Biomedical subjects
Publications and source records attributed to J E Wright.
The fortunate foreskin of an infant boy will usually be left well alone by everyone but its owner. Problems such as phimosis are not common, and can usually be treated medically without resort to circumcision.
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1. Primary orbital amyloidosis is a rare form of localized amyloidosis in which the precursor protein has not previously been identified. We report here the first extraction of amyloid fibrils from a tissue biopsy containing orbital amyloid, and characterization of the fibril protein. 2. The N-terminal nine residues were identical with residues 278-286 and 275-283 of the third constant (CH3) domains of IgG1 and IgG4 gamma heavy chains, respectively. The mass of the fibril subunit protein was 6125Da by time-of-flight mass spectrometry, compared with the expected masses of 6169.9Da and 6214.9Da for the CH3 domains of gamma 1 from residue 278 and gamma 4 from residue 275, respectively. The fibril protein thus appeared to consist exclusively of an immunoglobulin heavy chain constant domain. 3. Only two examples of immunoglobulin heavy chain derived amyloid have been reported previously and both of these, as well as all published cases of the usual immunoglobulin light chain derived amyloid, contained variable domain sequence. The present case therefore represents a form of local, presumably clonal, B-cell/plasma-cell disorder characterized uniquely by deposition of an amyloidogenic immunoglobulin heavy chain constant domain fragment.
In a paediatric surgical practice over a 10 year period, 59 children presenting with left sided abdominal pain, acute or chronic, were investigated and followed up to identify the cause. Only two were found to have an identifiable surgically significant cause, one being hydronephrosis and the other being congenital uterine abnormality. Other causes suspected were Mittelschmerz, faecal retention or gastroenteritis, functional, abdominal migraine and allergy. Two boys developed torsion of the testis within 2 years of an episode of left sided abdominal pain. This is considered significant and the examination of boys with left sided abdominal pain should include careful scrutiny of the testis and assessment of its disposition with the boy standing. In both sexes investigation should focus initially on the urinary tract.
A prospective study of the efficacy of topical steroid in the treatment of childhood phimosis is reported. Boys referred to a paediatric surgical practice with pathological non-retractable foreskins were treated for at least 1 month with topical beta methasone cream. One hundred and thirty-nine patients were treated and 111 completed the study. A satisfactory result, defined as foreskin retractability appropriate for the boys' age, was achieved in 80% of patients. In 10% the response was inadequate at the end of the study period, but these boys were still under treatment or surveillance because their parents declined circumcision. In 10%, circumcision was performed because of failure of treatment. In six patients this was due to balanitis xerotica obliterans (lichen sclerosis et atrophicus) which does not respond to conservative treatment. Successful treatment depends upon the presence of a normal, supple foreskin at the outset, and on parental compliance.
A prospective study of 50 children with beta haemolytic streptococcal perianal infection and related disorders identified oedematous perianal skin and cracking on parting the buttocks, forming superficial multiple fissuring, as the characteristic features of such infection, and confirmed the value of skin culture in its diagnosis. Treatment by oral amoxycillin with clavulanic acid and a topical ointment containing bacitracin was effective in all patients.
Exenteration, or removal of the globe with part or all of the surrounding orbital contents, is generally reserved for malignancy. The procedure may, however, be of value in the management of some benign orbital diseases. The indications for exenteration in management of benign orbital disease are threefold. Firstly, patients in whom diffuse disease, such as idiopathic inflammation, has resulted in an irretrievable situation of visual loss and clinically uncontrollable pain or disfigurement; in many such cases we consider exenteration to be preferable to the (often severe) side effects of prolonged and inadequate medical therapy. The second group are those patients with grossly disfiguring orbital abnormalities, such as teratomas, extensive varices, or massive optic nerve tumours. The last group comprises patients with tumours that, while histologically benign, may have malignant potential or show a tendency to diffuse or persistent infiltration of orbital soft tissues. Sixteen illustrative cases of full or partial exenteration for benign disease are described.
