Showing papers in "Swiss Medical Weekly in 2001"

Procalcitonin: how a hormone became a marker and mediator of sepsis.

Abstract: Calcitonin was discovered in the early 1960s [1], at which time it was assumed to be a single hormone with a yet-to-be-determined role in human physiology. Since then it has been found to be only one entity among a large array of related circulating peptides, at least one of which has a pivotal role in the host response to microbial infections [2, 3]. The aim of this review is to describe this metamorphosis of an endocrine hormone to a new class of hormokine mediators in infectious diseases.

Risk free simultaneous prenatal identification of fetal Rhesus D status and sex by multiplex real-time PCR using cell free fetal DNA in maternal plasma.

Abstract: Questions under study Pregnancies with a Rhesus constellation still present a considerable obstetric problem. In addition, pregnancies with male Rhesus D fetuses are more severely affected by haemolytic disease of the newborn, requiring more transfusions in utero and having a three fold higher mortality than female Rhesus D fetuses. Furthermore, almost 150 X-linked genetic deficiencies have now been characterised, increasing the need for prenatal sex determination in pregnancies at risk for such a disorder. In order examine these two important fetal loci in a risk free manner, we have developed a novel multiplex real-time PCR assay for the analysis of extracellular fetal DNA in maternal plasma. Methods Cell free DNA was isolated from 34 maternal plasma samples and examined by a multiplex real-time PCR assay for the Rhesus D gene and the SRY locus on the Y chromosome. Results Our study showed that we were able to genotype 12/13 Rhesus D males correctly. All 5 Rhesus d males were correctly identified. In addition a 100% concordance was found in the 16 samples obtained from pregnancies with female Rhesus D or Rhesus d fetuses. Conclusions By developing a novel multiplex real-time PCR assay we present the first report describing the determination of multiple fetal loci from cell free DNA in maternal plasma by these means. As this assay is suitable for automation, our data, therefore, suggest that such assays provide a good basis for the clinical examination of multiple fetal loci, in particular Rhesus D status or fetal sex, and can be performed effectively using real-time multiplex PCR assays.

Therapeutic efficacy of selective nerve root blocks in the treatment of lumbar radicular leg pain.

Abstract: The objective of this study was to investigate the clinical effectiveness of nerve root blocks (i.e., periradicular injection of bupivacaine and triamcinolone) for lumbar monoradiculopathy in patients with a mild neurological deficit. We have retrospectively analysed 30 patients (29-82 years) with a minor sensory/motor deficit and an unequivocal MRI finding (20 disc herniations, 10 foraminal stenoses) treated with a selective nerve root block. Based on the clinical and imaging findings, surgery (decompression of the nerve root) was justifiable in all cases. Twenty-six patients (87%) had rapid (1-4 days) and substantial regression of pain, five required a repeat injection. 60% of the patients with disc herniation or foraminal stenosis had permanent resolution of pain, so that an operation was avoided over an average of 16 months (6-23 months) follow-up. Nerve root blocks are very effective in the non-operative treatment of minor monoradiculopathy and should be recommended as the initial treatment of choice for this condition.

Folate and the risk of colorectal, breast and cervix cancer: the epidemiological evidence.

Abstract: It is only recently that folate deficiency has been implicated in the development of cancer The mechanisms by which folate might protect against cancer are not clear but may relate to its role in DNA methylation and DNA synthesis All case-control, cohort and intervention trials reported in English, French, or German, on folate intake or blood levels in relation to the risk of colorectal, breast, and cervix cancer were reviewed Twenty case-control, and 12 nested case-control or cohort studies were identified The epidemiological studies consistently show an inverse association between intake and/or levels of folate and the frequency of colorectal carcinomas, and less clearly of adenomas Long-term use of supplements of folate seems to be of greater benefit than dietary intake The effect of folate seems to be modulated by alcohol, methionine, and MTHFR polymorphisms Results from animal studies suggest that folate supplementation might decrease or increase cancer risk depending on dosage and timing Recent studies also suggest an inverse association between folate intake and breast cancer among women who regularly consume alcohol Conversely, epidemiological evidence remains uncertain for the role of folate in cervical cancer prevention; the results of two intervention trials on rates of cervical intraepithelial neoplasia regression or progression were negative An effect of folate later in carcinogenesis is not supported by the few (nested) case-control studies on invasive cervical cancer Some of the conflicting results may be due to the fact that dietary intake or blood levels of folate do not accurately reflect folate concentrations in the cells of cancer origin Furthermore, only a few studies have taken into account the modulating effect of alcohol, methionine, and MTHFR polymorphisms in their analyses The observed inverse associations between folate and risk of cancer, on the other hand, may be confounded by various factors, especially by other potentially protective constituents in fruits and vegetables Ongoing intervention studies can strengthen evidence for causality by excluding such confounding, but the optimal dose, duration, and stage of carcinogenesis and the appropriate (genetically predisposed) study group for folate chemoprevention are not yet defined

Diagnosis of acute haematogenous osteomyelitis and septic arthritis: 20 years experience at the University Children's Hospital Basel.

