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The many faces of systemic mastocytosis.

OBJECTIVE: This short review article will augment the reader's knowledge of mast cell physiology and will offer an overview of current information on the pathophysiology, heterogeneity, and treatment of human mastocystosis. DATA SOURCES AND STUDY SELECTION: Articles published since 1980, textbooks, information from computerized databases, references identified from bibliographies of relevant articles, and books published in the last 10 years. RESULTS AND CONCLUSIONS: Mastocytosis is a complex disease with a multitude of clinical presentations, often misdiagnosed, which can embrace characteristics of other diseases and generate a chameleon-like picture. Mast cells possess many important physiologic functions in the human body, but as a consequence of poorly understood events, they can also start a cascade of pathologic reactions. Although a great deal is known about mechanisms involved in physiologic and pathologic processes of mast cells, many areas are waiting to be explored in this millennium.

Female↗

Osteoporosis in men: prevalence and investigation.

In the past, osteoporosis was thought to affect only women; however, in the last decade it has become apparent that osteoporosis is common in men, particularly elderly men. Osteoporosis affects as many as 2 million men in the United States. Osteoporosis most commonly affects the hip and the lumbar vertebrae, but other bones, such as the radius, tibia, and ribs, may also fracture. The main feature of the etiology of the disease is that low bone mineral density results in increased susceptibility to bone fracture. The World Health Organization has defined osteoporosis as a bone mineral density T-score value >2.5 SDs below the mean observed in young adult women. Although the validity of this score for evaluating men has been questioned and it is not clear whether a male or female reference database should be used, it is nonetheless often used in this way. The disease affects men differently than women in a number of respects. It manifests itself later in life in men than in women, probably because men initially have greater bone mass. Mortality and morbidity associated with hip fractures are high in all elderly individuals, but they are substantially higher in men than in women. Unlike in women, there is an underlying cause for the osteoporosis in almost half of affected men. Thus, for elderly men, a complete history and physical examination may reveal some remediable conditions; treating these may stop further progression of the disease and prevent further morbidity or mortality. Corticosteroid therapy for arthritis or asthma is a common cause of osteoporosis in elderly men. Hypogonadism is a recognized cause of osteoporosis in men treated for carcinoma of the prostate with androgen withdrawal therapy; treatments to modify the effects of these agents on bone are available. Consumption of large amounts of alcohol will eventually result in osteoporosis in some elderly men. Moreover, alcohol can predispose confused elderly patients to falls and to fracture bones that are already osteoporotic. Hyperthyroidism is associated with a reduction in bone mineral density and an increased likelihood of bony fracture. A careful search for undiagnosed hyperthyroidism in elderly osteoporotic men may prove worthwhile. Vitamin D deficiency is common among older men and could contribute to an increase in fractures. Routine analyses of blood and biochemistry should be carried out in any older male patient with newly diagnosed osteoporosis. Dual x-ray energy absorptiometry should be performed on every new patient with newly diagnosed osteoporosis.

Bone Density↗

Systematic review of antidepressant therapies in Parkinson's disease.

Depression is the most common psychiatric disturbance in Parkinson's disease. We conducted a Cochrane systematic review to assess the efficacy and safety of antidepressant therapies in idiopathic Parkinson's disease. Relevant trials were identified from electronic databases, reference lists and queries to antidepressant manufacturers. Three randomised controlled trials examined oral antidepressants in 106 patients with Parkinson's disease. No eligible trials of electroconvulsive or behavioural therapy were found. In the first arm of the crossover trial by Andersen et al. (n=22), nortriptyline treated patients showed a larger improvement than placebo in a unique depression rating scale after 16 weeks although significance levels were not provided. A parallel group trial by Wermuth et al. (n=37) did not show any significant difference between citalopram and placebo in Hamilton score after 52 weeks. Rabey et al. (n=47) performed an open-label trial comparing fluvoxamine with amitriptyline. Similar numbers in each group had a 50% reduction in Hamilton score after 16 months. Major side effects including visual hallucinations and confusion were reported with fluvoxamine and amitriptyline. Insufficient data on the effectiveness and safety of antidepressant therapies in Parkinson's disease are available on which to make recommendations for their use. Large scale randomised controlled trials are urgently required.

Antidepressive Agents↗

Japanese experience of telemedicine in oncology.

