The main hepatic anatomic variations for the purpose of split-liver transplantation

BACKGROUND/AIMS: Variant hepatic anatomy must be recognized and appropriately managed during split-liver transplantation to ensure complete vascular and biliary supply to both grafts. The aim of this study is to demonstrate the importance of an assessment of the hepatic anatomical structures for the purpose of split-liver transplantation. METHODOLOGY: Human cadaveric livers (n = 60) were obtained from routine autopsies. The cadavers and the livers had to comply with the following requirements: 1) minimum age 18 years: 2) no liver pathology to be expected from medical history and 3) no liver pathology noted at the autopsy. Resections were carried out en bloc with liver, celiac trunk, left gastric artery, lesser omentum, superior mesenteric artery and head of the pancreas. The main anatomical structures of the liver as hepatic artery, portal vein, biliary tree and hepatic veins were dissected out and recorded in detail also correlating to hepatic segments for application of the liver splitting. RESULTS: The right, the median and left hepatic vein is unique, respectively, in 59 (98.3%), 53 (88.3%) and 46 (76.3%) cases. The portal vein trunk has been divided into right and left branch in 59 (98.3%) cases. A median branch appeared in 9 (15.2%) cases and no bifurcation of the portal vein occurred in 1 (1.6%) case. The right and left hepatic ducts were multiple, respectively, 47 (78.3%) and 57 (95%) cases, however, the median hepatic duct, was unique in 16 (26.6%) cases. Looking at the intrahepatic distribution of the right hepatic duct we found four branches in 28 (59%) cases, towards segments V, VI, VII, VIII; two branches in 11 (23%) cases, towards segments V, VI and two branches in 8 (17%) cases, towards segments VII, VIII. Fifty-seven cadavers had multiple left hepatic ducts. The intrahepatic dissection showed that the major branches distribution were towards hepatic segments II and III. Three separate branches of the left hepatic duct were found, in 11 (19%) cases towards hepatic segments II, III and IV. Two intrahepatic ducts, coming from hepatic segments V and VI, drained separate to left intrahepatic biliary tree in 1 (2%) case. The arterial irrigation of the liver was made basically by right and left hepatic artery, only in 9 (15%) cases was there a median hepatic artery. Right hepatic artery, coming from the superior mesenteric artery, was present in 15 (25%) cases and left hepatic artery originating from left gastric artery in only 2 (3.3%) cases. Left hepatic artery had two exceptional origins, in 1 (1.6%) case coming directly from the abdominal aorta and in another from the superior mesenteric artery. The right and left hepatic artery was accessory, respectively, in 11 (18.3%) and 2 (3.3%) cases. Right hepatic artery was dominant in 4 (6.6%) cases. The median hepatic artery directed, respectively, to segment IV in 6 (10%) and to segment II and III in 3 (4.9%) cases. CONCLUSIONS: The study has shown that technique of controlled liver splitting for transplantation in two recipients could be an acceptable method for increasing the number of liver allografts. The anatomical and technical details of the splitting procedure are critical to the success of this technique. Good graft function and avoidance of complications depends on each graft having an intact arterial and portal blood supply as well as biliary and venous drainage from all retained liver segments. The absence of bifurcation of the portal vein, is a rare anomaly, and would certainly contraindicate the partition of the liver.     

A high-resolution association mapping panel for the dissection of complex traits in mice

