Malaria-driven adaptation of MHC class I in wild bonobo populations.

The malaria parasite Plasmodium falciparum causes substantial human mortality, primarily in equatorial Africa. Enriched in affected African populations, the B*53 variant of HLA-B, a cell surface protein that presents peptide antigens to cytotoxic lymphocytes, confers protection against severe malaria. Gorilla, chimpanzee, and bonobo are humans' closest living relatives. These African apes have HLA-B orthologs and are infected by parasites in the same subgenus (Laverania) as P. falciparum, but the consequences of these infections are unclear. Laverania parasites infect bonobos (Pan paniscus) at only one (TL2) of many sites sampled across their range. TL2 spans the Lomami River and has genetically divergent subpopulations of bonobos on each side. Papa-B, the bonobo ortholog of HLA-B, includes variants having a B*53-like (B07) peptide-binding supertype profile. Here we show that B07 Papa-B occur at high frequency in TL2 bonobos and that malaria appears to have independently selected for different B07 alleles in the two subpopulations.

CD4 receptor diversity represents an ancient protection mechanism against primate lentiviruses.

Infection with human and simian immunodeficiency viruses (HIV/SIV) requires binding of the viral envelope glycoprotein (Env) to the host protein CD4 on the surface of immune cells. Although invariant in humans, the Env binding domain of the chimpanzee CD4 is highly polymorphic, with nine coding variants circulating in wild populations. Here, we show that within-species CD4 diversity is not unique to chimpanzees but found in many African primate species. Characterizing the outermost (D1) domain of the CD4 protein in over 500 monkeys and apes, we found polymorphic residues in 24 of 29 primate species, with as many as 11 different coding variants identified within a single species. D1 domain amino acid replacements affected SIV Env-mediated cell entry in a single-round infection assay, restricting infection in a strain- and allele-specific fashion. Several identical CD4 polymorphisms, including the addition of N-linked glycosylation sites, were found in primate species from different genera, providing striking examples of parallel evolution. Moreover, seven different guenons (Cercopithecus spp.) shared multiple distinct D1 domain variants, pointing to long-term trans-specific polymorphism. These data indicate that the HIV/SIV Env binding region of the primate CD4 protein is highly variable, both within and between species, and suggest that this diversity has been maintained by balancing selection for millions of years, at least in part to confer protection against primate lentiviruses. Although long-term SIV-infected species have evolved specific mechanisms to avoid disease progression, primate lentiviruses are intrinsically pathogenic and have left their mark on the host genome.

Dissection-enabled scaffold-assisted resection (DeSCAR): a novel technique for resection of residual or non-lifting GI neoplasia of the colon (with video).

BACKGROUND AND AIMS: As a result of previous manipulation or submucosal invasion, GI lesions referred for EMR frequently have flat areas of visible tissue that cannot be snared. Current methods for treating residual tissue may lead to incomplete eradication or not allow complete tissue sampling for histologic evaluation. Our aim is to describe dissection-enabled scaffold-assisted resection (DeSCAR), a new technique combining circumferential ESD with EMR for removal of superficial non-lifting or residual "islands" with suspected submucosal involvement/fibrosis. METHODS: From 2015 to 2017, lesions referred for EMR were retrospectively reviewed. Cases were identified where lifting and/or snaring of the lesion was incomplete and the DeSCAR technique was undertaken. Cases were reviewed for location, previous manipulation, rates of successful hybrid resection, and adverse events. RESULTS: Twenty-nine lesions underwent DeSCAR because of non-lifting or residual "islands" of tissue. Fifty-two percent of the patients were male and 48% were female; average age was 66 years (standard deviation ±9.9 years). Lesions were located in the cecum (n = 10), right side of the colon (n = 12), left side of the colon (n = 4), and rectum (n = 3). Average size was 31 mm (standard deviation ±20.6 mm). Previous manipulation had occurred in 28 of 29 cases (83% biopsy, 34% resection attempt, 52% tattoo). The technical success rate for resection of non-lifting lesions was 100%. There was one episode of delayed bleeding but no other adverse events. CONCLUSIONS: DeSCAR is a feasible and safe alternative to argon plasma coagulation and avulsion for the endoscopic management of non-lifting or residual GI lesions, providing en bloc resection of tissue for histologic review. Further studies are needed to demonstrate long-term eradication and for comparison with other methods.

