Genome-wide association studies and Mendelian randomization analyses provide insights into the causes of early-onset colorectal cancer.

BACKGROUND: The incidence of early-onset colorectal cancer (EOCRC; diagnosed <50 years of age) is rising globally; however, the causes underlying this trend are largely unknown. CRC has strong genetic and environmental determinants, yet common genetic variants and causal modifiable risk factors underlying EOCRC are unknown. We conducted the first EOCRC-specific genome-wide association study (GWAS) and Mendelian randomization (MR) analyses to explore germline genetic and causal modifiable risk factors associated with EOCRC. PATIENTS AND METHODS: We conducted a GWAS meta-analysis of 6176 EOCRC cases and 65 829 controls from the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), the Colorectal Transdisciplinary Study (CORECT), the Colon Cancer Family Registry (CCFR), and the UK Biobank. We then used the EOCRC GWAS to investigate 28 modifiable risk factors using two-sample MR. RESULTS: We found two novel risk loci for EOCRC at 1p34.1 and 4p15.33, which were not previously associated with CRC risk. We identified a deleterious coding variant (rs36053993, G396D) at polyposis-associated DNA repair gene MUTYH (odds ratio 1.80, 95% confidence interval 1.47-2.22) but show that most of the common genetic susceptibility was from noncoding signals enriched in epigenetic markers present in gastrointestinal tract cells. We identified new EOCRC-susceptibility genes, and in addition to pathways such as transforming growth factor (TGF) ß, suppressor of Mothers Against Decapentaplegic (SMAD), bone morphogenetic protein (BMP) and phosphatidylinositol kinase (PI3K) signaling, our study highlights a role for insulin signaling and immune/infection-related pathways in EOCRC. In our MR analyses, we found novel evidence of probable causal associations for higher levels of body size and metabolic factors-such as body fat percentage, waist circumference, waist-to-hip ratio, basal metabolic rate, and fasting insulin-higher alcohol drinking, and lower education attainment with increased EOCRC risk. CONCLUSIONS: Our novel findings indicate inherited susceptibility to EOCRC and suggest modifiable lifestyle and metabolic targets that could also be used to risk-stratify individuals for personalized screening strategies or other interventions.

Metabolically defined body size and body shape phenotypes and risk of postmenopausal breast cancer in the European Prospective Investigation into Cancer and Nutrition.

BACKGROUND: Excess body fatness and hyperinsulinemia are both associated with an increased risk of postmenopausal breast cancer. However, whether women with high body fatness but normal insulin levels or those with normal body fatness and high levels of insulin are at elevated risk of breast cancer is not known. We investigated the associations of metabolically defined body size and shape phenotypes with the risk of postmenopausal breast cancer in a nested case-control study within the European Prospective Investigation into Cancer and Nutrition. METHODS: Concentrations of C-peptide-a marker for insulin secretion-were measured at inclusion prior to cancer diagnosis in serum from 610 incident postmenopausal breast cancer cases and 1130 matched controls. C-peptide concentrations among the control participants were used to define metabolically healthy (MH; in first tertile) and metabolically unhealthy (MU; >1st tertile) status. We created four metabolic health/body size phenotype categories by combining the metabolic health definitions with normal weight (NW; BMI < 25 kg/m2 , or WC < 80 cm, or WHR < 0.8) and overweight or obese (OW/OB; BMI ≥ 25 kg/m2 , or WC ≥ 80 cm, or WHR ≥ 0.8) status for each of the three anthropometric measures separately: (1) MHNW, (2) MHOW/OB, (3) MUNW, and (4) MUOW/OB. Conditional logistic regression was used to compute odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Women classified as MUOW/OB were at higher risk of postmenopausal breast cancer compared to MHNW women considering BMI (OR = 1.58, 95% CI = 1.14-2.19) and WC (OR = 1.51, 95% CI = 1.09-2.08) cut points and there was also a suggestive increased risk for the WHR (OR = 1.29, 95% CI = 0.94-1.77) definition. Conversely, women with the MHOW/OB and MUNW were not at statistically significant elevated risk of postmenopausal breast cancer risk compared to MHNW women. CONCLUSION: These findings suggest that being overweight or obese and metabolically unhealthy raises risk of postmenopausal breast cancer while overweight or obese women with normal insulin levels are not at higher risk. Additional research should consider the combined utility of anthropometric measures with metabolic parameters in predicting breast cancer risk.

