Clinical anticancer drug development: targeting the cyclin-dependent kinases

Cell division involves a cyclical biochemical process composed of several step-wise reactions that have to occur once per cell cycle. Dysregulation of cell division is a hallmark of all cancers. Genetic and epigenetic mechanisms frequently result in deranged expression and/or activity of cell-cycle proteins including the cyclins, cyclin-dependent kinases (Cdks), Cdk inhibitors and checkpoint control proteins. The critical nature of these proteins in cell cycling raises hope that targeting them may result in selective cytotoxicity and valuable anticancer activity

Asteroseismology and Interferometry

Asteroseismology provides us with a unique opportunity to improve our understanding of stellar structure and evolution. Recent developments, including the first systematic studies of solar-like pulsators, have boosted the impact of this field of research within Astrophysics and have led to a significant increase in the size of the research community. In the present paper we start by reviewing the basic observational and theoretical properties of classical and solar-like pulsators and present results from some of the most recent and outstanding studies of these stars. We centre our review on those classes of pulsators for which interferometric studies are expected to provide a significant input. We discuss current limitations to asteroseismic studies, including difficulties in mode identification and in the accurate determination of global parameters of pulsating stars, and, after a brief review of those aspects of interferometry that are most relevant in this context, anticipate how interferometric observations may contribute to overcome these limitations. Moreover, we present results of recent pilot studies of pulsating stars involving both asteroseismic and interferometric constraints and look into the future, summarizing ongoing efforts concerning the development of future instruments and satellite missions which are expected to have an impact in this field of research.Comment: Version as published in The Astronomy and Astrophysics Review, Volume 14, Issue 3-4, pp. 217-36

Synaptic Reorganization in the Adult Rat's Ventral Cochlear Nucleus following Its Total Sensory Deafferentation

Ablation of a cochlea causes total sensory deafferentation of the cochlear nucleus in the brainstem, providing a model to investigate nervous degeneration and formation of new synaptic contacts in the adult brain. In a quantitative electron microscopical study on the plasticity of the central auditory system of the Wistar rat, we first determined what fraction of the total number of synaptic contact zones (SCZs) in the anteroventral cochlear nucleus (AVCN) is attributable to primary sensory innervation and how many synapses remain after total unilateral cochlear ablation. Second, we attempted to identify the potential for a deafferentation-dependent synaptogenesis. SCZs were ultrastructurally identified before and after deafferentation in tissue treated for ethanolic phosphotungstic acid (EPTA) staining. This was combined with pre-embedding immunocytochemistry for gephyrin identifying inhibitory SCZs, the growth-associated protein GAP-43, glutamate, and choline acetyltransferase. A stereological analysis of EPTA stained sections revealed 1.11±0.09 (S.E.M.)×109 SCZs per mm3 of AVCN tissue. Within 7 days of deafferentation, this number was down by 46%. Excitatory and inhibitory synapses were differentially affected on the side of deafferentation. Excitatory synapses were quickly reduced and then began to increase in number again, necessarily being complemented from sources other than cochlear neurons, while inhibitory synapses were reduced more slowly and continuously. The result was a transient rise of the relative fraction of inhibitory synapses with a decline below original levels thereafter. Synaptogenesis was inferred by the emergence of morphologically immature SCZs that were consistently associated with GAP-43 immunoreactivity. SCZs of this type were estimated to make up a fraction of close to 30% of the total synaptic population present by ten weeks after sensory deafferentation. In conclusion, there appears to be a substantial potential for network reorganization and synaptogenesis in the auditory brainstem after loss of hearing, even in the adult brain

Lifestyle factors and primary glioma and meningioma tumours in the Million Women Study cohort

Previous studies have reported inconsistent results on the effect of anthropometric and lifestyle factors on the risk of developing glioma or meningioma tumours. A prospective cohort of 1.3 million middle-aged women was used to examine these relationships. During 7.7 million women-years of follow-up, a total of 1563 women were diagnosed with a primary incident central nervous system tumour: 646 tumours were classified as glioma and 390 as meningioma. Our results show that height is related to the incidence of all central nervous system tumours with a risk of about 20% per 10 cm increase in height (relative risk=1.19, 95% CI=1.10–1.30 per 10 cm increase in height, P<0.001): the risks did not differ significantly between specified glioma and meningioma. Body mass index (BMI) was also related to central nervous system tumour incidence, with a risk of about 20% per 10 kg m−2 increase in BMI (relative risk=1.17, 95% CI=1.03–1.34 per 10 kg m−2 increase in BMI, P=0.02). Smoking status, alcohol intake, socioeconomic level, parity, age at first birth, and oral contraceptive use were not associated with the risk of glioma or meningioma tumours. In conclusion, for women in the United Kingdom, the incidence of glioma or meningioma tumours increases with increasing height and increasing BMI

Molecular mechanisms of glucocorticoids action: implications for treatment of rhinosinusitis and nasal polyposis

Intra-nasal glucocorticoids are the most effective drugs available for rhinosinusitis and nasal polyposis treatment. Their effectiveness depends on many factors and not all of them have been well recognized so far. The authors present the basic information on molecular mechanisms of glucocorticoid action, direct and indirect effects of glucocorticoids on transcription of genes encoding inflammatory mediators. They focus on recently proved nongenomic mechanisms which appear quickly, from several seconds to minutes after glucocorticoid administration and discuss clinical implications resulting from this knowledge. Discovery of nongenomic glucocorticoid actions allows for better use of these drugs in clinical practice

