Cardiff Royal Infirmary

A postal survey in two health board areas in Scotland, encompassing a population of about one million, identified 1477 patients with chronic ulcers of the leg. Women outnumbered men by a ratio of 2.8:1. The median age of the women was 74 and of the men 67. Seventy two (5%) were hospital inpatients, 174 (12%) were managed jointly by the primary care team and outpatient departments, and 1201 (83%) were managed entirely in the community. Efforts to improve the management of chronic ulcers of the leg should focus on primary health care.

OLIVER WRONG, H. E. F. DAVIES; THE EXCRETION OF ACID IN RENAL DISEASE, QJM: An International Journal of Medicine, Volume 28, Issue 2, 1 April 1959, Pages 2

TOTAL population studies are the only certain way of gaining reliable information on the prevalence of insidious conditions like chronic simple glaucoma.The sine qua non of a total population study is exact knowledge of the composition of the popula- tion.In the Rhondda valley the Medical Research Council has laboriously carried out a census so that the exact number of persons and their age and sex are known for this area.Over the past 15 years the M.R.C. has earned the co-operation of this population by its efforts in detecting miners' pneumoconiosis, pulmonary tuberculosis, and other diseases.Such a situation was admirably suited for a total population study of the prevalence of glaucoma, and in the summer of 1963 the authors carried out such a study.To our knowledge the only previous similar study is that done by Str6mberg (1962) at Skovde in Sweden.The aims of our study were fourfold:

PURPOSE: Antibody-directed chemotherapy for acute myeloid leukemia (AML) may permit more treatment to be administered without escalating toxicity. Gemtuzumab ozogamicin (GO) is an immunoconjugate between CD33 and calicheamicin that is internalized when binding to the epitope. We previously established that it is feasible to combine GO with conventional chemotherapy. We now report a large randomized trial testing the addition of GO to induction and/or consolidation chemotherapy in untreated younger patients. PATIENTS AND METHODS: In this open-label trial, 1,113 patients, predominantly younger than age 60 years, were randomly assigned to receive a single dose of GO (3 mg/m(2)) on day 1 of induction course 1 with one of the following three induction schedules: daunorubicin and cytarabine; cytarabine, daunorubicin, and etoposide; or fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin. In remission, 948 patients were randomly assigned to GO in course 3 in combination with amsacrine, cytarabine, and etoposide or high-dose cytarabine. The primary end points were response rate and survival. RESULTS: The addition of GO was well tolerated with no significant increase in toxicity. There was no overall difference in response or survival in either induction of consolidation. However, a predefined analysis by cytogenetics showed highly significant interaction with induction GO (P = .001), with significant survival benefit for patients with favorable cytogenetics, no benefit for patients with poor-risk disease, and a trend for benefit in intermediate-risk patients. An internally validated prognostic index identified approximately 70% of patients with a predicted benefit of 10% in 5-year survival. CONCLUSION: A substantial proportion of younger patients with AML have improved survival with the addition of GO to induction chemotherapy with little additional toxicity.

During the past 25 years, 24 randomized trials of intravenous (IV) fibrinolytic treatment have been reported, involving a total of some 6000 patients in the acute phase of myocardial infarction. Most tested IV streptokinase (SK), but a few tested IV urokinase (UK). In the past 2 or 3 years numerous small randomized trials of intracoronary (IC) SK have been started, 9 of which, involving a total of about 1000 such patients, have been reported. Because all of these IV and IC trials were small (the largest including only 747 patients), their separate results appear contradictory and unreliable. But, an overview of the data from these trials indicates that IV treatment produces a highly significant (22% +/- 5%, P less than 0.001) reduction in the odds of death, an even larger reduction in the odds of reinfarction, and an absolute frequency of serious adverse effects to set against this that is much smaller than the absolute mortality reduction. The apparent size of the mortality reduction in the IV trials was similar whether anticoagulants were compulsory or optional, whether treatment was in a coronary care unit or an ordinary ward and, surprisingly, whether treatment began early (less than 6 h from onset of symptoms) or late (generally 12-24 h). In addition, there was no evidence that UK was more effective than the less expensive SK, or that, despite their technical complexity, the new IC regimes were more effective than the old IV regimes. Even the IV schedules that have been studied in randomized trials were, however, quite complex, and the IC schedules were far more so. Perhaps partly because of this, none of them is widely used. If so, then some much simpler, and hence more widely practicable, IV SK regimes should be developed and tested. For example, a simple one hour high-dose IV SK infusion, without anticoagulation, will successfully convert virtually all of the available plasminogen into plasmin. But, it may be several years before the net effects on mortality of any more widely practicable IV SK regimes can be agreed unless many of the hospitals that do not wish routinely to use IC regimes or the complex previous IV regimes will collaborate in multicentre randomized trials that can, if necessary, continue rapid intake until some tens of thousands of patients have been randomized, and some thousands of deaths have been observed among the control and treated patients. The same, of course, may be true for any other fibrinolytic regimes (e.g. infusion of tissue plasminogen activator) if their net effects on mortality are comparable to those of IV SK.

