Biomedical subjects

D J Sharp

Publications and source records attributed to D J Sharp.

At least 37 records · Page 2Linked to original sources

PubMed2000

Estimation of cardiovascular risk in hypertensive patients in primary care.

Assessment of absolute cardiovascular risk is a rational method of managing hypertension. General practitioners and practice nurses were asked to estimate absolute risk in a group of elderly hypertensive patients during clinical practice. Risk was correctly estimated in 21% of patients, underestimated in 63% of patients, and overestimated in 16% of patients. Unless primary health care professionals use cardiovascular risk charts or tables, treatment decisions in primary care may not be made against realistic estimates of patients' susceptibility to cardiovascular disease.

Aged↗

PubMed2000

General practitioners miss disability and anxiety as well as depression in their patients with osteoarthritis.

BACKGROUND: General practitioners (GPs) integrate physical, psychological, and social factors when assessing patients, particularly those with chronic diseases. Recently, the emphasis has been on assessment of depression but not of other factors. AIM: To determine functional disability, psychological morbidity, social situation, and use of health and social services in patients with osteoarthritis and examine GP knowledge of these factors. METHOD: Two hundred patients completed a validated postal questionnaire about functional disability (Health Assessment Questionnaire [HAQ]), mood (Hospital Anxiety and Depression Scale [HAD]), employment status, who they lived with, welfare benefits received, and use of health and social services. A similar questionnaire was completed by the patient's GP, including a HAQ. However, a three-point scale was used to assess depression and anxiety. RESULTS: Forty-seven per cent of patients were moderately or severely disabled (HAQ > 1). GPs underestimated functional disability: mean patient HAQ = 1.04 (95% confidence interval [CI] = 0.92-1.16), mean GP HAQ = 0.74 (95% CI = 0.65-0.83), and there was low correlation between patient and GP scores (kappa = 0.24). There was moderate prevalence of depression and high prevalence of anxiety, which the GP often did not recognise: patient depression = 8.3% (95% CI = 4.1%-12.8%), GP depression = 6.0% (95% CI = 2.4%-9.6%), kappa = 0.11; patient anxiety = 24.4% (95% CI = 17.8%-31.0%), GP anxiety = 11.9% (95% CI = 6.9%-16.9%), kappa = 0.19. Only 46% of severely disabled patients (HAQ > 2) were receiving disability welfare benefits. GPs were often unaware of welfare benefits received or the involvement of other professionals. CONCLUSION: GPs frequently lack knowledge about functional disability, social factors, and anxiety as well as depression in their patients with osteoarthritis.

Adult↗

PubMed1999

The bipolar kinesin, KLP61F, cross-links microtubules within interpolar microtubule bundles of Drosophila embryonic mitotic spindles.

Previous genetic and biochemical studies have led to the hypothesis that the essential mitotic bipolar kinesin, KLP61F, cross-links and slides microtubules (MTs) during spindle assembly and function. Here, we have tested this hypothesis by immunofluorescence and immunoelectron microscopy (immunoEM). We show that Drosophila embryonic spindles at metaphase and anaphase contain abundant bundles of MTs running between the spindle poles. These interpolar MT bundles are parallel near the poles and antiparallel in the midzone. We have observed that KLP61F motors, phosphorylated at a cdk1/cyclin B consensus domain within the BimC box (BCB), localize along the length of these interpolar MT bundles, being concentrated in the midzone region. Nonphosphorylated KLP61F motors, in contrast, are excluded from the spindle and display a cytoplasmic localization. Immunoelectron microscopy further suggested that phospho-KLP61F motors form cross-links between MTs within interpolar MT bundles. These bipolar KLP61F MT-MT cross-links should be capable of organizing parallel MTs into bundles within half spindles and sliding antiparallel MTs apart in the spindle midzone. Thus we propose that bipolar kinesin motors and MTs interact by a "sliding filament mechanism" during the formation and function of the mitotic spindle.

Anaphase↗

PubMed1999

Obstacles on the path to a primary-care led National Health Service: complexities of outpatient care.

