Showing papers in "QJM: An International Journal of Medicine in 1998"

The clinical features of immunoglobulin light-chain (AL) amyloidosis with heart involvement.

Abstract: We reviewed clinical presentation, investigations, therapy, prognosis and outcome of 232 patients with primary (AL) cardiac amyloidosis. There were 142 men and 90 women. Median age at presentation was 59 years (range 29-85). AL heart disease was unusual both in patients under the age of 40 (3.0%) and in non-Caucasians (6.5%). Fatigue and weakness were the commonest presenting symptoms. Hallmark features of periorbital ecchymoses and macroglossia were present in 12.5% and 27.2%, respectively. AL cardiac amyloidosis was unusual in isolation (3.9%), and most frequently patients had features of multiorgan dysfunction; heavy proteinuria and features of malabsorption predominating in this respect. Heart involvement represents the worst prognostic indicator, with a median survival from diagnosis of 1.08 years, falling to 0.75 years with the onset of heart failure. Current therapeutic procedures appear to prolong survival, with left ventricular wall thickness, mass and ejection fraction on echocardiography and late potentials on signal averaged electrocardiography of use in prognostic stratification. Cardiac involvement from AL amyloidosis is rapidly fatal. It should be suspected in all patients with heart failure who have wall thickening on echo, normal chamber sizes, low EKG voltages and evidence suggesting a multisystem disease.

Diabetic peripheral neuropathy and quality of life.

Abstract: The quality of life (QOL) of 79 people with type 1 and type 2 diabetes and 37 non-diabetic controls was assessed using the Nottingham Health Profile (NHP). The NHP consists of six domains assessing energy, sleep, pain, physical mobility, emotional reactions and social isolation. Symptomatic diabetic neuropathy was present in 41 of the patients. The neuropathy patients had significantly higher scores (impaired QOL) in 5/6 NHP domains than either the other diabetic patients (p < 0.01) or the non-diabetic (p < 0.001) controls. These were: emotional reaction, energy, pain, physical mobility and sleep. The diabetic patients without neuropathy also had significantly impaired QOL for 4/6 NHP domains compared with the non-diabetic control group (p < 0.05) (energy, pain, physical mobility and sleep). This quantification of the detrimental effect on QOL of diabetes, and in particular of chronic symptomatic peripheral diabetic neuropathy, emphasizes the need for further research into effective management of these patients.

Management of male osteoporosis: report of the UK Consensus Group.

Abstract: Although osteoporosis is generally regarded as a disease of women, up to 30% of hip fractures and 20% of vertebral fractures occur in men. Risk factors for osteoporotic fractures in men include low body mass index, smoking, high alcohol consumption, corticosteroid therapy, physical inactivity, diseases that predispose to low bone mass, and conditions increasing the risk of falls. The key drugs and diseases that definitely produce a decrease in bone mineral density (BMD) and/or an increase in fracture rate in men are long-term corticosteroid use, hypogonadism, alcoholism and transplantation. Age-related bone loss may be a result of declining renal function, vitamin D deficiency, increased parathyroid hormone levels, low serum testosterone levels, low calcium intake and absorption. Osteoporosis can be diagnosed on the basis of radiological assessments of bone mass, or clinically when it becomes symptomatic. Various biochemical markers have been related to bone loss in healthy and osteoporotic men. Their use as diagnostic tools, however, needs further investigation. A practical approach would be to consider a bone density more than one SD below the age-matched mean value (Z < -1) as an indication for therapy. The treatment options for men with osteoporosis include agents to influence bone resorption or formation and specific therapy for any underlying pathological condition. Testosterone treatment increases BMD in hypogonadal men, and is most effective in those whose epiphyses have not closed completely. Bisphosphonates are the treatment of choice in idiopathic osteoporosis, with sodium fluoride and anabolic steroids to be used as alternatives.

The rise and fall of ebm

Abstract: The rise of Evidence-based Medicine (EBM) has been were never properly addressed—nonetheless CE was widely regarded as a refreshing approach that blew one of the more remarkable phenomena of the British health scene during the 1990s Tremendous away cobwebs and let in some light In particular, CE mobilized the enthusiasm of people to come to grips advances have been made in establishing the EBM brand name, obtaining massive government funding, with interpreting clinical data for themselves for use in their own clinical practice manoeuvring to a position of unchallenged authority within the NHS managerial and political hierarchy But the advocates of clinical epidemiology were ambitious of influence, and grew impatient A signi(and its priesthood among the BMJ editorial staff )— and promoting EBM as a marketing slogan for ficant change came when the name ‘Evidence-based Medicine’ or EBM was coined in 19922 Although lucrative conferences, courses, books, journals, people and organizations the term involves a calculatedly dishonest misrepresentation,3 this new nomenclature was an immediate The ‘fall’ of EBM is rather different; since it involves a quasi-theological ‘fall from grace’: a loss rhetorical success EBM effectively labelled itself as rational, objective and altruistic—while any opposiof clinical, scientific and educational integrity, even to the point of a decline into a ‘state of sin’ (if tion was implied to be promoting a practice that is illogical, self-indulgent and opposed to the evidence seeking and clinging to power at any costs is seen as sinful) This moral decline would—in the normal A set of mission-statements was proposed as definitive of EBM: these took the form of platitudes which course of events—be followed in due course by loss of status, income and power However, the EBM could not be opposed by any rational person;4 yet these content-free proclamations served to camoubarnacle may prove difficult to dislodge now it has a grip on the minds of politicians and managers flage controversial ways of operating and marginalize opponents as wicked or crazy Certainly, the phenomenon is ripe for re-evaluation