Shy and Drager (1960), on the basis of some 40 published case reports, described a clinical syndrome to which their names have subsequently been attached.The complete syndrome includes ortho- static hypotension, anhidrosis, urinary and faecal incontinence, sexual impotence, Parkinsonian signs, external ocular palsies, amyotrophy, and iris atrophy.A detailed post-mortem examination of one of their cases showed neuronal degeneration at many sites, including the intermediolateral columns of the spinal cord.They did not comment on the relation of this finding to the autonomic features of their patient's disorder.In 1965, Fichefet, Sternon, Franken, Demanet, and Vanderhaeghen described a case presenting with orthostatic hypotension, with subsequent development of Parkinsonism.The pathology was that of idiopathic paralysis agitans, with Lewy-type cyto- plasmic inclusions and loss of pigmented nerve cells.In addition, the authors observed some cell loss in the anterior and lateral horns of the spinal cord.In 1966, Johnson, Lee, Oppenheimer, and Spalding described the clinical, physiological, and pathological findings in two cases of orthostatic hypotension.In the first of these, the only associated disturbances were sexual impotence and loss of sweating.Lewy-type inclusions were found in the pigmented nuclei and elsewhere, but there was no detectable loss of pigmented cells.Cell loss in the intermediolateral columns was estimated at nearly 90%.In the second case, the autonomic disorder was followed, after a few years, by a progressive disorder of motor and cerebellar function.The lesions were those of olivo-ponto-cerebellar atrophy; in addition, there was cell loss, estimated at about 75 %, in the intermediolateral columns.Since then, there have been four reports on cases that have gone to necropsy-that of Nick, Contamin, Escourolle, Guillard, and Marcantoni (1967) and the two cases of Schwarz (1967)-all of which showed neuronal degeneration at various sites, including the inter-

BACKGROUND: Ulcerative colitis is largely a disease of nonsmokers. Because anecdotal reports suggest that smoking and nicotine may improve the symptoms of the disease, we examined the effect of nicotine as a supplemental treatment for ulcerative colitis. METHODS: We treated 72 patients with active ulcerative colitis with either transdermal nicotine patches or placebo patches for six weeks in a randomized, double-blind study. Incremental doses of nicotine were given; most patients tolerated doses of 15 to 25 mg per 24 hours. All the patients had been taking mesalamine, and 12 were receiving low doses of glucocorticoids; these medications were continued without change during the study. Clinical, sigmoidoscopic, and histologic assessments were made at base line and at the end of the study; symptoms were recorded daily on a diary card, and the clinician made a global assessment. Side effects and plasma nicotine and cotinine concentrations were monitored throughout the study. RESULTS: Seventeen of the 35 patients in the nicotine group had complete remissions, as compared with 9 of the 37 patients in the placebo group (P = 0.03). The patients in the nicotine group had greater improvement in the global clinical grade of colitis (P < 0.001) and the histologic grade (P = 0.03), lower stool frequency (a difference of 1.6 stools daily; P = 0.008), less abdominal pain (P = 0.05), and less fecal urgency (P = 0.009). More patients in the nicotine group had side effects (23, vs. 11 in the placebo group; P = 0.002), the most common of which were nausea, lightheadedness, headache, and sleep disturbance. Withdrawals due to ineffective therapy were more common in the placebo group (3 vs. 8, P = 0.12). CONCLUSIONS: The addition of transdermal nicotine to conventional maintenance therapy improves symptoms in patients with ulcerative colitis.

