Association of TNF-beta polymorphism with disease severity among patients infected with hepatitis C virus

The pathogenesis of chronic hepatitis C virus (HCV) infection remains unclear. Tumour necrosis factor alpha (TNF-alpha) is alleged to contribute in the pathogenesis of chronic HCV infection. Single nucleotide polymorphism in TNF-alpha and -beta genes could influence the outcome of HCV infection. The aim was to study single nucleotide polymorphism in TNF-alpha promoter region and Nco I polymorphisms in the TNF-beta gene in patients with chronic hepatitis C. Fifty-two patients with histologically proven chronic hepatitis, who had raised ALT levels (>1.5 x ULN) and were HCV RNA positive, were studied. Genotyping of -308 promoter variant of TNF-alpha was performed by PCR with primers that incorporated an Nco I restriction site. For PCR typing of the TNF-beta Nco I restriction fragment length polymorphism, sequence specific primers were used. Polymorphism in the TNF-alpha G/G, G/A and A/A allele was not different between HCV patients and healthy controls. TNF-beta A/A allele was significantly more common (P = 0.02) in patients (28.8%) as compared to controls (12.8%), whereas no significant difference was observed for TNF-beta G/A and G/G alleles [corrected]. Nco I TNF-beta A/A was strongly associated with -308 TNF-alpha G/G (RR of HCV persistence = 4.9), indicating possible linkage between TNF-beta A/A and TNF-alpha G/G allele. Patients with severe hepatic fibrosis more frequently had the TNF-beta A/A allele as compared to patients with mild disease (P = 0.04). Immunogenetic factors, such as single nucleotide polymorphisms in TNF-beta (A/A allele), may affect the natural course of HCV infection, in particular, the disease progression. Larger studies including cytokine expression profiles are needed to fully understand the contribution of the polymorphisms described in the pathogenesis of chronic hepatitis C.     

Proliferative characteristics of intestinalized mucosa in the distal esophagus and gastroesophageal junction (short-segment Barrett's esophagus): a case control study

Intestinalized epithelium in traditional long-segment Barrett's esophagus (BE) shows increased proliferative activity, which is postulated to be an early step in the metaplasia-dysplasia-carcinoma sequence. The aim of this study was to evaluate the proliferative activity of intestinalized epithelium of the distal esophagus and gastroesophageal junction (IMEGEJ). Tissue sections from 78 consecutive patients (20 with IMEGEJ, 58 without IMEGEJ) who had elective upper gastrointestinal endoscopy over a 6-month period were immunohistochemically stained with MIB-1, the Ki-67 proliferation-antigen-associated marker, for evaluation of the crypt MIB-1 proliferation index (PI), size of the proliferative zone (PZ), and the presence of surface epithelial staining. Data from the IMEGEJ and non-IMEGEJ groups, and from 15 age-matched patients with traditional long-segment BE (>3.0 cm), were compared statistically. IMEGEJ patients showed a statistically significant increase in the mean crypt PI compared with non-IMEGEJ controls (21.9+/-19.5 v 14.3+/-9.3; P=.01). In addition, IMEGEJ cases showed an increase in the mean crypt PZ (52.3+/-16.4 v 45.2+/-17.2; P=.05), and a trend toward an increase in the percentage of cases with MIB-1-positive surface epithelial cells (50% v 33%, P=.18). Patients with IMEGEJ did not differ from patients without IMEGEJ with respect to any other clinical or histological feature, including signs or symptoms of gastroesophageal reflux disease and presence or absence of esophagitis or carditis. The MIB-1 results of the patients with long-segment BE (MIB-1 PI = 22.6+/-20.5, MIB-1 PZ = 51.8+/-19.6, proportion of cases with MIB-1-positive surface cells = 66%) were similar to those with IMEGEJ. Intestinalized epithelium in the distal esophagus or gastroesophageal junction shows increased proliferative activity in comparison with patients without intestinalized epithelium. This finding supports an increased risk of carcinogenesis in patients with IMEGEJ.     

Large deformation three-dimensional image registration in image-guided radiation therapy

In this paper, we present and validate a framework, based on deformable image registration, for automatic processing of serial three-dimensional CT images used in image-guided radiation therapy. A major assumption in deformable image registration has been that, if two images are being registered, every point of one image corresponds appropriately to some point in the other. For intra-treatment images of the prostate, however, this assumption is violated by the variable presence of bowel gas. The framework presented here explicitly extends previous deformable image registration algorithms to accommodate such regions in the image for which no correspondence exists. We show how to use our registration technique as a tool for organ segmentation, and present a statistical analysis of this segmentation method, validating it by comparison with multiple human raters. We also show how the deformable registration technique can be used to determine the dosimetric effect of a given plan in the presence of non-rigid tissue motion. In addition to dose accumulation, we describe a method for estimating the biological effects of tissue motion using a linear-quadratic model. This work is described in the context of a prostate treatment protocol, but it is of general applicability.     

