Cortisol Release From Adipose Tissue by 11β-Hydroxysteroid Dehydrogenase Type 1 in Humans

OBJECTIVE—11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) regenerates cortisol from cortisone. 11β-HSD1 mRNA and activity are increased in vitro in subcutaneous adipose tissue from obese patients. Inhibition of 11β-HSD1 is a promising therapeutic approach in type 2 diabetes. However, release of cortisol by 11β-HSD1 from adipose tissue and its effect on portal vein cortisol concentrations have not been quantified in vivo

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Acute effects of transjugular intrahepatic portosystemic stent-shunt (TIPSS) procedure on renal blood flow and cardiopulmonary hemodynamics in cirrhosis

Objective: An acute increase in portal pressure is associated with an immediate reduction in renal blood flow. It has been suggested that this supports the presence of an hepatorenal reflex. In this study, we used TIPSS placement as a model to investigate the effect of an acute reduction in portal pressure on renal blood flow and cardiopulmonary hemodynamic parameters. Methods: Eleven cirrhotic patients were studied during elective TIPSS placement for variceal hemorrhage (n = 9) or refractory ascites (n = 2). Unilateral renal blood flow (RBF) was measured before and at 5, 15, 30, 45, and 60 min after shunt insertion. Heart rate (HR), mean arterial pressure (MAP), right atrial pressure (RAP), mean pulmonary artery pressure (PAP), pulmonary capillary wedge pressure (PCWP), cardiac output (CO), and systemic vascular resistance (SVR) were also measured before and 30 min after TIPSS placement. Results: Despite significant increases in CO (p = 0.001), RAP (p < 0.001), PAP (p < 0.001), and PCWP (p = 0.001), and a fall in SVR (p = 0.003), no change was observed in RBF, HR, or MAP after TIPSS placement. The fall in the portoatrial pressure gradient correlated only with the rise in CO (p < 0.05) and the drop in SVR (p < 0.05). Conclusion: Despite the fall in portal pressure and the systemic hemodynamic changes caused by TIPSS placement, there is no immediate effect on RBF. Any improvement in renal function after TIPSS procedure does not appear to be due to an acute increase in RBF

Acute effects of transjugular intrahepatic portosystemic stent-shunt (TIPSS) procedure on renal blood flow and cardiopulmonary hemodynamics in cirrhosis

Objective: An acute increase in portal pressure is associated with an immediate reduction in renal blood flow. It has been suggested that this supports the presence of an hepatorenal reflex. In this study, we used TIPSS placement as a model to investigate the effect of an acute reduction in portal pressure on renal blood flow and cardiopulmonary hemodynamic parameters. Methods: Eleven cirrhotic patients were studied during elective TIPSS placement for variceal hemorrhage (n = 9) or refractory ascites (n = 2). Unilateral renal blood flow (RBF) was measured before and at 5, 15, 30, 45, and 60 min after shunt insertion. Heart rate (HR), mean arterial pressure (MAP), right atrial pressure (RAP), mean pulmonary artery pressure (PAP), pulmonary capillary wedge pressure (PCWP), cardiac output (CO), and systemic vascular resistance (SVR) were also measured before and 30 min after TIPSS placement. Results: Despite significant increases in CO (p = 0.001), RAP (p < 0.001), PAP (p < 0.001), and PCWP (p = 0.001), and a fall in SVR (p = 0.003), no change was observed in RBF, HR, or MAP after TIPSS placement. The fall in the portoatrial pressure gradient correlated only with the rise in CO (p < 0.05) and the drop in SVR (p < 0.05). Conclusion: Despite the fall in portal pressure and the systemic hemodynamic changes caused by TIPSS placement, there is no immediate effect on RBF. Any improvement in renal function after TIPSS procedure does not appear to be due to an acute increase in RBF

Direct measurement of post-prandial portal haemodynamics in cirrhotic patients with a transjugular intrahepatic portosystemic stent-shunt

