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Daniel Brudney's clear-headed analysis, in this issue of the Hastings Center Report, of the difference between a patient's and a surrogate's right to make medical treatment decisions contributes to a longstanding conversation in bioethics. Brudney offers an epistemological and a moral argument for the patient's and the surrogate's right to decide. The epistemological argument is the same for both parties: the (competent) patient has a right to decide because she is presumed to know her own interests better than anyone else, and the surrogate is entitled to make decisions because she knows the patient better than anyone else. However, argues Brudney, the moral arguments are not parallel. The patient's moral right to decide for herself is an exercise of autonomy, but the only ground for the responsibility held by the surrogate, says Brudney, is that she knows the patient better than the health care professionals do. If in fact that's not the case, then she forfeits her right to be the patient's surrogate. For all the clarity and force of his argument, I think Brudney may be barking up the wrong tree. In cases of proxy decision-making, it's intimacy, not knowledge, that does the heavy moral lifting., (© 2018 The Hastings Center.)

Chronic myeloid leukemia (CML)-study IV was designed to explore whether treatment with imatinib (IM) at 400 mg/day (n=400) could be optimized by doubling the dose (n=420), adding interferon (IFN) (n=430) or cytarabine (n=158) or using IM after IFN-failure (n=128). From July 2002 to March 2012, 1551 newly diagnosed patients in chronic phase were randomized into a 5-arm study. The study was powered to detect a survival difference of 5% at 5 years. After a median observation time of 9.5 years, 10-year overall survival was 82%, 10-year progression-free survival was 80% and 10-year relative survival was 92%. Survival between IM400 mg and any experimental arm was not different. In a multivariate analysis, risk group, major-route chromosomal aberrations, comorbidities, smoking and treatment center (academic vs other) influenced survival significantly, but not any form of treatment optimization. Patients reaching the molecular response milestones at 3, 6 and 12 months had a significant survival advantage. For responders, monotherapy with IM400 mg provides a close to normal life expectancy independent of the time to response. Survival is more determined by patients' and disease factors than by initial treatment selection. Although improvements are also needed for refractory disease, more life-time can currently be gained by carefully addressing non-CML determinants of survival.

This essay lays out some of the many resources that a background in literary studies has to offer bioethics. After identifying four useful characteristics of stories, it briefly discusses some kinds of moral work that stories can be put to, including countering ethically undesirable stories and modeling ethically troubling situations. Stories can be invoked in our moral reasoning, compared and parsed, and used to teach moral lessons. They can help us discern which moral concepts are operative in a specific instance. Our personal identities consist of stories, which help us understand who we and other people are. Stories can also be parodied, for political or other effect. Stories can perform these moral functions only to the extent that the persons telling or invoking or parodying them are themselves morally competent. But given that competence, a scholarly grasp of literature and narrative can greatly enhance bioethical reflection.

Tyrosine kinase inhibitors represent today's treatment of choice in chronic myeloid leukemia (CML). Allogeneic hematopoietic stem cell transplantation (HSCT) is regarded as salvage therapy. This prospective randomized CML-study IIIA recruited 669 patients with newly diagnosed CML between July 1997 and January 2004 from 143 centers. Of these, 427 patients were considered eligible for HSCT and were randomized by availability of a matched family donor between primary HSCT (group A; N=166 patients) and best available drug treatment (group B; N=261). Primary end point was long-term survival. Survival probabilities were not different between groups A and B (10-year survival: 0.76 (95% confidence interval (CI): 0.69-0.82) vs 0.69 (95% CI: 0.61-0.76)), but influenced by disease and transplant risk. Patients with a low transplant risk showed superior survival compared with patients with high- (P<0.001) and non-high-risk disease (P=0.047) in group B; after entering blast crisis, survival was not different with or without HSCT. Significantly more patients in group A were in molecular remission (56% vs 39%; P=0.005) and free of drug treatment (56% vs 6%; P<0.001). Differences in symptoms and Karnofsky score were not significant. In the era of tyrosine kinase inhibitors, HSCT remains a valid option when both disease and transplant risk are considered.

Recent developments in professional healthcare pose moral problems that standard bioethics cannot even identify as problems, but that are fully visible when redefined as problems in the ethics of families. Here, we add to the growing body of work that began in the 1990 s by demonstrating the need for a distinctive ethics of families. First, we discuss what 'family' means and why families can matter so deeply to the lives of those within them. Then, we briefly sketch how, according to an ethics of families, responsibilities must be negotiated against the backdrop of family relationships, treatment decisions must be made in the light of these negotiated responsibilities and justice must be served, both between families and society more generally and within families themselves., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Serious illness puts pressure not only on individual family members but also on the family itself. The care of an acutely ill child requires the family to channel many of its resources toward a single member--an arrangement that can usually be sustained for a while but that cannot continue indefinitely while the other members do without. Illness disrupts ordinary familial functions and, if it is serious enough, threatens to break the family altogether. In this article, I argue that there are situations in which the threat to family integrity is so real and serious that the interests of parents or siblings or sometimes grandparents may override the interests of the pediatric patient., (Copyright © 2014 by the American Academy of Pediatrics.)

