MiR-205-driven downregulation of cholesterol biosynthesis through SQLE-inhibition identifies therapeutic vulnerability in aggressive prostate cancer.

Prostate cancer (PCa) shows strong dependence on the androgen receptor (AR) pathway. Here, we show that squalene epoxidase (SQLE), an enzyme of the cholesterol biosynthesis pathway, is overexpressed in advanced PCa and its expression correlates with poor survival. SQLE expression is controlled by micro-RNA 205 (miR-205), which is significantly downregulated in advanced PCa. Restoration of miR-205 expression or competitive inhibition of SQLE led to inhibition of de novo cholesterol biosynthesis. Furthermore, SQLE was essential for proliferation of AR-positive PCa cell lines, including abiraterone or enzalutamide resistant derivatives, and blocked transactivation of the AR pathway. Inhibition of SQLE with the FDA approved antifungal drug terbinafine also efficiently blocked orthotopic tumour growth in mice. Finally, terbinafine reduced levels of prostate specific antigen (PSA) in three out of four late-stage PCa patients. These results highlight SQLE as a therapeutic target for the treatment of advanced PCa.

[Change in therapy target and therapy limitations in intensive care medicine. Position paper of the Ethics Section of the German Interdisciplinary Association for Intensive Care and Emergency Medicine]. / Therapiezieländerung und therapiebegrenzung in der intensivmedizin. Positionspapier der Sektion Ethik der Deutschen Interdisziplinären Vereinigung für Intensiv- und Notfallmedizin.

The task of physicians is to maintain life, to protect and re-establish health as well as to alleviate suffering and to accompany the dying until death, under consideration of the self-determination rights of patients. Increasingly more and differentiated options for this are becoming available in intensive care medicine. Within the framework of professional responsibility physicians must decide which of the available treatment options are indicated. This process of decision-making is determined by answering the following question: when and under which circumstances is induction or continuation of intensive care treatment justified? In addition to the indications, the advance directive of the patient is the deciding factor. Medical indications represent a scientifically based estimation that a therapeutic measure is suitable in order to achieve a defined therapy target with a given probability. The ascertainment of the patient directive is achieved in a graded process depending on the state of consciousness of the patient. The present article offers orientation assistance to physicians for these decisions which are an individual responsibility.

Blood gas partition coefficient and pulmonary extraction ratio for propofol in goats and pigs.

The interpretation of continuously measured propofol concentration in respiratory gas demands knowledge about the blood gas partition coefficient and pulmonary extraction ratio for propofol. In the present investigation we compared both variables for propofol between goats and pigs during a propofol anaesthesia. In ten goats and ten pigs, expired alveolar gas and arterial and mixed venous blood samples were simultaneously drawn during total intravenous anaesthesia with propofol. The blood gas partition coefficient and pulmonary extraction ratio were calculated for both species. Non-parametric methods were used for statistical inference. The blood gas partition coefficient ranged between 7000 and 646,000 for goats and between 17,000 and 267,000 for pigs. The pulmonary extraction ratio ranged between 32.9% and 98.1% for goats and was higher for pigs, which ranged between -106.0% and 39.0%. The blood gas partition coefficient for propofol exceeded those for other known anaesthetic compounds so that it takes longer to develop a steady-state. The different pulmonary extraction rates in two species suggest that there are different ways to distribute propofol during the lung passage on its way from the blood to breathing gas. This species-specific difference has to be considered for methods using the alveolar gas for monitoring the propofol concentration in plasma.

Propofol concentration in exhaled air and arterial plasma in mechanically ventilated patients undergoing cardiac surgery.