Abstract: OBJECTIVE: To review the diagnostic experience with acute haematogenous osteomyelitis (AHOM) and/or septic arthritis at our institution. METHODS: Retrospective review of the medical records of those patients with a bacteriologically and/or radiologically confirmed diagnosis, hospitalised in the University Children's Hospital Basel, Switzerland between January 1980 and July 2000. RESULTS: 90 patients (61% males), 4 weeks to 14 years of age, met the inclusion criteria. Median duration of disease prior to hospitalisation was 3 days (range 0-14); 88% were admitted during the first week after onset of complaints. 81 patients received no antimicrobial therapy prior to hospitalisation and are the subject of this presentation. ESR (1st hour in mm; median 36; range 11-124), CRP (mg/l; median 64; range 0-221) and WBC (x 10(9)/l; median 13; range 5-34) were elevated in 100%, 82% and 58% of patients, respectively. Blood cultures (BC) and/or tissue cultures (TC) were performed in 79 (98%) patients. Overall, bacteria were isolated from 53 patients (65%) with Staph. aureus as the most frequent organism (n = 31; 50%). BC were performed in 67 patients and yielded 35 (52%) positive cultures; TC (n = 47) yielded 27 (57%) isolates. In 34 patients with both BC and TC performed, only 12 (35%) were positive in both tests. Diagnostic findings were observed in 23 (59%) of 39 plain radiographs, 31 (56%) of 55 sonograms, 39 (89%) of 44 99mTc-labeled bone scans and 4 (100%) of 4 MRI. 41 patients with diagnostic radiological findings had consecutive TC yielding 30 (73%) bacteriological isolates. Median duration of hospitalisation was 15 days (range 2-66). CONCLUSION: Our data indicate that the diagnostic procedures of choice should be 1) early bone scan or MRI, 2) BC and 3) TC. Of supportive laboratory parameters, ESR and CRP were most valuable in our hands.

The HMG-CoA reductase inhibitor simvastatin inhibits IFN-gamma induced MHC class II expression in human vascular endothelial cells.

Abstract: HMG-CoA reductase inhibitors, or statins, are lipid-lowering agents that have been shown to effectively decrease severe rejection periods and development of transplant coronary artery disease after heart transplantation. Precise regulation of major histocompatibility complex class II (MHC class II) gene expression plays a pivotal role in control of the immune response after transplantation. The aim of this study was to evaluate the potential role of HMG-CoA reductase inhibitors in regulating the immune response. We have examined the effects of simvastatin on MHC class II expression in primary human endothelial cells. Using RNAse protection assay and flow cytometry, we observed that simvastatin dose-dependently reduced interferon-gamma (IFN-gamma) induced MHC class II expression (mRNA and protein). In contrast, simvastatin did not affect the expression of MHC class I, pointing to specific actions in the MHC class II signalling cascade. The transcriptional coactivator CIITA is the general regulator of both constitutive and inducible MHC class II expression. After stimulation with IFN-gamma, the CIITA gene is selectively activated via one (promotor IV) of its four promoters. Interestingly, mRNA levels of CIITA were decreased after treatment with simvastatin. In addition, using transient transfections of promoter-reporter constructs we observed that the activity of CIITA promoter IV was decreased by simvastatin. In conclusion, simvastatin selectively decreases IFN-gamma-induced MHC class II expression in human primary endothelial cells through actions on the CIITA promoter IV. Thus, the beneficial effects of statins reported after heart transplantation may result from this immunosuppressive action, suggesting possible therapeutic use for other immunological disorders as well.

Mendelian susceptibility to mycobacterial infection in man.

Abstract: Selective susceptibility to weakly pathogenic mycobacteria, such as bacillus Calmette-Guerin (BCG) vaccine and environmental non-tuberculous mycobacteria (NTM), has long been suspected to be a Mendelian disorder but its molecular basis remained elusive. Recently, mutations in the interferon-gamma receptor ligand-binding chain (IFN gamma R1), interferon-gamma receptor signaling chain (IFN gamma R2), Signal Transducer and Activator of Transcription-1 (STAT-1), interleukin-12 p40 subunit (IL-12 p40), and interleukin-12 receptor beta 1 chain (IL-12R beta 1) genes have been identified in a number of patients with severe BCG or NTM infection. Dominant or recessive alleles causing complete or partial cellular defects have been found to define nine different inheritable disorders. Although genetically distinct, these conditions are immunologically related and highlight the essential role of interferon gamma-mediated immunity in the control of mycobacteria in man. The genetic and immunologic heterogeneity of this syndrome makes accurate diagnosis challenging but vital as decisions about the most appropriate treatment are best taken based on an accurate molecular diagnosis.

