High fractional excretion of glycation adducts is associated with subsequent early decline in renal function in type 1 diabetes

Increased protein glycation, oxidation and nitration is linked to the development of diabetic nephropathy. We reported levels of serum protein glycation, oxidation and nitration and related hydrolysis products, glycation, oxidation and nitration free adducts in patients with type 1 diabetes (T1DM) during onset of microalbuminuria (MA) from the First Joslin Kidney Study, a prospective case–control study of patients with T1DM with and without early decline in GFR. Herein we report urinary excretion of the latter analytes and related fractional excretion values, exploring the link to MA and early decline in GFR. We recruited patients with T1DM and normoalbuminuria (NA) (n = 30) or new onset MA with and without early GFR decline (n = 22 and 33, respectively) for this study. We determined urinary protein glycation, oxidation and nitration free adducts by stable isotopic dilution analysis liquid chromatography-tandem mass spectrometry (LC–MS/MS) and deduced fractional excretion using reported plasma levels and urinary and plasma creatinine estimates. We found urinary excretion of pentosidine was increased ca. twofold in patients with MA, compared to normoalbuminuria (0.0442 vs 0.0103 nmol/mg creatinine, P < 0.0001), and increased ca. threefold in patients with early decline in GFR, compared to patients with stable GFR (0.0561 vs 0.0176 nmol/mg creatinine, P < 0.01). Urinary excretion of all other analytes was unchanged between the study groups. Remarkably, fractional excretions of 6 lysine and arginine-derived glycation free adducts were higher in patients with early decline in GFR, compared to those with stable GFR. Impaired tubular reuptake of glycation free adducts by lysine and arginine transporter proteins in patients with early GFR decline is likely involved. We conclude that higher fractional excretions of glycation adducts are potential biomarkers for early GFR decline in T1DM and MA. Measurement of these analytes could provide the basis for identifying patients at risk of early decline in renal function to target and intensify renoprotective treatment

A specific group of genes respond to cold dehydration stress in cut Alstroemeria flowers whereas ambient dehydration stress accelerates developmental senescence expression patterns

Petal development and senescence entails a normally irreversible process. It starts with petal expansion and pigment production, and ends with nutrient remobilization and ultimately cell death. In many species this is accompanied by petal abscission. Post-harvest stress is an important factor in limiting petal longevity in cut flowers and accelerates some of the processes of senescence such as petal wilting and abscission. However, some of the effects of moderate stress in young flowers are reversible with appropriate treatments. Transcriptomic studies have shown that distinct gene sets are expressed during petal development and senescence. Despite this, the overlap in gene expression between developmental and stress-induced senescence in petals has not been fully investigated in any species. Here a custom-made cDNA microarray from Alstroemeria petals was used to investigate the overlap in gene expression between developmental changes (bud to first sign of senescence) and typical post-harvest stress treatments. Young flowers were stressed by cold or ambient temperatures without water followed by a recovery and rehydration period. Stressed flowers were still at the bud stage after stress treatments. Microarray analysis showed that ambient dehydration stress accelerates many of the changes in gene expression patterns that would normally occur during developmental senescence. However, a higher proportion of gene expression changes in response to cold stress were specific to this stimulus and not senescence related. The expression of 21 transcription factors was characterized, showing that overlapping sets of regulatory genes are activated during developmental senescence and by different stresses

Understanding the context of balanced scorecard implementation: a hospital-based case study in pakistan

Background: As a response to a changing operating environment, healthcare administrators are implementing modern management tools in their organizations. The balanced scorecard (BSC) is considered a viable tool in high-income countries to improve hospital performance. The BSC has not been applied to hospital settings in low-income countries nor has the context for implementation been examined. This study explored contextual perspectives in relation to BSC implementation in a Pakistani hospital. Methods: Four clinical units of this hospital were involved in the BSC implementation based on their willingness to participate. Implementation included sensitization of units towards the BSC, developing specialty specific BSCs and reporting of performance based on the BSC during administrative meetings. Pettigrew and Whipp\u27s context (why), process (how) and content (what) framework of strategic change was used to guide data collection and analysis. Data collection methods included quantitative tools (a validated culture assessment questionnaire) and qualitative approaches including key informant interviews and participant observation.Results: Method triangulation provided common and contrasting results between the four units. A participatory culture, supportive leadership, financial and non-financial incentives, the presentation of clear direction by integrating support for the BSC in policies, resources, and routine activities emerged as desirable attributes for BSC implementation. The two units that lagged behind were more involved in direct inpatient care and carried a considerable clinical workload. Role clarification and consensus about the purpose and benefits of the BSC were noted as key strategies for overcoming implementation challenges in two clinical units that were relatively ahead in BSC implementation. It was noted that, rather than seeking to replace existing information systems, initiatives such as the BSC could be readily adopted if they are built on existing infrastructures and data networks. Conclusion: Variable levels of the BSC implementation were observed in this study. Those intending to apply the BSC in other hospital settings need to ensure a participatory culture, clear institutional mandate, appropriate leadership support, proper reward and recognition system, and sensitization to BSC benefits

Genome-wide association study with 1000 genomes imputation identifies signals for nine sex hormone-related phenotypes.