A study was undertaken to estimate the incidence of periorbital trigeminal sensory loss with different types of orbital disease and to determine whether the area of loss is related to the location or nature of the underlying condition. A retrospective review was carried out of the clinical case notes of patients identified from the orbital diagnostic database held at Moorfields Eye Hospital. A total of 103 patients (51 male, 52 female), aged between 11 and 84 years (median 51 years), had signs of periorbital trigeminal sensory loss at the time of investigation for orbital disease and in 14/103 (13%) this sensory loss was symptomatic. Sensory loss was due to trauma in eight cases (8%), benign orbital disease in 54 (52%), and malignant disease in 41 cases (40%). The relative frequency of recorded sensory changes is about 9% for malignant tumours, 5% for benign tumours, 4% after orbital trauma, 3% for orbital inflammatory disease, and less than 1% for orbital structural anomalies. Relative corneal hypoaesthesia occurred in 40/103 (39%) cases. Periorbital sensory loss was recorded in about 3% of patients with orbital disease and, in contrast with commonly held views, malignancy was not the most common cause of sensory loss. The affected dermatome is a useful guide to the location of orbital disease, but a poor indication of underlying pathology. Relative corneal hypoaesthesia appears unrelated to the type of disease or to its location within the orbit.
OBJECTIVE: To examine the cardioprotective efficacy of allopurinol in patients undergoing elective coronary artery surgery. DESIGN: Prospective randomised trial. SETTING: London teaching hospital. PATIENTS: Twenty patients with at least moderately good left ventricular function undergoing elective coronary artery surgery and requiring at least two bypass grafts. INTERVENTIONS: Patients were randomised to receive allopurinol (1200 mg in two divided doses) or to act as controls. MAIN OUTCOME MEASURE: The primary determinant of the efficacy of myocardial protection was serial measurement (preoperatively and subsequently at one, six, 24, and 72 hours after the end of cardiopulmonary bypass) of cardiac troponin T (cTnT) a highly sensitive and specific marker of myocardial damage. Additional evidence was provided by serial measurement of the MB-isoenzyme of creatine kinase (CK-MB) and myoglobin, ECG changes, and clinical outcome. RESULTS: There was no significant difference in age, ejection fraction, number of grafts, bypass times, or cross clamp times between the two groups. In both groups there was a highly significant (p < 0.01) rise in cTnT, CK-MB, and myoglobin. Peak concentrations were reached between one (CK-MB and myoglobin) and six hours (cTnT) after the end of cardiopulmonary bypass. At 72 hours cTnT concentrations were six times higher than baseline concentrations whereas CK-MB and myoglobin were approximately double baseline concentrations. There was no significant difference in cTnT, CK-MB, or myoglobin between the allopurinol and control groups at any time. There was no diagnostic ECG evidence of perioperative infarction in any patient. CONCLUSION: Unlike previous reports this study did not show that allopurinol had a cardioprotective effect in patients with good left ventricular function undergoing elective coronary artery surgery.
OBJECTIVE: To compare the cardioprotective efficacy of cold crystalloid cardioplegia and intermittent ischaemic arrest in patients undergoing elective coronary artery surgery. DESIGN: Prospective randomised trial. SETTING: London teaching hospital. SUBJECTS: 20 patients with at least moderately good left ventricular function undergoing elective coronary artery surgery by one experienced surgeon and needing at least two bypass grafts. INTERVENTIONS: Patients were randomised to cold crystalloid cardioplegia or intermittent ischaemic arrest. MAIN OUTCOME MEASURES: The primary determinant of the efficacy of myocardial protection was serial measurement (before and at 1, 6, 24, and 72 hours after the end of cardiopulmonary bypass) of cardiac troponin T (cTnT), a highly sensitive and specific marker of myocardial damage. RESULTS: There was no significant difference in age, ejection fraction, number of grafts, bypass times, or cross clamp times between the two groups. One patient in the cardioplegia group had a perioperative infarct and was excluded from further study. In both groups there was a significant increase in cTnT, with peak concentrations being reached 6 hours after the end of cardiopulmonary bypass and remaining significantly high at 72 hours. At 6 hours the median (75% interquartile range) concentrations of cTnT were similar in both groups (1.8 (1.0-3.6) micrograms/l for cardioplegia v 1.9 (1.0-3.5) micrograms/l for intermittent ischaemic arrest). CONCLUSION: This trial shows that intermittent ischaemic arrest, even without systemic cooling or venting of the left ventricle, provides a similar level of myocardial protection to cardioplegia in patients with moderate left ventricular function and short ischaemic times.