The authority of surrogates-often close family members-to make treatment decisions for previously capacitated patients is said to come from their knowledge of the patient, which they are to draw on as they exercise substituted judgment on the patient's behalf. However, proxy accuracy studies call this authority into question, hence the Patient Preference Predictor (PPP). We identify two problems with contemporary understandings of the surrogate's role. The first is with the assumption that knowledge of the patient entails knowledge of what the patient's choice of treatment would be. The second is with the assumption that a good decision reproduces the content of that choice. If we are right, then the PPP, helpful though it might be in guiding surrogates' decisions, nevertheless would hold them to the wrong standards and in that way could add to, rather than relieve, the stress they experience as they try to do their job.

Background: Transcranial magnetic stimulation (TMS) of the human primary motor hand area (M1-HAND) can produce multiple descending volleys in fast-conducting corticospinal neurons, especially so-called indirect waves (I-waves) resulting from trans-synaptic excitation. Facilitatory interaction between these I-waves can be studied non-invasively using a paired-pulse paradigm referred to as short-interval intracortical facilitation (SICF)., Objective/hypothesis: We examined whether SICF depends on waveform and current direction of the TMS pulses., Methods: In young healthy volunteers, we applied single- and paired-pulse TMS to M1-HAND. We probed SICF by pairs of monophasic or half-sine pulses at suprathreshold stimulation intensity and inter-stimulus intervals (ISIs) between 1.0 and 5.0 ms. For monophasic paired-pulse stimulation, both pulses had either a posterior-anterior (PA) or anterior-posterior (AP) current direction (AP-AP or PA-PA), whereas current direction was reversed between first and second pulse for half-sine paired-pulse stimulation (PA-AP and AP-PA)., Results: Monophasic AP-AP stimulation resulted in stronger early SICF at 1.4 ms relative to late SICF at 2.8 and 4.4 ms, whereas monophasic PA-PA stimulation produced SICF of comparable size at all three peaks. With half-sine stimulation the third SICF peak was reduced for PA-AP current orientation compared with AP-PA., Conclusion: SICF elicited using monophasic as well as half-sine pulses is affected by current direction at clearly suprathreshold intensities. The impact of current orientation is stronger for monophasic compared with half-sine pulses. The direction-specific effect of paired-pulse TMS on the strength of early versus late SICF shows that different cortical circuits mediate early and late SICF., (Copyright © 2014 Elsevier Inc. All rights reserved.)

When treating children or adolescents with chronic disease one should take the specific age-related features of the course of disease, differential diagnosis, and the psychosocial environment, as well as the avoidance of complications and side effects of therapy into account. These may impair the patient's physical and psychosocial development and quality of life in the context of family, school and occupational life. Continued care of growing children from the start of the disease when they are infants to the point when they assume personal responsibility as adults is one of the major concerns of the pediatrician. This concept requires interdisciplinary cooperation and a large body of personnel which would include training programs, inclusion of family members and in some cases psychosomatic therapy. Given the increasing prevalence of chronic diseases in this age group and their sociopolitical significance it is important to activate preventive potentials in terms of content and structure - by quality assurance - especially to avoid long-term complications. Various care structures are used in Europe to achieve this goal. Asthma is the most common chronic disease in children and adolescents. It influences quality of life as well as the child's personal, educational and occupational development to a significant extent. The special aspects of the treatment of these patients will be addressed to illustrate the therapy of chronic disease., (© Georg Thieme Verlag KG Stuttgart · New York.)

Objective: Besides its use in epilepsy, lamotrigine (LTG) is also effective as mood stabilizer. The pathophysiology of mood disorders may incorporate a dysfunction of neuronal plasticity and animal experiments suggest that mood stabilizers influence induction of long-term potentiation (LTP) and -depression (LTD), two major forms of synaptic plasticity. However, the exact modes of action of LTG and its impact on neuronal plasticity in humans remain unclear., Methods: Here, we tested the effects of a single oral dose of LTG (300 mg) on motor cortical plasticity induced by paired associative stimulation (PAS(25)), a protocol that typically induces LTP-like plasticity, in 26 young healthy adults in a placebo-controlled, randomized, double-blind crossover design. We stratified analysis of the LTG effects according to the individual PAS(25) response in the placebo session (14 LTP-responders vs. 12 LTD-responders). Plasticity was indexed by motor evoked potential (MEP) amplitudes recorded before and for 60 min after PAS(25)., Results: LTG resulted in a significant reduction of the LTP-like MEP increase in the LTP-responders and a reduction of the LTD-like MEP decrease in the LTD-responders, with the majority of LTD-responders even showing an MEP increase., Conclusions: In summary, LTG differentially modulated cortical plasticity induced by non-invasive brain stimulation in human subjects depending on their individual intrinsic propensity for expressing LTP-like or LTD-like plasticity., Significance: Findings contribute to our understanding of the anticonvulsant and antidepressant clinical effects of LTG, which have been suggested to occur, at least in part, through downregulation of LTP (epilepsy) and LTD (depressive disorders)., (Copyright © 2012 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.)

