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Volume 141, No. 4142

Published October 10, 2011

Review article: Biomedical intelligence

  1. Alama El, I Hösli, M Nelle, D Surbek, J Wisser, R Zimmermann, JC Fauchère, AC Truttmann (Author)

    Perinatal care at the limit of viability between 22 and 26 completed weeks of gestation in Switzerland

    Perinatal care of pregnant women at high risk for preterm delivery and of preterm infants born at the limit of viability (22–26 completed weeks of gestation) requires a multidisciplinary approach by an experienced perinatal team. Limited precision in the determination of both gestational age and foetal weight, as well as biological variability may significantly affect the course of action chosen in individual cases.

    The decisions that must be taken with the pregnant women and on behalf of the preterm infant in this context are complex and have far-reaching consequences. When counselling pregnant women and their partners, neonatologists and obstetricians should provide them with comprehensive information in a sensitive and supportive way to build a basis of trust. The decisions are developed in a continuing dialogue between all parties involved (physicians, midwives, nursing staff and parents) with the principal aim to find solutions that are in the infant’s and pregnant woman's best interest.

    Knowledge of current gestational age-specific mortality and morbidity rates and how they are modified by prenatally known prognostic factors (estimated foetal weight, sex, exposure or nonexposure to antenatal corticosteroids, single or multiple births) as well as the application of accepted ethical principles form the basis for responsible decision-making. Communication between all parties involved plays a central role.

    The members of the interdisciplinary working group suggest that the care of preterm infants with a gestational age between 22 0/7 and 23 6/7 weeks should generally be limited to palliative care. Obstetric interventions for foetal indications such as Caesarean section delivery are usually not indicated. In selected cases, for example, after 23 weeks of pregnancy have been completed and several of the above mentioned prenatally known prognostic factors are favourable or well informed parents insist on the initiation of life-sustaining therapies, active obstetric interventions for foetal indications and provisional intensive care of the neonate may be reasonable.

    In preterm infants with a gestational age between 24 0/7 and 24 6/7 weeks, it can be difficult to determine whether the burden of obstetric interventions and neonatal intensive care is justified given the limited chances of success of such a therapy. In such cases, the individual constellation of prenatally known factors which impact on prognosis can be helpful in the decision making process with the parents.

    In preterm infants with a gestational age between 25 0/7 and 25 6/7 weeks, foetal surveillance, obstetric interventions for foetal indications and neonatal intensive care measures are generally indicated. However, if several prenatally known prognostic factors are unfavourable and the parents agree, primary non-intervention and neonatal palliative care can be considered.

    All pregnant women with threatening preterm delivery or premature rupture of membranes at the limit of viability must be transferred to a perinatal centre with a level III neonatal intensive care unit no later than 23 0/7 weeks of gestation, unless emergency delivery is indicated. An experienced neonatology team should be involved in all deliveries that take place after 23 0/7 weeks of gestation to help to decide together with the parents if the initiation of intensive care measures appears to be appropriate or if preference should be given to palliative care (i.e., primary non-intervention). In doubtful situations, it can be reasonable to initiate intensive care and to admit the preterm infant to a neonatal intensive care unit (i.e., provisional intensive care). The infant’s clinical evolution and additional discussions with the parents will help to clarify whether the life-sustaining therapies should be continued or withdrawn.

    Life support is continued as long as there is reasonable hope for survival and the infant’s burden of intensive care is acceptable. If, on the other hand, the health care team and the parents have to recognise that in the light of a very poor prognosis the burden of the currently used therapies has become disproportionate, intensive care measures are no longer justified and other aspects of care (e.g., relief of pain and suffering) are the new priorities (i.e., redirection of care). If a decision is made to withhold or withdraw life-sustaining therapies, the health care team should focus on comfort care for the dying infant and support for the parents.

  2. AL Lalive, U Rudolph, C Lüscher, KR Tan (Author)

    Is there a way to curb benzodiazepine addiction?