The General Practice Research Database. Scientific and Ethical Advisory Group

Abstract: We describe a powerful new information resource for pharmacovigilance, pharmaco-economic studies, clinical epidemiology and health service research, which involves automated linkage of demographic, diagnostic and prescription information on some 3.4 million patients enrolled in over 500 separate general practices. Information is subject to regular validation checks. Access to this resource is available for bona fide research workers, subject to appropriate safeguards for patient anonymity and for scientific and ethical standards of the proposed studies. This database has depended upon the participating general practitioners and has already resulted in a substantial output of studies in peer-reviewed literature. It has great potential for further work of major relevance to public health, and its increasing use is to be actively encouraged.

Localization of neuroendocrine tumours with [111In] DTPA-octreotide scintigraphy (Octreoscan): a comparative study with CT and MR imaging.

Abstract: A wide variety of neuroendocrine tumours express somatostatin receptors, and can be visualized by radiolabelled somatostatin analogue scintigraphy. To investigate the value of [111In]-octreotide scintigraphy (Octreoscan), 48 patients (37 with proven carcinoid, pancreatic endocrine and medullary carcinoma of thyroid tumours, 11 with neuroendocrine syndromes multiple endocrine neoplasia (MEN-I) and Zollinger-Ellison syndrome (ZES) were examined with 111In-DTPA-D-Phe1-octreotide. Scintigrams were obtained at 24 and 48 h, and the results were compared with CT and magnetic resonance imaging (MRI). Thirty-five of 48 patients had positive [111In]-octreotide scintigraphy (23/25 (92%) carcinoids, 8/9 (89%) PETs, 4/11 (36%) MEN-I & ZES). Of the 42 lesions located by conventional imaging techniques, 37 (88%) were also identified by Octreoscan. Unexpected lesions (40 sites), not detected by CT or MR imaging were found in 24/48 (50%) patients. [111In]-octreotide scintigraphy has a higher sensitivity for tumour detection, and is superior to MR imaging and CT scanning in the identification of previously unsuspected extraliver and lymph node metastases. It may also be helpful for the localization of clinically suspected tumours in patients with MEN-I and ZES.

Post-infection fatigue syndrome following Q fever.

Abstract: In 1989, 147 individuals in the West Midlands, UK, were infected with Q fever. Five years later, following anecdotal reports of fatigue, we used a questionnaire-based case-control study to determine the prevalence of chronic fatigue syndrome symptoms in this group. Replies from 71 patients were compared with those from 142 age- and sex-matched controls. Increased sweating (52.9% vs. 31.6%, p = 0.006), breathlessness (50.7% vs. 30.6%, p = 0.006), blurred vision (34.3% vs. 17.8%, p = 0.016) and undue tiredness (68.7% vs. 51.5%, p = 0.03) were found in controls compared to cases. These findings were similar to those in Australian abbatoir workers occupationally exposed to Q fever. CDC criteria for chronic fatigue syndrome were fulfilled by 42.3% of cases and 26% of controls. Using visual analogue scores, symptoms were more severe in cases than in controls. Our findings support the existence of a chronic fatigue state following acute Q fever, in a group of patients exposed just once to the organism, and in circumstances free of such confounding factors as lawsuits over compensation.

Medical application of millimetre waves.