Clinical ethicists tend to see themselves as moral experts to be called in when clinicians encounter a particularly difficult moral problem. Drawing on a naturalized moral epistemology, we argue that clinicians already have the moral knowledge they need-the norms and values that guide clinical practice are built right into the various health care professions. To reflect on their practice, clinicians need to (a) be aware of their own professional norms and values; (b) be able to express them to their colleagues, their patients, and the patients' families; and (c) work together with these other actors to provide ethically responsible care. The ethicist's job is to use her own training in three kinds of philosophical reflection as the basis for teaching clinicians how to think about what they do.

The women's movement rose to prominence decades ago, but women continue to be discriminated against in their encounters with medicine, as both patients and practitioners. How should bioethics think about this state of affairs?, (© 2012 by The Hastings Center.)

In an age of global capitalism, pandemics, far-flung biobanks, multinational drug trials and telemedicine it is impossible for bioethicists to ignore the global dimensions of their field. However, if they are to do good work on the issues that globalisation requires of them, they need theoretical resources that are up to the task. This paper identifies four distinct understandings of 'globalised' in the bioethics literature: (1) a focus on global issues; (2) an attempt to develop a universal ethical theory that can transcend cultural differences; (3) an awareness of how bioethics itself has expanded, with new centres and journals emerging in nearly every corner of the globe; (4) a concern to avoid cultural imperialism in encounters with other societies. Each of these approaches to globalisation has some merit, as will be shown. The difficulty with them is that the standard theoretical tools on which they rely are not designed for cross-cultural ethical reflection. As a result, they leave important considerations hidden. A set of theoretical resources is proposed to deal with the moral puzzles of globalisation. Abandoning idealised moral theory, a normative framework is developed that is sensitive enough to account for differences without losing the broader context in which ethical issues arise. An empirically nourished, self-reflexive, socially inquisitive, politically critical and inclusive ethics allows bioethicists the flexibility they need to pick up on the morally relevant particulars of this situation here without losing sight of the broader cultural contexts in which it all takes place.

Background: The genetic disease cystic fibrosis (CF) is characterised by reduced chloride secretion mediated by the cystic fibrosis transmembrane conductance regulator (CFTR) and Na(+) hyperabsorption through amiloride-sensitive epithelial sodium channels (ENaC). Mutations in CFTR cause the accumulation of thick mucus and dysfunction of mucociliary clearance in the respiratory tract., Material and Methods: In this project it was investigated whether Na(+) hyperabsorption is inhibited by the use of antisense oligonucleotides (AON). For functional analyses monolayers of human non-CF and CF nasal epithelial cells were measured in modified Ussing chambers. To analyse the AON effects on the protein level Western blotting analyses were carried out., Results: AON transfection significantly inhibits Na(+) absorption via ENaC in non-CF and CF cells. Furthermore, Western blot analyses demonstrate a suppression of the ENaC protein in AON transfected human non-CF cells., Conclusion: The inhibition of ENaC associated Na(+) absorption by specific AON could offer a new perspective for the regulation of the Na(+) hyperabsorption in CF patients.

Background: Cystic fibrosis (CF) respiratory epithelia are characterized by a defect Cl(-) secretion and an increased Na(+) absorption through epithelial Na(+) channels (ENaC). The present study aimed to find an effective inhibitor of human ENaC with respect to replacing amiloride therapy for CF patients. Therefore, we developed specific antisense oligonucleotides (AON) that efficiently suppress Na(+) hyperabsorption by inhibiting the expression of the alpha-ENaC subunit., Methods: We heterologously expressed ENaC in oocytes of Xenopus laevis for mass screening of AON. Additionally, primary cultures of human nasal epithelia were transfected with AON and were used for Ussing chamber experiments, as well as biochemical and fluorescence optical analyses., Results: Screening of several AON by co-injection or sequential microinjection of AON and ENaC mRNA in X. laevis oocytes led to a sustained decrease in amiloride-sensitive current and conductance. Using primary cultures of human nasal epithelia, we show that AON effectively suppress amiloride-sensitive Na(+) absorption mediated by ENaC in CF and non-CF tissues. In western blot experiments, it could be shown that the amount of ENaC protein is effectively reduced after AON transfection., Conclusions: Our data comprise an initial step towards a preclinical test with AON to reduce Na(+) hyperabsorption in CF epithelia.

