Biomedical subjects
Publications and source records attributed to M Hagan.
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The reaction dynamics of vibrationally excited vinyl bromide have been investigated using classical trajectory methods on a neural network potential surface that is fitted to an ab initio database of 12 122 configuration energies obtained from electronic structure calculations conducted at the MP4(SDQ) level of theory using a 6-31G(d,p) basis set for the carbon and hydrogen atoms and Huzinaga's (43334334) basis set augmented with split outer s and p orbitals (4332143214) and a polarization f orbital with an exponent of 0.5 for the bromine atom. The sampling of the 12-dimensional configuration hyperspace of vinyl bromide prior to execution of the electronic structure calculations is accomplished by combining novelty-sampling methods, chemical intuition, and trajectory sampling on empirical and neural network surfaces. The final potential is obtained using a two-layer feed-forward neural network comprising 38 and 1 neurons, respectively, with hyperbolic tangent sigmoid and linear transfer functions in the hidden and output layers, respectively. The fitting is accomplished using the Levenberg-Marquardt algorithm with early stopping and Bayesian regularization methods to avoid overfitting. The interpolated potentials have a standard deviation from the ab initio results of 0.0578 eV, which is within the range generally regarded as "chemical accuracy" for the purposes of electronic structure calculations. It is shown that the potential surface may be easily and conveniently transferred from one research group to another. The files required for transfer of the vinyl bromide surface can be obtained from the Electronic Physics Auxiliary Publication Service. Total dissociation rate coefficients for vinyl bromide are obtained at five different excitation energies between 4.50 and 6.44 eV. Branching ratios into each of the six open reaction channels are computed at 24 vibrational energies in the range between 4.00 and 6.44 eV. The distribution of vibrational energies in HBr formed via three-center dissociation from vinyl bromide is determined and compared with previous theoretical and experimental results. It is concluded that the combination of ab initio electronic structure calculations, novelty sampling with chemical intuition and trajectories on empirical analytic surfaces, and feed-forward neural networks provides a viable framework in which to execute purely ab initio molecular-dynamics studies on complex systems with multiple open reaction channels.
A neural network/trajectory approach is presented for the development of accurate potential-energy hypersurfaces that can be utilized to conduct ab initio molecular dynamics (AIMD) and Monte Carlo studies of gas-phase chemical reactions, nanometric cutting, and nanotribology, and of a variety of mechanical properties of importance in potential microelectromechanical systems applications. The method is sufficiently robust that it can be applied to a wide range of polyatomic systems. The overall method integrates ab initio electronic structure calculations with importance sampling techniques that permit the critical regions of configuration space to be determined. The computed ab initio energies and gradients are then accurately interpolated using neural networks (NN) rather than arbitrary parametrized analytical functional forms, moving interpolation or least-squares methods. The sampling method involves a tight integration of molecular dynamics calculations with neural networks that employ early stopping and regularization procedures to improve network performance and test for convergence. The procedure can be initiated using an empirical potential surface or direct dynamics. The accuracy and interpolation power of the method has been tested for two cases, the global potential surface for vinyl bromide undergoing unimolecular decomposition via four different reaction channels and nanometric cutting of silicon. The results show that the sampling methods permit the important regions of configuration space to be easily and rapidly identified, that convergence of the NN fit to the ab initio electronic structure database can be easily monitored, and that the interpolation accuracy of the NN fits is excellent, even for systems involving five atoms or more. The method permits a substantial computational speed and accuracy advantage over existing methods, is robust, and relatively easy to implement.
OBJECTIVE: To assess the skills of community health volunteers in diagnosing active trachoma and distributing azithromycin in the Northern Region of Ghana. METHODS: Six community health volunteers from Daboya were trained to diagnose trachoma and to treat the disease using azithromycin. They were also informed of the drug's possible side-effects. Under supervision, each volunteer then examined, and if necessary treated, 15 households. The dose of azithromycin was determined by weight; height was also measured. Tablets were given in preference to suspension when possible. RESULTS: The volunteers' diagnostic sensitivity for active trachoma was 63%; their specificity was 96%. At the household level, their "decision to treat" was correct in 83% of households. In 344 treatment episodes, volunteers planned a dose of azithromycin outside the range 15-30 mg/kg on only seven occasions (2.0% of all planned treatments). The volunteers' drug management skills were good, the response of the community was excellent, and adverse reactions were infrequent. Diagnosis of active trachoma, record-keeping skills, and knowledge of side-effects were found to need greater emphasis in any future education programme. Most people aged four years or older were able to swallow tablets. For those taking tablets, the correlation between the data gathered for height and weight shows that calculating azithromycin doses by height is a valid alternative to calculating it by weight. CONCLUSION: Trained community health volunteers have a potential role in identifying active trachoma and distributing azithromycin. To simplify training and logistics, it may be better to base dosage schedules on height rather than weight for those taking tablets, which included most people aged four years or more in the population studied.
