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PubMed2005

Genome-wide association studies: theoretical and practical concerns.

To fully understand the allelic variation that underlies common diseases, complete genome sequencing for many individuals with and without disease is required. This is still not technically feasible. However, recently it has become possible to carry out partial surveys of the genome by genotyping large numbers of common SNPs in genome-wide association studies. Here, we outline the main factors - including models of the allelic architecture of common diseases, sample size, map density and sample-collection biases - that need to be taken into account in order to optimize the cost efficiency of identifying genuine disease-susceptibility loci.

Animals↗
PubMed2001

Skeletal muscle pathology in autosomal dominant Emery-Dreifuss muscular dystrophy with lamin A/C mutations.

We present our observations on the skeletal muscle pathology of nine cases from seven families of autosomal dominant Emery-Dreifuss muscular dystrophy (ADEDMD) with identified mutations in the lamin A/C gene, aged 2-35 years at the time of biopsy. The severity of pathological change was moderate and the most common features were variation in fibre size (hypertrophy and atrophy), an increase in internal nuclei and smaller diameter fibres with high oxidative enzyme activity. Only one case showed necrosis, which was present in two separate samples taken from the quadriceps and tibialis anterior, at different ages. Immunocytochemistry detected an age-related reduction of laminin beta1 on the muscle fibres in adolescent and adult cases. Antibodies to lamins A and A/C, and emerin did not reveal any detectable differences from controls. Electron microscopy of two out of three cases showed an abnormal distribution of heterochromatin in many fibre nuclei. Our results show that dystrophic changes in skeletal muscle are not a major feature of ADEDMD, and that nuclear abnormalities may be detected with electron microscopy. Immunodetection of reduced laminin beta1 may be a useful secondary marker in adults with this disorder, as immunocytochemistry of lamins is not yet of diagnostic use.

Adolescent↗
PubMed2001

Cryptosporidiosis in Kuwaiti children: seasonality and endemicity.

OBJECTIVE: To detect the incidence of cryptosporidial infection in children presenting with gastrointestinal symptoms at the local hospital in Kuwait. METHODS: Over a period of 3 years, September 1995 to August 1997, a single fecal sample from 3549 children was analyzed by modified saframin-methylene blue (SM-B) staining and a direct immunofluorescence test for the presence of Cryptosporidium oocysts. RESULTS: Cryptosporidium oocysts were detected in 51 (10%) children with diarrhea. Prevalence was highest (73%) in children > 2 years of age compared with children < 2 years of age. The maximum number of cases, 38 of 51 (75%), was seen during the months January to April, indicating a marked seasonal variation. Polyparasitism was common in children with diarrhea; however, 43 of the 51 (84%) children with cryptosporidiosis had cryptosporidium infection only. Blastocystis hominis and Endolimax nana were the most common parasites detected (38% and 15%, respectively). Forty-seven of the 51 (90%) children with cryptosporidiosis were Kuwaiti and gave no history of travel abroad, suggesting that the infection was acquired indigenously. Sociodemographic information on children with cryptosporidiosis suggests three possible modes of transmission of infection: drinking contaminated water stored in overhead water tanks, person to person, or contact with infected animals. CONCLUSION: In this study, we observed water-borne transmission of cryptosporidium infection in children with diarrhea. The infection is seasonal and endemic.

Age Factors↗
PubMed2000

Assessing validity in written tests of general practice - exploration by factor analysis of candidate response patterns to paper 1 of the MRCGP examination.

OBJECTIVE: To investigate the content validity of Paper 1 of the MRCGP examination. METHOD: Exploratory factor analysis was carried out on candidate responses to Paper 1 of the May and October MRCGP examination in 1998. Contribution of each test question across factors was assessed using a pattern matrix of the oblique rotation. Common dimensions and variations between factor sets were identified. Key testing areas were then matched against the 'domains of competence' intended to be assessed by Paper 1 (as defined within the examination blueprint matrix). RESULTS: Whilst critical appraisal, disease prevention/evidence-based medicine and clinical management emerged as areas tested consistently, content variation was observed between factor sets extracted from both sittings. In addition, some overlap, in terms of domains tested, was seen among other assessment instruments used within the examination. CONCLUSION: Paper 1 conforms to the majority of its stated intentions. However, further development of techniques for investigating validity will be required in order to minimize content variation between both sittings of the examination as well as to help more closely define areas of competence to be tested by Paper 1 of the MRCGP examination.