The "metal transcription factor" MTF-1: biological facts and medical implications

Abstract: Metallothioneins (MTs) are a class of small, cysteine-rich proteins that have an important function in heavy metal metabolism and detoxification and in the management of various forms of cell stress. Several lines of evidence suggest a role for metallothioneins in therapy resistance of malignant tumours, regulation of blood pressure and protection against some neurological diseases. Basal and heavy metal-induced expression of the stress-inducible metallothionein-I and -II genes and some other stress-regulated genes depends on the zinc-finger transcription factor MTF-1. MTF-1 acts as a cellular stress-sensor protein and, besides its crucial role in metallothionein expression, is essential for liver development since mice null mutant for MTF-1 die in utero due to hepatocyte degeneration. Under pathological conditions, MTF-1 seems to be involved in clinically important processes such as tumour angiogenesis and drug resistance. It thus seems generally advisable to monitor MTF-1 activity in stress-related processes including aging and carcinogenesis.

Metabolic and endocrine effects of metabolic acidosis in humans.

Abstract: Metabolic acidosis is an important acid-base disturbance in humans. It is characterised by a primary decrease in body bicarbonate stores and is known to induce multiple endocrine and metabolic alterations. Metabolic acidosis induces nitrogen wasting and, in humans, depresses protein metabolism. The acidosis-induced alterations in various endocrine systems include decreases in IGF-1 levels due to peripheral growth hormone insensitivity, a mild form of primary hypothyroidism and hyperglucocorticoidism. Metabolic acidosis induces a negative calcium balance (resorption from bone) with hypercalciuria and a propensity to develop kidney stones. Metabolic acidosis also results in hypophosphataemia due to renal phosphate wasting. Negative calcium balance and phosphate depletion combine to induce a metabolic bone disease that exhibits features of both osteoporosis and osteomalacia. In humans at least, 1,25-(OH)2 vitamin D levels increase, probably through phosphate depletion-induced stimulation of 1-alpha hydroxylase. The production rate of 1,25-(OH)2 vitamin D is thus stimulated, and parathyroid hormone decreases secondarily. There is experimental evidence to support the notion that even mild degrees of acidosis, such as that occurring by ingestion of a high animal protein diet, induces some of these metabolic and endocrine effects. The possible role of diet-induced acid loads in nephrolithiasis, age-related loss of lean body mass and osteoporosis is discussed.

Recreational scuba diving, patent foramen ovale and their associated risks.

Abstract: Scuba diving has become a popular leisure time activity with distinct risks to health owing to its physical characteristics Knowledge of the behaviour of any mixture of breathable gases under increased ambient pressure is crucial for safe diving and gives clues as to the pathophysiology of compression or decompression related disorders Immersion in cold water augments cardiac pre- and afterload due to an increase of intrathoracic blood volume and peripheral vasoconstriction In very rare cases, the vasoconstrictor response can lead to pulmonary oedema Immersion of the face in cold water is associated with bradycardia mediated by increased vagal tone In icy water, the bradycardia can be so pronounced, that syncope results For recreational dives, compressed air (ie, 4 parts nitrogen and 1 part oxygen) is the preferred breathing gas Its use is limited for diving to 40 to 50 m, otherwise nitrogen narcosis ("rapture of the deep") reduces a diver's cognitive function and increases the risk of inadequate reactions At depths of 60 to 70 m oxygen toxicity impairs respiration and at higher partial pressures also functioning of the central nervous system The use of special nitrogen-oxygen mixtures ("nitrox", 60% nitrogen and 40% oxygen as the typical example) decreases the probability of nitrogen narcosis and probably bubble formation, at the cost of increased risk of oxygen toxicity Most of the health hazards during dives are consequences of changes in gas volume and formation of gas bubbles due to reduction of ambient pressure during a diver's ascent The term barotrauma encompasses disorders related to over expansion of gas filled body cavities (mainly the lung and the inner ear) Decompression sickness results from the growth of gas nuclei in predominantly fatty tissue Arterial gas embolism describes the penetration of such gas bubbles into the systemic circulation, either due to pulmonary barotrauma, transpulmonary passage after massive bubble formation ("chokes") or cardiac shunting In recreational divers, neurological decompression events comprise 80% of reported cases of major decompression problems, most of the time due to pathological effects of intravascular bubbles In divers with a history of major neurological decompression symptoms without evident cause, transoesophageal echocardiography must be performed to exclude a patent foramen ovale If a cardiac right-to-left shunt is present, we advise divers with a history of severe decompression illness to stop diving If they refuse to do so, it is crucial that they change their diving habits, minimising the amount of nitrogen load on the tissue There is ongoing debate about the long term risk of scuba diving Neuro-imaging studies revealed an increased frequency of ischaemic brain lesions in divers, which do not correlate well with subtle functional neurological deficits in experienced divers In the light of the high prevalence of venous gas bubbles even after dives in shallow water and the presence of a cardiac right-to-left shunt in a quarter of the population (ie, patent foramen ovale), arterialisation of gas bubbles might be more frequent than usually presumed

Survey of children supported by long-term mechanical ventilation in Switzerland

Abstract: The aim of the present study was to identify the number of children, from birth to 16 years of age, on long-term mechanical ventilation in Switzerland, and to establish their current location, underlying diagnoses and ventilatory needs.

Intensive care unit admission in patients with haematological disease: incidence, outcome and prognostic factors.