BACKGROUND: Measuring propofol concentration in plasma (c(P)PL) and in exhaled alveolar gas (c(P)G) during constant infusion provides information about their respective time courses. In the present study, we compared these time courses in patients undergoing cardiac surgery from the beginning of propofol anaesthesia until eye opening upon awakening. METHODS: The c(P)G was measured before, during, and after continuous infusion of propofol for general anaesthesia in 12 patients at two randomly allocated doses (3 or 6 mg kg(-1) h(-1)). Gas samples were collected on Tenax tubes. After thermodesorption, c(P)G was measured by gas chromatography mass spectrometry. Simultaneously with exhaled gas, arterial blood was sampled for measuring c(P)PL by reversed-phase high-performance liquid chromatography with fluorescence detection. In order to compare the time courses of c(P)PL and c(P)G as dimensionless values directly, each gas and plasma value was normalized by relating it to the corresponding value at the end of the initial infusion after 40 min. RESULTS: The c(P)G ranged between 2.8 and 22.5 ppb, whereas the corresponding c(P)PL varied between 0.3 and 3.3 microg ml(-1). Normalized concentration values showed a delayed increase in c(P)G compared with c(P)PL under constant propofol infusion before the onset of cardiopulmonary bypass, and a delayed decrease after stopping the propofol at the end of anaesthesia. CONCLUSIONS: Propofol can be measured in exhaled gas from the beginning until the end of propofol anaesthesia. The different time courses of c(P)PL and c(P)G have to be considered when interpreting c(P)G.

Patient mood and neuropsychological outcome after laparoscopic and conventional colectomy.

The study was designed to compare patients after laparoscopic and conventional colectomy with regard to early postoperative mood, cognitive function, and neurocognitive variables S100beta and neuron-specific enolase (NSE). Forty-five laparoscopic and 25 open colectomies were enrolled into the prospective study. Outcome measurements were positive and negative postoperative mood (BSKE), neuropsychological tests (Trail-Making Test; word reproduction; Stroop Test), and serum biochemical parameters (S100beta; NSE). Following laparoscopic procedure, patients described significantly better positive mood (P< .05), tended to require less time in the Trail-Making Test and Stroop Test, and had lower postoperative serum concentrations of S100beta compared to conventional colectomy patients (P< .01). The current results revealed several group differences, which, in their entirety, seem to represent a more beneficial outcome after laparoscopic colonic surgery.

[Confusion Assessment Method for the Intensive Care Unit (CAM-ICU): diagnosis of postoperative delirium in cardiac surgery]. / Confusion Assessment Method for the Intensive Care Unit (CAM-ICU): diagnostik des postoperativen delirs bei kardiochirurgischen Patienten.

OBJECTIVE: Since 2001 the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU), a method for the diagnosis of delirium, has been available for the Anglo American area which can also be applied to mechanically ventilated patients. This study was conducted to answer the following questions: 1. Can a German version of the CAM-ICU be applied to patients after cardiac surgery? 2. What is the prevalence rate of postoperative delirium after cardiac surgery diagnosed by the CAM-ICU? 3. Do patients with and without the diagnosis delirium differ in the clinical variables usually associated with this disorder in cardiac surgery? METHODS: A total of 194 patients undergoing cardiac surgery served as the analysis sample (85.5% of the total group). The CAM-ICU was carried out every day for 5 days after the operation. Sociodemographic and clinical variables were collected to examine the validity of CAM-ICU. Postoperative complaints were assessed by the Anaesthesiological Questionnaire for Patients (ANP). RESULTS: Postoperatively, the CAM-ICU could be applied to almost all patients without any problems. The prevalence rate of delirium was 28.4% and 85.5% of the delirium diagnosed was a hypoactive subtype when diagnosed for the first time. Patients with delirium diagnosed by CAM-ICU were older (p<0.001), had a lower educational level (p<0.05), longer anaesthesia time and operation time (p<0.05), a longer postoperative ICU stay (p<0.001), were mechanically ventilated for a longer time postoperatively (p<0.001), more often reintubated (p<0.01) and had higher leucocytes postoperatively (p<0.10). More patients with delirium had the lowest postoperatively measured oxygen saturation below 95% (p<0.01). CONCLUSION: The CAM-ICU is an economic method for the assessment of delirium which can easily be learned. It can be applied to patients after cardiac surgery without any problems.

