Biomedical subjects
Publications and source records attributed to D Moore.
Ligamentous laxity is common in Trisomy 21 (Down's syndrome). The literature has numerous reports of atlanto-axial instability, patellar instability, carpal instability and other manifestations of joint instability. To date, no report has been published in the English literature describing non-traumatic unilateral or bilateral wrist dislocation either in trisomy 21 or in any other condition.
The biological actions of extracellular nucleotides are mediated by two distinct classes of P2 receptor, P2X and P2Y. The G protein-coupled P2Y receptors comprise five mammalian subtypes, P2Y(1-11). The P2Y1 subtype is expressed abundantly throughout the human brain and is specifically localized to neuronal structures. In the present study, the distribution of the P2Y1 receptor was investigated in Alzheimer's disease (AD) brains. In contrast to control human brain, the P2Y1 receptor was localized to a number of characteristic AD structures such as neurofibrillary tangles, neuritic plaques and neuropil threads. Immunoblot analysis showed that this specific immunostaining observed over tangles was not a result of cross-reactivity between the anti-P2Y1 antiserum and abnormal tau protein, the major constituent of tangles. The significance of this altered P2Y1 cellular distribution in AD brains is at present unclear.
PURPOSE: We hypothesize that phosphorylated ErbB-2 (P-ErbB-2, identified by a novel antibody PN2A) may provide either more significant or additional prognostic marker data for breast cancer patients. This study was designed to compare the incidence and prognostic value of ErbB-2 (HER-2/neu) and P-ErbB-2 immunoexpression in archival breast cancer samples. MATERIALS AND METHODS: Eight hundred sixteen invasive breast cancers with a median of 16.3 years of follow-up were immunostained for ErbB-2 (using antibody CB11) and P-ErbB-2 (using antibody PN2A). ErbB-2 and P-ErbB-2 data were compared with clinical, histologic, immunohistochemical, and outcome variables. RESULTS: Of 816 primary breast cancers, 307 (38%) were positive for ErbB-2 and 37 (12% of ErbB-2 positive and 5% of the study population) expressed P-ErbB-2. P-ErbB-2 was not detected in ErbB-2-negative cases (n = 509). ErbB-2 immunohistochemical data were bimodal; patients with > or = 80% cellular expression had the shortest disease-free and disease-specific survival. P-ErbB-2 was associated with a higher percentage of ErbB-2-positive cells, a higher number of positive lymph nodes, and cellular proliferation. ErbB-2 and P-ErbB-2 were indicators of poor prognosis in node-positive patients in both univariate and multivariate analyses. We found that either P-ErbB-2 expression or high (> or = 80%) ErbB-2 expression provided the most significant prognostic value in node-positive cases by multivariate analyses. There were too few P-ErbB-2-positive cases and events in the node-negative patient group to allow statistical analysis of P-ErbB-2 in that subgroup. CONCLUSION: PN2A immunostaining identified a subset (approximately 12% of ErbB-2-positive breast cancers) with activation (phosphorylation) of the receptor ErbB-2. P-ErbB-2 expression was strongly associated with higher levels of ErbB-2 expression (> or = 80%), although it was not a surrogate. Identification of cases with a high percentage of invasive breast cancer cells expressing ErbB-2 or determination of receptor activation via P-ErbB-2 may provide additional prognostic value in node-positive breast cancers.
Previous research showed that age-related division of labor in honey bees is associated with changes in activity rhythms; young adult bees perform hive tasks with no daily rhythms, whereas older bees forage with strong daily rhythms. We report that this division of labor is also associated with differences in both circadian rhythms and mRNA levels of period, a gene well known for its role in circadian rhythms. The level of period mRNA in the brain oscillated in bees of all ages, but was significantly higher at all times in foragers. Elevated period mRNA levels cannot be attributed exclusively to aging, because bees induced to forage precociously because of a change in social environment had levels similar to normal age foragers. These results extend the regulation of a "clock gene" to a social context and suggest that there are connections at the molecular level between division of labor and chronobiology in social insects.
