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Pharmacogenetics of the vitamin D receptor and osteoporosis.

Osteoporosis is a major health care problem internationally with important implications for health care costs, morbidity, and mortality. Bone density, an important predictor of osteoporotic fracture risk, is affected by hormonal and environmental factors. However, in twin and family studies most of its age-specific variance is genetically determined. Common allelic variations in the vitamin D receptor (VDR) gene were the first to be linked to bone density. Recently, other candidate genes, notably oestrogen receptor, collagen 1alphaI, and PTH receptor genes and a chromosome 11 locus, have been associated with bone density and fracture. Polymorphisms in adjacent regulatory regions may be important mechanisms since functional coding region mutations have not been defined. For example, the polymorphic region in the collagen 1alphaI gene alters a SpI binding site and may alter collagen gene expression. At the pharmacogenetic level, VDR alleles predict differences in gut calcium absorption and long-term bone density response to calcium intake and active vitamin D analog treatment. Understanding the mechanisms underlying these allelic differences in relation to diet and lifestyle factors as well as response to therapy could aid selection of optimal therapy for osteoporosis prevention and treatment.

Alleles↗

[Ostium of maxillary sinus in endoscopic sinus surgery].

OBJECTIVE: To determine the clinical significance and operative method of maxillary sinus ostium in the treatment of chronic sinusitis and nasal polyps. METHODS: Fifty-six patients (112 sides) undergone endoscopic sinus surgery were studied. RESULTS: The patency rates of the maxillary ostia in patients with enlarged and unchanged maxillary ostia were 92.9% and 80.4% respectively. Fifty-one patients (64 sides) undergone Caldwell-Luc operations were retrospectively studied. The patency rate of inferior antrostomy was 40.6%. CT scans of the sinuses of 38 cases with unilateral sinisitis or nasal polyps were reviewed. The scaled values of the maxillary hiatus on CT images showed no difference between the normal group and the diseased group. Pneumatization and proliferation of middle turbinate and bent uncinate process were the most common anatomic variation in the diseased group. CONCLUSION: The results suggest that management of anatomic variations surrounding the ostia is very important in the treatment of maxillary ostium.

Adolescent↗

Common guidelines and equitable service: variation between adjacent districts regarding admissions to elderly care institutions.

With the increasing number of older people, the cost of providing institutional care has become a major issue. In 1993 the introduction of care management and a needs-led approach aimed to remove the existing 'perverse incentive' to institutional care and to ensure equality in the dependency levels of those who were admitted to care. To test this consistency, we examined the dependency levels of all persons aged > or = 65 years admitted to residential and nursing homes in two adjacent Health and Social Services (HSS) Community Trusts in Belfast, Northern Ireland, in the year following the introduction of care management. We measured differences between the Trusts with respect to number of admissions, levels of dependency as determined by several standard scoring systems, financial support, source of admission and demographic information. A total of 389 people were surveyed. Trust A had significantly higher levels of physical dependency and mental impairment in both residential and nursing homes than Trust B. We also identified differences in dependency with respect to funding status, with those who were self-funding in Trust B having lower physical dependency in residential and nursing homes and less mental impairment in nursing homes than supplemented residents. This study reports the existence of variations between adjacent Community Trusts operating under the same policy guidelines with respect to the dependency levels of admissions to residential and nursing care. These differences may relate to number of places available, the economic status of the population, and the assessment procedures of the two Community Trusts. The need for standard assessment and eligibility criteria is highlighted.

Aged↗

[Role of hemostatic markers in the pathogenesis of coronary diseases].

The underlying processes that lead to atheroma formation and coronary thrombosis are complex and still incompletely understood. There is a growing interest in defining a possible role of haemostatic markers for atherothrombotic risk. There is a large body of literature concerned with common genetic variations within genes of haemostatic factors, their plasma levels, and how they might influence the development of arterial thrombotic diseases. The aim of this review is to assess our current state of knowledge on this topic.

Biomarkers↗

Severe acute respiratory syndrome-associated coronavirus genotype and its characterization.