Abstract: The biological effects of millimetre waves (MWs) at tion resides in Soviet/Russian/Ukrainian reports on this topic published as conference abstracts. power levels <20 mW/cm2 were first discovered in However, their analysis allows us to reveal some the late 1960s, and within 10 years were studied in general features of MW therapy. Upon comparing various countries including the former USSR,1–4 the clinical information with the existing experiCanada,5,6 France7 and Germany.8,9 These early mental results, we can better understand the possible studies used a wide variety of objects ranging from mechanisms involved, as well as the most potentially biomolecules to bacteria to tissues of higher organbeneficial applications of MW therapy. isms. Poor reproducibility of some of the experimental results and the lack of acceptable theoretical models resulted in a significant delay to research activity in this area in the USA.10–12 Physical characteristics of millimetre In the meantime, based on the biological experiwaves ments, medical applications of MWs began in the former Soviet Union in the 1970s,13,14 and since the MWs belong to a relatively narrow range of electromid–1980s, have been in widespread usage. Use of magnetic waves with wavelengths from 1 to 10 mm MWs for medical purposes is known as ‘Millimetre (corresponding to frequencies from 300 to 30 GHz, Wave Therapy’ (MW therapy), ‘Extremely High with 1 GHz=109 oscillations per second). MW genFrequency (EHF) therapy’, or, less frequently, erators and related equipment were produced primar‘Microwave Resonance Therapy’. With numerous ily for military purposes (short-range radar), which, medical MW generators now employed in hospitals to a large extent, explains the secrecy and predominand clinics in the former USSR and some other ance of incomplete publications on this topic in the European states (some estimates range as high former USSR. as 50 000 units15), thousands of patients undergo The penetration depth of MWs into biological treatment with MWs every year. Some authors16,17 tissues is very small. Unlike centimetre and decimetre claim that there are several hundred thousand waves, MWs are absorbed in water and waterpatients who have been treated with MWs. The containing media (including biological structures) reported success rate of MW therapy for various within the first 0.3–0.5 mm from the surface, pathologies is astonishingly high. However, this treatdepending on the frequency used.18–20 With energy ment modality is almost unknown to Western medinsufficient to break chemical bonds directly,21,22 ical scientists and practitioners. There is only one and a low average incident power density of <20 publication on this subject in Western peer-reviewed mW/cm2, MWs usually produce an average heating medical journals. of an irradiated surface on the order of several tenths We present an overview of the available informaof a degree C, which is usually imperceptible. Obviously the range of reported biological and tion regarding MW therapy. The majority of informa-

Mannose binding protein deficiency is not associated with malaria, hepatitis B carriage nor tuberculosis in Africans

Abstract: We retrospectively studied MBP genotypes in patients with malaria, tuberculosis (TB), and persistent hepatitis B virus (HBV) carriage, in clinics and hospitals in The Gambia. Children under 10 years with cerebral malaria and/or severe malarial anaemia, were compared with children with symptomatic, mild malaria, and controls of the same age and ethnicity. Adult TB cases with smear-positive pulmonary TB were compared with healthy blood donors from the same ethnic groups. Malaria cases and controls were tested for hepatitis B core antibody (anti-HBc) and surface antigen (HBsAg). TB patients were tested for HIV antibodies. Genotyping used sequence-specific oligonucleotide analysis to identify MBP variant alleles. Overall, 46% (944/2041) of patients and controls were homozygous for the wild-type MBP allele, 45% (922/2041) were carriers of a single variant allele and 8.6% (175/2041) had two variant alleles. Neither homozygotes nor heterozygotes for MBP variants were at increased risk of clinical malaria, persistent HBV carriage or TB. The most common mutation in Africans, the codon 57 variant allele, was weakly associated with resistance to TB (221/794 in TB cases and 276/844 in controls, p = 0.037). MBP deficiency is not a significant risk factor for persistent HBV, severe malaria nor pulmonary TB in West Africa.

Likelihood ratios: getting diagnostic testing into perspective.

Abstract: In modern medicine, sophisticated laboratory tests and imaging studies are often emphasized at the expense of history and physical examination, rather than complementing clinical assessment. Ancillary testing often fails to advance the diagnostic process, and increases patient risk and the expense of medical care. The relative value of clinical evaluation and technological methods is rarely considered, and the power of the clinical evaluation is therefore underestimated. The likelihood ratio (LR) is a semiquantitative measure of the performance of diagnostic tests which indicates how much a diagnostic procedure modifies the probability of disease, and is calculated from the sensitivity and specificity of the test (or directly from the change in probability associated with the test result). We review the performance of frequently-used tests by their LRs, and compare them to the power of clinical assessment, with clinical cases to illustrate the application of LRs in the diagnostic process. The discriminative power of clinical assessment and ancillary tests is often similar, and the combination of the two greatly increases accuracy in the diagnostic process. Clinical assessment is indeed frequently more informative than current technical modalities. LRs assist in putting the value of testing in proper perspective. Practice in evaluating pre-test probabilities of disease and in the application of LRs should be enhanced in medical training.

The PRIME study: classical risk factors do not explain the severalfold differences in risk of coronary heart disease between France and Northern Ireland. Prospective Epidemiological Study of Myocardial Infarction.

Abstract: We are studying the contribution of risk and genetic factors, and their interaction, to the development of ischaemic heart disease (IHD) and other cardiovascular endpoints. The study is prospective, based in three centres in the south, east and north of France and in Northern Ireland. A total of 10,592 men aged 50-59 years were recruited from 1991 to 1993, and examined for evidence of IHD at baseline. Subjects are followed annually by questionnaire. Clinical information is validated from hospital and GP records. Demographic characteristics were similar in all four centres. Body mass index was highest in Strasbourg (mean 27.4 kg/m2 vs. 26.3 kg/m2 in Toulouse and Belfast), but total cholesterol, triglyceride and fibrinogen were highest in Belfast. In Belfast, 6.1% reported having had a coronary angiogram, compared to 3.0% in Toulouse. Conversely, 13.8% in Toulouse reported taking lipid-lowering drugs vs. 1.6% in Belfast. As predicted, a history of myocardial infarction (MI) was highest in Belfast (6.1%) and lowest in Toulouse (1.2%). Some 7.1% of Belfast men reported a medical diagnosis of angina vs. 1.5% in Toulouse. Subjects showing evidence of pre-existing IHD will be studied prospectively but treated in the analysis as an additional variable. These results provide a measure of reassurance that these cohorts are representative of the communities from which they are drawn and provide a reliable baseline for prospective evaluation and cross-sectional comparisons. The levels of the classical risk factors found in this study, particularly when examined in combination, as multiple logistic functions based on previous British studies, are very similar between centres and cannot explain the large differences in the incidence of IHD which exist. Additional risk factors may help explain, at least in part, the major differences in incidence of IHD between these study centres.