Outcomes of normothermic machine perfusion of liver grafts in repeat liver transplantation (NAPLES initiative).

BACKGROUND: Retransplantation candidates are disadvantaged owing to lack of good-quality liver grafts. Strategies that can facilitate transplantation of suboptimal grafts into retransplant candidates require investigation. The aim was to determine whether late liver retransplantation can be performed safely with suboptimal grafts, following normothermic machine perfusion. METHODS: A prospectively enrolled group of patients who required liver retransplantation received a suboptimal graft preserved via normothermic machine perfusion. This group was compared with both historical and contemporaneous cohorts of patient who received grafts preserved by cold storage. The primary outcome was 6-month graft and patient survival. RESULTS: The normothermic machine perfusion group comprised 26 patients. The historical (cold storage 1) and contemporaneous (cold storage 2) groups comprised 31 and 25 patients respectively. The 6-month graft survival rate did not differ between groups (cold storage 1, 27 of 31, cold storage 2, 22 of 25; normothermic machine perfusion, 22 of 26; P = 0.934). This was despite the normothermic machine perfusion group having significantly more steatotic grafts (8 of 31, 7 of 25, and 14 of 26 respectively; P = 0.006) and grafts previously declined by at least one other transplant centre (5 of 31, 9 of 25, and 21 of 26; P < 0.001). CONCLUSION: In liver retransplantation, normothermic machine perfusion can safely expand graft options without compromising short-term outcomes.

Liver transplantation is a life-saving procedure for many different diseases. In the UK, one in 10 patients awaiting transplant have had a previous liver transplant. These retransplant operations are complex, and the general belief is that a good-quality donor liver graft is required for best outcomes. However, there is a significant shortage of good-quality organs for liver transplantation, so many patients awaiting retransplantation spend longer on the waiting list. This study investigated whether a new technology, called normothermic machine perfusion, could be used to preserve lower-quality donor livers and have successful outcomes for patients undergoing retransplantation. Traditionally, good-quality livers are preserved in an ice box and the study compared the outcomes of these two different approaches. The aim was to prove that normothermic machine perfusion improves access to transplantation for this group of patients, without compromising outcomes. A group of patients who underwent retransplantation and received a lesser-quality liver preserved with normothermic machine perfusion was compared with two groups of patients who had received a transplant with traditional ice-box preservation. The complications, graft, and patient survival of the former group was compared with those in the latter two groups who underwent liver retransplantation with better-quality liver grafts. The rate of survival and adverse surgical outcomes were comparable between the groups of patients who received a liver preserved via traditional ice-box preservation, and those who received a lesser-quality liver preserved via normothermic machine perfusion. Normothermic machine perfusion can potentially expand the number of suitable donor livers available for retransplant candidates.

Endobronchial valve use in COVID-19 related pneumothorax and persistent air leak.

Pneumothoraces may occur rarely in coronavirus (COVID-19) patients, often resulting from a combination of fibrotic parenchymal changes and prolonged high-pressure ventilation. Very few studies have been published describing the management of pneumothorax in the novel COVID-19 pneumonia patients. Although chest drain insertion represents the first line of treatment, a persistent pneumothorax and air leak requiring intervention could be managed by a thoracoscopic procedure or, as is the case here, by endobronchial valve insertion. Endobronchial valve insertion is a minimally invasive technique that provides a treatment option in patients with severe parenchymal COVID-19 related lung disease. As far as the authors are aware this is the first report of the use of endobronchial valves in a COVID-19 patient.

Human papillomavirus (HPV) types among Alaska native women attending a colposcopy clinic in Anchorage, Alaska, 2009-2011.