An interpretive qualitative study was carried out as part of a large cohort study of factors affecting outpatient re-attendance. Individuals from three groups involved in the provision of care across the primary-secondary interface were interviewed: patients, general practitioners and consultants. The aim was to explore understandings concerning referral to and re-attendance at outpatients, and to elicit detailed descriptions of the complexities of the outpatient experience for both providers and recipients of care at the primary/secondary interface, given the policy commitment to a 'primary-care led National Health Service'. Semi-structured interviews were carried out with nine individuals currently attending outpatients, ten general practitioners, and ten consultants. Transcripts were analysed individually and cross-checked between analysts for validity of interpretation, to identify key themes and subthemes. Data were compared across the three groups. Negative case analysis was employed. Seven major issues were identified, some of which could be identified with interests and experience of the three obvious groupings, and some of which were common. The three groupings are not as homogeneous as is often supposed. From the cross-group analysis common themes included: interpersonal communication, knowledge, power relations and anxiety/reassurance. Issues of trust, social status, funding and consumerism/litigation were also highlighted. The analysis has implications for altering the balance of care across the interface, for example in the finding of what could be termed a dissonance in power perceptions, in that consultants perceived general practitioners as relatively powerful and able to influence things', whereas general practitioners often expressed themselves as relatively powerless and unable to be proactive in 'reclaiming' their patients. The analysis highlights the complexity of the outpatient experience, drawing attention to detailed areas of contradiction, irony and conflict in the total context of outpatient care. These areas should be addressed in policy development designed to shift the balance of care further towards the primary sector.

Ambulatory Care↗

PubMed1999

Antagonistic microtubule-sliding motors position mitotic centrosomes in Drosophila early embryos.

The positioning of centrosomes, or microtubule-organizing centres, within cells plays a critical part in animal development. Here we show that, in Drosophila embryos undergoing mitosis, the positioning of centrosomes within bipolar spindles and between daughter nuclei is determined by a balance of opposing forces generated by a bipolar kinesin motor, KLP61F, that is directed to microtubule plus ends, and a carboxy-terminal kinesin motor, Ncd, that is directed towards microtubule minus ends. This activity maintains the spacing between separated centrosomes during prometaphase and metaphase, and repositions centrosomes and daughter nuclei during late anaphase and telophase. Surprisingly, we do not observe a function for KLP61F in the initial separation of centrosomes during prophase. Our data indicate that KLP61F and Ncd may function by crosslinking and sliding antiparallel spindle microtubules in relation to one another, allowing KLP61F to push centrosomes apart and Ncd to pull them together.

Adenosine Triphosphatases↗

PubMed1999

Transferrin in the developing ovarian follicle: evidence for de-novo expression by granulosa cells.

Transferrin is produced primarily by the liver and is best known as a carrier of iron in the circulation. Transferrin is also produced extra-hepatically where it may serve to suppress the generation of reactive oxygen species and act as a growth factor, in addition to its role in the endocytosis of iron. There is evidence that transferrin and its cognate receptor are important for successful development of follicles but little is known about their precise roles in this context. To learn more about their modus operandi, we undertook immunocytochemical studies which revealed that transferrin and its receptor are distributed heterogeneously in human granulosa cells, with more pronounced expression in more mature follicles. Expression within the oocyte itself was not prominent until the antral stage of development. Using nested reverse trancription-polymerase chain reaction (RT-PCR), transferrin mRNA expression was demonstrated in granulosa cells of the human and mouse ovary but not in the oocyte. Hence it appears that local production of transferrin is possible in addition to the likely uptake of circulating protein into the follicle by endocytosis. Values of transferrin in the follicular fluid were found to be highly correlated with those in serum, suggesting that the small contribution made by its localized synthesis in the granulosa cell may be important for some as yet unknown mechanism in follicle maturation.

Adult↗

PubMed1999

Evaluation of ICD-10 PHC mental health guidelines in detecting and managing depression within primary care.

BACKGROUND: The prevalence of mental disorders in the community is high, yet many remain unrecognised, misdiagnosed or poorly managed within primary care. Hence, guidelines for diagnosing and managing mental disorders in primary care, ICD-10 PHC, have been developed. AIMS: To introduce the guidelines into primary care and to assess whether they improve recognition, accuracy of diagnosis and treatment standards. METHOD: GPs recorded information on all patients presenting with mental disorders before and after guidelines were introduced. A 10% sample of patients underwent interviews to establish a formal diagnosis. Recognition of mental disorders was assessed by screening of patients attending their GP. RESULTS: The guidelines had no impact on the overall detection of mental disorders, the accuracy of diagnosis or the prescription of antidepressants. There was a significant increase in the number of patients diagnosed with depression or unexplained somatic symptoms. The GPs also made increased use of psychological interventions. CONCLUSIONS: The success of the guidelines in bringing about change is by no means certain. Some areas appeared more susceptible to change than others.