We started telemedicine projects from 1990 with a telepathology system within Tsukiji Campus of National Cancer Center. In 1994, we connected Tsukiji Campus and Kashiwa Campus by 6 Mbps optical fiber leased line using IP protocol for data transmission, for teleconference, telepathology, and teleradiology projects. We also started connection of regional cancer centers and are now forming a cancer center network of 14 cancer centers. We are at present organizing 130 teleconferences per year with an attendance of more than 16000 people as summary. We have also used a high-resolution image transferring system, such as SHD (2000 pixelsx2000 pixels resolution) system on one side, and an economical telemedicine system using JAVA and a WWW browser (NCC_image) on the other side. We think that providing information is another field of telemedicine. We began the experimental gopher and WWW service in 1993. We are now providing official up-to-date cancer information for patients and healthcare professionals. We are getting more than 400000 hits per month. We are also providing a teleconference video session which is held every week on the Internet using a Real Video system with synchronized slide presentation on the WWW browser. We are also organizing a Cancer Image Reference Database System including DICOM images with viewer software. This paper is a summary of the telemedicine projects performed at the National Cancer Center.

Community Networks↗

The effectiveness and relative effectiveness of intravenous inotropic drugs acting through the adrenergic pathway in patients with heart failure-a meta-regression analysis.

AIMS: To review systematically the use of intravenous (IV) inotropic agents acting through the adrenergic signalling pathway, compared with placebo or an active agent, in patients with heart failure. METHODS: Studies investigating the use of intravenous inotropes in patients with heart failure published between 1966 and 2000 were identified using MEDLINE, the Cochrane register and Embase databases. Reference lists from relevant papers and reviews were hand searched for further papers. In total, 21 trials, that included 632 patients receiving IV inotropic drugs, placebo or non-treatment control, were identified. Drugs of the following classes were included, the beta-agonists; dobutamine, high-dose (>2.5 microg/kg/min) dopamine, dopexamine and the phosphodiesterase (PDE) inhibitors; amrinone, milrinone, enoximone and toborinone. Sixteen trials (474 patients) contributed data from acute invasive haemodynamic studies of symptomatically severe heart failure. Five trials (158 patients) were based on intermittent inotropic therapy in an outpatient context. RESULTS: With few exceptions, trials of intravenous inotropic agents were small and often failed to report clinically important outcomes. Compared to placebo, intravenous inotropic agents acting through the adrenergic system tended to increase mortality (odds ratio 1.50 (95% CI=0.51 to 3.92) but this did not reach significance and insufficient data were available to determine whether symptoms improved. There appeared to be little difference in the effect of beta-agonists compared to PDE inhibitors on patient outcomes but this could be attributed to the paucity of data. CONCLUSIONS: Intravenous inotropic agents acting through the adrenergic pathway are often used in patients with worsening heart failure to achieve arbitrary haemodynamic targets. Our analyses show that there is very little evidence that such treatment improves symptoms or patient outcomes and may not be safe. This highlights the need for further well designed randomised clinical trials.

Adrenergic beta-Agonists↗

Systematic review of multi-symptom conditions in Gulf War veterans.

BACKGROUND: Gulf War veterans have a number of health complaints. We therefore decided to carry out a systematic review to identify and summarize the findings from studies that have assessed multi-symptom conditions in Gulf War veterans and in an unexposed comparison group. METHOD: Studies published between January 1990 and May 2004 were identified by searching a large number of electronic databases. Reference lists and websites were also searched and key researchers were contacted. Studies were included if they compared the prevalence of chronic fatigue syndrome, multiple chemical sensitivity, CDC-defined chronic multi-symptom illness, fibromyalgia, or symptoms of either fatigue or numbness and tingling in Gulf War veterans and non-Gulf veterans. A total of 2401 abstracts were independently reviewed by two authors. RESULTS: Twenty-three publications fulfilled the inclusion criteria. Gulf deployment was most strongly associated with chronic fatigue syndrome (OR 3.8, 95% CI 2.2-6.7). Gulf War veterans were also approximately three and a half times more likely than non-Gulf veterans to report multiple chemical sensitivity or chronic multi-symptom illness as defined by CDC. The methodological quality of the studies varied but the later and larger studies were of a high methodological standard with robust sampling strategies, adequate response rates and good adjustment for confounders. CONCLUSIONS: The results support the hypothesis that deployment to the Gulf War is associated with greater reporting of multi-symptom conditions.

