Environmental exposure assessment of ethinyl estradiol (EE) from a combined hormonal vaginal contraceptive ring after disposal; leaching from landfills.

In this study an environmental exposure assessment and experiments were carried out to identify the leaching potential of ethinyl estradiol (EE) present in a vaginal contraceptive (NuvaRing) when disposed of in landfills. Landfill material and a sandy soil were used to investigate the mobility of EE. Log K(oc) values determined in the range of 3 to 4 indicate that EE does not have a high mobility in landfills and soils. Column experiments were used to estimate that it takes approximately 40 years before EE leaches from a column of 1 m of landfill material or sandy soil. This column experiment, which was performed with an EE concentration based on worst-case assumptions, demonstrates that the emission of EE from landfills is negligible. Sandy soils below landfills also act as a strong sorbent of EE, thereby further reducing the potential for groundwater contamination.

Antidepressants affect amine modulation of neurotransmission in the rat hippocampal slice--I. Delayed effects.

The effects of long-term treatment with the antidepressant drugs, desipramine (DMI) and mianserin (MIA) on neurotransmission in the hippocampal slice were studied by examining the actions of serotonin (5-HT), isoprenaline and (+/-)-baclofen on the population spike in the pyramidal cell layer, recorded in area CA1. The decrease in amplitude of the population spike by 5-HT (1-10 microM) was facilitated by long-term treatment with DMI but not significantly with MIA. Both DMI and MIA depressed the excitatory action of isoprenaline (0.3 microM), whereas the inhibitory responses to (+/-)-baclofen (0.3-3 microM) were unaffected. The results show that significant changes in serotonergic and beta-adrenergic neurotransmission can be demonstrated ex vivo after in vivo treatment with antidepressants and that these changes partly substantiate data measured in vivo.

Antidepressants affects amine modulation of neurotransmission in the rat hippocampal slice--II. Acute effects.

Treatment with single doses of the antidepressant drugs, desipramine (DMI) and mianserin (MIA) was performed 2.5 and 8 hr, respectively, before the start of the experiment in order to approximate the amount of drugs still present in the brain 24 hr after the last injection of a long-term treatment. The effects of this treatment with single doses of DMI and MIA on neurotransmission in the hippocampal slice, were studied by examining the actions of serotonin (5-HT), isoprenaline and (+/-)-baclofen on the population spike of the pyramidal cell layer, recorded in area CA1. The inhibitory responses to 5-HT (1-10 microM) and (+/-)-baclofen (0.3-3 microM) were not affected by treatment with either antidepressant drug. Single doses of DMI but not of MIA, attenuated the excitatory responses to isoprenaline (0.1-1 microM). These results suggest that the present study with single doses provides information to help in the understanding of delayed adaptive changes induced by antidepressants and that the DMI-induced decrease in the beta-adrenergic response in the hippocampus is not limited to long-term treatment.

The pharmacological profile of Org 6906, a potential non-sedative antidepressant that combines monoamine uptake inhibition with alpha 2-adrenolytic activity.

(dl)-(5 alpha,8 alpha,9 alpha)-5,8,9,10-Tetrahydro-5,9- methanobenzocycloocten-8-amine hydrochloride (Org 6906) is a potential new antidepressant agent, with a neurochemical profile quite different from that of the classical tricyclic antidepressant drugs. The compound was found active in behavioural tests which are considered to be predictive for antidepressant activity, such as the muricidal test in the rat and the acquired immobility model. Neurochemical studies showed that Org 6906 was an inhibitor of the reuptake of monoamines both in vitro and ex-vivo without having appreciable anticholinergic, antihistaminergic or alpha 1-adrenolytic activity. The facilitatory effect on monoaminergic neurotransmission was confirmed by the reversal of hypothermia induced by reserpine. The drug Org 6906 appeared to have selective alpha 2-adrenolytic properties. It facilitated potassium-stimulated release of noradrenaline from slices of cortex, displaced [3H]rauwolscine and [3H]dihydroergocryptine from their binding sites but only weakly blocked alpha 1-adrenoceptors. The alpha 2-adrenolytic properties were also apparent in behavioural interaction models. The compound antagonized the sleep-inducing effects of clonidine in chicks and mice and it antagonized the mydriasis induced by clonidine in the rat. Finally, it was shown that the two enantiomers of Org 6906 contributed almost equally to the relevant neurochemical and behavioural properties.

Quaternary naloxone enhances acquisition of a discriminated Y-maze escape and a one-way active avoidance task in mice.

Methylnaloxonium, a quaternary form of naloxone that does not readily cross the blood brain barrier, enhanced acquisition of a Y-maze shock escape and a one-way active avoidance response in mice in doses that did not affect shock-induced locomotor activity in an open field. Since methylnaloxonium is a opioid antagonist, it is likely that the observed enhancement of learning is due to the drug preventing endogenous opioid peptides from reaching their receptors. The results therefore suggest that manipulation of peripheral opioid systems alters the strength of a conditioned response.

