Interference of 6-mercaptopurine riboside, 6-methylmercaptopurine riboside and azathioprine with the morphogenetic differentiation of mouse extremities in vivo and in organ culture

Naunyn-Schmiedeberg's Archives of Pharmacology - The effect of the three purine antimetabolites 6-mercaptopurine riboside (6-MPr), 6-methylmercaptopurine riboside (6-MeMPr), and azathioprine on...     

Morning or evening activity improves neuropsychological performance and subjective sleep quality in older adults

STUDY OBJECTIVES: Sleep disturbances and decline in neuropsychological performance are common in older adults. Reduced social and physical activity is likely a contributing factor for these age-related changes in sleep and cognition. We previously demonstrated that a program of structured social and physical activity, with 2 daily activity sessions, 1 in the morning and 1 in the evening for a relatively short period of 2 weeks, improved sleep and neuropsychological performance in community-dwelling older adults. The goals of this pilot study were to determine whether a single daily morning or evening activity session for 2 weeks would also improve sleep and neuropsychological function and whether these effects were dependent on the timing of the activity sessions. DESIGN: We compared the effect of morning or evening structured activity sessions in a repeated-measures crossover design. Subjective mood, neuropsychological performance tasks, and subjective and objective measures of sleep were assessed at baseline and after the intervention. SETTING: All procedures took place in the participant's residence. PARTICIPANTS: Twelve older men and women (74.6 +/- 5.5 years of age). INTERVENTIONS: Subjects participated in 14 days of structured activity sessions in the morning (9:00-10:30 am) or evening (7:00-8:30 pm). Sessions consisted of stretching, low-impact aerobics, and game playing. MEASUREMENTS AND RESULTS: Exposure to either morning or evening activity significantly improved performance on a neuropsychological test battery. Morning activity sessions increased throughput on 4 of 8 performance tasks, while evening activity sessions improved throughput on 7 of the 8 performance tasks. Subjective sleep-quality ratings, measured by the Pittsburg Sleep Quality Index, improved following activity sessions in either the morning or the evening. Objective measures of sleep did not improve when measured by actigraphy or polysomnography. CONCLUSIONS: These results suggest that short-term exposure to either morning or evening social and physical activity improves objective measures of neuropsychological performance and subjective sleep quality in the elderly. Increasing exposure to social and physical activity may be a useful intervention to improve sleep quality and daytime function in older adults.     

Substandard factors in perinatal care in The Netherlands: a regional audit of perinatal deaths

BACKGROUND: To determine: 1) whether substandard factors were present in cases of perinatal death, and to what extent another course of action might have resulted in a better outcome, and 2) whether there were differences in the frequency of substandard factors by level of care, particularly between midwives and gynecologists/obstetricians and between home and hospital births. METHODS: Population-based perinatal audit, with explicit evidence-based audit criteria. SETTING: The northern part of the province of South-Holland in The Netherlands. All levels of perinatal care (primary, secondary and tertiary care, and home and hospital births) were included. CASES: Three hundred and forty-two cases of perinatal mortality (24 weeks of pregnancy--28 days after birth). MAIN OUTCOME MEASURES: Scores by a Dutch and a European audit panel. Score 0: no substandard factors identified; score 1, 2 or 3: one or more substandard factors identified, which were unlikely (1), possibly (2) or probably (3) related to the perinatal death. RESULTS: In 25% of the perinatal deaths (95% Confidence Interval: 20-30%) a substandard factor was identified that according to the Dutch panel was possibly or probably related to the perinatal death. These were mainly maternal/social factors (10% of all perinatal deaths; most frequent substandard factor: smoking during pregnancy), and antenatal care factors (10% of all perinatal deaths; most frequent substandard factor: detection of intra-uterine growth retardation). We did not find statistically significant differences in scores between midwives and gynecologists/obstetricians or between home and hospital births. The European panel identified more substandard factors, but these were again equally distributed by level of care. CONCLUSIONS: Perinatal deaths might be partly preventable in The Netherlands. There is no evidence that the frequency of substandard factors is related to specific aspects of the perinatal care system in The Netherlands.     

Genome-based identification of chromosomal regions specific for Salmonella spp

Acquisition of genomic elements by horizontal gene transfer represents an important mechanism in the evolution of bacterial species. Pathogenicity islands are a subset of horizontally acquired elements present in various pathogens. These elements are frequently located adjacent to tRNA genes. We performed a comparative genome analysis of Salmonella enterica serovars Typhi and Typhimurium and Escherichia coli and scanned tRNA loci for the presence of species-specific, horizontally acquired genomic elements. A large number of species-specific elements were identified. Here, we describe the characteristics of four large chromosomal insertions at tRNA genes of Salmonella spp. The tRNA-associated elements harbor various genes previously identified as single virulence genes, indicating that these genes have been acquired with large chromosomal insertions. Southern blot analyses confirmed that the tRNA-associated elements are specific to Salmonella and also indicated a heterogeneous distribution within the salmonellae. Systematic scanning for insertions at tRNA genes thus represents a tool for the identification of novel pathogenicity islands.     