Tuberculous meningitis in South African urban adults.

Abstract: We retrospectively reviewed 56 adults with culture-proven tuberculous meningitis (TBM), investigating clinical signs, cerebrospinal fluid (CSF) findings and outcome. There were 50 patients, aged 18-59 years, 39 with and 11 without human immunodeficiency virus (HIV) infection. Six were aged 60 years or older. Neurological signs of TBM in 18-59-year-olds were unaffected by HIV serostatus while, compared to those > or = 60 years of age, there were more patients with meningism (86.0% vs. 33.3%; p = 0.011) and fewer with seizures (12.0% vs. 50.0%; p = 0.046). The HIV-infected 18-59-year-olds had significantly more extrameningeal tuberculosis compared to the non-HIV-infected (76.9% vs. 9.1%; p = 0.0001) and 23.1% had 'breakthrough' TBM. CSF analysis revealed 12 patients (21.4%) with acellular fluid (more common in those > or = 60 years of age, p = 0.016), of whom three had completely normal CSF. A neutrophil predominance was found in 22 patients (39.3%). Only three patients (5.4%) had a positive CSF smear for acid-fast bacilli. In-hospital mortality occurred in 39 patients (69.1%), was similar in all study groups, and was not related to neurological stage. The diagnosis of TBM can be masked by lack of meningism in the elderly and by atypical CSF findings.

Coeliac disease detected by screening is not silent-simply unrecognized

Abstract: Coeliac disease (CD) is associated with a wide spectrum of clinical presentation and may be overlooked as a diagnosis. There is some evidence that untreated CD is associated with a doubling of mortality, largely due to an increase in the incidence of malignancy and small intestinal lymphoma, which is decreased by a strict gluten-free diet. We studied the clinical features of screening-detected coeliacs compared to age- and sex-matched controls as a 3-year follow-up to a population screening survey, and followed-up subjects who had had CD-associated serology 11 years previously to determine whether they have CD or an increased mortality rate compared to the general population. Samples of the general population (MONICA 1991 and 1983) were screened for CD-associated serology and followed-up after 3 and 11 years, respectively, and assessed by a clinical questionnaire, screening blood tests and jejunal biopsy. Mortality rates for 'all deaths' and 'cancer deaths' were compared in subjects with positive serology in 1983 with reference to the general population. Thirteen coeliacs were diagnosed by villous atrophy following screening, compared to two patients with clinically detected CD, giving a prevalence of 1:122. Clinical features or laboratory parameters were not indicative of CD compared to controls. Subjects with positive serology followed up after 11 years did not have an excess mortality for either cancer deaths or all causes of death. Screening-detected CD is rarely silent and may be associated with significant symptoms and morbidity. In this limited study with small numbers, there does not appear to be an increased mortality from screening-detected CD, although the follow-up may be too short to detect any difference.

Clusters of Pneumocystis carinii pneumonia: analysis of person-to-person transmission by genotyping.

Abstract: Genotyping at the internal transcribed spacer (ITS) regions of the nuclear rRNA operon was performed on isolates of P. carinii sp. f. hominis from three clusters of P. carinii pneumonia among eight patients with haematological malignancies and six with HIV infection. Nine different ITS sequence types of P. carinii sp. f. hominis were identified in the samples from the patients with haematological malignancies, suggesting that this cluster of cases of P. carinii pneumonia was unlikely to have resulted from nosocomial transmission. A common ITS sequence type was observed in two of the patients with haematological malignancies who shared a hospital room, and also in two of the patients with HIV infection who had prolonged close contact on the ward. In contrast, different ITS sequence types were detected in samples from an HIV-infected homosexual couple who shared the same household. These data suggest that person-to-person transmission of P. carinii sp. f. hominis may occur from infected to susceptible immunosuppressed patients with close contact within hospital environments. However direct transmission between patients did not account for the majority of cases within the clusters, suggesting that person-to-person transmission of P. carinii sp. f. hominis infection may be a relatively infrequent event and does not constitute the major route of transmission in man.