Genetic factors contribute strongly to sex hormone levels, yet knowledge of the regulatory mechanisms remains incomplete. Genome-wide association studies (GWAS) have identified only a small number of loci associated with sex hormone levels, with several reproductive hormones yet to be assessed. The aim of the study was to identify novel genetic variants contributing to the regulation of sex hormones. We performed GWAS using genotypes imputed from the 1000 Genomes reference panel. The study used genotype and phenotype data from a UK twin register. We included 2913 individuals (up to 294 males) from the Twins UK study, excluding individuals receiving hormone treatment. Phenotypes were standardised for age, sex, BMI, stage of menstrual cycle and menopausal status. We tested 7,879,351 autosomal SNPs for association with levels of dehydroepiandrosterone sulphate (DHEAS), oestradiol, free androgen index (FAI), follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin, progesterone, sex hormone-binding globulin and testosterone. Eight independent genetic variants reached genome-wide significance (P<5 × 10(-8)), with minor allele frequencies of 1.3-23.9%. Novel signals included variants for progesterone (P=7.68 × 10(-12)), oestradiol (P=1.63 × 10(-8)) and FAI (P=1.50 × 10(-8)). A genetic variant near the FSHB gene was identified which influenced both FSH (P=1.74 × 10(-8)) and LH (P=3.94 × 10(-9)) levels. A separate locus on chromosome 7 was associated with both DHEAS (P=1.82 × 10(-14)) and progesterone (P=6.09 × 10(-14)). This study highlights loci that are relevant to reproductive function and suggests overlap in the genetic basis of hormone regulation.We thank Roche Diagnostics Australia Pty Limited, Castle Hill, Australia, who provided support for the analysis of the hormones. We thank the volunteer twins for their participation in the study. Twins UK received funding support from NIHR Biomedical Research Centre (grant to Guys’ and St. Thomas’ Hospitals and King’s College London); the Chronic Disease Research Foundation; Canadian Institutes of Health Research, the Canadian Foundation for Innovation, the Fonds de la Recherche en Santé Québec, The Lady Davis Institute, the Jewish General Hospital and Ministère du Développement économique, de l'Innovation et de l'Exportation du Quebec. The Australian National Health and Medical Research Council (NHMRC project grants 1010494, 1048216), and Sir Charles Gairdner Hospital Research (grant PP2009/028). This work was supported by funding from the Wellcome Trust (092447/Z/10/Z) and Medical Research Council (MC_U106179472).This is the final version of the article. It first appeared from NPG via http://dx.doi.org/10.1038/ejhg.2015.10

Monitoring of post-match fatigue in professional soccer: Welcome to the real world

Participation in soccer match-play leads to acute and transient subjective, biochemical, metabolic and physical disturbances in players over subsequent hours and days. Inadequate time for rest and regeneration between matches can expose players to the risk of training and competing whilst not entirely recovered. In professional soccer, contemporary competitive schedules can require teams to compete in-excess of 60 matches over the course of the season while periods of fixture congestion occur prompting much attention from researchers and practitioners to the monitoring of fatigue and readiness to play. A comprehensive body of research has investigated post-match acute and residual fatigue responses. Yet the relevance of the research for professional soccer contexts is debatable notably in relation to the study populations and designs employed. Monitoring can indeed be invasive, expensive, time-inefficient and difficult to perform routinely and simultaneously in a large squad of regularly competing players. Uncertainty also exists regarding the meaningfulness and interpretation of changes in fatigue response values and their functional relevance, and practical applicability in the field. The real-world need and cost-benefit of monitoring must be carefully weighed up. In relation to professional soccer contexts, this opinion paper intends to: 1) debate the need for PMF monitoring, 2) critique the real-world relevance of the current research literature, 3) discuss the practical burden relating to measurement tools and protocols and the collection, interpretation and application of data in the field, and, 4) propose future research perspectives

