Trials and tribulations of vascular surgical benchmarking

The purpose of this study was to review the efficacy of a protracted venous infusion of 5-fluorouracil (PVI 5-FU)-based chemotherapy in advanced small bowel adenocarcinoma. Data on all patients with small bowel malignancy who were seen at a single institution over a 5-year period were retrieved from the gastrointestinal unit and hospital databases, and these cases were reviewed. Eight patients with advanced small bowel adenocarcinoma received PVI 5FU-based chemotherapy. The overall response rate in assessable patients was 37.5% (3/8). The median overall survival was 13 months (range 1-28), and progression-free survival was 7.8 months (range 0-15). Overall, the treatment was well tolerated and symptomatic benefit was seen. In conclusion, PVI 5-FU has activity in this disease. This should be assessed either as a single agent or as part of a combination regimen such as epirubicin/cisplatin/PVI FU (ECF) in a multicentre randomized study.     

Malignant fibrous histiocytoma in a child''s hand

Mycobacterium szulgai is a rare cause of human infections, and when present it is mostly known to cause lung infection. We report the first case of isolated Mycobacterium szulgai osteomyelitis in a 68-year-old woman on chronic immunosuppressive therapy. Review of the literature revealed a total of three other cases of M. szulgai osteomyelitis. In all these cases there was evidence of hematogenous or contiguous spread, including one with extensive dissemination. Pulmonary M. szulgai infections tend to occur in patients with chronic lung disease and/or concomitant lung infections, whereas osteomyelitis tends to occur in patients who have severe immunosuppression secondary to disease or drugs.     

Highly active antiretroviral therapy results in a decrease in CD8+ T cell activation and preferential reconstitution of the peripheral CD4+ T cell population with memory rather than naive cells

Criteria for detection of chromosome aberrations by Comparative Genomic Hybridization (CGH) are not standardized and improvement of this part of the analysis is of paramount importance to the applicability of the technique. The aim of this work was to suggest CGH detection criteria that increase the specificity and sensitivity and at the same time include chromosome regions previously excluded from CGH analysis. We analyzed 33 hybridizations with normal DNA and modified our CGH software in order to use a selection of these normal analyses as a model for interpretation of analyses of unknown samples. This approach was successfully tested on 14 samples with known aberrations.     

Structure of the MscL homolog from Mycobacterium tuberculosis: a gated mechanosensitive ion channel

Mechanosensitive ion channels play a critical role in transducing physical stresses at the cell membrane into an electrochemical response. The MscL family of large-conductance mechanosensitive channels is widely distributed among prokaryotes and may participate in the regulation of osmotic pressure changes within the cell. In an effort to better understand the structural basis for the function of these channels, the structure of the MscL homolog from Mycobacterium tuberculosis was determined by x-ray crystallography to 3.5 angstroms resolution. This channel is organized as a homopentamer, with each subunit containing two transmembrane alpha helices and a third cytoplasmic alpha helix. From the extracellular side, a water-filled opening approximately 18 angstroms in diameter leads into a pore lined with hydrophilic residues which narrows at the cytoplasmic side to an occluded hydrophobic apex that may act as the channel gate. This structure may serve as a model for other mechanosensitive channels, as well as the broader class of pentameric ligand-gated ion channels exemplified by the nicotinic acetylcholine receptor.     

Effect of heart failure on muscle capillary geometry: implications for 02 exchange

There is strong evidence that chronic heart chronic heart failure (CHF) impairs skeletal muscle function independent of blood flow and bulk O2 delivery. Purpose: This investigation sought to determine whether alterations in muscle capillary geometry and surface area that are thought to be primary determinants of the efficacy for blood-tissue 02 exchange might be altered in CHF and contribute to these changes. Methods: Plantaris (fast twitch) and soleus (slow twitch) muscles from control (C) and 6- to 7-wk post myocardial infarcted (CHF) rates were perfusion-fixed in situ. These muscles were analyzed using morphometric techniques that facilitated determination of muscle sarcomere length fiber cross-sectional area, capillary tortuosity and branching coefficient (c(K,0)), capillary length, volume, and surface area. Results: Normalized to a sarcomere length of 2.1 microns, plantaris fiber cross-sectional area decreased by 21% (P < 0.05), and capillary-to-fiber ratio decreased from 2.05 +2- 0.07 in C to 1.79 +2- 0.04 (P < 0.05) in CHF, but these variables were unchanged in soleus. These was no change in c(K,0) or capillary diameter in either muscle, and thus capillary length and surface area per fiber volume remained unchanged. From the measured fiber atrophy and capillary involution in plantaris reductions of total muscle capillary length, volume, and surface area of 11%, 9% and 17%, respectively, are estimated. Conclusion: These changes, coupled with reduced blood flow may impair the effective matching of muscle fiber 02 delivery to 02 requirement during repeated muscle contractions (i.e. exercise). The scenario is expected to reduce intramyocyte 02 partial pressure and thereby contribute to the greater fatigability characteristic of the CHF condition.     

