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To investigate the relationship between donor liver cold preservation, lung surfactant (LS) changes and acute lung injury (ALI) after liver transplantation.
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Peritransplant anticoagulation therapy was beneficial to graft outcome, in both the acute and chronic phases. Moreover, specific inhibition of coagulation Xa protease further protected kidney grafts, with better recovery and decreased expression of chronic lesion markers. Surgical relevance The increasing use of marginal donors highlights the importance of organ quality in transplantation. Renal ischaemia-reperfusion injury (IRI), which includes a deleterious activation of coagulation, plays a central role in determining graft quality and outcome. Using an established porcine renal autotransplantation preclinical model with high clinical relevance, the benefits of anticoagulation therapy using an antifactor Xa molecule were evaluated. Peritransplantion anticoagulation treatment, specifically with an anti-Xa compound, protected marginal kidney grafts, improving functional recovery and reducing chronic lesions. This study demonstrates the benefits of anticoagulation therapy at the time of organ collection, particularly for marginal organs, encountered in cases of extended criteria and deceased after circulatory death donors. This anticoagulation strategy could be an important addition to current donor and organ management protocols in order to limit IRI and improve outcome.
Cold ischemia and reperfusion during renal transplantation result in release of reactive oxygen species. The aim of this study is to examine whether cold storage induced cell injury can be ameliorated by adding flavonoids directly to preservation solutions.
Determination method of allopurinol has been studied by the second derivative oscillopolarography. Well-defined linear relationship between concentrations and the wave height in the range 3 X 10(-7)-1 X 10(-4) mol/L and 5 X 10(-7)-1 X 10(-4) mol/L was observed, respectively, in 0.50 mol/L H2SO4 and pH 5.5 HAc-NaAc buffer. The contents of allopurinol in tablets and urine were determined. The character of the electrode reaction was explored preliminarily.
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In all livers, ATP, ADP, and AMP degraded over 4 hours. In UW and LS groups, degradation beyond hypoxanthine was halted, and it continued in the HTK group. This blockade led to a significant reduction in the accumulation of xanthine and uric acid. Histological analysis showed protected architecture and maintenance of reticulin scaffolds in the UW and LS groups, whereas tissue breakdown was seen from earlier time points in the HTK group. Additionally, throughout ischemia, signs of pathological injury were more pronounced with UW- than with LS-preserved tissue.
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Allupurinol is a commonly prescribed drug. However, the use of this drug is not based on evidence and guidelines. We audited Allopurinol prescriptions in patients aged 65 years and over in a teaching hospital over 22 weeks. In 47% of patients the dose was higher than recommended and in 40% it was lower. Quality use of medications is an important issue to maintain quality of life in the elderly.
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Livers of adult male Sprague-Dawley rats (N = 3 to 4 per group) were impaled with intracellular microelectrodes prior to and at various time periods for 6 hours following complete hepatic resection. Just prior to resection, each liver was perfused with preservation solutions associated with high (normal saline [NS]), moderate (Euro-Collins [EC]), and low (University of Wisconsin solution [UW]) risks of reperfusion injury.
Microparticles (MPs) released by activated or apoptotic cells increase in number in the blood of subjects with vascular or metabolic diseases and may contribute to thrombotic complications.
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Imperfect myocardial protection during prolonged ischaemia results in adverse changes during reperfusion. Clinical studies carried out during cardiac surgery show that: (1) Oxygen free radicals produced during reperfusion can lead to chromosomal damage in leukocytes. However, this effect seems to be prevented by the addition of allopurinol in the cardioplegic solution. (2) Polymorphonuclear leukocytes are directly implicated in situ in the genesis of free radicals responsible for reperfusion injury. (3) Pre-treatment with trimetazidine, an anti-ischaemic drug with antioxidant properties, and addition of the drug to the cardioplegic solution reduced oxygen free radical damage, as shown by a reduced release of malondialdehyde increase and of myosin; moreover, pre-treatment with trimetazidine enabled patients to undergo surgery with improved left ventricular function.
