A High Incidence of Intussusception Revealed by a Retrospective Hospital-Based Study in Nha Trang,Vietnam between 2009 and 2011

Rotavirus is a leading cause of severe diarrhea among children worldwide. Thus, the World Health Organization recommended including rotavirus vaccines in national immunization programs. One concern about rotavirus vaccine, however, is a possible association with intussusception. Thus, it is crucial to know the baseline incidence of intussusception in the first year of life. A study conducted in Hanoi, Vietnam showed that the incidence of intussusception was the highest in the world. This retrospective cross-sectional study was undertaken to determine the incidence of intussusception among children <5 years of age in Nha Trang, Vietnam. Hospital charts between 2009 and 2011 were reviewed in Khanh Hoa Provincial General Hospital where virtually all cases of intussusception occurring in the city were assumed to have been encountered. The incidence of intussusception among children <1 year of age was 296 per 100,000 person-years (95% confidence interval [CI]: 225–382), and that among children <5 years of age was 196 per 100,000 person-years (95% CI: 169–226), confirming the high incidence of intussusception in Vietnam. Nevertheless, there was no intussusception in the first three months of life. We therefore recommend that the first dose of any rotavirus vaccine be administered to infants between 6 and 12 weeks of age.     

Genetic susceptibility to diclofenac-induced hepatotoxicity: contribution of UGT2B7, CYP2C8, and ABCC2 genotypes

BACKGROUND & AIMS: Diclofenac is a widely used nonsteroidal anti-inflammatory drug and is among the most common drugs causing idiosyncratic hepatotoxicity in several recent series with up to 20% mortality in jaundiced subjects. We hypothesized that susceptibility to hepatotoxicity would be associated with genetic polymorphisms in the genes encoding the enzymes UGT2B7 and CYP2C8, which determine the formation of reactive diclofenac metabolites and in ABCC2 encoding the transporter MRP2 contributing to the biliary excretion of the reactive metabolite. METHODS: Twenty-four patients (19 female) aged 24-70 (mean, 50.8) years who had suffered diclofenac hepatotoxicity, 48 subjects (35 female) aged 22-77 (mean, 52) years who were taking diclofenac for 0.3-20 (mean, 4) years without developing hepatotoxicity (hospital controls), and 112 healthy controls were investigated. Genotyping for several polymorphisms in the genes encoding UGT2B7, CYP2C8, and ABCC2 was performed and haplotypes assigned. RESULTS: The UGT2B7*2 allele was more common in diclofenac hepatotoxicity patients compared with hospital controls (odds ratio [OR], 8.5, P = .03) and healthy controls (OR, 7.7, P = .03). The ABCC2 C-24T variant was more common in hepatotoxicity patients compared with hospital (OR, 5.0, P = .005) and healthy controls OR: 6.3, P = .0002). Haplotype distributions for CYP2C8 were different in patients compared with hospital controls (P = .04). CONCLUSIONS: Allelic variants of UGT2B7, CYP2C8, and ABCC2, which may predispose to the formation and accumulation of reactive diclofenac metabolites are associated with diclofenac hepatotoxicity. Increased level of reactive metabolites may lead to higher levels of protein-diclofenac adducts and subsequently hepatotoxicity.     

Most CML patients who have a suboptimal response to imatinib have low OCT-1 activity: higher doses of imatinib may overcome the negative impact of low OCT-1 activity