OBJECTIVE: To study the severe acute respiratory syndrome (SARS)-associated coronavirus genotype and its characteristics. METHODS: A SARS-associated coronavirus isolate named ZJ01 was obtained from throat swab samples taken from a patient in Hangzhou, Zhejing province. The complete genome sequence of ZJ01 consisted of 29,715 bp (GenBank accession: AY297028, version: gi: 30910859). Seventeen SARS-associated coronavirus genome sequences in GenBank were compared to analyze the common sequence variations and the probability of co-occurrence of multiple polymorphisms or mutations. Phylogenetic analysis of those sequences was done. RESULTS: By bioinformatics processing and analysis, the 5 loci nucleotides at ZJ01 genome were found being T, T, G, T and T, respectively. Compared with other SARS-associated coronavirus genomes in the GenBank database, an A/G mutation was detected besides the other 4 mutation loci (C:G:C:C/T:T:T:T) involved in this genetic signature. Therefore a new definition was put forward according to the 5 mutation loci. SARS-associated coronavirus strains would be grouped into two genotypes (C:G:A:C:C/T:T:G:T:T), and abbreviated as SARS coronavirus C genotype and T genotype. On the basis of this new definition, the ZJ01 isolate belongs to SARS-associated coronavirus T genotype, first discovered and reported in mainland China. Phylogenetic analysis of the spike protein gene fragments of these SARS-associated coronavirus strains showed that the GZ01 isolate was phylogenetically distinct from other isolates, and compared with groups F1 and F2 of the T genotype, the isolates of BJ01 and CUHK-W1 were more closely related to the GZ01 isolate. It was interesting to find that two (A/G and C/T) of the five mutation loci occurred in the spike protein gene, which caused changes of Asp to Gly and Thr to Ile in the protein, respectively. CONCLUSION: Attention should be paid to whether these genotype and mutation patterns are related to the virus's biological activities,epidemic characteristics and host clinical symptoms.

Genotype↗

Sports vision and the high school student athlete.

Thorough sports vision evaluations (SVE) utilizing a 30-test battery of established sports vision tests, variations of commonly accepted procedures, and newly designed instruments and/or methods were performed by the Wisconsin Sports Vision Project (WSVP) staff on 232 teenage male and female high school student athletes. Tests are described and results reveal that a state tournament qualifying girls volleyball team (n = 8) demonstrated significantly better visual skills and abilities than 1) the male and female general high school athlete sample (n = 224), 2) the female athlete sample (n = 78), and 3) the other female volleyball players in the sample (n = 46) in some areas of dominant eye vision contrast sensitivity, distance judgement, dynamic visual acuity, tachistoscopic skills, low light and glare-affected vision.

Adolescent↗

[Principles of the acoustic communication between humans and birds].

We analyzed the mechanism of alarm call generation in various bird species, species-specific calls in closely related species, and intraspecific differences in calls. Production of these signals proved to rely on common mechanism: variation of temporal indices within the frequency range limited by morphological structures of the vocal apparatus. These mechanisms underlie development of acoustic synthesizers mediating communication with birds and control of their behavior. The obtained data are discussed in terms of these signals processing by the auditory system of birds.

Acoustics↗

Greater hepatic vulnerability after alcohol intake in African Americans compared with Caucasians: a population-based study.

AIMS OF THE STUDY: In the last 40 years, African Americans have experienced higher age-adjusted liver cirrhosis mortality rates than whites. Alcohol use has been hypothesized to be the likely determinant of this disparity in liver disease mortality. This study was aimed at evaluating racial variations in common biomarkers of liver injury, such as gamma-glutamyltransferase (GGT), aspartate amino transferase (AST) and alanine amino transferase (ALT), by categories of drinking status and levels of current alcohol use. METHODS: A cross-sectional analysis of a general population sample of 3304 residents of Erie and Niagara counties in New York State, 35-80 years of age and free from known hepatic disease, stratified by racial group (African-American and white). RESULTS: Concentrations of GGT were higher for African-Americans than for whites in all categories of drinking status (lifetime abstainers, former and current drinkers) after adjustment for potential confounders (age, sex, education, smoking, and body mass index). However, differences in enzyme mean values between the two racial groups were consistently larger among current drinkers than for either lifetime abstainers or former drinkers. In analyses based on tertiles of alcohol consumption in the last 30 days, differences in GGT mean values between the two races tended to amplify with increasing amounts of consumption. CONCLUSIONS: These findings seem to support the hypothesis of greater sensitivity to alcohol-induced hepatotoxicity among African-Americans than for whites.

Adult↗

Plasmid-mediated multiple antibiotic resistance in Proteus mirabilis isolated from patients with urinary tract infection.

