Showing papers in "QJM: An International Journal of Medicine in 2005"

Delays in the administration of antibiotics are associated with mortality from adult acute bacterial meningitis.

Abstract: Background: Bacterial meningitis continues to cause high mortality. Few studies address the possible association between this mortality and antibiotic administration delays. Aim: To determine whether delays in antibiotic administration are associated with mortality from bacterial meningitis, and to identify inappropriate diagnostic–treatment sequences leading to such delays. Design: Retrospective case record study. Methods: We reviewed 123 cases of adult acute bacterial meningitis in 119 patients aged ⩾16 years admitted to hospital from January 1990 to March 2002, using multivariate regression analysis to assess the association between meningitis mortality and door-to-antibiotic time (the time elapsed between emergency room presentation and antibiotics administration). Results: The case fatality rate was 13% (16/123). Adjusted odds ratios (OR) for mortality were: 8.4 (95%CI 1.7–40.9) for door-to-antibiotic time >6 h; 39.4 (95%CI 4.3–358.1) for afebrility at presentation; and 12.6 (95%CI 2.2–72.0) for severely impaired mental status at presentation. Factors associated with a door-to-antibiotic time of >6 h were: (i) failure to administer antibiotics prior to transfer from another institution (OR 21.8); (ii) the diagnostic–treatment sequence: head CT then lumbar puncture, then antibiotics (OR 5.6); and (iii) the absence of the classic meningitis triad (OR 4.9). Discussion: There is an independent incremental association between delays in administrating antibiotics and mortality from adult acute bacterial meningitis. Inappropriate diagnostic–treatment sequences were significant predictors of such treatment delays.

Incidence and risk of arm oedema following treatment for breast cancer: a three-year follow-up study

Abstract: Summary Background: Breast-cancer-related lymphoedema is a chronic condition with estimates of incidence ranging from 6 to 83%. Lymphoedema has been associated with a variety of risk factors. However, this evidence has suffered from methodological weaknesses, and so has had little impact upon clinical practice. Aim: To examine incidence and risk factors [hospital skin puncture, surgical procedure, Body Mass Index (BMI), age, axillary node status, number of axillary nodes removed, radiotherapy and surgery on dominant side] for breast cancer-related arm lymphoedema. Design: Prospective observational study, with measurement of limbs pre-operatively and at regular intervals post-operatively. Methods: We recruited 251 women who had surgical treatment for breast cancer that involved sampling, excision or biopsy of axillary nodes, aged 518 years, and free of advanced disease and psychological co-morbidities. Of these, 188 (74.9%) were available for 3-year follow-up. Results: At follow-up, 39 (20.7%) had developed lymphoedema. Hospital skin puncture (vs. none) (RR 2.44, 95%CI 1.33–4.47), mastectomy (vs. wide local excision or lumpectomy) (RR 2.04, 95%CI 1.18–3.54), and BMI5 26 (vs. BMI 19–26) (RR 2.02, 95%CI 1.11–3.68) were the only significant risk factors. Discussion: Lymphoedema remains a significant clinical problem, with 1:5 women in this sample developing the condition following treatment for breast cancer. Risk factors are identified in the development of lymphoedema that should be taken into account in clinical practice.

Reverse cholesterol transport and cholesterol efflux in atherosclerosis

Abstract: Reverse cholesterol transport (RCT) is a pathway by which accumulated cholesterol is transported from the vessel wall to the liver for excretion, thus preventing atherosclerosis. Major constituents of RCT include acceptors such as high-density lipoprotein (HDL) and apolipoprotein A-I (apoA-I), and enzymes such as lecithin:cholesterol acyltransferase (LCAT), phospholipid transfer protein (PLTP), hepatic lipase (HL) and cholesterol ester transfer protein (CETP). A critical part of RCT is cholesterol efflux, in which accumulated cholesterol is removed from macrophages in the subintima of the vessel wall by ATP-binding membrane cassette transporter A1 (ABCA1) or by other mechanisms, including passive diffusion, scavenger receptor B1 (SR-B1), caveolins and sterol 27-hydroxylase, and collected by HDL and apoA-I. Esterified cholesterol in the HDL is then delivered to the liver for excretion. In patients with mutated ABCA1 genes, RCT and cholesterol efflux are impaired and atherosclerosis is increased. In studies with transgenic mice, disruption of ABCA1 genes can induce atherosclerosis. Levels of HDL are inversely correlated with incidences of cardiovascular disease. Supplementation with HDL or apoA-I can reverse atherosclerosis by accelerating RCT and cholesterol efflux. On the other hand, pro-inflammatory factors such as interferon-gamma (IFN-gamma), endotoxin, tumour necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1beta), can be atherogenic by impairing RCT and cholesterol efflux, according to in vitro studies. RCT and cholesterol efflux play a major role in anti-atherogenesis, and modification of these processes may provide new therapeutic approaches to cardiovascular disease. Further research on new modifying factors for RCT and cholesterol efflux is warranted.

Primary systemic vasculitis: clinical features and mortality.

