Showing papers in "Swiss Medical Weekly in 2007"

TLR9 signaling in B cells determines class switch recombination to IgG2a

Abstract: Although IgG2a is the most potent Ab isotype in the host response to viral and bacterial infections, the regulation of class switch recombination to IgG2a in vivo is not yet well understood. Recognition of pathogen-associated molecular patterns by dendritic cells expressing TLRs, like TLR7, recognizing ssRNA, or TLR9, recognizing DNA rich in nonmethylated CG motifs (CpG), favors induction of Th1 responses. It is generally assumed that these Th1 responses are responsible for the TLR-mediated induction of IgG2a. Using virus-like particles loaded with CpGs, we show here that TLR9 ligands can directly stimulate B cells to undergo isotype switching to IgG2a. Unexpectedly, TLR9 expression in non-B cells did not affect isotype switching in the Ab response against virus-like particles. Thus, TLR9 can regulate isotype switching to IgG2a directly by interacting with B cells rather than indirectly by inducing Th1 responses.

Statistical errors in medical research--a review of common pitfalls.

Abstract: Background standards in the use of statistics in medical research are generally low. A growing body of literature points to persistent statistical errors, flaws and deficiencies in most medical journals. Methods in this paper we present a comprehensive review of common statistical pitfalls which can occur at different stages in the scientific research process, ranging from planning a study, through conducting statistical data analysis and documenting statistical methods applied, to the presentation of study data and interpretation of study results. Results 47 potential statistical errors and shortcomings, differentiated for the distinct phases of medical research are presented and discussed. Conclusions statisticians should be involved early in study design, as mistakes at this point can have major repercussions, negatively affecting all subsequent stages of medical research. Consideration of issues discussed in this paper, when planning, conducting and preparing medical research manuscripts, should help further enhance statistical quality in medical journals.

Obesity is associated with increased serum TSH level, independent of thyroid function.

Abstract: OBJECTIVE To reinvestigate the relationship between circulating TSH levels and adiposity in a cohort of obese people, who have normal thyroid function. METHODS Retrospective cross-sectional analysis was carried out on 226 euthyroid obese or overweight female patients. Thirty-nine female lean and euthyroid subjects (BMI<25 kg/m2) were included in the study group. TSH, free thyroxine (FT4), free triiodothyronine (FT3), fasting plasma levels of insulin and glucose, homeostasis model assessment (HOMA) for insulin resistance (HOMA-IR) and insulin secretion (HOMA-b cell), body weight, height, body mass index (BMI) and waist circumference were assessed. RESULTS Serum TSH levels were higher in the obese than in the lean subjects. In the study group (lean and obese subjects), there was a significant positive correlation between serum TSH and body weight (r=0.231, p<0.001), BMI (r=0.270, p<0.001), waist circumference (r=0.219, p=0.001), fasting insulin (r=0.201, p=0.002) and HOMA-IR (r=0.201, p=0.002); there was no correlation between serum FT4 and any of the parameters. A multivariate linear regression analysis revealed that only BMI (p=0.012, 95% CI=0.01-0.08) contributed significantly to the variance of TSH. CONCLUSIONS This study strongly supports existing, but contradictory evidence that serum TSH levels are positively correlated with the degree of obesity and some of its metabolic consequences in overweight people with normal thyroid function.

The integration of BNP and NT-proBNP into clinical medicine.

Abstract: B-type natriuretic peptide (BNP) and NTproBNP have been shown to be extremely helpful in the diagnosis and management of patients with heart failure (HF). These neurohormones are predominately secreted from the left and the right cardiac ventricle in response to volume and pressure overload. BNP and NT-proBNP can be seen as quantitative markers of HF summarizing the extent of systolic and diastolic left ventricular dysfunction. Research data from clinical studies and six years of clinical experience with BNP allow us to provide clear recommendations regarding the integration of BNP/NT-proBNP into clinical medicine. With multiple additional indications in prospect, current evidence clearly supports the use of BNP and NT-proBNP in three clinical settings: patients with acute dyspnoea, prior to discharge in patients hospitalised with acute HF, and the longterm management of patients with HF.

The Swiss Childhood Cancer Registry: rationale, organisation and results for the years 2001-2005.

Abstract: QUESTIONS UNDER STUDY: Childhood cancer is a rare but severe disease. Therefore central registration of all cases is essential for surveillance and management. This paper describes the methodology and basic results of the Swiss Childhood Cancer Registry (SCCR). METHODS: The SCCR was established in 1976, originally as a national hospital-based registry of childhood malignancies. All 9 paediatric oncology-haematology clinics in Switzerland provide baseline and follow-up information on all children diagnosed with cancer. These data are registered centrally and diagnoses are coded according to the International Classification of Childhood Cancer. RESULTS: From 2001-2005, 887 cases of childhood cancer in Swiss residents under the age of 15 years were registered in the SCCR. Of these, 281 (31.7%) were leukaemias, 223 (24.0%) were CNS tumours, and 116 (13.1%) were lymphomas. The age-standardised annual incidence per 1 Million person-years (age below 15 years; world standardisation) was 154.0 (95% CI 143.7-164.3; N = 887). The incidence was higher for boys (170.2, 155.0-185.4; N = 501) than for girls (136.9, 123.0-150.8; N = 386). CONCLUSION: The close collaboration between all paediatric oncologists-haematologists in Switzerland and a university department allowed the creation of a national population-based cancer registry with detailed clinical information. The SCCR produces cancer type specific incidence and survival estimates and allows the development of nested research projects on childhood cancer aetiology, management and outcome, both on a national and on an international level.