Localization of putative tumor suppressor loci by genome-wide allelotyping in human pancreatic endocrine tumors

Only two tumor suppressor gene loci, one on 3p25 and the MEN1 gene on 11q13, have thus far been implicated in the pathogenesis of sporadic human pancreatic endocrine tumors (PETs). A genome-wide allelotyping study of 28 human PETs was undertaken to identify other potential tumor suppressor gene loci. In addition to those on chromosomes 3p and 11q, frequent allelic deletions were identified on 3q (32%), 11p (36%), 16p (36%), and 22q (29%). Finer deletion mapping studies localized the smallest regions of common deletion to 3q27, 11p13, and 16p12.3-13.11. Potential candidate genes at these loci include WT1 (11p13), TSC2 (16p13), and NF2 (22q12), but no known tumor suppressor gene localizes to 3q27. The mean fractional allelic loss among these human PETs is 0.126, and no correlation was observed between allelic loss and clinical parameters, including age, sex, hormonal subtype, and disease stage. These findings highlight novel locations of tumor suppressor gene loci that contribute to the pathogenesis of human PETs, and several of these on 3p, 3q, and 22q are syntenic with loci on mouse chromosomes 9 and 16 that are implicated in a murine transgenic model of PETs.     

Enhancement of adenovirus-mediated gene transfer to human bone marrow cells

Adenovirus infection of CD34+ hematopoietic stem/progenitor cells is dependent on the multiplicity of infection (MOI), time of incubation, the volume in which the co-incubation occurs and the presence or absence of growth factors. Studies revealed that a brief co-incubation (1-8 hours), resulted in low levels of transgene expression, suggesting that adenovirus infection of CD34+ cells occurs slowly, and optimal transduction requires a 24 hour exposure to adenovirus. Infection by Ad/beta-gal or Ad/p53 at a MOI of 500:1 provided a high transduction efficiency but inhibited hematopoietic function. However, treatment at a MOI of 50-100 resulted in efficient transduction (10.7-15.7% positive) without detectable toxicity. Secondary proof of adenovirus transgene expression was demonstrated by detection of mRNA for p53 in Ad/p53 infected stem cells. We conclude that a 24 hour exposure to recombinant adenovirus encoding p53 or beta-gal, at a MOI of 50-100 is optimal for in vitro gene transfer to BM cells and has no significant effect on hematopoietic function. Adenovirus-mediated transduction of BM cells can also be modulated by growth factors (IL-3, GM-CSF and G-CSF) with improved gene delivery and maintenance of hematopoietic function. In summary, adenovirus vectors can be used to transiently transduce stem cells, and conditions have been defined to maximize expression and limit inhibitory effects on CD34+ cells. These data support continued investigation of this vector for local cytokine delivery and purging of stem cell products.     

Human diploid cell culture rabies vaccine (HDCV) and purified chick embryo cell culture rabies vaccine (PCECV) both confer protective immunity against infection with the silver-haired bat rabies virus strain (SHBRV)

The demonstration of extensive differences in the antigenic makeups of the silver-haired bat rabies virus (SHBRV) and canine rabies virus (COSRV) strains raised concerns as to whether current licensed rabies vaccines are sufficiently protective against SHBRV. NIH mouse protection test results show that both the human diploid cell culture rabies vaccine (HDCV) and the purified chicken embryo cell rabies vaccine (PCECV) protected against lethal infection with SHBRV as well as the canine rabies strain COSRV. However, in this investigation, the potencies of both vaccines in mice were found to be significantly higher for COSRV than for SHBRV. The in vivo protection data are confirmed by in vitro virus neutralizing antibody (VNA) test results which demonstrate that mice immunized with HDCV or PCECV develop significantly higher VNA titres against COSRV than against SHBRV. In contrast, VNA tests of sera from individuals immunized with HDCV or PCECV showed that humans, as opposed to mice, develop significantly higher VNA titres against SHBRV than against COSRV. These data suggest that HDCV and PCECV will protect humans against infection with the silver-haired but rabies virus strain in addition to canine rabies virus strains.     

Gains and losses of the XII-VII component of the "baby-sitter" procedure: a morphometric analysis

The classic hypoglossal transfer to the facial nerve is invariably followed by complications caused by tongue atrophy. In 1984, Terzis introduced the "baby-sitter" procedure which involved a formal cross-facial procedure, in addition to partial neurectomy of the hypoglossal nerve, and an end-to-side coaptation with the ipsilateral facial nerve. This reported study provides, for the first time, quantification of the number of hypoglossal motor fibers needed to successfully restore eye sphincter function, using an end-to-side coaptation with preservation of the tongue. Thirty adult Sprague-Dawley rats were divided into six groups: control, denervated, perineurial window, 20 percent partial neurectomy (PN), 40 percent PN, and 80 percent PN. The procedure involves interposing a nerve graft (saphenous) between the partially severed XII nerve and the upper zygomatic branch of the facial nerve. Evaluation of the behavioral data (blink reflex) revealed good-to-superb return of the blinking mechanism in the 40 percent group, without significant tongue atrophy. Electrophysiologic data in the 40 percent neurectomy group demonstrated superiority to the other groups. Quantitative axonal morphometry of the coaptation sites and graft, as well as motor end-plates of the orbicularis oculi muscle and tongue showed the 40 percent partial neurectomy group to be the optimal group.