Validation of the NAFLD fibrosis score in a Chinese population with low prevalence of advanced fibrosis

OBJECTIVES:  Nonalcoholic fatty liver disease (NAFLD) is increasing in prevalence worldwide. This study aimed to validate the NAFLD fibrosis score in the Chinese population.
METHODS:  NAFLD patients were prospectively recruited for liver biopsy and blood tests. The NAFLD fibrosis score was calculated as −1.675 + 0.037 × age (yr) + 0.094 × BMI (kg/m²) + 1.13 × impaired fasting glucose/diabetes (yes = 1, no = 0) + 0.99 × AST/ALT ratio–0.013 × platelet (×10⁹/L)−0.66 × albumin (g/dL). Advanced fibrosis was defined as stage 3 to 4 fibrosis.
RESULTS:  One hundred sixty-two patients (age 46 ± 10 yr, male 59%) were included in the study. Advanced fibrosis was found in 18 (11%) patients. Only 11 of 128 patients with the NAFLD fibrosis score below the proposed low cutoff point (<−1.455) were under-staged, resulting in a high negative predictive value of 91%. Only two patients exceeded the proposed high cutoff point (>0.676), but neither had advanced fibrosis. If the NAFLD fibrosis score was implemented in the Chinese population, 79% of liver biopsies could be avoided.
CONCLUSIONS:  The NAFLD fibrosis score has high negative predictive value in excluding advanced fibrosis in the Chinese population, and can reduce the burden of liver biopsy in the vast majority of cases. Since there were few cases of advanced fibrosis in this cohort, this study had limited power in validating the high cutoff point.     

Recombinant human interleukin-11 stimulates multilineage hematopoietic recovery in mice after a myelosuppressive regimen of sublethal irradiation and carboplatin

Interleukin-11 (IL-11) is a novel multifunctional hematopoietic cytokine capable of stimulating cells of the myeloid, lymphoid, erythroid, and megakaryocytic lineages in vitro. We have tested the pleiotropic properties of this cytokine on the hematopoietic recovery of mice after a combined regimen of sublethal irradiation and carboplatin administration. This regimen results in severe myelosuppression, characterized by a prolonged period of thrombocytopenia and severe anemia. Administration of recombinant human IL-11 (rhIL-11; 250 micrograms/kg/d) had multilineage effects on bone marrow and spleen hematopoietic activity, increasing the number of megakaryocyte, erythroid, granulocyte, and macrophage progenitors compared with the vehicle-treated controls. This was reflected in the peripheral circulation by a reduction of both the platelet and hematocrit nadirs and a significantly reduced period of thrombocytopenia and anemia in the rhIL-11-treated mice. The results from this study support the broad spectrum of biologic activities that have been attributed to rhIL-11 in vitro and suggest that this cytokine may be an effective agent in the treatment of myelosuppression associated with cancer chemotherapy and bone marrow transplantation.     

X-linked chronic granulomatous disease: correction of NADPH oxidase defect by retrovirus-mediated expression of gp91-phox

Chronic granulomatous disease (CGD) is an inherited immunodeficiency resulting from the inability of an individual's phagocytes to produce superoxide anions because of defective NADPH oxidase. The disease may be treated by bone marrow transplantation and as such is a candidate for somatic gene therapy. Two thirds of patients have defects in an X- linked gene (X-CGD) encoding gp91-phox, the large subunit of the membrane cytochrome b-245 component of NADPH oxidase. Epstein-Barr virus-transformed B-cell lines from patients with CGD provide a model system for the disease. We have used retrovirus-mediated expression of gp91-phox to reconstitute functionally NADPH oxidase activity in B-cell lines from three unrelated patients with X-CGD. The protein is glycosylated and membrane associated, and the reconstituted oxidase is appropriately activated via protein kinase C. The kinetics of superoxide production by such reconstituted cells is similar to that of normal B-cell lines. These data show the potential of gene therapy for this disease.     

Altered Pharmacokinetics in Prolonged Infusions of Sedatives and Analgesics Among Adult Critically Ill Patients: A Systematic Review

Purpose

The pharmacokinetic (PK) parameters of many drugs are altered as a consequence of the pathophysiological changes associated with critical illness. The critically ill population presents challenges when titrating infusions of sedatives and analgesics to maintain optimal sedation and pain levels. This systematic review examined the PK data in critically ill adult patients with prolonged infusions (>24 hours) of commonly used sedatives and analgesics to highlight possible altered PK parameters compared with noncritically ill patients.