The biological actions of extracellular nucleotides are exerted via two families of P2 receptors, P2X and P2Y. The metabotropic P2Y receptors comprise at least 7 distinct subtypes, which have been cloned from a number of species. However, none of the P2Y receptor proteins have been visualised yet in human brain. In the present study, the regional and cellular distribution of the P2Y(1) receptor was investigated in the human brain by using immunohistochemistry. Polyclonal antibodies were raised against a synthetic peptide from the C-terminus of the P2Y(1) protein. Immunoblot analysis demonstrated that P2Y(1) antiserum specifically recognised a 63-kDa band in human and rat brain membranes. Similarly, the antiserum specifically detected the human P2Y(1) receptor in transfected 1321N1 cells. Immunohistochemical analysis on perfusion-fixed human brain tissue showed a widespread distribution for this receptor throughout the brain. At the cellular level, the P2Y(1) receptor was strikingly localised to neuronal structures of the cerebral cortex, cerebellar cortex, hippocampus, caudate nucleus, putamen, globus pallidus, subthalamic nucleus, red nucleus, and midbrain. Expression of the P2Y(1) receptor was not detected in other non-neuronal cell types. These results provide the first characterisation of the cellular distribution of a P2Y receptor in the human brain. The widespread and abundant distribution of the P2Y(1) receptor suggests its involvement in a number of important functions within the human brain. The neuronal localisation of this receptor points towards a possible role in neurotransmission, and also highlights a major role for extracellular nucleotides as signaling molecules within the brain.
Gastric cancer is still a major cause of mortality due to cancer worldwide. The most common type of gastric cancer is intestinal type carcinoma, which usually occurs in stomachs containing chronic atrophic gastritis. Individuals with chronic atrophic gastritis are considered to be at increased risk for developing intestinal type carcinoma of the stomach. To examine the association between chronic atrophic gastritis and other gastric cancer risk factors, a cross-sectional study was conducted using serum samples and questionnaire information collected from 776 persons of full Japanese ancestry in the greater Seattle area in 1994. The presence of chronic atrophic gastritis and Helicobacter pylori infection was determined by measurement of serum pepsinogen levels and H. pylori antibodies, respectively. Based on multiple logistic regression, the significant predictors of chronic atrophic gastritis were age over 50 years, H. pylori infection, and 20 years or more lived in Japan. Alcohol consumption, smoking, prior peptic ulcer, and history of gastric cancer in parents were not significantly associated with chronic atrophic gastritis. The results imply that H. pylori infection since earlier life and other unknown exposure factors in Japan might have played an important role in the development of chronic atrophic gastritis.
Factor B and C2 are two central enzymes for complement activation. They are multidomain serine proteases and require cofactor binding for full expression of proteolytic activities. We present a 2.1 A crystal structure of the serine protease domain of factor B. It shows a number of structural motifs novel to the chymotrypsin fold, which by sequence homology are probably present in C2 as well. These motifs distribute characteristically on the protein surface. Six loops surround the active site, four of which shape substrate-binding pockets. Three loops next to the oxyanion hole, which typically mediate zymogen activation, are much shorter or absent. Three insertions including the linker to the preceding domain bulge from the side opposite to the active site. The catalytic triad and non-specific substrate-binding site display active conformations, but the oxyanion hole displays a zymogen-like conformation. The bottom of the S1 pocket has a negative charge at residue 226 instead of the typical 189 position. These unique structural features may play different roles in domain-domain interaction, cofactor binding and substrate binding.