Abstract: Background: Wegener's granulomatosis (WG), Churg Strauss syndrome (CSS) and microscopic polyangiitis (MPA) are primary systemic vasculitides (PSV), the clinical features of which have been described from tertiary centres. Aim: To provide the first clinical description of MPA from a general hospital and compare clinical features with WG and CSS. Design: Retrospective analysis of patient records. Methods: Records of 99 PSV patients attending a single hospital, from 1988 to 2000, were reviewed for: clinical features, date/age at diagnosis, sex, duration of illness, anti-neutrophil cytoplasmic antibodies (ANCA), treatment, comorbidity and deaths. Cases were classified using ACR, CHCC and Lanham criteria/definitions. Birmingham vasculitis activity scores (BVAS) and damage index (VDI) were calculated. Survival was assessed using Cox proportional hazards model and standardized mortality ratios (SMRs). Results: Compared to previous reports there was more ENT (29%) and respiratory (29%) but less renal (92%) involvement in MPA, and less ENT involvement in WG (81%). CSS showed high neurological (72%), cardiovascular (28%) and gastrointestinal (17%) involvement and the highest median (range) VDI ( p = 0.01 vs. WG; p = 0.001 vs. MPA). BVAS1 was significantly lower in MPA than in WG [median (range) 15 (4–29) vs. 21 (6–39), ( p = 0.001)] but not in CSS [20 (7–28), p = 0.08]. SMR (95%CI) for PSV was 4.8 (3.0–6.6); 5-year survival was 45.1% for MPA, 75.9% for WG and 68.1% for CSS. Age was a significant risk, but only to the same extent as in the reference population. When age was adjusted for, no other significant factor was found. Discussion: The clinical characteristics seen here are similar to those in previous series. There are difficulties in using the MPA CHCC definitions in classification. There is a high proportion of neurological involvement in CSS, causing permanent damage. MPA may have a poorer prognosis than WG or CSS.

Drugs for exceptionally rare diseases: do they deserve special status for funding?

Abstract: Ultra-orphan drugs are medicines used to treat exceptionally rare diseases that are chronically debilitating or life-threatening. Low patient numbers make it difficult for pharmaceutical companies to recoup research and development costs, and consequently these medicines are generally expensive on a per patient basis. European Union (EU) regulations promote the development of orphan drugs; but to contain costs, some EU healthcare systems assess the cost-effectiveness of therapies when deciding if they should be funded. As ultra-orphan drugs are invariably cost-ineffective, factors in addition to cost-effectiveness need to be considered if ultra-orphan drugs are to be provided by public health services. Health service funding of ultra-orphan drugs, which varies across the EU and within the UK, has led to geographical inequities in patients' access to treatment. In some instances, support for these drugs would appear to have been approved on the basis that diseases that are rare and severe are a special case. We explore whether ultra-orphan drugs merit special status by considering efficiency, effectiveness and equity criteria. Mechanisms are discussed for creating a policy that would reduce geographical inequalities in provision across Europe.

Vitamin D inadequacy among post-menopausal women: a systematic review.

Abstract: Background: Vitamin D inadequacy has been studied extensively, due to concerns about ageing populations, associations with osteoporosis and other disorders (including non-musculoskeletal), and high prevalence. Aim: To review recent reports on the prevalence of vitamin D inadequacy among post-menopausal women with and without osteoporosis and/or other musculoskeletal diseases. Design: Systematic review. Methods: We reviewed publications in the past 10 years reporting prevalence estimates for vitamin D inadequacy, reported as serum 25(OH)D values below various levels. Thirty published studies in the English language were identified, from January 1994 through April 2004. Results: In osteoporotic populations, the prevalence of 25(OH) vitamin D concentration <12 ng/ml ranged from 12.5% to 76%, while prevalence rates reached 50% to 70% of patients with a history of fracture(s) using a cut-off of 15 ng/ml. In post-menopausal women, the prevalence of 25(OH) vitamin D concentrations ⩽20 ng/ml ranged from 1.6% to 86% for community-living and institutionalized women, respectively. The most common factors associated with inadequate vitamin D levels included limited sun exposure, lack of dietary vitamin D intake, nursing home environment, wintertime, and increasing age (over 70 years). Discussion: The prevalence of inadequate vitamin D levels appears to be high in post-menopausal women, especially in those with osteoporosis and history of fracture. Vitamin D supplementation in this group might offer scope for prevention of falls and fracture, especially in elderly and osteoporotic populations.

Heart rate variability measurements and the prediction of ventricular arrhythmias.

Abstract: Heart rate variability (HRV) is the temporal variation between sequences of consecutive heartbeats. On a standard electrocardiogram (ECG), the maximum upwards deflection of a normal QRS complex is at the peak of the R wave (Figure 1), and the duration between two adjacent R wave peaks is termed the R-R interval. The ECG signal requires editing before HRV analysis can be performed, a process requiring the removal of all non-sinus-node-originating beats. The resulting period between adjacent QRS complexes resulting from sinus node depolarizations is termed the N-N (normal-normal) interval.1 HRV is the measurement of the variability of the N-N intervals. Figure 1. The normal electrocardiogram with component waves labelled. Although counter-intuitive, it is possible that HRV confers a survival advantage. Any system exhibiting intrinsic variability is primed to respond rapidly and appropriately to demands placed upon it. HRV is a measure of the balance between sympathetic mediators of heart rate (HR) (i.e. the effect of epinephrine and norepinephrine, released from sympathetic nerve fibres, acting on the sino-atrial and atrio-ventricular nodes), which increase the rate of cardiac contraction and facilitate conduction at the atrio-ventricular node, and parasympathetic mediators of HR (i.e. the influence of acetylcholine, released by the parasympathetic nerve fibres, acting on the sino-atrial and atrio-ventricular nodes), leading to a decrease in the HR and a slowing of conduction at the atrio-ventricular node. Sympathetic mediators appear to exert their influence over longer time periods and are reflected in the low frequency power (LFP) of the HRV spectrum (between 0.04 Hz and 0.15 Hz.2,,3 Vagal mediators exert their influence more quickly on the heart, and principally affect the high frequency power (HFP) of the HRV spectrum (between 0.15 Hz and 0.4 Hz).4 Thus, at any point in time, the LFP:HFP ratio is a proxy for the sympatho-vagal balance. Physiological and pathological process … Address correspondence to Dr M.J. Reed, Emergency Department, Royal Infirmary of Edinburgh, 51 Little France Crescent, Edinburgh EH16 4SA. e-mail: mattreed1{at}hotmail.com

A simple score for estimating the long-term risk of fracture in patients using oral glucocorticoids