OBJECTIVES: To evaluate trends in referrals for emergency operations after percutaneous transluminal coronary angioplasty (PTCA) complications; to analyse morbidity and mortality and assess the influence of PTCA backup on elective surgery. DESIGN: A retrospective analysis of patients requiring emergency surgical revascularisation within 24 hours of percutaneous transluminal coronary angioplasty. PATIENTS: Between January 1980 and December 1990, 75 patients requiring emergency surgery within 24 hours of percutaneous transluminal coronary angioplasty. SETTING: A tertiary referral centre and postgraduate teaching hospital. RESULTS: 57 patients (76%) were men, the mean age was 55 (range 29-73) years, and 30 (40%) had had a previous myocardial infarction. Before PTCA, 68 (91%) had severe angina, 59 (79%) had multivessel disease, and six (8%) had a left ventricular ejection fraction of less than 40%. A mean of 2.1 grafts (range one to five) were performed; the internal mammary artery was used in only one patient. The operative mortality was 9% and inhospital mortality was 17%. There was a need for cardiac massage until bypass was established in 19 patients (25%): this was the most important outcome determinant (P = 0.0051) and was more common in those patients with multivessel disease (P = 0.0449) and in women (P = 0.0388). In 10 of the 19 cases a vacant operating theatre was unavailable, the operation being performed in the catheter laboratory or anaesthetic room. These 19 patients had an operative mortality of 32% and inhospital mortality of 47%, compared with 2% and 7% respectively for the 56 patients who awaited the next available operating theatre. Complications included myocardial infarction, 19 patients (25%); arrhythmias, 10 patients (3%); and gross neurological event, two patients (3%). The mean intensive care unit stay was 2.6 days (range 1 to 33 days) and the mean duration of hospital admission was 13 days (range 5-40 days). CONCLUSIONS: Patients undergoing emergency surgery after PTCA complications have a substantially increased inhospital mortality and morbidity. PTCA in this unit continues to require surgical cover. Delays in operating on stable patients in centres which operate a "next available theatre" backup policy may not differ from some units performing PTCA with offsite cover for PTCA complications. Particularly in the presence of multivessel disease, however, PTCA complications may be associated with the need for "crash" bypass and such patients are unlikely to survive hospital transfer. The proportion of patients requiring "crash" bypass has increased during the period reviewed because of the extent of disease in the emergency surgical group increased. These results indicate that surgery should not be denied to these patients.