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BACKGROUND: A multicentre study was carried out in Ghana and southern India to determine the aetiology of suppurative keratitis in two regions located at similar tropical latitudes. Studies of fungal keratitis from the literature were reviewed. METHODS: Patients presenting at rural and urban eye units with suspected microbial keratitis were recruited to the study. Corneal ulceration was defined as loss of corneal epithelium with clinical evidence of infection with or without hypopyon. Microscopy and culture were performed on all corneal specimens obtained. RESULTS: 1090 patients were recruited with suspected microbial keratitis between June 1999 and May 2001. Overall the principal causative micro-organisms in both regions were filamentous fungi (42%): Fusarium species and Aspergillus species were the commonest fungal isolates. Pseudomonas species were most frequently isolated from cases of bacterial keratitis in Ghana but in India the commonest bacterial isolates were streptococci. CONCLUSION: Infections of the cornea due to filamentous fungi are a frequent cause of corneal damage in developing countries in the tropics and are difficult to treat. Microscopy is an essential tool in the diagnosis of these infections. A knowledge of the "local" aetiology within a region is of value in the management of suppurative keratitis in the event that microscopy cannot be performed.
An attempt was made to assess the true public-health importance of onchocercal skin disease throughout the African region and hence provide an objective basis for the rational planning of onchocerciasis control in the area. The seven collaborative centres that participated in the study (three in Nigeria and one each in Ghana, Cameroon, Tanzania and Uganda) were all in areas of rainforest or savannah-forest mosaic where onchocercal blindness is not common. A cross-sectional dermatological survey was undertaken at each site following a standard protocol. At each site, the aim was to examine at least 750 individuals aged 5 years and living in highly endemic communities and 220-250 individuals aged 5 years and living in a hypo-endemic (control) community. Overall, there were 5459 and 1451 subjects from hyper-and hypo-endemic communities, respectively. In the highly endemic communities, the prevalence of itching increased with age until 20 years and then plateaued, affecting 42% of the population aged 20 years. There was a strong correlation between the prevalence of itching and the level of endemicity (as measured by the prevalence of nodules; r=0.75; P<0.001). The results of a multivariate logistic regression analysis showed that, at the individual level, the presence of onchocercal reactive skin lesions (acute papular onchodermatitis, chronic papular onchodermatitis and/or lichenified onchodermatitis) was the most important risk factor for pruritus, with an odds ratio (OR) of 18.3 and 95% confidence interval (CI) of 15.19-22.04, followed by the presence of palpable onchocercal nodules (OR=4.63; CI=4.05-5.29). In contrast, non-onchocercal skin disease contributed very little to pruritus in the study communities (OR=1.29; CI=1.1-1.51). Onchocercal skin lesions affected 28% of the population in the endemic villages. The commonest type was chronic papular onchodermatitis (13%), followed by depigmentation (10%) and acute papular onchodermatitis (7%). The highest correlation with endemicity was seen for the prevalence of any onchocercal skin lesion and/or pruritus combined (r=0.8; P<0.001). Cutaneous onchocerciasis was found to be a common problem in many endemic areas in Africa which do not have high levels of onchocercal blindness. These findings, together with recent observations that onchocercal skin disease can have major, adverse, psycho-social and socio-economic effects, justify the inclusion of regions with onchocercal skin disease in control programmes based on ivermectin distribution. On the basis of these findings, the World Health Organization launched a control programme for onchocerciasis, the African Programme for Onchocerciasis Control (APOC), that covers 17 endemic countries in Africa.