Antidepressive Agents↗

PubMed1998

Racial and ethnic differences in serum cotinine levels of cigarette smokers: Third National Health and Nutrition Examination Survey, 1988-1991.

CONTEXT: Cotinine, a metabolite of nicotine, is a marker of exposure to tobacco smoke. Previous studies suggest that non-Hispanic blacks have higher levels of serum cotinine than non-Hispanic whites who report similar levels of cigarette smoking. OBJECTIVE: To investigate differences in levels of serum cotinine in black, white, and Mexican American cigarette smokers in the US adult population. DESIGN: Third National Health and Nutrition Examination Survey, 1988-1991. PARTICIPANTS: A nationally representative sample of persons aged 17 years or older who participated in the survey. OUTCOME MEASURES: Serum cotinine levels by reported number of cigarettes smoked per day and by race and ethnicity. RESULTS: A total of 7182 subjects were involved in the study; 2136 subjects reported smoking at least 1 cigarette in the last 5 days. Black smokers had cotinine concentrations substantially higher at all levels of cigarette smoking than did white or Mexican American smokers (P<.001). Serum cotinine levels for blacks were 125 nmol/L (22 ng/mL) (95% confidence interval [CI], 79-176 nmol/L [14-31 ng/mL]) to 539 nmol/L (95 ng/mL) (95% CI, 289-630 nmol/L [51-111 ng/mL]) higher than for whites and 136 nmol/L (24 ng/mL) (95% CI, 85-182 nmol/L [15-32 ng/mL]) to 641 nmol/L (113 ng/mL) (95% CI, 386-897 nmol/L [68-158 ng/mL]) higher than for Mexican Americans. These differences do not appear to be attributable to differences in environmental tobacco smoke exposure or in number of cigarettes smoked. CONCLUSIONS: To our knowledge, this study provides the first evidence from a national study that serum cotinine levels are higher among black smokers than among white or Mexican American smokers. If higher cotinine levels among blacks indicate higher nicotine intake or differential pharmacokinetics and possibly serve as a marker of higher exposure to cigarette carcinogenic components, they may help explain why blacks find it harder to quit and are more likely to experience higher rates of lung cancer than white smokers.

Adolescent↗

PubMed1997

Identification of a microtubule-associated motor protein essential for dendritic differentiation.

The quintessential feature of the dendritic microtubule array is its nonuniform pattern of polarity orientation. During the development of the dendrite, a population of plus end-distal microtubules first appears, and these microtubules are subsequently joined by a population of oppositely oriented microtubules. Studies from our laboratory indicate that the latter microtubules are intercalated within the microtubule array by their specific transport from the cell body of the neuron during a critical stage in development (Sharp, D.J., W. Yu, and P.W. Baas. 1995. J. Cell Biol. 130:93- 104). In addition, we have established that the mitotic motor protein termed CHO1/MKLP1 has the appropriate properties to transport microtubules in this manner (Sharp, D.J., R. Kuriyama, and P.W. Baas. 1996. J. Neurosci. 16:4370-4375). In the present study we have sought to determine whether CHO1/MKLP1 continues to be expressed in terminally postmitotic neurons and whether it is required for the establishment of the dendritic microtubule array. In situ hybridization analyses reveal that CHO1/MKLP1 is expressed in postmitotic cultured rat sympathetic and hippocampal neurons. Immunofluorescence analyses indicate that the motor is absent from axons but is enriched in developing dendrites, where it appears as discrete patches associated with the microtubule array. Treatment of the neurons with antisense oligonucleotides to CHO1/MKLP1 suppresses dendritic differentiation, presumably by inhibiting the establishment of their nonuniform microtubule polarity pattern. We conclude that CHO1/MKLP1 transports microtubules from the cell body into the developing dendrite with their minus ends leading, thereby establishing the nonuniform microtubule polarity pattern of the dendrite.

