Functional characterization of the ectopically expressed olfactory receptor 2AT4 in human myelogenous leukemia.

The olfactory receptor (OR) family was found to be expressed mainly in the nasal epithelium. In the last two decades members of the OR family were detected to be functional expressed in different parts of the human body such as in liver, prostate or intestine cancer cells. Here, we detected the expression of several ORs in the human chronic myelogenous leukemia (CML) cell line K562 and in white blood cells of clinically diagnosed acute myeloid leukemia (AML) patients by RT-PCR and next-generation sequencing. With calcium-imaging, we characterized in greater detail the cell biological role of one OR (OR2AT4) in leukemia. In both cell systems, the OR2AT4 agonist Sandalore-evoked strong Ca(2+) influx via the adenylate cyclase-cAMP-mediated pathway. The OR2AT4 antagonist Phenirat prevented the Sandalore-induced intracellular Ca(2+) increase. Western blot and flow cytometric experiments revealed that stimulation of OR2AT4 reduced the proliferation by decreasing p38-MAPK phosphorylation and induced apoptosis via phosphorylation of p44/42-MAPK. Furthermore, Sandalore increased the number of hemoglobin-containing cells in culture. We described for the first time an OR-mediated pathway in CML and AML that can regulate proliferation, apoptosis and differentiation after activation. This mechanism offers novel therapeutic options for the treatment of AML.

[Off-label use of drugs in pediatric emergencies: limitations and grey areas of drug approval]. / Off label use von Notfallmedikamenten im Kindesalter: Grenzen und Grauzonen der Medikamentenzulassung.

In the medical treatment of children drugs are frequently used outside the boundaries of the approved licensing and use under the terms of off-label use is possible. However, this requires critical reasoning and experience with the drug involved. With help of a traffic light colored spreadsheet this article illustrates the limitations, problems and possibilities of pharmacotherapy in pediatric emergencies or pediatric anesthesia. Of the 45 emergency drugs listed in this article most can be used in childhood, at least under specific conditions. Licensing restrictions occur especially in the newborn period and infancy resulting in frequent off-label use. Severe pitfalls, such as the propofol infusion syndrome after long-term sedation with propofol under the age of 16 years, emphasize the need for serious reflection on the substances involved. Decisions regarding pharmaceutical therapy should be based on the current standard of medical knowledge. When official recommendations from pharmaceutical companies are missing, treatment decisions for off-label use can be based on guidelines, study and literature databases or recommendations in medical journals.

[Tools for drug dosing in life-threatening pediatric emergencies]. / Hilfsmittel für die Dosierung von Notfallmedikamenten im Kindesalter.

Life-threatening pediatric emergencies are rare events in which precise, correct and fast drug dosing is essential. Intravenous drugs are most commonly dosed based on the child's weight in mg/kg. Numerous tools exist for aiding the physician in the error prone calculation, none of which meet all criteria for the perfect tool. Besides frequent training of practical skills and awareness of the problem of calculating the exact drug dose, it seems indispensable to have a localized tool at hand for these critical events.

[Cessation of anesthesia after newly occurring anisocoria without light reflexes]. / Abbruch der Anästhesie bei neu aufgetretener Anisokorie mit fehlenden Lichtreflexen.

Anisocoria during general anaesthesia is rare. The combination of anisocoria and absence of any reaction to light is highly suspicious of an intracerebral lesion. This article reports the case of a patient with known Adie's syndrome where anisocoria led to an unnecessary immediate interruption of anesthesia. A preoperative examination, including inspection of the pupils, frequent perioperative check ups and documentation of diagnostic findings, even if negative, has to be standard for every anesthesia.

[Future-oriented design of ambulatory surgery. Organizational aspects and medical options]. / Zukunftsorientierte Gestaltung des ambulanten Operierens. Organisationsaspekte und medizinische Möglichkeiten.

Ambulatory surgery continues to grow and is slowly becoming routine in the majority of cases. Although the development of ambulatory surgery in Germany appears to be somewhat delayed, this is actually a chance to learn from worldwide experiences and avoid the mistakes others made earlier. This article investigates current trends and developments in day case surgery and discusses the extended role and influence of the anesthetist in the perioperative setting.

Intraoperative thrombolysis in a patient with cardiopulmonary arrest undergoing caesarean delivery.