Abstract: BACKGROUND: Previous analyses of risk factors for glucocorticoid (GC)-induced osteoporosis have focused on the estimation of relative rather than absolute fracture probability. AIM: To estimate risk scores for the individual probability of fracture in GC users. DESIGN: Retrospective data analysis. METHODS: We evaluated all patients aged 40 years or older with a prescription for oral GCs in the General Practice Research Database (GPRD), which comprises the computerized medical records of around 7 million UK subjects. Individual risk factors for osteoporotic fractures were identified, and combined in a predictive model for 10-year absolute fracture risk. RESULTS: Of 191 752 oral GC users aged > or =40 years, 7412 experienced an osteoporotic fracture. Several characteristics independently contributed to the fracture risk score (GC therapy, age, gender, fall history, fracture history, body mass index, smoking, previous diagnoses, use of medication, recent hospitalization and indication for GC treatment). Scores of 30, 40 and 50 corresponded to absolute 5-year fracture risks of 6.2%, 15.3% and 35.2%, respectively. A woman aged 65 years with RA, low BMI, and a previous history of fracture and falls, who used 15 mg GC daily (total risk score 54) would have a 5-year fracture risk of 47% (a man with similar history, 30.1%). Short-term use of high-dose GC therapy (> or =30 mg) was associated with only a small increased risk of osteoporotic fracture (RR 1.21, 95%CI 1.04-1.42) in patients with a history of GC use. DISCUSSION: This risk score helps to predict an individual's risk of fracture during GC use. Decisions about bone protection treatment could be based on long-term risks of fracture.

Type D personality : the heart, stress, and cortisol

Abstract: Many studies have demonstrated the role of psychosocial and behavioural risk factors in the aetiology and pathogenesis of cardiovascular disorders. Recently, a new personality construct, the type D or 'distressed' personality, has been proposed. Type D behaviour is characterized by the joint tendency to experience negative emotions and to inhibit these emotions while avoiding social contacts with others. The observation that cardiac patients with type D personality are at increased risk for cardiovascular morbidity and mortality underlines the importance of examining both acute (e.g. major depression) and chronic (e.g. certain personality features) factors in patients at risk for coronary events. Both type D dimensions (negative affectivity and social inhibition) are associated with greater cortisol reactivity to stress. Elevated cortisol may be a mediating factor in the association between type D personality and the increased risk for coronary heart disease and, possibly, other medical disorders. Studies of the effect of age on hypothalamic-pituitary-adrenal (HPA) function in healthy humans have produced inconsistent results. This may relate to a different prevalence of type D individuals in study samples (i.e. some type D individuals may have alterations within the HPA axis that are similar to HPA axis changes in depressed patients). Further studies of the psychological and biological features of type D individuals may help develop treatment approaches to improve the psychological and physical health of individuals with type D personality.

TNF-α, chronic hepatitis C and diabetes: a novel triad

Abstract: Summary Patients with chronic hepatitis C virus (HCV) infection have a significantly increased prevalence of type 2 DM compared to controls or HBV-infected patients, independent of the presence of cirrhosis. Moreover, antecedent HCV infection markedly increases the risk of developing DM in susceptible subjects. Even non-diabetic HCV patients have insulin resistance and specific defects in the insulinsignalling pathway. Activation of the tumour necrosis factor (TNF)-a system has a pivotal role in the inflammatory process of chronic hepatitis C, and TNF-a levels correlate with the degree of inflammation. TNF-a is known to cause insulin resistance, with similar defects in the insulin signalling pathway to those described in HCV infection. A model of mice transgenic for the HCV core protein demonstrated insulin resistance, glucose intolerance, and elevated intrahepatic TNF-a mRNA; all of which were ameliorated by anti-TNF-a antibodies. In addition, diabetic HCV patients have significantly higher levels of soluble TNF-a receptors, compared to non-diabetic HCV patients and controls. TNF-a may be the link between HCV infection and diabetes, suggesting an additional mechanism of diabetes with important implications for prognosis and therapy.

Osteoporosis and atherosclerosis: biological linkages and the emergence of dual-purpose therapies.

Abstract: Osteoporosis and atherosclerosis are both widely prevalent in an ageing population, and induce serious morbidities and death. There is growing evidence that in addition to their relationship to ageing, osteoporosis and atherosclerosis are also linked by biological associations. This article reviews their clinical interrelations, discusses the basic biology of bone and the arterial wall, and presents five examples that illustrate their biological linkages. Current therapeutic approaches emerging from these linkages, including statins, bisphosphonates, and the thiazolidinediones, have dual effects on bone and the vasculature. Additional therapies derived from experimental studies that enhance bone density and reduce atherogenesis hold further promise to diminish the morbidity and mortality of osteoporosis and atherosclerosis, with attendant benefits to society.

Under-use of beta-blockers in patients with ischaemic heart disease and concomitant chronic obstructive pulmonary disease.

Abstract: Background: Beta-blockers (BB) improve morbidity and mortality in ischaemic heart disease. There is a general reluctance to use BB, especially in patients with chronic obstructive pulmonary disease (COPD), which is perceived as an absolute contraindication. As large numbers of patients are labelled with COPD without objective evidence, they may miss out on the benefit from these drugs. Aim: To assess the use of BB in patients with COPD admitted with acute coronary syndrome (ACS), and to assess the supporting evidence for the diagnosis of COPD in these patients. Method: Case-note review and retrospective analysis of 457 consecutive patients admitted with troponin-positive ACS between October 2002 and October 2003. Results: Of 457 ACS patients studied, 246 (54%) were discharged on a BB. Cardiologists prescribed BB in ACS patients more frequently than did general physicians, (70% vs. 30%, respectively). The reasons for withholding BB were: not documented 27%, COPD 33%, heart failure 24%, others 16%. Ninety-four patients (21%) had a diagnosis of COPD; only 58 (62%) of these had been reviewed by a chest physician or had previous pulmonary function tests. Of the 94 patients with COPD, only 15 (16%) were prescribed BB during the admission: 9 by cardiologists and 6 by non-cardiologists. BB were discontinued in two patients due to an increase in dyspnoea. Conclusion: Many patients with a diagnosis of COPD have no objective evidence to support the diagnosis and are denied the prognostic benefits of BB when presenting with ACS. Before withholding beta-blockers, COPD and reversibility should be ascertained by pulmonary function testing. The overall use of beta-blockers remains sub-optimal and could be improved in this setting.

