Development and characterisation of a large diameter decellularised vascular allograft.

The aims of this study were to develop a biological large diameter vascular graft by decellularisation of native human aorta to remove the immunogenic cells whilst retaining the essential biomechanical, and biochemical properties for the ultimate benefit of patients with infected synthetic grafts. Donor aortas (n = 6) were subjected to an adaptation of a propriety decellularisation process to remove the cells and acellularity assessed by histological analysis and extraction and quantification of total DNA. The biocompatibility of the acellular aortas was determined using standard contact cytotoxicity tests. Collagen and denatured collagen content of aortas was determined and immunohistochemistry was used to determine the presence of specific extracellular matrix proteins. Donor aortas (n = 6) were divided into two, with one half subject to decellularisation and the other half retained as native tissue. The native and decellularised aorta sections were then subject to uniaxial tensile testing to failure [axial and circumferential directions] and suture retention testing. The data was compared using a paired t-test. Histological evaluation showed an absence of cells in the treated aortas and retention of histoarchitecture including elastin content. The decellularised aortas had less than 15 ng mg-1 total DNA per dry weight (mean 94% reduction) and were biocompatible as determined by in vitro contact cytotoxicity tests. There were no gross changes in the histoarchitecture [elastin and collagen matrix] of the acellular aortas compared to native controls. The decellularisation process also reduced calcium deposits within the tissue. The uniaxial tensile and suture retention testing revealed no significant differences in the material properties (p > 0.05) of decellularised aorta. The decellularisation procedure resulted in minimal changes to the biological and biomechanical properties of the donor aortas. Acellular donor aorta has excellent potential for use as a large diameter vascular graft.

Mast cells: new therapeutic target in helminth immune modulation.

Helminth infection and their secreted antigens have a protective role in many immune-mediated inflammatory disorders such as inflammatory bowel disease, rheumatoid arthritis and multiple sclerosis. However, studies have focused primarily on identifying immune protective mechanisms of helminth infection and their secreted molecules on dendritic cells and macrophages. Given that mast cells have been shown to be implicated in the pathogenesis and progression of many inflammatory disorders, their role should also be examined and considered as cellular target for helminth-based therapies. As there is a dearth of studies examining the interaction of helminth-derived antigens and mast cells, this review will focus on the role of mast cells during helminth infection and examine our current understanding of the involvement of mast cells in TH 1/TH 17-mediated immune disorders. In this context, potential mechanisms by which helminths could target the TH 1/TH 17 promoting properties of mast cells can be identified to unveil novel therapeutic mast cell driven targets in combating these inflammatory disorders.

Fasciola hepatica tegumental antigens indirectly induce an M2 macrophage-like phenotype in vivo.

The M2 subset of macrophages has a critical role to play in host tissue repair, tissue fibrosis and modulation of adaptive immunity during helminth infection. Infection with the helminth, Fasciola hepatica, is associated with M2 macrophages in its mammalian host, and this response is mimicked by its excretory-secretory products (FhES). The tegumental coat of F. hepatica (FhTeg) is another major source of immune-modulatory molecules; we have previously shown that FhTeg can modulate the activity of both dendritic cells and mast cells inhibiting their ability to prime a Th1 immune response. Here, we report that FhTeg does not induce Th2 immune responses but can induce M2-like phenotype in vivo that modulates cytokine production from CD4(+) cells in response to anti-CD3 stimulation. FhTeg induces a RELMα expressing macrophage population in vitro, while in vivo, the expression of Arg1 and Ym-1/2 but not RELMα in FhTeg-stimulated macrophages was STAT6 dependent. To support this finding, FhTeg induces RELMα expression in vivo prior to the induction of IL-13. FhTeg can induce IL-13-producing peritoneal macrophages following intraperitoneal injection This study highlights the important role of FhTeg as an immune-modulatory source during F. hepatica infection and sheds further light on helminth-macrophage interactions.

Metabolism of theophylline to caffeine in human fetal liver.

Caffeine (1,3,7-trimethylxanthine) is a biotransformation product of theophylline (1,3-dimethylxanthine) in the human fetus. Liver explants, obtained from human fetuses with gestational ages of 12 to 20 weeks, were incubated with theophylline and produced caffeine and, in lesser amounts, 1,3-dimethyluric acid and 3-methylxanthine. These findings suggest that the predominant pathway in theophylline metabolism in the fetus and newborn infant is the methylation reaction producing caffeine. This may contribute to the neonate's exceedingly slower elimination of caffeine relative to theophylline. Caffeine produced from theophylline may add to the pharmacologic effects of theophylline in newborn infants with apnea.

Caffeine metabolism in the newborn.

