Contrasting effects of recombinant human granulocyte-macrophage colony- stimulating factor (CSF) and granulocyte CSF treatment on the cycling of blood elements in childhood-onset cyclic neutropenia

Recombinant human granulocyte colony-stimulating factor (G-CSF) treatment has been shown to increase average neutrophil counts substantially in patients with childhood-onset cyclic neutropenia (or "cyclic hematopoiesis"), but not to eliminate the cyclic oscillations of neutrophil counts or those of other blood elements (monocytes, platelets, eosinophils, and reticulocytes) that are characteristic of this hematopoietic disorder. Indeed, oscillations of neutrophil counts are amplified during G-CSF treatment. We have compared the effects of recombinant granulocyte-macrophage-CSF (GM-CSF) with those of G-CSF in three patients with this disease (2 men and 1 woman, 17, 30, and 32 years of age). These patients were treated with GM-CSF (2.1 micrograms/kg/day, subcutaneously) for 6 weeks, preceded and followed by 6 to 13 weeks of detailed observation to document changes in the cyclic oscillations of blood neutrophils and other blood elements; two of the patients were subsequently treated with G-CSF (5.0 micrograms/kg/d, subcutaneously) and observed for comparable periods of time. Unlike G-CSF treatment, which increased average neutrophil counts more than 20-fold, GM-CSF increased neutrophil counts only modestly, from 1.6- to 3.9-fold, although eosinophilia of varying prominence was induced in each patient. However, at the same time, GM-CSF treatment dampened or eliminated the multilineage oscillations of circulating blood elements (neutrophils, monocytes, platelets, and/or reticulocytes) in each of the patients. In contrast, G-CSF treatment of the same patients markedly amplified the oscillations of neutrophil counts and caused the cycling of other blood elements (monocytes in particular) to become more distinct. These findings support the conclusion that the distinctive cycling of blood cell production in childhood-onset cyclic neutropenia results from abnormalities in the coordinate regulation of both GM-CSF-responsive, multipotential progenitor cells and G-CSF-responsive, lineage-restricted, neutrophil progenitors.     

运动性心律失常

运动性心律失常是指发生于机体剧烈运动期间或之后的心律失常。临床表现不一,从心悸、头晕、晕厥、心绞痛、急性心肌梗死和充血性心力衰竭,甚至到心脏性猝死。运动性心律失常可见于心肌缺血,如患有动脉粥样硬化性心脏病以及患有原发性或继发性心肌病的患者。然而,也可能发生在似乎健康的个体。在后一组人群中,运动性心律失常可以是良性的,但也可以是获得性(如药物诱发)或先天性(如先天性长QT综合征或致心律失常性右室发育不良)心电活动或结构的异常而呈恶性。这种潜在病理生理学机制的复杂性,使运动性心律失常的诊断和治疗成为临床医学上的…     

IMPROVED ORAL ABSORPTION OF L-365 260, A POORLY SOLUBLE DRUG

L-365 260, a specific and potent nonpeptide antagonist of the CCK_B receptor, is under investigation for its potential utility in the treatment of anxiety and panic disorders. This drug has a very low aqueous solubility (<2μg mL⁻¹). When L-365 260 was given orally as a suspension in 0·5% methylcellulose (5 mg kg⁻¹, the absorption was rapid but incomplete. The peak concentrations occurred in about 30–40 min, and the bioavailability was 8·6% for the dog and 13·6% for the rat. The poor bioavailability could be attributed to poor absorption or extensive first-pass metabolism. By comparing the drug concentrations in the systemic circulation during portal and femoral (or cephalic) vein infusion, the hepatic first-pass metabolism was estimated to be 0·30 for the rat and 0·14 for the dog, suggesting that first-pass metabolism is not the main reason for the low bioavailability of the drug in rats and dogs. The limited bioavailability is, therefore, more likely due to its poor absorption as a result of its poor aqueous solubility and slow dissolution rate. However, while the absorption was substantially improved when the drug was given orally as a solution in PEG 600 solution, the bioavailability increased threefold to fourfold in rats and sixfold to sevenfold in dogs. Although the underlying mechanism for the improved absorption is unknown, PEG 600 may have exerted a cosolubilizing effect which enhances the dissolution rate of L-365 260 in the GI tract, resulting in better absorption. Kinetic analysis by a deconvolution technique revealed that PEG 600 increased both the extent and rate of absorption. These results are consistent with the notion that absorption of L-365 260 is rate limited by its dissolution rate. The data from these animal studies provides valuable information in selecting the formulation for clinical trials.     