BACKGROUND: Worldwide surveillance of antimicrobial resistance among urinary tract pathogens is useful to determine important trends and geographical variation for common Gram negative and positive species. We initiated this study to learn the drug resistance pattern and its location (genomic or plasmid-borne) among the strains of Proteus mirabilis, one of the most common causative agents of urinary tract infection (UTI). MATERIAL/METHODS: A total of 200 urine samples were collected from UTI patients, followed by isolation and identification of Proteus milabilis strains. Antibiotic sensitivity and resistance analysis was performed by the disc diffusion method, employing multiple antibiotic discs. The sensitivity was monitored by visualizing the zone of inhibition around the disc. Plasmid isolation was performed by the method of Kado and Liu. Transfer of the R-Plasmid to recipient E.coli C600 cells was achieved using the method of Lederberg and Cohen. RESULTS: Clinical study revealed that this infection is more common in young pregnant women. Various strains of Proteus mirabilis isolated during the course of the study were found to show multiple antibiotic resistance, which was further characterized as plasmid-borne drug resistance. CONCLUSIONS: Proteus mirabilis is one of the important causative agents of urinary tract infection in young women especially during the state of pregnancy. Multiple antibiotic resistance markers of Proteus strains were identified as plasmid mediated.

Adolescent↗

Aggressive forms of non-Hodgkin's lymphoma in two patients bearing coinfection of Epstein-Barr and hepatitis C viruses.

Although epidemiologic and experimental data suggest an etiopathogenetic role for both hepatitis C virus (HCV) and Epstein-Barr virus (EBV) infection in development of B-cell non-Hodgkin's lymphoma (NHL), potential interactions between EBV and HCV during progression of B-cell NHL have not yet been fully investigated. In the present study, tumor biopsy specimens from patients with both B-cell NHL and chronic HCV infection (HCV(+)) were analyzed for the presence of EBV-encoded RNA (EBER) by in situ hybridization (ISH). VH and VL gene segments were amplified from tumor biopsy specimen DNA by PCR. EBV infection (EBV(+)) was detected in tumors from 2 of 31 (6%) HCV(+) B-cell NHL patients. Clinical histories of these two EBV(+)/HCV(+) B-cell NHL patients indicated a particularly aggressive course of disease. Chemotherapy failed to induce long lasting remission for either of these EBV(+)/HCV(+) B-cell NHL patients. Amplification of CDR3 of the Ig heavy chain gene from DNA isolated from each EBV(+)/HCV(+) B-cell NHL indicated the presence of monoclonal B-cell expansion. Rearrangement of Ig genes in neoplastic B-cell clones from both EBV(+)/HCV(+) patients was similar to that previously reported for EBV(-)/HCV(+) B-cell NHL patients. Additionally, neoplastic B-cell clones from these two EBV(+)/HCV(+) B-cell NHL patients did not exhibit intraclonal variation. Previous studies have demonstrated that intraclonal variation is common among neoplastic B-cell clones from EBV(-)/HCV(+) patients. EBV infection may have prevented evolution of variant neoplastic B-cell clones by suppressing antibody affinity maturation. Together, these data suggest that EBV infection may cooperate with HCV infection during progression of B-cell NHL in immunocompetent individuals. Such an interaction may accelerate the course of disease in B-cell NHL patients.

Aged↗

Individualized immunosuppression: new strategies from pharmacokinetics, pharmacodynamics and pharmacogenomics.

BACKGROUND: The ultimate goal of transplantation is the donor-specific immune tolerance, but at least in the first 15 to 20 years of this century, immunosuppressive agents are still the determinant of clinical outcome of transplant recipients. Individualizing patient's immunosuppression to optimize the balance between therapeutic efficacy and the occurrence of adverse events poses a great challenge to physicians. DATA SOURCES: The data in this article were taken mostly from MEDLINE (2000-2004), part of which were from the research of the authors. RESULTS: Individualized immunosuppression remains a problem because of the narrow therapeutic index and wide inter- and intra-patient variation of commonly used immunosuppressants. Recent progress in study of pharmacokinetics and pharmacodynamics improved the clinical outcome of transplant recipients. More importantly, the emergence of pharmacogenomics might provide a promising and complementary tool for traditional therapeutic drug monitoring (TDM). CONCLUSIONS: Individualizing organ recipient's immunosuppression to balance the therapeutic efficacy and the adverse events represents a great challenge to transplant clinicians. Pharmacogenomics shows great promise for an interesting and hopefully better future.