Animals↗

PubMed1997

Inhibition of a mitotic motor compromises the formation of dendrite-like processes from neuroblastoma cells.

Microtubules in the axon are uniformly oriented, while microtubules in the dendrite are nonuniformly oriented. We have proposed that these distinct microtubule polarity patterns may arise from a redistribution of molecular motor proteins previously used for mitosis of the developing neuroblast. To address this issue, we performed studies on neuroblastoma cells that undergo mitosis but also generate short processes during interphase. Some of these processes are similar to axons with regard to their morphology and microtubule polarity pattern, while others are similar to dendrites. Treatment with cAMP or retinoic acid inhibits cell division, with the former promoting the development of the axon-like processes and the latter promoting the development of the dendrite-like processes. During mitosis, the kinesin-related motor termed CHO1/MKLP1 is localized within the spindle midzone where it is thought to transport microtubules of opposite orientation relative to one another. During process formation, CHO1/ MKLP1 becomes concentrated within the dendrite-like processes but is excluded from the axon-like processes. The levels of CHO1/MKLP1 increase in the presence of retinoic acid but decrease in the presence of cAMP, consistent with a role for the protein in dendritic differentiation. Moreover, treatment of the cultures with antisense oligonucleotides to CHO1/MKLP1 compromises the formation of the dendrite-like processes. We speculate that a redistribution of CHO1/MKLP1 is required for the formation of dendrite-like processes, presumably by establishing their characteristic nonuniform microtubule polarity pattern.

Animals↗

PubMed1997

Profiling outpatient workload: practice variations between consultant firms and hospitals in south west England.

OBJECTIVES: To describe the variation in outpatient new to old ratios between consultants and between providers for seven high volume specialties (four surgical, three medical). DESIGN: This was a descriptive study at consultant and provider unit level based upon patient administration system data from the South and West Regional Health Authority for the financial year 1992-93. Additional components of variance analysis was used to distinguish individual consultant effects from host institution effects. SETTING: The former South Western Regional Health Authority area from Gloucestershire to Cornwall. SUBJECTS: Altogether 345 consultant firms in seven specialties grouped into 13 provider unit groups. MAIN MEASURES: New to old ratio, omitting elective inpatients followed up as outpatients. RESULTS: Variation between consultants is greater in surgical than in medical specialties, while absolute levels of new to old ratios tend to be higher in surgical specialties than in medical. Variation between provider unit groups is also greater in surgical specialties. Analysis of variance shows that more total variance is attributable to provider unit group in gynaecology than in other specialties. CONCLUSIONS: Within individual specialties there is evidence of substantial variation that is not attributable to underlying differences in morbidity patterns. There is evidence of marked variation in terms of both individual consultants and institutions, a finding that provides the springboard for further analytical work. Published routine outpatient activity statistics should distinguish between new referrals, inpatient follow up, and clinic rebookings.

Analysis of Variance↗

PubMed1997

Expression of a minus-end-directed motor protein induces Sf9 cells to form axon-like processes with uniform microtubule polarity orientation.

Neurons extend two types of processes with distinct morphologies and patterns of microtubule polarity orientation. Axons are thin cylindrical processes containing microtubules that are uniformly oriented with their plus-ends-distal to the cell body while dendrites are stout tapering processes that contain nonuniformly oriented microtubules. We have proposed that these distinct microtubule patterns are established by molecular motors that transport microtubules into each type of process with the appropriate orientation. To test the feasibility of this proposal, we have embarked on a series of studies involving the expression of vertebrate motors in insect Sf9 cells. We previously focused on a kinesin-related protein termed CHO1/MKLP1, which localizes to the midzone of the mitotic spindle, and which has been shown to have the appropriate properties to transport microtubules of opposite orientation relative to one another. Expression of a fragment of CHO1/MKLP1 containing its motor domain induces Sf9 cells to extend processes with a stout tapering morphology and a nonuniform microtubule polarity pattern similar to dendrites. Here we focus on a minus-end-directed kinesin-related motor protein termed CHO2, which localizes to the non-overlapping regions of the mitotic spindle, and which has been shown to have the appropriate properties to transport microtubules with plus-ends-leading. Sf9 cells induced to express a fragment of CHO2 containing its motor domain extend processes with a long cylindrical morphology and a uniformly plus-end-distal microtubule polarity pattern similar to axons. These results show that motor proteins have the capacity to organize distinct patterns of microtubule polarity orientation during process outgrowth, and that these patterns are intimately related to the unique morphological characteristics of the processes. Moreover, mutation of three amino acids corresponding to the ATP binding site necessary for motor function suppresses the capacity of the CHO2 fragment to induce process formation and microtubule reorganization, indicating that at least in the case of CHO2, the transport properties of the motor are essential for it to elicit these effects.

