medicine  2012;53(5):772-778.
Excretion of conjugated bile acids into bile is an essential function of the liver, and impairment of canalicular bile acid secretion leads to cholestatic liver injury. However, hepatic excretory function cannot be quantified in vivo because of the lack of suitable methods. Cholylsarcosine is an analog of the endogenous bile acid conjugate cholylglycine and exhibits characteristics in vivo that led us to hypothesize that the 11C-labeled form, that is, [N-methyl-11C]cholylsarcosine (11C-cholylsarcosine), would be a suitable PET tracer for quantification of hepatic excretory function.
Methods
A method for radiosynthesis of 11C-cholylsarcosine was developed involving 11C-methylation of glycine followed by conjugation with cholic acid. Blood-to-liver uptake and liver-to-bile excretion were investigated in vivo by dynamic 11C-cholylsarcosine PET/CT of 2 anesthetized pigs. In pig 1, a second dynamic 11C-cholylsarcosine PET/CT examination was preceded by a high dose of the endogenous bile acid conjugate cholyltaurine to investigate possible inhibition of the transhepatocellular transport of 11C-cholylsarcosine. In pig 2, a second 11C-cholylsarcosine administration was given to determine the biodistribution of the tracer by means of 5 successive whole-body PET/CT recordings. Possible formation of 11C-metabolites was investigated by analysis of blood and bile samples from a third pig.
Results
The radiochemical yield was 13% ± 3% (n = 7, decay-corrected) and up to 1.1 GBq of 11C-cholylsarcosine was produced with a radiochemical purity greater than 99%. PET/CT studies showed rapid blood-to-liver uptake and liver-to-bile excretion of 11C-cholylsarcosine, with radioactivity concentrations being more than 90 times higher in the bile ducts than in liver tissue. Cholyltaurine inhibited the transhepatocellular transport of 11C-cholylsarcosine, indicating that the tracer is transported by one or more of the same hepatic transporters as cholyltaurine. 11C-cholylsarcosine underwent an enterohepatic circulation and reappeared in liver tissue and bile ducts after approximately 70 min. There were no detectable 11C-metabolites in the plasma or bile samples, indicating that the novel conjugated bile acid 11C-cholylsarcosine was not metabolized in the liver or in the intestines. The effective absorbed dose of 11C-cholylsarcosine was 4.4 μSv/MBq.
Conclusion
We have synthesized a novel conjugated bile acid analog, 11C-cholylsarcosine, and PET/CT studies on anesthetized pigs showed that the hepatic handling of tracer uptake from blood and excretion into the bile was comparable to that for the endogenous bile acid cholyltaurine. This tracer may be valuable for future studies of normal and pathologic hepatic excretory functions in humans.
doi:10.2967/jnumed.111.098731
PMCID: PMC3390910  PMID: 22454486
enterohepatic circulation; bile salt export pump; sodium–taurocholate cotransporting polypeptide; liver function; positron emission tomography
4.  The galactose elimination capacity and mortality in 781 Danish patients with newly-diagnosed liver cirrhosis: a cohort study 
BMC Gastroenterology  2009;9:50.
Background
Despite its biologic plausibility, the association between liver function and mortality of patients with chronic liver disease is not well supported by data. Therefore, we examined whether the galactose elimination capacity (GEC), a physiological measure of the total metabolic capacity of the liver, was associated with mortality in a large cohort of patients with newly-diagnosed cirrhosis.
Methods
By combining data from a GEC database with data from healthcare registries we identified cirrhosis patients with a GEC test at the time of cirrhosis diagnosis in 1992–2005. We divided the patients into 10 equal-sized groups according to GEC and calculated all-cause mortality as well as cirrhosis-related and not cirrhosis-related mortality for each group. Cox regression was used to adjust the association between GEC and all-cause mortality for confounding by age, gender and comorbidity, measured by the Charlson comorbidity index.
Results
We included 781 patients, and 454 (58%) of them died during 2,617 years of follow-up. Among the 75% of patients with a decreased GEC (<1.75 mmol/min), GEC was a strong predictor of 30-day, 1-year, and 5-year mortality, and this could not be explained by confounding (crude hazard ratio for a 0.5 mmol/min GEC increase = 0.74, 95% CI 0.59–0.92; adjusted hazard ratio = 0.64, 95% CI 0.51–0.81). Further analyses showed that the association between GEC and mortality was identical for patients with alcoholic or non-alcoholic cirrhosis etiology, that it also existed among patients with comorbidity, and that GEC was only a predictor of cirrhosis-related mortality. Among the 25% of patients with a GEC in the normal range (≥ 1.75 mmol/min), GEC was only weakly associated with mortality (crude hazard ratio = 0.79, 95% CI 0.59–1.05; adjusted hazard ratio = 0.80, 95% CI 0.60–1.08).
Conclusion
Among patients with newly-diagnosed cirrhosis and a decreased GEC, the GEC was a strong predictor of short- and long-term all-cause and cirrhosis-related mortality. These findings support the expectation that loss of liver function increases mortality.
doi:10.1186/1471-230X-9-50
PMCID: PMC2721849  PMID: 19566919
5.  Sildenafil does not influence hepatic venous pressure gradient in patients with cirrhosis 
AIM: To investigate if sildenafil increases splanchnic blood flow and changes the hepatic venous pressure gradient (HVPG) in patients with cirrhosis. Phosphodiesterase type-5 inhibitors are valuable in the treatment of erectile dysfunction and pulmonary hypertension in patients with end-stage liver disease. However, the effect of phosphodiesterase type-5 inhibitors on splanchnic blood flow and portal hypertension remains essentially unknown.
