Doxorubicin-induced cell death requires cathepsin B in HeLa cells.

The cysteine protease cathepsin B acts as a key player in apoptosis. Cathepsin B-mediated cell death is induced by various stimuli such as ischemia, bile acids or TNFα. Whether cathepsin B can be influenced by anticancer drugs, however, has not been studied in detail. Here, we describe the modulation of doxorubicin-induced cell death by silencing of cathepsin B expression. Previously, it was shown that doxorubicin, in contrast to other drugs, selectively regulates expression and activity of cathepsin B. Selective silencing of cathepsin B by siRNA or the cathepsin B specific inhibitor CA074Me modified doxorubicin-mediated cell death in Hela tumor cells. Both Caspase 3 activation and PARP cleavage were significantly reduced in cells lacking cathepsin B. Moreover, mitochondrial membrane permeabilization as well as the release of cytochrome C and AIF from mitochondria into cytosol induced by doxorubicin were significantly diminished in cathepsin B suppressed cells. In addition, doxorubicin associated down-regulation of XIAP was not observed in cathepsin B silenced cells. Lack of cathepsin B significantly modified cell cycle regulatory proteins such as cdk1, Wee1 and p21 without significant changes in G(1), S or G(2)M cell cycle phases maybe indicating further cell cycle independent actions of these proteins. Consequently, cell viability following doxorubicin was significantly elevated in cells with cathepsin B silencing. In summary, our data strongly suggest a role of cathepsin B in doxorubicin-induced cell death. Therefore, increased expression of cathepsin B in various types of cancer can modify susceptibility towards doxorubicin.

Consideration of online rainfall measurement and nowcasting for RTC of the combined sewage system.

In Berlin, Germany, the demand for enhanced protection of the environment and the growing economic pressure have led to an increased application of control concepts within the sewage system. A global control strategy to regulate the pumpage of the combined sewage system to the treatment plant was developed and evaluated in a theoretical study. The objective was to reduce CSO. In this paper an extension of the existing control algorithm by information from online rainfall measurement and radar nowcasting is described. The rainfall information is taken into account by two additive terms describing the predicted volume from rainfall runoff. On the basis of numerical simulation the potential of these two complementary forecast terms in the global control algorithm to further reduce CSO is evaluated. The investigations are based on long-time simulations that are conducted with the dynamic flow routing model InfoWorks for three subcatchments of the Berlin drainage system. The results show that at the current Berlin system a CSO reduction of only 0.8% is possible. The effect of the forecast terms is limited by operational constraints. Limits are set to both, the delivery from each individual pump station and the total pumpage to the treatment plant.

Association analysis of the functional monoamine oxidase A gene promoter polymorphism in psychiatric disorders.

Functional characterization studies revealed that transcriptional activity of the human monoamine oxidase A (MAOA) gene is modulated by a polymorphic repetitive sequence located approximately 1.2 kb upstream of the ATG codon. To investigate the possible influence of the allelic variants of the MAOA gene-linked polymorphic region (MAOA-LPR) on the genetic predisposition to psychiatric disorders, we have performed a case-control association study. 174 patients with affective disorders and 258 patients with schizophrenia according to DSM-IV, as well as 229 population controls were tested. Statistical analysis showed no significant differences in allele or genotype frequencies between control and patient groups. Our results suggest that there is no association between MAOA-LPR genotype and susceptibility to recurrent major depression, bipolar disorder, and schizophrenia in our population.

Paleonutritional analysis of the pre-Hispanic population from Fuerteventura (Canary Islands).

In this study, from histological and chemical perspectives, we analyse the human remains belonging to the pre-Hispanic inhabitants from Fuerteventura (one of the Canary Islands) and compare the results with those obtained on a sample of pre-Hispanic inhabitants from Gran Canaria (Canary Islands). We observe that trabecular bone mass was normal in the samples from Fuerteventura except for an elderly woman; this result is in sharp contrast with the decreased bone mass observed in the population from Gran Canaria. The pre-Hispanic population from Fuerteventura showed lower bone strontium, Sr/Ca ratio, and bone barium, but slightly higher bone copper, than that from Gran Canaria. All these data indicate a greater consumption of marine products by the population of Fuerteventura. The high prevalence of osteoporosis observed in the population from Gran Canaria may be interpreted as a consequence of protein-calorie malnutrition, a condition which seemed to be not so prevalent in the population of Fuerteventura.