Deficiency in Nucleotide Excision Repair Family Gene Activity, Especially ERCC3, Is Associated with Non-Pigmented Hair Fiber Growth

We conducted a microarray study to discover gene expression patterns associated with a lack of melanogenesis in non-pigmented hair follicles (HF) by microarray. Pigmented and non-pigmented HFs were collected and micro-dissected into the hair bulb (HB) and the upper hair sheaths (HS) including the bulge region. In comparison to pigmented HS and HBs, nucleotide excision repair (NER) family genes ERCC1, ERCC2, ERCC3, ERCC4, ERCC5, ERCC6, XPA, NTPBP, HCNP, DDB2 and POLH exhibited statistically significantly lower expression in non- pigmented HS and HBs. Quantitative PCR verified microarray data and identified ERCC3 as highly differentially expressed. Immunohistochemistry confirmed ERCC3 expression in HF melanocytes. A reduction in ERCC3 by siRNA interference in human melanocytes in vitro reduced their tyrosinase production ability. Our results suggest that loss of NER gene function is associated with a loss of melanin production capacity. This may be due to reduced gene transcription and/or reduced DNA repair in melanocytes which may eventually lead to cell death. These results provide novel information with regard to melanogenesis and its regulation

Molecular targets in the discovery and development of novel antimetastatic agents: current progress and future prospects

Tumour invasion and metastasis have been recognized as major causal factors in the morbidity and mortality among cancer patients. Many advances in the knowledge of cancer metastasis have yielded an impressive array of attractive drug targets, including enzymes, receptors and multiple signalling pathways. The present review summarizes the molecular pathogenesis of metastasis and the identification of novel molecular targets used in the discovery of antimetastatic agents. Several promising targets have been highlighted, including receptor tyrosine kinases, effector molecules involved in angiogenesis, matrix metalloproteinases (MMPs), urokinase plasminogen activator, adhesion molecules and their receptors, signalling pathways (e.g. phosphatidylinositol 3-kinase, phospholipase Cγ1, mitogen-activated protein kinases, c-Src kinase, c-Met kinases and heat shock protein. The discovery and development of potential novel therapeutics for each of the targets are also discussed in this review. Among these, the most promising agents that have shown remarkable clinical outcome are anti-angiogenic agents (e.g. bevacizumab). Newer agents, such as c-Met kinase inhibitors, are still undergoing preclinical studies and are yet to have their clinical efficacy proven. Some therapeutics, such as first-generation MMP inhibitors (MMPIs; e.g. marimastat) and more selective versions of them (e.g. prinomastat, tanomastat), have undergone clinical trials. Unfortunately, these drugs produced serious adverse effects that led to the premature termination of their development. In the future, third-generation MMPIs and inhibitors of signalling pathways and adhesion molecules could form valuable novel classes of drugs in the anticancer armamentarium to combat metastasis

Prostate cancer bone metastases promote both osteolytic and osteoblastic activity

Advanced prostate cancer is frequently accompanied by the development of metastasis to bone. In the past, prostate cancer bone metastases were characterized as being osteoblastic (i.e., increasing bone density) based on radiographs. However, emerging evidence suggests that development of prostate cancer bone metastases requires osteoclastic activity in addition to osteoblastic activity. The complexities of how prostate tumor cells influence bone remodeling are just beginning to be elucidated. Prostate cancer cells produce a variety of pro-osteoblastic factors that promote bone mineralization. For example, both bone morphogenetic proteins and endothelin-1 have well recognized pro-osteoblastic activities and are produced by prostate cancer cells. In addition to factors that enhance bone mineralization prostate cancer cells produced factors that promote osteoclast activity. Perhaps the most critical pro-osteoclastogenic factor produced by prostate cancer cells is receptor activator of NFΚB ligand (RANKL), which has been shown to be required for the development of osteoclasts. Blocking RANKL results in inhibiting prostate cancer-induced osteoclastogenesis and inhibits development and progression of prostate tumor growth in bone. These findings suggest that targeting osteoclast activity may be of therapeutic benefit. However, it remains to be defined how prostate cancer cells synchronize the combination of osteoclastic and osteoblastic activity. We propose that as the bone microenvironment is changed by the developing cancer, this in turn influences the prostate cancer cells' balance between pro-osteoclastic and pro-osteoblastic activity. Accordingly, the determination of how the prostate cancer cells and bone microenvironment crosstalk are important to elucidate how prostate cancer cells modulate bone remodeling. © 2003 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/34904/1/10662_ftp.pd