The uses and misuses of orchids in medicine

Abstract: We are now aware that medicines need to be tested before being consumed by human beings. Today, this takes the form of experimentation to assess toxicity, and subsequent randomized control trials to assess both efficacy and adverse effects. However, orchid products, the tubers, leaves or flowers, were introduced into medicine with no such testing, and ultimately their use has declined, not through being proven ineffective, but more through lack of evidence and changes in fashion. This article examines the medicinal uses of orchid plants in the Orient, Europe, the Americas, Australia and Africa, and concludes by examining their usage today. There is no doubt that the Chinese were the first to cultivate and describe orchids, and they were almost certainly the first to describe orchids for medicinal use. Reinikka reports1 a Chinese legend that Shen-nung described Bletilla striata and a Dendrobium species in his Materia Medica of the 28th century BC. The earliest Middle East report of plant remedies is in a 4000-year-old Sumerian clay tablet,2 but I do not know if this included any orchids. Shen-nung's herbal ‘cures’ were probably published many times, but were certainly published in 1600 in the Pun-tsae , a pharmacopoeia.2–4 Confucius (551–479 BC) called the orchid ( lan in Chinese) the ‘King of Fragrant Plants’, and Chinese writings indicated that they stood for many things: ‘retirement, friendship, perfection, numerous progeny, all things feminine, noble and elegant’1—and some of these themes were echoed in Europe. The Chinese were also the first to write books devoted to orchids. In 1233, Chao Shih-K![Graphic][1] ng wrote Chin Chan Lan P'u , and described 20 species and how to grow them.3 In 1247, Wang Kuei-hsueh wrote his Treatise on Chinese orchids , and described 37 species. The first Western volumes dedicated to orchids did … [1]: /embed/inline-graphic-1.gif

Long-term persistence of Coxiella burnetii after acute primary Q fever.

Abstract: Background: Long-term persistence of C. burnetii in infected animals was established in the 1950s and 60s, but the implications for human Q fever are not fully explored. Aim: To compare the prevalence of markers of infection in a cohort of Q fever patients in Australia (up to 5 years after infection) with those in the 1989 Birmingham cohort (12 years after infection). Design: Case follow-up study. Methods: C. burnetii was tested for by: (i) antibodies to Phase 1 and 2 antigens in the three immunoglobulin classes; (ii) detection of DNA in bone marrow and peripheral blood mononuclear cells by PCR assays directed against several different targets in the genome; and (iii) attempts to isolate coxiellas in cell culture or mice from PCR-positive samples. Amplicon specificity was verified by fluorometric probing and by sequencing. Cross-contamination was excluded by extensive use of non-template controls, and in particular by the use of certain IS 1111 a target sequences. Results: Irrespective of clinical state, both groups remained seropositive, principally exhibiting medium levels of IgG antibody against C. burnetii Phase 2 antigen. C. burnetii genomic DNA was detected by PCR in 65% of bone marrow aspirates from Australian patients and ∼88% of Birmingham patients. No coxiella were isolated from PCR positive samples. Discussion: We propose a provisional model for persistence. In Q fever without sequelae, the process is largely confined to the bone marrow. In Q fever fatigue syndrome (QFS), it is modulated by the patient's immunogenetic background to give higher levels of coxiella genomes in bone marrow and increased shedding into the peripheral blood. In Q fever endocarditis, late pregnancy, or during iatrogenic or other immunosuppression, the multiplication cycle is prolonged, and a potential source of live organisms.

Why do older patients die in a heatwave

Abstract: More than 11 000 people were registered as dying in France during the first two weeks of August, 2003.1 This confirmed a significant increase in mortality compared with a similar period in recent years. The majority of excess mortality appears to have occurred in older, frail individuals who were thought to have tolerated poorly the extremes of heat experienced in France at that time.2 Some potential mechanisms underlying this increase in death rate are discussed in this article. A diagnosis of heat stroke requires a core body temperature of >40°C and central nervous system dysfunction to be present. Symptoms of altered consciousness and disseminated intravascular coagulopathy are frequently profound in the setting of hyperthermia. Subsequent multi-organ dysfunction and failure contributes to mortality in heat stroke.3 However, many of the physiological changes in renal function and water and electrolyte homeostasis which occur with increasing age could be pertinent to the excess mortality noted in older patients in extremely hot weather. Older subjects have a lower threshold for the development of renal failure, and diminished renal tubular conservation of sodium and water during periods of dehydration. This occurs for a number of reasons. Firstly, the exponential fall in sodium excretion that occurs in younger subjects who are …

N-terminal connective tissue growth factor is a marker of the fibrotic phenotype in scleroderma.