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Drug-induced urinary calculi, although they account for only 1-2% of urinary calculi, deserve consideration because most of them are preventable. In the drug-containing calculi resulting from the crystallization of a certain drug and its metabolites in the urine, stone analysis can identify the responsible drug. While, in the drug-induced metabolic calculi caused by interference with calcium, oxalate and purine metabolism, careful clinical inquiry is necessary to reveal involvement of a certain drug in stone formation. Better awareness of the possible drugs with lithogenic potential and close surveillance of patients on long-term treatment with these drugs are necessary. Especially, in patients with a history of urolithiaisis, prescription of lithogenic drugs deserve careful consideration.
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From a population of hyperuricaemic veterans of [serum urate level >416 micromol/l (7.0 mg/dl)] at least 40 years of age, we compared the risk of death between incident allopurinol users (n = 2483) and non-users (n = 7441). We estimated the multivariate mortality hazard ratio (HR) of allopurinol use with Cox proportional hazards models.
HTK (histidine-tryptophane-ketoglutarate) organ preservation solution has been shown to be effective in human kidney transplantation, but the efficacy of HTK for extended liver preservation has not been determined. In this study, canine livers were preserved in HTK and compared with livers preserved in University of Wisconsin solution. First, the right and left liver lobes in dogs were flushed separately with cold HTK and UW, respectively, according to a double-flush method. After splitting the liver, the right and left lobes were stored at 4 degrees C in either solution for 24 hr and 48 hr and assessed microscopically for parenchymal cell swelling, and enzyme histochemically for 5'-nucleotidase (5'-NT) as a marker of ischemic liver injury. Unlike livers preserved in UW (n = 5), HTK-preserved livers (n = 5) showed progressive parenchymal cell swelling after 24-hr and 48-hr storage. The 5'-NT scores in HTK livers were lower than in UW livers, indicating increased storage injury (0-5% and 66-85% in HTK- and UW-preserved livers, respectively, after 48-hr storage). Second, graft function was tested in an orthotopic liver transplantation model in the dog. Whole livers were flushed in situ with cold HTK or UW and stored at 4 degrees C for 24 hr or 48 hr. Liver grafts stored in HTK were not washed out prior to reflow in the recipient, in contrast to grafts stored in UW. Livers preserved for 24 hr using HTK showed life-supporting function after transplantation (n = 5, survival 12 hr-8 days). All grafts preserved for 48 hr in HTK did not function (n = 5, survival < 10 hr). UW-preserved grafts all functioned after 24-hr storage (n = 5, survival > 6 days), as well as after 48-hr storage (n = 6, survival > 6 days). Peak serum glutamic oxaloacetic transaminase (SGOT) values after transplantation of 24-hr and 48-hr HTK-preserved livers did not differ from peak SGOT values of UW-preserved livers after similar preservation times. In conclusion, UW solution is more effective than HTK solution in extended preservation of canine liver grafts: 24-hr storage of livers preserved with HTK solution is feasible, whereas 48-hr storage results in a nonfunctioning graft.
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We have studied the pathogenesis of murine cytomegalovirus (MCMV) pneumonitis in immunocompetent ICR mice and in mice treated with cyclophosphamide (CP). Intranasal infection of immunocompetent mice with MCMV resulted in transient and self-limited pulmonary lesions. When mice were given 200 mg/kg of CP one day before virus infection, transient splenic atrophy and subsequent splenic hypertrophy were induced, and the lesions in the lung were markedly augmented in their number and size although there was no significant enhancement of the virus growth. The augmentation coincided with the period of splenic hypertrophy. A marked increase in the number of pulmonary lesions was also induced in mice given 100 mg/kg of CP every 4 days following the initial dose of 200 mg/kg. In these mice, however, continuous splenic atrophy and augmented replication of MCMV in the lung were observed. When the activity of xanthine oxidase (XO) in lung tissue homogenates was measured, the activity was found to significantly increase after intranasal infection with MCMV irrespective of CP administration and there was a good correlation between the elevation of XO activity and the degree of pathological changes in the lung. In addition, we found that the administration of allopurinol, a specific inhibitor of XO and superoxide dismutase, a superoxide radical scavenger, reduced the number of the pulmonary lesions. These results suggest that superoxide radicals are involved in the pathogenesis of MCMV-associated pneumonitis in ICR mice.