American bioethicists lack the theoretical resources to work in cross-cultural settings. All we have are two approaches to ethics--principles vs. narratives--that are mostly at odds, and neither of which is up to the job. If moral principles are too abstract to be useful, and if stories cannot provide moral authority, then where do we find our moral norms?

The non-invasive tension-time index of the inspiratory muscles at rest (TTMUS) can be used for assessing respiratory muscle function in children with cystic fibrosis (CF). This study aimed to investigate how TTMUS becomes altered with increasing pulmonary impairment, and which factors determine TTMUS changes in CF. We assessed TTMUS in 47 patients with stable CF ranging in age from 9 to 26 years and in 47 controls of same age and gender. Pulmonary impairment was assessed by the pulmonary function score (PFS) according to Cropp (PFS 0-2 = no, 3-7 = mild, 8-12 = moderate, and 13-18 = severe dysfunction). Median TTMUS was significantly higher in the entire CF-group than in controls ((0.112 (0.079-0.174) vs. 0.07 (0.052-0.094), P < 0.001)). It was nearly identical in CF-patients without (0.079 (0.056-0.114)) and mild (0.080 (0.059-0.128)) pulmonary dysfunction. It was non-significantly higher in subjects with moderate (0.118 (0.103-0.173)) and grossly elevated in individuals with severe (0.232 (0.211-0.31), P < 0.001)) respiratory impairment when compared to the other PFS-groups. TTMUS was significantly related to percent predicted airway resistance (Raw%pred) (r = 0.60, P < 0.001), percent predicted Forced Expiratory Volume in 1 sec (r = -0.49, P < 0.001), percent predicted Vital Capacity (-0.57, P < 0.001), Functional Residual Capacity in percent Total Lung Capacity (r = 0.42, P = 0.003), and transcutaneous oxygen saturation (r = -0.49, P < 0.001). By contrast, Raw%pred was the only variable that had a significant effect on TTMUS (P = 0.01), when a multivariate logistic regression was applied, using the median of the entire CF-cohort to dichotomise TTMUS. These findings suggest that subjects with stable CF and severe pulmonary dysfunction are prone to respiratory muscle fatigue, and that airway obstruction is an important factor contributing to the increase of TTMUS in CF. Regular determination of TTMUS may be clinically useful during course of disease, and may aid the decision to institute therapies like respiratory muscle training or non-invasive intermittent ventilation., ((c) 2008 Wiley-Liss, Inc.)

In capnovolumetry, the expiratory CO2 concentration of exhaled air is plotted against the volume and thereby allows to determine functional dead space volumes. This method might offer additional information in lung function testing in children and adolescents with bronchial asthma. We aimed at determining whether a bronchospasmolysis (BSL) effect in the lower airways could also be detected by capnovolumetry as reflected by changes in the functional threshold dead space volumes (VDT). In 47 patients (aged 4-16 years) with a mild persistent bronchial asthma, VDT were determined before and after bronchodilation prior to starting therapy with inhaled steroids and after 6 months of treatment. Additionally, spirometry and body plethysmography were performed in all patients. There were significantly higher VDT values after BSL before and after 6 months of therapy (P<0.0001). VDT values before BSL were tendatively higher after 6 months of therapy compared with baseline values (P=0.07). VDT values correlated with parameters derived from conventional pulmonary function testing, i.e. vital capacity, forced expiratory volume in 1 s (FEV1), and maximum expiratory flow (MEF50). As VDT values particularly reflect the volumes of the lower bronchi this method may provide supplementary information to conventional lung function tests which are based on breathing mechanics. This seems to be especially helpful in situations where body plethysmography is not available or cooperation in forced expiration manoeuvres is insufficient.

Chronic airway inflammation in children with asthma might be present even in the absence of pathological lung function tests and is known to increase the risk of permanent pulmonary damage. Thus, we aimed at investigating to what extent inflammatory markers such as leukotrienes (LTs) in exhaled breath condensate (EBC) or fractional exhaled nitric oxide (FE(NO)) reflect therapeutic effects in these patients. Fifty steroid-naive patients (aged 8.8 +/- 2.7 years) were included in the study. EBC was collected before and 6 months after therapy with inhaled corticosteroids. LTs were determined by using commercially available ELISA. In addition, FE(NO) was measured by means of a chemiluminescence analyzer. Conventional lung function testing was performed revealing vital capacity, forced expiratory volume, maximum expiratory flow, and specific resistance. In EBC, LTE(4) but not LTB(4) levels significantly decreased after steroid therapy from 45.3 +/- 36.0 pg/mL to 17.2 +/- 11.4 pg/mL (p < 0.0001) concomitant with a slight, but significant improvement of lung function parameters. Mean FE(NO) also indicated therapeutic success; however, in 20 of 50 patients, exhaled NO concentrations were higher after therapy. These findings suggest that LTE(4) in breath condensate may be helpful in latent inflammatory activity in the bronchial mucosa in children with asthma.