Anxiety Disorders↗

Safety of fluoxetine during the first trimester of pregnancy: a meta-analytical review of epidemiological studies.

BACKGROUND: This study was designed to examine whether there is an increased risk for major malformations following the use of fluoxetine during the first trimester of pregnancy. METHODS: Published and unpublished reports were identified through computerized and manual searches of bibliographical databases, reference lists from primary articles, and letters to editors, agencies, foundations and content experts. Meta-analysis was undertaken of prospective controlled and uncontrolled studies on the use of fluoxetine during first trimester of pregnancy. RESULTS: The pooled relative risk and 95% confidence interval for major malformations does not suggest an association between the use of fluoxetine during the first trimester and an increased risk of major malformations. Combination of controlled and uncontrolled studies shows a weighted risk of 26% (95% CI 1-4.2%). The summary odds ratio from the two controlled studies (OR = 1.33, 95% CI 0.49-3.58) was not significant. Homogeneity testing shows that the effect sizes are similar throughout all studies. Power analysis indicates that 26 controlled studies of similar size, would be required, to reverse this finding. CONCLUSIONS: The use of fluoxetine during the first trimester of pregnancy is not associated with measurable teratogenic effects in human.

Abnormalities, Drug-Induced↗

Estimated costs of postoperative wound infections. A case-control study of marginal hospital and social security costs.

A cohort of 4515 surgical patients in ten selected intervention groups was followed. Three hundred and seventeen developed postoperative wound infections, and 291 of these cases were matched 1:1 to controls by operation, sex and age. In comparison to the controls the cases stayed longer in hospital after the intervention and had more contact after discharge with the social security system. Using data from a national sentinel reference database of the incidence of postoperative wound infections, and using national activity data, we established an empirical cost model based on the estimated marginal costs of hospital resources and social sick pay. It showed that the hospital resources spent on the ten groups, which represent half of the postoperative wound infections in Denmark, amounted to approximately 0.5% of the annual national hospital budget. This stratified model creates a better basis for selecting groups of operations which need priority in terms of preventive measures.

Adolescent↗

A systematic review of the prevalence and covariates of anxiety in caregivers of people with dementia.

BACKGROUND: Caregiving for people with dementia has consistently been linked with psychological problems, usually in terms of caregiver burden, general psychological distress and depressive symptomatology, while morbidity due to anxiety has been relatively neglected in this group. METHODS: We conducted a systematic review of the literature, searching electronic databases, reference lists, relevant systematic reviews and contacting experts in the field. We used Centre for Evidence Based Medicine (CEBM) criteria for inclusion and rating the validity of all studies that reported (1) the prevalence, predictors and covariates of anxiety disorders or anxiety caseness, and (2) covariates and predictors of the level of anxiety symptoms. RESULTS: Thirty-three studies met our inclusion criteria. Clinically, significant anxiety affects about a quarter of caregivers for people with dementia and was more common than in matched controls. Such caregivers have higher anxiety levels than controls, and that confrontative and escape avoidance coping, caregiver burden and poorer caregiver physical health are factors associated with higher anxiety levels from cross-sectional studies. CONCLUSIONS: Coping style may be more associated with anxiety than depression while other covariates (burden and poor physical health) are similar to those for caregiver depression. We found no conclusive evidence about factors associated with anxiety disorders or predicting anxiety from longitudinal studies. Neither care recipient cognition nor ADL impairment; nor caregiver age nor duration of caring are associated with caregiver anxiety levels. Good quality cohort studies are needed to determine whether these factors also predict anxiety disorders.

Aged↗

Prediction of substructure and toxicity of pesticides with temperature constrained-cascade correlation network from low-resolution mass spectra.

Artificial neural networks are trained to predict the toxicity or active substructures of organophosphorus pesticides and then are applied to screening GC/MS data for environmentally hazardous compounds. Every mass spectral scan in the chromatographic run is classified, and separate chromatograms are obtained for either toxicity or substructure classes. Classification of mass spectra allows the detection of chromatographic peaks from potentially hazardous compounds that may be missing from the reference database. The neural network models predict substructures and toxicity from mass spectra without first determining the complete configurational structure of the pesticides. Temperature constrained-cascade correlation networks (TCCCN) were used because they are self-configuring networks that train rapidly and robustly. The toxicity classes are defined by the World Health Organization, and the substructure classes are standard organophosphorus pesticide groupings. The TCCCN models are used to mathematically resolve peaks in the chromatograms by substructure and toxicity. Evaluations yielded classification rates of 97 and 84% for substructure and toxicity, respectively.