Cognition, mood and fatigue in patients in the early stage of multiple sclerosis.

Abstract: QUESTION UNDER STUDY: Cognitive impairment occurs during multiple sclerosis (MS) and contributes to the burden of the disease, but its effect in the initial phase of MS still needs to be better understood. METHODS: We prospectively studied 127 early MS patients presenting with a clinically isolated syndrome (CIS) or definite MS, a mean disease duration of 2.6 years, and with minor disability (mean Expanded Disability Status Scale score 1.8). Patients were tested for long-term memory, executive functions, attention, fatigue, mood disorders, functional handicap and quality of life (QoL). Twenty-one CIS patients were excluded from study as the diagnosis of MS could not be confirmed. RESULTS: Over the 106 MS patients analysed, 31 (29.3%) were cognitively impaired (23.6% for memory, 10.4% for attention and 5.7% for executive functions). Cognitive deficits were already present in CIS patients in whom the diagnosis was not yet confirmed (20%). Impaired cognition was associated with anxiety (p = 0.05), depression(p = 0.004), fatigue (p = 0.03), handicap (p <0.001) and a lower QoL (p <0.001). After adjustment for QoL, handicap, depression, anxiety and fatigue were no longer associated with the presence of cognitive deficits. CONCLUSIONS: In this well-defined early MS group one third of the patients already exhibited cognitive deficits, which were usually apparent in an effortful learning situation and were generally mild. Mood disorders, fatigue, handicap and decreased QoL were all associated with the occurrence of cognitive deficits. QoL itself appeared to take all the other factors into account. Our results confirm the existence of an interplay between cognitive, affective and functional changes and fatigue in early MS.

Screening for tuberculosis infection before the initiation of an anti-TNF-alpha therapy.

Abstract: a Abteilung fur Gastroenterologie Universitatsspital, Basel b Service de rhumatologie, Hopital Nestle, Lausanne c Departement de medecine interne, Division de Gastroenterologie, CHUV, Lausanne d Klinik fur Pneumologie / DMLL, Inselspital, Bern e Departement DMLL, Gastroenterologische Abteilung, Inselspital, Bern f Klinik fur Rheumatologie und Klinische Immunologie / Allergologie, Inselspital, Bern g Policlinique Medicale Universitaire, Lausanne

Intravenous ketamine therapy in a patient with a treatment-resistant major depression

Abstract: Background Recently, reports from North America have indicated that the intravenous infusion of ketamine hydrochloride (an N-methyl-d-aspartate receptor antagonist) results in a sudden and robust improvement of depression symptoms. Objective To corroborate antidepressant effectiveness of IV ketamine in a patient with a co-occurring substance use disorder for the first time in a European clinical setting. Design Open label trial Methods: A 55-year-old male subject with a treatment-resistant major depression and a co-occurring alcohol and benzodiazepine dependence received an intravenous infusion of 0.5 mg/kg ketamine over a period of 50 minutes. Effects were assessed by means of a clinical interview, the 21-item Hamilton Depression Rating scale (HDRS), and the 21-item Beck Depression Inventory (BDI) at baseline, 1 hour, 1 day, 2 days, and 7 days after intervention. Results Following the administration of ketamine the subject experienced a significant improvement of his symptoms peaking on the 2nd day post infusion (HDRS from 36 to 16; -56.6%, BDI from 26 to 9; -65.4%). The subject first reported improvements 25 min. into the infusion and continued to describe positive effects throughout the subsequent 7 days. Conclusion Ketamine not only seems to have strong antidepressant effects but also to act very swiftly. These actions were unaffected by an alcohol or benzodiazpine dependence.

Effect of low level laser therapy in rheumatoid arthritis patients with carpal tunnel syndrome

Abstract: Objective the aim of the present study was to evaluate the efficacy of low level laser therapy (LLLT) in patients with rheumatoid arthritis (RA) with carpal tunnel syndrome (CTS). Material and methods a total of 19 patients with the diagnosis of CTS in 19 hands were included and randomly assigned to two treatment groups; LLLT (Group 1) (10 hands) with dosage 1.5 J/ per point and placebo laser therapy group (Group 2) (9 hands). A Galium-Aluminum-Arsenide diode laser device was used as a source of low power laser with a power output of 50 mW and wavelength of 780 nm. All treatments were applied once a day on week days for a total period of 10 days. Clinical assessments were performed at baseline, at the end of the treatment and at month 3. Tinel and Phalen signs were tested in all patients. Patients were evaluated for such clinical parameters as functional status scale (FSS), visual analogue scale (VAS), symptom severity scale (SSS) and grip-strength. However, electrophysiological examination was performed on all hands. Results were given with descriptive statistics and confidence intervals between group means at 3 months adjusted for outcome at baseline and for the difference between unadjusted group proportions. Results clinical and electrophysiological parameters were similar at baseline in both groups. Improvements were significantly more pronounced in the LLLT group than placebo group. A comparison between groups showed significant improvements in pain score and functional status scale score. Group mean differences at 3 months adjusted at baseline were found to be statistically significant for pain score and functional status scale score. The 95% significant confidence intervals were [-15 - (-5)] and [-5 - (-2)] respectively. There were no statistically significant differences in other clinical and electrophysiological parameters between groups at 3 months. Conclusions our study results indicate that LLLT and placebo laser therapy seems to be effective for pain and hand function in CTS. We, therefore, suggest that LLLT may be used as a good alternative treatment method in CTS patients with RA.