Thromboembolic events during pregnancy remain a major cause of morbidity and mortality with possible catastrophic sequelae for the patient. The decision whether to use high-risk therapeutic thrombolytics during pregnancy or perinatally is complicated and many considerations pertain. We report on the thrombolytic management of a 34-year-old woman who had an asystolic cardiac arrest secondary to massive pulmonary embolism while undergoing emergency caesarean delivery. The patient was thrombolysed during successful cardiopulmonary resuscitation. Return of spontaneous circulation was accompanied by massive uterine bleeding. Instead of performing a postpartum hysterectomy, the uterus was preserved through continuous manual pressure and packing for four hours by the obstetric team until haemostasis was achieved. The patient survived and was later discharged without any major neurological deficit.

Continuous spinal anesthesia versus continuous femoral nerve block for elective total knee replacement.

BACKGROUND: Continuous spinal analgesia (CSA) and continuous femoral nerve blockade (CFNB) are well-established procedures for postoperative pain relief. This study compares the efficacy, adverse effects and complications associated with these two analgesic methods in patients undergoing total knee arthroplasty (TKA). METHODS: Data were analyzed from consecutive patients undergoing TKA under either CSA or spinal anesthesia plus CFNB. Quality of analgesia was assessed based on opioid consumption and pain intensity (visual analogue scale [VAS] where 0=no pain and 10=utmost imaginable pain) until postoperative day 4. In addition, joint mobility was assessed, and any adverse reactions or side effects were noted. RESULTS: Sixty-two patients had satisfactory postoperative pain relief, and maximum pain scores were reported between 12 and 24 hrs. Median pain scores in the CSA group were significantly lower than those in the CFNB group (1.0 [0.9-1.9] vs. 2.0 [1.5-3.6] for resting pain and 2.0 [1.7-3.1] vs. 5.0 [3.0-5.5] for dynamic pain, respectively; P<0.001 for days 0 and 1; P<0.05 for all other days). Piritramide consumption was significantly higher in the CFNB group (P<0.01). There were no significant differences between the groups for postoperative mobility of the joint or patient satisfaction. CONCLUSION: Both methods demonstrated analgesic efficacy after total knee arthroplasty, although there was less pain severity and opioid consumption use reported with continuous spinal analgesia. However, the use of continuous spinal analgesia is limited by concerns about the risk profile and absence of approved devices for continuous intrathecal infusion.

[Scoliosis surgery in children from the viewpoint of anaesthesiology]. / Skoliosechirurgie bei Kindern aus anästhesiologischer Sicht.

Anaesthesia for scoliosis surgery in children is a challenge for the paediatric anaesthesiologist. The large range of underlying pathologies causing deranged physiology in an inhomogeneous patient group ranging from neonates to adolescents necessitates diligent and individual preparation for each case. Due to the invasiveness of the operation demanding anaesthetic care is necessary. This review highlights current approaches to monitoring, anaesthetic regimen, positioning of the patient, blood conservation and transfusion, age-related pathophysiology, ventilation and postoperative pain therapy. The introduction of neurophysiologic spinal cord monitoring requires certain adaptations of the anaesthetic regimen to suit technological advances.

Continuous spinal analgesia or opioid-added continuous epidural analgesia for postoperative pain control after hip replacement.

BACKGROUND AND OBJECTIVE: Continuous spinal anaesthesia and continuous epidural anaesthesia are both able to provide adequate postoperative pain relief. Combining local anaesthetics and opioids results in synergistic effects. The purpose of this randomized, prospective study was to compare quality of analgesia, side-effects and patient's satisfaction between spinal bupivacaine alone and epidural bupivacaine with sufentanil postoperatively. METHODS: Fifty-nine patients scheduled for hip arthroplasty were randomly assigned either to Group 1 receiving continuous spinal anaesthesia or Group 2 receiving continuous epidural anaesthesia. Postoperatively, those in Group 1 received a 1 mL bolus followed by a continuous infusion of 10 mL/24 h of bupivacaine 0.25 %. Those in Group 2 received a 5 mL bolus of lidocaine 2%, followed by a continuous infusion of bupivacaine 0.25% with sufentanil 0.001 mg mL(-1) at 4 mL h(-1). Pain was measured using a verbal rating score and a visual analogue scale. RESULTS: Group 1 and Group 2 of 43.3% and 37.9% reported complete analgesia on the verbal rating score. No statistically significant difference was found in the visual analogue scale. Nausea and vomiting occurred significantly more often in Group 2. The patient satisfaction rates did not differ significantly. CONCLUSIONS: Continuous spinal analgesia with bupivacaine alone and continuous epidural analgesia with bupivacaine/sufentanil are both effective for postoperative pain relief after hip replacement. Those patients in the epidural group reported better analgesia but had a higher rate of postoperative nausea and vomiting. Efficacy of pain therapy did not correlate with patient satisfaction.