BACKGROUND: The first HPV vaccines licensed targeted two HPV types responsible for most cervical cancers. A 9-valent vaccine (9vHPV), targeting 5 additional types, was introduced in 2016 and is currently the only HPV vaccine available in the United States. Previous studies demonstrated high rates of HPV infection in Alaska Native (AN) women. We sought to measure prevalence of high risk HPV types in AN women undergoing colposcopy and to determine those preventable by vaccination. METHODS: For this cross-sectional study, we recruited women who were undergoing colposcopy for clinical indications at Alaska Native Medical Center to obtain cervical brush biopsy samples. Specimens were shipped to Atlanta, Georgia for DNA extraction, HPV detection, and typing using L1 PCR with type-specific hybridization to detect 37 HPV types. RESULTS: Four hundred eighty eight specimens from 489 women were tested. At least one HPV type was found in 458 (94%) specimens. Of 458 participants who were HPV positive, 332 (72%) had two or more types. At least one type targeted by 9vHPV was detected in 95% of participants with CIN 3 (21/22), 82% with CIN 2 (37/45), and 65% with CIN 1 (119/184). (p < 0.001) HPV 16 or 18 were detected in 77% (17/22) with CIN 3, 53% (24/45) with CIN 2, and 36% (67/184) with CIN 1. (p < 0.001). CONCLUSIONS: A substantial proportion of AN women attending colposcopy clinic had evidence of HPV 16/18 infection, as well as other high risk types targeted by 9vHPV. At least one 9vHPV type was detected in 62% of the participants overall, and 95% of participants with CIN3. AN women are expected to benefit from vaccination against HPV 16/18, and will have greater benefit from 9vHPV. Information from this study could be used to develop public health strategies to increase vaccine uptake, or to track HPV genotype prevalence over time.

Insulin-like growth factor-1, insulin-like growth factor-binding protein-3, and breast cancer risk: observational and Mendelian randomization analyses with ∼430 000 women.

BACKGROUND: Epidemiological evidence supports a positive association between circulating insulin-like growth factor-1 (IGF-1) concentrations and breast cancer risk, but both the magnitude and causality of this relationship are uncertain. We conducted observational analyses with adjustment for regression dilution bias, and Mendelian randomization (MR) analyses allowed for causal inference. PATIENTS AND METHODS: We investigated the associations between circulating IGF-1 concentrations and incident breast cancer risk in 206 263 women in the UK Biobank. Multivariable hazard ratios (HRs) and 95% confidence intervals (CI) were estimated using Cox proportional hazards models. HRs were corrected for regression dilution using repeat IGF-1 measures available in a subsample of 6711 women. For the MR analyses, genetic variants associated with circulating IGF-1 and IGF-binding protein-3 (IGFBP-3) levels were identified and their association with breast cancer was examined with two-sample MR methods using genome-wide data from 122 977 cases and 105 974 controls. RESULTS: In the UK Biobank, after a median follow-up of 7.1 years, 4360 incident breast cancer cases occurred. In the multivariable-adjusted models corrected for regression dilution, higher IGF-1 concentrations were associated with a greater risk of breast cancer (HR per 5 nmol/l increment of IGF-1 = 1.11, 95% CI = 1.07-1.16). Similar positive associations were found by follow-up time, menopausal status, body mass index, and other risk factors. In the MR analyses, a 5 nmol/l increment in genetically-predicted IGF-1 concentration was associated with a greater breast cancer risk (odds ratio = 1.05, 95% CI = 1.01-1.10; P = 0.02), with a similar effect estimate for estrogen-positive (ER+) tumours, but no effect found for estrogen-negative (ER-) tumours. Genetically-predicted IGFBP-3 concentrations were not associated with breast cancer risk (odds ratio per 1-standard deviation increment = 1.00, 95% CI = 0.97-1.04; P = 0.98). CONCLUSION: Our results support a probable causal relationship between circulating IGF-1 concentrations and breast cancer, suggesting that interventions targeting the IGF pathway may be beneficial in preventing breast tumorigenesis.