Epidemiology and pathophysiology of obesity as cause of cancer.

Abstract: According to World Health Organisation estimates 1.1 billion people were overweight or obese worldwide in the year 2000 with the prevalence rapidly increasing. Compelling evidence suggests that excess body weight is a risk factor for several cancer types including cancer of the colon, breast, endometrium, kidney, oesophagus, as well as possibly additional sites. According to previous meta-analyses and systematic literature reviews, an important proportion of cancer has been estimated to be attributable to excess body weight. The extrapolation of a European meta-analysis [1] to the Swiss situation broadly estimates that around 700 cancers could be prevented in the absence of overweight and obesity in this country. The data presented highlights the public health relevance of preventing excess body weight. Several interacting metabolic and hormonal pathways seem to underlie the association between being overweight and cancer with insulin-resistance playing a central role. Since evidence is mounting that excess body weight can also adversely affect cancer prognosis, obesity is a primary target for cancer control programs.

Tissue engineered heart valves based on human cells.

Abstract: Valvular heart disease is still a significant cause of morbidity and mortality worldwide. Clinically used valve replacements including mechanical valves as well as fixed biological xeno- or homografts are associated with several major disadvantages. Alternatively, tissue engineering aims at the fabrication of autologous living cardiovascular replacements with the potential to grow and to repair, particularly for paediatric applications. Therefore, autologous cells are harvested and seeded onto three-dimensional matrices followed by biomimetic in vitro conditioning enabling the development of the neo-heart valve tissue. Here, we review different human cell sources such as vessels, bone marrow, umbilical cord tissue and blood, and chorionic villi with particular regard to cell phenotypes and their suitability for extracellular matrix production for tissue engineering purposes.

Results of conservative treatment for perforated gastroduodenal ulcers in patients not eligible for surgical repair

Abstract: Conservative treatment of perforated gastroduodenal ulcer has been shown to be associated with good results in patients whose general condition is good. However, its use in patients not eligible for surgical repair has not been supported. The aim of this study is to evaluate the results of conservative treatment in these patients in the era of proton pump inhibitor.

Dietary intake and physical activity of normal weight and overweight 6 to 14 year old Swiss children.

Abstract: Principles and questions under study: The prevalence of overweight is increasing in Swiss children, and they are at increased risk for hypertension and insulin resistance. Better understanding of how food intakes and activity patterns differ between overweight and normal weight children is needed to develop intervention strategies to control childhood adiposity. The aim of the study was therefore to compare nutrient intake, dietary patterns and physical activity in overweight and normal weight children in Switzerland. Methods: The subjects were healthy 6 to 14-year-old normal weight and overweight children (n = 74 and n = 68 respectively). Dietary intakes were assessed during three home visits with two 24-hour recalls and one 1-day food record. Questionnaires on physical activity and social background were completed. Results: The carbohydrate and fat contents of the diet as a percent of energy did not differ comparing normal and overweight children, but the percentage of protein was significantly higher in overweight children. Intakes of energy, carbohydrates and fat were not significantly correlated with body mass index (BMI) standard deviation scores (SDS) after controlling for age, gender and total energy (for carbohydrates and fat). However, protein intake significantly predicted BMI-SDS after controlling for age, gender and total energy. Similarly, meat intake predicted BMI-SDS after controlling for age, gender and total energy, but none of the other analysed food groups were predictors. Time spent watching television and time spent in organised sports activity were significantly correlated with BMI-SDS. The educational level of mothers of overweight children was significantly lower than of mothers of normal weight children. Conclusion: Intakes of fat and saturated fat in Swiss children are 20% and 50% higher, respectively than recommended intakes. Higher protein intake, higher intake of meat and more hours spent watching TV and playing computer games are associated with overweight in primary school-aged Swiss children.

Worldwide trends in childhood obesity.