Studies on the mode of action of PT523 [N alpha-(4-amino-4-deoxypteroyl)-N delta-hemiphthaloyl-L-ornithine], a potent nonpolyglutamatable antifolate, were carried out in sensitive and resistant H35 rat hepatoma cell lines in culture, to compare it with other antifolates, including three dihydrofolate reductase (DHFR) inhibitors, i.e., methotrexate (MTX), gamma-fluoro-MTX, and trimetrexate (TMQ), two thymidylate synthase inhibitors, i.e., N10-propargyl-5,8- dideazafolate (PDDF) and 2-desamino-2-methyl-N10-propargyl-5,8-dideazafolate (dmPDDF), and the glycinamide ribonucleotide formyltransferase inhibitor 5,10-dideaza-5,6,7,8-tetrahydrofolate. PT523 was the most active compound in this group against the parental H35 cells, with an IC50 ranging from 2.5 nM for 72 hr of treatment to 0.21 microM for 2 hr of treatment. Sublines resistant to MTX by virtue of a transport defect or a combination of defective transport and increased DHFR activity were resistant to PT523 and MTX but not to PDDF, whereas sublines resistant to fluoropyrimidines by virtue of increased thymidylate synthase activity were resistant to PDDF but not to PT523, TMQ, or MTX. Inhibition of H35 cell growth by PT523 was associated with a concentration- and time-related decrease in de novo dTMP and purine biosynthesis. Growth inhibition by PT523, MTX, and TMQ was prevented by leucovorin or a combination of thymidine (dThd) and hypoxanthine but not by dThd or hypoxanthine alone; in contrast, growth inhibition by dmPDDF was prevented by dThd alone. Intracellular reduced folate polyglutamate pools were markedly altered by PT523 treatment, with the most pronounced effect being an increase in 7,8-dihydrofolate mono- and polyglutamates and a decrease in 5,10-methylene-5,6,7,8-tetrahydrofolate mono- and polyglutamates, 5,6,7,8-tetrahydrofolate mono- and polyglutamates, and 10-formyl-5,6,7,8-tetrahydrofolate mono- and polyglutamates. This pattern was qualitatively similar to that observed with MTX and TMQ but different from that observed with dmPDDF or 5,10-dideaza-5,6,7,8-tetrahydrofolate, which resulted in little or no change in the folate species. Uptake of [3H]MTX and [3H]folinic acid, but not [3H]folic acid, by H35 cells was inhibited in a dose-related manner by PT523, suggesting that penetration of the cell probably involves, at least in part, active transport by the MTX/reduced folate carrier. To determine whether the potent cellular effects of PT523 might be due to chemical or enzymic clevage to N'-(4-amino-4-deoxypteroyl)-L-ornithine, a potent inhibitor of folylpolyglutamate synthetase, the formation of [3H]MTX polyglutamates in CCRF-CEM lymphoblasts pulsed with [3H]MTX after preincubation with PT523 was examined.(ABSTRACT TRUNCATED AT 400 WORDS)
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A series of eight previously undescribed 2,4-diaminothieno[2,3-d]pyrimidine analogues of the potent dihydrofolate reductase (DHFR) inhibitors trimetrexate (TMQ) and piritrexim (PTX) were synthesized as potential drugs against Pneumocystis carinii and Toxoplasma gondii, which are major causes of severe opportunistic infections in AIDS patients. 2,4-Diamino-5-methyl-6-(aryl/aralkyl)thieno[2,3-d]pyrimidines with 3,4,5-trimethoxy or 2,5-dimethoxy substitution in the aryl/aralkyl moiety and 2,4-diamino-5-(aryl/aralkyl)thieno[2,3-d]pyrimidines with 2,5-dimethoxy substitution in the aryl/aralkyl moiety were obtained by reaction of the corresponding 2-amino-3-cyanothiophenes with chloroformamidine hydrochloride. The aryl group in the 5,6-disubstituted analogues was either attached directly to the hetero ring or was separated from it by one or two carbons, whereas the aryl group in the 5-monosubstituted analogues was separated from the hetero ring by two or three carbons. 2-Amino-3-cyano-5-methyl-6-(aryl/alkyl)thiophene intermediates for the preparation of the 5,6-disubstituted analogues were prepared from omega-aryl-2-alkylidene-malononitriles and sulfur in the presence of a secondary amine, and 2-amino-3-cyano-4-(aryl/aralkyl)thiophene intermediates for the preparation of the 5-monosubstituted analogues were obtained from omega-aryl-1-chloro-2-alkylidenemalononitriles and sodium hydrosulfide. Synthetic routes to the heretofore unknown ylidenemalononitriles, and the ketone precursors thereof, were developed. The final products were tested in vitro as inhibitors of DHFR from Pneumocystis carinii, Toxoplasma gondii, rat liver, beef liver, and Lactobacillus casei. A selected number of previously known 2,4-diaminothieno[2,3-d]pyrimidines lacking the 3,4,5-trimethoxyphenyl and 2,5-dimethoxyphenyl substitution pattern of TMQ and PTX, respectively, were also tested for comparison. None of the compounds was as potent as TMQ or PTX, and while some of them showed some selectivity in their binding to Pneumocystis carinii and Toxoplasma gondii versus rat liver DHFR, this effect was not deemed large enough to warrant further preclinical evaluation.