    Benzodiazepines are widely prescribed drugs used to treat anxiety and insomnia, induce muscle relaxation, control epileptic seizures, promote anaesthesia or produce amnesia. Benzodiazepines are also abused for recreational purposes and the number of benzodiazepine abusers is unfortunately increasing. Within weeks of chronic use, tolerance to the pharmacological effects can develop and withdrawal becomes apparent once the drug is no longer available, which are both conditions indicative of benzodiazepine dependence. Diagnosis of addiction (i.e. compulsive use despite negative consequences) may follow in vulnerable individuals. Here, we review the historical and current use of benzodiazepines from their original synthesis, discovery and commercialisation to the recent identification of the molecular mechanism by which benzodiazepines induce addiction. These results have identified the mechanisms underlying the activation of midbrain dopamine neurons by benzodiazepines, and how these drugs can hijack the mesocorticolimbic reward system. Such knowledge calls for future developments of new receptor subtype specific benzodiazepines with a reduced addiction liability.

Original article

  1. N Nigro, P Schütz, S Neidert, NG Morgenthaler (Author)

    The use of copeptin, the stable peptide of the vasopressin precursor, in the differential diagnosis of sodium imbalance in patients with acute diseases

    BACKGROUND: Sodium imbalance is common in-hospital electrolyte disturbance and is largely related to inequalities in water homeostasis. An important mechanism leading to dysnatraemic disorders is inadequately secreted plasma arginine vasopressin (AVP). Unfortunately, AVP measurement is cumbersome and not reliable. Copeptin is secreted in an equimolar ratio to AVP and is a promising marker in the differential diagnosis of hyponatraemia and possibly hypernatraemia in stable hospitalised patients. This study assessed copeptin concentrations in sick patients with serum sodium imbalance of different aetiology on admission to the emergency department.

    METHODS:This is a secondary analysis of three previous prospective studies including patients with lower respiratory tract infections (LRTI) and acute cerebrovascular events. Patients were classified into different aetiological groups of hyponatraemia and hypernatraemia based on gold standard diagnostic algorithms. Copeptin levels were compared between different volaemic states and different aetiologies, firstly within the different study populations and secondly in an overall pooled analysis using hierarchical regression analysis adjusted for age and gender.

    RESULTS:In LRTI, hyponatraemia was found in 10.6% (58/545) and hypernatraemia in 3.7% (20/545). For acute cerebrovascular events, the corresponding numbers were 4.3% (22/509) and 8.4% (43/509). In LRTI patients with hyponatraemia, copeptin levels were only lower in the subgroup of patients with gastrointestinal losses compared to the group of patients with renal failure (mean difference: –73.6 mmol/l, 95%CI –135.0, –12.3). For hypernatraemic patients and stoke patients with hypo- and hypernatraemia, no differences were observed. In the combined analysis, copeptin levels in the hyponatraemic population were higher in patients with a hypervolaemic volume state and in patients with heart failure and renal failure. When focusing on severity, copeptin levels increased with increasing severity of disease, as classified by the Pneumonia Severity Index (p <0.0001) or the National Institute of Health Stroke Scale Score (p <0.0001).

    CONCLUSION:Although limited by small sample size, this study found that plasma copeptin level appears to add very little information to the work up of sodium imbalance in this cohort of medical inpatients. It is likely that the non-osmotic “stress”-stimulus in acute hospitalised patients is a major confounder and overrules the osmotic stimulus.

  2. E Perrin, M Berthoud, M Pott, Vera Toledo, D Perrenoud, Demicheli Bianchi (Author)

    Clinical course in women undergoing termination of pregnancy within the legal time limit in French-speaking Switzerland

    BACKGROUND: In 2002, Swiss citizens voted to accept new laws legalising the termination of pregnancy (TOP) up to 12th week of pregnancy. As a result the cantons formulated rules of implementation. Health institutions then had to modify their procedures and practices.

    QUESTIONS UNDER STUDY/PRINCIPLES: One of the objectives of these changes was to simplify the clinical course for women who decide to terminate a pregnancy. Have the various health institutions in French-speaking Switzerland attained this goal? Are there differences between cantons? Are there any other differences, and if so, which ones?

