More on glucose transporters: The acinar organization for hepatic glucose transport

The “erythroid/brain” glucose transporter (GT) isoform is expressed only in a subset of hepatocytes, those forming the first row around the terminal hepatic venules, while the “liver” GT is expressed in all hepatocytes. After 3 d of starvation, a three- to fourfold elevation of expression of the erythroid/brain GT mRNA and protein is detected in the liver as a whole; this correlates with the expression of this GT in more hepatocytes, those forming the first three to four rows around the hepatic venules. Starvation-dependent expression of the erythroid/brain GT on the plasma membrane of these additional hepatocytes is lost within 3 h of glucose refeeding; however, by immunoblotting we show that the protein is still present. Its loss from the surface is possibly explained by internalization.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/38356/1/1840130432_ftp.pd

Hepatology elsewhere

No Abstract.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/38403/1/1840180637_ftp.pd

Brown pigment gallstones: The role of bacterial hydrolases and another missed opportunity

The bile acids in brown pigment stones and gallbladder bile were fractionated into free acids, glycine and taurine conjugates, and sulfates, using diethylamino-hydroxypropyl-Sephadex LH-20 (DEAPLH-20) column chromatography, and were quantitated by gas chromatography. Twenty-eight cases of brown pigment stones were studied and divided into two groups: those with and those without bacteria possessing bile acid-deconjugating activity. In the former, free bile acid amounted to 62 ± 34% of the total bile acid, while in the latter, only 0.1% of total bile acid was free bile acid. The fraction of total bile acid made up of free bile acids was found to be consistently higher in brown pigment stones than in the corresponding bile, irrespective of the presence or absence of biliary infection. Free bile acid is present in negligible amounts in normal bile. Total bile acid concentration in the bile of patients with brown pigment stones was significantly less than that of controls (13 vs. 50 mg/ml). Biliary infection is almost always present in cases with brown pigment stones. These findings suggest that bacterial infection is present at the initiation of brown pigment stone formation as well as during the period of ensuing stone growth.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/38351/1/1840130335_ftp.pd

Avances en la inclusión de intereses y necesidades de mujeres rurales en políticas públicas agropecuarias y de cambio climático: el caso de Colombia

La agricultura en Colombia es considerada una de las principales actividades económicas. De los 48 millones de habitantes que tiene el país, 24% vive en áreas rurales y 3,4 millones de ellos están activamente empleados en la producción agrícola primaria. De estos, 75% son hombres y 25% son mujeres4. Ahora bien, el 80% de las tierras en Colombia está en manos del 14% de los propietarios. Según cifras del Instituto Geográfico Agustín Codazzi, la concentración de la tierra en el país en términos del Gini de tierras es de 0,84 para el año 20096. A esta evidente desigualdad en la concentración de la propiedad de la tierra se le suma que dicha propiedad tiende a ser informal. Así mismo, con unas condiciones muy particulares de despojo y reconfiguración de tierras y territorios en el marco de un conflicto armado de más de sesenta años, de una constante lucha por la explotación legal e ilegal de los recursos naturales y de la falta de un sistema de información actualizado de catastro. El género se refiere a roles, responsabilidades, derechos, relaciones e identidades de hombres y mujeres que se definen o atribuyen dentro de una sociedad8. Para efectos de este documento, se hará referencia a las relaciones de género en contextos rurales productivos, es decir, cómo se relacionan mujeres y hombres en el hogar, en la producción agropecuaria, en el acceso y administración de los recursos y en los procesos de toma de decisión en un contexto dado, con el fin de comprender necesidades e intereses de mujeres y hombres y la importancia de que éstos se tomen en cuenta en políticas públicas agropecuarias y de cambio climático