Abstract: The prevalence of childhood obesity is raising rapidly worldwide [1]. While paediatric obesity has long been associated with western countries, accumulating evidence shows that the epidemic extends to developing countries as well, in addition to an ongoing problem of under-nutrition in the latter [1]. In children as in adults, obesity is associated with chronic conditions such as type 2 diabetes or hypertension. In addition, obese children are at high risk of becoming obese adults. It has been suggested that failing to address the epidemic of overweight would expose current children generations to shorter life expectancy than their parents due to increased obesity-related disease burden [2]. We compared trends in the prevalence of obesity in school children aged 6–12 years from Switzerland and the USA – as examples of industrialised high-income countries – and in children from Seychelles – as an example of a middle-income developing country experiencing rapid health transition [3]. We chose the 6–12 age range because one recent national survey available in Switzerland was limited to this range [4]. We used published aggregated data for Switzerland [4–6] and the USA [7–9], and raw data for Seychelles [3]. In Switzerland, data are available from regional surveys in the city of Zurich in 1960/65 (n = 232) [4, 5] and 1980/90 (n = 205) [4, 6] and from a nationally representative sample of children aged 6–12 years in 2002 (n = 2431) [4]. For the United States of America, we report the prevalence of obesity among children aged 6–11 years from six national surveys in 1963/65 (n = 7119), 1971/74 (n = 2062), 1976/80 (n = 1725), 1988/94 (n = 1064), 1999/2002 (n = 1049) and 2003/04 (n = 981) [7–9]. For the Seychelles, we report the prevalence of obesity from seven national surveys conducted yearly between 1998 and 2004 in all students of all schools in four selected school grades (daycare, 4th, 7th and 10th years of mandatory school), from which we calculated the estimates for students aged 6–12 (n = 16996) [3]. For all three countries, obesity was defined according to the criteria of the American Centres for Disease Control and Prevention (CDC), ie a body-mass index (BMI) at or above the ageand sex-specific 95th percentile from the “2000 CDC Growth Charts: United States” (notice that these 2002 CDC data are based on anthropometric measurements made in the 1970–80s, before the obesity epidemic) [10]. In Switzerland, the prevalence of obesity among school children aged 6–12 years was very low until the 1980s (figure 1). In 2002, the prevalence was 6.5% [4]. If the prevalence reported in the city of Zurich in the 80s was considered to be representative for the general population of Switzerland, this would correspond to an absolute increase of approximately 0.3 percentage point per year over the 20 past years. In the USA, the prevalence was 4.2% in the 1960s [7, 8] and it progressively rose to 18.8% in 2003/04 [9]: the increase of obesity was of 0.2 percentage point per year between 1964 and 1978, 0.4 between 1978 and 1991, and 0.6 between 1991 and 2003/04. In the Seychelles, the prevalence of obesity was 4.6% in 1998 and rose to 9.4% in 2004 [3], an increase of 0.8 percentage point per year over that period. The steepest increase over time was therefore observed in the Seychelles, where the prevalence of obesity has more than doubled in seven years and could now exceed the prevalence in Switzerland (figure 1). The trends shown in the figure were similar when examined separately in boys and girls. Other surveys have assessed the prevalence of obesity in Switzerland. However, other definitions for obesity were used [11–13] and/or children of other age categories were considered [13, 14]. In Lausanne, in a cohort of school children (n = 1203), the prevalence of obesity at age of 5–12 was 1.7% in boys and 2.7% in girls in 1985/91 [12]. In this survey, obesity was defined with the criteria of the International Obesity Task Force (IOTF) which tend to give lower estimates for obesity compared to the CDC criteria. In a nationally representative survey performed in 1999 (n = 595), the prevalence of obesity at age 6–12 was 9.7% in 1999 [11]. In this survey, obesity was based on the former US definition of obesity, which tends to give higher estimates than the CDC criteria [15]. We recently reported a prevalence of obesity of 3.6% among 5207 children of the 6th grade of the canton of Vaud (mean age: 12.3 years (SD: 0.5); range: 10–14) (open circle on the figure) [14]. Prevalence of obesity was reported to be lower in young adolescents compared to younger children [1, 13] and may differ between regions of the country or between cities and countryside, depending on ethnicity and socio-economic characteristics of the population. The trends that we report for Switzerland are consistent with findings in other European countries: the annual increase in the prevalence of childhood obesity (IOTF criteria) rose from below 0.1% per year in the 1980s to 0.3% per year in the late 1990s [16]. By 2010, it is expected that one of ten school children will be obese in Europe [16]. In Switzerland, as in many other western countries, paediatric obesity is associated inversely with socio-economic status [1, 14]. The rapidly increasing prevalence of paediatric obesity in the Seychelles is consistent with rapid socio-economic development, as observed in other developing populations like Brazil or Chile [1]. Our results in the Seychelles (gross domestic product of US$ 8000/ year per capita) are also consistent with the finding that the prevalence of obesity increases rapidly when a country’s gross domestic product reaches about 5000 international dollars [17]. Decreasing physical activity and increasing sedentary behaviours are likely to be main forces driving the obesity epidemic [18]. In Switzerland, a decrease in sports practice was reported in adolescents during the last decade [19]. In the Seychelles, walking time and leisure physical activity decreased between 157 Original article S W I S S M E D W K LY 2 0 0 7 ; 1 3 7 : 1 5 7 – 1 5 8 · w w w. s m w. c h Letter to the editor P er eviewed clinical letter

The effect of retirement on health: a panel analysis using data from the Swiss Household Panel.

Abstract: QUESTIONS UNDER STUDY Despite the importance of the relationship between retirement and health only a limited amount of empirical research has addressed this issue, particularly concerning physical health. This study examines whether retirement has a short-term influence on six health measures. METHODS Using data from the Swiss Household Panel from 1999 to 2003, we perform an ordinal regression on changes in health for each of the six health measures. RESULTS We found that retirement has no shortterm effect on the health of the large majority of individuals. Moreover, for those individuals whose health status did change, retirement had a primarily positive effect. This positive impact of retirement is mainly reflected by less frequent depression and anxiety, and by the lower degree to which health is an impediment in everyday activities. CONCLUSIONS The positive changes in health after retirement may be due to the cessation of work-related stress and to an increase in physical and leisure activities.