Animals↗

PubMed1997

A community waterborne outbreak of salmonellosis and the effectiveness of a boil water order.

OBJECTIVES: A 1993 large water-borne outbreak of Salmonella typhimurium infections in Gideon, Mo, a city of 1100 with an unchlorinated community water supply, was investigated to determine the source of contamination and the effectiveness of an order to boil water. METHODS: A survey of household members in Gideon and the surrounding township produced information on diarrheal illness, water consumption, and compliance with the boil water order. RESULTS: More than 650 persons were ill; 15 were hospitalized, and 7 died. Persons consuming city water were more likely to be ill (relative risk [RR] = 9.1, 95% confidence interval [CI] = 2.9, 28.4), and the attack rate increased with increased water consumption. S. typhimurium was recovered from samples taken from a city fire hydrant and a water storage tower. Persons in 31% (30/ 98) of city households had drunk unboiled water after being informed about the boil water order, including 14 individuals who subsequently became ill. Reasons for noncompliance included "not remembering" (44%) and "disbelieving" (25%) the order. CONCLUSIONS: Communities with deteriorating water systems risk widespread illness unless water supplies are properly operated and maintained. Effective education to improve compliance during boil water orders is needed.

Data Collection↗

PubMed1996

Protamines of reptiles.

We have characterized for the first time the complete primary structure of the main protamine components of the sperm from four reptiles: Chrysemys picta (turtle), Elaphe obsoleta (snake), Anolis carolinensis (lizard), and Alligator mississipiensis (crocodilian). These species were chosen to represent one of each of the main phylogenetic branches of this taxonomic group. Comparison of these protamine sequences with those already available from other vertebrate groups allows us to define properly the chemical consensus composition of protamines and provides a unique insight into their molecular evolution and classification.

Alligators and Crocodiles↗

PubMed1996

Expression of a kinesin-related motor protein induces Sf9 cells to form dendrite-like processes with nonuniform microtubule polarity orientation.

The microtubules (MTs) within neuronal processes are highly organized with regard to their polarity and yet are not attached to any detectable nucleating structure. Axonal MTs are uniformly oriented with their plus ends distal to the cell body, whereas dendritic MTs are of both orientations. Here, we sought to test the capacity of motor-driven MT transport to organize distinct MT patterns during process outgrowth. We focused on CHO1/MKLP1, a kinesin-related protein present in the midzonal region of the mitotic spindle where MTs of opposite orientation overlap. Insect ovarian Sf9 cells induced to express the N-terminal portion of the molecule form MT-rich processes with a morphology similar to that of neuronal dendrites (Kuriyama et al., 1994). Nascent processes contain uniformly plus-end-distal MTs, but these are joined by minus-end-distal MTs as the processes continue to develop. Thus, this CHO1/MKLP1 fragment establishes a nonuniform MT polarity pattern and does so by a similar sequence of events as occurs with the dendrite, the antecedent of which is a short process with a uniform MT polarity orientation. Two lines of evidence suggest that these results are elicited by motor-driven MT transport. First, there is a depletion of MTs from the cell body during process outgrowth. Second, the same polarity pattern is obtained when net MT assembly is suppressed pharmacologically during process formation. Collectively, these findings provide precedent for the idea that motor-driven transport can organize MTs into distinct patterns of polarity orientation during process outgrowth.

Cells, Cultured↗

PubMed1996

Breast screening: a randomised controlled trial in UK general practice of three interventions designed to increase uptake.