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterized by the combined occurrence of parathyroid, pancreatic islet and anterior pituitary tumours. To facilitate a screening programme for MEN1, we investigated 709 people (364 males and 345 females, age range 1-84 years) from 62 MEN1 families, and 36 non-familial MEN1 patients. Of those investigated, 220 (95 males and 125 females, age range 8-79 years) suffered from MEN1. Parathyroid, pancreatic and pituitary tumours occurred in 95%, 41% and 30% of the patients, respectively. Parathyroid tumours were the first manifestation of MEN1 in 87% of patients, and amongst the pituitary and pancreatic tumours, somatotrophinomas and gastrinomas were more common in patients above the age of 40 years, whilst insulinomas occurred more frequently in patients below the age of 40 years. Biochemical screening indicated that the penetrance of MEN1 by the ages of 20, 35 and 50 years was 43%, 85% and 94%, respectively, and that the development of MEN1 was confined to first-degree relatives in 91% of patients and to second-degree relatives in 9% of patients. These findings have helped to define a proposed screening programme for MEN1.

PURPOSE: There has been little survival improvement in older patients with acute myeloid leukemia (AML) in the last two decades. Improving induction treatment may improve the rate and quality of remission and consequently survival. In our previous trial, in younger patients, we showed improved survival for the majority of patients when adding gemtuzumab ozogamicin (GO) to induction chemotherapy. PATIENTS AND METHODS: Untreated patients with AML or high-risk myelodysplastic syndrome (median age, 67 years; range, 51 to 84 years) were randomly assigned to receive induction chemotherapy with either daunorubicin/ara-C or daunorubicin/clofarabine, with (n = 559) or without (n = 556) GO 3 mg/m(2) on day 1 of course one of therapy. The primary end point was overall survival (OS). RESULTS: The overall response rate was 69% (complete remission [CR], 60%; CR with incomplete recovery [CRi], 9%), with no difference between GO (70%) and no GO (68%) arms. There was no difference in 30- or 60-day mortality and no major increase in toxicity with GO. With median follow-up of 30 months (range, 5.5 to 54.6 months), 3-year cumulative incidence of relapse was significantly lower with GO (68% v 76%; hazard ratio [HR], 0.78; 95% CI, 0.66 to 0.93; P = .007), and 3-year survival was significantly better (25% v 20%; HR, 0.87; 95% CI, 0.76 to 1.00; P = .05). The benefit was apparent across subgroups. There was no interaction with other treatment interventions. A meta-analysis of 2,228 patients in two United Kingdom National Cancer Research Institute trials showed significant improvements in relapse (HR, 0.82; 95% CI, 0.72 to 0.93; P = .002) and OS (HR, 0.88; 95% CI, 0.79 to 0.98; P = .02). CONCLUSION: Adding GO (3 mg/m(2)) to induction chemotherapy reduces relapse risk and improves survival with little increase in toxicity.

Seven hundred and thirty one men admitted to medical wards were interviewed to identify problem drinkers who had not received previous treatment for alcoholism and who had some social support. One hundred and sixty one met the diagnostic criteria; 156 agreed to a follow up interview and were allocated to one of two groups. One group received a session of counselling about their drinking habits from a nurse while the other received only routine medical care. Both groups reported a reduction in alcohol consumption when interviewed 12 months later, but the counselled group had a significantly better outcome than the control group. It is concluded that systematic screening for alcohol consumption and related problems should become a routine part of medical assessment and that advice on drinking habits is effective if given before irreversible physical or psychosocial problems have developed.

We studied 140 consecutive patients beginning continuous ambulatory peritoneal dialysis (CAPD) at one of seven hospitals to assess the relation of the nasal carriage of Staphylococcus aureus to subsequent catheter-exit-site infection or peritonitis. Shortly before the implantation of the catheters, the patients' anterior nares were cultured for the presence of S. aureus. Antibiotics were not prescribed for the S. aureus carriers, but all the patients were monitored for signs of catheter infection (median follow-up, 10.4 months). At the initiation of CAPD, 63 patients (45 percent) carried S. aureus in the nares. Nasal carriage was more frequent among the 30 patients with diabetes (77 percent) than among the 110 without the disease (36 percent). The carriers of S. aureus had a significantly higher rate of exit-site infection than the noncarriers (0.40 vs. 0.10 episode per year; P = 0.012). Of these episodes, 24 of 34 were caused by S. aureus. The rates of peritonitis of all bacterial types did not differ significantly between the groups, but all 11 episodes of peritonitis caused by S. aureus occurred among the carriers. In 85 percent of the patients with clinical S. aureus infections, the strain from the nares and the strain causing the infection were similar in phage type and antibiotic profile. We conclude that in patients beginning ambulatory peritoneal dialysis, the nasal carriage of S. aureus is associated with an increased risk of catheter-exit-site infection and that the performance of nasal cultures before the implantation of the catheter can identify patients at high risk of subsequent morbidity.