["We must relate to ourselves". Substance, causality, and narrative text]. / "Wir müssen uns erzählen". Substanz, Kausalität, narrativer Text.

Since Aristotle the concept of "substance" has described those features of an object which remain constant over time despite varying additional stochastic factors (coincidences). "Causality" places several or more chronological events into a direct relationship. The change of stochastic factors on a substance always has a causal justification. Based on these metaphysical considerations the present contemplations will apply the concept of substance to people. The causal explanation for changes during the lifetime is achieved by narrative sentences. These are, therefore, decisive for the maintenance of the identity of individuals and collectives despite all time-linked changes. The conclusion is reached that speech and thought processes based on speech patterns are essential for humans.

Quality of life in elderly men with androgen deficiency.

The partial androgen deficiency in aging male (PADAM) has been of great interest to investigators and the public in the last few years. For males, androgens are said to be essential for the maintenance of quality of life (QoL) but there are no data available with respect to QoL and PADAM yet. In order to evaluate changes of individual well-being of males older than 50 years and with subnormal levels of free testosterone (FT) (<200 pmol l(-1)), these men were asked to fill in a questionnaire regarding QoL. The objective of this study was to compare age-matched males with androgen deficiency (group 1; n = 24) and normoandrogenic elderly men (group 2; n = 24) with respect to QoL and somatic indicators of the endocrine status. Participants suffered from benign prostatic hyperplasia (BPH) and were hospitalized for prostate surgery. Health-related QoL was assessed by the SF-12 Health Survey, including the physical health index and the mental health index. The SF-12 was enlarged by the scales 'vitality' and 'psychological well-being' of the SF-36. Additionally, patients were asked about social and clinical items. There were no statistically significant differences between the two groups regarding social and clinical parameters. The physical health index was reduced in group 1 (P < 0.05; effect size was medium (d = 0.57)) whereas the mental health index was similar in both groups. The correlation between the two health indices was very low and not statistically significant (r = 0.05, P = 0.72). Patients of group 1 described a lower vitality compared to group 2 (P < 0.05), but no differences could be observed regarding psychological well-being. Therefore, androgen-deficient patients seem to have the impression of a reduced physical ability. Our data emphasize that the subjective description of health-related aspects of QoL is a very sensitive methodological approach to discover psychological differences between patients. For the differentiation between androgen-deficient patients and those with normal testosterone levels the physical health index seems to be more sensitive than the mental health index. A question of interest is whether this difference remains detectable if testosterone is supplemented to androgen-deficient men. Whether testosterone supplementation is beneficial to these patients has to be carefully considered.

Effects of intra-aortic balloon counterpulsation on parameters of tissue oxygenation.

BACKGROUND AND OBJECTIVE: To investigate the effects of intra-aortic balloon pump therapy on parameters of global and regional oxygenation in patients undergoing cardiac surgery. METHODS: As part of a large surveillance study in cardiac surgery patients (n=266) we retrospectively analyzed the course of 28 patients requiring intra-aortic balloon pump therapy. Patients were grouped according to the time point of pump insertion (during weaning from cardiopulmonary bypass: group early intra-aortic balloon pumping (n=17); after admission to the intensive care unit: group late intra-aortic balloon pumping (n=9). Haemodynamic and tonometric variables, arterial lactate, and use of catecholamines were measured hourly. MEASUREMENTS AND RESULTS: Cardiac index increased in both groups after intra-aortic balloon pump insertion (2.2+/-0.5 baseline; 3.4+/-0.8 L min-1 m-2 4 h later (group early intra-aortic balloon pumping); 2.8+/-0.5 baseline, 3.6+/-L min-1 m-2 4 h later (group later intra-aortic balloon pumping), each P<0.05), there were no differences between groups. Arterial lactate values increased in group later intra-aortic balloon pumping after pump insertion to a maximum 2 h later (8.4+/-6.1 mmol L-1 baseline; 12.7+/-7.4 mmol L-1, P<0.05), and decreased continuously afterwards. The difference of arterial and gastric CO2 showed a sharp decrease after pump insertion in group later intra-aortic balloon pumping (26.4+/-9.8 baseline; 7.0+/-11.1 mmHg, P<0.05). There were no differences between groups. Epinephrine doses were higher in group later intra-aortic balloon pumping (P<0.05). CONCLUSIONS: Intra-aortic balloon pump therapy improved global and regional splanchnic oxygenation in cardiac surgery patients with low-cardiac-output syndrome. Gastro-intestinal tonometry could provide additional information concerning tissue oxygenation. Patients with later intra-aortic balloon pump insertion needed more catecholamine therapy to achieve similar haemodynamic values.