Abstract: Objectives: To examine incidence and outcome of intensive care unit (ICU) admission in patients with haematological malignancy and analyse prognostic factors associated with outcome. Design: Retrospective cohort study in an intensive care unit of a tertiary referral center. Patients: 78 patients with severe haematological malignancy were admitted 97 times between 1990-97 to the medical ICU for septic shock (18), respiratory failure (30), postoperative monitoring (19), cardiovascular (10), and central nervous complications (8), or for other reasons (12). Median age was 43 (4-73) years, average duration of ICU stay was 4 (1-43) days. Forty-two patients required mechanical ventilation, 46 vasopressors and 8 haemodialysis. Results: Rates of ICU admission differed by treatment of the underlying disease. There were 18, 10 and 27 ICU admission per 100 treatments in patients undergoing chemotherapy for acute leukaemia, autologous and allogeneic stem cell transplantation (p 100 IU/ L (p <0.007), but not age, sex, primary disease and treatment of the underlying disease predicted outcome. Conclusion: Multi-organ failure and evidence of liver damage but no other patient, disease, or treatment related factor predict outcome in patients with haematological disease admitted to the ICU.

Compression stockings prophylaxis of emergent varicose veins in pregnancy: a prospective randomised controlled study.

Abstract: Questions under study: To determine the efficacy of compression stockings in preventing emergent varicose veins in pregnancy. Methods: A prospective randomised controlled study in the outpatient department of the University Hospital of Zurich, Switzerland, including women with uncomplicated pregnancies <12 weeks at outset of study. A no-stockings control group (n = 15) was compared with two treatment groups: group 1 (n = 12) wore compression class I stockings (18-21 mm Hg) on the left leg and class 11 stockings (25-32 mm Hg) on the right; in group 2 (n = 15), the compression classes were reversed. Stockings were worn from study entry to term. Endpoints were emergence and worsening of superficial varicose veins, long saphenous vein reflux at the sapheno-femoral junction, and leg symptoms (pain, discomfort, cramps) during pregnancy. Results: Both classes of compression stockings failed to prevent the emergence of superficial varicose veins. However, long saphenous vein reflux at the sapheno-femoral junction was observed in the third trimester in only ½7 treated women vs. 4/15 controls (p = 0.047); in addition, more treated women reported improved leg symptoms (7/27 vs. 0/15 controls; p = 0.045). Emergent varicose changes, however, did not differ significantly (7/14 controls vs. 5/12 in group 1 and 8/14 in group 2; 3×3 table, Fisher's exact = 0.94). Conclusions: Although compression stockings do not prevent the emergence of gestational varicose veins, they significantly decrease the incidence of long saphenous vein reflux at the sapheno-femoral junction and improve leg symptoms. Our results also suggest that superficial varices and deep venous insufficiency may have a different actiology.

The controversial early history of cyclosporin.

Abstract: The biological effects of cyclosporin, namely immunosuppression and absence of cytotoxicity, were discovered-in the course of a general screening program in which many scientists at Sandoz were involved. Contrary to some statements in the literature both Dr J. Borel and Dr H. Stahelin markedly contributed to the discovery and characterisation of the biological profile of the drug. In its subsequent exploitation Borel played the leading role. The outstanding clinical importance and the extraordinary commercial success of cyclosporin explain the widespread interest in the history of its discovery and development. It is also understandable that the recollection of the events by the individuals involved in the early phases of this history is influenced by subjective impressions and interpretations, which do not always reflect the historical facts. It is the purpose of this report to record and interpret the facts as accurately and as completely as possible on the basis of the available records.

Regression of HIV-associated pulmonary arterial hypertension and long-term survival during antiretroviral therapy.

Abstract: In a 37-year-old patient HIV infection was diagnosed in June 1986. Eight years later the patient complained of increasing shortness of breath and occasional syncopes on exertion. He developed peripheral oedema and ascites. Echocardiography revealed severe pulmonary hypertension. Right ventricular systolic pressure (RVSP) was 77 mm Hg. There was no evidence of left ventricular dysfunction, valvular heart disease, thromboembolic disease or obstructive or restrictive lung disease, nor were there other known causes or risk factors of pulmonary hypertension. HIV-associated pulmonary arterial hypertension was diagnosed. Oral anticoagulation and zidovudine were begun, but RVSP rose to 96 mm Hg. After the introduction of lamivudine, and later stavudine and nelfinavir, HIV-RNA copies decreased from 133 400 to below 50 copies per mL. Six years after the diagnosis of HIV-associated pulmonary arterial hypertension RVSP had continually fallen to 49 mm Hg and the grossly enlarged right heart dimensions had nearly normalised without vasodilator treatment. The patient remains in excellent health and his sole complaint is of mild dyspnoea on exertion.

Graves' ophthalmopathy: natural history and treatment outcomes.

Abstract: The pathogenesis of Graves' ophthalmopathy has not been yet clarified, and from a therapeutic standpoint Graves' ophthalmopathy remains an enigma. The natural course and effects of different treatment regimens are poorly documented.