Churg-Strauss syndrome in a district hospital

Abstract: Published series on Churg-Strauss syndrome (CSS) come from tertiary referral centres. We retrospectively studied 23 patients with CSS (18 male) seen over 14 years (1982-1995) in a District General Hospital serving a population of 500,000. Mean age of onset of vasculitis was 57, 10-19 years older than in previous series. The commonest clinical features were asthma (22) and eosinophilia > 1.5 x 10(9)/l (21). Systemic vasculitis involving two or more extrapulmonary organs occurred in 22 patients, with specific organ involvement of nervous system (18), joints (13), muscles (13), lungs (11), skin (11), kidneys (11), heart (10), and bowel (7). Various classification systems were applied including the Lanham criteria, which were met in 19 patients; the American College of Rheumatology criteria, met in 14; Churg and Strauss criteria, met in four; and the Chapel Hill Consensus definition, met only in two. ANCA was detected in 10/17 patients where measured. Treatment included corticosteroids (21), cyclophosphamide (8), azathioprine (9), immunoglobulin (2), and methotrexate (1). During follow-up six patients died, two due to myocardial vasculitis (mean age 52 years), three due to infection (mean age 80 years), and one cause unknown. Significant long-term disability was due to asthma in five and neuropathy in six.

Assessment of swallowing and referral to speech and language therapists in acute stroke

Abstract: The best clinical assessment of swallowing following acute stroke, in order to decide whether to refer a patient to a speech and language therapist (SLT), is uncertain. Independently of the managing clinical team, we prospectively investigated 115 patients (51 male) with acute stroke, mean age 75 years (range 24-94) within 72 h of admission, using a questionnaire, structured examination and timed water swallowing test. Outcome variables included referral to and intervention by a speech and language therapist (SLT), dietary modification, respiratory complications and death. Of those patients in whom an SLT recommended intervention, 97% were detected by an abnormal quantitative water swallowing test; specificity was 69%. An SLT was very unlikely to recommend any intervention if the test was normal. Inability to perform a water test and/or abnormality of the test was associated with significantly increased relative risks of death, chest infection and dietary modification. A timed water swallowing test can be a useful test of swallowing and may be used to screen patients for referral to a speech and language therapist after acute stroke.

Pyrin/marenostrin mutations in familial Mediterranean fever

Abstract: Familial Mediterranean fever (FMF) is an inherited inflammatory disease that is frequently complicated by reactive systemic (AA) amyloidosis It is principally recognized in certain Mediterranean populations, and the diagnosis depends on clinical features Four mutations strongly linked to FMF have lately been identified in a gene encoding a novel protein that has been named pyrin or marenostrin We studied 27 consecutive patients of varied ethnic origin, including an English man, who had classical, probable or possible FMF Pyrin/marenostrin genotypes were determined, and AA amyloidosis was sought using serum amyloid P component scintigraphy Among the 23 patients with classical or probable FMF, 17 were homozygotes or compound heterozygotes for pyrin/marenostrin mutations, and in five, only single allele mutations were identified Two new mutations, T6811 and delta M694, were discovered in addition to the four described previously No mutations were identified in three of the four patients with possible FMF Nine patients had AA amyloidosis, but this association was not restricted to any particular genotype Most patients with FMF have mutations in both pyrin/marenostrin alleles, and genotyping at this locus is a valuable diagnostic test Unidentified second mutations are likely to occur in FMF patients who have apparently solitary mutations, and therefore genotype results must be interpreted in conjunction with the clinical picture

Coeliac disease and epilepsy.

Abstract: Whether there is an association between coeliac disease and epilepsy is uncertain. Recently, a syndrome of coeliac disease, occipital lobe epilepsy and cerebral calcification has been described, mostly in Italy. We measured the prevalence of coeliac disease in patients attending a seizure clinic, and investigated whether cerebral calcification occurred in patients with both coeliac disease and epilepsy. Screening for coeliac disease was by IgA endomysial antibody, measured by indirect immunofluorescence using sections of human umbilical cord. Of 177 patients screened, four patients were positive. All had small-bowel histology typical of coeliac disease. The overall frequency of coeliac disease in this mixed patient sample was 1 in 44. In a control group of 488 pregnant patients, two serum samples were positive (1 in 244). Sixteen patients with both coeliac disease and epilepsy, who had previously attended this hospital, were identified. No patient had cerebral calcification on CT scanning. Coeliac disease appears to occur with increased frequency in patients with epilepsy, and a high index of suspicion should be maintained. Cerebral calcification is not a feature of our patients with epilepsy and coeliac disease, and may be an ethnically-or geographically-restricted finding.

Antibodies against double-stranded DNA and development of polymyositis during treatment with interferon.

Abstract: Alpha interferons have become effective palliative treatments for patients with neuroendocrine tumours such as carcinoids and endocrine pancreatic tumours. However, several reports indicate an increased incidence of both autoantibodies and autoimmune diseases in patients treated with interferon-alpha (IFN-alpha). We studied the development of antibodies against double-stranded DNA (dsDNA) and clinical signs of autoimmune disease in 214 patients with malignant carcinoids or endocrine pancreatic tumours consecutively admitted for treatment with IFN-alpha. Seventeen patients (8%) developed antibodies against dsDNA, predominantly females (12 females and 5 males). One patient had clinical and laboratory signs of polymyositis. Among the other 16 patients, three developed hypothyroidism and in six patients the anti-dsDNA autoantibodies normalized despite continuing therapy. Although a significant number of patients developed autoantibodies against dsDNA, overt autoimmune disease related to these antibodies is a rare event and many patients spontaneously normalize these titres despite continuing IFN-alpha treatment.