[Psychological traits, course of surgery and recovery following hernia repair in patients preferring general or local anaesthesia]. / Psychologische Persönlichkeitsmerkmale, Operationsverlauf und Genesung bei Patienten mit Präferenz für Allgemein- oder Lokalanästhesie: Untersuchung an Patienten mit Leistenhernienoperation.

OBJECTIVE: This study addresses two questions concerning open inguinal hernia repair patients: (1) are there differences in psychological traits between patients opting for local vs. general anaesthesia and (2) assuming comparable operations, are there any differences between the two groups during surgery and postoperative recovery? METHODS: A total of 69 male patients aged between 18 and 80 took part in the study. After having been briefed about anaesthesia, they opted for either local (n=40) or general anaesthesia (n=29). In order to determine psychological traits, patients filled out questionnaires before the operation [NEO Five-Factor-Inventory (NEO-FFI) and the Stress Coping Questionnaire (SVF)] and the Anaesthesiological Questionnaire (ANP) after the operation. Data about the surgery (duration of anaesthesia and operation, blood pressure and heart rate) and the convalescence period (time spent in recovery room, length of stay in hospital) were also recorded. The patients' information processing skills were measured preoperatively and postoperatively using the "Trail Making Test". RESULTS: Patients preferring local anaesthesia were significantly older than those who chose general anaesthesia. Therefore two similar age groups were formed by using the method of matched samples (n=2x26). Between these groups no significant differences were found with reference to psychological traits, but markedly extraverted patients favoured local anaesthesia. There were no differences in the duration of anaesthesia and surgery. Local anaesthesia patients spent less time in the recovery room and in hospital than general anaesthesia patients. Postoperatively, the cognitive state and the satisfaction with the anaesthesia were comparable between both groups. CONCLUSION: Psychological traits do not have a significant impact on the choice of either local or general anaesthesia. However, highly extraverted patients prefer local anaesthesia while extreme introverts prefer general anaesthesia. Our findings suggest that local anaesthesia will become more widely adopted for the repair of groin hernia. Future studies should focus on optimising the perioperative care for patients who choose local anaesthesia.

Post-dural puncture headache in young adults: comparison of two small-gauge spinal catheters with different needle design.

BACKGROUND: To reduce the risk of post-dural puncture headache (PDPH) in continuous spinal anaesthesia, small-gauge spinal catheter systems with different techniques of dural perforation have been developed. METHODS: Two systems, the catheter through-needle technique (MicroCatheter, Portex, UK) and the catheter over-needle technique (22G Spinocath, B. Braun, Germany), were used in 18 young healthy volunteers (age 18-30 yr), who were enrolled in a neuroendocrinological investigation for analysis of neuropeptides in cerebrospinal fluid (CSF). After intermittent sampling of CSF (17 x 0.5 ml over 4 h), the catheter was removed and the development of PDPH and pain intensity were documented prospectively by the subjects in a standardized headache assessment (11-point numerical rating scale [NRS]). RESULTS: The study revealed a high overall incidence of PDPH (78%) with no significant differences between groups (P=0.26). However, the over-needle group showed a significantly shorter duration of PDPH (2.4 [SD 2.3] vs 5.1 [3.1] days, P=0.050) and lower maximum pain intensity (3.1 [2.9] vs 7.3 [3.4] NRS, P=0.014) than the through-needle group. CONCLUSIONS: The results demonstrate a potential benefit of the catheter over-needle technique for the reduction of the duration and intensity of PDPH.

