Extended follow‐up of pediatric liver transplantation patients receiving once daily calcineurin inhibitor

We describe longitudinal results in a cohort of pediatric liver transplant patients successfully minimized to once daily CNI monotherapy for longer than five yr and assess changes in liver biochemistries and liver histology. A retrospective chart review of all pediatric liver transplant patients at a single center was performed. Biopsies and serum biochemistries (AST, ALT, total bilirubin, direct bilirubin, INR, creatinine) are reported at time points: PM, five‐yr, seven‐yr, and nine‐yr post‐minimization. Biopsies were assessed for inflammation and fibrosis using Ishak and Batts grading systems. Successful minimization to daily CNI monotherapy was defined as normal liver enzymes with no episodes of rejection. Thirty‐three patients have successfully remained on once daily CNI for >5 yr, and 19/33 of these patients have serial liver biopsies available for review. We report on the clinical and histological findings of these 19 patients. All 19 patients continue to have normal liver biochemistries. On post‐minimization biopsies, fibrosis progressed by ≥2 stages in one patient (5.3%) despite normal liver biochemistries. Carefully selected patients can tolerate minimization to once daily CNI monotherapy as few have progression of fibrosis.     

Incidence and survival trends of lip,intra-oral cavity and tongue base cancers in south-east England

Background

Oral cavity cancers are on the increase in the UK. Understanding site-specific epidemiological trends is important for cancer control measures.This study demonstrates the changing epidemiological trends in lip, intra-oral cavity and tongue base cancers in south-east England from 1987 to 2006.

Aim: Methods

This was a retrospective study using anonymised data obtained from the Thames Cancer Registry (TCR) London. Data were analysed using SPSS v.17 and survival analyses with Kaplan-Meier and Cox regression. Age standardisation of the incidence rates was performed. It was conducted in south-east England, which has an average population of 12 million. The study analysed 9,318 cases (ICD-10 code C00–C06, C14). Kent Research Ethics Committee UK granted ethical approval.

Results

Oral cancers were more common in men, with male: female ratio of 1.6:1. Tongue cancers had the highest frequency at 3,088 (33.1%).Incidence varied with each cancer type. Mean incidence (per 1,000,000) ranged from 2.3 (lip cancer) to 13.8 (tongue cancer). There has been a statistically significant increase in incidence for cancers of the tongue base, other parts of tongue, gum and palate (p<0.001).Median survival time varied by sub-site, with lip cancer having the best median survival time (11.09 years) compared with tongue base cancer (2.42 years). Survival analyses showed worse prognosis for men, older age at diagnosis, and presence of synchronous tumours (p<0.001).

Conclusion

There is a rising incidence of tongue and tongue base, gum and palate cancers in south-east England with wide variability in survival. Oral cancer awareness and screening programmes should be encouraged.     

Paediatric hepatocellular carcinoma due to somatic CTNNB1 and NFE2L2 mutations in the setting of inherited bi-allelic ABCB11 mutations

Hepatocellular carcinoma (HCC) rarely occurs in childhood. We describe a patient with new onset of pruritus at 8 months of age who at 17 months of age was found to have a 2.5 cm HCC. To delineate the possible genetic basis of this tumour, we performed whole exome sequencing (WES) of the germline DNA and identified two novel predictably deleterious missense mutations in ABCB11, encoding bile salt export pump (BSEP), confirmed in the parental DNA as bi-allelic and inherited. Although inherited ABCB11 mutations have previously been linked to HCC in a small number of cases, the molecular mechanisms of hepatocellular carcinogenesis in ABCB11 disease are unknown. WES of the HCC tissue uncovered somatic driver mutations in the beta-catenin (CTNNB1) and nuclear-factor-erythroid-2-related-factor-2 (NFE2L2) genes. Moreover, clonality analysis predicted that the CTNNB1 mutation was clonal and occurred earlier during carcinogenesis, whereas the NFE2L2 mutation was acquired later. Interestingly, background liver parenchyma showed no inflammation or fibrosis and BSEP expression was preserved. This is the first study to identify somatic CTNNB1 and NFE2L2 mutations in early childhood arisen in the setting of inherited bi-allelic ABCB11 mutations. Rapid WES analysis expedited this child’s diagnosis and treatment, and likely improved her prognosis.     