RSV is an important cause of lower respiratory tract illness in infants and the elderly worldwide. The components involved in immunity and those that contribute to inflammation of RSV-induced disease are not clearly understood. To address the relationship between activation antigen and cytokine expression, intracellular levels of IL-2, IL-4, IL-5 and IFN-gamma were determined for CD3, CD44, CD49d, CD54, CD62L and CD102 lymphocytes from the bronchoalveolar lavage and spleen. To examine activation at the DNA level, lymphocytes expressing IL-2, IL-4, IL-5 or IFN-gamma were analysed for G2+M DNA content or phosphatidylserine expression (apoptosis). Trafficking of lymphocytes to the BAL was detected at day 5 p.i., peaked day 7 p.i., and predominately involved CD54(+)and CD102(+)lymphocytes expressing high levels of IL-2, IL-4, IL-5 and IFN-gamma. Lymphocytes expressing CD44(+), CD49d(+)and CD62L(lo)were also observed, however they expressed these cytokines to a lesser extent. DNA analysis of lymphocytes expressing IL-2 or IFN-gamma revealed higher G2'M levels compared to lymphocytes expressing IL-4 or IL-5, suggesting greater activation of Th(1)-type lymphocytes in the lung. These data demonstrate that RSV-induced pulmonary inflammation involves extensive cellular activation and cytokine expression, particularly by CD54(+)and CD102(+)lymphocytes in the lung.
In the study this article explores, the meaning of gender identity for religious and secular Jewish and Arab women in Israeli society is examined. The study focuses on how Israeli women, rank gender identity, relative to other identities like being Jewish/Arab, being Israeli/Palestinian, religious or secular, of a certain ethnic group, and political identity. It examines the characteristics of gender identity and the attitudes that are associated with it. The analysis shows that the hierarchies of identities are different for religious and secular Jewish and Arab women, and that this is related to having different sociopolitical attitudes (e.g., Women's social and political involvement, social obedience, social influence). Thus, the hierarchy of identities and the sociopolitical attitudes of religious women indicate a more consensual acceptance of the social order than the hierarchy of identities and the sociopolitical attitudes of secular women, especially among Arab women.
Long term results of children with supracondylar humeral fractures treated with manipulation and strapping and manipulation followed by pin fixation were evaluated. Forty patients were regarded as Gartland type II injuries. 33 of these were treated with closed reduction and collar and cuff immobilisation and 7 with closed reduction and percutaneous pinning. Two cases of cubitus varus were reported one from each treatment modality. Forty-four patients were included as Gartland type III injuries. Of these 14 were treated with closed reduction and collar and cuff immobilisation, 25 with closed reduction and percutaneous pinning and five with open reduction and pinning. There were two cases of cubitus varus and one case of cubitus valgus following pin fixation. In addition one case of extension lag and one significant ulnar nerve neurapraxia was recorded following pin fixation. One case of cubitus varus was seen following manipulation and collar and cuff treatment. There was no statistical difference between either treatment modality in terms of predicting a better outcome (p0.05). We conclude that pin fixation has no advantages over simple immobilisation in certain Gartland II and III type injuries. Although pin fixation is beneficial in unstable injuries collar and cuff immobilisation continues to have an important role in the treatment of stable supracondylar fractures.
OBJECTIVES: The current gold standard for diagnosis of benign paroxysmal positional vertigo (BPPV) is the Dix-Hallpike maneuver. However, because of fatigability, the Dix-Hallpike is often falsely normal. The objective of this study was to evaluate the utility of vestibular autorotation testing in the diagnosis of BPPV. METHODS: The charts of 210 patients at a tertiary referral center for vertiginous disorders were reviewed. All patients underwent clinical evaluation, Dix-Hallpike testing, audiometry, electronystagmography, and vestibular autorotation testing. The vestibular autorotation results of patients with BPPV were compared with the findings in patients with non-BPPV vestibular disorders. The sensitivity and specificity of vestibular autorotation testing in diagnosing BPPV were calculated. RESULTS: Ninety-one patients (42.9%) had BPPV, 76 patients (36.2%) had vertigo of uncertain cause, 28 (13.3%) had unilateral vestibular hypofunction, 9 patients (4.3%) had Meniere's disease, and 2 patients (1.0%) had perilymphatic fistula. Patients with BPPV were 3.32 times more likely to have a normal horizontal gain (95% CI = 1.54-7.19). A normal horizontal gain is 85% sensitive but only 36% specific for BPPV. Patients with BPPV were 1.9 times more likely to have vertical phase lead (95% CI = 0.95-3.93). Patients with BPPV were 2.20 times more likely to have both normal horizontal gain and vertical phase lead (95% CI = 1.03-4.69) The sensitivity of the combination of normal horizontal gain and vertical phase lead on vestibular autorotation testing is 87% specific but only 25% sensitive in the diagnosis of BPPV. CONCLUSION: A normal horizontal gain or vertical phase lead on vestibular autorotation testing in a vertiginous patient is suggestive of but not exclusive to a diagnosis of BPPV. The combination of a normal horizontal gain and vertical phase lead on vestibular autorotation testing is highly suggestive of the diagnosis of BPPV. Adjuvant use of these parameters in vestibular autorotation testing may prove to be helpful in the diagnosis of BPPV.