Psychological correlates of opioid use in patients with chronic nonmalignant pain: a preliminary test of the downhill spiral hypothesis.

There is still controversy surrounding the use of opioid medication for patients with chronic nonmalignant pain. Schofferman has argued that long-term opioid use leads to a "downhill spiral" associated with loss of functional capacity and a corresponding increase in depressed mood. The present study was a retrospective comparison of opioid users vs. non-users to determine whether: (a) users have higher levels of disability, medical visitation, depression, and pain; (b) the behavioral problems associated with opioid use persist after controlling for the influence of other medication; (c) opioid use is in fact a predictor of illness behavior; and (d) higher levels of opioid consumption are associated with higher levels of disability and depression. A consecutive series of 243 patients with nonmalignant pain about to enroll at a tertiary clinic were retrospectively assigned to either an Opioid User (n = 87) or Non-User (n = 156) group. Compared to Non-Users, Opioid Users were more likely to be physically disabled ( P <0.05) and depressed ( P<0.05), as well as more likely to report pain at higher levels (P<0.001) and in more locations ( P<0.05). Despite the appearance of a downhill spiral, we were unable to demonstrate an association between opioid use and any measure of illness behavior after controlling for benzodiazepine use (with the possible exception of domestic disability). Instead, we found that benzodiazepine use was significantly associated with activity level ( P<0.05), medical visitation ( P<0.01), domestic disability ( P<0.01), depression ( P <0.01), and to a lesser degree, disability days (P<0.1). Using somatization as a reference variable, we found that opioid use failed to explain a comparable amount of variance in illness behavior. Finally, there was no evidence that higher levels of opioid use were associated with higher levels of disability or depression.

Arctic ozone loss due to denitrification

Measurements from the winter of 1994-95 indicating removal of total reactive nitrogen from the Arctic stratosphere by particle sedimentation were used to constrain a microphysical model. The model suggests that denitrification is caused predominantly by nitric acid trihydrate particles in small number densities. The denitrification is shown to increase Arctic ozone loss substantially. Sensitivity studies indicate that the Arctic stratosphere is currently at a threshold of denitrification. This implies that future stratospheric cooling, induced by an increase in the anthropogenic carbon dioxide burden, is likely to enhance denitrification and to delay until late in the next century the return of Arctic stratospheric ozone to preindustrial values.

Decreased mivacurium requirements and delayed neuromuscular recovery during sevoflurane anesthesia in children and adults.