Education, Medical, Undergraduate↗
PubMed1996

The NodA proteins of Rhizobium meliloti and Rhizobium tropici specify the N-acylation of Nod factors by different fatty acids.

Rhizobia synthesize mono-N-acylated chitooligosaccharide signals, called Nod factors, that are required for the specific infection and nodulation of their legume hosts. The biosynthesis of Nod factors is under the control of nodulation (nod) genes, including the nodABC genes present in all rhizobial species. The N-acyl substitution can vary between species and can play a role in host specificity. In Rhizobium meliloti, an alfalfa symbiont, the acyl chain is a C16 unsaturated or a (omega-1) hydroxylated fatty acid, whereas in Rhizobium tropici, a bean symbiont, it is vaccenic acid (C18:1). We constructed R. meliloti derivatives having a non-polar deletion of nodA, and carrying a plasmid with either the R. meliloti or the R. tropici nodA gene. The strain with the R. tropici nodA gene produced Nod factors acylated by vaccenic acid, instead of the C16 unsaturated or hydroxylated fatty acids characteristic of R. meliloti Nod factors, and infected and nodulated alfalfa with a significant delay. These results show that NodA proteins of R. meliloti and R. tropici specify the N-acylation of Nod factors by different fatty acids, and that allelic variation of the common nodA gene can contribute to the determination of host range.

Acylation↗
PubMed2001

Warfarin toxicity in the emergency department: recommendations for management.

OBJECTIVE: To examine patients who presented to a hospital emergency department with evidence of warfarin toxicity, and to review the available published literature to determine what guidelines are available for management of this problem. METHOD: A retrospective analysis of all adult patients who presented to The Geelong Hospital Emergency Department between 1 January 1996 and 30 June 1998 with international normalized ratio > 6 due to warfarin toxicity. RESULTS: A total of 84 patients with international normalized ratio > 6 were included in the study. The average age was 68.3 years. Fifty-three per cent were women. The international normalized ratio was between 6 and 10 in 33 patients (39%), and greater than 10 in 51 patients (61%). Major bleeding occurred in 16.7% of patients, minor bleeding in 17.8%. Sixty-five per cent had no bleeding. Seven patients died, four of those with bleeding. Patients with an international normalized ratio > 10 were more likely to receive fresh frozen plasma (77.6% vs 28.6%; P < 0.001) and in greater amounts (3.0 units vs 0.8 units; P < 0.001) than those with an international normalized ratio of 6-10. There were also more episodes of major bleeding, although not significant. Patients with major bleeding were older (mean 75.4 years vs 67.5 years; P = 0.04), more likely to be admitted (P = 0.046), were more often given fresh frozen plasma (P = 0.003) and in greater amounts (3.28 units vs 2.0 units; P = 0.02). CONCLUSION: Warfarin toxicity is a common problem, and variation in management is not surprising considering the lack of consensus in the literature on this topic. Current recommendations are summarized and a simple flowchart for management of this problem is provided.

Adult↗
PubMed1997

Maternally inherited diabetes and deafness: a diabetic subtype associated with a mutation in mitochondrial DNA.

Diabetes mellitus is a common disease with variations in its clinical expression and different modes of pathogenesis. The purpose of this review is to discuss a recently identified diabetic subtype. Based on the triad diabetes, maternal inheritance and impaired hearing in this subtype we have proposed the name Maternally Inherited Diabetes and Deafness (MIDD). This diabetic subtype associates in the vast majority of cases with a single mutation in mitochondrial DNA, at position 3243. The clinical presentation of MIDD which can be IDDM-like or NIDDM-like, its frequency of occurrence, possible pathogenic mechanisms and the contribution of other mitochondrial DNA mutations to the development of diabetes will be discussed.