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A case of chronic veno-occlusive disease of the liver manifested by ascites in a 59-year-old Japanese male is described. The patient had not been exposed to pyrrolizidine alkaloids, but had been receiving allopurinol for hyperuricemia, the only drug taken throughout the period in which the hepatic lesion developed. The hepatic veins and inferior vena cava were patent according to angiography. The first biopsy showed histological characteristics of the disease and the following two biopsies demonstrated the progression of the hepatic lesion from central fibrosis to non-portal cirrhosis. Morphometric analysis of the sublobular and central veins in the three serial biopsy specimens demonstrated stepwise decrease of the ratio of the veins per portal triad and stepwise increase of severely obliterative veins.
Acquired perforating dermatosis (APD) is characterized by umbilicated 1- to 10-mm-measuring papulonodules with a central adherent oystershell-like keratotic plug, typically on the dorsa of the hands, forearms and over the knees. APD is associated with systemic diseases, especially diabetes mellitus and/or renal failure. Histologically the lesions show transepidermal elimination of altered dermal components into a cup-shaped epidermal depression. We present a 69-year-old man with coexisting APD and Poland syndrome (PS), an association not yet described. PS (OMIM 173800) is a rare congenital anomaly consisting of unilateral partial or total absence of the greater pectoralis muscle and ipsilateral symbrachydactyly. Most cases of PS are sporadic as it was in our case. Our patient had, in addition, an untreated diabetic condition, hyperuricaemia, dilated cardiomyopathy and a very recent pulmonary embolism. He responded to therapy with allopurinol.
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We report on a case of a multiple congenital anomalies in a newborn infant whose mother was on allopurinol treatment through the pregnancy. The pattern of congenital anomalies that was noted in our patient was similar to the pattern described in a number of published reports following mycophenolate mofetil [CellCept®] treatment during pregnancy. The anomalies present in our patient include: diaphragmatic hernia, unilateral microtia and absence of external auditory canal, micrognathia, microphthalmia, optic nerve hypoplasia, hypoplasia of the corpus callosum, unilateral renal agenesis, pulmonary agenesis, and cleft lip and palate. Since both allopurinol and mycophenolate mofetil act by disrupting purine biosynthesis and given the similarities in anomalies seen after prenatal exposure, we suggest that allopurinol should also be considered a teratogen.
The stimulation of hepatic glycogenolysis by platelet activating factor (AGEPC) or increased perfusate potassium concentration ([K+]o), but not phenylephrine, causes a transient increase in uric acid release into the effluent perfusate of perfused rat livers. Uric acid was identified in chromatograms of perfusate samples using reversed-phase h.p.l.c., which show a peak which co-elutes with authentic uric acid, and by the fact that the A293 of perfusate samples decreases in the presence of uricase. Uric acid release is dose-dependent with respect to both AGEPC and [K+]o, and is blocked completely by prior exposure of the perfused liver to 5 mM-allopurinol, a specific inhibitor of xanthine oxidase (XOD). Allopurinol inhibits the increase in portal vein pressure induced by AGEPC, increased [K+]o or phenylephrine; the inhibitory effect increases with increasing concentrations of the agents. Also, allopurinol inhibits the second phase of O2 uptake and glucose release characteristic of concentrations of AGEPC or increased [K+]o equal to or greater than their reported half-maximal concentration for glucose release. The ratio of xanthine dehydrogenase (XDH) to XOD activity in extracts of freeze-clamped perfused livers is not affected by treatment of the livers with AGEPC or increased [K+]o. The results suggest that uric acid production may be an indicator of ischaemia within localized hepatic sinusoids, and that allopurinol partially protects the hepatocyte from the effects of AGEPC or increased [K+]o by inhibiting XOD-dependent superoxide production. We propose that the second phase of the glycogenolytic response to these agents results from ischaemia and subsequent reperfusion. Activation of XOD in vivo and hence O2-derived free radical production may be involved in the response of the liver to vasoactive agonists under a variety of pathophysiological conditions.