UNLABELLED: The purpose of this study was to compare the mivacurium infusion requirements and neuromuscular recovery in adults and children during propofol/opioid and sevoflurane anesthesia. Seventy-five adult and 75 pediatric patients were randomized to receive propofol/opioid 0.5 or 1.0 minimum alveolar anesthetic concentration (MAC) (age-related) sevoflurane anesthesia. Plasma cholinesterase (PChE) activity was measured. Neuromuscular blockade was monitored by train-of-four (TOF) stimulation every 10 s and adductor pollicis electromyography. A bolus of 2 x the 95% effective dose of mivacurium (0.25 mg/kg) was followed by an infusion titrated to maintain 90%-95% blockade. Mivacurium doses were recorded every 5 min. At the end of surgery, the infusion was stopped, and recovery from mivacurium was monitored until TOF > or =0.7. PChE concentrations were within the normal range (adults 4-12 KU/L, children 6-16 KU/L) and correlated with mivacurium dose. Mivacurium infusion rates were higher in children than in adults: at 30 min, the rates in children were 13.1 +/- 6.4, 8.1 +/- 4.7, and 5.2 +/- 2.9 microg x kg(-1) x min(-1) at 0, 0.5, and 1.0 MAC sevoflurane, respectively; the corresponding rates in adults were 5.9 +/- 3.1, 4.3 +/- 1.7, and 2.9 +/- 0.7 microg x kg(-1) x min(-1) (P < 0.01). Sevoflurane decreased mivacurium requirements, maximal decreases at 45 min in children and 10 min in adults, and delayed neuromuscular function recovery. Children recovered twice as quickly as adults, achieving TOF > or =0.7 at 9.8 +/- 2.5, 11.4 +/- 2.8, and 19.6 +/- 6.3 min compared with 19.9 +/- 5.4, 26.4 +/- 8.3, and 32.9 +/- 9.8 min in adults (P < 0.0001). In conclusion, mivacurium requirements were correlated with PChE, were greater in children than in adults, and were reduced by sevoflurane. Neuromuscular recovery occurred more rapidly in children and was delayed by sevoflurane. IMPLICATIONS: The mivacurium infusion requirement to maintain constant 90%-95% neuromuscular block during anesthesia is correlated with plasma cholinesterase activity. It is increased in children and reduced by the inhaled anesthetic sevoflurane. Despite the larger dose administered to children, recovery from block occurred more rapidly in children than in adults and was delayed by sevoflurane.

The effectiveness of clonidine as an analgesic in paediatric adenotonsillectomy.

PURPOSE: To compare the analgesic effects of preoperative oral clonidine with intraoperative intravenous fentanyl in children undergoing tonsillectomy or adenotonsillectomy. METHODS: This randomized, controlled, double-blind study of 36 ASA I-II children, age 7-12 yr undergoing adenotonsillectomy was conducted at a tertiary care paediatric teaching hospital. Either 4 micrograms.kg-1 clonidine po was given 60-90 min preoperatively or 3 micrograms.kg-1 fentanyl i.v. was given intraoperatively. Postoperatively visual analog pain scores (VAS) were recorded at rest and on swallowing every 10 min for the first 30 min and then every 15 min for two hours. Morphine 0.05 mg.kg-1 i.v. was given for VAS > or = 5. If > 3 doses were required, 1.5 mg.kg-1 codeine po and 20 mg.kg-1 acetaminophen po were given. Sedation and anxiety scores were recorded preoperatively. Haemodynamic changes, blood loss, recovery scores, and the incidence of vomiting, hypotension, and airway obstruction were recorded. RESULTS: Children who received clonidine had a higher incidence of preoperative sedation (63%) than those receiving fentanyl (6%). Preinduction mean arterial pressure was lower in the clonidine group but required no intervention. VAS scores were similar throughout the observation period. There was no difference either in the number of morphine or codeine rescue doses administered or in the incidence of side effects. CONCLUSION: Oral clonidine is an effective analgesic and sedative for children undergoing tonsillectomy or adenotonsillectomy.

Dose responses for neostigmine and edrophonium as antagonists of mivacurium in adults and children.