Evidence for Elizabethkingia anophelis Transmission from Mother to Infant,Hong Kong

Elizabethkingia anophelis, recently discovered from mosquito gut, is an emerging bacterium associated with neonatal meningitis and nosocomial outbreaks. However, its transmission route remains unknown. We use rapid genome sequencing to investigate 3 cases of E. anophelis sepsis involving 2 neonates who had meningitis and 1 neonate’s mother who had chorioamnionitis. Comparative genomics revealed evidence for perinatal vertical transmission from a mother to her neonate; the 2 isolates from these patients, HKU37 and HKU38, shared essentially identical genome sequences. In contrast, the strain from another neonate (HKU36) was genetically divergent, showing only 78.6% genome sequence identity to HKU37 and HKU38, thus excluding a clonal outbreak. Comparison to genomes from mosquito strains revealed potential metabolic adaptations in E. anophelis under different environments. Maternal infection, not mosquitoes, is most likely the source of neonatal E. anophelis infections. Our findings highlight the power of genome sequencing in gaining rapid insights on transmission and pathogenesis of emerging pathogens.     

Predictors of fatal arrhythmic events in patients with non-compaction cardiomyopathy: a systematic review

Heart Failure Reviews - Left ventricular non-compaction cardiomyopathy (LVNC) is a congenital heart disease with autosomal dominant inheritance. This review aims to summarize the existing data...     

Effect of manganese chloride and Verapamil on automaticity of digitalized Purkinje fibers.

The effects of manganese chloride (MnCl2) and verapamil on automaticity of digitlazied Purkinje fibers were studied using conventional microelectrode techniques. The stduied wer made in isolated, spontaneously beating Purkinje prearations. Quabain alone consistently increased the automatic rate, whereas no such increase was observed when the preparations were superfused with a mixture of ouabain adn MnCl2. MnCl2 was also shown to be effective is suppressing the enhanced automaticity induced by ouabain. Mncl2 alone did not have a significant effect on the spontaneous rate of Purkinje fibers. The effect of verapamil was similar to that of MnCl2 in preventing and suppressing the ouabain-induced increase in automaticity. MnCl2 and verapamil have been shown to inhibt tha slow inward calcium current of cardiac fibers. The results therefore suggest that an inward calcium ion current may play a role in the development of digitalis-induced increase in the stope of phase 4 depolarization in Purkinje fibers.     

Long-term outcome in patients with chronic atrial fibrillation after successful internal cardioversion

Internal cardioversion is safe and effective in restoring sinus rhythm, even in patients with persistent AF of prolonged duration. Up to 40% to 50% of patients with AF lasting >1 year but <3 years could be maintained in sinus rhythm using a class III antiarrhythmic drug after successful internal cardioversion, and amiodarone appears to be more effective than sotalol in this patient population.     

Clonal evolution of high‐grade serous ovarian carcinoma from primary to recurrent disease

High‐grade serous carcinoma (HGSC) is the most common and fatal form of ovarian cancer. While most tumours are highly sensitive to cytoreductive surgery and platinum‐ and taxane‐based chemotherapy, the majority of patients experience recurrence of treatment‐resistant tumours. The clonal origin and mutational adaptations associated with recurrent disease are poorly understood. We performed whole exome sequencing on tumour cells harvested from ascites at three time points (primary, first recurrence, and second recurrence) for three HGSC patients receiving standard treatment. Somatic point mutations and small insertions and deletions were identified by comparison to constitutional DNA. The clonal structure and evolution of tumours were inferred from patterns of mutant allele frequencies. TP53 mutations were predominant in all patients at all time points, consistent with the known founder role of this gene. Tumours from all three patients also harboured mutations associated with cell cycle checkpoint function and Golgi vesicle trafficking. There was convergence of germline and somatic variants within the DNA repair, ECM, cell cycle control, and Golgi vesicle pathways. The vast majority of somatic variants found in recurrent tumours were present in primary tumours. Our findings highlight both known and novel pathways that are commonly mutated in HGSC. Moreover, they provide the first evidence at single nucleotide resolution that recurrent HGSC arises from multiple clones present in the primary tumour with negligible accumulation of new mutations during standard treatment.