Evidence from many sources suggests that similar phenotypes are begotten by functionally related genes. This is most obvious in the case of genetically heterogeneous diseases such as Fanconi anemia, ...Bardet‐Biedl or Usher syndrome, where the various genes work together in a single biological module. Such modules can be a multiprotein complex, a pathway, or a single cellular or subcellular organelle. This observation suggests a number of hypotheses about the human phenome that are now beginning to be explored. First, there is now good evidence from bioinformatic analyses that human genetic diseases can be clustered on the basis of their phenotypic similarities and that such a clustering represents true biological relationships of the genes involved. Second, one may use such phenotypic similarity to predict and then test for the contribution of apparently unrelated genes to the same functional module. This concept is now being systematically tested for several diseases. Most recently, a systematic yeast two‐hybrid screen of all known genes for inherited ataxias indicated that they all form part of a single extended protein–protein interaction network. Third, one can use bioinformatics to make predictions about new genes for diseases that form part of the same phenotype cluster. This is done by starting from the known disease genes and then searching for genes that share one or more functional attributes such as gene expression pattern, coevolution, or gene ontology. Ultimately, one may expect that a modular view of disease genes should help the rapid identification of additional disease genes for multifactorial diseases once the first few contributing genes (or environmental factors) have been reliably identified.
Shoulder pain is the third most common musculoskeletal complaint in orthopedic practice. It is usually due to a defect of the rotator cuff and/or an impingement syndrome.
This review is based on ...pertinent literature retrieved by a selective search of the Medline database.
Patients with shoulder impingement syndrome suffer from painful entrapment of soft tissue whenever they elevate the arm. The pathological mechanism is a structural narrowing in the subacromial space. A multiplicity of potential etiologies makes the diagnosis more difficult; it is established by the history and physical examination and can be confirmed with x-ray, ultra - sonography, and magnetic resonance imaging. The initial treatment is conservative, e.g., with nonsteroidal antiinflammatory drugs, infiltrations, and patient exercises. Conservative treatment yields satisfactory results within 2 years in 60% of cases. If symptoms persist, decompressive surgery is performed as long as the continuity of the rotator cuff is preserved and there is a pathological abnormality of the bursa. The correct etiologic diagnosis and choice of treatment are essential for a good outcome. The formal evidence level regarding the best treatment strategy is low, and it has not yet been determined whether surgical or conservative treatment is better.
Randomized controlled therapeutic trials are needed so that a standardized treatment regimen can be established.
Background: The responsible genes have not yet been identified for many genetically mapped disease loci. Physically interacting proteins tend to be involved in the same cellular process, and ...mutations in their genes may lead to similar disease phenotypes. Objective: To investigate whether protein–protein interactions can predict genes for genetically heterogeneous diseases. Methods: 72 940 protein–protein interactions between 10 894 human proteins were used to search 432 loci for candidate disease genes representing 383 genetically heterogeneous hereditary diseases. For each disease, the protein interaction partners of its known causative genes were compared with the disease associated loci lacking identified causative genes. Interaction partners located within such loci were considered candidate disease gene predictions. Prediction accuracy was tested using a benchmark set of known disease genes. Results: Almost 300 candidate disease gene predictions were made. Some of these have since been confirmed. On average, 10% or more are expected to be genuine disease genes, representing a 10-fold enrichment compared with positional information only. Examples of interesting candidates are AKAP6 for arrythmogenic right ventricular dysplasia 3 and SYN3 for familial partial epilepsy with variable foci. Conclusions: Exploiting protein–protein interactions can greatly increase the likelihood of finding positional candidate disease genes. When applied on a large scale they can lead to novel candidate gene predictions.
Background: Walker-Warburg syndrome (WWS) is an autosomal recessive condition characterised by congenital muscular dystrophy, structural brain defects, and eye malformations. Typical brain ...abnormalities are hydrocephalus, lissencephaly, agenesis of the corpus callosum, fusion of the hemispheres, cerebellar hypoplasia, and neuronal overmigration, which causes a cobblestone cortex. Ocular abnormalities include cataract, microphthalmia, buphthalmos, and Peters anomaly. WWS patients show defective O-glycosylation of α-dystroglycan (α-DG), which plays a key role in bridging the cytoskeleton of muscle and CNS cells with extracellular matrix proteins, important for muscle integrity and neuronal migration. In 20% of the WWS patients, hypoglycosylation results from mutations in either the protein O-mannosyltransferase 1 (POMT1), fukutin, or fukutin related protein (FKRP) genes. The other genes for this highly heterogeneous disorder remain to be identified. Objective: To look for mutations in POMT2 as a cause of WWS, as both POMT1 and POMT2 are required to achieve protein O-mannosyltransferase activity. Methods: A candidate gene approach combined with homozygosity mapping. Results: Homozygosity was found for the POMT2 locus at 14q24.3 in four of 11 consanguineous WWS families. Homozygous POMT2 mutations were present in two of these families as well as in one patient from another cohort of six WWS families. Immunohistochemistry in muscle showed severely reduced levels of glycosylated α-DG, which is consistent with the postulated role for POMT2 in the O-mannosylation pathway. Conclusions: A fourth causative gene for WWS was uncovered. These genes account for approximately one third of the WWS cases. Several more genes are anticipated, which are likely to play a role in glycosylation of α-DG.