Determining priority for joint replacement: comparing the views of orthopaedic surgeons and other professionals.

OBJECTIVE: To assess which patient characteristics influence the assessments of urgency for surgery by orthopaedic surgeons and non-orthopaedic professionals. DESIGN, SETTING AND PARTICIPANTS: Cross-sectional study of 80 patients requiring elective hip or knee replacement attending a public hospital orthopaedic outpatient clinic or orthopaedic surgeon's private rooms. Patients were interviewed after being placed on the surgery waiting list. The interview asked about the severity of their joint disease and its effects on physical capability, psychological distress and social circumstances. Patient interviews were summarised and presented to assessors who ranked groups of eight patients in order of their perceived urgency for surgery. Eleven orthopaedic surgeon assessors completed 360 patient ratings and nine non-orthopaedic assessors from various professions, including physiotherapy, social work, research, management and engineering, completed 720 patient ratings. MAIN OUTCOME MEASURES: Visual analogue scale rating of patient urgency for surgery; patient rankings for surgery; scores for individual domain contributions to urgency rating. RESULTS: A broad spread of perceived urgency was evident among the patients. For each group of eight patients, there was moderate agreement on overall urgency rankings between the two groups of assessors. Linear regression demonstrated that pain was the dominant determinant of urgency score for both assessor groups. Orthopaedic surgeons also took into account limitations to mobility and concurrent medical illness but gave less priority to psychological distress or social circumstances. For the non-orthopaedic assessors, limitations to mobility, social circumstances and psychological distress also contributed to urgency. CONCLUSION: Both orthopaedic surgeons and non-orthopaedic professionals considered pain the most important factor in establishing urgency and priority for joint replacement. Only the non-orthopaedic professionals considered psychosocial factors important when determining priority for surgery. Broader community discussion about prioritisation for elective surgery is needed to facilitate agreement about which patients factors should be considered.

Arginase-1: a new immunohistochemical marker of hepatocytes and hepatocellular neoplasms.

The distinction of hepatocellular carcinoma (HCC) from metastatic tumor in the liver often presents a diagnostic challenge that carries significant impact on prognostication and therapy. The number of diagnostically useful immunohistochemical markers of hepatocytes is limited to hepatocyte paraffin antigen (HepPar-1), polyclonal carcinoembryonic antigen, and CD10, with alpha-fetoprotein and glypican-3 labeling HCCs. Arginase-1 (Arg-1) is a binuclear manganese metalloenzyme that catalyzes the hydrolysis of arginine to ornithine and urea. We used immunohistochemistry to compare the sensitivity of Arg-1 to that of HepPar-1 in 151 HCCs. We found that the overall sensitivities of Arg-1 and HepPar-1 are 96.0% and 84.1%, respectively. The sensitivities of Arg-1 in well, moderately, and poorly differentiated HCCs are 100%, 96.2%, and 85.7%, respectively, whereas, in comparison, HepPar-1 demonstrated sensitivities of 100%, 83.0%, and 46.4% for well, moderately, and poorly differentiated tumors, respectively. There were no HCCs in our study that were reactive for HepPar-1 but nonreactive for Arg-1. We also examined Arg-1 expression in nonhepatocellular tumors, including many that are potential mimics of HCC (renal cell carcinomas, neuroendocrine tumors, melanomas, gastric adenocarcinomas, and adrenocortical carcinomas) and found that only 2 non-HCC tumors were reactive for Arg-1. Arg-1 represents a sensitive and specific marker of benign and malignant hepatocytes that may ultimately prove to be a useful diagnostic tool in routine surgical pathology practice.

Recent developments in liver pathology.