The concentrations of caffeine and metabolites in urine have been examined as a function of age to explore the remarkably slow elimination of caffeine by human infants. Urine samples were obtained from 3 adults and 10 infants aged 8 days to 8 months during therapeutic treatment with caffeine. A high-performance liquid chromatographic (HPLC) procedure involving reversed-phase partition chromatography was developed to separate caffeine and 13 of its metabolites. During the first month of life, caffeine accounted for more than 85% of the identifiable products in urine. Caffeine remained the predominant component for the first 3 months, but its percentage decreased gradually to the adult value of less than 2% by the age of 7 to 9 months. This change reflected increasing metabolite production, not decreasing urinary caffeine concentration. The adult metabolite pattern of partially demethylated xanthines and urates was attained by 7 to 9 months. The data indicate that the 4-day plasma t1/2 of caffeine characteristic of the newborn depends in large part on slow urinary excretion of unchanged drug since there is little or no metabolism. Subsequent decrease in the t1/2 to about 4 hr by the age of 8 months correlates closely with the rise in metabolite production.

The psychopharmacology of hallucinogens.

Hallucinogenic drugs have been inhaled, ingested, worshipped, and reviled since prehistory. With the purification and synthesis of bontanical preparations and the ensuing discovery of chemically unique agents, hope was raised regarding their therapeutic potential, but this hope has been clouded by an epidemic of abuse and an inventory of adverse effects. This review examines aspects of that controversy, including the history of hallucinogens, epidemiology of current hallucinogen abuse, the association of LSD use with prolonged psychoses and hallucinogen persisting perception disorder, and the efforts to demonstrate the drug's therapeutic efficacy. Human subject ramifications in hallucinogen experimentation are discussed. Future lines of research are suggested in human, animal, and tissue culture paradigms.

Adverse consequences of lysergic acid diethylamide.

The continued endemic use of hallucinogenic drugs, and of LSD in particular, raises concern regarding their short and long term adverse consequences. The epidemiology of LSD abuse is reviewed suggesting an increase in LSD use among the young as the prevalence rates for other substances continues to fall. Evidence supports the association of LSD use with panic reactions, prolonged schizoaffective psychoses and post-hallucinogen perceptual disorder, the latter being present continually for as long as 5 years. Evidence does not support claims of genetic disorders arising from hallucinogens. In light of the foregoing, current data confirm earlier findings of long lasting psychopathology arising in vulnerable individuals from the use of LSD. A hypothetical long term molecular mechanism of adverse effects is proposed.

QT prolongation and torsades de pointes induced by an antifungal agent, D0870, in conscious dogs.

D0870 ((R)-2-(2,4-difluoro-phenyl)-1-[3-[(E)-4-(2,2,3,3-tetrafluoropropoxy+ ++)-styryl]-1H-1,2,4-triazol-1-yl]-3-(1H-1,2,4-triazole-1-yl) propan-2-ol), a novel bis-triazole antifungal agent, induced sudden deaths at a high dose of 5 mg/kg/day in a 6-month toxicity study in dogs. In the present study, we intended to elucidate the cause of the sudden death in dogs. When used in a single dose, D0870 induced prolongation of QTc intervals in proportion to its plasma concentration, and the threshold plasma concentration of the drug causing 10% QTc prolongation was estimated to be 3.8 microg/ml. Then, we conducted a study to induce sudden death in dogs using loading (50 mg/kg) and maintenance (5 mg/kg/day) doses with long-term ambulatory electrocardiographic monitoring. Marked QTc prolongation (52-96%), ventricular premature contractions, and T-wave alternans were observed in all 10 animals treated with the drug, and seven out 10 animals died of ventricular fibrillation (VF) associated with torsades de pointes (TdP) when the dogs were treated with D0870 for 14 or 16 days. The TdPs were elicited in both tachycardia and bradycardia, and some of them in the former proceeded to VF. Consequently, we clarified that D0870-induced sudden death is primarily attributable to the development of TdP preceding VF and may be enhanced by sympathetic nervous tone produced by emotional or physical stress.

Erosion and perforation of colon by synthetic mesh in a recurrent paracolostomy hernia.

Parastomal hernia, particularly when recurrent, presents a troublesome problem to the surgeon. Since the late 1970s, prosthetic-mesh repairs have been used increasingly, though, as yet, there is no consensus on the best technique of repair. We report a case of failure of a polypropylene-mesh repair of a recurrent parastomal hernia, complicated by erosion of the mesh edge into the colon proximal to the stoma. This entailed further resection of the colon, excision of the mesh and relocation of the colostomy. The case highlights the potential for serious morbidity from this form of repair and the need for careful assessment of symptoms before contemplating a surgical approach to any type of parastomal hernia.

Pre-vascular hernia: a rare cause of chronic obscure groin pain after inguinal hernia repair.

A rare case of pre-vascular hernia is reported in a woman complaining of chronic obscure groin pain following an inguinal hernia repair. The condition was only diagnosed by means of a herniogram, emphasising the value of this investigation in unexplained groin pain. The hernia was successfully repaired using a polypropylene mesh plug, a simple technique widely employed in both femoral and recurrent inguinal hernia, but never before described in pre-vascular hernia.

Marketing organ donation around the globe.

Marketing to potential organ donors in different countries requires knowledge about religious beliefs and cultural norms that might influence the decision to donate. Because beliefs vary so widely from country to country, marketers need to consider whether a standardized or adaptive approach is suitable for marketing organ donation in different countries. This article takes a look at the variables that influence the decision to donate an organ and suggests marketing strategies that may work in various parts of the world.