Abstract: Background: Over-expression of connective tissue growth factor (CTGF) is a hallmark of fibrotic disease, including scleroderma. CTGF acts with the pro-fibrotic cytokine TGFβ to promote sustained fibrotic responses in vivo . Elevated production of CTGF might be responsible for maintenance of the fibrotic phenotype in scleroderma. Assays of CTGF or of its fragments are potential non-invasive measures of the fibrotic response in scleroderma. Aim: To determine the utility of whole, N-terminal, and C-terminal CTGF as surrogate markers for fibrosis in scleroderma. Design: Cross-sectional controlled study. Methods: Plasma was collected prospectively from 47 scleroderma patients (26 diffuse scleroderma, 21 limited scleroderma) and 18 healthy controls. At the same time, dermal interstitial fluid was derived by a suction blister technique from the lesional skin of scleroderma patients, and from the forearm skin of healthy controls. Whole, N-terminal, and C-terminal CTGF were assayed by ELISA, using monoclonal antibodies specific for N- and C-terminal epitopes. Results: N-terminal cleavage products of CTGF were present at elevated levels in the plasma and dermal interstitial fluid of scleroderma patients, compared to healthy controls. N-terminal CTGF levels in plasma and dermal interstitial fluid correlated with severity of skin disease and (negatively) with disease duration. Whole and C-terminal CTGF levels were low in blister fluid and plasma levels were not elevated in disease. Discussion: These results support a role for CTGF in scleroderma-associated fibrosis and the utility of N-terminal CTGF as a marker of fibrosis.

Clinical and immunological aspects of HLA class I deficiency.

Abstract: Human leukocyte antigen (HLA) class I deficiency is a rare disease with remarkable clinical and biological heterogeneity. The spectrum of possible manifestations extends from the complete absence of symptoms to life-threatening disease conditions. It is usually diagnosed when HLA class I serological typing is unsuccessful; flow cytometric studies then reveal a severe reduction in the cell surface expression of HLA class I molecules (90-99% reduction compared to normal cells). In most cases to date, this low expression is due to a homozygous inactivating mutation in one of the two subunits of the transporter associated with antigen processing (TAP), critically involved in the peptide loading of HLA class I molecules. Although asymptomatic cases have been described, TAP deficiencies are usually characterized by chronic bacterial infections of the upper and lower airways, evolving to bronchiectasis, and in half of the cases, also skin ulcers with features of a chronic granulomatous inflammation. Despite the defect in HLA class-I-mediated presentation of viral antigens to cytotoxic T cells, the patients do not suffer from severe viral infections, presumably because of other efficient antiviral defence mechanisms such as antibodies, non-HLA-class-I-restricted cytotoxic effector cells and CD8+ T-cell responses to TAP-independent antigens. Treatment is at present exclusively symptomatic, and should particularly focus on the prevention of bronchiectasis, which requires early detection.

Primary angiitis of the central nervous system: emerging variants

Abstract: Background: Primary angiitis of the central nervous system (PACNS), a serious disease, has not featured prominently in the spectrum of multi-organ disease seen in vasculitis clinics. Aim: To evaluate the presentation, natural history and features of PACNS variants and compare to those of systemic vasculitides. Design: Retrospective analysis. Methods: Patients ( n = 105) presented during 1988–2003 to a tertiary regional vasculitis clinic receiving unselected disease types. Data were collected from a clinical database, patient and laboratory records. Results: The frequency of PACNS presentation rose over the study period, compared with most of the other vasculitides. When PACNS was divided into small- and middle-sized vessel disease (SVD/MVD), their clinical courses differed substantially. SVD PACNS was responsive to immunosuppressive drugs, but relapsed during prolonged periods in all patients on maintenance immunosuppressives, or after withdrawal of treatment, causing recurrent, severe and irreversible CNS injury. MVD PACNS had isolated episodes at presentation, with a paucity of relapses during prolonged follow-up. Discussion: Similarities between SVD PACNS and microscopic polyarteritis suggest the former may represent a limited form of the latter. MVD PACNS has a distinctly more benign relapse pattern than its multisystem counterpart polyarteritis nodosa. Acute-phase serology was useful in designating inflammatory processes at presentation of patients presenting with encephalopathy caused by SVD only, but were unhelpful in defining relapses in this form of PACNS, the definition of which in all cases rested on clinical assessment and MR scanning. Direct cerebral angiography was not diagnostic in any case of SVD PACNS; positive brain biopsy is diagnostically unequivocal, but the total clinical syndrome with imaging may establish a diagnosis with highest probability. In MVD PACNS, angiography with MR scan proved diagnostic. We suggest an algorithm for a rational, minimally invasive approach to investigation. In PACNS, SVD and MVD are important variants, and decisions about therapy should incorporate these distinctions.

Impaired glucose metabolism in patients with acute stroke and no previous diagnosis of diabetes mellitus.

Abstract: Background About a third of patients with acute stroke and no prior diagnosis of diabetes have hyperglycaemia during the acute phase of stroke. Whether this is an acute stress response or a reflection of underlying diabetes is controversial. Aim To assess whether impaired glucose metabolism in patients with acute ischaemic stroke and no previous diagnosis of diabetes persists after 3 months, and whether such persistence can be predicted. Design Prospective observational study. Methods We enrolled 106 patients with acute ischaemic stroke and no history of diabetes. Fasting blood glucose, serum insulin and the insulin resistance index HOMA were recorded during hospital stay. A standard oral glucose tolerance test was performed at discharge and 3 months later. Results Ten patients did not complete the study. Eighty-one patients (84.4%) had abnormal glucose metabolism at discharge and 62 (64.6%) after 3 months. Thirty-seven (38.5%) had impaired glucose tolerance at discharge and 26 (27.1%) after 3 months. Forty-four (45.8%) had diabetes at discharge, and 36 (37.5%) at 3 months. Post-load hyperglycaemia at discharge was a predictor of diabetes after 3 months. A plasma glucose cut-off of 11.7 mmol/l (210 mg/dl) had a specificity of 90.0% and a positive predictive value of 81.3%. HOMA increased progressively from patients with normal glucose metabolism to those with newly diagnosed diabetes. Discussion Impaired glucose tolerance and previously unrecognized diabetes could be detected early in the stroke course, and persisted after 3 months in more than two-thirds of our patients. Post-load hyperglycaemia during the acute phase of stroke may be useful in identifying patients with abnormal glucose metabolism, which places them at risk for adverse outcomes, including cardiovascular disease.