Progression of hepatitis C in the haemophiliac population in Ireland, after 30 years of infection in the pre-DAA treatment era.

INTRODUCTION: Prior to the introduction of viral inactivation of factor concentrates and screening of blood, 225 people with haemophilia became infected with hepatitis C (HCV) in Ireland. AIM: Our aim was to assess liver disease progression and mortality in this population after 30 years of infection. METHODS: Demographic and clinical data were collected from medical records in five hepatology units and one infectious disease unit retrospectively in 2005, and on four subsequent occasions. RESULTS: The participation rate was 73% (165/225). Eighty three percent of patients, who had been tested for RNA (n = 106/128), developed chronic HCV infection. Thirty four percent were co-infected with HIV. All-cause mortality, after approximately 30 years of infection with chronic HCV, was 44% in HIV positive patients and 29% in HIV negative patients. Liver-related mortality was 12.5% and did not vary significantly by HIV status. Thirty seven percent of patients had developed advanced liver disease, including 20% with cirrhosis and 9% with hepatocellular carcinoma. In the pre-interferon-free direct acting antivirals era, 57% (n = 60/106) of patients were treated for HCV, 65% of whom achieved a sustained virological response. Successfully treated patients had few adverse liver outcomes. CONCLUSION: After 30 years of infection, 40% of the patients who had evidence of chronic HCV had developed advanced liver disease, such as cirrhosis and HCC, or had died from liver-related causes. This proportion is high relative to similar international cohorts despite good anti-HCV treatment uptake and responses.

Alcohol consumption and the risk of renal cancers in the European Prospective Investigation into Cancer and Nutrition (EPIC). Wozniak MB, Brennan P, Brenner DR, Overvad K, Olsen A, Tjønneland A, Boutron-Ruault MC, Clavel-Chapelon F, Fagherazzi G, Katzke V, Kühn T, Boeing H, Bergmann MM, Steffen A, Naska A, Trichopoulou A, Trichopoulos D, Saieva C, Grioni S, Panico S, Tumino R, Vineis P, Bueno-de-Mesquita HB, Peeters PH, Hjartåker A, Weiderpass E, Arriola L, Molina-Montes E, Duell EJ, Santiuste C, Alonso de la Torre R, Barricarte Gurrea A, Stocks T, Johansson M, Ljungberg B, Wareham N, Khaw KT, Travis RC, Cross AJ, Murphy N, Riboli E, Scelo G.Int J Cancer. 2015 Oct 15;137(8):1953-66. [Epub 2015 Apr 28]. doi: 10.1002/ijc.29559.

Epidemiologic studies have reported that moderate alcohol consumption is inversely associated with the risk of renal cancer. However, there is no information available on the associations in renal cancer subsites. From 1992 to 2010, 477,325 men and women in the European Prospective Investigation into Cancer and Nutrition cohort were followed for incident renal cancers (n = 931). Baseline and lifetime alcohol consumption was assessed by country-specific, validated dietary questionnaires. Information on past alcohol consumption was collected by lifestyle questionnaires. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated from Cox proportional hazard models. In multivariate analysis, total alcohol consumption at baseline was inversely associated with renal cancer; the HR and 95% CI for the increasing categories of total alcohol consumption at recruitment vs. the light drinkers category were 0.78 (0.62-0.99), 0.82 (0.64-1.04), 0.70 (0.55-0.90), and 0.91 (0.63-1.30), respectively, (ptrend = 0.001). A similar relationship was observed for average lifetime alcohol consumption and for all renal cancer subsites combined or for renal parenchyma subsite. The trend was not observed in hypertensive individuals and not significant in smokers. In conclusion, moderate alcohol consumption was associated with a decreased risk of renal cancer.

Perinatal determinants of D-dimer levels in a cross-sectional study of low risk pregnant women.