METHODS: Ten patients with biopsy proven cirrhosis (five females/five males, mean age 54 ± 8 years) and an HVPG above 12 mmHg were studied after informed consent. Measurement of splanchnic blood flow and the HVPG during liver vein catheterization were done before and 80 min after oral administration of 50 mg sildenafil. Blood flow was estimated by use of indocyanine green clearance technique and Fick's principle, with correction for non-steady state.
RESULTS: The plasma concentration of sildenafil was 222 ± 136 ng/mL 80 min after administration. Mean arterial blood pressure decreased from 77 ± 7 mmHg to 66 ± 12 mmHg, P = 0.003, while the splanchnic blood flow and oxygen consumption remained unchanged at 1.14 ± 0.71 L/min and 2.3 ± 0.6 mmol/min, respectively. Also the HVPG remained unchanged (18 ± 2 mmHg vs 16 ± 2 mmHg) with individual changes ranging from -8 mmHg to +2 mmHg. In seven patients, HVPG decreased and in three it increased.
CONCLUSION: In spite of arterial blood pressure decreases 80 min after administration of the phosphodiesterase type-5 inhibitor sildenafil, the present study could not demonstrate any clinical relevant influence on splanchnic blood flow, oxygen consumption or the HVPG.
doi:10.3748/wjg.14.6208
PMCID: PMC2761583  PMID: 18985812
Cirrhosis; Sildenafil; Portal hypertension; Portal hemodynamics; Hepatic blood flow; Erectile dysfunction; Hepatic venous pressure gradient
6.  Glucose ingestion attenuates the exercise-induced increase in circulating heat shock protein 72 and heat shock protein 60 in humans 
Cell Stress & Chaperones  2004;9(4):390-396.
Heat shock protein (Hsp) 72 is a cytosolic stress protein that is highly inducible by several factors including exercise. Hsp60 is primarily mitochondrial in cellular location, plays a key role in the intracellular protein translocation and cytoprotection, is increased in skeletal muscle by exercise, and is found in the peripheral circulation of healthy humans. Glucose deprivation increases Hsp72 in cultured cells, whereas reduced glycogen availability elevates Hsp72 in contracting human skeletal muscle. To determine whether maintained blood glucose during exercise attenuates the exercise-induced increase in intramuscular and circulating Hsp72 and Hsp60, 6 males performed 120 minutes of semirecumbent cycling at ∼65% maximal oxygen uptake on 2 occasions while ingesting either a 6.4% glucose (GLU) or sweet placebo (CON) beverage throughout exercise. Muscle biopsies, obtained before and immediately after exercise, were analyzed for Hsp72 and Hsp60 protein expression. Blood samples were simultaneously obtained from a brachial artery, a femoral vein, and the hepatic vein before and during exercise for the analysis of serum Hsp72 and Hsp60. Leg and hepatosplanchnic blood flow were measured to determine Hsp72-Hsp60 flux across these tissue beds. Neither exercise nor glucose ingestion affected the Hsp72 or Hsp60 protein expression in, or their release from, contracting skeletal muscle. Arterial serum Hsp72 increased (P < 0.05) throughout exercise in both trials but was attenuated (P < 0.05) in GLU. This may have been in part because of the increased (P < 0.05) hepatosplanchnic Hsp72 release in CON, being totally abolished (P < 0.05) in GLU. Serum Hsp60 increased (P < 0.05) after 60 minutes of exercise in CON before returning to resting levels at 120 minutes. In contrast, no exercise-induced increase in serum Hsp60 was observed in GLU. We detected neither hepatosplanchnic nor contracting limb Hsp60 release in either trial. In conclusion, maintaining glucose availability during exercise attenuates the circulating Hsp response in healthy humans.
doi:10.1379/CSC-24R1.1
PMCID: PMC1065278  PMID: 15633297
7.  Highly Sensitive Methods for Quantitation of Human Immunodeficiency Virus Type 1 RNA from Plasma, Cells, and Tissues 
Journal of Clinical Microbiology  1999;37(5):1260-1264.
Precise and sensitive quantitation of viral RNA in specimens from human immunodeficiency virus (HIV) type 1 (HIV-1)-infected individuals has become an indispensable tool for the monitoring of the efficacy of highly active antiretroviral combination therapy. The present report describes reproducible and efficient protocols with enhanced sensitivity for quantitation of HIV-1 RNA from plasma, peripheral blood mononuclear cells, and tissues with Qiagen silica columns for RNA purification combined with the Roche Amplicor HIV-1 Monitor test for quantitative reverse transcription-PCR (RT-PCR). Extraction of RNA from 0.5 ml of plasma resulted in the detection of fewer than 20 HIV RNA copies/ml of plasma, equivalent to the centrifugation-based boosted RT-PCR assay. Silica extraction of cellular RNA resulted in the detection of fewer than 3 HIV-1 RNA copies/μg of total RNA. These techniques facilitate direct comparisons of viral loads between liquid and cellular specimens. Application of these sensitive methods may improve the assessment of the response to new antiretroviral regimens.
PMCID: PMC84745  PMID: 10203467

Results 1-7 (7)