    METHODS: Comparative study of cantonal rules of implementation. Study by questionnaire of what happened to 281 women having undergone a TOP in French-speaking Switzerland. Quantitative and qualitative method.

    RESULTS: The comparative legal study of the six cantonal rules of implementation showed differences between cantons.

    The clinical course for women are defined by four quantifiable facts: 1) the number of days to wait between the woman’s decision (first step) and TOP; 2) the number of appointments attended before TOP; 3) the method of TOP; 4) the cost of TOP. On average, the waiting time was 12 days and the number of appointments was 3. The average cost of TOP was 1360 CHF. The differences, sometimes quite large, are explained by the size of the institutions (large university hospitals; average-sized, non-university hospitals; private doctors’ offices).

    CONCLUSIONS: The cantonal rules of implementation and the size of the health care institutions play an important role in these courses for women in French-speaking Switzerland.

  3. A Bischoff, M Schneider (Author)

    The cost of war and the cost of health care – an epidemiological study of asylum seekers

    BACKGROUND: The aim of this study was to explore differences in health care costs for asylum seekers from countries experiencing violent conflict and those from countries experiencing no violent conflict.

    METHDODS: Data were collected from a representative sample of refugees in an urban Swiss canton who were assigned to a Health Maintenance Organisation that covered all their health care costs. Cost differences for individuals coming from countries experiencing violent conflicts and from countries experiencing no violent conflict were tested by using multiple regression techniques and by controlling for confounding demographic, clinical and migration-related variables.

    RESULTS: Health care costs were higher for patients from countries with violent conflict. The higher costs could be attributed in part to increased frequencies of somatic diseases, however, the higher costs were linked primarily to the duration of the asylum seeker’s enrolment in the insurance programme, the number of visits to the medical facility, and the procedural status of the person’s application for asylum.

    CONCLUSIONS: Despite a higher prevalence of illness in patients from countries with violent conflict, the length of time spent in administrative “asylum seeker” status seemed to be the main driver of health care costs. Language barriers may be skewing results, with respect to the importance of specific diagnoses (especially mental health disorders), in driving costs upward. These results indicate a need for more comprehensive screening strategies for asylum seekers in receiving countries, particularly for those from countries in conflict.

  4. G Ferrari, PA Eng (Author)

    IgE-mediated food allergies in Swiss infants and children

    OBJECTIVE: To determine the most frequent food allergens causing immediate hypersensitivity reactions in Swiss children of different age groups and to investigate the clinical manifestation of IgE-mediated food allergies in young patients.

    PATIENTS AND METHODS: The study was a prospective analysis of children referred for assessment of immediate type I food hypersensitivity reactions. The diagnostic strategy included a careful history, skin prick tests with commercial extracts and native foods, in vitro determination of specific IgE to food proteins and food challenges when appropriate. A total of 278 food allergies were identified in 151 children with a median age of 1.9 years at diagnosis.

    RESULTS: Overall, the most frequent food allergens were hen’s egg (23.7%), cow’s milk (20.1%), peanut (14.0%), hazelnut (10.4%), wheat (6.1%), fish (4.3%), kiwi and soy (2.2% each). In infancy, cow’s milk, hen’s egg and wheat were the most common allergens. In the second and third year of life however, the top three food allergens were hen’s egg, cow’s milk and peanut, whereas above the age of 3 years, peanut was number one, followed by hen’s egg and fish. Overall, urticaria (59.0%) and angioedema (30.2%) were the most frequent clinical manifestations. Gastrointestinal symptoms were found in 25.9% and respiratory involvement in 25.2%. There were 13 cases (4.7%) of anaphylaxis to peanut, fish, cow’s milk, hen’s egg, wheat and shrimps.

    CONCLUSIONS:A total of eight allergens account for 83% of IgE-mediated food allergies in Swiss infants and children, with differences in the distribution and order of the most frequently involved food allergens between paediatric age groups.