Several criticisms of the Groningen Protocol rest on misunderstandings about how it works or which babies it concerns. Some other objections-about quality-of-life judgments and parents' role in making decisions about their children-cannot be easily cleared away, but at least in the context of Dutch culture and medicine, the protocol is acceptable.

Background: The aim was to examine the handling of the recently developed breath actuated dry powder inhaler Auto-Jethaler (PulmoTec GmbH/Höchstädt, launch by Ratiopharm and CT Berlin)., Method: 75 patients suffering from asthma, cystic fibrosis or primary ciliary dysfunction (age: 3 to 34 years; 29 female, 46 male) with mild or moderate bronchial obstruction took part in the study. Lung function testing including body plethysmography was performed to measure bronchial obstruction independent of effort. Peak Inspiratory Flow (PIF) was measured using a Fleisch pneumotachograph equipped with or without a Auto-Jethaler. Instead of the commercially available drug tablet a stainless steal ring device of equivalent resistance, easy to disinfect, was used. Actuation of the rotation mechanism which was triggered by inspiration at an inspiratory flow of about 40 L/min was accompanied by a rattling noise. Aims of the study were to examine, whether the subjects were able to handle the new device, and to measure PIF without and via Auto-Jethaler., Results: Handling of the Auto-Jethaler was found to be easy. All patients managed to reach or surpass the critical value of 40 L/min, even those with mild to moderate bronchial obstruction. PIF without Jethaler was 85 to 599 L/min, via Auto-Jethaler 40 to 215 L/min. PIF was significantly age dependent (p<0.001)., Conclusions: These findings suggest that the Auto-Jethaler will be an appropriate device for drug administration in children older than 3 years provided that they understand the inspiratory breathing manoeuvre.

The prevalence of insect venom allergy in the European population is approximately 5%. Hymenoptera venom allergy is an important epidemiological problem. Ten to 40 deaths are reported annually in Germany. In contrast to conventional dose increase schedules lasting a minimum of 5 days, shorter protocols reduce the patient's stay in the hospital and provide an earlier protection toward stings. Clinical studies on ultrarush protocols have been published for adult patients, but very little data are currently available for children. Therefore, we investigated the safety and tolerability of a shortened insect venom immunotherapy (VIT) in children and adolescents. Forty-three children and adolescents (aged 4-18 years) with insect venom allergy were treated in this study. Five children were hyposensitized according to the ultrarush protocol with nine injections (as suggested by Brehler et al. (Safety of a two-day ultrarush insect VIT protocol in comparison with protocols of longer duration and involving a larger number of injections. J Allergy Clin Immunol 105:1231-1235,2000); 38 children received the modified ultrarush schedules with only eight subcutaneous injections. With both protocols the maintenance dose (100 microg) was achieved in 24 hours. Twenty-five patients (58.1%) showed no reaction after the injections. In 11 patients (25.6%), extensive erythema (>5 cm, maximum of 20 cm) was found at the injection site. Erythema and edema (>5 cm, maximum of 15 cm) were observed in seven patients (16.2%). The maintenance dose was well tolerated, with no systemic reaction in any patient. The modified ultrarush protocol for insect VIT used in this study showed very good tolerability and safety in children and adolescents. This dose regimen can increase compliance by shortening inpatient stay and reduces hospital costs.

I argue that the field of bioethics is gendered feminine, but that the methods it uses to resist this gender identity pose real harm to actual women. Starting with an explanation of what I take 'gender' to be, I enumerate four drawbacks to being gendered feminine. I then argue that bioethics suffers from three of the same four drawbacks. I show how the field escapes the fourth disadvantage by adopting a masculine persona that inflicts damage on women, and conclude by urging bioethicists to reflect on their complicity in abusive power systems such as gender, race and class.

Background: Previous studies have suggested that sexuality following surgery for rectal cancer is better in women than in men and differs with type of surgery in terms of impact on Quality of Life. However, the findings were inconsistent. The aim of the presented study was to address these issues., Methods: 570 patients that had undergone surgery for rectal cancer in our department from 1992 to 1999 were included. After determination of survival status questionnaires on Quality of Life were sent to 370 patients one to two years post surgery. We analysed data from 215 patients of which 103 were female and 112 male. 248 patients died during the time observed. Statistical analysis was done with descriptive methods, Kaplan-Meier analysis (log rank test), T-test and analysis of variance using SPSS 11.0 for Windows., Results: Significant differences were seen in symptom scales between men and women. Women scored higher for distress through medical treatment and had higher values for insomnia, fatigue and constipation. Both sexes had impaired sexual life but men had significantly higher values and felt more distressed by the impairment of sexuality than women. For patients receiving abdominoperineal resection sexuality was most impaired. Anterior resection with pouch had a detrimental effect on diarrhoea and treatment strain., Conclusion: The study showed that sexuality is influenced by gender and type of surgery and impacts Quality of Life after surgery for rectal cancer. Assessing quality of life with generic and specific instruments is helpful to determine differences between surgical procedures, age, gender, and adjuvant therapy where standard parameters such as survival have their limitations.