DNA, Mitochondrial↗
PubMed2001

Absence of the brachial artery: report of a rare human variation and review of upper extremity arterial anomalies.

Variations in the arterial anatomy of the upper extremities, although uncommon, occur in up to one in five patients. Most of these variants occur in either the radial or ulnar artery; brachial artery variations are less common. The case we report is a rare anomaly consisting of brachial artery agenesis or regression. The brachial artery was absent from its origin but reconstituted as a normal-appearing vessel 3 cm above the antecubital fossa. The profunda brachii artery and the superior and inferior ulnar collateral arteries were also absent in this patient. The axillary artery served as the main collateral to the forearm. This constellation of anomalies has not been previously described or explained by developmental models in humans and other primates. We speculate that failure of development or arrest of specific vascular anlage in the upper extremity occurs at particular embryological stages because of unknown factors.

Angiography↗
PubMed2002

Predicting the effects of climate change on avian life-history traits.

Across North America, tree swallows have advanced their mean date of clutch initiation (lay date) by approximately 9 days over the past 30 years, apparently in response to climate change. In a sample of 2,881 nest records collected by the lay public from 1959 to 1991, we examined whether clutch size has also responded to climate change. We found that clutch size is strongly related to lay date, both within and among years, and there has been no significant temporal variation in the slopes or intercepts of the clutch-size/lay-date regressions. As a consequence, we expected increases in clutch size with advancement in lay date; however, we detected no such trend over time. The distributions of egg-laying dates were more constricted in the warmest (and earliest) years, suggesting that changes in mean clutch size might be constrained by changes in the distribution of laying dates. If spring temperatures continue to increase, we predict further reductions of variance in laying dates and relatively small increases in clutch size. Such constraints on life-history variation probably are common and need to be considered when modeling the effects of climate change on reproduction in natural populations. Predicting the long-term effects of constraints and interpreting changes in life-history traits require a better understanding of both adaptive and demographic effects of climate change.

Animals↗
PubMed2003

Contrast-enhanced MRA and 3D visualization of pulmonary venous anatomy to assist radiofrequency catheter ablation.

In pulmonary vein isolation as a treatment for atrial fibrillation the proximal part of the pulmonary veins is catheterized. A protocol for preinterventional assessment of pulmonary vein anatomy was developed, based on contrast-enhanced magnetic resonance angiography (MRA) in combination with three-dimensional visualization to tailor periprocedural angiography. The results allow for assessment of the number, morphology, and location of the ostia of the pulmonary veins, as well as complicating anatomical variations, such as common trunks and aberrant courses.

Adult↗
PubMed2003

A comparison of normalization methods for high density oligonucleotide array data based on variance and bias.

MOTIVATION: When running experiments that involve multiple high density oligonucleotide arrays, it is important to remove sources of variation between arrays of non-biological origin. Normalization is a process for reducing this variation. It is common to see non-linear relations between arrays and the standard normalization provided by Affymetrix does not perform well in these situations. RESULTS: We present three methods of performing normalization at the probe intensity level. These methods are called complete data methods because they make use of data from all arrays in an experiment to form the normalizing relation. These algorithms are compared to two methods that make use of a baseline array: a one number scaling based algorithm and a method that uses a non-linear normalizing relation by comparing the variability and bias of an expression measure. Two publicly available datasets are used to carry out the comparisons. The simplest and quickest complete data method is found to perform favorably. AVAILABILITY: Software implementing all three of the complete data normalization methods is available as part of the R package Affy, which is a part of the Bioconductor project http://www.bioconductor.org. SUPPLEMENTARY INFORMATION: Additional figures may be found at http://www.stat.berkeley.edu/~bolstad/normalize/index.html

Algorithms↗
PubMed2006

Flexible empirical Bayes models for differential gene expression.