In a continuing investigation of determinants of their 200-fold methotrexate resistance and their collateral sensitivity to gamma-tert-butyl methotrexate, the ability of CEM/MTX cells to transport the two drugs was analyzed and compared with that of CEM cells. The Km and Vmax values for the influx of methotrexate into CEM cells did not differ significantly from those of CEM/MTX cells, and this was the case for gamma-tert-butyl methotrexate as well. Surface binding and influx rates were proportional to cell surface area, but differences in efflux rates and methotrexate uptake were too large to be explained on this basis. Neither methotrexate nor trimetrexate competed with gamma-tert-butyl methotrexate influx in CEM cells. However, both drugs perturbed the gamma-tert-butyl methotrexate steady state in CEM cells, resulting in slightly less uptake than with gamma-tert-butyl methotrexate alone. However, the major difference between the two cell types was in the methotrexate uptake plateau, which was much greater in the case of the parental cell line. A related observation was the more rapid efflux of methotrexate from CEM/MTX cells than from CEM cells. The poor uptake, the associated meager capacity to polyglutamylate methotrexate and the enhanced methotrexate efflux appear to be responsible for its decreased activity against CEM/MTX cells. Half-lives for gamma-tert-butyl methotrexate efflux were the same in both cell lines, allowing the drug to accumulate to cytotoxic levels despite its inability to form polyglutamates.
A double-blind controlled trial was performed to assess the effectiveness of wound infiltration with bupivacaine for postoperative pain relief after appendicectomy in children. Sixty children entered the trial and 52 completed it; they were randomized to receive bupivacaine or placebo. Assessment of postoperative pain using a numerical scoring system was made by the child, the recovery sister and the ward sister, and by measurement of the time between the end of the operation and the need for narcotic injection. Analysis revealed significantly less pain (P < 0.03) in the immediate postoperative period in the treated group. The use of bupivacaine wound infiltration as a supplement to other current methods of pain control is recommended.
A new method of detecting occult glove punctures was devised to determine its frequency during cardiac operations. Glove puncture is of relevance to the transmission of infectious diseases and the potential contamination of implanted cardiac prostheses. A study was therefore carried out in 48 adult patients undergoing open heart operations in which gloves worn by surgeons and nurses were collected and evaluated at the end of each procedure. In 22 of these cases, gloves were changed at three different stages of the cardiac operation for the principal operators: stage I, skin incision to commencement of cardiopulmonary bypass; stage II, cardiopulmonary bypass to sternotomy closure; and stage III, sternotomy closure to skin closure. One hundred sixty-two gloves (31.5%) had one or more punctures out of a total of 514 gloves tested. Only 20 glove punctures were recognized either at the time or at the end of the operation. There were 185 occult glove punctures. The majority (60%) of punctures were on the nondominant hand, with 30% of perforations located in the nondominant index finger. Using the chi 2 test with two degrees of freedom, there is no significant difference between the glove perforation rates for the principal operators in stages I, II, and III. The most important finding from this study was that 61% of gloves worn by scrub nurses had one or more punctures compared with 23.6% of surgeons.