Blockade of the receptor for advanced glycation end products attenuates acetaminophen-induced hepatotoxicity in mice

BACKGROUND AND AIM: Severe injury to the liver, such as that induced by toxic doses of acetaminophen, triggers a cascade of events leading to hepatocyte death. It is hypothesized that activation of the receptor for advanced glycation end products (RAGE) might contribute to acetaminophen-induced liver toxicity by virtue of its ability to generate reactive oxygen species, at least in part via nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, and thereby activate downstream signaling pathways leading to cellular injury. METHODS: A model was employed in which toxic doses of acetaminophen (1125 mg/kg) were administered to C57BL/6 mice. To block RAGE, mice received murine soluble (s) RAGE, the extracellular ligand binding domain of the receptor that acts as a decoy to interrupt ligand-RAGE signaling. RESULTS: Animals treated with sRAGE displayed increased survival compared with vehicle treatment, and markedly decreased hepatic necrosis. Consistent with an important role for RAGE-triggered oxidant stress in acetaminophen-induced injury, a significant reduction of nitrotyrosine protein adducts was observed in hepatic tissue in sRAGE-treated versus vehicle-treated mice receiving acetaminophen, in parallel with significantly increased levels of glutathione. In addition, pro-regenerative cytokines tumor necrosis factor-alpha and interleukin-6 were increased in sRAGE-treated versus vehicle-treated mice. CONCLUSION: These findings implicate RAGE-dependent mechanisms in acetaminophen-induced liver damage and suggest that blockade of this pathway may impart beneficial effects in toxin-induced liver injury.     

Assessment of dyslipidemia in pre-dialysis patients in south-west Nigeria

Background:

Majority of chronic kidney disease (CKD) patients are more likely to die of cardiovascular complications before reaching end stage renal disease. The Kidney Disease Outcomes Quality Initiative (K/DOQI) recommends that all CKD patients should be evaluated for dyslipidemia and for treatment to reduce the risk of cardiovascular events.

Patients and Methods:

A cross-sectional case control study to determine the frequency of occurrence of lipid abnormalities in patients with CKD and compare these abnormalities with that of normal controls. A total of 100 patients and 100 controls were recruited for the study. Demographic and clinical data were obtained using structured questionnaire. Weight, height and waist circumference, body mass index (BMI) and blood pressure were also obtained. Subjects had their fasting lipid profile and fasting plasma glucose assayed after overnight fast of 8-14 hours. Low-density lipoprotein (LDL) was obtained using Friedwald formula.

Result:

The study revealed that total cholesterol (TC) was elevated above normal levels in 44% of cases compared with 6% in controls (P < 0.001), with the mean (SD) value of 5.82 ± 3.28 mmol/l for cases compared with 3.9 ± 1.0 mmol/l (P < 0.001) in controls. Low density lipoprotein was elevated in 48% of cases compared with 14% in controls (P < 0.001), with the mean (SD) values of 4.15 ± 2.74 mmol/l and 2.57 ± 0.95 mmol/l for cases and controls, respectively, (P < 0.001). Triglyceride (TG) was elevated above normal level in 26% of cases compared with none in the controls (P < 0.001), with the mean (SD) values of 1.41 ± 1.10 mmol/l and 0.64 ± 0.24 mmol/l for cases and controls, respectively (P < 0.001). All Lipid fractions except HDL also correlated significantly with levels of proteinuria TC (r = 0.345, P = 0.001), TG (r = 0.268, P = 0.011) LDL (r = 0.366, P = 0.001).

Conclusion:

Dyslipidemia is common among patients with CKD. Regular evaluation of all CKD patients for dyslipidemia and treatment need be instituted.     