Spironolactone and canrenoate: Different antialdosteronic diuretic agents

Plasma levels of canrenone and androgen receptoractive materials (ARM) were determined during long-term oral K-canrenoate or spironolactone therapy in cirrhotics with chronic recurrent ascites. Mean plasma canrenone level was approximately 3 times higher under K-canrenoate than under spironolactone treatment; moreover, the levels were not dose related. Either type of treatment did not affect plasma aldosterone and testosterone concentrations. Plasma ARM during K-canrenoate treatment did not change, whereas in the spironolactone group a 3-fold increase of ARM occurred (p 0.05). Our study questions the traditional view that the mode of action of spironolactone is via its metabolite canrenone. The two antialdosterone drugs, although equally effective in clearing ascites from cirrhotics, appear to act through partially different metabolites. The lower incidence of antiandrogenic or estrogen-like side effects during K-canrenoate seems to be related to metabolites other than canrenone itself.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/38359/1/1840130531_ftp.pd

Is the multidrug resistance an ATP channel?

The multidrug resistance ( mdr1 ) gene product, P-glycoprotein, is responsible for the ATP-dependent extrusion of a variety of compounds, including chemotherapeutic drugs, from cells. The data presented here show that cells with increaed levels of the P-glycoprotein release ATP to the medium in proportion to the concentration of the protein in their plasma membrane. Furthermore, measurements of whole-cell and single-channel currents with patch-clamp electrodes indicate that the P-glycoprotein serves as an ATP-conducting channel in the plasma membrane. These findings suggest an unusual role for the P-glycoprotein.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/38396/1/1840180131_ftp.pd

Thyroxine-binding globulin, hyperthyroxinemia and hepatocellular carcinoma

To determine serum thyroxine-binding globulin (TBG) levels, we used radioimmunoassay, and compared the results obtained with other tests in 231 patients with chronic hepatitis B virus infection to evaluate its clinical implications. All of these patients were hepatitis B surface antigen (HBsAg)-positive. Among them, 38 patients had hepatocellular carcinoma (HCC), 18 had chronic persistent hepatitis, 70 had chronic lobular or active hepatitis (grouped as CAH), 31 had active cirrhosis (AC), 25 had inactive cirrhosis, 20 had decompensated cirrhosis, and 29 were “healthy” HBsAg carriers. Twenty-seven patients with acute hepatitis, 12 with cancer metastasis to the liver, and 81 normal adults served as disease or normal controls. The results showed that serum TBG level increased significantly in patients with CAH, AC, or HCC. Serum TBG did not correlate with albumin or bilirubin level, but correlated with alanine aminotransferase (ALT) positively in patients with CAH ( p < 0.001) and negatively in patients with HCC ( p < 0.01) (slope difference p < 0.05). Serial determination of serum TBG and ALT also showed parallel changes in 15 patients with CAH, but not in nine patients with HCC. In contrast, the fall and rise of serum TBG levels in patients with HCC coincided with tumor resection and recurrence. The data suggest that serum TBG elevation in patients with hepatitis activity is the result of hepatocellular damage, whereas that in patients with HCC is due to increased synthesis. Whether serum TBG elevation without concomitant rise of ALT could be used as a marker of HCC awaits further study.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/38358/1/1840130434_ftp.pd