Humans↗

Clinical placements in residential aged care facilities: the impact on nursing students' perception of aged care and the effect on career plans.

OBJECTIVES: Undergraduate nursing students have often found clinical placements in aged care unsatisfactory and/or unsettling, dissuading them from considering aged care as an employment option on graduation. This study asked which elements of the clinical placement experience produced that outcome; and what changes could yield more positive outcomes. DESIGN: A descriptive qualitative pilot study was carried out in late 2003. A combination of nominal groups and semi-structured interviews was used with students and experienced nurses to identify commonalities and variations in issues nominated as important and in the views expressed on those issues. Transcripts were independently analysed by two experienced investigators. Themes identified were discussed among the researchers. SUBJECTS: Fourteen volunteer undergraduate nursing students, all of whom had completed clinical placements in residential care and some of whom had prior experience in such facilities, participated in the nominal groups. Twelve registered nurses who had acted as clinical teachers in aged care facilities were interviewed. RESULTS: Perceived issues included: unexamined assumptions about nursing's core skills; lack of pre-placement orientation to the residential care environment; the appeal of and apprehension aroused by autonomous practice; and status, income and career progression considerations. CONCLUSIONS: Analysis of the sometimes ambivalent and conflicting views expressed pointed to possible changes, all within the domain of training and employing institutions, capable of bringing submerged issues to the surface for examination and resolution as part of raising student understanding of gerontology as a demanding specialty and residential care as a rewarding career.

Attitude of Health Personnel↗

[Regulation of the tracheobronchial and lung vascular system: innervation and receptors].

The regulation of airway smooth muscle shows species variation. The common embryologic origin of the lung and the gut is evidenced by the fact that the morphology and function of innervation, ganglion cell population, smooth muscle cells and receptors are similar to analogous structures in the gastrointestinal tract. Human airway smooth muscle possesses the following anatomic, morphologic and functional characteristics: cholinergic excitatory nerves, non-adrenergic non-cholinergic (NANC) inhibitor nerves, non-cholinergic non-adrenergic excitatory nerves, no adrenergic nerves, an ultrastructural morphology of the ganglia, similar to the one in the gastro intestinal tract, smooth muscle cell-to-cell connection of the gap junction or nexus type, a possible spontaneous myogenic activity, Beta-2-receptors with inhibitory effect and Alpha-1-receptors with excitatory effect. The pulmonary vascular bed is a low pressure system. Pulmonary vascular tone is influenced and probably regulated by multiple neurohumoral factors. These include the autonomic nervous system and a variety of vasoactive peptides and lipides. The autonomic neurogenic influences include the alpha- and beta-adrenergic and cholinergic components, as well as a third, non-adrenergic non-cholinergic component which may be mediated by the neuropeptide Vasoactive Intestinal Polypeptide (VIP). Lung peptides - some present in neuroendocrine cells - have potent actions (relaxation or constriction) on pulmonary vessels and may participate in regulating vascular tone. Leukotriens and other biological active lipides generally constrict pulmonary vessel and promote microvascular permeability.

Adrenergic Fibers↗

The effects of combinations of the recombinant growth factors GM-CSF, G-CSF, IL-3, and CSF-1 on leukemic blast cells in suspension culture.

The blast cells of acute myeloblastic leukemia may be considered as a renewal population maintained by stem cells that are capable of both self-renewal and differentiation. Blast stem cells grow in culture usually when stimulated by growth factors normally active on myelopoietic cells. Two culture methods permit an evaluation of the balance between self-renewal and differentiation; previous studies have shown that this balance can be affected by recombinant growth factors. These include interleukin 3 (IL-3) and granulocyte-macrophage colony stimulating factor (GM-CSF), active on early cells in normal myelopoiesis, and G-CSF and CSF-1, restricted in normal hemopoiesis to the granulopoietic and macrophage/monocytic lineages, respectively. In this paper we report the results of evaluating the effects on these recombinant growth factors alone or in mixtures of two at optimal concentrations. The results were obtained either using titrations of colony formation in methylcellulose or growth in suspension. Star diagrams, a technique from exploratory data analysis, were used to provide quantitative and graphic displays of the results of the recombinant factors on the balance between blast self-renewal and differentiation. Blasts from 4 acute myeloblastic leukemia patients and one patient with the blast crisis of chronic myeloblastic leukemia were examined in detail. The great patient-to-patient variation usually observed was seen in both plating efficiency in methylcellulose and growth pattern in suspension. In spite of this variation, a common pattern of response to growth factors emerged. When the early acting factors, IL-3 and GM-CSF, were combined, the effect was quantitatively and qualitatively similar to the largest stimulation seen with either of the factors alone. In contrast, late-acting factors, G-CSF and CSF-1, influenced each other's effects when present together and each affected the activities of GM-CSF and IL-3. Notably, CSF-1, which often led to the accumulation of adherent, terminal cells in suspension, usually maintained or increased this differentiation-like activity in combination. G-CSF also favored differentiation in combination, although the effect was usually to increase the number of colonies in methylcellulose, most of which consist of blast cells incapable of further divisions. The results are discussed as they relate to the postulated structure of the blast population and the normal targets of the recombinant growth factors.