  5. B Wagner, V Boucsein, A Maercker (Author)

    The impact of forensic investigations following assisted suicide on post-traumatic stress disorder

    In Switzerland, all deaths through assisted suicide are reported as unnatural deaths and investigated by a forensic team (police, medical examiner, and state attorney). However, there is limited knowledge concerning the impact these forensic investigations have on the development of post-traumatic stress disorder, complicated grief, or depression in those who have lost a loved one. A cross-sectional survey of 85 family members or close friends who were present at an assisted suicide was conducted in December 2007. The Impact of Event Scale, Inventory of Complicated Grief, and Brief Symptom Inventory were used to assess mental health. The newly developed Forensic Investigation Experience Scale measured the emotional experience of the legal investigation at the death scene. The data suggest that the diagnosis of post-traumatic stress disorder is significantly related to having experienced the forensic investigation as emotionally difficult. Thus, the way the forensic investigation is conducted immediately after an unnatural death is evidently associated with the development of post-traumatic stress. It is recommended that a protocol be developed establishing a standardised response to cases of assisted suicide and that specific training be provided for the legal professionals involved.

  6. C Martin, Elm von, E Boltshauser (Author)

    Delayed diagnosis of acute ischemic stroke in children – a registry-based study in Switzerland

    QUESTIONS UNDER STUDY/PRINCIPLES: After arterial ischemic stroke (AIS) an early diagnosis helps preserve treatment options that are no longer available later. Paediatric AIS is difficult to diagnose and often the time to diagnosis exceeds the time window of 6 hours defined for thrombolysis in adults. We investigated the delay from the onset of symptoms to AIS diagnosis in children and potential contributing factors.

    METHODS: We included children with AIS below 16 years from the population-based Swiss Neuropaediatric Stroke Registry (2000–2006). We evaluated the time between initial medical evaluation for stroke signs/symptoms and diagnosis, risk factors, co-morbidities and imaging findings.

    RESULTS: A total of 91 children (61 boys), with a median age of 5.3 years (range: 0.2–16.2), were included. The time to diagnosis (by neuro-imaging) was <6 hours in 32 (35%), 6–12 hours in 23 (25%), 12–24 hours in 15 (16%) and >24 hours in 21 (23%) children. Of 74 children not hospitalised when the stroke occurred, 42% had adequate outpatient management. Delays in diagnosis were attributed to: parents/caregivers (n = 20), physicians of first referral (n = 5) and tertiary care hospitals (n = 8). A co-morbidity hindered timely diagnosis in eight children. No other factors were associated with delay to diagnosis. A total of 17 children were inpatients at AIS onset.

    CONCLUSIONS:One-third of children with AIS were diagnosed within six hours. Diagnostic delay was predominately caused by insufficient recognition of stroke symptoms. Increased public and expert awareness and immediate access to diagnostic imaging are essential. The ability of parents/caregivers and health professionals to recognise stroke symptoms in a child needs to be improved.

  7. F zhou, Z yu, T jiang, H lv, R yao, J liang (Author)

    Genetic polymorphisms of GSTP1 and XRCC1: prediction of clinical outcome of platinum-based chemotherapy in advanced non-small cell lung cancer (NSCLC) patients

    PRINCIPLES: Platinum agents cause DNA cross-linking and oxidative damage. Genetic polymorphisms of GSTP1 and XRCC1 involved in glutathione metabolic and DNA repair pathways may explain inter individual differences in chemosensitivity and clinical outcome in NSCLC patients treated with platinum-based regimens.

    METHODS: We used DNA sequencing methods to evaluate genetic polymorphisms of the GSTP1A313G and XRCC1G28152A in 111 patients with stage IV NSCLC treated with platinum-based chemotherapy. Clinical response was evaluated according to RECIST criteria after 2–3 cycles of chemotherapy and time to progression (TTP) was calculated from the time of initial treatment to disease progression.

    RESULTS: GSTP1A313G and XRCC1G28152A polymorphisms, both alone and in combination, were significantly associated with response to treatment and clinical outcome (p<0.05) in NSCLC patients treated with platinum-based chemotherapy. These polymorphisms independently predicted clinical outcome even after taking into account age, gender, tumour histology, tumour differentiation and chemotherapy regimens.