Carbazepine, Tegretol (5-carbamyl-dibenz (b,f)- azepin), originally known as G.32883 and introduced in 1959 as an anticonvulsant, was first shown to have some effect in relieving the pain oftrigeminal neural- gia by Blom (1962Blom ( , 1963)).Since then Spillane (1963Spillane ( , 1964)), McArdle (1963), and Taylor (1963) have confirmed that this drug has a specific effect in relieving the pain of trigeminal neuralgia in some 60 to 80 % of patients.This paper describes a controlled trial of carbaze- pine carried out simultaneously at

Over the past 20 years at least 11 randomised trials of the prevention with diuretics of pre-eclampsia and its sequelae have been undertaken. Nine of these were reviewed. Reliable data from the remaining two were not available. The nine reviewed had investigated a total of nearly 7000 people. Significant evidence of prevention of "pre-eclampsia" was overwhelming, even when oedema was not included as a diagnostic criterion. But as the definitions of pre-eclampsia that had been used depended heavily on increases in blood pressure this evidence may simply have reflected the well known ability of diuretics to reduce blood pressure. When the data on perinatal death were reviewed a little difference was seen in postnatal survival. The incidence of stillbirths was reduced by about one third with treatment, but, perhaps owing to small numbers (only 37 stillbirths), the difference was not significant. Thus these randomised trials failed to provide reliable evidence of either the presence or the absence of any worthwhile effects of treatment with diuretics on perinatal mortality. The implications of this for current and future trials of beta blockers and other agents in the prevention of pre-eclampsia and its sequelae are that extremely large, ultra simple randomised trials are needed, of a size sufficient to permit direct assessment of the effects of treatment not on pre-eclampsia but on perinatal mortality itself. This may require the study of tens of thousands of pregnancies.

took a median of 30 minutes to arrive at the patient's home and 20 minutes to reach the hospital.When the same variables were analysed in the patients subsequently confirmed to have definite or probable acute myocardial infarction it was found that the decision time was shorter if relatives were with the patient at the onset of symptoms.The interval between admission to hospital and administration of streptokinase in those given the drug was the longest single delay (median 102 minutes).No factors were identified that significantly influenced the time of administration of streptokinase.Thus most elderly patients reach hospital in time to benefit from thrombolytic treatment but many elderly patients are not admitted to coronary care units.Not only must attention be given to shorten- ing the time to administration of thrombolytic treatment but elderly patients with suspected acute myocardial infarction should have the potential benefit of specialised coronary care.

Thirty patients with deep vein thrombosis of the legs of less than four days' duration were allocated at random to treatment with heparin, streptokinase, or Arvin under laboratory control. When the fate of the thrombi was assessed by objective techniques-phlebography and the (125)I-labelled fibrinogen test-the incidence of complete thrombolysis was greatest in the streptokinase group. Complications arose during treatment in each group but were least with Arvin. The natural history of the disease favours clinical but not always anatomical recovery.

One thousand and sixty women aged 18 or over, randomly selected from a defined geographical area in South Wales, were interviewed at home about their urinary symptoms. Ninety-five per cent co-operated, of whom 45% admitted to some degree of incontinence. "Stress' incontinence was reported by 22% of women, "urge' incontinence by 10%, and both types combined--"complex'--by 14%. In most women urinary loss was both small and infrequent but 5% of all women experienced a loss sufficient to necessitate a change of clothes; in 2.6% such loss occurred daily. Over 3% of all women reported that incontinence interfered with their social or domestic life but only half of these had sought medical advice.