BACKGROUND: To examine perinatal determinants of the antenatal levels of D-dimers. METHODS: Cross-sectional study of 760 low risk pregnant women recruited into five gestational groups. Variables examined in antenatal groups included maternal age, body mass index, parity, smoking, family history venous thromboembolism (VTE) and previous use of the oral contraceptive pill (OCP). Onset of labour and mode of delivery were also examined in the post-natal group. RESULTS: D-dimer levels in group 4 (38-40 + 6) were significantly lower in the women with a history of taking the OCP when compared to those that had not taken it in the past (P = 0.027). In the day 2 post-natal group, the median level of D-dimer was significantly higher in primparous when compared to multiparous women (P = 0.015). The median D-dimer levels were significantly lower in the elective Caesarean section group in comparison to spontaneous onset (P = 0.003) and induction of labour (P = 0.016). When the mode of delivery was examined, the median D-dimer levels were significantly lower in those that had an elective Caesarean section when compared to normal vaginal delivery (P = 0.008) and instrumental vaginal delivery (P = 0.007). Women post elective Caesarean section had a significantly lower D-dimer than those after emergency Caesarean section (P = 0.008). DISCUSSION: There are some significant differences in D-dimer levels when certain perinatal determinants are examined. This work is potentially beneficial to the future diagnosis of VTE in pregnancy as it supports previously published recommended D-dimer levels for the diagnosis of VTE in pregnancy.

The pulsed light inactivation of veterinary relevant microbial biofilms and the use of a RTPCR assay to detect parasite species within biofilm structures.

The presence of pathogenic organisms namely parasite species and bacteria in biofilms in veterinary settings, is a public health concern in relation to human and animal exposure. Veterinary clinics represent a significant risk factor for the transfer of pathogens from housed animals to humans, especially in cases of wound infection and the shedding of faecal matter. This study aims to provide a means of detecting veterinary relevant parasite species in bacterial biofilms, and to provide a means of disinfecting these biofilms. A real time PCR assay was utilized to detect parasite DNA in Bacillus cereus biofilms on stainless steel and PVC surfaces. Results show that both Cryptosporidium and Giardia attach to biofilms in large numbers (100-1000 oo/cysts) in as little as 72 hours. Pulsed light successfully inactivated all test species (Listeria, Salmonella, Bacillus, Escherichia) in planktonic and biofilm form with an increase in inactivation for every increase in UV dose.

Fruit and vegetable consumption in relation to hepatocellular carcinoma in a multi-centre, European cohort study.

BACKGROUND: Vegetable and/or fruit intakes in association with hepatocellular carcinoma (HCC) risk have been investigated in case-control studies conducted in specific European countries and cohort studies conducted in Asia, with inconclusive results. No multi-centre European cohort has investigated the indicated associations. METHODS: In 486,799 men/women from the European Prospective Investigation into Cancer and nutrition, we identified 201 HCC cases after 11 years median follow-up. We calculated adjusted hazard ratios (HRs) for HCC incidence for sex-specific quintiles and per 100 g d(-1) increments of vegetable/fruit intakes. RESULTS: Higher vegetable intake was associated with a statistically significant, monotonic reduction of HCC risk: HR (100 g d(-1) increment): 0.83; 95% CI: 0.71-0.98. This association was consistent in sensitivity analyses with no apparent heterogeneity across strata of HCC risk factors. Fruit intake was not associated with HCC incidence: HR (100 g d(-1) increment): 1.01; 95% CI: 0.92-1.11. CONCLUSIONS: Vegetable, but not fruit, intake is associated with lower HCC risk with no evidence for heterogeneity of this association in strata of important HCC risk factors. Mechanistic studies should clarify pathways underlying this association. Given that HCC prognosis is poor and that vegetables are practically universally accessible, our results may be important, especially for those at high risk for the disease.

Utility of near infrared light to determine tissue oxygenation during hepato-biliary surgery.