The shape of a patient's face is commonly used as a reference to select the shape of the maxillary central incisors in edentulous patients. The validity of this relationship has not been proved. The objective of this clinical study was to determine whether a relationship exists between maxillary central incisors and face shapes. Casts were made of the maxillas of 50 men and 50 women. A standardized digital photographic procedure was used to record frontal views of each subject's face and of the maxillary central incisors of the dental casts. The shapes of the maxillary central incisors were compared with the face forms. Shape matches were evaluated according to their Hausdorff distance (HDD). The function h(A,B) is called the directed HDD from shape A to shape B (this function is not a true distance). It reflects the distance of the point of shape A that is farthest from any point of shape B and vice versa. The similarity of both shapes is given as a non-negative number. The value 0.0 indicates that the figures are identical (after scaling and shifting). Higher values indicate that shapes differ more substantially. Significant differences on the 5% level were calculated using the non-parametric Mann-Whitney U and Kruskal-Wallis tests. The face shape from the chin margin to the eyebrow line (superior edges of the eyebrows) produced a better match than the one from the chin to the hairline (P < 0.0001). On average, the maxillary central incisors displayed a variability (0.084 +/- 0.028) that was higher by a factor of 1.9 than the face shapes (chin margin to the eyebrow line, 0.045 +/- 0.015). In the interindividual comparison, the shapes of the maxillary central incisors of women displayed a significantly smaller HDD than the ones of the men (P < 0.0001).

Background: In Germany the prevalence of insect venom allergy in the population is about 5 %, 10-40 deaths are reported every year. With a success rate of 95 % venom immunotherapy (SIT) has a convincing protective effect. The purpose of this study was to investigate the safety of the original ultra-rush-protocol in children and reduce from 9 to 8 doses by avoiding a second application of 100 micro g insect venom., Methods: Nineteen children and adolescents with insect venom allergy were treated according to the modified ultra-rush-protocol. The first 5 children were hyposensitized according to the original protocol suggested by Brehler et al., the remaining 14 children (age 6-18 years) received only 8 injections (0.01/0.1/1/10/20/40/80/100 micro g). 5 patients were discharged on the second day four hours after the final application of 100 micro g insect venom., Results: Extensive reddening due to inflammation was found in injection spot in 5 patients. Four patients had an amplified wheal formation. No systemic reactions were observed. The maintenance therapy was well tolerated., Conclusion: The modified ultra-rush-protocol increases compliance by short inpatient stay. In addition the modified hyposensitization was sure and well tolerated.

Multiple sclerosis (MS), a disease of presumably autoimmune aetiology, is characterized by inflammation, demyelination and axonal degeneration in the central nervous system. Current treatment concepts target the inflammatory activity, reducing the number of relapses and inflammatory lesions on magnetic resonance imaging as well as the proinflammatory cytokine production in blood lymphocytes. Recently, the neuroprotective aspect of inflammation has been documented and is thought to be mediated by neurotrophins, like brain-derived neurotrophic factor (BDNF). The question whether the in vitro BDNF production in MS patients and healthy controls is influenced by the immunomodulatory agents interferon beta (IFN-beta) and immunoglobulin G (Ig) is addressed. A significantly increased BDNF production in MS patients was found compared with normal controls (mean +/- SD: 492 +/- 172 pg/mL versus 217 +/- 55 pg/mL, P < 0.001). IFN-beta and low-dose Ig had no effect on BDNF production, whereas high-dose Ig reduced in vitro BDNF production in MS patients significantly (to 409 +/- 125 pg/mL, P = 0.001). These in vitro findings might indicate that Igs in high doses potentially interfere with neuroprotective mechanisms despite their potent anti-inflammatory properties.