BACKGROUND: Reversal of neuromuscular blockade induced with pancuronium, d-tubocurarine, or doxacurium is achieved using smaller doses of neostigmine in adults than in children. Also, pancuronium- and doxacurium-induced blockade is reversed with smaller doses of edrophonium in children than in adults. The purpose of this study was to compare the spontaneous and neostigmine- and edrophonium-assisted recovery of mivacurium-induced neuromuscular block in adults and children. METHODS: Fifty-four adults, aged 40.1 +/- 10.9 yr, and 54 children, aged 4.9 +/- 0.7 yr, physical status ASA 1-2, were studied during propofol/fentanyl/nitrous oxide anesthesia. A Datex relaxograph was used to monitor the electromyographic response of the adductor pollicis to train-of-four stimulation of the ulnar nerve every 10 s. After induction of anesthesia, 0.2 mg x kg(-1) intravenous mivacurium was administered followed by an infusion to maintain 90-95% T1 block. At the end of surgery, one of four doses of neostigmine (5, 10, 20, and 50 micrograms x kg(-1)) or edrophonium (100, 200, 400, and 1,000 micrograms x kg(-1)) or placebo was given, by random allocation, when T1 had recovered to 10%. Values of T1 and train-of-four were measured for 10 min. RESULTS: Spontaneous recovery proceeded more rapidly in children than in adults. At 10 min, T1 had recovered to 97 +/- 2% (SD) in children compared with 69 +/- 11% in adults and train-of-four to 84 +/- 5% versus 30 +/- 13% (P<0.0001). In children, 10 min after reversal, recovery of T1 and train-of-four was not different from control after edrophonium and was enhanced only by the larger doses of neostigmine. In adults, recovery was accelerated by both edrophonium and neostigmine. Five minutes after reversal, recovery was improved by either drug in adults and in children. CONCLUSIONS: Spontaneous recovery from mivacurium- induced neuromuscular block is more rapid in children than in adults. Ten minutes after attempted reversal, recovery is accelerated by edrophonium and usually by neostigmine in adults but not in children. Thus, when reversal is required, edrophonium may be preferred to neostigmine.

Residual block after mivacurium with or without edrophonium reversal in adults and children.

BACKGROUND: The rapid recovery from mivacurium- induced neuromuscular block has encouraged omission of its reversal. The purpose of this study was to determine, in children and in adults, whether failure to reverse mivacurium neuromuscular block was associated with residual neuromuscular block on arrival in the postanesthesia care unit. METHODS: In 50 children, aged 2-12 yr, and 50 adults, aged 20-60 yr, anesthesia was induced and maintained with propofol and fentanyl, and neuromuscular block was achieved by an infusion of mivacurium, to maintain one or two visible responses to train-of-four (TOF) stimulation of the ulnar nerve. At the end of surgery, mivacurium infusion was stopped, and 10 min later, reversal was attempted with saline or 0.5 mg x kg(-1) edrophonium by random allocation. On arrival in the postanesthesia care unit, a blinded observer assessed patients clinically and by stimulation of the ulnar nerve with a Datex electromyogram in the uncalibrated TOF mode. RESULTS: Children arrived in the postanesthesia care unit 8.2 +/- 3-4 min after reversal of neuromuscular block and showed no sign of weakness, either clinically or by TOF stimulation. Although TOF ratio was greater in children who had received edrophonium (1.00 +/- 0.05 vs. 0.93 +/- 0.01, P<0.01), TOF was >0.7 in all children. Adults arrived in the postanesthesia care unit 12.9 +/- 5.3 min after reversal of neuromuscular block(P<0.01 vs. children). Six in the saline group demonstrated weakness (two required immediate reversal of neuromuscular block, and TOF was <0.7 in four others), compared with TOF <0.7 in only one of the edrophonium group (P<0.05). CONCLUSIONS: This study demonstrated that, in adults, failure to reverse mivacurium neuromuscular block was associated with an increased incidence of residual block. Such weakness was not observed in children receiving similar anesthetic and neuromuscular blocking regimens.

Reversal of doxacurium and pancuronium neuromuscular blockade with neostigmine in children.