Corticotropin-releasing hormone (CRH) is a neuropeptide thought to play a role in appetite regulation. In this report, we used a serial cerebrospinal fluid (CSF) sampling technique to examine the relationship between CSF CRH, plasma ACTH and cortisol and perceptions of hunger and satiety in fasting and sated volunteers. CSF was withdrawn continuously from 11:00 AM to 5:00 PM via an indwelling subarachnoid catheter. Blood was withdrawn every 10 min via an antecubital vein catheter. Fed subjects received a meal at 1:00 PM. Subjects who were fed had lower post-prandial ratings on hunger scales and higher ratings on satiety scales. Fed subjects also had slightly lower levels of CSF CRH after feeding. Furthermore, fed subjects had higher ACTH and cortisol concentrations in the first 3 h; by the fourth h the opposite was true. Our findings do not support the hypothesis that CNS CRH is a central satiety factor in the human. Instead our findings of slightly diminished CSF CRH levels after feeding may be accounted for by the rises in glucocorticoids and their associated negative feedback effects on CNS CRH. Alternatively, our findings could also reflect changes in CRH levels associated with feeding in multiple brain areas and in the spinal cord with the net effect being in the negative direction.
These studies examine the role(s) played by the mitogen-activated protein kinase (MAPK) pathway after exposure of DU145 prostate carcinoma cells to radiation. Radiation (2 Gy) was found to cause both immediate primary (0-30 min) and prolonged secondary activations (90-1440 min) of the MAPK pathway. These activations of the MAPK pathway were abolished by inhibition of epidermal growth factor receptor (EGFR) function. The secondary activation was also abolished by addition of a neutralizing monoclonal antibody against transforming growth factor alpha (TGFA). Activation of the MAPK pathway could be induced in nonirradiated cells by the transfer of medium from irradiated cultures. Neutralizing antibody to TGFA blocked this effect, indicating that radiation causes secondary activation of the MAPK pathway by release of TGFA in DU145 cells. Radiation induced a transient G(2)/M-phase growth arrest that was prolonged for up to 24 h by inhibition of the MAPK pathway. Inhibition of the MAPK pathway significantly increased the ability of radiation to cause apoptosis 24 h after exposure. The ability of DU145 cells to proliferate after irradiation became dependent on MAPK signaling. When cells were subjected to single doses or fractionated radiation exposure, continuous inhibition of the MAPK pathway significantly decreased clonogenic survival. Only a small fraction of this cell killing could be accounted for by apoptosis within the first 96 h. Thus inhibition of the MAPK pathway increased radiation-induced cell killing likely by both apoptotic and nonapoptotic mechanisms. Collectively, our findings indicate that disruption of the TGFA/EGFR/MAPK pathway may represent a strategy that could be exploited to manipulate prostate carcinoma growth and cell survival after irradiation.
OBJECTIVE: The aim of this paper is to determine the efficacy of dexamphetamine in adult attention deficit hyperactivity disorder (ADHD) in a naturalistic setting. METHOD: A randomised, double-blind, placebo-controlled study of dexamphetamine was conducted by two psychiatrists in private practice who saw a total of 68 consecutive referrals of patients thought to have ADHD by their referring general practitioners. Patients were admitted to the study if their current level of ADHD symptoms satisfied DSM-IV criteria (modified for use in adults), and were not currently comorbid for major mood disturbance or substance abuse. Response to medication was assessed by repeated administration of these modified DSM-IV criteria, self- and relatives' rating, as well as clinician rating using the Clinical Global Impressions Scale. More general outcome measures included the Brief Symptom Inventory and a patient satisfaction questionnaire. Medication side effects were recorded, including monitoring blood pressure and weight change. Urinalysis monitored concurrent substance usage and compliance. RESULTS: Dexamphetamine had a significant therapeutic response exceeding the placebo response (p = 0.045). The response was similar in both genders and across the age range. It was detected by patients, their relatives and the two clinicians. The only significant side effect was weight loss. One patient on dexamphetamine discontinued the trial because of an event possibly related to the medication. CONCLUSIONS: In the short term, dexamphetamine appears to be efficacious in treating adult ADHD. As this is the first study in the literature, the result requires replication. Given that stimulant medication use in adult ADHD appears to be long-term, studies of long-term efficacy need to be carried out.
PURPOSE: This study examines the effect of 5-fluorouracil administration during preoperative irradiation on rectal cancer tumor proliferation. PATIENTS AND METHODS: One hundred and fifty-three patients with locally advanced rectal cancer received 45 to 50 Gy of preoperative irradiation with (103 patients) and without (50 patients) concurrent 5-fluorouracil, followed by surgery. Pretreatment tumor biopsies and postirradiation surgical specimens were scored for proliferative activity by assaying the extent of Ki-67 and proliferating cell nuclear antigen immunostaining and the number of mitoses per ten high-powered fields. Postirradiation specimens were also assessed for downstaging. RESULTS: Although 5-fluorouracil did not improve downstaging rates, marked decreases in the activity of all three markers of proliferation (mitotic counts, Ki-67, and proliferating cell nuclear antigen immunostaining) were seen in rectal cancers of patients receiving the drug. No significant decreases were noted in patients undergoing irradiation only. CONCLUSION: The addition of 5-fluorouracil to preoperative irradiation resulted in a more complete inactivation of the proliferating population. Frequency of downstaging, however, was unaffected. Thus, the quiescent cell population appears to represent a substantial barrier to further downstaging. New treatment strategies should be aimed at controlled recruitment of quiescent tumor cells at the time of irradiation.