Bosentan therapy for chronic thromboembolic pulmonary hypertension. A national open label study assessing the effect of Bosentan on haemodynamics, exercise capacity, quality of life, safety and tolerability in patients with chronic thromboembolic pulmonary hypertension (BOCTEPH-Study).

Abstract: we performed an open-label national study to evaluate the effects of Bosentan on haemodynamics, exercise capacity, quality of life, safety and tolerability in patients with chronic thromboembolic pulmonary hypertension (CTEPH). fifteen patients with CTEPH not eligible or waiting for surgery were enrolled. The primary endpoint was the change in pulmonary vascular resistance (PVR). Secondary endpoints included quality of life (measured by the Minnesota living with heart failure questionnaire, MLHF), 6 minute walk distance (6MWD), World Health Organization (WHO) functional class, Borg dyspnoea scale, plasma endothelin, serum values of disease severity such as uric acid, N-terminal-pro brain natriuretic peptide (NTproBNP), C-reactive protein measured by a highly sensitive method (CRPs) and other serum and haemodynamic parameters. after six months of treatment with bosentan, the PVR decreased from 852 (319) to 657(249) dyn*s*m-5 (p = 0.02). Quality of life considerably improved from a mean total score of 48(14) to 35(17) (p = 0.003) with improvements in the physical (from 25(5) to 17(7)) and emotional (from 11(6) to 6(5)) subscores (p = 0.005 and 0.011), respectively. The 6MWD improved from 389(78) to 443(79) meters (p = 0.005). 4 patients (27%) improved and 11 patients (73%) maintained their WHO class with no deterioration during the six months of bosentan treatment (p = 0.02). Uric acid serum levels declined from 525(145) to 453(151) micromol/l (p = 0.006), NTproBNP and CRPs declined insignificantly. Endothelin serum levels increased from 4.3(1.5) to 5.9(2.2) pg/ml (p = 0.025). Patients tolerated the treatment well, and there were no severe adverse events or deaths. this open-label study suggests a beneficial effect of bosentan therapy not only on pulmonary haemodynamics, but also on quality of life and exercise capacity for patients with severe CTEPH.

CD4+CD25+Foxp3+ regulatory T cells: from basic research to potential therapeutic use.

Abstract: Regulatory T cells control immune responses to self- and foreign-antigens and play a major role in maintaining the balance between immunity and tolerance. This article reviews recent key developments in the field of CD4+CD25+Foxp3+ regulatory T (TREG) cells. It presents their characteristics and describes their range of activity and mechanisms of action. Some models of diseases triggered by the imbalance between TREG cells and effector pathogenic T cells are described and their potential therapeutic applications in humans are outlined.

Ketamine and the potential role for rapid-acting antidepressant medications.

Abstract: Ketamine appears to be the first medication to produce a rapid, although short-lasting, antidepressant response. This finding emerges from two studies: the first was a pilot study published in 2000 by a group of investigators at Yale University [1], and the second was a larger study published last year by an investigative team based at the U.S. National Institute of Mental Health Intramural Research Program [2]. Both studies make the same essential points: 1) depressed patients who had not responded to other antidepressant treatments began to show an antidepressant response within hours of ketamine administration that was significantly better than placebo, 2) for a subgroup of patients (it is difficult to estimate the true size of this group given the small sample sizes for the two studies) this response constituted a remission of their depressive symptoms, 3) that the antidepressant response to a single dose of ketamine persisted for a week or more in some patients, 4) that ketamine administration in these patients was associated with transient cognitive impairments and perceptual changes consistent with psychotigenic effects of ketamine reported in healthy individuals, and 5) overall, ketamine was safe and well-tolerated by the depressed patients studied to date. It is important to note that ketamine is not the first rapid-acting antidepressant treatment identified. That distinction probably belongs to sleep deprivation, whose transient antidepressant effects have been known for over 35 years [3], but whose underlying mechanisms still remain unclear. One can imagine many uses for a rapid-acting antidepressant medication. For example, it might be used to prevent suicide, to reduce the need for hospitalisation for psychiatric patients, to minimise depression-related disability or social disruption, and to simply reduce the distress associated with an episode of depression. However, a medication that induces a transient remission of depression is not, by itself, a treatment for depression. A critical question is whether a rapid-acting antidepressant can play a role within “real world” treatment planning. To this end, we need to know the answers to many questions including: 1) can ketamine be administered repeatedly or combined with another treatment to sustain improvement in depression; 2) does ketamine produce any adverse effects with regard to subsequent antidepressant response; 3) is there any risk of long-lasting psychoses after ketamine administration; 4) may ketamine be administered safely to bipolar depressed patients as well as unipolar depressed patients; 5) are there ways to predict who will respond favourably to ketamine?

The Swiss registry for pulmonary arterial hypertension: the paediatric experience.