MOTIVATION: Inference about differential expression is a typical objective when analyzing gene expression data. Recently, Bayesian hierarchical models have become increasingly popular for this type of problem. The two most common hierarchical models are the hierarchical Gamma-Gamma (GG) and Lognormal-Normal (LNN) models. However, to facilitate inference, some unrealistic assumptions have been made. One such assumption is that of a common coefficient of variation across genes, which can adversely affect the resulting inference. RESULTS: In this paper, we extend both the GG and LNN modeling frameworks to allow for gene-specific variances and propose EM based algorithms for parameter estimation. The proposed methodology is evaluated on three experimental datasets: one cDNA microarray experiment and two Affymetrix spike-in experiments. The two extended models significantly reduce the false positive rate while keeping a high sensitivity when compared to the originals. Finally, using a simulation study we show that the new frameworks are also more robust to model misspecification. AVAILABILITY: The R code for implementing the proposed methodology can be downloaded at http://www.stat.ubc.ca/~c.lo/FEBarrays. SUPPLEMENTARY INFORMATION: The supplementary material is available at http://www.stat.ubc.ca/~c.lo/FEBarrays/supp.pdf.

Algorithms↗
PubMed1996

Salivary gland anticoagulants in culicine and anopheline mosquitoes (Diptera:Culicidae).

Female salivary gland extracts from 9 mosquito species representing the 2 hematophagous subfamilies delayed coagulation of human plasma. All extracts significantly delayed recalcification time, prothrombin time, and activated partial thromboplastin time, indicating an effect on the common coagulation pathway. Chromogenic assays to determine the coagulation inhibition site were performed for coagulation factor Xa (FXa) and thrombin, the major components of the common pathway. Although variation existed in the degree of inhibition, all anophelines have thrombin-directed anticoagulants, and culicine mosquitoes have FXa-directed anticoagulants. Differences in the site of action of the anticoagulants most likely reflected the long period of independent adaptation of the 2 subfamilies to the challenges presented by vertebrate hemostasis.

Aedes↗
PubMed1998

Functional anatomy and computed tomography imaging of the paranasal sinuses.

Standard radiographs are suboptimal in the display of the regional morphology in the nasal cavity and paranasal sinuses, especially the ethmoid sinus. The preferred radiographic modality for the evaluation of the nasal cavity and paranasal sinuses is computed tomography (CT). Coronal CT imaging perpendicular to the bony palate affords the best display of the ostiomeatal channels and facilitates the surgeon's perception of this regional morphology because it most closely resembles the endoscopic view. The purpose of this article is to familiarize the reader with the regional anatomy of the nasal cavity and paranasal sinuses, specifically the 14 anatomic structures the examiner must understand and systematically check in the evaluation of this morphologic area. A description of the most commonly found anatomic variations that influence the patency of the ostiomeatal channels as well as specific relationships between the paranasal sinuses, the orbits, and the intracranial compartment are also detailed. Although less helpful in the display of paranasal sinus chronic inflammatory disease, magnetic resonance imaging is beneficial in the diagnosis of fungal disease, neoplastic disease, and the display of inflammatory extension into the intracranial and intraorbital compartments.

Humans↗
PubMed2001

Horseshoe kidney transplantation within the eurotransplant region: a case control study.

BACKGROUND: The horseshoe kidney is the most common anatomic renal variation, with an incidence of 1 in 600 to 800. It represents a fusion anomaly, usually of the lower poles. Horseshoe kidneys can be transplanted en bloc or after division of the renal isthmus. However, the great variation in origin, number, and size of renal arteries and veins leads to some reluctance to use horseshoe kidneys for transplantation. The aim of this study is to assess the results of horseshoe kidney transplantation. METHODS: All data concerning horseshoe kidney transplantations within the Eurotransplant region were collected and were divided into en bloc and split transplantations. A matched control group was defined, and the three groups were analyzed with respect to the occurrence of primary nonfunction, graft survival, patient survival, and finally posttransplant serum creatinine values. RESULTS: From 1983 to 2000, 8 horseshoe kidneys were transplanted en bloc and 26 were split and transplanted into 47 recipients. The results of these transplantations were compared with 110 transplantations in the control group. No significant differences among the three groups could be found, either in the short- or long-term posttransplant results. CONCLUSIONS: The results of horseshoe kidney transplantation, either en bloc or split, are equal to the posttransplant results of kidneys with a normal anatomy. Bearing in mind the shortage of donors, horseshoe kidneys should certainly be used for transplantation.