NH tautomerism in the natural chlorin derivatives.

The NH tautomerism of five Mg-free chlorophyll a and b derivatives 2-6 was studied utilizing NMR spectroscopy and molecular modeling. The results from the dynamic NMR measurements of the chlorins revealed that substituent effects contribute crucially to the free energy of activation (DeltaG(double dagger)) in the NH tautomeric processes. An intermediate tautomer for the total tautomeric NH exchange in a chlorin was observed for the first time, when the (1)H NMR spectra of chlorin e(6) TME (3) and rhodin g(7) TME (4) (TME = trimethyl ester) were measured at lower temperatures. The lower energy barriers (DeltaG(1)(double dagger)) obtained for the formation of the intermediate tautomers of 3 and 4, assigned to the N(22)-H, N(24)-H trans-tautomer, were 10.8 and 10.6 kcal/mol, respectively. The energy barrier (DeltaG(2)(double dagger) value) for the total tautomeric NH exchange in the five chlorins was found to vary from 13.6 kcal/mol to values higher than 18 kcal/mol. The lowest DeltaG(2)(double dagger) value (13.6 kcal/mol) was obtained for rhodochlorin XV dimethyl ester (2), which was the only chlorophyll derivative lacking the C(15) substituent. In the case of chlorins 4 and 5, the steric crowding around the methoxycarbonylmethyl group at C(15) raised the DeltaG(2)(double dagger) activation free-energy to 17.1 kcal/mol. However, the highest energy barrier with DeltaG(2)(double dagger) > 18 kcal/mol was observed for the NH exchange of pyropheophorbide a methyl ester (6), possessing the macrocycle rigidifying isocyclic ring E. Our results demonstrate that the steric strain, arising either from the steric crowding around the bulky substituent at C(15) or the macrocycle rigidifying isocyclic ring E, slows down the NH tautomeric process. We suggest that deformations in the chlorin skeleton are closely connected to the NH tautomeric exchange and that the exchange occurs by a stepwise proton-transfer mechanism via a hydrogen bridge.

Treatment of pain in trauma patients with injuries of the upper limb.

Since preoperative pain therapy of a trauma patient did not play an outstanding role in the past, this article shall give information about the adequate treatment of such patients, which can be mainly divided into three phases: the prehospitalisation phase with stabilisation of the trauma patient, the early phase of hospitalisation with further stabilisation, diagnosis and surgery, and finally the postoperative phase with corresponding treatment. An optimal analgesic in the prehospitalisation phase should guarantee good analgesic effects, rapid onset and good controllability, simple handling and the opportunity to combine it with other medication. In addition, it should prevent a wide therapeutic range and the absence of side effects. Opioids and ketamine are available for acute pain therapy after trauma. The main opioids used are piritramide and pethidine, with piritramide acting as a sedative at the same time and with pethidine preventing the stronger analgesic effect. The intravenous use of ketamine has become established in trauma patients because of its excellent analgesia at subanaesthetic doses. Especially in multiple trauma patients, the indication for general anaesthesia with intubation should be established on a liberal basis. Nevertheless, for some patterns of injury regional techniques may be advantageous; therefore, this article describes the possible regional procedures (such as intravenous regional anaesthesia or block of peripheral nerves). Concerning the postoperative phase, an individual pain management can be guaranteed by systemic pharmacotherapy and regional catheter techniques, for example the brachial plexus blockade that results in a long period of free pain.

Effects of the phlebotropic drug Daflon 500 mg on postischemic microvascular disturbances in striated skin muscle: an intravital microscopic study in the hamster.