Recovery after doxacurium and pancuronium neuromuscular blockade and their acceleration by neostigmine have not been compared in children. Therefore, 60 paediatric surgical patients aged 2-10 yr (ASA 1-2) were studied. They were randomized to receive doxacurium 30 micrograms.kg-1 or pancuronium 70 micrograms.kg-1 iv during propofol, fentanyl, isoflurane and nitrous oxide anaesthesia. Electromyographic (EMG) responses of the adductor pollicis to train-of-four (TOF) stimulation of the ulnar nerve were recorded every ten seconds using a Datex NMT monitor. Six patients in each relaxant group received neostigmine (0, 5, 10, 20 or 40 micrograms.kg-1) with atropine by random allocation when first twitch height (T1) had recovered to 25% of control. Spontaneous recovery after ten minutes was similar following doxacurium (mean +/- SEM values of 45.0 +/- 3.9 vs 49.5 +/- 10.0% for T1 and 25.2 +/- 3.8 vs 14.8 +/- 3.6% for TOF ratios). Dose-responses to neostigmine were calculated from the log dose vs logit of T1 or TOF ratio after ten minutes. Neostigmine-assisted recovery was not different in the two groups, with ED70 and ED90 doses for T1 of 14.3 +/- 1.8 and 25.7 +/- 2.7 micrograms.kg-1 for doxacurium and 12.5 +/- 1.7 and 25.3 +/- 2.3 micrograms.kg-1 for pancuronium. Time to recovery of TOF ratio to 70% after neostigmine 40 micrograms.kg-1 was 2.3 +/- 1.0 and 4.2 +/- 1.7 min (P = NS) following pancuronium and doxacurium, respectively. Adjusted recovery due to neostigmine alone (spontaneous recovery subtracted from the total) required two to three times higher doses of neostigmine.(ABSTRACT TRUNCATED AT 250 WORDS)

Propofol anaesthesia reduces early postoperative emesis after paediatric strabismus surgery.

Propofol anaesthesia may reduce postoperative emesis. The purpose of this study was to compare the incidence of emesis after propofol anaesthesia with and without nitrous oxide, compared with thiopentone and halothane anaesthesia, in hospital and up to 24 hr postoperatively, in outpatient paediatric patients after strabismus surgery. Seventy-five ASA class I or II, unpremedicated patients, aged 2-12 yr were randomly assigned to one of three groups: Thiopentone, 6.0 mg.kg-1 i.v. induction followed by halothane and N2O/O2 for maintenance (T/H); propofol for induction, followed by propofol and oxygen for maintenance (P/O2); and propofol for i.v. induction, followed by propofol infusion and N2O/O2 for maintenance (P/N2O). All received vecuronium, controlled ventilation, and acetaminophen pr. Morphine was given as needed for postoperative analgesia. There were no differences in age, weight, number of eye muscles operated upon, duration of anaesthesia or surgery. The P/N2O group (255 +/- 80 micrograms.kg-1 x min-1) received less propofol than the P/O2 group (344 +/- 60 micrograms.kg-1 x min-1) (P < or = 0.0001) and had shorter extubation (P < 0.001) and recovery (P < 0.01) times. Emesis in the hospital, in both the P/N2O (4.0%) and P/O2 group (4.0%) was less than in the T/H group (32%) (P < 0.01). Antiemetics were required in four patients in the T/H group (16.0%). Overall emesis after surgery was not different among the groups: T/H (48%), P/O2 (28%) and P/N2O (42%). The use of propofol anaesthesia with and without N2O decreased only early emesis. This supports the concept of a short-acting, specific antiemetic effect of propofol.

EDTA treatment of intermittent claudication--a double-blind, placebo-controlled study.

A double-blind, randomized multicentre study was undertaken to evaluate the possible effect of chelation treatment with ethylenediamine-tetraacetic acid (EDTA) in patients with severe intermittent claudication. A total of 153 patients received 20 intravenous infusions of either 3 g Na2EDTA or placebo during a period of 5-9 weeks. Vitamin, mineral and trace element supplements were administered orally. The changes observed in the pain-free and maximal walking distances, measured on a treadmill, were similar in the two groups. During the 3-month (n = 149) and 6-month (n = 123) follow-up period, no long-term therapeutic effect of EDTA could be demonstrated. The ankle-brachial blood pressure index remained unchanged throughout the study period. This study failed to demonstrate any effect of EDTA chelation treatment in intermittent claudication.

Low-dose bupivacaine does not improve postoperative epidural fentanyl analgesia in orthopedic patients.