In vitro interaction of ACTH with rat brain muscarinic receptors.

ACTH-(1-24) inhibits the in vitro binding of the muscarinic antagonist [3H]QNB to membranes from rat brain. The magnitude of inhibition is dependent on the concentration of ACTH-(1-24). Kinetic analysis indicates a pure competitive inhibition which is suggestive of a reversible interaction of ACTH with muscarinic receptors. A mechanism involving an interaction of ACTH-(1-24) with the phospholipid core of the receptors is suggested. Structure activity studies point to a relation with reported effects of intracerebroventricularly administered ACTH on the turnover rate of acetylcholine and the ACTH-induced stretching and yawning syndrome.

Gentamycin reduces bacteremia and mortality rates associated with the treatment of experimental peritonitis with recombinant tissue plasminogen activator.

BACKGROUND: Recombinant tissue plasminogen activator (rtPA), administered intraperitoneally, reduces intra-abdominal abscess formation in rats with fecal peritonitis at the costs of increased mortality and early Escherichia coli bacteremia. It was determined whether or not mortality and bacteremia could be prevented by gentamycin in these rats. STUDY DESIGN: Fecal peritonitis was induced by intraperitoneal injection of sterile feces contaminated with 10(8) (experiment 1) or 10(4) (experiment 2) colony forming units (cfu) E. coli and 10(4) cfu Bacteroides fragilis. Male Wistar rats were randomly assigned to receive either methyl hydroxy propyl cellulose (MHPC) gel alone (M) or 0.5 mg/mL rtPA dissolved in MHPC gel (M-tPA). Three hours after inoculation, one-half of the rats in each of these groups received 6 mg/kg gentamycin sulfate (G) intramuscularly (group M-G and M-tPA-G). At one, three, six, 12, and 24 hours after inoculation, blood cultures were taken. At five days after inoculation, intra-abdominal abscess formation was assessed and abscesses were cultured (experiment 2). RESULTS: All rats in groups M and M-tPA in experiment 1 developed bacteremia and died within 24 hours. Bacteremia occurred significantly earlier in group M-tPA compared with group M (p < 0.05). Gentamycin significantly reduced the number of rats with bacteremia, the bacteria concentration in the blood, and mortality rates. Although in experiment 2 none of the rats developed bacteremia, gentamycin prevented mortality associated with the use of rtPA. The number of abscesses in groups M-tPA and M-tPA-G was significantly lower than in those in groups M and M-G (p < 0.01). Gentamycin did not influence the number of abscesses. CONCLUSIONS: Gentamycin reduces bacteremia and mortality rates in rats with fecal peritonitis treated with rtPA intraperitoneally to prevent intra-abdominal abscess formation.

Effect of recombinant tissue plasminogen activator on intra-abdominal abscess formation in rats with generalized peritonitis.

BACKGROUND: During generalized peritonitis, intraabdominal fibrin deposition is stimulated whereas fibrinolytic activity is reduced, which predisposes intra-abdominal abscess formation. We investigated the effects of increasing the intra-abdominal fibrinolytic activity on abscess formation by intra-abdominal administration of recombinant tissue plasminogen activator (rt-PA). Potential side effects, such as bacteremia and bleeding, were also assessed. STUDY DESIGN: A rat model of generalized peritonitis, induced by intraperitoneal injection of sterile feces contaminated with 10(4) cfu per mL Escherichia coli (E. coli) and 10(4) cfu per mL Bacteroides fragilis, was used. RESULTS: Rats treated with rt-PA dissolved in methyl hydroxy propyl cellulose (MHPC) gel (0.5 mg per mL), had significantly less intra-abdominal abscesses than rats in the control group, treated with either Ringer's lactate solution or MHPC gel alone (p < 0.01). Other than E. coli, cultures of abscesses revealed species originating from the intestine, demonstrating bacterial translocation. The mortality rate was significantly higher in the rats treated with rt-PA as compared with rats in the control group (p < 0.01), which was surprising considering the absence of bacteremia. By challenging the rats with a higher dose of E. coli, early bacteremia was observed in the rats treated with rt-PA, not related to increased mortality rates. Intraabdominal use of rt-PA was not associated with an increased incidence of bleeding events. CONCLUSIONS: Recombinant tissue plasminogen activator prevents abscess formation in rats with generalized peritonitis. However, early bacteremia and increased mortality rates are serious drawbacks of the intra-abdominal use of rt-PA in this rat model.

Differential interactions of muscarinic drugs with binding sites of [3H]pirenzepine and [3H]quinuclidinyl benzilate in rat brain tissue.