Impact of an acute medical admission unit on length of hospital stay, and emergency department 'wait times'.

Abstract: Background: While many UK hospitals have introduced an acute medical admissions unit (AMAU) to facilitate an efficient emergency admission process and reduce length of hospital stay (LOS), there is a lack of such data in the Republic of Ireland Aim: To determine the impact of an AMAU on emergency department (ED) wait times for a hospital bed, consultant practice, and LOS. Design: Retrospective analysis of data recorded in the hospital in-patient enquiry (HIPE) system. Methods: We studied all emergency medical patients admitted to St James’ Hospital Dublin between 1 January 2002 and 31 December 2003. In 2002, patients were admitted directly to a variety of wards, many of which were not affiliated with a medical specialty, under the care of a named consultant physician. In 2003, two centrally located wards were re-configured to function as an AMAU, and all emergency patients were admitted to this unit. Results: For all physician teams, median LOS shortened significantly from 2002 to 2003 (6 vs. 5 days, p <0.0001). Overall, patients seen by general physicians had a shorter LOS (5 days) than that of those seen by sub-specialists (6 days) ( p <0.0001). The number of patients waiting in the ED for a hospital bed was reduced by 30% from 2002 to 2003 ( p <0.001). Extrapolated cost savings for the hospital with the introduction of the AMAU were estimated at approximately 4039 bed-days and €1 714 152. Discussion: Introduction of the AMAU speeded access to acute medical service and reduced costs.

Divalproex sodium in the management of post-herpetic neuralgia: a randomized double-blind placebo-controlled study.

Abstract: Background: Post-herpetic neuralgia is difficult to treat. Divalproex sodium (valproic acid and sodium valproate in molar ratio 1:1) has been used successfully in the management of various painful neuropathies. Aim: To study the effectiveness and safety of divalproex sodium in the management of post-herpetic neuralgia. Design: Randomized double-blind placebo-controlled trial. Methods: We enrolled 48 consecutively attending out-patients with post-herpetic neuralgia, out of whom three were excluded (two had insufficient pain, one withdrew consent). Quantification of pain was by Short Form-McGill pain questionnaire (SF-MPQ), visual analogue scale (VAS), present pain intensity score (PPI) and 11 point Likert scale (11 PLS) at the beginning of the study, after 2 weeks, 4 weeks and at the end of the study (8 weeks). We also assessed patients' global impression of change by questionnaire at the end of the study. Results: After 8 weeks treatment with 1000 mg/day divalproex sodium, there was significant reduction in pain: SF-MPQ, 20.47 ± 2.29 to 11.90 ± 6.52 ( p < 0.0001); PPI 4.0 ± 0.52 to 1.95 ± 1.29 ( p < 0.0001); VAS 70.17 ± 9.21 to 31.27 ± 29.74 ( p < 0.0001) and 11 PLS 6.97 ± 0.73 to 3.63 ± 2.34 ( p < 0.0001) in comparison to placebo (means ± SEM). The ‘global impression of change’ questionnaire showed much or moderate improvement in pain in 58.2% of patients receiving divalproex vs. 14.8% of those receiving placebo. The drug was well tolerated by all patients, except one who developed severe vertigo after 10 days of treatment. Discussion: Divalproex sodium provides significant pain relief in patients of post-herpetic neuralgia, with very little incidence of adverse reactions. These data provide a basis for longer trials in a larger group of patients.

Democracy and health

Abstract: Scholars of population and global health have grappled for decades with the complex relationship between health and its determinants. This growing literature has taught us much about proximal and distal health determinants, especially those in the socio-economic realm. Economics as it relates to health, in particular, has received considerable and recent investigation,1 but mounting evidence suggests that a country's economic status alone cannot entirely explain differences in health and health policy.2–8 Thus, societies with similar levels of economic development, such as Afghanistan and the Indian state of Kerala, can have radically different levels of health and health system development. It is therefore important to extend our analysis to broader structural factors, such as political institutions, to better understand global health inequalities. A country's political structure affects virtually every aspect of society, including health. There are few studies on the relationship between political institutions and health, at both theoretical and empirical levels9–11. One reason must certainly stem from the complexity of the health-politics nexus and the difficulty of identifying independent and interactive influences in both directions. The relationship can be defined in many ways, ranging from the study of political systems (e.g. democratic or authoritarian, legislative and executive governance, proportional or majoritarian electoral systems, constitutional structure); culture (e.g. political values); institutions (e.g. centralized or fragmented, presidential or parliamentary, responsiveness to citizenry, political parties); state capacity (technical and administrative capacity, level of corruption); and philosophy, to more nuts-and-bolts political process factors, such as personal politics (e.g. political leadership, powerful personalities, presidential tactics), political strategy and interest group representation (e.g. its strength or weakness in a political system). More recent influences on health policy include re-election incentives, financial contributions (e.g. in the US), and the depth and range of public opinion.12,,13 A recent issue of the …

Diagnostic approach to a patient with hyponatraemia: traditional versus physiology-based options.

Abstract: The usual diagnostic approach to a patient with hyponatraemia is based on the clinical assessment of the extracellular fluid (ECF) volume, and laboratory parameters such as plasma osmolality, urine osmolality and/or urine sodium concentration. Several clinical diagnostic algorithms (CDA) applying these diagnostic parameters are available to the clinician. However, the accuracy and utility of these CDAs has never been tested. Therefore, we performed a survey in which 46 physicians were asked to apply all existing, unique CDAs for hyponatraemia to four selected cases of hyponatraemia. The results of this survey showed that, on average, the CDAs enabled only 10% of physicians to reach a correct diagnosis. Several weaknesses were identified in the CDAs, including a failure to consider acute hyponatraemia, the belief that a modest degree of ECF contraction can be detected by physical examination supported by routine laboratory data, and a tendency to diagnose the syndrome of inappropriate secretion of antidiuretic hormone prior to excluding other causes of hyponatraemia. We conclude that the typical architecture of CDAs for hyponatraemia represents a hierarchical order of isolated clinical and/or laboratory parameters, and that they do not take into account the pathophysiological context, the mechanism by which hyponatraemia developed and the clinical dangers of hyponatraemia. These restrictions are important for physicians confronted with hyponatraemic patients and may require them to choose different approaches. We therefore conclude this review with the presentation of a more physiology-based approach to hyponatraemia, which seeks to overcome some of the limitations of the existing CDAs.