Abstract: Pulmonary arterial hypertension is a rare disease with a poor prognosis. Epidemiological data are scarce, particularly in the paediatric population. A registry was recently developed in order to collect epidemiological data on patients with pulmonary arterial hypertension (PAH) in Switzerland. This is the first description of the paediatric data. Paediatric patients aged 0-18 years with the diagnosis of PAH were enrolled in the registry from 1999 to 2005 with informed consent from their parents. Patient characteristics, PAH aetiology, functional capacity, exercise capacity, treatments and outcome were among the most important data collected. A total of 23 patients (12 male, 11 female) have been thus far included in the registry. Median age at time of diagnosis was 3 years (range 1 month-18 years) and median follow-up was 3.47 years (range 1 day-12.6 years). PAH aetiologies are diagnosed as idiopathic in 8/23 patients (34.8%) and associated with congenital heart diseases in 12/23 (52.2%) or with pulmonary diseases in 3/23 patients (13.0%). Death occurred in 1 patient before treatment was initiated. Single treatments include medications with a calcium channel blocker in 2/23 patients, with bosentan in 10/23, and with inhaled iloprost in 1/23. Combined therapies include bosentan and inhaled iloprost in 7/23 patients, bosentan and sildenafil in 2/23 patients, and bosentan, sildenafil and inhaled iloprost in 2/23 patients. Additional oral anticoagulation is given to 14/23 patients and 8/23 patients are on oxygen therapy. NYHA class at baseline visit was obtained in 22/23 patients (4 NYHA 2, 17 NYHA 3 and 1 NYHA 4). Changes in NYHA class were observed over a 2-year period in 3/22 patients who improved from NYHA 3 to NYHA 2. Initial improvement of 6-minute walk distance was observed in 6/13 patients with a sustained improvement in 4. These preliminary results provide information on the epidemiology of PAH in children in Switzerland and demonstrate that most paediatric patients show stabilisation of the disease under new treatments. This underscores the utility of registries for rare diseases in providing crucial information in the era of new therapies. It may also help to improve the future medical approach.

Matrix-bound growth factors in tissue repair.

Abstract: Morphogenesis in tissue development and repair is guided by a variety of signals from the extracellular milieu, including growth factors that are sequestered in the extracellular matrix. Bioengineering approaches have been developed to mimic the natural interactions between growth factors and the extracellular matrix, by engineering biomolecules as novel growth factors and as novel matrix components.

Effect of polyhexanide and gentamycin on human osteoblasts and endothelial cells.

Abstract: Questions under study Infection of total joint replacements is painful, disabling and difficult to treat because of the increasing bacterial resistance against antibiotics. In view of this, antiseptics show limited bacterial tolerance and have a broad-spectrum antimicrobial activity. However, the application of antiseptics to bone is insufficiently studied in literature. Therefore, we investigated the biocompatibility of the antiseptic polyhexanide with bone related cells and asked whether supplementation to bone cement is appropriate in the management of total arthroplasty infections. Methods We performed an in vitro study with immortalised human foetal osteoblast cells (hFOB 1.19) and human endothelial cells (EAhy 926). The cultured cells were exposed to media containing various concentrations of gentamicin (12.5-800 microg/ml) and polyhexanide (0.0006-0.01%) for six hours. We measured the phase-contrast microscopy images, the cell viability, cell number and the alkaline phosphatase activity as a parameter for osteogenic function. Results The exposure of hFOB and endothelial cells to polyhexanide showed a severe reduction of viability and cell number. Gentamicin did not have negative effects on hFOB and endothelial cell number and viability. The alkaline phosphatase activity of hFOB showed a significant decrease after exposure to polyhexanide and gentamicin. The viability and the cell number of endothelial cells seem more negatively affected by polyhexanide than the parameters of the hFOB-cells. Conclusions The exposure of human osteoblasts and endothelial cells to polyhexanide at concentrations with questionable antibacterial activity resulted in severe cell damage whereas exposure to high dosed gentamicin did not. These results raise questions as to the feasibility of using antiseptics in bone cement for the treatment of total arthroplasty infections. Further in vivo studies are necessary to show the in vivo relevance of these in vitro findings.

Fast tracking in liver transplantation. Immediate postoperative tracheal extubation: feasibility and clinical impact.

Abstract: Increased survival rates after orthotopic liver transplantation (OLT) in patients with end-stage liver disease have become possible due to an advanced understanding of the pathophysiology of liver disease, the establishment of multiorgan procurement and preservation techniques, and the development of safer and more potent immunosuppressive drugs. In addition, standardisation of surgical techniques and advances in anaesthetic management have contributed significantly to this development. The up-to-date concept of improving patient outcome following OLT includes a fast track approach in selected patient populations, which may shorten ICU and/or hospital stay and reduce costs. In particular, immediate postoperative extubation has been identified as an excellent tool to achieve both improved clinical results and a reduced drain on financial resources. Studies on fast tracking protocols have shown clearly that prolonged mechanical ventilation following surgery is no longer justified in the majority of patients. On current evidence at least 70-80% of transplant recipients can be extubated immediately following surgery. The incidence of reintubation is not increased hereafter when compared to patients extubated later. However, special attention should be focused on liver transplant recipients in poor clinical condition at the time of OLT, undergoing complicated surgery, or receiving liver grafts with severe preservation injury. These patients might not be eligible for fast tracking protocols and may be at increased risk of prolonged postoperative mechanical ventilation.

The forthcoming role of treatment with oestrogens in mental health.