Background: Adjuvant chemotherapy for colon cancer has been established during the past decade. From 1990 until recently treatment with 5- fluorouracil (5-FU) and levamisole (LEV) lasting 12 months was recommended as standard treatment. At the initiation of this study in 1993 improvement of adjuvant therapy was expected by the modulation of 5-FU with folinic acid (FA). Therefore, we decided to perform a prospective randomized multicenter trial to compare standard 5-FU/LEV to 5-FU/FA for either 6 or 12 months., Patients and Methods: Patients with stage III colon cancer after curative en bloc resection were randomized in 3 treatment groups: arm A (5-FU/LEV, weekly, 12 months), arm B (5-FU/FA, days 1-5, every 4 weeks, 12 months) and arm C (like B, 6 months)., Results: Between March 1993 and November 1997, 180 patients were randomized into the study, 155 were eligible for further evaluation. The interim analysis in November 2000 showed no significant difference for recurrence and disease-free survival in arm B and C, therefore the data from both 5-FU/FA treatment arms (B+C) were combined for comparison with 5-FU/LEV-treatment (A). Most pronounced toxicity in all treatment arms was mild nausea, loss of appetite and leukopenia. A tendency for more diarrhea and stomatitis was observed in arm B+C. After a median follow-up of 36.2 months no significant difference was seen for disease free survival (p = 0.9) and overall survival (p = 1.0). 3-year recurrence rates were 39.6% in arm A and 39.1% in arm B+C, 3-year survival rates amounted to 74.1% in arm A and 74.9% in arm B+C., Conclusion: Only a limited number of patients could be recruited in this study. The observed data support the results of other studies, which concluded that 6 months (or 12 months) treatment with 5-FU/FA is equivalent to 12 months treatment with 5-FU/LEV. Therefore the 6 months treatment with 5-FU/FA can be supported as standard for adjuvant therapy of stage III colon cancer., (Copyright 2002 S. Karger GmbH, Freiburg)

Background: Postoperative radio-chemotherapy has been established as standard treatment for stage II and III rectal cancer patients in the last decade. To improve the efficacy of this therapy, we decided to evaluate continuous 24-hour infusion of 5-fluorouracil (5-FU) with folinic acid (FA) in combination with local radiation versus standard bolus 5-FU/FA with local radiation in a randomized study. Here we report on the first 28 patients to receive the experimental treatment., Patients and Methods: Patients with stage II and III rectal cancer received weekly 2-hour infusions of FA 500 mg/m2 followed by continuous 24-hour infusions of 5-FU 2,600 mg/m2 postoperatively via a Port-A-Cath system. The first cycle included 8 consecutive weekly administrations, the 1st-4th in full dose, the 5th-8th with 50% reduced dose while local irradiation (45 or 50.4 Gy) was performed. Thereafter, two further chemotherapy cycles (6 weekly administrations, 100% dose) followed., Results: 28 patients received continuous 5-FU/FA treatment, of whom only 21 were evaluable for tolerability. 19 patients (90.4%) completed the first cycle, only 14 patients entered the second treatment cycle. Especially during the combined radiochemotherapy, increased toxicity was observed with grade III/IV diarrhea (n = 2), nausea (n = 1), leukopenia (n = 1), and cardiac toxicity (n = 1)., Conclusion: The high rate of premature treatment dropout indicate that the chosen schedule of weekly high-dose 5-FU/FA continuous infusion and combined postoperative radiotherapy should not be recommended for further use in postoperative adjuvant treatment., (Copyright 2001 S. Karger GmbH, Freiburg)

Nitric oxide (NO) has been reported to activate Cl- secretion via the cystic fibrosis transmembrane conductance regulator (CFTR) and inhibit epithelial Na+ absorption mediated by amiloride-sensitive epithelial Na+ channels (ENaC). These ion transport systems are defective in cystic fibrosis (CF): Cl- secretion by CFTR is impaired and Na+ absorption by ENaC is dramatically increased. By activating CFTR and depressing ENaC, NO is a potentially beneficial therapeutic agent for ion transport defects in human CF respiratory epithelia. To assess the effects of NO on human respiratory epithelial cells, the NO donors sodium nitroprusside (SNP) and spermine NONOate were applied to primary cultured nasal cells, surgically obtained from non-CF and CF patients. Measurements of transepithelial short-circuit current (ISC) showed that NO has no inhibitory potency against amiloride-sensitive nasal ENaC (nENaC) or amiloride-insensitive Na+-absorbing mechanisms in non-CF and CF epithelia. Furthermore, NO had no stimulatory effect on Cl- secretion by CFTR or any other Cl- conductance pathway in either tissue. Although NO elevated the intracellular Ca2+ concentration, we did not detect any activation of Ca2+-dependent Cl- channels. These results demonstrate that NO has no beneficial effect on CF epithelial cells of the upper airways.

During a diagnostic CO2-hysteroscopy in general anesthesia, a manifest gas embolism with a resulting drop of the endexpiratory CO2 partial pressure occurred upon insertion of the instrument. By ending the procedure and through appropriate anesthesiological measures, the occurrence was brought under control and the embolism had no clinical consequences. The incidence encouraged us to reconsider the CO2-hysteroscopy examination technique. As a result, we describe an up to now neglected mechanism which may lead to air embolism in gas hysteroscopy: Similar to hysteroscopy with fluid distension, the whole system has to be purged from air by insufflating CO2 prior to examination. If this step is neglected, up to 40 cm3 of room air may be insufflated into the patient, considering a connective tubing of 200 cm length and 0.5 cm lumen. The scientific organisations as well as the endoscopic training centers and the manufacturers of hysteroflators are challenged to deal with this newly described potential cause of complications.