    CONCLUSION: Genetic polymorphisms of GSTP1 and XRCC1 may be important predictive factors in platinum-treated patients with advanced NSCLC. Assessment of genetic variations of GSTP1 and XRCC1 could facilitate therapeutic decisions for individualised therapy in advanced NSCLC.

  8. JP Tsai, JH Liou, KT Yeh, HC Tai, YW Cheng, HR Chang (Author)

    Intensity of cytosol expression of 8-OHdG in normal renal tubules is associated with the severity of renal fibrosis

    INTRODUCTION:It has been proposed thatreactive oxygen species play a role in renal fibrosis. 8-OHdG, a metabolite of oxidative damage to leukocyte DNA, has been identified as a marker of oxidative stress in patients with chronic renal failure.

    MATERIALS AND METHODS:Seventy-four patients following nephrectomy were retrospectively enrolled. Immunohistochemical analysis of the renal expression of 8-OHdG in the nephrectomised kidneys was performed and associations between renal expression of 8-OHdG and renal fibrosis were evaluated.

    RESULTS:Patients with higher interstitial fibrosis scores (IFS) and glomerular fibrosis scores (GFS) had significantly higher serum creatinine, lower estimated glomerular filtration rate (eGFR), increased percentage of chronic kidney disease (CKD) and urothelial cell carcinoma. The renal tissues with higher IFS had lower expressions of 8-OHdG in normal tubular cytoplasm (NTc) (35.7% vs. 64.3%, p = 0.011) and normal tubular nuclei (NTn) (28.6% vs. 71.4%, p = 0.023). Univariate analysis showed that IFS and GFS correlated with the NTc 8-OHdG expression and IFS negatively correlated with NTn 8-OHdG expression. Multivariate stepwise regression revealed that serum creatinine (r = 0.351 for IFS, p = 0.021; r = 0.563 for GFS, p <0.001) and intensity of 8-OHdG expression in NTc (r = 0.397 for IFS, p = 0.01; r = 0.278 for GFS, p = 0.043) were the independent factors predicting IFS or GFS.

    CONCLUSION:This study demonstrated that the intensity of 8-OHdG expression in NTc was associated with the severity of renal fibrosis.

Short communication

  1. CD Ochoa, HG Garg, CA Hales, DA Quinn (Author)

    Low molecular weight hyaluronan, via AP-1 and NF-κB signalling, induces IL-8 in transformed bronchial epithelial cells

    QUESTIONS UNDER STUDY: New evidence demonstrated that high tidal volume mechanical ventilation results in substantial bronchial airway mechanical strain. In addition, high tidal volume mechanical ventilation has been shown to increase IL-8 production in a mechanism mediated, at least in part, by low molecular weight hyaluronan (LWM-HA). In the present study, it was investigated whether LMW-HA synthesised in the lung, in response to cyclic stretch, increased IL-8 production in the bronchial epithelium.

    METHODS: This question was approached by stimulating a transformed human bronchial epithelial cell line with LMW-HA isolated from stretched human lung fibroblasts and probed for the activation of extracellular signal-regulated kinase pathways.

    RESULTS: LMW-HA increased IL-8 secretion in transformed bronchial epithelial cells. Additionally, LMW-HA augmented the levels of phospho c-Jun NH2-terminal kinase (JNK) and phospho extracellular signal-regulated kinase 1/2 (ERK1/2), and also mobilised nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) from the cytoplasm to the nucleus. The inhibition of JNK, ERK1/2 and NF-κB blocked IL-8 secretion in response to LMW-HA.

    CONCLUSION: The data suggest that LMW-HA produced by lung fibroblasts in response to cyclic stretch increases the secretion of IL-8 in transformed bronchial epithelial cells via AP-1 and NF-κB signalling pathways. These findings support the hypothesis that LMW-HA plays an active role in acute lung inflammation triggered by mechanical strain.

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