Liver disease complicating bone marrow transplantation: A clinical audit

Abstract Hepatic dysfunction following bone marrow transplantation (BMT) may present complex management issues. The incidence and aetiology of abnormal liver function following allogeneic and autologous BMT was reviewed over a 2 year period in Royal Perth Hospital and these findings were related to management decisions and patient outcome. Abnormal serum liver biochemistry during the first 12 post-transplant months occurred in all allogeneic ( n = 31) and 14 of 23 (61%) autologous transplant patients; 13 (41%) allogeneic and three (13%) autologous patients developed severe hepatic dysfunction. In allogeneic transplants, the most common causes of liver disease were graft-versus-host disease (33%), drug hepatotoxicity (19%) and post-transplant viral hepatitis (15%); in autologous patients, disease recurrence (28%) and sepsis (17%) were the most frequent identifiable cause of abnormal liver function. The aetiology of abnormal liver biochemistry was not determined in 13 instances, but this did not adversely affect patient outcome. Percutaneous liver biopsy or endoscopic cholangiography were only required in three patients. Liver disease contributed to death in two allogeneic patients with multiple causes for liver dysfunction, and in one patient with refractory severe hepatic graft-versus-host disease. It was concluded that hepatic dysfunction is common after BMT, the cause of which can be determined in many cases with simple non-invasive tests used in conjunction with the clinical setting. Specific treatment, where necessary, is then able to be commenced in a majority of patients without the need for invasive investigation.     

In-vitro exoerythrocytic development of Plasmodium cynomolgi bastianellii inhibitory activity of monoclonal antibodies against sporozoites of different P. cynomolgi strains and of P. knowlesi

The inhibitory effect of anti-sporozoite monoclonal antibodies (MoAb) on the in-vitro development of liver stages of Plasmodium cynomolgi bastianellii (NIH strain) was evaluated using primary cultures of rhesus monkey hepatocytes. MoAbs against the circumsporozoite proteins of five strains of P. cynomolgi (NIH, London, Gombak, Ceylon, Berok), and of P. knowlesi (H strain) were used. Incubation of sporozoites of P. cynomolgi bastianellii with the anti-NIH strain MoAbs entirely prevented liver-stage development; MoAbs produced against the other four strains had no apparent activity. The anti-P. knowlesi MoAbs had a partially inhibitory effect on parasite development. These functional studies complement previous immunological studies on P. cynomolgi strain specificity, and confirm the cross-reactivity observed previously between sporozoites of P. cynomolgi bastianellii and P. knowlesi (H strain).     

Comparison of Cutting Balloon Angioplasty and Percutaneous Balloon Angioplasty of Arteriovenous Fistula Stenosis: A Meta‐Analysis and Systematic Review of Randomized Clinical Trials

Background

Hemodialysis (HD) access failure is a common cause of increased morbidity and healthcare cost in patients with end stage renal disease (ESRD). Percutaneous balloon angioplasty has been used to treat hemodialysis access stenosis but is complicated by a high rate of restenosis. Percutaneous cutting balloon (PCB) angioplasty is an alternative approach that has shown to reduce restenosis.

Objectives

The aim of the study is to assess the safety and efficacy of PCB angioplasty in comparison with conventional and high‐pressure balloon angioplasty in the treatment of hemodialysis access site stenosis.

Methods

We searched PubMed, EMBASE and the Cochrane Central register of controlled trials (CENTRAL) databases through August 2014 and selected studies using the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) checklist. We included all randomized clinical trials with a head‐to‐head comparison between PCB and conventional or high‐pressure balloon angioplasty

Results

Three studies with 1034 participants (age 60.7 (±12.9) years and 50.1% males) with 525 in PCB and 509 in control arm were included in the analysis. The immediate procedural success rate was not significantly different in the PCB angioplasty and control arm respectively, (87.2% vs. 83.7% RD ?0.02; 95%CI ?0.06 to 0.01; P = 0.38). The six‐month target lesion patency was significantly higher in the PCB angioplasty arm (67.2% vs. 55.6% RD 0.12; 95%CI 0.05–0.19; P < 0.05) with number needed to treat (NNT) of 9. The device related complications were not statistically significant between groups (RD 0.03; 95%CI ?0.02 to 0.07; P = 0.26).