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This study showed that allopurinol has a protective effect, but not a therapeutic effect, on cerebral ischemia.
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Large-scale isolation of islets of Langerhans is one of the major obstacles in islet transplantation. Until now, isolation methods relied on enzymatic digestion, the duration of which relies on a decision dictated by the operator's experience. This approach has always hindered development of an automated method. The aim of this study was to develop a one-step method based on complete digestion of the pancreas. The original aspect of the technique (derived from the Ricordi method) is use of the University of Wisconsin (UW) solution in the digestion medium and a continuous flow collagenase processing circuit with local cooling and rewarming to allow tissue digestion to proceed at 37 degrees C while settling of the cell suspension takes place at 4 degrees C. A stopcock system permits the alternate use of two settling chambers so that while one is in the circuit, the other can be removed for centrifugation, resuspension of the crude islet preparation in collagenase in free UW solution, and further purification in a density gradient system. Ten experiments were performed, and 545,750 +/- 48,670 purified pig islets were obtained per totally digested pancreas. Histological studies showed cell integrity. Insulin secretion in response to double glucose stimulation under perfusion conditions demonstrated the functional viability of the isolated islets. In conclusion, this one-step method makes it possible to obtain a high number of viable islets of Langerhans in the absence of any decision by an operator, and it should therefore provide basis for an automated method.
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Stevens-Johnson Syndrome (SJS), Overlap Syndrome (OS) and Toxic Epidermal Necrosis (TEN) are rare medical emergencies associated with a high morbidity and mortality. The literature on the characteristics of these diseases in Portugal is scarce. A retrospective study was conducted based on the clinical notes of the 20 patients admitted to São José Burn Unit in the previous 15 years with the diagnosis of SJS, OS or TEN. Most patients had TEN (65%), followed by OS (25%) and SJS (10%). Average age was 57,1 ± 19,0 years. The mean duration of stay in the Burn Unit was 12,6 ± 7,8 days. Mortality was 50%, being significantly higher than the 16,4% overall mortality in the general Burn Unit population in the same period (p < 0,01). The mean surface area involved was 43,9 ± 28,6 %. Allopurinol was the causal agent most frequently implicated (35%) followed by UV light exposure (15%). Fourteen patients (70%) were treated with steroids in the first days, whereas six patients were treated conservatively (30%). Mortality was inferior in the patients treated with steroids (42,8 vs. 66,7%), even though this difference did not reach statistical significance. Infection rates were not significantly different between the two groups. SCORTEN score proved to be a good predictor of mortality. Further studies are needed to reduce mortality in these diseases.
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In 50 livers harvested for transplantation, injury was assessed by determination of the enzymes in the effluent perfusate after cold ischemia. The results were compared to the histology and the clinical course after transplantation. Whereas the release of the markers of endothelial cell injury did neither correlate with the history of the graft nor with the postoperative course, the release of hepatocellular enzymes in the perfusate did indicate preexisting damage of the liver even when the biopsy showed normal liver tissue. Of 12 livers with high activity of hepatocellular enzymes in the effluent (activity of more than twice the median), 7 showed delayed onset of function or a primary non-function. In the other 38 livers with an enzyme activity below this borderline no delayed function or primary non-function was observed. Because of additional influences a prognosis of the function after transplantation was not possible, but the determination of the enzymes in the effluent of marginal livers probably allows the preoperative recognition of organs which will do well.