Systems genetics relies on common genetic variants to elucidate biologic networks contributing to complex disease-related phenotypes. Mice are ideal model organisms for such approaches, but linkage analysis has been only modestly successful due to low mapping resolution. Association analysis in mice has the potential of much better resolution, but it is confounded by population structure and inadequate power to map traits that explain less than 10% of the variance, typical of mouse quantitative trait loci (QTL). We report a novel strategy for association mapping that combines classic inbred strains for mapping resolution and recombinant inbred strains for mapping power. Using a mixed model algorithm to correct for population structure, we validate the approach by mapping over 2500 cis-expression QTL with a resolution an order of magnitude narrower than traditional QTL analysis. We also report the fine mapping of metabolic traits such as plasma lipids. This resource, termed the Hybrid Mouse Diversity Panel, makes possible the integration of multiple data sets and should prove useful for systems-based approaches to complex traits and studies of gene-by-environment interactions.Human complex trait genetics has been revolutionized by the ability to carry out association studies on a genome-wide basis. Such genome-wide association studies (GWAS) have now been applied to numerous complex traits and have resulted in the identification of hundreds of novel genes for traits, such as diabetes, cancer, and various inflammatory diseases (Altshuler et al. 2008; Manolio 2009). This success can be attributed to many factors, including technological developments in acquiring high-throughput genotype data (Matsuzaki et al. 2004; Gunderson et al. 2005), development of catalogs of common human variation, such as the HapMap (The International HapMap Consortium 2005), and development of analytic methodologies for association studies (de Bakker et al. 2005). These have allowed the human genetics community to leverage the increased power and resolution of association studies compared to linkage analyses. Despite these successes, the fraction of the genetic component that is explained by the associated genes in GWA studies has been relatively modest for most traits (Hardy and Singleton 2009). For example, traits such as type 2 diabetes and lipoprotein levels have relatively high heritability, in the range of 50%, and yet the genes discovered by GWAS for these traits explain in aggregate less than 10% of the phenotypic variance. This can likely be attributed to several factors; in particular, the effects of a single common variant on a disease trait tend to be very weak and GWA studies have low power to detect rare variation involved in disease (Cohen et al. 2004; Frikke-Schmidt et al. 2004).Mouse models have been used effectively for the identification of genes contributing to simple Mendelian traits, but unfortunately there have been few successes for genes contributing to complex, multigenic traits. Traditional genetic analysis in mice involves crossing different inbred strains and mapping the traits of interest using linkage analysis. An important problem has been the lack of resolution in identifying the causal gene(s) from the results of a linkage study. Fine mapping in such cases generally requires the construction of congenic strains, in which the region of interest from one strain is transferred onto the background of the second strain by a series of crosses. But this frequently proves difficult because the alleles contributing to complex traits generally exhibit subtle effects that approach the levels of noise (Flint and Mott 2008), and several closely linked genes may influence the trait at a given locus.Encouraged by the success of human association studies, several groups have proposed mouse genome-wide association studies. These initial pioneering studies demonstrated the potential of mouse genome-wide association studies with their early successes, but they have also raised some important challenges including complex population stratification among the mouse strains and concerns about the lack of power to detect loci with modest effects (Pletcher et al. 2004; de Bakker et al. 2005; Payseur and Place 2007). In fact, these two issues are intimately related. Population structure inflates the association statistics, both creating spurious associations, as well as artificially increasing the apparent strength of true association signals. The initial mouse genome-wide association studies reported a tremendous number of genome-wide significant signals, some of which overlapped with known loci. This, combined with the knowledge that mouse strains have high heritability for traits, suggested that mouse association studies had sufficient statistical power. However, these initial studies did not adequately correct for population structure, which when taken into account, eliminates the vast majority of predicted associations (Kang et al. 2008). Thus, the inability to correct for population structure in the initial studies led them to severely overestimate their statistical power.We have explored a wide range of possible designs for mouse association studies using simulations that can accurately measure statistical power after correction for population structure. We assembled a combined set of inbred strains, which we term the “Hybrid Mouse Diversity Panel” (HMDP) that includes 100 commercially available inbred strains consisting of 29 classic inbred (CI) strains and three sets of recombinant inbred (RI) strains. Here, we report that the HMDP has sufficient power to map traits that contribute to 10% of the overall variance. Importantly, the resolution of the panel is an order of magnitude better than linkage analysis. Practical advantages of the HMDP include the elimination of costly genotyping, as these strains have now been genotyped at over 135,000 SNPs (http://mouse.cs.ucla.edu/mouseHapMap/), and the availability of the strains from The Jackson Laboratory. In addition, each strain is renewable and, therefore, diverse molecular and phenotypic data can be collected ad infinitum. Thus, this panel should be useful for the analysis of gene-by-environment interactions where multiple individuals of the same genotype need to be studied. Moreover, the fact that the data involving clinical, expression, proteomic, and metabolic traits are cumulative makes this resource ideal for systems biology.     

Anterior Hepatic Transection for Caudate Lobectomy

Resection of the caudate lobe (segment I- dorsal sector, segment IX- right paracaval region, or both) is often technically difficult due to the lobe’s location deep in the hepatic parenchyma and because it is adjacent to the major hepatic vessels (e.g., the left and middle hepatic veins).A literature search was conducted using Ovid MEDLINE for the terms “caudate lobectomy” and “anterior hepatic transection” (AHT) covering 1992 to 2007.AHT was used in 110 caudate lobectomies that are discussed in this review. Isolated caudate lobectomy was performed on 28 (25.4%) patients, with 11 case (11%) associated with hepatectomy, while 1 (0.9%) was associated with anterior segmentectomy. Complete caudate lobectomy was performed on 82 (74.5%) patients. Hepatocellular carcinoma was observed in 106 (96.3%) patients, while 1 (0.9%) had hemangioma and 3 (2.7%) had metastatic caudate tumors. AHT was used in 108 (98.1%) caudate resections, while AHT associated with a right-sided approach was performed in 2 (1.8%) cases. AHT is recommended for tumors located in the paracaval portion of the caudate lobe (segment IX). AHT is usually a safe and potentially curative surgical option.     

Periurban Trypanosoma cruzi-infected Triatoma infestans, Arequipa, Peru

In Arequipa, Peru, vectorborne transmission of Chagas disease by Triatoma infestans has become an urban problem. We conducted an entomologic survey in a periurban community of Arequipa to identify risk factors for triatomine infestation and determinants of vector population densities. Of 374 households surveyed, triatomines were collected from 194 (52%), and Trypanosoma cruzi-carrying triatomines were collected from 72 (19.3%). Guinea pig pens were more likely than other animal enclosures to be infested and harbored 2.38x as many triatomines. Stacked brick and adobe enclosures were more likely to have triatomines, while wire mesh enclosures were protected against infestation. In human dwellings, only fully stuccoed rooms were protected against infestation. Spatially, households with triatomines were scattered, while households with T. cruzi-infected triatomines were clustered. Keeping small animals in wire mesh cages could facilitate control of T. infestans in this densely populated urban environment.     