A novel method for single cell detection of in situ telomerase or histone H3 in combination with clonal analysis by FISH

A novel method for simultaneously detecting clonality by FISH, and presence of telomerase activity (telo+ cells) or histone H3 mRNA (H3+) in single cells from a mixed leukemic population is reported. The methods were validated using K562 cells mixed with peripheral blood granulocytes and bone marrow aspirate cells from newly diagnosed AML patients. Fifty patients with AML were analyzed for telo+ cells, while eight AML patients were analyzed for FISH-Telomerase and FISH-H3+ during remission induction therapy. Our results demonstrate that: (1). changes in the leukemic populations during therapy could be followed; (2). a favorable response to chemotherapy occurred when there was a reduction in both the cytogenetically abnormal cells along with reduction in telo+ cells within this abnormal population; (3). reduction of either telo+ cells or FISH+ cells alone did not correlate with good response. H3+ could be detected in only 4% of the leukemic population, most of which were cytogenetically abnormal. These newly established methods allow sub-populations of cells to be followed during disease progression and treatment and to elucidate factors that give a specific clone proliferative advantage.     

Acute renal response to the non-peptide vasopressin V2-receptor antagonist SR 121463B in anesthetized rats

Vasopressin V2-receptor antagonists are promising agents for the use in water-retaining diseases. Potential renal mechanisms of action include effects on water permeability in the collecting duct as well as on electrolyte transport in the thick ascending limb of Henle's loop (TALH). To elucidate sites of action upstream of the distal tubule, e.g., in TALH, micropuncture experiments were performed in anesthetized rats during application of the V2-receptor antagonist SR 121463B. As compared to vehicle-treated rats, SR 121463B (0.3 mg/kg i.v.) did not affect mean arterial blood pressure (means +/- SEM, n=10 rats per group: 108+/-4 mmHg vs. 107+/-4 mmHg), whole kidney GFR (1.1+/-0.1 ml/min vs. 1.1+/-0.1 ml/min), or whole kidney fractional reabsorption (FR) of potassium (66+/-5% vs. 68+/-4%). The drug, however, reduced whole kidney FR of fluid (92+/-1% vs. 99+/-1%), increased urinary flow rate (84+/-7 microl/min vs. 8+/-1 microl/min) and electrolyte-free-water clearance (72+/-8 microl/min vs. 2+/-1 microl/min), and reduced urinary osmolality (148+/-11 mosmol/kg vs. 1,200+/-185 mosmol/kg). This pronounced diuretic response was associated with a minor reduction in whole kidney FR of sodium (99.6+/-0.1% vs. 99.9+/-0.1%) and chloride (98.3+/-0.2% vs. 98.9+/-0.1%). As compared to vehicle application, SR 121463B did not significantly alter single nephron GFR (39+/-2 nl/min vs. 39+/-1 nl/min, n=22 and 23 nephrons, respectively) or the FR up to the early distal tubule of fluid (76+/-2% vs. 76+/-1%), sodium (92+/-1% vs. 93+/-1%), potassium (91+/-1% vs. 90+/-1%) or chloride (90+/-1% vs. 91+/-1%). Together these data indicate a predominant aquaretic effect of SR 121463B which is located downstream of the early distal tubule. This response is compatible with blockade of vasopressin V2-receptors in the collecting duct and, as directly demonstrated by immunohistochemistry, subsequent retrieval of aquaporin-2 from apical plasma membrane, which inhibits water permeability and transport.     

A novel case of infantile sacral teratoma and a constitutional t(12;15)(q13;q25) pat

Cytogenetic analysis of peripheral lymphocytes of an infantile patient with a sacral teratoma revealed a constitutional translocation (12;15)(q13;q25) pat. The same translocation was found in four additional relatives. Loss of heterozygosity analysis of the patient's tumor material showed retention of both translocation-derived chromosomes. Since allelic loss in the 12q13 region has been observed in germ cell tumors, we hypothesize that disregulation of genes located at or near the 12q13 breakpoint may be related to the development of this sacral teratoma. As a first step towards the identification of these genes, a 12q13 genomic contig that spans the breakpoint has been constructed.     

Peptides in body fluids and tissues as markers of disease

The general awareness of the importance of peptides in physiology and pathophysiology has increased strongly over the last few years. With worldwide progress in the analysis of whole genomes, the knowledge base in gene sequence and expression data useful for protein and peptide analysis has drastically increased. The medical need for relevant biomarkers is enormous. This is particularly true for the many types of cancer, but other diseases such as Type 2 diabetes also lack useful and adequate diagnostic markers with high specificity and sensitivity. Despite advances in imaging technologies for early detection of diseases, proteomic and peptidomic multiplex techniques have evolved in recent years. This review focuses on the application of peptidomics technologies to peptides in health and disease. Peptidomics technologies provide new opportunities for the detection of low-molecular-weight proteome biomarkers (peptides) by mass spectrometry. Improvements in peptidomics research are based on separation of peptides and/or proteins by their physicochemical properties in combination with mass spectrometric detection, identification and sophisticated bioinformatics tools for data analysis. Therefore, peptidomics technologies offer an opportunity to discover novel biomarkers for diagnosis and management of disease (e.g., prognosis, treatment decision and monitoring response to therapy).