Epidural infusions of 10 micrograms/mL fentanyl combined with low-dose bupivacaine (0.1%) were compared with epidural infusions of fentanyl alone for postoperative analgesia after total knee joint replacement. There were no detectable differences between the two groups in analgesia (visual analogue scale ranging between 15 and 40 mm), infusion rates (which averaged 7-9 mL/h), or serum fentanyl levels (which reached 1-2 ng/mL). The incidence of side effects, including nausea, vomiting, and pruritus, was also similar. Of the patients receiving fentanyl and low-dose bupivacaine, one developed a transient unilateral motor and sensory loss, and one developed significant hypotension and respiratory depression. The addition of low-dose bupivacaine does not improve epidural fentanyl infusion analgesia after knee surgery and may increase morbidity.

[Femoro-popliteal bypass surgery in Denmark 1983-1987]. / Femoro-popliteal bypass-kirurgi i Danmark 1983-1987.

In a retrospective study of femoro-popliteal bypass surgery in Denmark during the period 1983 to 1987, a total of 1,532 operations were performed. Approximately 2/3 of the patients were operated upon for limb salvage, the remainder for severe disabling claudication. The perioperative lethality was below two per cent in all departments. Early occlusion rate was found to be between 21 and 11 per cent, leading to major amputation in about half of the patients.

[Femoro-crural reconstruction in Denmark 1983-1987]. / Femoro-krurale rekonstruktioner i Danmark 1983-1987.

From 1983 to 1987, 293 femoro-crural bypasses were performed in eight centers for vascular surgery in Denmark. The activity increased in the period from 15 to 135 bypasses per year. The increase took place particularly 1986, when the in situ saphenous vein bypass was introduced in Denmark. A total of 203 bypasses were performed at the University Hospital of Copenhagen, Rigshospitalet: 108 in situ bypasses, 51 bypasses with arterial protheses and 44 bypasses using reversed vein. The cumulated graft patency after one year was 76% for the in situ bypasses, 26% for the bypasses with arterial protheses and 32% for reversed vein. The cumulated limb survivals after one year were 90%, 66% and 63%, respectively.

[Surgical treatment of abdominal aorta aneurysm 1983-1987. A multicenter study. 1266 operations, development and early results]. / Operative behandling af abdominalt aorta-aneurysme 1983-1987. Multicenterundersøgelse. 1,266 operationer, udvikling og tidlige resultater.

During the years 1983-1987, 1,266 operations for abdominal aortic aneurysm (AAA) were carried out in eight surgical departments with vascular surgical function. The activity increased constantly corresponding to 311 patients in 1987 or 50% more than in 1983. During this period the distribution between patients subjected to elective operation and those operated upon as emergencies was very uniform. In the latter group, only a slight increase in the number of AAA patients with rupture was observed. The risk of complications was low with a significant decrease in the need for dialysis. The early mortality was constant for the patients subjected to elective operation remained constant about 5.5%. A marked decrease in the early mortality was observed for the patients operated upon as emergencies with rupture from 63 to 50% and without rupture from 37 to 25%. At the conclusion of the period, ultrasonic scanning became the preoperative investigation of election and introduction of an aortic prosthesis the method of operation of election. Patients with AAA should be recognized so that elective surgery can be offered before a condition endangering life develops.

[Vascular surgery in Denmark]. / Karkirurgi i Danmark 1983-1987.

This report presents vascular surgical operations performed in Denmark 1983-1987, the first five years after the establishment of the speciality. The number of vascular surgical operations increased by 18 per cent during the five years to nearly 2,000 operations in 1987. Approximately 50 per cent of all vascular procedures were intraabdominal operations, while 30 per cent were peripheral reconstructions. In 1987 40 operations/100,000 inhabitants were made, a level considerably below the activity performed in the other Scandinavian countries. We conclude that vascular surgical activity will increase in Denmark in the years to come.

[Hemangioendothelial sarcoma of the thyroid]. / Haemangioendoteliosarkom i glandula thyreoidea.

Haemangioendothelial sarcoma in the thyroid gland is a very rare disease in regions where goitre is not endemic. The case history of a man aged 65 years who had previously enjoyed good health who developed this disease is reviewed as regards diagnosis, treatment and course of the condition and this emphasizes the poor prognosis in this condition.