Objective: Portal haemodynamics vary in response to eating and other stimuli, but any increase in portal venous pressure (PVP) in cirrhotic patients may be a risk factor for variceal bleeding. We directly assessed postprandial splanchnic haemodynamics in cirrhotic patients with a transjugular intrahepatic portosystemic stent-shunt (TIPSS) in situ. Methods: A thermodilution catheter was inserted via the patent TIPSS into the portal vein in 12 cirrhotic patients. PVP, portal venous flow (PVF) (thermodilution method), portal vascular resistance (PVR), porto-atrial pressure gradient (PPG), heart rate, mean arterial pressure (MAP) and right atrial pressure (RAP) were measured. A 505 kcal meal was given and all haemodynamic measurements were repeated at 15 min intervals for 60 min. Results: Following the meal, there was a significant rise in PVP from 11.2 ± 1.5 to 14.0 ± 1.9 mmHg at 15 min, and 14.0 ± 1.8 mmHg at 30 min (P< 0.001); in PPG from 9.5 ± 1.4 to 12.7 ± 2.2 mmHg at 15 min and 12.7 ± 2.1 mmHg at 30 min (P < 0.005); and in PVF from 1110.2 ± 141.1 to 1543.2 ± 227.6 ml/min at 30 min (P< 0.01). PVR fell from 0.08 ± 0.01 to 0.05 ± 0.01 RU at 30 min (P < 0.05). Heart rate increased from 77 ± 4.1 to 80.5 ± 5.4 bpm at 15 min (P< 0.05), but MAP and RAP remained unchanged. Conclusion: In cirrhotic patients with TIPSS, significant changes in portal haemodynamics occur at 15–30 min following a meal, with minimal effect on systemic haemodynamics. This model offers a new technique to directly assess the causes for and possible treatments of post-prandial splanchnic hyperaemia in cirrhosis

A prospective evaluation of changes in neuropsychological and liver function tests following transjugular intrahepatic portosystemic stent-shunt

Background/Aims: This study was designed to assess changes in: (a) neuropsychological tests, measures of memory, quality of life and scores for anxiety and depression; (b) liver function tests; and (c) the relationship between these following transjugular intrahepatic portosystemic stent-shunt. Methods: Twenty-nine patients undergoing transjugular intrahepatic portosystemic stent-shunt for recurrent variceal haemorrhage, 12 matched patients with cirrhosis and variceal haemorrhage manage with variceal band ligation and 16 normal controls were studied. Patients in any of the groups who were clinically encephalopathic were excluded from the study. Serial changes in the conventional liver function tests and Indocyanine green clearance, and psychometric function (Hospital Anxiety Depression Scale, Rivermead Behavioral Memory Test, Quality of Life and the memory and reaction sub-tests of the Cambridge Automated Neuropsychological Test Assessment Battery) were measured prior to and 1, 3, 9 and 15 months following transjugular intrahepatic portosystemic stent-shunt. Results: Over a mean follow up of 9.1 months in the transjugular intrahepatic portosystemic stent-shunt group (range 3-28), one patient (3%) developed clinically detectable encephalopathy. Sixty-seven percent of patients with cirrhosis showed evidence of subclinical encephalopathy as compared with the control population. Significant deterioration occurred in the reaction sub-tests of the Cambridge Automated neuropsychological Test Assessment Battery in patients, both in the transjugular intrahepatic portosystemic stent-shunt group and the controls with cirrhosis, during follow up. Transjugular intrahepatic portosystemic stent-shunt was followed by significant deterioration in levels of anxiety and psychological component of the quality of life. The Rivermead Behavioural Memory Test and the memory sub-test of the Cambridge Automated Neurpsychological Test Assessment Battery did, however, improve significantly at 1 and 15 months after transjugular intrahepatic portosystemic stent-shunt, respectively. Serum alanine aminotransferase, bilirubin and indocyanine green clearance deteriorated significantly following transjugular intrahepatic portosystemic stent-shunt (p less than 0.001, p less than 0.001 and p less than 0.0001, respectively). Significant correlation was observed between changes in the indocyanine green clearance and changes in the complex and simple reaction time subtests of the Cambridge Automated Neuropsychological Test Assessment Battery (r=0.6 and r=0.66, respectively). Conclusions: The results of this study showed that about 67% of patients with cirrhosis were subclinically encephalopathic and that temporary deterioration occurred in the Cambridge Automated Neuropsychological Test Assessment Battery during follow up, both in patients having transjugular intrahepatic portosystemic stent-shunt and in the controls with cirrhosis. These parallel the changes in the liver function tests and indocyanine green clearance. Temporary deterioration was also observed in the Quality of Life and Hospital Anxiety Depression Scale in the transjugular intrahepatic portosystemic stent-shunt group, although the measures of memory improved. Further studies should address the biochemical mechanisms of these changes and the role of prophylactic measures