The objective of this study was to investigate the effects of the micronized purified flavonoid fraction Daflon 500 mg (90% diosmin and 10% hesperidin) on I/R-induced microvascular leukocyte-endothelium interaction and leakage of the high molecular weight plasma tracer FITC-dextran (relative molecular mass, 150 kd) as assessed in the striated skin muscle of the dorsal skin fold chamber model in the hamster. Intravital fluorescence microscopy was used for analysis of microvascular perfusion, leukocyte-endothelium interaction, and macromolecular leakage of FITC-dextran 150 kd in the striated skin muscle of the hamster. A tourniquet ischemia of 4 hours' duration was induced followed by reperfusion. Animals were treated with an oral administration of Daflon 500 mg (n = six) or its vehicle (5% Arabic gum solution, n = six) for 8 days at a daily dose of 30 mg/kg body weight. Measurements in the microcirculation were made before the 8-day feeding protocol before induction of ischemia and at 0.5, 2, and 24 hours of reperfusion. In the absence of I/R, no differences in microvascular perfusion, leukocyte-endothelium interaction, and macromolecular leakage were found in Daflon 500 mg and vehicle-treated control animals before and after administration of the drugs. Induction of ischemia and reperfusion, however, elicited a significant increase in venular leukocyte rolling and sticking in vehicle-treated animals, which was accompanied by enhancement of leakage of FITC-dextran 150 kd into the perivascular tissue. Treatment with Daflon 500 mg had no effect on postischemic leukocyte rolling and sticking, and macromolecular leakage of FITC-dextran 150 kd from arterioles and postcapillary venules was significantly reduced. These data indicate that Daflon 500 mg preserves the endothelial barrier function of striated skin muscle arterioles and venules after I/R, which appears to be independent of an action on postischemic intravascular leukocyte rolling and sticking.

Effects of the phlebotropic drug Daflon 500 mg on postischemic reperfusion injury in striated skin muscle: a histomorphologic study in the hamster.

The objective of this study was to investigate the effects of the purified, micronized, flavonoid fraction Daflon 500 mg (S 5682, 90% diosmin and 10% hesperidin) on tissue damage and leukocyte emigration in striated skin muscle after ischemia-reperfusion, as assessed by histomorphometric analysis. The experimental model used was the transparent dorsal skin fold chamber in the awake Syrian golden hamster. Sixty-four animals were randomly allotted to two treatment groups and time points of investigation. Animals were fed with 30 mg kg(-1) body weight Daflon 500 mg (n = 32) or its vehicle, 5% Arabic gum solution (n = 32), as control 8 hours before ischemia. Before induction of a tourniquet ischemia of 4 hours' duration and at 0.5, 2, and 24 hours of reperfusion, tissue sections were preserved for light and electron microscopic analysis (n = seven or eight animals per time point). The number of intravascular and extravascular leukocytes was determined by light microscopic analysis of esterase-positive leukocytes. For quantitative analysis of ischemia-induced endothelial cell damage, the endothelial thickness of capillaries was calculated by a computer-assisted imaging system, whereas the ischemic tissue damage was assessed by means of a score system (grade 0-3) by an independent investigator. The number of emigrated leukocytes was significantly reduced in Daflon 500 mg-treated animals compared with numbers found in control animals. The histomorphologic muscle fiber damage increased after reperfusion in both groups but was significantly reduced in the Daflon 500 mg-treated animals 2 and 24 hours after reperfusion. These results suggest that the emigration of leukocytes plays an important role in the development of postischemic reperfusion injury of striated skin muscle.

Continuous spinal anaesthesia or continuous epidural anaesthesia for post-operative pain control after hip replacement?

Both continuous spinal anaesthesia and continuous epidural anaesthesia are supposed to provide adequate post-operative pain relief. The purpose of this randomized, prospective study was to compare the quality of analgesia, occurrence of side effects and patient satisfaction between spinal and epidural administration of bupivacaine during the first post-operative 72 h. One hundred and two patients scheduled for hip arthroplasty were randomly assigned to one of two groups: Group 1 received continuous spinal anaesthesia for intra-operative and post-operative management, Group 2 received continuous epidural anaesthesia. Immediately after surgery, the continuous spinal anaesthesia-group received a 1-mL bolus (bupivacaine 0.25%), followed by a continuous infusion of 10 mL over 24 h. The continuous epidural anaesthesia-group received a 10-mL bolus (bupivacaine 0.25%), followed by 2 mL h-1. The level of pain was gauged from a verbal rating score and from a visual analogue scale; the degree of motor blockade was recorded using the Bromage score. In the continuous spinal anaesthesia-group 90.2% reported complete analgesia on the verbal rating scale, but only 21.6% of the continuous epidural anaesthesia-group did. The visual analogue scale scores given by the continuous spinal anaesthesia-group were significantly lower than those of the continuous epidural anaesthesia-group. The percentage of patients with a motor block was significantly higher in the continuous spinal anaesthesia-group on the day of surgery and at the first post-operative day. During the first 24 h, nausea and vomiting occurred more often in the continuous epidural anaesthesia-group. The satisfaction was considered excellent in 92.2% of the continuous spinal anaesthesia-group and in 70.6% of the continuous epidural anaesthesia-group. It is concluded that continuous spinal anaesthesia and continuous epidural anaesthesia are effective and safe for post-operative pain relief after hip replacement. Compared with continuous epidural anaesthesia, continuous spinal anaesthesia provides faster onset of pain relief, ensures better analgesia and results in more satisfied patients.