Effects of Olax gambecola methanol extract on smooth muscle and rat blood pressure

A methanol extract of the roots of Olax gambecola induced a biphasic contractile response consisting of a transitory initial rapid contraction (Phase I), followed by a slowly developing sustained increase in basal tone (Phase II) on rat fundus, antrum, guinea pig taenia coli, rabbit jejunum and aorta. The Phase I contraction was abolished by atropine, attenuated significantly by indomethacin and potentiated by physostigmine while the Phase II response was unaffected. Hexamethonium, morphine, serotonin (5-HT) antagonists or desensitization of 5-HT receptors did not alter either the Phase I or the Phase II contractions. Calcium channel blockers and procedures affecting calcium translocation abolished the Phase I contraction while only reducing the Phase II contractions. Transmural electrical stimulation produced contractions of the fundus which were attenuated by the extract. Single bolus injections of extract produced a rapid fall in blood pressure in both normotensive and spontaneously hypertensive rats but intravenous infusion resulted in a sustained fall in blood pressure which was maintained throughout the infusion period. Chronic i.p. administration of extract to spontaneously hypertensive rats reduced blood pressure markedly but did not alter the blood pressure of normotensive animals. The hypotensive response to single bolus injections was abolished by atropine and potentiated by physostigmine. The activity profile of the extract suggests the presence of at least two active principles in the crude extract of Olax gambecola used in this study.     

20‐ to 25‐year patient and graft survival following a single pediatric liver transplant—Analysis of the United Network of Organ Sharing database: Where to go from here

To understand factors contributing to liver graft loss and patient death, we queried a national database designed to follow pediatric patients transplanted between 1987 and 1995 till adulthood. A comparison was made to a cohort transplanted between 2000 and 2014. The 5‐, 10‐, 15‐, 20‐, and 25‐year patient survival and graft survival were 95.5%, 93.7%, 89.1%, 80.8%, and 73.1%, and 92.5%, 86.7%, 77.6%, 68.7%, and 62.2%, respectively. The twenty‐year patient/graft survival was significantly worse in those transplanted between 5 and 17 years of age compared to those transplanted at <5 years of age (P < 0.001). For the modern era cohort, the 3‐year patient survival was significantly lower in children transplanted at 16‐17 years of age compared to those transplanted at <5 and 11‐15 years of age (P ≤ 0.02). The 3‐year graft survival was similarly lower in children transplanted at 16‐17 years of age compared to those transplanted at <5, 5‐10, and 11‐15 years of age (P ≤ 0.001). Infection as a cause of death occurred either early or >15 years post‐transplant. Chronic rejection remained the leading cause of graft loss in both cohorts and the commonest indication for retransplantation 20‐25 years following primary transplant. Further research is required to identify modifiable factors contributing to development of chronic rejection.     

An evaluation of the effectiveness of sterilization of infant formulas by thermal heating and an aseptic method

Ready mixed, or reconstituted infant formulas, were prepared using a “Terminal Heating” or an “Aseptic “technique. Bacterial counts were made on samples both before and after refrigeration for 53 and 96 days. A second batch of samples were subjected to alternating intervals of incubation and refrigeration. The formulas were tested for taste and palatability. Up to 56 days of refrigeration, the formulas were satisfactory from a microbiological point of view, but after 96 days, one sample reconstituted in a disposable feeding bottle was completely spoiled. Formula reconstituted and refrigerated in a pitcher also showed evidence of contamination. Spoilage of two other samples were attributed to the use of non‐sterile utensils or equipment and chemical changes of a non‐biological nature. Although Terminal Heating and the Aseptic Method were both effective when carried out by a trained microbiologist, contamination during use of the Aseptic Method is possible. Under field conditions strict control of sterility is unlikely, therefore Terminal Heating of infant formulas is recommended in preference to the Aseptic technique described.     

Frequency,pattern, and associations of generalized osteoarthritis among Nigerians with knee osteoarthritis

Clinical Rheumatology - Osteoarthritis (OA) is a common degenerative condition leading to significant pain, functional limitation, and economic loss. Generalized OA (GOA) is associated with greater...