BACKGROUND: Ensuring adequate haemostasis is a major difficulty in the field of liver surgery. This study aimed to evaluate a novel fibrin sealant (Vivostat), designed for autologous preparation, in a porcine model of partial hepatectomy. METHODS: Thirty-six Large White Landrace pigs underwent partial left hepatectomy by finger fracture under portal vascular inflow occlusion. Animals were randomized to treatment of the resected surface with either fibrin sealant (Vivostat, n = 12) or regenerated oxidized cellulose gauze (Surgicel, n = 12), or were left untreated (controls, n = 12). Blood loss from the resection margin was measured at 2-min intervals for 10 min, and the time to haemostasis was recorded. Following complete haemostasis the animals recovered for 7 days. RESULTS: Median (range) blood loss in the control group was 94.3 (17.3-467.0) g, and was significantly reduced with Vivostat (13.8 (5.5-150.9) g) and Surgicel (22.8 (5.8-67.3) g). Median (range) time to haemostasis in controls (31 (12-52) min) was also significantly reduced by Vivostat (8 (0-32) min) and Surgicel (10 (0-19) min) (both P < 0.001 versus controls, Kruskal-Wallis test). CONCLUSION: The novel fibrin sealant, Vivostat, is as effective as Surgicel cellulose gauze in achieving haemostasis after porcine partial hepatic lobectomy.
This paper reports on a clinical exchange programme that formed part of a pre-registration European nursing degree run by three collaborating institutions in England, Holland and Spain. The course included: common and shared learning including two summer schools; and the development of a second language before the students went on a three-month clinical placement in one of the other base institutions' clinical environments. The aim of the course was to enable students to become culturally sensitive carers. This was achieved by developing a programme based on transcultural nursing principles in theory and practice. Data were gathered by interview, focus groups, and questionnaires from 79 exchange students, fostering the strategies of illuminative evaluation. The paper examines: how the aims of the course were met; the factors that inhibited the attainment of certain goals; and how the acquisition of a second language influenced the students' learning about nursing. A model is presented to illustrate the process of transformative learning from the exchange experience.
1. A high throughput screening (HTS) method for the evaluation of the seven major human hepatic CYP isoform activities was developed on a 96-well format, with automation. The method utilized pooled human liver microsomes and seven probe substrates, generic conditions for incubation, reaction termination and metabolite extraction with solid phase extraction (SPE) plates. Metabolites from the seven reactions were pooled and quantified using a generic liquid chromatography and tandem mass spectrometry (LCMS/MS) method. 2. The HTS method was validated based on Km values obtained, which were in agreement with literature data. 3. The isoform inhibition profiles of ketoconazole, quinidine, sulfaphenazole, tranylcypromine, alpha-naphthoflavone, and 4-methylpyrazole against CYPs 3A4, 2D6, 2C9, 2A6 land 2C19), 1A2 and 2E1, respectively, were obtained by this HTS method. Graphically obtained IC50 values are in agreement with literature reported values. 4. The HTS method represents a significant efficiency and selectivity improvement over traditional methods, and can be used for CYP inhibition assay and can be extended for liver activity profiling.
BACKGROUND: The treatment of telangiectasia of the lower limbs has mainly consisted of injection sclerotherapy and the use of a variety of different lasers. Some patients do not respond well and others have a variety of local side-effects. Alternative treatments would be helpful in managing many patients. OBJECTIVE: To evaluate a microwave device for the treatment of lower limb telangiectasia less than 2 mm in diameter. METHODS: Twenty subjects were enrolled and evaluated with clinical and photographic assessment before and for up to 3 months after treatment. RESULTS: Improvement was seen in 18 of 20 patients. Two patients achieved greater than 75% improvement, six patients 51-75%, four patients 26-50% and six patients less than 25% improvement. CONCLUSION: A microwave delivery device improved lower limb telangiectasia in 18 of 20 patients.