CONTEXT: Hepatocellular carcinoma is the sixth most common malignancy and the third leading cause of cancer deaths worldwide, making pathologic identification of precursor lesions essential. Recent molecular genetic, pathologic, and clinical data have led to the stratification of hepatic adenomas into subgroups with unique molecular profiles and varying potential for malignant transformation, as well as to the reclassification of telangiectatic focal nodular hyperplasia as telangiectatic adenoma. Clinical, morphologic, and molecular genetic studies have also established juvenile hemochromatosis and pediatric nonalcoholic steatohepatitis as entities distinct from their adult counterparts. OBJECTIVE: To review the recent molecular genetic characterization of telangiectatic hepatic adenomas and juvenile hemochromatosis, as well as the recent clinicopathologic characterization of pediatric nonalcoholic steatohepatitis. DATA SOURCES: Literature review, personal experience, and material from the University of Chicago. CONCLUSIONS: Basic science and translational research have led to the classification of many pathologic entities of the liver according to molecular genetic and protein expression profiles that correspond to traditional morphologic categories. Insights into signal transduction pathways that are activated in, and protein expression patterns unique to, an individual disease may lead to the development of new therapeutic agents and novel diagnostic biomarkers.

Is the risk of concomitant invasive esophageal cancer in high-grade dysplasia in Barrett's esophagus overestimated?

BACKGROUND & AIMS: Recent studies have claimed long neoplasia-free survival rates with endoscopic mucosal resection of high-grade dysplasia (HGD) in Barrett's esophagus (BE). However, reports have contended that approximately 40% of patients who have esophagectomy for HGD have occult invasive cancer. The aim of this study was to use explicit criteria to determine the true prevalence of invasive adenocarcinoma in reports of patients who had esophagectomy for HGD in BE. METHODS: Studies reporting rates of esophageal cancer in patients who underwent esophagectomy for HGD in BE were gathered using MEDLINE and PUBMED. We defined invasive esophageal adenocarcinoma (IEAC) as tumor with submucosal invasion or beyond. Intramucosal carcinoma (IMC) was not considered IEAC. RESULTS: Twenty-three articles were selected for analysis. Most investigators reported rates of invasive cancer in the esophagectomy specimen, and the pooled average was 39.9% among the 441 patients who underwent an esophagectomy for HGD. Reported rates varied from 0% to 73%. A total of 267 patients had American Joint Committee on Cancer stage 0 postoperatively, 132 patients had stage I, 23 patients had stage IIa, 10 patients had stage IIb, and 9 patients had stage III. Fourteen studies provided differentiation between intramucosal and submucosal invasion. Among 213 patients, only 12.7% had IEAC, whereas 87.3% had HGD or IMC. The IEAC rate of 11% among patients with visible lesions is greater than the rate of 3% among patients with no visible lesion. CONCLUSIONS: By using strict pathologic definitions of invasive disease, the present study indicates the true prevalence of IEAC in BE and HGD may have been overestimated significantly. Separating IMC from IEAC is clinically relevant because endoscopic techniques potentially may treat IMC.

Rab11a immunohistochemical analysis does not distinguish indefinite, low-, and high-grade dysplasia in Barrett esophagus.

Our aim was to determine whether p53 and Rab11a immunoreactivity enhance diagnostic assessment of esophageal dysplasia. Histologic sections from 68 cases of Barrett esophagus obtained as part of a 12-institution study were stained with antibodies to p53 and Rab11a, randomized, and coded. The mucosal surface layer and deeper glands were scored blindly on a semiquantitative scale. The correlations between p53 and Rab11a scoring with the consensus diagnosis of dysplasia were analyzed. The histologic scale was as follows: no dysplasia, indefinite, low-grade dysplasia, high-grade dysplasia, intramucosal carcinoma, and invasive carcinoma. Rab11a staining was most prominent in epithelia negative for dysplasia but with regenerative features. There was an inverse relationship between Rab11a staining and findings of surface dysplasia (P < .02, chi(2)). However, statistical significance largely reflected loss of Rab11a immunoreactivity in intramucosal and invasive carcinoma, which was not a diagnostic dilemma. There was a strong positive correlation of p53 immunoreactivity with an increasing degree of epithelial dysplasia and carcinoma (P < .03, chi(2)). Rab11a immunoreactivity did not enhance the diagnostic assessment of dysplasia in Barrett esophagus. The previously reported positive correlation of p53 immunoreactivity with the presence of dysplasia in Barrett esophagus was confirmed.

Joint replacement surgery.

Joint replacement is the most effective healthcare measure in improving patient quality-of-life outcomes. More than 46000 hip and knee replacements were performed in Australia between July 2000 and July 2001. The need for joint replacements will increase as the population ages. More than 90% of hip and/or knee replacements survive for 10-15 years. Prosthesis selection needs to be tailored to each patient, although rationalisation of types of prosthesis used is required.