Faecal calprotectin in the assessment of Crohn's disease activity.

Abstract: Background: Clinical and laboratory assessment of activity in Crohn's disease (CD) correlate poorly with endoscopic findings. Calprotectin is a calcium-binding protein abundant in neutrophil cytosol, and extremely stable in faeces. Faecal calprotectin (FC) is an excellent surrogate marker of neutrophil influx into the bowel lumen. Aim: To assess whether FC concentration from a spot stool sample reliably detects active inflammation in patients with CD. Design: Cross-sectional comparative study. Methods: Subjects had a previously confirmed diagnosis of CD and were suspected on clinical grounds to be in the midst of a relapse. Thirty-five entered the study; they underwent radiolabelled white cell scanning (WCS) and had a stool sample collected for calprotectin measurement on the same day. A Crohn's disease activity index (CDAI) was also calculated for each. The WCS scans were scored at six standard sites to give a mean total, ‘extent‘, ‘severity’ and ‘combined extent and severity’ scores. Results: FC was significantly and positively correlated with mean total ( r = 0.73, p 100 µg/g gave a sensitivity of 80%, specificity of 67%, positive predictive value of 87% and a negative predictive value of 64% in identifying those with and without any inflammation on WCS. There was, however, no significant correlation between CDAI and mean total WCS score ( r = 0.21, p = 0.24), nor between CDAI and FC ( r = 0.33, p = 0.06). Discussion: While the CDAI does not accurately reflect inflammatory activity in CD, a one-off FC reliably detects the presence or absence of intestinal inflammation in adult patients with CD, compared to WCS.

Analysis of an adult Duchenne muscular dystrophy population

Abstract: Background: Advances in management have led to increasing numbers of patients with Duchenne muscular dystrophy (DMD) reaching adulthood. Older patients with DMD are necessarily severely disabled, and their management presents particular practical issues. Aim: To review the management of a late adolescent and adult DMD population, and to identify areas in which the present service provisions may be inadequate to their needs. Design: Retrospective review. Methods: We studied 25 patients with DMD referred to an adult neuromuscular clinic over a 7-year period. Clinical details were obtained retrospectively, from case notes or direct observations. Results: There were 24 males and one symptomatic female carrier. Nine patients died during the observation period. There was no significant correlation between age of wheelchair confinement and age of death. Sixteen patients received non-invasive positive pressure support. Twelve attended mainstream schools and 12, residential special schools. All the patients lived at home for some or all of the time, when their main carers were either one or both of the parents. The most striking difficulties were with the provision of practical aids, including appropriate hoists and belts, feeding and toileting aids, and the conversion of accommodation. Patients rarely wished to discuss the later stages of their disease, and death was often more precipitate than expected. Death usually occurred outside hospital and the final cause was often difficult to establish. Discussion: Adult patients with DMD develop progressive impairment, due to respiratory, orthopaedic and general medical factors. However, the particular areas of difficulty in this study often reflected inadequate and poorly directed social and medical support, illustrating the need for improvements in the structure, co-ordination and breadth of rehabilitation services for adult patients with DMD.

Cost-effectiveness of integrated stroke services

Abstract: Background: Randomized trials have shown that integrating services for acute stroke care may lead to organizational improvements, higher efficiency and better patient outcomes in the acute phase. Aim: To compare the costs and effects of stroke services in an experimental group of patients compared to a group of patients receiving conventional care. Design: Prospective non-randomized controlled trial. Methods: We compared all consecutively hospitalized stroke patients in three experimental stroke service settings (Delft, Haarlem and Nijmegen, n = 411) with concurrent patients receiving conventional stroke care ( n = 187) over 6 months follow-up. Main end-points were total costs per patient and total health-adjusted days per 100 patients as measured by the EuroQol-5D score during follow-up. Results: Mean total costs per patient were €16 000 (95%CI €14 670–€16 930): €13 160 in Delft, €16 790 in Haarlem, €20 230 in Nijmegen, and €13 810 in the control regions. Early discharge in Delft saved about €2500 hospital costs per patient. General patient health in Delft was significantly better than in the control regions; Haarlem and Nijmegen showed no difference in health. Discussion: Our study confirms the potential to improve stroke outcomes in a cost-effective way in Dutch settings. This was seen in the group of patients in Delft, a complete and relatively simple stroke service, but not in two other regions with more complex stroke services. Important factors are reduction of hospital days and, most likely, adequate multidisciplinary rehabilitation.