Gas Chromatography-Mass Spectrometry↗

Comparison of knowledge-based and distance geometry approaches for generation of molecular conformations.

A knowledge-based approach for generating conformations of molecules has been developed. The method described here provides a good sampling of the molecule's conformational space by restricting the generated conformations to those consistent with the reference database. The present approach, internally named et for enumerate torsions, differs from previous database-mining approaches by employing a library of much larger substructures while treating open chains, rings, and combinations of chains and rings in the same manner. In addition to knowledge in the form of observed torsion angles, some knowledge from the medicinal chemist is captured in the form of which substructures are identified. The knowledge-based approach is compared to Blaney et al.'s distance geometry (DG) algorithm for sampling the conformational space of molecules. The structures of 113 protein-bound molecules, determined by X-ray crystallography, were used to compare the methods. The present knowledge-based approach (i) generates conformations closer to the experimentally determined conformation, (ii) generates them sooner, and (iii) is significantly faster than the DG method.

Algorithms↗

Assessing the discriminatory power of scoring functions for virtual screening.

The efficiency of scoring functions for hit identification is usually quantified in terms of enrichment factors and enrichment curves. Close inspection of simulated and real score distributions from virtual screening, however, suggests that 'analysis of variance' (ANOVA) is a more reliable method for assessing their performance. Using ANOVA to quantify the discriminatory power of scoring functions with respect to ligands, decoys, and a reproducible reference database has the potential to facilitate the advancement of scoring functions significantly.

Journal Article↗

Proteome analysis of primary neurons and astrocytes from rat cerebellum.

Neurons and astrocytes are predominant cell types in brain and have distinguished morphological and functional features. Although several proteomics studies were carried out on the brain, work on individual brain cells is limited. Generating individual proteomes of neurons and astrocytes, however, is mandatory to assign protein expression to cell types rather than to tissues. We aimed to provide maps of rat primary neurons and astrocytes using two-dimensional gel electrophoresis with subsequent in-gel digestion, followed by MALDI-TOF/TOF. 428 protein spots corresponding to 226 individual proteins in neurons and 406 protein spots representing 228 proteins in astrocytes were unambiguously identified. Proteome data include proteins from several cascades differentially expressed in neurons and astrocytes, and specific expressional patterns of antioxidant, signaling, chaperone, cytoskeleton, nucleic acid binding, proteasomal, and metabolic proteins are demonstrated. We herein present a reference database of primary rat primary neuron and astrocyte proteomes and provide an analytical tool for these structures. The concomitant expressional patterns of several protein classes are given and potential neuronal and astrocytic marker candidates are presented.

Animals↗

Improving mass and liquid chromatography based identification of proteins using bayesian scoring.

We present a method for peptide and protein identification based on LC-MS profiling. The method identified peptides at high-throughput without expending the sequencing time necessary for CID spectra based identification. The measurable peptide properties of mass and liquid chromatographic elution conditions are used to characterize and differentiate peptide features, and these peptide features are matched to a reference database from previously acquired and archived LC-MS/MS experiments to generate sequence assignments. The matches are scored according to the probability of an overlap between the peptide feature and the database peptides resulting in a ranked list of possible peptide sequences for each peptide submitted. This method resulted in 6 times more peptide sequence identifications from a single LC-MS analysis of yeast than from shotgun peptide sequencing using LC-MS/MS.

Algorithms↗

Proteome profiling in the rat Harderian gland.

The Harderian gland is an orbital gland located behind the ocular bulb in most terrestrial vertebrates probably functioning for production of lipid secretion to protect the eye. We herein present a protein reference database of the rat Harderian gland that may serve as analytical tool for future proteomic work, report lipid and porphyrin handling cascades, address sequence conflicts and report structures that have not been so far described by proteomics methods.

Amino Acid Sequence↗

Antibiotic resistance analysis of fecal coliforms to determine fecal pollution sources in a mixed-use watershed.