Structural chemistry of A3CuBO6 (A = Ca, Sr; B = Mn, Ru, Ir) as a function of temperature.

Variable temperature X-ray and neutron powder diffraction techniques have been used to identify structural phase transitions in Cu-rich A(3)A'BO(6) phases. A transition from monoclinic to rhombohedral symmetry was observed by X-ray diffraction between 700 and 500 K in Sr(3)Cu(1-x)M(x)IrO(6) (M = Ni, Zn; 0 < or = x < or = 0.5). The temperature of the phase change decreased in a linear manner with Cu-content and was essentially independent of the nature of M. Ca(3.1)Cu(0.9)MnO(6) was shown to pass from a rhombohedral phase to a triclinic phase on cooling below 290 K; the structure of the triclinic phase was refined against neutron diffraction data collected at 2 K. Ca(3.1)Cu(0.9)RuO(6) undergoes a transition between a disordered rhombohedral phase and an ordered monoclinic phase when cooled below 623 K. Neutron diffraction has been used to determine the structure as a function of temperature in the range 523 < or =T/K < or = 723 and hence to determine an order parameter for the low temperature phase; the second-order transition is shown to be incomplete 100 K below the critical temperature.

Women priests: from exclusion to accommodation.

The debate within the Church of England on opening the priesthood to women is analysed from the perspective of grid/group theory as a struggle between two competing models of the Church: the accommodationist and the exclusivist. The ascendancy of the accommodationist Church reflects the decline of status professionalism and rise of the formally rational modern profession, in which the criteria of occupational closure are themselves rationalized.

Histological assessment of colorectal adenomas by size. Are polyps less than 10 mm in size clinically important?

OBJECTIVE: To define the relative risk of malignant transformation in colorectal adenomas less than 10 mm in diameter. DESIGN: Prospective study. SETTING: District general hospital, UK. SUBJECTS AND MATERIALS: 1228 polyps detected endoscopically in 445 patients over the 10-year period 1989-1999. MAIN OUTCOME MEASURES: Site, size, histological type and dysplastic grade of polyp. RESULTS: 657 of the 1228 polyps were adenomas: 281 (43%) tubular, 339 (51%) tubulovillous and 37 (6%) villous. In the 357 adenomas less than 10 mm in diameter, 11 (3%) were severely dysplastic and 2 carcinomas were detected, though neither was less than 5 mm in size. The relative risk of malignancy or severe dysplasia in adenomas of 10 mm or more compared with those of less than 10 mm was 3.8 (p < 0.0001). CONCLUSIONS: Although severe dysplasia and malignancy do occur in adenomas less than 10 mm in size, they are rare in lesions of less than 5 mm. We recommend routine destruction of all polyps 5 mm or more in size, though it is not essential to remove those of less than 5 mm if they are kept under surveillance.

Studies on the metabolism of meptazinol, a new analgesic drug.

1 The absorption, metabolism and excretion of the new analgesic meptazinol has been studied in male volunteers following oral and intravenous administration of a mixture of the [1-14C] and [7-3H] labelled compound. 2 After oral dosage, absorption from the gastrointestinal tract was rapid as evidenced by the early attainment of peak plasma radioactivity levels and near complete as shown by only small amounts of radioactivity recovered in the faeces. 3 Although the absorption of the drug was good, the systemic bioavailability was relatively low. Plasma levels of the unchanged drug remained below the limit of detection (20 ng/ml) after an oral dose of 200 mg. However, after intravenous administration of only 20 mg the peak plasma level was approximately 58 ng/ml. Subsequent elimination was rapid and proceeded in an apparently mono exponential manner with a half-life of approximately 2 hours. 4 Excretion of radioactivity was rapid irrespective of the dosage route and took place chiefly via the urine. Over 60% of the administered radioactivity was recovered in the 0-24 h urine collection. Less than 10% of the administered dose was excreted in the faeces. 5 Less than 5% of the drugs was excreted unchanged. The major metabolite appeared to be the glucuronide conjugate of the parent drug. No evidence was found for N-demethylation of the compound. A minor metabolite of the drug which accounted for approximately 7% of the recovered radioactivity has been tentatively identified as 6-ethyl - 6 - (3-hydroxyphenyl) - 1 - methyl-hexahydroazepin - (2H)-2-ONE.

Pharmacokinetics and metabolism of the new analgesic meptazinol in rats and patas monkeys.

1. The absorption of meptazinol following oral administration to rats and monkeys was extensive, 63-88% of the administered dose being recovered in the urine. However, the rate of absorption was slower in the monkey than that in the rat. 2. Distribution studies showed higher concentrations of unchanged drug in tissues and plasma of rats than in those of monkeys after the same dosage. 3. Elimination of the drug from plasma occurred rapidly in both species. The major route of excretion was the urine, over 60% of the dose appearing in the 0-24 h collection. 4. Metabolism of the drug was extensive, less than 6% being excreted unchanged by either rats or monkeys. The major route of biotransformation in both species was conjugation of parent drug with glucuronic acid. Only male rats exhibited demethylation of the drug.