Industrial Ecology: a new perspective on the future of the industrial system

Abstract: Industrial ecology? A surprising, intriguing expression that immediately draws our attention. The spontaneous reaction is that "industrial ecology" is a contradiction in terms, something of an oxymoron, like "obscure clarity" or "burning ice". Why this reflex? Probably because we are accustomed to considering the industrial system as isolated from the Biosphere, with factories and cities on one side and nature on the other, as well as the recurrent problem of trying to minimise th impact of the industrial system on what is "beyond" it: its surroundings, the "environment". As early as the 1950's, this end-of-pipe angle was the one adopted by ecologists, whose first serious studies focused on the consequences of the various forms of pollution on nature. In this perspective on the industrial system, human industrial activity as such remained outside the field of research. Industrial ecology explores the opposite assumption: The industrial system can be seen as a certain kind of ecosystem. After all, the industrial system, just as natural ecosystems, can be described as a particular distribution of materials, energy, and information flows. Furthermore, the entire industrial system relies on resources and services provided by the Biosphere, from which it cannot be dissociated. (It should be specified that "industrial", in the context of industrial ecology, refers to all human activities occurring within modern technological society. Thus, tourism, housing, medical services, transportation, agriculture, etc. are part of the industrial system.) Besides its rigorous scientific conceptual framework (scientific ecology), industrial ecology can also be seen as a practical approach to sustainability. It is an attempt to address the question, "How can the concept of sustainable development be made operational in an economically feasible way?" Industrial ecology represents precisely one of the paths that could provide concrete solutions. Governments have traditionally approached development and environmental issues in a fragmented and compartmentalised way. This is illustrated in the classical end-of-pipe strategy for the treatment of pollution, which has proven to be quite useful, but not adequate to make an efficient use of limited resources, in the context of a growing population with increasing economic aspirations. Thus, industrial ecology emerges at a time when it is becoming increasingly clear that the traditional pollution treatment approach (end-of-pipe) is not only insufficient to solve environmental problems, but also too costly in the long run.

Use of the Internet by medical doctors in Switzerland.

Abstract: Questions under study: To investigate the utilisation of the Internet by primary care physicians for medical purposes during their daily practice, and to clarify the reasons for use or non-use of this technology.

Immunomodulating mechanisms in the lower respiratory tract: nitric oxide mediated interactions between alveolar macrophages, epithelial cells, and T-cells.

Abstract: A number of immunomodulating mechanisms are necessary to prevent uncontrolled inflammation in the lower respiratory tract. Proliferative responses of immune cells are tightly controlled in both bronchi and alveoli in the healthy lung. In diseases such as bronchial asthma, there is not only a partial failure of these mechanisms, but also an immune-deviation with a propensity towards a Th2-cell involvement. The role of alveolar macrophages (AM) controlling T- and B-cell activation in the lower respiratory tract is discussed by considering mainly published results. This review focuses on immunomodulating mechanisms exerted via cytokines, such as Interleukin-10 (IL-10), transforming growth factor-beta (TGF-beta), and Interleukin-1 receptor-antagonist (IL-1ra), prostaglandins, such as prostaglandin E2 (PGE2), and especially nitric oxide (NO). The Th1 and Th2 concept in asthma is introduced, being the best-described mechanism of immune-deviation in the lung. The possibility of re-inducing T-cell unresponsiveness is of particular interest. The physiological immunomodulating mechanisms used by AM are explained in detail, as they offer many possibilities for therapeutic immunomodulation. Special emphasis is put on the cGMP/phosphatase dependent, reversible mechanism of NO-mediated immunomodulation and differences in the activation of NO synthases between murine and human alveolar macrophages are mentioned.

Alternative functions for TRAIL receptors in eosinophils and neutrophils.

Abstract: Background Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in many tumour cells but only rarely in normal cells. The receptors of TRAIL belong to the superfamily of tumour necrosis factor (TNF)/nerve growth factor (NGF) receptors. Here we investigate TRAIL receptor expression and function in eosinophils and neutrophils. Methods Granulocytes were isolated from human blood and purified using standard protocols. Receptor expression was analysed by reverse transcription (RT)-PCR and flow cytometry. Cell death was analysed by the ethidium bromide exclusion test. Apoptosis was determined by analysing phosphatidyl serine (PS) surface exposure and morphological evaluation. Results Freshly purified eosinophils and neutrophils expressed TRAIL-R1, TRAIL-R3, and TRAIL-R4, but not TRAIL-R2 surface proteins. Stimulation of eosinophils with TRAIL resulted in either inhibition of apoptosis or no effect, depending on the individual from whom the cells were isolated. In neutrophils, TRAIL stimulation did not influence apoptosis. In eosinophils and neutrophils which showed no effect on TRAIL stimulation alone, TRAIL partially blocked cytokine-mediated antiapoptosis. Conclusions Both eosinophils and neutrophils express functional TRAIL receptors on their surface. In contrast to tumour cells, TRAIL does not induce apoptosis in granulocytes but rather induces survival in eosinophils from approximately 50% of the donors. Alternatively, TRAIL may limit cytokine-mediated antiapoptosis under certain inflammatory conditions.