Cabozantinib for relapsed neuroblastoma: Single institution case series

Relapsed high‐risk neuroblastoma has few effective therapies currently available or in development. Cabozantinib is an Food and Drug Administration approved multitargeted tyrosine kinase inhibitor for select adult malignancies with preclinical data suggesting efficacy against neuroblastoma. A safe and tolerable dose has been identified for children, but its efficacy remains unknown. We describe four children with relapsed metastatic neuroblastoma treated with cabozantinib. All four patients had extended disease control (two complete responsesfor >12 months, 2 stable disease >6 months) with manageable predictable toxicities requiring dose reduction in two patients. We discuss the potential for the use of cabozantinib in neuroblastoma.     

Microarray analysis of aberrant gene expression in actinic keratosis: effect of the Toll-like receptor-7 agonist imiquimod

BACKGROUND: The molecular events leading to actinic keratosis (AK) are not well understood. OBJECTIVE: To identify and compare gene expression changes in AK lesions and in sun-exposed nonlesional skin and to determine the effect of imiquimod 5% cream on these changes. METHOD: A double-blind, vehicle-controlled, randomized study was conducted to evaluate the molecular changes in AK treated with imiquimod. Seventeen male subjects with >/= 5 AK lesions on the scalp applied vehicle or imiquimod three times a week for 4 weeks. Gene expression analysis using Affymetrix oligonucleotide arrays was performed on shave biopsies of lesions taken before and after treatment. Confocal microscopy was performed on the study area as an adjunctive diagnostic procedure. RESULTS: We identified gene expression changes which occur in sun-exposed, nonlesional skin as well as in AK lesions. These changes include, but are not limited to, the overexpression of oncogenic and proliferative genes and diminished expression of tumour suppressor genes. The gene expression changes observed in AK lesions and in sun-exposed, nonlesional skin were consistent with the confocal microscopy observations, which showed abnormalities in the sun-exposed, nonlesional skin, similar in nature but less pronounced than abnormalities seen in AK. Imiquimod partially or totally reversed the aberrant expression of some of the genes observed in AK, consistent with clearing of lesions and normalization of confocal cellular images. CONCLUSIONS: The data show that profound gene expression changes occur in sun-exposed, nonlesional skin which progress further in AK lesions. The data also suggest that imiquimod may play a role in normalizing gene expression and cellular morphology in sun-damaged skin.     

Attitudes towards seafood and patterns of consumption in an Australian coastal town

Regular seafood consumption plays a protective role against chronic conditions and obesity, which account for the majority of the burden of disease in Australia. Despite public health recommendations, Australians consume less than the recommended levels of omega‐3s (n‐3) to reduce the risk of chronic disease. The best source of long‐chain n‐3 is oil‐rich fish. This paper reports on results from a community survey on attitudes and patterns of seafood consumption conducted in a coastal town in Western Australia. Data were collected through a self‐administered questionnaire and 300 valid responses were received (60.7% aged 55 years or over; 65.7% female). Weekly patterns of seafood consumption were observed. Almost all participants (93.7%) thought seafood was an important part of a healthy, balanced diet. Overall, participants (73.3%) did not perceive seafood as inconvenient to prepare, and had a high level of confidence around cooking and serving seafood. There were no gender or age differences in confidence except for those aged under 30 years with only a third (36.4%) expressing confidence in cooking and serving. All participants, across all ages and genders (78.7–90.7%) made informed decisions when purchasing seafood and they sought more point‐of‐sale information. They identified affordability, availability, easy‐to‐understand food labels and quick‐and‐easy recipes at point of purchase as the main enablers towards increased seafood consumption.