Near-infrared spectrophotometry assesses cerebral oxygen saturation (ScO2) based on the absorption spectra of oxygenated and deoxygenated hemoglobin, and the translucency of biological tissue, in the near-infrared band. There is increasing evidence that optimising cerebral oxygenation, guided by ScO2, is associated with improved outcomes in a variety of high risk surgical settings. However, in patients with liver disease, bilirubin can potentially render cerebral oximetry inaccurate. As a result, measurement of cerebral oxygen saturation is rarely undertaken in patients undergoing hepatobiliary surgery. We prospectively measured baseline and intraoperative cerebral oxygen saturation in patients undergoing major pancreatic surgery. Indices including bilirubin, sodium, platelets and maximum amplitude on thromboelastography were associated with low baseline ScO2. However, those patients with low ScO2 (≤51%) maintained a similar trend in cerebral oximetry values both at induction and intraoperatively to those with a normal ScO2. We conclude that the pattern of cerebral oximetry is similar in patients undergoing major pancreatic surgery regardless of their underlying liver dysfunction. Therefore, cerebral oximetry may have a role in monitoring neurological function in this high risk group of patients.

Is the NHS best practice tariff for type 1 diabetes applicable in the Irish context?

The National Health Service in the UK has identified thirteen key standards of paediatric diabetes care. Funding depends on services meeting these standards. The aim of this study was to determine if these standards are applicable in an Irish setting. All patients attending the diabetes service during 2012 were included. Patient charts, electronic appointments, nursing notes and computerised results were used to ascertain relevant information for comparison with the NHS standards. Patients attended a mean 2.97 (SD 0.7) medical and 2.2 (SD 2.9) nursing appointments per year, with a median additional contacts of 8 nurse phone calls (range 0 - 125). Most standards were met by this service. In comparing our service to the NHS standard, we have identified a number of areas for improving our service provision. Limited resources and staff shortages make a number of these standards unachievable, namely annual dietetic review and three monthly outpatient appointments.

Comparison of energy metabolism in liver grafts from donors after circulatory death and donors after brain death during cold storage and reperfusion.

BACKGROUND: Donation after circulatory death (DCD) liver grafts have supplemented the donor organ pool, but certain adverse outcomes have prevented exploration of the full potential of such organs. The aim of this study was to determine key differences in basic energy metabolism between DCD and donation after brainstem death (DBD) grafts. METHODS: Microdialysis samples from DCD and DBD allograft parenchyma from cold storage to 48 h after reperfusion were analysed by colorimetric methods. Interstitial lactate, pyruvate and glycerol levels were measured and the lactate/pyruvate ratio was calculated to estimate energy depletion of the grafts. Histological features of ischaemia and reperfusion injury were assessed. RESULTS: Donor age, extent of steatosis and cold ischaemia time were comparable between ten DCD and 20 DBD organs. DCD grafts had higher levels of interstitial lactate (median 11.6 versus 1.2 mmol/l; P = 0.015) and increased lactate/pyruvate ratio (792 versus 38; P = 0.001) during cold storage. There was no significant difference in glycerol levels between DCD and DBD grafts (225.1 versus 127.5 µmol/l respectively; P = 0.700). Rapid restoration of energy levels with lactate clearance, increased pyruvate levels and reduced lactate/pyruvate ratio was seen following reperfusion of functioning DCD grafts, parallel with levels in DBD grafts. Histology revealed more pronounced glycogen depletion in DCD grafts. Three allografts that failed owing to primary non-function showed energy exhaustion with severe glycogen depletion. CONCLUSION: Liver grafts from DCD donors exhibited depletion of intracellular energy reserves during cold storage. Failed allografts showed severe energy depletion. Modified organ preservation techniques to minimize organ injury related to altered energy metabolism may enable better utilization of donor organs after circulatory death.

The evolving course of HNF4A hyperinsulinaemic hypoglycaemia--a case series.