OBJECTIVE: To determine the effects of ivermectin in annual, 3-monthly and 6-monthly doses on onchocercal skin p6isease (OSD) and severe itching. METHOD: A multicentre, double-blind placebo controlled trial was conducted among 4072 residents of rural communities in Ghana, Nigeria and Uganda. Baseline clinical examination categorized reactive skin lesions as acute papular onchodermatitis, chronic papular onchodermatitis and lichenified onchodermatitis. Presence and severity of itching was determined by open-ended and probing questions. Clinical examination and interview took place at baseline and each of 5 subsequent 3-monthly follow-up visits. RESULTS: While prevalence and severity of reactive lesions decreased for all 4 arms, those receiving ivermectin maintained a greater decrease in prevalence and severity over time. The difference between ivermectin and placebo groups was significant for prevalence at 9 months and for severity at 3 months. Differences between placebo and ivermectin groups were much more pronounced for itching. From 6 months onward, the prevalence of severe itching was reduced by 40-50% among those receiving ivermectin compared to the trend in the placebo group. CONCLUSION: This is an important effect on disease burden as severe itching is for the affected people the most troubling complication of onchocerciasis. The difference among regimens was not significant, and the recommended regimen of annual treatment for the control of ocular onchocerciasis appears also the most appropriate for onchocerciasis control in areas where the skin manifestations predominate. The final determination of the effect on skin lesions requires a longer period of study.
The clinical features of onchocercal dermatitis include itching, papular and papulomacular rash, skin atrophy and depigmentation. The results of a multi-country study have shown that > 30% of the population in communities where onchocerciasis is endemic have onchocercal dermatitis. The most troubling symptom suffered by those affected was itching and this was closely related to reactive onchocercal dermatitis (acute papular, chronic papular and/or lichenified lesions). Reactive onchocercal dermatitis and troublesome itching were common in all age-groups and were an important cause of stigma in most endemic communities, those affected suffering from poor self-esteem. Concern about onchocercal depigmentation varied between study sites and subjects.
Coronary heart disease (CHD) and cancers of the breast, prostate, and colon are more common in industrialized countries than in the developing world, and to some degree, these conditions appear to share risk factors. To investigate whether there is an association between these cancers and a prior history of CHD, a hospital-based case-control study was conducted at Columbia-Presbyterian Medical Center in New York. The study was based on 252 breast cancer cases, 256 colorectal cancer cases, and 322 benign surgical controls, all of whom underwent biopsy or surgery between January 1989 and December 1992, and on 319 prostate cancer cases and 189 benign prostatic hypertrophy controls diagnosed between January 1984 and December 1986 (prior to widespread use of prostate-specific antigen screening). Medical records were reviewed on each, focusing on the preoperative anesthesia and surgical clearances. No association was found between a history of CHD and breast or colorectal cancer, but an elevated risk was found for prostate cancer (odds ratio, 2.00; 95% confidence interval, 1.18-3.39), using unconditional logistic regression with adjustment for appropriate confounders. No association was found between cigarette smoking and any of the three cancers. Aspirin use was protective for colorectal cancer (odds ratio, 0.35; 95% confidence interval, 0.17-0.73) but had no association with breast or prostate cancer. The study suggests that individuals with CHD are at elevated risk for prostate cancer but not breast or colorectal cancer. Etiological risk factors associated with CHD should be investigated with regard to prostate cancer. Patients with CHD may represent a high-risk group for prostate cancer and potential future targets for prostate cancer screening interventions.