CMV infection is associated with transplant renal artery stenosis

Abstract: Transplant renal artery stenosis (TRAS) is a significant cause of graft dysfunction, with no clearly defined aetiology. Evidence suggests a role for cytomegalovirus (CMV) infection in cardiac transplant vasculopathy and in native coronary artery restenosis after angioplasty. We investigated the relationship between CMV infection after renal transplantation and subsequent development of TRAS. Of 917 patients receiving renal transplants at a single centre from 1978 to 1994, 75 had TRAS diagnosed by angiography. Each was paired with a control transplanted patient with no TRAS, matched for age, sex, year of transplant and number of grafts. Incidence of CMV infection between transplantation and the time of diagnosis of TRAS was assessed in both groups, using clinical and serological criteria to assign patients to three groups: definite CMV infection (CMV-DEF), possible infection (CMV-POSS) and no evidence of infection (CMV-NUL). CMV-DEF was significantly more common in TRAS than in controls (36 vs. 12, respectively, p < 0.001) and CMV-NUL was less common (TRAS 15, controls 33). We have previously reported an increased incidence of acute rejection in patients with TRAS. The subset of patients with no rejection episodes also had significantly more CMV-DEF cases in the TRAS group (54%) than in controls (10%) (p = 0.002). The data are consistent with the hypothesis that CMV infection can contribute to the development of TRAS. The relationship between CMV and TRAS did not arise from an excess of anti-rejection treatment in the TRAS group. CMV-induced large-vessel damage in immunosuppressed patients may occur through local infection and the mitogenic actions of viral gene products within cells of the vessel wall.

Cytokine dysregulation in the post-Q-fever fatigue syndrome.

Abstract: The post-Q-fever fatigue syndrome (QFS) (inappropriate fatigue, myalgia and arthralgia, night sweats, changes in mood and sleep patterns) follows about 20% of laboratory-proven, acute primary Q-fever cases. Cytokine dysregulation resulting from chronic immune stimulation and modulation by persistence of Coxiella burnetii cells or their antigens is hypothesized. We studied cytokine release patterns of peripheral blood mononuclear cells (PBMC) stimulated with various ligands in short-term culture, from 18 patients with active QFS, and 27 controls: six with resolving QFS, five who had had acute primary Q-fever without subsequent QFS, eight healthy Q-fever vaccinees and eight healthy subjects without Q-fever antibody. Conditioned media (CM) from PBMC stimulated in short-term culture with Q-fever antigens, PHA or measles antigen (as an unrelated antigen) were assayed for IL-2, IL-4, IL-5, IL-6, IL-10 and IFN gamma by AgEIA, and for IL-1 and TNF alpha/beta by bioassay. Aberrant cytokine release patterns were observed with PBMC from QFS patients when stimulated with Q-fever antigens: an accentuated release of IL-6 which was significantly [p = 0.01, non-parametric one-way analysis of variance (ANOVA)] in excess of medians for all four control groups. With IL-2, the number of responders in the active QFS group was decreased relative to control groups (Fisher's exact test, p = 0.01) whereas the number of IFN gamma responders was increased (Fisher's exact test, p = 0.0008). Significant correlations were observed between concentrations of IL-6 in CM, total symptom scores, and scores for other key symptoms.

Winning the battle but losing the war: methicillin-resistant Staphylococcus aureus (MRSA) infection at a teaching hospital.

Abstract: A methicillin-resistant Staphylococcus aureus (MRSA) control policy, aimed at eradication, was established at a 1000-bed hospital in 1985, applied consistently for 10.5 years, and then relaxed. Its components included screening of high-risk patients, transfer of carriers to exhaust-ventilated isolation rooms, closure of wards to new admissions when local transmission was detected, MRSA screening during outbreaks, and prospective collection of clinical and epidemiological information. During the eradication policy period, every 6 months, a mean of 5.1 patients (range 1-12) already carrying MRSA were admitted, and a mean of 3.6 (range 0-16) acquired carriage in the hospital. The largest outbreak comprised 11 patients despite epidemic MRSA strain EMRSA-16 being introduced six times, and MRSA did not become endemic. MRSA-positive admissions increased progressively from 1993; nursing staff workload increased, areas available for alternative patient accommodation were reduced, the resulting ward closures interfered with clinical services, and hence the control policy was relaxed in mid-1995. Isolation facilities were overwhelmed with 622 new patient-isolates in the next 18 months, and there were 67 clinical infections in 1996. The proportion of blood cultures positive for MRSA rose nearly sevenfold by 1996 and 27-fold by 1997. Thus, repeated eradication of MRSA, even epidemic strains, by use of a stringent policy, is possible given sufficient resources, whereas flexible national guidelines designed to control, but not eradicate, epidemic staphylococci, are currently unlikely to be successful. The costs of eradication policies need to be weighed against those of endemicity.