[Risk factors for back pain in children and adolescents]. / Risikofaktoren für Rückenschmerzen bei Kindern und Jugendlichen in Industrienationen.

Factors that have led to the increasing prevalence of back pain amongst children and adolescents living in industrialized nations are mostly unknown. The following literature review was aimed at determining the risk factors for back pain amongst children and adolescents. We searched both PUBMED and MEDLINE between the years 1985 and 2003 for the keywords "children or adolescents" and "back pain". Only data published in original articles were used. The risk for suffering back pain is influenced by physical, behavioural, emotional and social factors. The effects of physical activity, sitting, muscle status, weight of schoolbags, exercise, television and computer use, as well as age and gender on the development of back pain in children and adolescents were examined. Associations between continuous or recurring back pain and psychosocial factors (lifestyle, emotional factors, social relationships) could be demonstrated. There was no relationship between changes of the spine seen by radiological tests and the development of chronic back pain. Longitudinal epidemiological studies are urgently needed to delineate the risk factors for the development as well as the natural history of chronic back pain in the young.

[100 years of Draeger Medical Technology (1902 - 2002) -- working for the applicability of oxygen]. / 100 Jahre Dräger-Medizintechnik (1902 - 2002) - oder: im Zentrum steht der Sauerstoff... Zur Bedeutung der Druckgastechnik für die Begründung der modernen Sauerstofftherapie und der Anästhesiologie.

This survey analyses the history of 100 years of Draeger Medical Technology. Between 1889 and 1902 a number of inventions on the field of pressure gas technology allowed to solve application problems, which until then proved major obstacles to the safe and efficient use of compressed gases such as oxygen, nitrous oxide or carbon dioxide for medical and industrial purposes. A special significance is to be awarded here to pressure reducing valves, but also reliable manometers, nozzles and valves for pressure tanks were not generally available until then. These were first successfully and on a really significant scale introduced into international medical and non-medical pressure-gas technology by Draeger Inc. (Luebeck/Germany), and proved particularly successful in anaesthesia and rescue-devices (e. g. in the "Roth-Draeger Anaesthesia Apparatus" (1902). Consequently, starting in 1902, Draeger Inc. increasingly put an emphasis on developing medical and rescue technology and -- by doing so -- gained an important influence on the history of the implementation of modern oxygen therapy and of inhalative anaesthesia. A survey of the historically most important Draeger-Developments is provided.

Mental competence and surrogate decision-making towards the end of life.

German legislation demands that decisions about the treatment of mentally incompetent patients require an 'informed consent'. If this was not given by the patient him-/herself before he/she became incompetent, it has to be sought by the physician from a guardian, who has to be formally legitimized before. Additionally this surrogate has to seek the permission of a Court of Guardianship (Vormundschaftsgericht), if he/she intends to consent to interventions, which pose significant risks to the health or the life of the person under his/her care. This includes 'end-of-life decisions'. Deviations from this procedure are only allowed in acute emergencies or cases of 'medical futility'. On the basis of epidemiological and demographical data it can be shown that the vast majority of surrogate decisions on incompetent patients in Germany is not covered by legally valid consent. Moreover, the data suggests that if consent were to be requested according to the legal regulations, both the legal and medical system could realistically never cope with the practical consequences of this. Additionally, empiric research has revealed serious deficits concerning medical 'end of life-decisions' and practical performance in palliative care. As a consequence a multidisciplinary discussion has developed in Germany about the reform of present legislation with respect to key-issues like the assessment of mental competence, the options for exercising patient self-determination via advance directives and durable powers of attorney, the improvement of palliative care facilities, the clarification of formal procedures for surrogate decision-making in health care and towards the end of life and the possibilities and their limitations of controlling these decision-making processes 'externally' (e.g., by Guardianship Courts or committees). The authors discuss those proposals, which clearly dominate the present debate: They all aim to comply with the scientific basis of German law, jurisdiction and the European traditions of philosophy of health care and bioethics.