Adolescent↗
PubMed2004

Anatomical variations of the extensor tendons to the fingers over the dorsum of the hand: a study of 50 hands and a review of the literature.

The extensor tendons to the fingers were studied in dissections of 50 fresh cadaveric hands, and the divisions of the tendons, as well as the communications (juncturae), were analyzed. The pattern of distribution most frequently observed was as follows. The extensor digitorum communis provided one tendon to the index finger, one to the middle finger, two to the ring finger, and none to the little finger. The extensor indicis exhibited one tendon, whereas the extensor digiti minimi exhibited two tendons. The extensor indicis tendon was always observed to lack a junctura tendinum. The extensor indicis was absent in both hands of one cadaver. A tendon slip from the extensor digiti minimi to the ring finger was observed in one hand. All surgeons must bear in mind the existence of these variations when performing common tendon transfers.

Aged↗
PubMed1996

The presence of two S-layer-protein-encoding genes is conserved among species related to Lactobacillus acidophilus.

Previously we have shown that the type strain of Lactobacillus acidophilus possesses two S-protein-encoding genes, one of which is silent, on a chromosomal segment of 6 kb. The S-protein-encoding gene in the expression site can be exchanged for the silent S-protein-encoding gene by inversion of this slp segment. In this study the presence of S-protein and corresponding S-protein-encoding genes of strains belonging to species that are closely related to L. acidophilus was determined. All strains investigated were identified by numerical comparison of highly standardized one-dimensional SDS-PAGE whole-cellular-protein patterns. Western blot and Southern blot methods were used to identify the presence of, and homology between, S-proteins and S-protein-encoding genes. From these analyses we conclude that strains of L. acidophilus, L. crispatus, L. amylovorus and L. gallinarum possess an S-layer and contain two slp genes. Strains of L. helveticus possess an S-layer but have only one intact slp gene. Strains of L. gasseri, L. johnsonii and L. delbrueckii subsp. bulgaricus have neither an S-layer nor S-protein-encoding genes hybridizing with probes derived from the L. acidophilus slpA or slpB region. The presence of a highly conserved 5' region in the slp genes of strains of L. acidophilus, L. crispatus, L. amylovorus and L. gallinarum suggests that S-layer variation is a common feature for strains of these species.

Bacterial Proteins↗
PubMed2005

Characterization of new DsbB-like thiol-oxidoreductases of Campylobacter jejuni and Helicobacter pylori and classification of the DsbB family based on phylogenomic, structural and functional criteria.

In Gram-negative bacterial cells, disulfide bond formation occurs in the oxidative environment of the periplasm and is catalysed by Dsb (disulfide bond) proteins found in the periplasm and in the inner membrane. In this report the identification of a new subfamily of disulfide oxidoreductases encoded by a gene denoted dsbI, and functional characterization of DsbI proteins from Campylobacter jejuni and Helicobacter pylori, as well as DsbB from C. jejuni, are described. The N-terminal domain of DsbI is related to DsbB proteins and comprises five predicted transmembrane segments, while the C-terminal domain is predicted to locate to the periplasm and to fold into a beta-propeller structure. The dsbI gene is co-transcribed with a small ORF designated dba (dsbI-accessory). Based on a series of deletion and complementation experiments it is proposed that DsbB can complement the lack of DsbI but not the converse. In the presence of DsbB, the activity of DsbI was undetectable, hence it probably acts only on a subset of possible substrates of DsbB. To reconstruct the principal events in the evolution of DsbB and DsbI proteins, sequences of all their homologues identifiable in databases were analysed. In the course of this study, previously undetected variations on the common thiol-oxidoreductase theme were identified, such as development of an additional transmembrane helix and loss or migration of the second pair of Cys residues between two distinct periplasmic loops. In conjunction with the experimental characterization of two members of the DsbI lineage, this analysis has resulted in the first comprehensive classification of the DsbB/DsbI family based on structural, functional and evolutionary criteria.

Amino Acid Sequence↗