Gender differences in coronary artery size per 100 g of left ventricular mass in a population without cardiac disease.

Abstract: OBJECTIVES To determine whether there is a gender difference in coronary artery size normalised for left ventricular (LV) mass. BACKGROUND Small coronary artery caliber may play a role as a risk factor for coronary artery disease in women. However, the existence of a gender difference in coronary artery size is controversial. Furthermore, coronary artery size ought to be normalised for LV mass, since there is a theoretical relation of coronary artery size to LV mass according to the law of minimum viscous energy loss for the transport of blood in the coronary circulation. METHODS In 200 individuals (100 women) without cardiac disease and with normal Doppler echocardiography, left main (LCA) and right coronary artery (RCA) size were determined using transoesophageal echocardiography. LV mass was assessed by transgastric M-mode echocardiography. RESULTS Age (44 +/- 15 years in women; 41 +/- 16 years in men), the presence of non-cardiac diseases, cardiovascular risk factors and medication were similar in women and men. LV mass in women was lower than in men (148 +/- 36 g, 189 +/- 45 g; p < 0.0001). LCA and RCA cross-sectional areas in women were smaller than those in men (LCA: 10 +/- 3 and 16 +/- 5 mm2, p < 0.0001; RCA: 4 +/- 2 and 7 +/- 3 mm2, p < 0.0001, respectively). LCA and RCA cross-sectional areas of women were smaller even after normalisation for LV mass (LCA: 7 +/- 3 and 9 +/- 3 mm2/100 g LV mass, p < 0.0001; RCA: 3 +/- 1 and 4 +/- 1 mm2/100 g LV mass, p = 0.002, respectively). LCA caliber of women ranged below the theoretically expected size according to the law of minimum viscous energy loss for the transport of blood in the coronary circulation, whereas those of men tended to be above it. CONCLUSIONS In a population without cardiac disease, women have smaller coronary artery size even after normalisation for left ventricular mass.

Motivation for smoking cessation: what role do doctors play?

Abstract: PRINCIPLES Cigarette smoking causes an estimated 13% of all deaths in Switzerland. Though most smokers will eventually become ex-smokers of their own volition, physicians play an important role in accelerating the process of quitting among smoking patients. Even brief advice from physicians is effective in doing so. The purpose of this study was to investigate which smokers were asked about their smoking habits, and how often, whether they received advice to quit, and how this correlates with the patient's desire to quit. METHODS Telephone interviews were carried out with a random sample of smokers and ex-smokers from the German-speaking Swiss population (n = 993). We collected information on personal characteristics, smoking habits, and recall of physicians' advice. Data was analysed descriptively and by logistic regression. RESULTS 88% recalled being asked by a doctor about their smoking habits. In contrast, only 34% of smoking patients recalled being advised to stop. Women, older people and those in poor subjective health were asked more frequently. Heavier smokers and those in poor subjective health were advised more frequently. Current smokers more frequently express the desire to quit if they are heavier smokers and have been advised to quit by their physician, compared with those who have not received such advice. CONCLUSIONS Similarly to the international findings, smoking patients in Switzerland receive brief advice with insufficient frequency. Action should therefore be taken to encourage health professionals not only to question all smoking patients but to advise and motivate them to quit smoking.

Late effects in long-term survivors of ALL in childhood: experiences from the SPOG late effects study.

Abstract: With the use of more intensive regimens including prophylactic CNS treatment, the prognosis of children with ALL has dramatically improved over the last three decades. The aim of this cross-sectional, nationwide study was to comprehensively assess long-term toxicity in ALL survivors, with special attention given to neuropsychological morbidity, and to look for possible differences in cognitive outcome between children having received prophylactic cranial irradiation and those not having received it. Between 1994 and 1996, long-term survivors of ALL were assessed in a multi-center setting according to a standardized protocol which included, besides usual clinical and laboratory investigations, a comprehensive endocrine work-up. Additionally, children having received anthracyclines were checked for possible late cardio-toxicity with echocardiography and ECG. Intellectual performance was evaluated with standardized neuropsychological tests (age-adapted versions of the Wechsler test). One-hundred and fifty patients were eligible for the study. The median age at diagnosis was 5 years and at evaluation 16 years, for a median follow-up of 10 years. Thirty-five patients had cranial irradiation as part of the prophylactic CNS treatment. One-hundred and forty (93%) of the 150 eligible patients were completely evaluated in terms of global long-term toxicity: 117 (83%) long-term survivors had no (n = 61) or only minimal (n = 56) late toxicity; 19 (14%) suffered from moderate impairments; 4 (3%) showed severe somatic or neuropsychological sequelae. Intellectual performance could be assessed in 147 (98%) of the 150 eligible patients. The mean global, verbal and non-verbal IQs (103, 105 and 101 respectively) of the ALL survivors as a group were comparable with those found in the general population. The results of the comparison between children having and those not having received prophylactic cranial irradiation showed: 1) significantly higher scores in chemotherapy-only treated patients, both for the global and the verbal performances; 2) significantly poorer results in specific items of the Wechsler test (short-term verbal memory, arithmetics, concentration/speed of processing) in irradiated children. These findings which show the deleterious role of cranial irradiation correlate well with many other reports found in the literature. However, they could have been influenced by the significantly longer time interval observed between therapy and evaluation in our irradiated patients. Prospective studies are needed to further characterize the potential neuropsychological hazards of chemotherapy and their evolution over time.