Protein tyrosine phosphatase activity in insulin-resistant rodent Psammomys obesus

Phosphotyrosine phosphatase (PTPase) activity and its regulation by overnight food deprivation were studied in Psammomys obesus (sand rat), a gerbil model of insulin resistance and nutritionally induced diabetes mellitus. PTPase activity was measured using a phosphopeptide substrate containing a sequence identical to that of the major site of insulin receptor (IR) beta-subunit autophosphorylation. The PTPase activity in membrane fractions was 3.5-, 8.3-, and 5.9-fold lower in liver, fat, and skeletal muscle, respectively, compared with corresponding tissues of albino rat. Western blotting of tissue membrane fractions in Psammomys showed lower PTPase and IR than in albino rats. The density of PTPase transmembrane protein band was 5.5-fold lower in liver and 12-fold lower in adipose tissue. Leukocyte antigen receptor (LAR) and IR were determined by specific immunoblotting and protein bands densitometry and were also found to be 6.3-fold lower in the liver and 22-fold lower in the adipose tissue in the hepatic membrane fractions. Liver cytosolic PTPase activity after an overnight food deprivation in the nondiabetic Psammomys rose 3.7-fold compared with postprandial PTPase activity, but it did not change significantly in diabetic fasted animals. Similar fasting-related changes were detected in the activity of PTPase derived from membrane fraction. In conclusion, the above data demonstrate that despite the insulin resistance, Psammomys is characterized by low level of PTPase activities in membrane and cytosolic fractions in all 3 major insulin responsive tissues, as well as in liver. PTPase activity does not rise in activity as a result of insulin resistance and nutritionally induced diabetes.     

Gradual loss of pancreatic beta-cell insulin, glucokinase and GLUT2 glucose transporter immunoreactivities during the time course of nutritionally induced type-2 diabetes in Psammomys obesus (sand rat)

The Psammomys obesus (sand rat) is a well-established model of nutritionally induced non-insulin-dependent type-2 diabetes. When fed a high-energy (HE) diet, the diabetes-prone animals develop hyperinsulinaemia and hyperglycaemia. Within 1 week, all animals become hyperinsulinaemic. However, a loss of immunostaining for insulin as well as for the GLUT2 glucose transporter in the plasma membrane and the glucokinase in the cytoplasm of the pancreatic beta cells became evident only when the animals subsequently developed hyperglycaemia. After 1 week of HE diet feeding, the pancreatic beta-cell volume was reduced by one-third in hyperglycaemic Psammomys. Insulin immunostaining as well as GLUT2 glucose transporter immunostaining in the plasma membrane and glucokinase immunostaining in the cytoplasm were reduced by more than 50%. After 3 weeks of HE diet feeding, all changes observed after 1 week were even more pronounced, with reductions in the range of 70-95%. The reduction of the total beta-cell volume of the pancreas due to beta-cell death and the diminution of insulin content of the remaining beta cells in the islets during the HE diet feeding was accompanied by a parallel fall of the pancreas insulin content. For all changes observed, there was a significant correlation with the increase of the blood glucose concentration (r>0.9) but not with the increase of the plasma insulin concentration (r>0.2). Thus, increasing glycaemia appears to be the factor responsible for the deterioration of the pancreatic beta-cell function and the resulting loss of the insulin secretory capacity in Psammomys. The final result of this development is an irreversible diabetic state due to the feeding of the HE diet.     

Increased concentration of the complement split product C5a in acute pyelonephritis during pregnancy.

OBJECTIVE: Pregnant women with acute pyelonephritis develop acute respiratory distress syndrome (ARDS) more frequently than non-pregnant women. The reasons for this remain unknown. The complement system is a complex set of self-assembling proteins that have been implicated in the pathophysiology of ARDS and sepsis. The purpose of this study was to determine if activation of the complement system occurs in pregnant women with acute pyelonephritis. METHODS: A cross-sectional study was conducted to determine the plasma concentrations of C3a, C4a and C5a (i.e., complement split products) in pregnant patients with acute pyelonephritis (n=38) and normal pregnant women (n=38). The complement split products C3a, C4a and C5a were measured using ELISA. Data were analyzed using non-parametric statistics. RESULTS: 1) The median plasma concentration of C5a in pregnant patients with acute pyelonephritis was significantly higher than that in normal pregnant women (p<0.001); 2) there was no statistical difference in the median plasma concentration of C3a and C4a between the two groups (p>0.05); and 3) concentrations of C3a, C4a and C5a were not different among patients with acute pyelonephritis with and without bacteremia. CONCLUSIONS: 1) Pyelonephritis in pregnant women is associated with an increased plasma concentration of C5a, but not C3a and C4a; and 2) an excess of C5a can predispose pregnant women to develop ARDS and multi-organ failure in pyelonephritis. This finding may have clinical implications since blocking C5a improves ARDS in experimental sepsis.