Interpatient variability in intracellular uptake and retention (IUR) of imatinib may be due to variable function of the OCT-1 influx pump. OCT-1 activity was measured in pretherapy blood from chronic myeloid leukemia (CML) patients by calculating the difference in IUR of [(14)C]-imatinib with and without OCT-1 inhibition. Of patients with higher than median (high) OCT-1 activity, 85% achieved major molecular response (MMR) by 24 months, versus 45% with no more than a median (low) OCT-1 activity. Assessing patients receiving 600 mg imatinib per day and those averaging fewer than 600 mg over 12 months of therapy revealed patients with high OCT-1 activity achieved excellent molecular response regardless of dose, whereas response of patients with low OCT-1 activity was highly dose dependent. Of patients with low OCT-1 activity who received fewer than 600 mg, 45% failed to achieve a 2-log reduction by 12 months, and 82% failed to achieve a MMR by 18 months, compared with 8% and 17% in the cohort with high OCT-1 activity and dose less than 600 mg/day (P = .017 and P = .022). OCT-1 activity is an important determinant of molecular response to imatinib, with predictive value closely linked to dose. This pretherapy assay identifies patients at greatest risk of suboptimal response where dose intensity is critical, and those likely to respond equally well to standard dose imatinib.     

Pharmacological management of Cushing's syndrome: an update

The treatment of choice for Cushing's syndrome remains surgical. The role for medical therapy is twofold. Firstly it is used to control hypercortisolaemia prior to surgery to optimize patient's preoperative state and secondly, it is used where surgery has failed and radiotherapy has not taken effect. The main drugs used inhibit steroidogenesis and include metyrapone, ketoconazole, and mitotane. Drugs targeting the hypothalamic-pituitary axis have been investigated but their roles in clinical practice remain limited although PPAR-gamma agonist and somatostatin analogue som-230 (pasireotide) need further investigation. The only drug acting at the periphery targeting the glucocorticoid receptor remains Mifepristone (RU486). The management of Cushing syndrome may well involve combination therapy acting at different pathways of hypercortisolaemia but monitoring of therapy will remain a challenge.     

Epidural analgesia after scoliosis surgery: electrophysiologic and clinical assessment of the effects of bupivacaine 0.125% plus morphine versus ropivacaine 0.2% plus morphine

STUDY OBJECTIVE: To study the electrophysiologic and clinical effects of epidural morphine combined with either bupivacaine 0.125% or ropivacaine 0.2%. DESIGN: Comparative, randomized, double-blind study. SETTINGS: Intensive care unit and hospital ward of a university hospital. PATIENTS: 18 adult ASA physical status I and II patients with degenerative or idiopathic scoliosis, undergoing posterior spinal fusion with instrumentation. INTERVENTIONS: Patients received epidural administration of 10-mL bolus of either bupivacaine or ropivacaine followed by a 6-mL/h infusion for 48 hours of unlabeled local anesthetic. In all patients, epidural morphine 5 mg was added daily. MEASUREMENTS: Assessment was focused mainly on somatosensory cortical evoked potentials, soleus H-reflex, and F waves. These electrophysiologic data were recorded before and after epidural medications. Second, respiratory rate, Paco(2), visual analog score (VAS), and side effects such as postoperative nausea and vomiting (PONV), gastrointestinal (GI) transit delay, and urinary retention were noted. MAIN RESULTS: Bupivacaine 0.125% + morphine was given to 9 patients, and ropivacaine 0.2% + morphine was given to 9 other patients. H-reflex, F waves, and somatosensory cortical evoked potential recording remained unchanged across the time of assessment. Respiratory rate and Paco(2) values were normal. VASs were indifferently low at rest, but they were lower with bupivacaine than with ropivacaine on mobilization. The frequency of PONV was indifferently high. No altered GI transit or urinary retention was noted. CONCLUSION: After epidural administration during the study conditions, bupivacaine 0.125% and ropivacaine 0.2% combined with morphine allow for neurologic examination.     