Abstract: Questions under study: An overview of the influence of the menopause on women’s mental health is provided, with special emphasis on the role of oestrogens. Some controversial topics are highlighted, in particular the role of oestrogencontaining hormone replacement therapy as adjuvant treatment in mental disorders. Methods: Selective review of literature. Results: The gonadal source of oestrogen production is lost at the menopause. As oestrogens have important neuro- and psychoprotective activities, this loss may trigger or aggravate mental disorders in vulnerable women. Notwithstanding, the influence of menopause on mental health is still controverted, particularly since the publication of study results denying the potential benefits of oestrogen replacement therapy after the menopause. However, many of these studies suffer from methodological limitations and the ensuing discussion often fails to differentiate clearly between perimenopause and postmenopause, between menopausal transition and aging, between clear-cut mental disorders and minor changes in wellbeing. And, most importantly, authors often do not distinguish between prophylactic and therapeutic administration of oestrogens. Conclusions: A subgroup of vulnerable women may suffer from the hormonal changes naturally occurring during the perimenopause and coinciding with the manifold psychosocial changes coming together during this phase of life. Oestrogen replacement therapy may be helpful in these cases but also carries some risks. More research is needed on the indications and contraindications for hormone replacement therapy in the context of mental disorders. Summary

Recent advances in immunotherapy for hepatocellular cancer.

Abstract: There is a continuing need for innovative, alternative therapies for hepatocellular carcinoma (HCC). Immunotherapy of cancer is attractive because of the exquisite specificity of the immune response. Activation of an HCC-specific response can be accomplished by strategies targeting tumour-associated antigens (for example: alpha fetoprotein (AFP)) or viral antigens in those patients infected with hepatitis B or C. Uncharacterised and mutated antigens can also be targeted with whole tumour cell or tumour lysate-based immunisation strategies. Viral vectors coding for genes which make the patient's tumour immunogenic can allow the immune system to naturally evolve specificity against immunogenic target antigens. Strategies which have been tested in human clinical trials include adoptive transfer of lymphocytes, cytokine injections, autologous tumour-pulsed dendritic cells (DC) as well as AFP-derived peptides in adjuvant and pulsed onto autologous DC. These trials, testing novel immune-based interventions in HCC subjects, have resulted in immunological responses and some have impacted recurrence and survival of HCC subjects.

Quality of life of survivors of paediatric intensive care

Abstract: OBJECTIVE: The mortality rate in paediatric intensive care units (PICU) has fallen over the last two decades. More advanced treatment is offered to children with life-threatening disease and there is substantial interest in knowing whether long term outcome and quality of life after intensive care are acceptable. SETTING: 12-bed paediatric and neonatal intensive care unit. INTERVENTION: Prospective follow-up study with telephone interview 1 and 2 years after discharge. METHODS: Four domains of quality of life (physical function, role function, social-emotional function and health problem) were recorded by calculating the health state classification (HSC) index. Outcome was classified good (HSC 1.0-0.7), moderate (HSC 0.69-0.3), poor (HSC 0.29-0) and very poor (HSC <0). RESULTS: 661 patients were admitted to the PICU in the year 2001 with a mortality within the unit of 3.9%. Over 2 years follow-up there were 21 additional deaths (3.2%). 574 patients could be followed up after 1 year and 464 patients after 2 years. After two years the outcome was good in 77%, moderate in 15% and poor in 8%. Patients with respiratory disease had the best outcome, similar to those admitted for neurological and medical reasons. Patients admitted for postoperative care and for cardiovascular disease had a poorer quality of life. 31% of the children had preexisting health care problems and 21% of all patients had new chronic disease after intensive care. CONCLUSION: The majority of survivors admitted to the PICU have a good outcome. The overall mortality rate doubled if assessed two years after discharge.

In utero haematopoietic stem cell transplantation. Experiences in mice, sheep and humans.

Abstract: Early prenatal diagnosis and in utero therapy of certain fetal diseases have the potential to reduce fetal morbidity and mortality. The intrauterine transplantation of stem cells provides in some instances a therapeutic option before definitive organ failure occurs. Clinical experiences show that certain diseases, such as immune deficiencies or inborn errors of metabolism, can be successfully treated using stem cells derived from bone marrow. However, a remaining problem is the low level of engraftment that can be achieved. Efforts are made in animal models to optimise the graft and study the recipient's microenvironment to increase long-term engraftment levels. Our experiments in mice show similar early homing of allogeneic and xenogeneic stem cells and reasonable early engraftment of allogeneic murine fetal liver cells (17.1% donor cells in peripheral blood 4 weeks after transplantation), whereas xenogeneic HSC are rapidly diminished due to missing self-renewal and low differentiation capacities in the host's microenvironment. Allogeneic murine fetal liver cells have very good long-term engraftment (49.9% donor cells in peripheral blood 16 weeks after transplantation). Compared to the rodents, the sheep model has the advantage of body size and gestation comparable to the human fetus. Here, ultrasound-guided injection techniques significantly decreased fetal loss rates. In contrast to the murine in utero model, the repopulation capacities of allogeneic ovine fetal liver cells are lower (0.112% donor cells in peripheral blood 3 weeks after transplantation). The effect of MHC on engraftment levels seems to be marginal, since no differences could be observed between autologous and allogeneic transplantation (0.117% donor cells vs 0.112% donor cells in peripheral blood 1 to 2 weeks after transplantation). Further research is needed to study optimal timing and graft composition as well as immunological aspects of in utero transplantation.