STUDY OBJECTIVES: To determine the relative effectiveness of three interventions designed to increase the uptake of breast screening. DESIGN: Randomised controlled trial of a nurse visit with health education (group A), nurse visit without health education (group B), and GP letter (group C). SETTING: The area of south east London served by the Butterfly Walk Breast Screening Unit in Camberwell. PARTICIPANTS: Women aged between 50 and 64 years who were registered with 27 GPs in the Lambeth, Southwark and Lewisham family health services authority and who had not attended for first round screening. MAIN RESULTS: Altogether 799 women were randomly allocated to the three groups. In general, delivering the nurse based interventions proved difficult. In group A, 11.4% (95% CI 7.9, 14.9%) of women subsequently attended for screening compared with 7.8% (95% CI 5.1, 11.4%) in group B and 13.1% (95% CI 7.9, 18.4%) in group C. The differences between the groups (95% CIs) were not statistically significant: A versus C, -1.7% (-8.0, +4.6%); B versus C, -5.3% (-11.3, +0.7%); A versus B, +3.6% (-1.0, +8.2%). CONCLUSIONS: A personal letter from the GP seems to be at least as effective at increasing the uptake of breast screening in non-attenders as a nurse making a home visit to discuss the issue of breast screening, and is not noticeably less effective than a visit at which a health education intervention is delivered. It is possible that the GP letter is considerably more effective than either of the two interview-based interventions. With regard to implementing strategies which will increase breast screening uptake and are cost effective, further trials of similar minimal interventions in primary care are required.

Breast Neoplasms↗

PubMed1995

Lung cancer in nonsmoking women. Histology and survival patterns.

BACKGROUND: Despite the widespread view that important clinical and etiologic differences exist between histologic categories of lung cancer, few studies have examined the accuracy of hospital-reported pathologic diagnoses of lung cancer. METHODS: A review of pathologic material and an assessment of survival patterns were conducted in conjunction with a recently completed case-control study of lung cancer among nonsmoking women in Missouri. Using established protocols, tissue slides from tumors of 482 patients were reviewed by 3 pathologists. RESULTS: Adenocarcinoma was the most common histologic type among former smokers and lifetime nonsmokers. The overall agreement rate between the original and review diagnoses was 65.6%. The positive predictive value ranged from 0.33 for bronchioalveolar carcinomas to 0.84 for adenocarcinomas. Agreement rates for small, medium, and large hospitals were 63.1, 66.6, and 66.2%, respectively. Survival rates were highest for bronchioalveolar carcinoma and lowest for small cell carcinoma. CONCLUSION: Given the importance of lung cancer to public health and the need to examine risk by histologic type, these data indicate that pathologic review of registry-reported lung cancer cases may be an important component of large scale studies of etiology.

Adenocarcinoma↗

PubMed1995

Transport of dendritic microtubules establishes their nonuniform polarity orientation.

The immature processes that give rise to both axons and dendrites contain microtubules (MTs) that are uniformly oriented with their plus-ends distal to the cell body, and this pattern is preserved in the developing axon. In contrast, developing dendrites gradually acquire nonuniform MT polarity orientation due to the addition of a subpopulation of oppositely oriented MTs (Baas, P. W., M. M. Black, and G. A. Banker. 1989. J. Cell Biol. 109:3085-3094). In theory, these minus-end-distal MTs could be locally nucleated and assembled within the dendrite itself, or could be transported into the dendrite after their nucleation within the cell body. To distinguish between these possibilities, we exposed cultured hippocampal neurons to nanomolar levels of vinblastine after one of the immature processes had developed into the axon but before the others had become dendrites. At these levels, vinblastine acts as a kinetic stabilizer of MTs, inhibiting further assembly while not substantially depolymerizing existing MTs. This treatment did not abolish dendritic differentiation, which occurred in timely fashion over the next two to three days. The resulting dendrites were flatter and shorter than controls, but were identifiable by their ultrastructure, chemical composition, and thickened tapering morphology. The growth of these dendrites was accompanied by a diminution of MTs from the cell body, indicating a net transfer of MTs from one compartment into the other. During this time, minus-end-distal microtubules arose in the experimental dendrites, indicating that new MT assembly is not required for the acquisition of nonuniform MT polarity orientation in the dendrite. Minus-end-distal microtubules predominated in the more proximal region of experimental dendrites, indicating that most of the MTs at this stage of development are transported into the dendrite with their minus-ends leading. These observations indicate that transport of MTs from the cell body is an essential feature of dendritic development, and that this transport establishes the nonuniform polarity orientation of MTs in the dendrite.

Animals↗