Fatty Liver Disease: Predictors of Nonalcoholic Steatohepatitis and Gallbladder Disease in Morbid Obesity

BACKGROUND: Nonalcoholic steatohepatitis (NASH) and gallbladder disease (GD) are members of metabolic syndrome in morbidly obesity. Insulin resistance is a risk factor for NASH and GD. The aim of the present study was to investigate the relationship between insulin resistance (HOMA-IR), liver fibrosis, NASH and GD in morbidly obese patients who presented with fatty liver during preoperative abdominal ultrasonography examination. METHODS: We studied 152 morbid obese patients with fatty liver disease including 54 with NASH, 11 with GD and two with concurrent NASH and GD that were undergoing laparoscopic bariatric surgery. Clinical data (gender, age, body mass index [BMI], and associated diseases), laboratory evaluation, and histopathology were obtained from the patient databases. We analyzed the relationship between clinical characteristics, histological parameters, HOMA-IR, and fibrosis stage associated with NASH and GD in morbid obese patients. RESULTS: Among the 152 patients with fatty liver disease, 93 were females and 59 were males. The mean age was 30.3 +/- 8.9 years and the mean BMI was 44.9 +/- 5.4 kg/m(2). Fifty-four patients (54/152, 35.5%) were diagnosed as NASH and 11 patients (11/152, 7.2%) received concomitant laparoscopic cholecystectomy because of gallbladder disease (GD). Morbidly obese patients with fatty liver disease and GD were significantly older (P = 0.020), had higher serum levels of cholesterol (P = 0.020) and low-density lipoprotein (LDL)-cholesterol (P = 0.044), and had lower serum levels of total bilirubin (P = 0.044), C-peptide (P = 0.023), and insulin (P = 0.039) than the NASH group. Histopathology factors of hepatic steatosis (P = 0.012), ballooning degeneration (P = 0.001), lobular inflammation (P = 0.019), fibrosis (P = 0.026), and glycogenated nuclei (P = 0.028) were significantly different between NASH and GD groups. However, further multivariate analysis failed to demonstrate any independent clinicopathological factor. The prevalence of chronic hepatitis B and NASH was the same (18%) in all 11 GD patients. Besides, when we compared NASH patients (n = 54) with concurrent NASH-GD patients (n = 2), we found that waist (P = 0.016), waist/hip (P = 0.039), and HOMA-IR (P = 0.040) were independent associated factors. We further assessed the HOMA-IR distribution and the relationship between fibrosis stage in patients with NASH and GD. In the NASH group, HOMA-IR distribution progressively decreased when the severity of fibrosis was plotted as a function of insulin resistance. CONCLUSION: The prevalence of NASH in gallbladder disease was 18% in morbid obese population. We concluded that age, serum cholesterol, and low-density lipoprotein cholesterol levels were risk factors associated with gallbladder disease and fatty liver disease. Insulin resistance was more common in concurrent NASH and gallbladder disease. The mechanism between insulin resistance, fibrosis stage, NASH, and gallbladder disease is unknown.     

Optimization of antibody binding to FcgammaRIIa enhances macrophage phagocytosis of tumor cells

The contribution of Fc-mediated effector functions to the therapeutic efficacy of some monoclonal antibodies has motivated efforts to enhance interactions with Fcgamma receptors (FcgammaR). Although an early goal has been enhanced FcgammaRIIIa binding and natural killer (NK) cell antibody-dependent cell-mediated cytotoxicity (ADCC), other relevant cell types such as macrophages are dependent on additional activating receptors such as FcgammaRIIa. Here, we describe a set of engineered Fc variants with diverse FcgammaR affinities, including a novel substitution G236A that provides selectively enhanced binding to FcgammaRIIa relative to FcgammaRIIb. Variants containing this substitution have up to 70-fold greater FcgammaRIIa affinity and 15-fold improvement in FcgammaRIIa/FcgammaRIIb ratio and mediate enhanced phagocytosis of antibody-coated target cells by macrophages. Specific double and triple combination variants with this substitution are simultaneously capable of exhibiting high NK-mediated ADCC and high macrophage phagocytosis. In addition, we have used this unique set of variants to quantitatively probe the relative contributions of individual FcgammaR to effector functions mediated by NK cells and macrophages. These experiments show that FcgammaRIIa plays the most influential role for macrophages and, surprisingly, that the inhibitory receptor FcgammaRIIb has little effect on effector function. The enhancements in phagocytosis described here provide the potential to improve the performance of therapeutic antibodies targeting cancers.