No risk of metal toxicity in combined spinal-epidural anesthesia.

UNLABELLED: Using the single level needle-through-needle technique for combined spinal-epidural anesthesia (CSE) may introduce very fine metal particles abraded by the spinal needle from the inner ground edge of the Tuohy needle into the patient. Either the local anesthetic administered epidurally or the peridural catheter may also pass intrathecally through the hole in the dura made by the spinal needle. To examine these concerns, the needle-through-needle technique was simulated in an in vitro model (18-gauge Tuohy needle; 27- or 29-gauge Quincke needle). The presence of abraded metal particles was identified by atomic absorption spectrography (AAS). The needles were then examined under an electron microscope. Metal particles could not be identified by using AAS in the needle-through-needle technique after normal clinical use, nor could traces of use be revealed by using an electron microscope to examine the Tuohy needle. With intentionally rough handling and caudal orientation of the spinal needle tip, minimal scratches could be seen by using an electron microscope, but there were no metal particles detected by AAS. In an anatomical preparation, the possible passage of the epidural catheter anesthetic through the dural puncture hole into the cerebrospinal fluid compartment was investigated endoscopically. Neither passage of dyed epidural local anesthetic nor penetration of the epidural catheter into the cerebrospinal fluid compartment could be demonstrated by endoscopy. We conclude that the needle-through-needle-technique is an acceptable way of performing CSE anesthesia. Endangering the patient by an unintentionally intrathecal misplacement of the epidural catheter seems to be very unlikely based on our in vitro model if small spinal needles (27- or 29-gauge) are used. IMPLICATIONS: Atomic absorption spectrography shows no contamination of the intrathecal compartment by abraded metal particles from the Tuohy needle by combined spinal-epidural anesthesia with the needle-through-needle technique. In vitro, neither passage of dyed epidural local anesthetic nor penetration of the epidural catheter into the cerebrospinal fluid compartment could be demonstrated by endoscopy.

In vitro investigation of cerebrospinal fluid leakage after dural puncture with various spinal needles.

UNLABELLED: Postspinal headache is one of the most common complications of spinal anesthesia and has repeatedly led to controversy concerning needle size and configuration. In an in vitro investigation, we measured cerebrospinal fluid (CSF) leakage with Sprotte, Whitacre, Quincke, and Atraucan needles under physiological conditions in human dura. The puncture characteristics were examined under an electron microscope. The pencil-point needles show 2-3 times less leakage of CSF compared with the cutting Quincke needles of corresponding size. Between the Sprotte and the Whitacre needles, there were no significant differences. The least loss of CSF occurred with the 26-gauge Atraucan needle. Under the electron microscope, a sharply delineated, persistent perforation channel was shown with the Quincke needles, which may explain the high CSF loss. With pencil-point needles, which push the tissue apart bluntly, a large opening on the inside is found, with some tearing of the dura. However, in contrast to the cutting needles, a persistent perforation channel is not manifested. The 26-gauge Atraucan needle, which both cuts and pushes apart conically, shows a relatively discrete opening on the inside, with slight tears in the dura and arachnoidea but without a visible perforation channel. The results of our study show that larger needles (26-gauge Atraucan) that are easier to handle can lead to good and, in some cases even better, puncture results if they have characteristics of both the cutting and the pencil-point needles. IMPLICATIONS: We compared several brands of pencil-point and standard cutting spinal needles of varying sizes. All pencil-point needles had less cerebrospinal fluid leakage, the least loss occurring with 26-gauge Atraucan needles. Electron microscopic examination of the dura after puncture showed characteristic findings with each needle type. We conclude that the combined cutting and pencil-point characteristics seen in the Atraucan needle may have clinical advantages.