In this study the cross-sectional area (in n = 14 female controls, 15 male controls, 11 female patients with schizophrenia, 15 male patients with schizophrenia) and fibre composition (in n = 11 female controls, 10 male controls, 10 female patients with schizophrenia, 10 male patients with schizophrenia) of the corpus callosum in post-mortem control and schizophrenic brains was examined. A gender x diagnosis interaction (P = 0.005) was seen in the density of axons in all regions of the corpus callosum except the posterior midbody and splenium. Amongst controls, females had greater density than males; in patients with schizophrenia this difference was reversed. A reduction in the total number of fibres in all regions of the corpus callosum except the rostrum was observed in female schizophrenic patients (P = 0.006; when controlling for brain weight, P = 0.053). A trend towards a reduced cross-sectional area of the corpus callosum was seen in schizophrenia (P = 0.098); however, this is likely to be no more than a reflection of an overall reduction in brain size. With age, all subregions of the corpus callosum except the rostrum showed a significant reduction in cross-sectional area (P = 0.018) and total fibre number (P = 0.002). These findings suggest that in schizophrenia there is a subtle and gender-dependent alteration in the forebrain commissures that may relate to the deviations in asymmetry seen in other studies, but the precise anatomical explanation remains obscure.

A "six strand" method of tendon repair has been used to treat 36 fingers with flexor tendon lacerations. Following surgery, active mobilisation in a protective splint was begun immediately. 63% of lacerations were in zone 2 and 27% in zone 1. 69% and 100% respectively achieved an excellent or good result using Buck-Gramcko's assessment method. 81% of all the fingers were rated excellent or good.

Metalloproteinases have been implicated in the pathogenesis of multiple sclerosis. We report longitudinal serum levels of gelatinase B and of the tissue inhibitors of matrix metalloproteinases (TIMP), TIMP-1 and TIMP-2, in 21 patients with relapsing multiple sclerosis. Patients had monthly clinical and gadolinium-enhanced MRI follow-up for 10 months. Longitudinal samples in nine healthy controls and cross-sectional samples from 12 patients with inflammatory CNS disease and 15 patients with other neurological diseases were used for comparison. Average serum gelatinase B, TIMP-1 and TIMP-2 levels were significantly higher in multiple sclerosis patients and those with other neurological diseases than in healthy controls. In the patients with multiple sclerosis, gelatinase B levels were significantly higher during clinical relapse compared with periods of clinical stability. Multiple sclerosis patients with high mean serum gelatinase B levels had significantly more T1-weighted gadolinium-enhancing MRI lesions than those with mean levels within the control range. TIMP-1 levels were not different during relapse and between relapses. There was a trend for TIMP-2 levels to be lower during relapse compared with non-relapse periods. For similar levels of serum gelatinase B, associated TIMP-1 levels were significantly lower and TIMP-2 levels significantly higher in multiple sclerosis patients compared with the inflammatory CNS control group. We propose that an abnormality in the inhibitory response to metalloproteinases may play an aetiological role in the chronicity of multiple sclerosis.

BACKGROUND: Ulcerative colitis is largely a disease of nonsmokers. Having found previously that treatment with transdermal nicotine patches and mesalamine (5-aminosalicylic acid) has a beneficial effect on active colitis, we examined the value of transdermal nicotine for the maintenance of remission. METHODS: We treated 80 patients with ulcerative colitis in remission with either transdermal nicotine or placebo patches for six months in a randomized, double-blind study. Incremental doses of nicotine were given for the first three weeks to achieve a maintenance dose; most patients tolerated 15 mg for 16 hours daily. All patients were taking mesalamine preparations as maintenance treatment at entry into the study; this treatment was stopped once the maintenance dose of nicotine was achieved. Clinical, sigmoidoscopic, and histologic assessments were made at the beginning and the end of the study, or at relapse. Side effects and serum nicotine and cotinine concentrations were monitored throughout the study. RESULTS: There was no significant difference in the number of relapses between the groups. Twenty-two patients in the nicotine group were prematurely withdrawn from the study, 14 because of relapse and 8 for other reasons, including side effects and protocol violations. In the placebo group, 20 patients were withdrawn prematurely, 17 because of relapse and 3 for other reasons. Among patients using 15-mg nicotine patches, serum nicotine and cotinine concentrations were lower than expected and may reflect poor compliance. Side effects were reported by 35 patients--21 in the nicotine group and 14 in the placebo group--the most common of which were nausea, lightheadedness, and itching. CONCLUSIONS: Transdermal nicotine alone was no better than placebo in the maintenance of remission of ulcerative colitis, and premature withdrawal due to side effects was more common in the nicotine group.