BACKGROUND: Hepatocyte nuclear factor 4 alpha (HNF4A) gene mutations have a well-recognized role in maturity-onset diabetes of the young and have recently been described in congenital hyperinsulinism. A biphasic phenotype has been postulated, with macrosomia and congenital hyperinsulinism in infancy, and diabetes in young adulthood. In this case series, we report three children with HNF4A mutations (two de novo) and diazoxide-responsive congenital hyperinsulinism, highlighting the potential for ongoing diazoxide requirement and the importance of screening for these mutations even in the absence of family history. CASE REPORTS: All patients presented with macrosomia (mean birthweight 4.26 kg) and hyperinsulinaemic hypoglycaemia soon after birth (median age 1 day). All three (age range 7 months to 11 years 10 months) remain on diazoxide therapy, with dose requirements increasing in one patient. There was no prior family history of diabetes, neonatal hypoglycaemia or macrosomia. Parents were screened for HNF4A mutations post-diagnosis and one father was subsequently found to have maturity-onset diabetes of the young. CONCLUSIONS: This case series follows the evolving course of three patients with confirmed HNF4A-mediated congenital hyperinsulinism, highlighting (1) the variable natural history of these mutations, (2) the potential for prolonged diazoxide requirement, even into adolescence, and (3) the need for screening, regardless of family history.

Influence of preformed donor-specific antibodies and C4d on early liver allograft function.

INTRODUCTION. The impact of preformed donor-specific antibodies (DSA) is incompletely understood in liver transplantation. The incidence and impact of preformed DSA on early post liver transplant were assessed and these were correlated with compliment fragment C4d on allograft biopsy. METHODS. Pretransplant serum from 41 consecutive liver transplant recipients (brain dead donors; DBD = 27 and cardiac death donors; DCD = 14) were tested for class-specific anti-human leukocyte antigen (HLA) and compared against donor HLA types. Liver biopsies were taken during cold storage (t-1) and post-reperfusion (t0) stained with C4d and graded for preservation-reperfusion injury (PRI). RESULTS. Of the 41 recipients, 8 (20%) had anti-HLA class I/II antibodies pretransplant, 3 (7%) were confirmed preformed DSA; classes I and II (n=1) and class I only (n=2). No biopsies showed definite evidence of antibody-mediated rejection. Graft biopsies in overall showed only mild PRI with ischemic hepatocyte C4d pattern similar in both positive and negative DSA patients. One DSA-positive (33%) compared with four DSA-negative patients (10%) had significant early graft dysfunction; severe PRI causing graft loss from primary nonfunction was seen only in DSA-negative group. Allograft biopsy of preformed DSA-positive patient demonstrated only minimal PRI; however, no identifiable cause could be attributed to graft dysfunction other than preformed DSA. CONCLUSION. Preformed DSA are present in 5-10% liver transplant recipients. There is no association between anti-HLA DSA and PRI and C4d, but preformed DSA may cause early morbidity. Larger studies on the impact of DSA with optimization of C4d techniques are required.

Short stature in child with early-onset diabetes.

We present a girl who initially presented at 12 weeks of age with antibody negative diabetes. Genetic screening for common mutations of monogenic diabetes was negative. She was noted to have short stature at 8 years of age (height <0.4 centile), as well as overlapping toes and distal abnormalities of her fingers. On reevaluation, further investigation revealed an EIF2AK3 mutation, and a diagnosis of Wolcott Rallison syndrome was made. This case highlights the importance of close follow up of patients with neonatal diabetes for the development of syndromic features that may lead to a unifying diagnosis.

The effect of behavioural risk factors on osteoporosis in Irish women.