The development of bladder tumors has been associated with a number of causative agents, including schistosomiasis. Schistosome-related cancers show different clinical and pathological features compared with non-schistosome-related bladder cancers, occurring in younger patients, and being predominantly of squamous cell type. This study addresses the difference between squamous and transitional tumor types in the presence of schistosome infection as a measure of the relationship between tumor genotype and phenotype. We have used comparative genomic hybridization to analyze primary muscleinvasive schistosome-related bladder tumors in 54 patients. Twenty-six of these tumors were squamous cell carcinomas; the remaining 28 were of transitional cell type. On average, transitional cell tumors showed 1.8 times the number of chromosomal aberrations as squamous cell tumors (14.4 versus 8.2, P: < 0.001). For both groups combined, the most prevalent genetic alterations were losses of 8p and 18q, and gains of 8q. Transitional cell cancers also showed frequent losses involving 5q, 9p, 10q, 11p and 11q, and gains at 1q and 17q. Loss of 11p was significantly more frequent in TCC than in SCC tumors (50 versus 4%, P: = 0.01). Squamous cell cancers showed more frequent losses of 17p and 18p than transitional tumors, which was clearly significant given the overall reduced frequency of changes in squamous cancers (P: = 0.001 and P: = 0.03, respectively). These data show that different histologic subgroups of bladder tumors are characterized by distinct patterns of chromosomal alterations. The genetic changes found in the transitional cell group are similar to those reported in non-schistosome-related transitional cell tumors, but differ from tumors exhibiting squamous differentiation.
A distinct clinical presentation of respiratory syncytial virus (RSV) infection of humans is bronchiolitis, which has clinical features similar to those of asthma. Substance P (SP), a tachykinin neuropeptide, has been associated with neurogenic inflammation and asthma; therefore, we chose to examine SP-induced inflammation with RSV infection. In this study, we examined the production of pulmonary SP associated with RSV infection of BALB/c mice and the effect of anti-SP F(ab)(2) antibodies on the pulmonary inflammatory response. The peak production of pulmonary SP occurred between days 3 and 5 following primary RSV infection and day 1 after secondary infection. Treatment of RSV-infected mice with anti-SP F(ab)(2) antibodies suggested that SP may alter the natural killer cell response to primary and secondary infection. In mice challenged after formalin-inactivated RSV vaccination, SP appears to markedly enhance pulmonary eosinophilia as well as increase polymorphonuclear cell trafficking to the lung. Based on studies with a strain of RSV that lacks the G and SH genes, the SP response to RSV infection appears to be associated with G and/or SH protein expression. These data suggest that SP may be an important contributor to the inflammatory response to RSV infection and that anti-SP F(ab)(2) antibodies might be used to ameliorate RSV-associated disease.
Five genes potentially encoding novel matrix metalloproteinases (MMPs) have been identified on the Arabidopsis thaliana data base. The predicted proteins have a similar domain structure to mammalian MMP-7, with a propeptide and catalytic domain but no C-terminal hemopexin-like domain. Four of the A. thaliana MMPs (At-MMPs) have a predicted C-terminal transmembrane domain. The At-MMPs are differentially expressed in flower, leaf, root, and stem tissues from 14-day-old plants. The cDNA for one of the At-MMPs (At1-MMP) was cloned and expressed in Escherichia coli. Following refolding and purification, the proenzyme At1-MMP was shown to undergo autolytic activation in the presence of an organomercurial with a concomitant decrease in M(r). In contrast to this, trypsin-treatment led to the formation of an inactive product. The activated At1-MMP digested myelin basic protein, but was unable to digest gelatin or casein. Three peptide substrates for MMPs were also cleaved by At1-MMP. The enzyme activity of At1-MMP was inhibited by human tissue inhibitors of metalloproteinases 1 and 2 and the hydroxamate inhibitor BB-94.