Variation in the diagnostic performance of D-dimer for suspected deep vein thrombosis

Abstract: Background: Numerous studies have evaluated the accuracy of D-dimer in diagnosing suspected deep vein thrombosis (DVT), but results are conflicting. Aim: To overview estimates of the diagnostic accuracy of D-dimer and identify causes of variation. Design: Systematic review, meta-analysis and meta-regression. Methods: We searched Medline, EMBASE, CINAHL, Web of Science, Cochrane Database of Systematic Reviews, Cochrane Controlled Trials Register, Database of Reviews of Effectiveness, the ACP Journal Club, citation lists, and contacted manufacturers. We selected studies that compared D-dimer to a reference standard in patients with suspected DVT. Data were analysed by random effects meta-analysis and meta-regression. Results: We included 97 studies reporting 198 assays in 99 different patient groups. Overall estimated sensitivity and specificity of D-dimer were 90.5% and 54.7%, but both estimates were subject to significant heterogeneity ( p < 0.001). Meta-regression identified that some heterogeneity was explained by study setting, exclusion criteria, whether recruitment was consecutive or the study prospective, whether D-dimer and the reference standard were measured blind, and whether the D-dimer threshold was determined a priori . Sensitivity and specificity also varied between ELISA (94% and 45% respectively), latex (89% and 55%) and whole blood agglutination assays (87% and 68%). Sensitivity was higher for proximal than distal DVT. Specificity was dependent upon whether clinical probability of DVT was high (specificity 51%), intermediate (67%) or low (78%). Discussion: D-dimer has good sensitivity, but poor specificity, for DVT. Estimates are subject to substantial heterogeneity from various sources. D-dimer specificity appears to be strongly dependent upon the pre-test clinical probability of DVT.

Pharmacy-implemented guidelines on switching from intravenous to oral antibiotics: an intervention study.

Abstract: Background: A high proportion of medical in-patients in the UK receive intravenous (IV) antibiotic therapy. This may be inappropriate in non-severe infections, or unnecessarily prolonged. Aim: To assess the impact of guideline implementation on IV antibiotic prescribing in medical admissions to a general hospital. Design: Observational intervention study. Methods: Data relating to infection and antibiotic therapy were collected for 4 weeks pre-intervention (group 1) and 4 weeks post intervention (group 2). Six months later, data were collected for a further 4 weeks following a second intervention (group 3). Interventions consisted of pharmacy-led implementation of guidelines incorporating criteria for IV therapy and switching to the oral route. The second intervention also included pharmacy-initiated feedback on prescribing. The main outcome measures were IV antibiotic duration, and appropriateness of the IV route and switching. Results: Of 2365 admissions, 757 (32%) had 806 treated episodes. IV therapy was used in 40%, 46% and 36% (groups 1, 2 and 3, respectively) and was appropriate in 92% vs. 100% (group 1 vs. 2). In groups 2 and 3, oral switch timing was appropriate in 90% and 88%, vs. 17% in group 1 ( p <0.001). Between groups 1 and 2, median duration of IV therapy was reduced from 3 to 2 days ( p = 0.01). More patients in group 2 received appropriate exclusively IV therapy (65% vs. 96%, p <0.01). Duration of stay in IV-treated patients reduced from 13 to 10 days in groups 2 and 3 ( p = 0.047). IV antibiotic expenditure reduced by 13% per patient admitted between groups 1 and 2. Discussion: Pharmacy-led introduction of antibiotic guidelines appears to result in clinically appropriate reductions in IV therapy.

Benign paroxysmal positional vertigo: clinical characteristics of dizzy patients referred to a Falls and Syncope Unit

Abstract: Background: Dizziness is a common symptom in older people that affects quality of life and increases the risk of falls. Benign paroxysmal positional vertigo (BPPV) is a common cause of dizziness that increases in prevalence with age, and is potentially curable. Aim: To compare patients with BPPV referred initially to a Falls and Syncope Unit (FSS group) with those initially referred to a Regional ENT/Balance Service (ENT group). Design: Retrospective case-note review. Methods: Medical notes, investigations and outcomes were reviewed for all patients. Results: Of 59 patients with BPPV confirmed by Dix-Hallpike test, 31 (53%) were initially referred to the FSS (2.6 patients per month, 71% females) and 28 (47%) were initially referred to ENT (4.7 patients per month, 86% females). Compared to those referred initially to ENT, FSS patients were significantly older (mean ± SD 69 ± 13 vs. 55.4 ± 13 years, p = 0.0003) and had dizzy symptoms for longer before diagnosis (median (range) 12 (4–120) vs. 6 (1–36) months, p = 0.0273). FSS patients were more likely to have more than one type of dizziness (16% vs. 0%, p = 0.001), more likely to have cerebrovascular or cardiovascular co-morbidity (13% vs. 4%, p = 0.0152) and were taking significantly more medications (3.2 vs. 1.7; p = 0.0271). Cure rates on intervention were similar (83% FSS, 86% ENT). Discussion: BPPV is a potentially curable cause for dizziness in older people. Older people are frequently referred directly to Falls units, who will be seeing increasing numbers of patients with dizziness. A high index of suspicion allows early identification and treatment of this condition.

Fungal infections as a complication of therapy for sarcoidosis

Abstract: Background: Treatment of symptomatic sarcoidosis usually includes systemic immunosuppressive agents. These agents may render the patient more susceptible to opportunistic infections. In addition, the fungal infection may be difficult to distinguish from the underlying sarcoidosis. Aim: To examine the presentation and management of invasive fungal infections in sarcoidosis patients. Design: Retrospective record review. Methods: We reviewed the notes of all sarcoidosis patients ( n = 753) seen at our clinic over an 18-month period. Results: Seven patients (0.9%) with previously diagnosed sarcoidosis developed fungal infections: two each with Histoplasma capsulatum and Blastomyces dermatitidis and three others with Cryptococcus neoformans . No cases of invasive aspergillus or tuberculosis were identified. The diagnosis of fungal infection was made by bronchoscopy (four cases), open-lung biopsy (one case), bone-marrow aspirate (one case), and spinal fluid examination (one case). All patients were receiving corticosteroids at the time of worsening chest X-ray or clinical status. Four patients were also receiving methotrexate prior to infection. No patient with systemic fungal infection was receiving either infliximab or cyclophosphamide. All patients responded to anti-fungal therapy and a reduction in immunosuppression. Discussion: Fungal infections occur rarely in treated patients with sarcoidosis. Deterioration of chest X-ray, especially a localized infiltrate, warrants investigation.