Haemodynamic parameters predicting variceal haemorrhage and survival in alcoholic cirrhosis

Abstract: The relationship between the various haemodynamic abnormalities observed in cirrhosis and their prognostic value remains unclear We report haemodynamic measurements on 96 patients with alcoholic cirrhosis (mean Childs-Pugh Score, CPS, 90 +/- 02, mean age 556 +/- 10 years) and assess their value in predicting variceal bleeding and death during a mean follow-up of 193 +/- 15 months Baseline CPS correlated with hepatic venous pressure gradient (HVPG) (p = 0001), azygos blood flow (p 16 mmHg than in those with HVPG 12 mmHg (vs HVPG < 12 mmHg, p < 005) HVPG also predicted death and variceal haemorrhage on univariate and multivariate analyses No other haemodynamic parameter predicted death or bleeding In alcoholic cirrhosis, severity of liver disease is related to HVPG, collateral blood flow and degree of systemic circulatory abnormalities HVPG is a useful predictor of survival and variceal bleeding in these patients

Oral cyclophosphamide versus chlorambucil in the treatment of patients with membranous nephropathy and renal insufficiency.

Abstract: We treated patients with idiopathic membranous nephropathy (iMGN) and renal insufficiency, using: (i) (n = 15) monthly cycles of steroids (1 g methyl-prednisolone i.v. on three consecutive days, followed by oral prednisone 0.5 mg/kg/day months 1, 3 and 5) and chlorambucil (0.15 mg/kg/day months 2, 4 and 6); or (ii) (n = 17) oral cyclophosphamide (1.5-2.0 mg/kg/day for 1 year) and steroids in a comparable dose. The groups were comparable in age, renal function and levels of proteinuria. During the 6 months preceding treatment, serum creatinine levels increased from 148 +/- 50 to 219 +/- 73 mumol/l in the chlorambucil group and from 164 +/- 86 to 274 +/- 126 mumol/l in the cyclophosphamide group. Median (range) follow-ups were: chlorambucil 38 months (8-71); cyclophosphamide 26 months (5-68) (NS). Renal function improved in both groups, but the improvement was short-lived in the chlorambucil group; 12 months after starting treatment, mean serum creatinine was 6.3 mumol/l lower in the chlorambucil group and 121 mumol/l lower in the cyclophosphamide group (p < 0.01). Four chlorambucil-treated patients developed ESRD, and five needed a second course of therapy, whereas only one cyclophosphamide-treated patient developed ESRD (p < 0.05). Remissions of proteinuria occurred more frequently after cyclophosphamide treatment (15/17 vs. 5/15; p < 0.01). Side-effects necessitated interruption of treatment in six patients on cyclophosphamide and in 11 on chlorambucil (p < 0.05). In our patients, oral cyclophosphamide was better tolerated than oral chlorambucil. The suggested greater efficacy of the oral cyclophosphamide regimen needs to be ascertained by longer follow-up.

Evolving strategies in the treatment of sepsis and systemic inflammatory response syndrome (SIRS).

Abstract: In recent years, much basic science research has investigated the predisposing factors, initiation, propagation, and resolution of Gram-negative sepsis, endotoxaemic shock, and the newly defined entity of systemic inflammatory response syndrome (SIRS). A major cause of morbidity and mortality in the post-surgical, neonatal, and geriatric hospital population, sepsis has proven itself notoriously resistant to classical modes of therapy, including antibiotics, fluid/pressor and respiratory support. Recently, the widespread nosocomial isolation of new antibiotic-resistant strains of endotoxin-producing bacteria has further complicated management. For these reasons, there is much interest in alternative treatment modalities which focus upon the endotoxin molecule itself and the systemic inflammatory response it provokes via the cytokine, complement, and coagulation cascades. In this review, recent experimental approaches to the therapy of sepsis and SIRS are discussed in light of each step in the complex inflammatory cascade and in comparison to traditional approaches to prevention and therapy of Gram-negative bacteraemia and septic shock.

Tumour necrosis factor alpha as a predictor of impaired peak leg blood flow in patients with chronic heart failure.

Abstract: Tumour necrosis factor alpha (TNF alpha) is increased in patients with cardiac cachexia, a condition associated with reduced peripheral blood flow both at rest and after interventions causing vasodilation. By contrast, in patients with chronic heart failure (CHF), higher TNF levels are associated with a greater capacity for vasodilation in the arm. To clarify the relationship between peripheral blood flow and TNF in CHF, we studied the relation between TNF alpha and blood flow in the leg (plethysmography, post maximal exercise and 5 min ischaemia) in 34 patients (age 63 +/- 2 years, ejection fraction 29 +/- 3%, peak VO2 16.6 +/- 1.1 ml/kg/min, mean +/- SEM). Peak leg blood flow correlated significantly with total TNF alpha (r = 0.68, p < 0.0001, peak VO2 (r = 0.54), and soluble TNF receptors 1 (r = 0.56) and 2 (r = 0.52, all p < 0.002). TNF alpha, soluble TNF receptors 1 and 2 and aldosterone correlated with peak blood flow independently of age, ejection fraction, peak VO2 and functional NYHA class. TNF alpha was the only parameter that showed strong correlations for peak blood flow in all clinically relevant subgroups (severe vs. mild, ischaemic vs. dilated, cachectic vs. non-cachectic patients). This study shows a close and inverse relationship between peak leg blood flow and the plasma concentration of TNF alpha, suggesting a pathophysiological role for TNF alpha in reducing peak peripheral blood flow in CHF.