Conclusions

PCB angioplasty is effective in treatment of hemodialysis access stenosis, with significantly higher six‐month patency compared to balloon angioplasty. (J Interven Cardiol 2015;28:288–295)

     

Tuberculosis at extremes of age

Although tuberculosis (TB) has its highest burden among young adults, especially since the advent of HIV infection, two other groups with low immunity, the very young (<1 year) with immature immunity and the elderly (>65 years) with waning immunity, are vulnerable groups not to be forgotten. This review describes the epidemiology, clinical aspects, public health aspects and outcome of TB in patients at the extremes of age. The epidemiology differs therein that TB in infants occurs in developing countries with high incidences of TB and HIV, while TB in the elderly occurs in developed countries with ageing populations. The clinical presentation may be non‐specific, history of contact with TB is often not known and TB is often not considered at these age extremes, and when the diagnosis is considered, disease progression may already be advanced. Anti‐TB treatment regimens are the same as in other age groups, but drug dosages may need adjustment according to weight, renal function, liver function and other potentially complicating factors. Adverse events are more difficult to observe and both the young and the elderly are reliant on others for adherence to treatment. Mortality at both age extremes is higher than in the general TB population. For all the above reasons, public health measures to: prevent transmission of infection; identify those infected and providing preventive therapy; high index of suspicion in order to make an early diagnosis; and timely initiation of treatment are important in both the very young and the elderly.     

THE INFLUENCE OF CIMETIDINE ON PEPTIC ULCER IN PATIENTS WITH ARTHRITIS TAKING ANTI-INFLAMMATORY DRUGS

Patients with arthritis who take nonsteroidal anti-inflammatorydrugs (NSAIDs) often develop peptic ulceration. Withdrawal ofthe NSAID may lead to increased debility and thus it may bedesirable to continue the NSAID while attempting to heal theulceration by additional therapeutic measures. We have investigatedthe effect of cimetidine in this role. Patients with gastroscopically-provenpeptic ulcer associated with NSAID ingestion were given eithercimetidine or placebo treatment while continuing to take theirNSAIDs. It was found that the ulceration healed in some patientsover a 6-week period even on placebo treatment. There was nostatistical difference found between the healing of these ulcerswhen compared with the cimetidine-treated group. The mechanismof NSAID-induced ulceration and the reason for the above findingis discussed.     

Intracoronary Irradiation with 186/188Rhenium Following Balloon Overstretch Injury Reduces Neointima But Does Not Impair Vasoreactivity of Porcine Coronary Arteries

Objective: The purpose of this study was to assess the effect of ^186/188rhenium (^186/188Re) on the neointimal proliferation and on the vasomotion of irradiated porcine coronary arteries following balloon injury. Background: Intracoronary radiation (IR) at doses of 10–25 Gy reduces intimal hyperplasia in animal models and lowers restenosis in clinical trials. The response of coronary arteries to acetylcholine (ACh) has been used to examine endothelial function, but this has not been reported in porcine coronary arteries subjected to overstretch balloon injury (BI) and subsequent IR. Methods: Vasomotor response was studied at baseline and at 2 weeks in 20 swine. Baseline vasomotor study without BI was carried out in six animals (12 arteries; Group I, no injury, no radiation). Subsequently the left anterior descending (LAD) and the left circumflex (LCX) arteries of 11 animals were subjected to BI. Eight of these animals (15 arteries) were subjected to IR with ^186/188Re in the LAD and LCX arteries in doses of 15 Gy followed by vasomotor studies at 2 weeks (Group II, BI, radiation). Three animals, (six arteries) of the BI group were not subjected to IR and their vasomotor functions assessed two weeks later (Group HI, BI, no radiation). Endothelium dependent vasomotion was assessed by Doppler flow wire and by quantitative coronary angiography (QCA) following selective infusion of serial doses of ACh proximal to the injured and irradiated segments. Nitroglycerin (200 μg) was injected intracoronary to detect endothelium independent vasodilatation. Histomorphometry and QCA analysis was performed to confirm the effect of IR on intimal area (IA), and IA corrected for fracture length (IA/FL). Results: Responses to ACh infusion and coronary flow reserve were similar at baseline before injury and at 2 weeks following injury with and without radiation. The irradiated vessels demonstrated normal vasodilatation responses to nitroglycerin. The irradiated vessels showed a marked reduction in IA and IA/FL. Conclusion: The vasoreactivity of irradiated coronary arteries is preserved at doses that inhibit neointima formation in the porcine model.     