Sleep and respiration in children: time to wake up!

Abstract: The interest in paediatric sleep disorders over the last few decades has had its main focus on the sudden infant death syndrome (SIDS) - healthy infants who go to sleep and never wake up again. Overall, this is the most dramatic form of paediatric sleep disordered breathing. By contrast, classical presentations of sleep disordered breathing in children, such as snoring and obstructive sleep apnoea as well as their clinical implications have been greatly neglected and underestimated in the past. In contrast to snoring in adults, snoring in children has so far generally been regarded as noisy breathing with no significant impact on the general health of children. This is also to a lesser extent true for obstructive sleep apnoea syndrome (OSAS). The sometimes dramatic complications of OSAS, such as cor pulmonale and developmental retardation have at least indicated that OSAS in children is important and may have a great impact on the general health of children. This has led to an increased interest from a clinical as well as a scientific point of view with some important findings, mainly that sleep disordered breathing in childhood varies from sleep disordered breathing in adulthood and that even mild to moderate disease has a huge impact on the general health of children, mainly on neurocognitive development.

Respiratory polygraphy in sleep apnoea diagnosis. Report of the Swiss respiratory polygraphy registry and systematic review of the literature.

Abstract: Background Sleep related breathing disorders (SBD) are common and associated with morbidity and mortality. Since polysomnography, the conventional diagnostic gold standard is costly and not generally available, ambulatory respiratory polygraphic sleep studies (RP) are used. To evaluate whether RP reimbursement by health insurance companies was justified, the Swiss Federal Office of Public Health (FOPH) requested registration of RP during 36 months and a literature review on RP. The results are reported here. Methods RP reimbursed from July 2002 to December 2005 by Swiss health insurance companies were analysed. A review of the literature from 2003 comparing RP with PSG was updated. The outcome of interest was the apnoea/hypopnoea index. Results Datasets on 11,485 RP were evaluated, 8179 were performed to evaluate suspected obstructive sleep apnoea syndrome (OSAS). In patients with snoring, witnessed apnoea and hypersomnia (n = 4180), 80.2% of RP confirmed OSAS, 3.5% of RP were inconclusive prompting polysomnography. Six studies published between 2003 and 2005 were pooled with a former review of 12 studies. With a mean pre-test probability of 64% for OSAS, the post-test probability after a negative result ranged from 8% (negative likelihood ratio of 0.05) to 23% (negative likelihood ratio of 0.20). The post-test probability after a positive result was within a range of 98% (positive likelihood ratio of 23.8) to 90% (positive likelihood ratio of 5.7). Conclusions In selected patients with clinically suspected OSAS RP allows accurate and simple diagnosis of OSAS. According to the practice in Switzerland as reflected by the registry additional PSG are rarely required, suggesting relevant cost savings by RP. Granting reimbursement for RP as introduced in the meantime by the FOPH seems justified.

Missed appointments in an adolescent outpatient clinic: descriptive analyses of consultations over 8 years.

Abstract: Question under study: Missed appointments represent an important medical and economical issue. Few studies on the subject are reported in the literature, particularly regarding adolescents. Our aim was to characterize missed and cancelled appointments in a multidisciplinary outpatient clinic for adolescents, to assess the effectiveness of a policy aimed at reducing missed appointments by introducing payment for those missed ap- pointments not cancelled in advance, and to com- pare the rates between staff and resident physi- cians. Methods: A total of 32,81� consultations (rep- resenting 35�� patients aged 12-20 years, 82.4% females) between 1999 and 200� were analysed. Results: The missed appointment rate was 11.8% whilst another 10.9% were cancellations. Females cancelled more than males (11.3% vs. 8.4%, AOR 1.31, 99% CI 1.08-1.59), but there was no difference for missed appointments (11.�% vs. 12.3%, AOR 0.88, 99% CI 0.�1-1.08). April and June to October (vacation months) were associated with more missed appointments. Glob- ally mornings had higher rates of missed appoint- ments than afternoons (13.�% vs. 11.2%, AO R 1.25, 99% CI 1.11-1.40). There was a slight dif- ference in missed appointment rates between staff physicians and residents (10.4%; 11.8%, AO R 1.20, 99% CI 1.08-1.33). Missed appointment rates before and after the new policy on missed appointments were similar (1999-2003: 11.9%; 2004-200�: 11.�%, AOR 0.9�, 99% CI 0.83- 1.10). Conversely, cancellation rates increased from 8.4% (1999-2003) to 14.5% (2004-200�) (AOR 1.83, 99% CI 1.�3-2.05). Conclusion: Attendance rates among adoles- cents show variations depending on vacation and school hours. Being attentive to these factors could help prevent missed appointments. Al- though having to pay for missed appointments does not increase attendance, it increases cancel- lations with the advantage that the appointment can be rescheduled. Summary

Efficacy and safety of universal valganciclovir prophylaxis combined with a tacrolimus/mycophenolate-based regimen in kidney transplantation.

Abstract: Immunosuppressive and antiviral prophylactic drugs are needed to prevent acute rejection and infection after transplantation. We assessed the efficacy and safety of the introduction of universal valganciclovir prophylaxis in combination with a tacrolimus/mycophenolate-based regimen in kidney transplantation at our centre