Gene therapy of cancer.

Abstract: Gene therapy was initially thought of as a means to correct single gene defects in hereditary disease. In the meantime, cancer has become by far the most important indication for gene therapy in clinical trials. In the foreseeable future, the best way to achieve reasonable intratumoral concentrations of a transgene with available vectors is direct intratumoral injection with or without the aid of various techniques such as endoscopy or CT-guidance. At present, viral and non-viral methods of gene transfer are used either in vivo or ex vivo/in vitro. The most important viral vectors currently in use in clinical trials comprise retroviruses, adenoviruses, adeno-associated viruses, and herpes viruses. None of the available vectors satisfies all the criteria of an ideal gene therapeutic system, and vectors with only minimal residues of their parent viruses ("gutless vectors") as well as completely "synthetic viral vectors" will gain more and more importance in the future. Non-viral gene therapy methods include liposomes, injection of vector-free DNA ("naked DNA"), protein-DNA complexes, delivery by "gene gun," calcium-phosphate precipitation, electroporation, and intracellular microinjection of DNA. The first clinical trial of gene therapy for cancer was performed in 1991 in patients with melanoma, and since then more than 5000 patients have been treated worldwide in more than 400 clinical protocols. With the exception of a case of fatal toxicity in a young man with hereditary liver disease treated intrahepatically with high doses of adenovirus, side effects have been rare and usually mild in all these studies and expression of the transgene could be demonstrated in patients in vivo. However, despite anecdotal reports of therapeutic responses in some patients, unequivocal proof of clinical efficacy is still lacking for most of the varied approaches to gene therapy in humans. As well as our only fragmentary understanding of the molecular pathophysiology of many diseases, the principal reason for the present lack of clinical success of gene therapy is the very low transduction and expression efficiency in vivo of available vectors. Despite the complexities of gene therapy for cancer, the numerous different approaches can be subdivided into three basic concepts: (1) strengthening of the immune response against a tumour, (2) repair of cell cycle defects caused by losses of tumour suppressor genes or inappropriate activation of oncogenes, and (3) suicide gene strategies. In addition, the importance of gene marker studies and gene therapeutic protection of normal tissue are briefly covered in this review. Language: en

Hepatitis C: an update.

Abstract: Hepatitis C virus (HCV) infection is a leading cause of chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma worldwide. While current therapeutic options for hepatitis C are limited, recent progress in the understanding of the biology of HCV led to the identification of novel targets for antiviral intervention. In addition, molecular and immunotherapeutic strategies to inhibit HCV replication or gene expression and to enhance the cellular immune response against HCV are being explored. These and other novel antiviral strategies may eventually complement existing therapeutic modalities. Here, we briefly review current concepts of the epidemiology, molecular virology, pathogenesis, natural history, diagnosis, therapy, and prevention of hepatitis C.

Carbamoylation of glomerular and tubular proteins in patients with kidney failure: A potential mechanism of ongoing renal damage

Abstract: Background Cyanate formed spontaneously from urea carbamoylates non-protonated amino groups of protein, irreversibly altering function, charge and structure. Carbamoylated proteins in renal tissue have not been examined hitherto. Objectives To identify homocitrulline (epsilon-amino-carbamoyl-lysine), a result of in vivo carbamoylation by urea-derived cyanate, from patients with renal disease or in newly transplanted kidneys by immunohistochemistry. To evaluate enzymatic activity of carbamoylated and non-carbamoylated matrix metalloproteinase-2 and correlate this with renal tissue carbamoylated in vivo. Design Anti-homocitrulline antibody is specific for homocitrulline and was used to identify carbamoylation of epsilon-amino-lysine in renal biopsies from patients with elevated BUN, with isolated proteinuria, and as controls, from normal donors at time of transplantation. Enzymatic activity of matrix metalloproteinase-2 carbamoylated in vitro was evaluated. Results Homocitrulline was present in glomerular basement membrane (8/10), mesangium (8/10), tubular epithelium and cytoplasm (7/10) and Bowman's capsule (1/10) in patients with elevated BUN. The discordant patterns of glomerular and tubular localization of homocitrulline versus immune complexes indicated that the carbamoylated proteins were not a component of immune deposits but were modified proteins in renal tissue. No homocitrulline was found in transplanted kidneys (14/15) or in proteinuric patients (2/2). Enzymatic activity of both human and rat matrix metalloproteinase-2 was strongly inhibited in a dose-dependent fashion when incubated with cyanate. Conclusions In situ carbamoylation in proteins occurred in kidneys of patients with renal dysfunction but not in normal newly transplanted kidneys. Decreased enzymatic activity of carbamoylated enzymes may alter specific renal regulatory mechanisms. Carbamoylated proteins with altered function and charge may represent a previously underestimated mechanism in renal pathophysiology.