Integrative care for the management of low back pain: use of a clinical care pathway

<p>Abstract</p> <p>Background</p> <p>For the treatment of chronic back pain, it has been theorized that integrative care plans can lead to better outcomes than those achieved by monodisciplinary care alone, especially when using a collaborative, interdisciplinary, and non-hierarchical team approach. This paper describes the use of a care pathway designed to guide treatment by an integrative group of providers within a randomized controlled trial.</p> <p>Methods</p> <p>A clinical care pathway was used by a multidisciplinary group of providers, which included acupuncturists, chiropractors, cognitive behavioral therapists, exercise therapists, massage therapists and primary care physicians. Treatment recommendations were based on an evidence-informed practice model, and reached by group consensus. Research study participants were empowered to select one of the treatment recommendations proposed by the integrative group. Common principles and benchmarks were established to guide treatment management throughout the study.</p> <p>Results</p> <p>Thirteen providers representing 5 healthcare professions collaborated to provide integrative care to study participants. On average, 3 to 4 treatment plans, each consisting of 2 to 3 modalities, were recommended to study participants. Exercise, massage, and acupuncture were both most commonly recommended by the team and selected by study participants. Changes to care commonly incorporated cognitive behavioral therapy into treatment plans.</p> <p>Conclusion</p> <p>This clinical care pathway was a useful tool for the consistent application of evidence-based care for low back pain in the context of an integrative setting.</p> <p>Trial registration</p> <p>ClinicalTrials.gov NCT00567333</p

Restaurant outbreak of Legionnaires' disease associated with a decorative fountain: an environmental and case-control study

BACKGROUND: From June to November 2005, 18 cases of community-acquired Legionnaires' disease (LD) were reported in Rapid City South Dakota. We conducted epidemiologic and environmental investigations to identify the source of the outbreak. METHODS: We conducted a case-control study that included the first 13 cases and 52 controls randomly selected from emergency department records and matched on underlying illness. We collected information about activities of case-patients and controls during the 14 days before symptom onset. Environmental samples (n = 291) were cultured for Legionella. Clinical and environmental isolates were compared using monoclonal antibody subtyping and sequence based typing (SBT). RESULTS: Case-patients were significantly more likely than controls to have passed through several city areas that contained or were adjacent to areas with cooling towers positive for Legionella. Six of 11 case-patients (matched odds ratio (mOR) 32.7, 95% CI 4.7-infinity) reported eating in Restaurant A versus 0 controls. Legionella pneumophila serogroup 1 was isolated from four clinical specimens: 3 were Benidorm type strains and 1 was a Denver type strain. Legionella were identified from several environmental sites including 24 (56%) of 43 cooling towers tested, but only one site, a small decorative fountain in Restaurant A, contained Benidorm, the outbreak strain. Clinical and environmental Benidorm isolates had identical SBT patterns. CONCLUSION: This is the first time that small fountain without obvious aerosol-generating capability has been implicated as the source of a LD outbreak. Removal of the fountain halted transmission

Structural variation in the chicken genome identified by paired-end next-generation DNA sequencing of reduced representation libraries

<p>Abstract</p> <p>Background</p> <p>Variation within individual genomes ranges from single nucleotide polymorphisms (SNPs) to kilobase, and even megabase, sized structural variants (SVs), such as deletions, insertions, inversions, and more complex rearrangements. Although much is known about the extent of SVs in humans and mice, species in which they exert significant effects on phenotypes, very little is known about the extent of SVs in the 2.5-times smaller and less repetitive genome of the chicken.</p> <p>Results</p> <p>We identified hundreds of shared and divergent SVs in four commercial chicken lines relative to the reference chicken genome. The majority of SVs were found in intronic and intergenic regions, and we also found SVs in the coding regions. To identify the SVs, we combined high-throughput short read paired-end sequencing of genomic reduced representation libraries (RRLs) of pooled samples from 25 individuals and computational mapping of DNA sequences from a reference genome.</p> <p>Conclusion</p> <p>We provide a first glimpse of the high abundance of small structural genomic variations in the chicken. Extrapolating our results, we estimate that there are thousands of rearrangements in the chicken genome, the majority of which are located in non-coding regions. We observed that structural variation contributes to genetic differentiation among current domesticated chicken breeds and the Red Jungle Fowl. We expect that, because of their high abundance, SVs might explain phenotypic differences and play a role in the evolution of the chicken genome. Finally, our study exemplifies an efficient and cost-effective approach for identifying structural variation in sequenced genomes.</p

Number of addictive substances used related to increased risk of unnatural death: A combined medico-legal and case-record study

<p>Abstract</p> <p>Background</p> <p>Substance use disorders have repeatedly been found to lead to premature death, i.e. drug-related death by disease, fatal intoxications, or trauma (accidents, suicide, undetermined suicide, and homicide). The present study examined the relationship between multi-drug substance use and natural and unnatural death.</p> <p>Methods</p> <p>All consecutive, autopsied patients who had been in contact with the Addiction Centre in Malmö University Hospital from 1993 to 1997 inclusive were investigated. Drug abuse was investigated blindly in the case records and related to the cause of death in 387 subjects.</p> <p>Results</p> <p>Every substance apart from alcohol used previously in life added to the risk of unnatural death in a linear way. There were independent increased risks of fatal heroin overdoses or undetermined suicide. Death by suicide and violent death were unrelated to additional abuse.</p> <p>Conclusion</p> <p>The number of drugs used was related to an increased risk of unnatural death by undetermined suicide (mainly fatal intoxications) and heroin overdose.</p