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Gout is the most common cause of inflammatory arthritis worldwide. Despite clinical cure being achievable and multiple evidence-based guidelines having been published, the incidence and prevalence continues to increase and the condition remains undertreated. Concerns regarding allopurinol have limited its use in those with renal impairment. Febuxostat, a novel xanthine oxidase inhibitor requiring no dose adjustment in mild-moderate renal impairment was launched in the United Kingdom (UK) in 2010. We review published data on the efficacy, safety and tolerability of febuxostat and provide an opinion on its place in the management of gout in the UK in the context of other published guidelines. One phase II trial, multiple phase III trials [febuxostat versus allopurinol controlled trial (FACT), APEX, CONFIRMS] and two open-label extension trials have demonstrated febuxostat given at the doses commonly used in UK practice (80 mg, 120 mg) to reduce serum urate more effectively than those receiving fixed-dose allopurinol. Overall adverse event rates were comparable across treatment groups aside from gout flare (more common in febuxostat-treated patients) and concerns regarding cardiovascular toxicity are being further evaluated in two large trials. If the outcomes of these are favourable, we would anticipate a marked increase in the use of febuxostat in the UK market. We would advocate the use of febuxostat to target a serum urate < 0.3 mmol/l (5 mg/dl) as a second-line urate-lowering therapy in patients with hyperuricaemia, and clinical gout in those intolerant of allopurinol, or in those in whose renal function precludes optimal dose escalation to achieve target serum urate. We would advise prophylaxis against gouty flare with colchicine, nonsteroidal anti-inflammatory drugs (NSAIDs), or Cyclo-oxygenase-2 selective NSAID (COXIB) after febuxostat initiation.
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Toxic epidermal necrolysis (TEN) is a rare, life threatening, drug induced cutaneous reaction first reported by Lyell in 1956. He named the condition TEN to distinguish it from staphylococcal scalded skin syndrome. It is characterized by a separation of the epidermis and dermis with subsequent desquamation of skin. The denuded areas of skin have the appearance of second-degree burn. Drug induced TEN is a disease of severe morbidity and high mortality. The drugs most frequently associated with onset of the condition are sulfonamides, anticonvulsants, non-steroidal anti-inflammatory drugs, and allopurinol. This study reports the occurrence of TEN in a patient receiving Quinidine.
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One hundred cases of acute gouty arthritis were randomly divided into an observation group and a control group. The observation group were treated with local blocking and electroacupuncture at Yinbai (SP 1), Taichong (LR 3), Sanyinjiao (SP 6), Zusanli (ST 36), Fenglong (ST 40), Yinlingquan (SP 9) and Ashi points, and the control group were treated with oral administration of 25 mg Indomethacin, thrice each day, and 100 mg Allopurinol, thrice daily. The therapeutic effects and changes of pain score, serum uric acid were observed in the two groups.
To assess the effects of ulcerogenic agents on actin cytoskeleton and cell motility and the contribution of oxidative stress.
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Dilution of urine samples did not have a significant effect on consistency of xanthine concentration measured for up to 12 weeks of storage. Although xanthine concentration did not differ significantly between undiluted and diluted urine samples, average xanthine concentration measured in diluted samples was consistently higher, compared with that in undiluted samples. Compared with baseline values, plasma xanthine concentration was significantly lower at 6, 9, and 12 weeks of storage.
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The Celsior solution improves vascular endothelial injury in livers from NHBDs and may have advantages in graft flush and preservation of grafts from NHBDs.
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A 78-year-old man, with a 6-year history of stable chronic myelomonocytic leukaemia (CMML), presented with general deterioration and worsening pancytopenia. Bone marrow biopsy showed that his disease had transformed into acute myeloid leukaemia (AML). He was started on a supportive transfusion regimen and did not receive any chemotherapy or corticosteroids. Several weeks later, he developed acute renal failure and was admitted to a medical admissions ward. Spontaneous tumour lysis syndrome (sTLS, grade 1) was diagnosed, as per the Cairo and Bishop criteria. He was treated with intravenous fluids, rasburicase and allopurinol. His renal function improved and he recovered from the sTLS. The authors believe that this is the first published case of sTLS occurring as a result of CMML transforming into AML; it highlights the importance of recognising sTLS as a cause of renal failure and electrolyte disturbance before cancer treatment begins.
Lungs isolated from Sprague-Dawley rats (n = 36) were flushed and stored in University of Wisconsin solution at 4 degrees C for the following periods: Group 1: no storage (n = 12); Group 2: 4 hours (n = 8); Group 3: 18 hours (n = 8); and Group 4: 24 hours (n = 8). After storage in University of Wisconsin solution, all lungs were reperfused with homologous venous blood exsanguinated from donor rats using a pulsatile perfusion system. Pulmonary variables, including lung airway resistance, dynamic lung compliance, total pulmonary vascular resistance, and blood gas analysis, were assessed during reperfusion.