BACKGROUND: Osteoporosis constitutes a major public health concern and its underlying pathogenesis is complex and multifactorial. Although hereditary factors strongly contribute to bone health, behavioural factors can modulate the genetically determined pattern of skeletal modelling and remodelling. AIM: The aim of this study was to investigate the effect(s) of behavioural risk factors on osteoporosis in Irish women. METHODS: Pre- and post-menopausal adult women (n = 189; 44 ± 15 years) participated in this cross-sectional study. Demographic, anthropometric and lifestyle data were collected during a single clinic visit. Dietary calcium intake and lifetime physical activity (PA) were assessed for each subject. Lumbar and femoral bone mineral density (BMD) was measured by dual energy X-ray absorptiometry (DXA). Multivariate analysis was used to determine the independent predictors of low BMD. RESULTS: Low BMD was present in 59% of subjects (42% pre- and 77% post-menopausal). Smoking was the strongest behavioural predictor of lumbar and femoral BMD. Age, height, family history, smoking, metabolic (MET) and mechanical (MECH) PA (lifetime) and weight (body mass) accounted for 39% of the variance in lumbar BMD. Age, height, family history, alcohol consumption, MET and MECH PA (lifetime) and weight accounted for 41% of the variance in femoral BMD. CONCLUSIONS: Prevalence of osteopenia and osteoporosis is high in Irish women and is associated with modifiable risk factors. A clearer focus should be paid to educate Irish women on preventative health behaviours for osteoporosis to curb the prevalence of this disease and the human and fiscal costs associated with it.

Ghrelin prevents levodopa-induced inhibition of gastric emptying and increases circulating levodopa in fasted rats.

BACKGROUND: Levodopa (L-dopa) is the most commonly used treatment for alleviating symptoms of Parkinson's disease. However, L-dopa delays gastric emptying, which dampens its absorption. We investigated whether ghrelin prevents L-dopa action on gastric emptying and enhances circulating L-dopa in rats. METHODS: Gastric emptying of non-nutrient methylcellulose/phenol red viscous solution was determined in fasted rats treated with orogastric or intraperitoneal (i.p.) L-dopa, or intravenous (i.v.) ghrelin 10 min before orogastric L-dopa. Plasma L-dopa and dopamine levels were determined by high pressure liquid chromatography. Plasma acyl ghrelin levels were assessed by radioimmunoassay. Fos expression in the brain was immunostained after i.v. ghrelin (30 µg kg(-1)) 10 min before i.p. L-dopa. KEY RESULTS: Levodopa (5 and 15 mg kg(-1)) decreased significantly gastric emptying by 32% and 62%, respectively, when administered orally, and by 91% and 83% when injected i.p. Ghrelin (30 or 100 µg kg(-1), i.v.) completely prevented L-dopa's (15 mg kg(-1), orogastrically) inhibitory action on gastric emptying and enhanced plasma L-dopa and dopamine levels compared with vehicle 15 min after orogastric L-dopa. Levodopa (5 mg kg(-1)) did not modify plasma acyl ghrelin levels at 30 min, 1, and 2 h after i.v. injection. Levodopa (15 mg kg(-1), i.p.) induced Fos in brain autonomic centers, which was not modified by i.v. ghrelin. CONCLUSIONS & INFERENCES: Ghrelin counteracts L-dopa-induced delayed gastric emptying but not Fos induction in the brain and enhances circulating L-dopa levels. Potential therapeutic benefits of ghrelin agonists in Parkinson's disease patients treated with L-dopa remain to be investigated.

Spectral analysis and connectivity of porous microstructures in bone.

Cancellous bone is a porous composite of calcified tissue interspersed with soft marrow. Sea ice is also a porous composite, consisting of pure ice with brine, air, and salt inclusions. Interestingly, the microstructures of bone and sea ice exhibit notable similarities. In recent years, we have developed mathematical and experimental techniques for imaging and characterizing the brine microstructure of sea ice, such as its volume fraction and connectivity, as well as a range of theoretical approaches for studying fluid, thermal, and electromagnetic transport in sea ice. Here we explore the application of our sea ice techniques to investigate trabecular bone. For example, percolation theory that quantifies brine connectivity and its thermal evolution can also help assess the impact of osteoporosis on trabecular structure. Central to our approach is the spectral measure of a composite material, which contains detailed information about the mixture geometry, and can be used in powerful integral representations to compute the effective properties. The spectral measure is obtained from the eigenvalues and eigenvectors of a self-adjoint operator determined exclusively by the composite microgeometry. Here we compute the spectral measures for discretizations of images of healthy and osteoporotic bone. The measures are used to compute the effective electromagnetic properties of the bone specimens. These data are then inverted to reconstruct the porosity of the original specimens, with excellent agreement.