Treating the syndrome of inappropriate ADH secretion with isotonic saline.

Abstract: It has been widely accepted that there is little use for saline treatment in the syndrome of inappropriate secretion of ADH (SIADH). However, having observed that most SIADH patients increased their plasma sodium (PNa) after 2 l isotonic saline over 24 h, we investigated whether urine osmolality or the sum of urinary sodium and potassium (UNa + K) predicted this response, in 17 consecutive patients with chronic SIADH. The initial measure of urinary sodium plus potassium (UNa + K t0) was weakly correlated to the change in PNa (DPNa) after infusion (r = -0.51; p 530 mOsm/kg, had their hyponatraemia aggravated by 2 l isotonic saline. Many SIADH patients have lower UOSM; in most such patients, 2 l of isotonic saline will improve PNa.

Long-term treatment of lupus nephritis with cyclosporin A.

Abstract: We evaluated the efficacy and safety of long-term treatment with cyclosporin A (CSA) in type IV lupus nephritis. Seventeen patients with biopsy-proven WHO type IV lupus nephritis were enrolled in a prospective, open study. Twelve of the 17 completed 48 months of treatment with CSA and prednisolone. Three patients required the addition of azathioprine, at 12, 38 and 47 months, respectively, for cutaneous disease flare with refractory rashes. One patient was lost to follow-up at 40 months. The mean +/- SD duration of treatment was 43.2 +/- 10.1 months (range 15.7-48 months). A significant reduction of proteinuria and a significant rise in serum albumin were noted 1 month after initiation of treatment. Improvement was maintained throughout the study except for three patients who relapsed with recurrence of nephrotic syndrome. There were no significant changes in serum creatinine level or creatinine clearances throughout the study. Repeat renal biopsy at 12 months following treatment with CSA showed histological improvement, with WHO type II changes in all 17 patients accompanying significant reduction in activity indices. Patients with baseline haemoglobin (Hgb) levels < 12 g/dl showed significant improvement. Serum C3 and C4 levels were not changed significantly. Corticosteroid-sparing effects were noted. Side-effects included hypertension, gum hypertrophy and mild hirsuitism, but were not serious. Combination therapy using CSA and prednisone is effective and safe for long-term treatment in lupus patients with WHO type IV nephritis.

Long-term complications in newly diagnosed Sri Lankan patients with type 2 diabetes mellitus

Abstract: We screened 597 newly-diagnosed diabetic patients (201 women) mean +/- SD age 42.3 +/- 6.2 years to determine the prevalence of diabetic complications; 22% presented because of symptoms of diabetes, 27% were diagnosed when hyperglycaemia was discovered at a health screening, and 36% were diagnosed while being treated for intercurrent illness. Neuropathy was present in 25.1%, nephropathy in 29%, retinopathy in 15%, coronary vascular disease in 21%, stroke in 5.6%, peripheral vascular disease in 4.8%, hypertension in 23%, obesity in 16%, central obesity in 21.3%, hypercholesterolaemia in 11%, hypertriglyceridaemia in 14%, and low high-density lipoprotein cholesterol in 12%. The prevalence of coronary vascular disease, hypertension, stroke, neuropathy and retinopathy at the time of diagnosis were higher in our patients than in Caucasian and Indo-Asian patients in the UK. Both a genetic predisposition to develop complications, and exposure to a longer duration of asymptomatic hyperglycaemia due to poor access to adequate health care, may contribute to the high frequency of complications at diagnosis. Since complications are already present at diagnosis, there is a case for implementing primary prevention programmes combined with screening for diabetes in high-risk groups.

Delay in presentation of patients with acute stroke to hospital in Oxford.

Abstract: We identified prospectively all patients (181 patients, 183 episodes) admitted to hospital in Oxford with acute stroke from 1 January to 30 June 1997. Data were inadequate in 30, leaving 153 episodes in 151 patients (63 men, 90 women). Structured interviews were used to investigate the timing of events preceding admission. Most strokes (91%) occurred at home, and 36% of patients were alone. After a median delay of 15 min, 56% called a GP (median 30 min response), 41% an ambulance (median 48 min to admission), and 3% went directly to AE onset not at home (p < 0.001); symptoms improving between onset and admission (p < 0.002); and altered consciousness (p < 0.002). The stroke was not recognized by 44% of patients, but no significant delay resulted. Overall, 31% were admitted within 3 h of onset, 46% within 6 h. Initial contact with the GP is a major determinant of delay. If acute therapies for stroke become available, GPs should be the primary targets for an educational initiative.