Antibiotic resistance analysis was performed on fecal coliform (FC) bacteria from a mixed-use watershed to determine the source, human or nonhuman, of fecal coliform contamination. The study consisted of discriminant analysis of antibiotic resistance patterns generated by exposure to four concentrations of six antibiotics (ampicillin, gentamicin sulfate, kanamycin, spectinomycin dihydrochloride, streptomycin sulfate, and tetracycline hydrochloride). A reference database was constructed from 1125 fecal coliform isolates from the following sources: humans, domestic animals (cats and dogs), agricultural animals (chickens, cattle, and horses), and wild animals. Based on similar antibiotic resistance patterns, cat and dog isolates were grouped as domestic animals and horse and cattle isolates were grouped as livestock. The resulting average rate of correct classification (ARCC) for human and nonhuman isolates was 94%. A total of 800 FC isolates taken from the watershed during either a dry event or a wet event were classified according to source. Human sources contribute a majority (> 50%) of the baseflow FC isolates found in the watershed in urbanized areas. Chicken and livestock sources are responsible for the majority of the baseflow FC isolates found in the rural reaches of the watershed. Stormwater introduces FC isolates from domestic (approximately 16%) and wild (approximately 21%) sources throughout the watershed and varying amounts (up to 60%) from chicken and livestock sources. These results suggest that antibiotic resistance patterns of FC may be used to determine sources of fecal contamination and aid in the direction of water quality improvement.

Animals↗

Comparison of correlation vector methods for ligand-based similarity searching.

Correlation vector methods were tested for their usefulness in ligand-based virtual screening. Three molecular descriptors--two based on potential pharmacophore points and one on partial atom charges--and three similarity measures--the Manhattan distance, the Euclidian distance and the Tanimoto coefficient--were compared. The alignment-free descriptors seem to be particularly applicable when a course-grain filtering of data sets is required in combination with a high execution speed. Significant enrichment of actives was obtained by retrospective analysis. The cumulative percentages for all three descriptors allow for the retrieval of up to 78% of the active molecules in the first five percent of the reference database. Different descriptors retrieved only weakly overlapping sets of active molecules among the top-ranking compounds. If a single similarity index is to be used, the Manhattan distance seems to be particularly applicable. Generally, none of the three different descriptors tested in this study clearly outperformed the others. The suitability of a descriptor critically depends on the ligand-receptor interaction under investigation. For ligand-based similarity searching it is recommended to exploit several descriptors in parallel.

Algorithms↗

Speed of sound in bone at the tibia: is it related to lower limb bone mineral density in spinal-cord-injured individuals?

STUDY DESIGN: A cross-sectional study evaluating BMD at the hip and tibia, and SOS at the radius and mid-tibia in individuals with spinal cord injury (SCI) and a subgroup of non-SCI individuals. OBJECTIVES: To investigate the speed of sound (SOS) in bone in relation to bone mineral density (BMD). SETTING: Kinesiology Department, McMaster University, Ontario, Canada. METHODS: In 14 individuals with SCI and 10 non-SCI individuals, proximal femur and tibia BMD were measured using dual energy X-ray absorptiometry, and radius and tibia SOS were measured with an ultrasonometer. T-scores were calculated using healthy reference databases. Inter-relationships between measurement techniques were determined using Pearson's correlation coefficients. P-values less than 0.05 were considered statistically significant. RESULTS: : The average ages of the SCI and non-SCI groups were 33+/-9 and 27+/-6 years, respectively. Lesion level ranged from C4 to T12 and average time postinjury was 12 years, with a range of 1.6-25 years. Using the WHO criteria for osteoporosis, nine of 14 SCI subjects were osteoporotic at the hip, with the remainder in the osteopenic range. Tibia SOS T-scores were in the osteoporotic range for one subject with SCI, and two were in the osteopenic range. Among non-SCI individuals, one male had a tibia SOS T-score of -1.4, all others were within the normal range. Hip BMD and tibia SOS were significantly correlated (r=0.46, P<0.01). Hip BMD and tibia BMD were more strongly correlated (r=0.80, P<0.0005). Tibia BMD was not significantly correlated with SOS at the tibia (r=0.35, P=0.09). Radius SOS T-scores were positive and not significantly correlated with any lower limb variable. CONCLUSION: Lower-limb bone mass is reduced in spinal cord-injured individuals, but SOS at the mid-tibia is not. It remains to be determined whether ultrasound measurements can predict fracture in the SCI population.

Absorptiometry, Photon↗