BACKGROUND: This study was performed to determine whether antibodies against the amino-terminus of the beta-chain of fibrin (anti-beta) could noninvasively distinguish actively enlarging thrombi from thrombi stabilized with anticoagulants. METHODS AND RESULTS: Dogs with unilateral femoral vein thrombi were allocated into three groups: (1) no anticoagulation, (2) intravenous heparin maintained in the "therapeutic" range (0.2 to 0.5 U/mL plasma), and (3) "excess" heparin, maintained at >1.0 U/mL plasma. Thrombolysis was suppressed with tranexamic acid. (111)In-labeled anti-beta was infused, and gamma scans of the legs were performed at regular intervals for 24 hours. Scans were interpreted in a blinded fashion. In addition, for each scan, the number of gamma counts from the femoral area on the thrombosed side was compared with the contralateral side. Clot/blood isotope density was determined postmortem. Leg thrombi in the no-anticoagulation group were 100% detectable, mean (+/-SD) relative count in the thrombosed femoral area was 186% (+/-30%) of the contralateral side, and clot/blood ratio was 14.7 (+/-2.0). Thrombi in the therapeutic heparin group were only 75% detectable, relative counts in the thrombosed femoral areas decreased to 125% (+/-20%), and clot/blood ratio declined to 11.3 (+/-3.5). In the "excess heparin" group, leg thrombi were only 50% detectable, the thrombosed femoral area had relative counts of 118%+/-17%, and the clot/blood ratio fell to 7.8+/-1.9. CONCLUSIONS: Radiolabeled anti-beta noninvasively distinguishes propagating thrombi from those stabilized by anticoagulants. They may be useful for detecting thrombosis clinically as well as for monitoring the efficacy of anticoagulation.
In follow-up of a screening program for prostate cancer, 192 men from the urban Denver area and 244 men from rural northeastern Colorado completed a mailed questionnaire addressing their health and medical care, insurance coverage, lifestyles, and desire for health education and screening programs. Rural respondents were older and more were self-insured. Twice as many urban men were prompted to participate in the prostate screening program by media announcements (51.0% vs 23.4%), while spouses (21.3% vs 9.4%) and physicians (13.1% vs 6.8%) played greater roles in motivating rural participants. The primary topics for health information and education needs perceived by the rural men were cancer-related, while those for urban men concentrated on cardiac risk factors. Both preferred that this information be provided in the form of written materials or through their personal physicians. This pilot study suggests certain differences in the present health practices, motivational factors, and health information and education needs in urban versus rural men. These differences should be explored further and be considered in the design of cancer prevention and screening programs for these populations.
BACKGROUND: Serum ferritin is normally a marker of iron overload. Ferritin genes are sited at chromosomes 19 and 11. Regulation of ferritin synthesis involves an interaction between an iron regulatory protein (IRP) and part of the ferritin mRNA designated the iron regulatory element (IRE). A disorder of ferritin synthesis resulting in hyperferritinaemia in the absence of iron overload has been described recently. PATIENTS AND METHODS: Hyperferritinaemia in the absence of iron overload was detected in a patient who was investigated for possible haemochromatosis. Serum iron, transferrin saturation, and ferritin concentration were studied in 11 members of this patient's family from three generations. Eight members had DNA samples analysed by direct cycle sequencing of the 5' untranslated region of the L ferritin gene. RESULTS: Six of the family members studied had serum ferritin concentrations greater than 900 micrograms/l. However, serum iron and transferrin saturation were normal in these subjects who all had evidence of cataracts. Three affected family members who had genetic studies of the L ferritin gene on chromosome 19 had an A to G point mutation which was not found in unaffected members. CONCLUSIONS: There was complete concordance between a mutated IRE, cataracts, and hyperferritinaemia in three generations of this family. This family study confirms the finding that hereditary hyperferritinaemia in the absence of iron overload is an autosomal dominant inherited disorder.
UNLABELLED: Accurate non-invasive diagnosis of deep venous thrombosis and pulmonary embolism remains an elusive goal. Radiolabeled antibodies specific for the epitope exposed on the beta-chain of fibrin after fibrino-peptide B release (anti-beta) enabled in situ imaging of thrombi in experimental subjects with nuclear medicine techniques. When used in patients anticoagulated for thrombo-embolic disease, however, the antibody was unable to reliably image the thrombi. We postulated that the neoepitope on the beta-chain of fibrin is covered up as fibrin organizes into a polymer network and is therefore exposed to the antibody only during active incorporation of fibrin subunits. We determined the equilibrium binding kinetics of an anti-beta monoclonal antibody to fibrin in various stages of organization. The concentration of exposed epitopes on immobilized fibrin monomers was equal to the molar concentration of fibrin beta-chains. The percentage of beta-chains exposed to the antibodies markedly decreased as the fibrin network was allowed to organize, a process catalyzed by calcium. CONCLUSIONS: The beta-chain amino terminus of fibrin is exposed transiently as subunits are added to the enlarging fibrin network. Anti-beta antibodies bind preferentially to actively enlarging fibrin polymers.