Cystic fibrosis (CF) is the most commonly inherited disease in Caucasians and is caused by a mutation in the gene encoding a membrane transport protein. This cystic fibrosis transmembrane conductance regulator (CFTR) is thought to be an apical Cl- channel activated by intracellular cAMP. Most recent findings suggest that CFTR is more than a pure Cl- channel and might be involved in the regulation of other transport systems. In the present study we show that CFTR as a Cl- channel plays only a minor role in primary cultured human nasal epithelium derived from non-CF and CF patients. These findings are especially of interest for non-CF human nasal epithelia in which CFTR is correctly inserted. In both tissues Cl- secretion is negligible as compared with Na+ absorption. We confirm and expand our previous observations that Na+ absorption in human nasal epithelium is the dominant ion transport process and that Cl- secretion is detectable in both CF and non-CF tissue. Moreover, we show that cAMP and ATP were not able to stimulate any silent Cl- channels in CF or non-CF human nasal epithelial cells. We further give evidence that in human nasal CF and non-CF epithelium Na+ absorption is mediated by epithelial Na+ channels (ENaC) that are either different from those of other epithelia or which exhibit altered regulation. These differences between Na+ channels of human nasal epithelium and "classical" epithelial Na+ channels include lack of activation by the intracellular second messenger cAMP and the steroid hormone aldosterone. We show further that human nasal Na+ channels are inhibited by Cl- channel blockers and exhibit a different pharmacology towards common Na+ channel blockers.

Na+ and Cl- currents were studied in primary cultures of human nasal epithelium derived from non-cystic fibrosis (non-CF) and cystic fibrosis (CF) patients. We found that Na+ absorption dominates transepithelial transport and the Na+ current contains an amiloride-sensitive and amiloride-insensitive component. In non-CF tissue both components contribute about equally to the entire short-circuit current (ISC), whereas in CF tissues the major part of the current is amiloride-sensitive. Na+ removal reduced ISC to values close to zero. Several Cl- channel blockers were used to identify the remaining tiny Na+-independent current. Under unstimulated, physiological conditions in the presence of Cl- on both sides and amiloride on the apical side of the epithelium diphenylamine-2-carboxic acid (DPC), 4,4'-diisothiocyanatostilbene-2, 2'- disulfonic acid (DIDS) and 5-nitro-2-(3-phenylpropylamino)-benzoic acid (NPPB) failed to induce clearcut inhibition of ISC. cAMP as well as ATP did not affect ISC either in CF or in non-CF epithelia. Reduction of apical Cl- increased ISC and depolarized transepithelial potential; however, the observed increase was insensitive to DIDS, DPC and NPPB. From these data we conclude that Cl- conductances in primary cultures of human nasal epithelium derived from CF patients as well as from non-CF patients are present only in low numbers or do not contribute significantly to transepithelial ion transport.

Objective: The aim of the present study was to investigate the efficacy of two frequently used physiotherapies (PTs) for the removal of bronchial secretions in cystic fibrosis (CF) lung disease: autogenic drainage (AD) and the Flutter (Desitin in Germany). AD is believed to improve mucus clearance from peripheral to central airways due to airway caliber changes in combination with a special breathing technique. The Flutter is an easy-to-use physiotherapy device based on oscillations of a steel ball during expiration through a pipe-type device., Materials and Methods: To evaluate the acute and chronic physiotherapy effects of these two techniques, 14 CF patients underwent either twice daily AD or Flutter treatment for 4 consecutive weeks in a randomized crossover design. Prior to each therapy interval, for a 1-week wash-out period, no PT was administered, but patients continued regular medication. At the beginning and end of each 4-week interval, pulmonary function was measured before and after an acute 30-min therapy. At the end of the PT session, sputum was collected, weighed, and deep frozen until analyzed. The viscoelasticity of the sputum was evaluated using a magnetic microrheometer., Results: No significant changes were noted for FVC, FEV1, or sputum volume throughout the study. Sputum viscoelasticity (rigidity index), however, was significantly lower (p<0.01) after therapy with the Flutter in comparison with AD, predicting improvements in mucociliary and cough clearability of the secretions. In a companion in vitro experiment, oscillations generated by passing humidified air over CF sputum lining an acrylic tube connected to a Flutter de-ice were found to decrease sputum elasticity, as measured by a filancemeter. These findings suggest that applied oscillations are capable of decreasing mucus viscoelasticity within the airways at frequencies and amplitudes achievable with the Flutter device, and provide direct evidence that PT can reduce the viscoelasticity of sputum.