Angiotensin II receptor antagonists Burnier, M; Brunner, HR
The Lancet (British edition),
02/2000, Letnik:
355, Številka:
9204
Journal Article
Recenzirano
Blockade of the renin-angiotensin system began as a way of studying the pathogenesis of cardiovascular disease with specific pharmacological probes. Oral activity, achieved by shortening the original ...peptide structures, transformed the probes into therapeutic agents, the angiotensin-converting enzyme (ACE) inhibitors. However, ACE is a non-specific target for blocking the renin-angiotensin enzymatic cascade. The availability of orally active drugs turned ACE inhibition into a therapeutic breakthrough but more specific blockade always seemed desirable. This goal has now been achieved with the orally active angiotensin II receptor antagonists; six are on the market and more are under development. This new class of drugs is equal in efficacy to ACE inhibitors, at least in hypertensive patients. Trials now underway will demonstrate whether angiotensin II receptor antagonists can prevent target-organ damage and reduce cardiovascular morbidity and mortality. If they do, these compounds might one day replace ACE inhibitors.
ABSTRACT The COSMOS-Legacy survey is a 4.6 Ms Chandra program that has imaged 2.2 deg2 of the COSMOS field with an effective exposure of ks over the central 1.5 deg2 and of ks in the remaining area. ...The survey is the combination of 56 new observations obtained as an X-ray Visionary Project with the previous C-COSMOS survey. We describe the reduction and analysis of the new observations and the properties of 2273 point sources detected above a spurious probability of 2 × 10−5. We also present the updated properties of the C-COSMOS sources detected in the new data. The whole survey includes 4016 point sources (3814, 2920 and 2440 in the full, soft, and hard band). The limiting depths are 2.2 × 10−16, 1.5 × 10−15, and 8.9 × 10−16 in the 0.5-2, 2-10, and 0.5-10 keV bands, respectively. The observed fraction of obscured active galactic nuclei with a column density >1022 cm−2 from the hardness ratio (HR) is ∼50 %. Given the large sample we compute source number counts in the hard and soft bands, significantly reducing the uncertainties of 5%-10%. For the first time we compute number counts for obscured (HR > −0.2) and unobscured (HR < −0.2) sources and find significant differences between the two populations in the soft band. Due to the unprecedent large exposure, COSMOS-Legacy area is three times larger than surveys at similar depths and its depth is three times fainter than surveys covering similar areas. The area-flux region occupied by COSMOS-Legacy is likely to remain unsurpassed for years to come.
•First paper on the importance of incineration from a urban metabolism point of view.•Proves that incineration is necessary for sustainable waste management.•Historical and technical overview of ...100years development of MSW incineration.
Human activities inevitably result in wastes. The higher the material turnover, and the more complex and divers the materials produced, the more challenging it is for waste management to reach the goals of “protection of men and environment” and “resource conservation”. Waste incineration, introduced originally for volume reduction and hygienic reasons, went through a long and intense development. Together with prevention and recycling measures, waste to energy (WTE) facilities contribute significantly to reaching the goals of waste management. Sophisticated air pollution control (APC) devices ensure that emissions are environmentally safe. Incinerators are crucial and unique for the complete destruction of hazardous organic materials, to reduce risks due to pathogenic microorganisms and viruses, and for concentrating valuable as well as toxic metals in certain fractions. Bottom ash and APC residues have become new sources of secondary metals, hence incineration has become a materials recycling facility, too. WTE plants are supporting decisions about waste and environmental management: They can routinely and cost effectively supply information about chemical waste composition as well as about the ratio of biogenic to fossil carbon in MSW and off-gas.
ABSTRACT We construct the rest-frame 2-10 keV intrinsic X-ray luminosity function (XLF) of active galactic nuclei (AGNs) from a combination of X-ray surveys from the all-sky Swift BAT survey to the ...Chandra Deep Field South. We use ∼3200 AGNs in our analysis, which covers six orders of magnitude in flux. The inclusion of XMM and Chandra COSMOS data has allowed us to investigate the detailed behavior of the XLF and evolution. In deriving our XLF, we take into account realistic AGN spectrum templates, absorption corrections, and probability density distributions in photometric redshift. We present an analytical expression for the overall behavior of the XLF in terms of the luminosity-dependent density evolution, smoothed two-power-law expressions in 11 redshift shells, three-segment power-law expression of the number density evolution in four luminosity classes, and binned XLF. We observe a sudden flattening of the low luminosity end slope of the XLF slope at z 0.6. Detailed structures of the AGN downsizing have also been revealed, where the number density curves have two clear breaks at all luminosity classes above . The two-break structure is suggestive of two-phase AGN evolution, consisting of major merger triggering and secular processes.
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