Renal pathology and premortem clinical presentation of Caucasian patients with AIDS: an autopsy study from the era prior to antiretroviral therapy

Abstract: PRINCIPLES Renal disease in patients with HIV infection is becoming increasingly frequent. A particular form of HIV-associated nephropathy (HIVAN) has been found in patients of predominantly African-American and Hispanic origin. However, only limited data are available on renal pathology and premortem clinical presentation of kidney disease in Caucasian patients with AIDS. METHODS To determine the prevalence, clinical presentation and aetiology of renal disease in Caucasian patients with AIDS at the time of death we have performed a prospective autopsy study with 239 patients who died of AIDS between 1981 and 1989. None of these patients had received HIV-specific antiretroviral therapy. Autopsies and histological analyses were performed on the basis of a standardised protocol. Clinical and laboratory data were gathered according to a uniform questionnaire. RESULTS 95% of patients were of Caucasian race. 75% of all patients had extended AIDS (stage IV). Clinical signs of nephropathy prior to death were found in 36% of patients, including proteinuria (18%), abnormal urinary sediment (19.5%), and renal insufficiency (11%). Histopathological lesions were present in 43% of the autopsies, with two or more distinct structural lesions in 12.5% of patients. Of the pathological findings 28% were glomerular or vascular, 33% were non-glomerular, and 29% were combined lesions. The remaining 10% were renal infiltrations of infectious agents or neoplastic tissue. The most common findings were ischaemic changes and vascular scars (18% of patients), as well as pyelo- and interstitial nephritides (12.2%). Importantly, FSGS was present in only 1.7% of patients, and only a single African patient had classical HIVAN. CONCLUSIONS Renal involvement in HIV disease is very common at the time of death among patients of Caucasian origin. However, classical HIV-associated nephropathy is absent in this population. These findings suggest that kidney disease affects all races and supports the hypothesis that HIVAN is specifically related to non-Caucasian ethnicity. The results reflect renal disease unaffected by HIV-specific antiretroviral therapy.

Lethal ingestion of stored Amanita phalloides mushrooms.

Abstract: We report the first case of a lethal Amanita phalloides intoxication from stored mushrooms. After picking the mushrooms were kept in a freezer for 7-8 months. This case is in accordance with the well-known stability of the amatoxins and demonstrates the possibility of A. phalloides poisoning at any time of year.

Prevalence of Helicobacter pylori infection in peptic ulcer perforations.

Abstract: BACKGROUND Most patients with chronic peptic ulcer disease have Helicobacter pylori (H. pylori) infection. In the past, immediate acid-reduction surgery has been strongly advocated for perforated peptic ulcers because of the high incidence of ulcer relapse after simple closure. Simple oversewing procedures either by an open or laparoscopic approach together with H. pylori eradication appear to supersede definitive ulcer surgery. METHODS In 47 consecutive patients (mean age = 64 years, range 27-91) suffering from acute peptic ulcer perforation the preoperative presence of H. pylori (CLO test), the surgical procedure (laparoscopy or open surgery), the outcome of surgery, and the success of H. pylori eradication with a triple regimen were prospectively studied. RESULTS Of these patients 73.3% were positive for H. pylori, regardless of the previous use of nonsteroidal anti-inflammatory drugs (NSAIDs). Thirty-eight per cent underwent a simple laparoscopic repair. Conversion rate to laparotomy reached a high of 32%. The main reasons for conversion were the size of the ulcer, and/or diffuse peritonitis for a duration of over 12 hours with fibrous membranes difficult to remove laparoscopically. In the H. pylori positive patients, eradication was successful in 96% of the cases. Mortality and morbidity rates were greater in the laparoscopic group (p < 0.05). Follow-up (median 43.5 months) revealed no need for reoperation for peptic ulcer disease and no mortality. CONCLUSION We have found a high prevalence of H. pylori infection in patients with perforated peptic ulcers. An immediate and appropriate H. pylori eradication therapy for perforated peptic ulcers reduces the relapse rate after simple closure. Response rate to a triple eradication protocol was excellent in the hospital setting.

Transplantation of islets of Langerhans: new developments.

Abstract: The clinical results recently reported by the Edmonton group in recipients of allogeneic islet grafts, all of whom achieved at least temporary insulin independence, has rekindled interest in transplantation of islets of Langerhans as a means to cure diabetes. Long-term islet graft survival has been achieved in a non-human primate pre-clinical model with a protocol of T-cell signaling blockade using a new monoclonal antibody. Islet xenotransplantation (namely the use of animal islets, with the aim of transplanting them into humans), or stem cell technology (the controlled differentiation of stem cells to obtain specialised cells for the treatment of diabetes) are other procedures currently being evaluated in animal models. The recent clinical success suggests that, in the near future, diabetes might be treated by islet transplantation early in the clinical course of the disease before the development of complications, and without the risks associated with conventional immunosuppression.