DNA integration sites and hepatocellular carcinoma

This study is part of an ongoing analysis of woodchuck hepatitis virus integration sites in the host genome of hepatocellular carcinomas. The study of woodchuck hepatitis virus-DNA integration sites may shed light on the oncogenic mechanisms involved in cellular transformation and tumor formation. Viral integration enhancing cellular proto-oncogene expression is one such mechanism and has been well documented for oncogenic retroviruses such as mouse mammary tumor virus and interleukin-1. By cloning a woodchuck hepatitis virus integration site from a woodchuck hepatocellular carcinoma the authors were able to identify a new member of the myc gene family, N- myc -2. Examination of 30 additional woodchuck hepatomas revealed viral integration commonly occurred near N- myc loci with an additional five woodchuck hepatitis virus integrants near the N- myc -2 gene and one viral integrant near N- myc -1. Three of these N- myc -2 viral integrations were further evaluated and found to be localized within 200 bp of the translation stop codon. This 3′ noncoding region has recently been identified as a common site of murine leukemia virus integration in virally induced T-cell lymphomas and results in increased expression of the N- myc gene. Similar mechanisms can be proposed for hepatocellular carcinoma formation. Woodchuck hepatitis virus integration near cell-growth related protooncogenes, such as N- myc , can juxtapose viral enhancer elements and growth-regulatory genes. Virally induced overexpression of proto-oncogene messenger RNA could result from enhanced transcription or increased messenger RNA stability. To search for such effects the authors analyzed N- myc -2 RNA levels in 30 woodchuck hepatitis virus-related hepatomas. Increased levels of N- myc -2 RNA were found in 18 of 30 tumors, whereas nontumorous portions of the same livers had no detectable N- myc -2 RNA. Taken together these findings suggest that woodchuck hepatitis virus integration can result in altered N- myc -2 gene expression in a significant proportion of woodchuck hepatocellular carcinomas. The deregulation of N- myc gene expression could result in cellular transformation and ultimately tumor formation. Such examples of hepadnavirus-specific oncogenic mechanisms lend credence to theories of hepatitis B virus-induced tumorigenesis and provide models to design molecular investigations of human hepatocellular carcinoma formation.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/38347/1/1840130229_ftp.pd

Treatment of hepatocellular carcinoma

Fifty-one patients with unresectable hepatocellular carcinoma were treated by embolization of the hepatic artery with Gelfoam powder, contrast material and three chemotherapeutic agents (doxorubicin, mitomycin, cisplatin). Twelve patients (24%) had a partial response with a decrease in the tumor diameter by at least 50%, 13 patients (26%) had only minor responses, 12 (24%) had stabilization of disease and the remainder had progressive disease. Tumor liquefaction was noted on computed tomographic scanning in 70% of patients, and 23 of 34 patients with elevations in serum alphafetoprotein values had a greater than 50% reduction following treatment. The median patient survival time from treatment was 207 days. Most patients experienced transient pain, fever, nausea and elevations in serum aminotransferase activities as a result of therapy. Ascites developed in 14 patients. There were two treatment-related deaths: one from tumor hemorrhage and one from liver failure. Chemoembolization therefore appears to have significant activity in patients with hepatocellular carcinoma and is relatively well tolerated. This study reports the results of resection in 72 cirrhotic patients with hepatocellular carcinoma from Europe. One and 3 year survival rates were 68% and 51% respectively. Survival was significantly higher in Child's class A than in class B or C patients. Patients with a thickly encapsulated tumor lived longer than those with an infiltrating tumor and also had a significantly lower recurrence rate. There was no relationship between the size of the tumor or the presence of symptoms and survival. These data suggest that good results can be achieved by resection of hepatocellular carcinoma in European cirrhotic patients. A thickly encapsulated tumor and good liver function are the main determinants of low cancer recurrence and high survival.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/38355/1/1840130431_ftp.pd

A YY1-dependent increase in aerobic metabolism is indispensable for intestinal organogenesis

During late gestation, villi extend into the intestinal lumen to dramatically increase the surface area of the intestinal epithelium, preparing the gut for the neonatal diet. Incomplete development of the intestine is the most common gastrointestinal complication in neonates, but the causes are unclear. We provide evidence in mice that Yin Yang 1 (Yy1) is crucial for intestinal villus development. YY1 loss in the developing endoderm had no apparent consequences until late gestation, after which the intestine differentiated poorly and exhibited severely stunted villi. Transcriptome analysis revealed that YY1 is required for mitochondrial gene expression, and ultrastructural analysis confirmed compromised mitochondrial integrity in the mutant intestine. We found increased oxidative phosphorylation gene expression at the onset of villus elongation, suggesting that aerobic respiration might function as a regulator of villus growth. Mitochondrial inhibitors blocked villus growth in a fashion similar to Yy1 loss, thus further linking oxidative phosphorylation with late-gestation intestinal development. Interestingly, we find that necrotizing enterocolitis patients also exhibit decreased expression of oxidative phosphorylation genes. Our study highlights the still unappreciated role of metabolic regulation during organogenesis, and suggests that it might contribute to neonatal gastrointestinal disorders