The effect of nematode infection upon intestinal smooth muscle function

Nematode infections are useful in studying both host defence and inflammation induced changes in intestinal physiology, including increased contraction by intestinal muscle. Our initial studies of the heightened muscle function found during T. spiralis infection led to investigations of the role of immune and inflammatory cells and mediators in the immunodulation of intestinal muscle function. By infecting various immunodeficient mouse strains, as well as gene transfer to the intestine, T lymphocytes, and in particular the CD4^+ve subset were found to be responsible for altering smooth muscle function. However, eosinophils as well as the cytokine interleukin-4 may also be involved. Investigations also indicate a potential role for increased muscle function and propulsive activity in expelling nematode parasites. Mutant mice which suffer aberrant intestinal propulsion, or based upon an immunodeficiency, undergo reduced changes in muscle function during infection, undergo prolonged infections. While increased muscle function may be an adaptive host response, the changes in muscle function may persist long after the resolution of the infection. Thus understanding the mechanisms behind the immunomodulation of intestinal muscle function may also impact upon clinical gastroenterology, since motility disturbances in man often occur following enteric infections, or other inflammatory conditions of the bowel .     

Three-year follow-up of the Oxford Cholesterol Study: assessment of the efficacy and safety of simvastatin in preparation for a large mortality study

We report the results of a randomized single-centre study designedto assess the effects of simvastatin on blood lipids, bloodbiochemistry, haematology and other measures of safety and tolerabilityin preparation for a large-scale multicentre mortality study.Six hundred and twenty-one individuals considered to be at increasedrisk of coronary heart disease were randomized, following a2-month placebo ‘run-in’ period, to receive 40 mgdaily simvastatin, 20 mg daily simvastatin or matching placebo.Their mean age was 63 years, 85% were male, 62% had a historyof prior myocardial infarction (MI), and the mean baseline totalcholesterol was 7·0 mmol. 1^–1. Median follow-upin the present report is 3·4 years. Eight weeks after randomization, 40 mg daily simvastatin hadreduced non-fasting total cholesterol by 29·2% ±1·1 (2·03 ± 0·08 mmol. 1^–1)and20 mg daily simvastatin had reduced it by 26·8% ±1·0 (1·87 ± 0·07 mmol. 1^–1).Almost all of tile difference in total cholesterol at 8 weekswas due to the reduction in LDL cholesterol (40·8±1·6and 38·2%±1·4 among patients allocated40mg and 20mg of simvastatin daily respectively), but simvastatinalso reduced triglycerides substantially (19·0% and 17·3%)and produced a small increase in HDL cholesterol (6·4%and 4·8%). These effects were largely sustained overthe next 3 years, with 40 mg daily simvastatin producing a slightlygreater reduction in total cholesterol at 3 years (25·7%±1·9reduction) than did 20 mg daily simvastatin (22·2%±1·8). There were no differences between the treatment groups in thenumbers of reports of ‘possible adverse effects’of treatment or of a range of different symptoms or conditions(including those related to sleep or mood) recorded at regularclinic follow-up. Mean levels of alanine aminotransferase, aspartateaminotransferase and creatine kinase were slightly increasedby treatment, but there were no significant difference betweenthe treatment groups in the numbers of patients with significantlyelevated levels. A slightly lower platelet count in the simvasatingroup was the only haematological difference from placebo, withno difference in the numbers of patients with low platelet counts. In summary, the simvastatin regimens studied produced largesustained reductions in total cholesterol, LDL cholesterol andtriglyceride and small increases in HDL cholesterol. They werewell tolerated, with no evidence of serious side-effects duringthe first 3 years of this study. Consequently, simvastatin providesan opportunity to conduct large randomized studies that assessthe effects of cholesterol lowering on total mortality and oncause-spec mortality. Even with such an effective cholesterollowering treatment, however such mortality studies will stillneed to be prolonged and to involve some tens of thousands ofpatients at substantial risk of coronary heart disease if clearevidence is to emerge.