Cell Differentiation↗

Eccrine sweat gland reaction. A histological and immunocytochemical study.

Secondary alteration of eccrine sweat glands is frequent in neoplastic and inflammatory skin diseases. The histological changes are characterized by a remarkable variability. However, a systematic classification of these reactions does not exist. We examined routine histological sections of biopsy specimens and found morphological alterations of eccrine sweat gland in the secretory coil, the duct, and the surrounding connective tissue. Dilation with or without retention was the most common histological variation seen in the secretory segments and the ducts. In association with dilation, flattening of the secretory and ductal cells occurs. Other cell changes were hydropic alteration and vacuolization of the secretory cells; seldom was a thickening of the cuticle observed. A striking phenomenon was the proliferation of ductal epithelium in different skin tumors. We found histological changes of the surrounding connective tissue less frequently: marked periglandular fibrosis and mucinous degeneration occurred.

Biopsy↗

Inference based on type II censored samples.

A method for drawing inferences about the mean of a normal population from small censored samples is discussed. The modified standardized statistic presented takes into account the correlation between the estimates of the mean and standard deviation and thus gives asymmetrical confidence intervals in contrast to the common standardized variate. A bias correction is suggested which improves the performance of the proposed statistic for small samples.

Biometry↗

Oligosaccharide structures of human colonic mucin.

Purified human colonic mucin was separated into six distinct components by DEAE-cellulose chromatography, and the structures of oligosaccharide side chains from the three most abundant species were determined. Oligosaccharide side chains were isolated from colonic mucin species III, IV, and V after alkaline borohydride reductive cleavage in the presence of sodium borotritide. After initial separation of acidic and neutral oligosaccharides by ion exchange chromatography, individual oligosaccharides were isolated by sequential chromatography on Bio-Gel P-4 and Bio-Gel P-2 resins followed by preparative normal phase high performance liquid chromatography. Composition and structure of individual oligosaccharides were determined by combination of gas chromatography, methylation analysis, and sequential glycosidase digestion. Collectively, 21 discrete oligosaccharide structures were identified in the major human colonic mucin species including 10 acidic oligosaccharides and 11 neutral structures which ranged in size from 2 to 12 sugar residues. Although detailed structures were defined for each oligosaccharide, the majority of the structures identified were variations of a relatively small number of "basic" structures, and several generalizations pertained. First, many oligosaccharides represented variations of a biantennary structure in which branch chains arise in N-acetylglucosaminyl residues linked to C3 and C6 of a galactosyl residue linked in turn to a GlcNAc beta (1-3)GalNAc core; second, non-branched oligosaccharides appeared to be linear chain derivatives of the same core structure; third, all acidic oligosaccharides could be derived from neutral structures present in the mucin species; fourth, sialic acid substitution was limited to few sites and always included substitution in alpha 2-6 linkage to the reducing terminal N-acetylgalactosamine, and finally several structures contained both sialic acid and fucose residues. Individually, mucin species III, IV, and V were found to contain unique mixtures of 13, 14, and 10 oligosaccharide structures, respectively. These data demonstrate that human colonic mucin contain a wide range of oligosaccharides reflecting variations of common core oligosaccharide structures. The major chromatographically defined constituents of normal colonic mucin appear to possess characteristic and distinguishable combinations of oligosaccharide structures. These findings support the concept that colonic mucin contains structurally and functionally distinct subpopulations.

Carbohydrate Conformation↗