Biomedical subjects
Publications and source records attributed to N J Harris.
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Formaldehyde oxime <--> nitrosomethane tautomerism, isomeric nitrone, and their common cations and anions are studied with Gaussian-2 theory using MP2(full)/6-31G geometries and with density functional theory using B3LYP/6-311+G**. Geometrical parameters, harmonic vibrational frequencies, relative stabilities, conformational stabilities, and ionization energies are compared with experimental gas-phase data when available. The formaldehyde oxime <--> nitrosomethane tautomerism is compared with the amide <--> imidol, imine <--> enamine, keto <--> enol, and nitro <--> aci-nitro tautomeric processes. Solvent effects are estimated by the self-consistent isodensity polarizable continuum model (SCIPCM). The influence of hydrogen bonding interactions with the solvent is addressed by including two water molecules. In the final evaluation, formaldehyde oxime is 15.8 kcal/mol more stable than nitrosomethane when the aqueous solvation correction of 3.8 kcal/mol is applied to the G2 energies. Unsolvated formaldehyde oxime is estimated to be 11.1 kcal/mol more stable than nitrone. The estimated gas-phase ionization energies (G2) are 362.5 kcal/mol for formaldehyde oxime, 350.6 kcal/mol for nitrosomethane, and 351.4 kcal/mol for nitrone.
The aim of this study was to identify the number of accidents and types of injury related to the Supertram system in Sheffield. Data was collected prospectively over an 18 month period, commencing in April 1994, on all patients attending the Accident and Emergency department at the Royal Hallamshire Hospital whose injuries were related to the tram system. Ninety patients were included in the study, 54 males and 36 females with a median age of 39 years (range 16-82), representing approximately 0.13% of the patients attending the department during the study period. Forty one patients were cyclists, twenty three pedestrians, twelve were motorists or motorcyclists and fourteen sustained injuries due to ongoing construction work. Thirty one patients sustained fractures, most commonly involving the upper limb/shoulder girdle (63%), with cyclists suffering 83% of these serious upper limb injuries. Following assessment 38 patients were discharged, 29 patients were referred to fracture clinic, 12 were sent for physiotherapy and 11 admitted to hospital. Eight patients required a total of 13 operations during the study period. We have demonstrated a significant number of injuries in this study related to the tram system in Sheffield. Cyclists appear to be the group at highest risk, followed by pedestrians and motor vehicle users.
An intact lactone ring of camptothecins is a structural requirement for their anticancer activity. Propionate esters of camptothecin (CPT) and 9-nitrocamptothecin (9NC), CZ48 and CZ112, respectively, have been synthesized as derivatives resistant to lactone hydrolysis and are chemotherapeutically active. In this study, we have examined the mechanism of action of CZ48 and CZ112 and their distribution, metabolism, and toxicity. CZ112 incubated in human plasma retained its lactone structure longer than 9NC (t1/2: 10.5 and < 1 hr for CZ112 and 9NC, respectively). This resistance to lactone hydrolysis was also observed in mouse plasma or albumin solutions. Neither CZ48 nor CZ112 inhibit topoisomerase I and thus are prodrugs dependent on hydrolysis to CPT or 9NC, respectively. Rates of hydrolysis of CZ48 to CPT are higher by homogenates of mouse liver, spleen, lung, and kidney than by plasma. Rates of hydrolysis by tumor cells in culture vary and were higher by breast cancer and melanoma cells than by colon cancer cells. On the basis of these and other data, it is proposed that CZ48 and CZ112 may act as anticancer agents by resisting hydrolysis to camptothecins while in circulation. Hydrolysis in tissues may release intact lactone in target tissues.
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Four patients with mucolipidosis type III, three of them brothers, were seen initially in the first two decades of life. Their main symptoms were carpal tunnel syndrome, trigger fingers and generalized joint stiffness. Radiographs showed spinal deformities and hip dysplasia, but these were not causing pain. Carpal tunnel syndrome was treated surgically but joint stiffness and hip and knee contractures were managed by physiotherapy. Up to the age of 24 none of these patients has had pelvic osteotomy for hip dysplasia; this operation, not yet reported in mucolipidosis type III, may eventually be necessary.
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We report a case of bilateral symptomatic scaphoid exostoses associated with osteoarthritis of the wrist. These were treated by surgical excision with good short-term results.
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We have determined that 9-nitro-20(S)-camptothecin (9NC) converts to 9-amino-20(S)-camptothecin (9AC) in humans, dogs, and mice. Following a single oral dose of 0.1 mg/kg of 9NC, the human plasma concentration reached a maximum concentration of 483 ng/ml at 3.4 h with an area under the curve (AUC) of 2.6 micrograms.h/ml and a half-life of 2.5 h. As conversion of 9NC to 9AC occurred, the maximum calculated concentration of 9AC was 14.0 ng/ml at 10.3 h with an AUC of 311 ng.h/ml and a half-life of 7.1 h. Following a single oral dose of 1.0 mg/kg of 9NC, the maximum concentration of 9NC in the human volunteer was 1247 ng/ml at 5.3 h with an AUC of 17194 ng.h/ml and a half-life of 4.9 h. In this human, the Cmax of 9AC was 208 ng/ml at 17.2 h; the AUC was determined to be 9121 ng.h/ml, and the half-life was 13.1 h. In a dog after a single oral dose of 1.0 mg/kg 9NC, the maximum concentration for 9NC was 19.1 ng/ml at 0.7 h with a half-life of 6.4 h and an AUC of 186 ng.h/ml. The maximum concentration of 9AC in this dog was 9.2 ng/ml at 2.9 h with an AUC of 310 ng.h/ml and a half-life of 21.1 h. The maximum concentration of 9NC in the mouse after a single oral dose of 4.1 mg/kg of 9NC was 732 ng/ml at time 0.1 h with an AUC of 441 ng.h/ml and a half-life of 10.0 h. The maximum concentration of 9AC in the mouse was 26 ng/ml at 0.6 h. The AUC was 63 ng.h/ml, and the half-life was 1.2 h. Incubation of mouse liver, spleen, kidney, brain, and muscle tissue with 9NC all indicated conversion to 9AC, yet no conversion was observable in cell-free plasma from human or mouse blood. Structural identification of 9AC was confirmed by mass spectrometry.
Meningococcal septicaemia is a severe systemic illness which has an overall mortality of 15 per cent. It differs from meningococcal meningitis in clinical presentation, treatment, complications and prognosis. Skin and extremity loss are particular problems seen in meningococcal septicaemia. As critical care improves more patients are being seen with these complications. We report two patients in which these complications are demonstrated. Both patients underwent multiple autogenic and allogenic skin grafting procedures for skin loss. Apparently necrotic extremities were initially treated conservatively, with good results. The total area of necrotic tissue reduced dramatically with this treatment. Despite this, however, one patient required a Syme amputation, in the other, two toes on the affected foot separated painlessly at the metatarsophalangeal joint. We also discuss some of the pathophysiology behind skin necrosis. A popular view at present is that endotoxin from the cell wall of Neisseria meningiditis initiates the release of vasoactive cytokines by the host. High levels of interleukin-1 and interleukin-6 have been associated with a greater likelihood of fatality.
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