Histochemical similarities between human and animal globoid cells in Krabbe's disease: a lectin study

Summary Lectin-histochemical studies were performed on paraffin-embedded brain tissue sections to identify the specific sugar residues of undegraded stored substances in the cytoplasm of globoid cells from patients with globoid cell leukodystrophy. We studied brain tissues from six human patients with galactosylceramide lipidosis (i. e., Krabbe's disease) and compared them to brain tissues from animals with a similar enzyme deficiency including seven Twitcher mice, three dogs and two cats. The globoid cells in all 18 cases studied stained with succinylated-wheat germ agglutinin (S-WGA), but did not stain withDilichos biflorus agglutinin, soybean agglutinin orUlex europaeus agglutinin-I.Bandeirea simplicifolia agglutinin-I stained the globoid cells in Twitcher mice, dogs and cats but not those in humans.Concanavalia ensiformis agglutinin, wheat germ agglutinin andRicinus communis agglutinin-I all stained each of the globoid cells in the mouse, dog and cat tissues, but only in some of the human cases. Peanut agglutinin, however, variably stained globoid cells in the mouse and dog cases but not at all in the human and cat cases. These results demonstrate a common terminal carbohydrate residueN-acetyl glucosamine, which binds S-WGA in the undergraded material stored within the globoid cells in galactoceramide lipidosis. These cells also contained various other stored molecules with sugar residues whose nature is determined by species or individually.Supported by grants NS21765 and HD05515 from the National Institutes of Health     

Closed Transverse Pinning for Reduction and Fixation of Metatarsal Neck Fractures: Surgical Technique

Most metatarsal neck fractures can be successfully treated non-operatively in a cast boot. Displaced metatarsal neck fractures tend to be less stable and have a propensity for the distal fragment to angulate, secondary to the strong flexor tendons, which often forces the distal fracture fragment in a plantar direction and leads to relative metatarsal shortening. Most literature is focussed on antegrade fixation of metatarsal neck fractures using pre-bent K wires or thin elastic nails. Apart from the technical challenges, this technique is limited when bones are osteoporotic as the pre-bent distal end of the K-wire may penetrate the plantar cortex of the proximal metatarsal and prevent the wire from entering the medullary canal of the metatarsal and advancing to the fracture site. Furthermore, when the medullary canal is narrow especially in Asian patients, it may be difficult to pass a bent K-wire through the isthmus of the metatarsal shaft. We describe an innovative technique of closed transverse wiring of the metatarsal head necks that has a distinct advantage in Asian population with osteoporotic bones. With percutaneous manipulation using digital pressure, closed reduction of fracture fragments of the most displaced fracture is done under fluoroscopic guidance to achieve a satisfactory alignment followed by closed transverse wiring of the metatarsal heads. With this procedure, adjacent fractures remain stable within an acceptable range because of intermetatarsal ligaments connected to the adjacent intact head. Our technique has a relatively short operating time and allows for early motion of the metatarso-phalangeal joint. This is especially useful for those with osteoporosis, narrow canal, soft tissue compromise, intra-operative failure of ante-grade pinning and in scenarios of limited surgical equipment/expertise.     

Trends in management of ureteral urothelial carcinoma and effects on survival: a hospital-based registry study

BackgroundHigh-risk ureteral tumors represent an understudied subset of upper tract urothelial carcinoma, whose surgical management can range from a radical nephroureterectomy (NU) to segmental ureterectomy (SU).ObjectivesTo evaluate contemporary trends in the management of high-risk ureteral tumors, the utilization of lymphadenectomy and peri-operative chemotherapy, and their impact on overall survival (OS).Design, setting, and participantsWe performed a retrospective cohort study of patients in the National Cancer Database from years 2006 to 2013 with clinically localized high-risk ureteral tumors treated with NU or SU.Outcome measurements and statistical analysisChi-squared tests were utilized to assess differences in clinicodemographic features and peri-operative treatment delivery between SU and NU cohorts. Cochran-Armitage tests and linear regressions were performed to evaluate temporal trends in treatment utilization. Multivariable logistic regression models were employed to assess predictors of treatment delivery. Multivariable Cox proportional hazards models evaluated associations with OS.ResultsOf the 1,962 patients included, NU was more commonly performed than SU (72.4%, 1,421/1,962 vs. 27.6%, 541/1,962). Only 22.7% (446/1,962) of the population underwent lymphadenectomy, and 24.8% (271/1,092) of those with advanced pathology (≥pT2 or pN+) received adjuvant chemotherapy. Lymphadenectomy was associated with improved OS in NU patients when more than 3 nodes were removed (hazard ratio [HR] 0.58, 95% confidence interval [CI] 0.39–0.89). Receipt of adjuvant chemotherapy for advanced pathology had no impact OS in both the NU (HR 1.10, 95% CI 0.84–1.44) and SU (HR 0.94, 95% CI 0.61–1.46) cohorts. Performance of SU was not associated with poorer OS on multivariable analysis (HR 1.02, 95% CI 0.89–1.21, P = 0.83).ConclusionOur study suggests that SU may be an appropriate alternative to NU for the management of high-risk ureteral tumors. Further, lymphadenectomy may play an important role at the time of NU, and adjuvant chemotherapy is infrequently utilized in patients with advanced pathology.