Some atypical muscarinic drugs were compared with classical drugs with respect to inhibition of specific binding of [3H]pirenzepine ([3H]PZ) and [3H]quinuclidinyl benzilate ([3H]QNB) to membrane preparations of rat brain. The interactions of the agonists McN-A343 and carbachol with [3H]QNB at muscarinic sites in brain stem preparations were differently modulated in the presence of an excess of PZ. Moreover, McN-A343 exhibited a preferential affinity for [3H]PZ sites in whole brain membranes whereas carbachol bound with high affinity to [3H]QNB sites in brain stem preparations. Various muscarinic agonists and antagonists displayed different affinity patterns in the [3H]PZ and [3H]QNB binding. These data are indicative of two populations of pharmacologically distinguishable binding sites and support the concept of muscarinic receptor heterogeneity in rat brain.

Leu-enkephalin actions on avoidance conditioning are mediated by a peripheral opioid mechanism.

Leu-enkephalin (100 micrograms/kg, i.p.) administered to mice 5 min before training in a one way active avoidance task significantly reduced the number of avoidances observed in the peptide treated animals. This impairing action of Leu-enkephalin was partially attenuated by methylnaloxonium (naloxonium), a quarternary form of naloxone with a limited ability to penetrate the blood brain barrier. Passive immunization (i.v.) of mice with a Leu-enkephalin antiserum 4 hrs before training produced an effect on avoidance conditioning that was the opposite to that observed with Leu-enkephalin alone. That is, passive immunization increased the number of avoidances observed in the treated mice. The results suggest that Leu-enkephalin actions on avoidance conditioning are mediated by a peripheral opioid mechanism, that leu-enkephalin may have a primary site of action outside the blood brain barrier, and that peripheral Leu-enkephalin systems may normally operate to influence conditioned avoidance behavior.

Degradation of ethinyl estradiol by nitrifying activated sludge.

Degradation of ethinyl estradiol (EE2) by nitrifying activated sludge was studied with micro-organisms grown in a reactor with feedback of sludge fed with only a mineral salts medium containing ammonium as the sole energy source. Ammonium was oxidised by this sludge at a rate of 50 mg NH4+ g(-1) DW h(-1). This activated sludge was also capable of degrading EE2 at a maximum rate of 1 microg g(-1) DW h(-1). Using sludge with an insignificant nitrifying capacity of 1 mg NH4+ g(-1) DW h(-1), no degradation of EE2 was detected. Oxidation of EE2 by nitrifying sludge resulted in the formation of hydrophilic compounds, which were not further identified. Most probably degradation by nitrifying sludge results in a loss of estrogenic activity, as hydroxylated derivatives of EE2 are known to have a substantially lower pharmacological activity than EE2.

Fractures of the distal radius and scaphoid.

Simultaneous fractures of the distal radius and scaphoid is an uncommon wrist injury. During the period 1980 to 1993, 23 patients with a median age of 39 years were treated for this injury. The median follow-up period was 7 years. All scaphoid fractures were undisplaced and located in the waist or distal third. An extraarticular distal radial fracture was observed in 15 wrists. A below elbow cast including the thumb was applied in 18 wrists for a mean duration of 9 weeks, and operative treatment was used in only 5 patients. All scaphoid fractures healed without complications. During conservative treatment there were three redisplacements of distal radial fractures. The final functional results were good in 18, fair in four, and poor in one patient. Because complications occurred at the distal radius we have changed our conservative treatment policy from a below elbow cast including the thumb to a dorsal splint for 6 weeks.

Validation of fluoroscopy-based navigation in the hip region: what you see is what you get?

Fluoroscopy-based navigation systems can be used for internal fixation of intracapsular femoral neck fractures, with the object of optimizing positioning of the implant and reducing radiation exposure. With this technique, the virtual position and direction of a reamer can be simultaneously superimposed on anteroposterior (AP) and axial (AX) fluoroscopic images. However, surgeons have to rely on the accuracy of these systems, because the only intraoperative feedback on the true position of the reamer is the projection of a virtual reamer superimposed on two fluoroscopic images. The objective of this study was to evaluate the accuracy of the displayed position of the virtual reamer in relation to the true position of the instrument when using a fluoroscopy-based navigation system (medivision, Oberdorf, Switzerland). Secondary to this, the accuracy of the drill-channel measuring tool of the system was analyzed. The study was performed on 20 sawbones. To evaluate the position of the virtual reamer, an 8-mm Perspex bar was inserted in predefined drill channels in each sawbone. AP and AX fluoroscopic images of the sawbones with the Perspex bar were loaded into the workstation. The Perspex bar was then removed and exchanged for a navigated dynamic hip screw (DHS) reamer. The position of the Perspex bar in the images represented the true position of the reamer. Subsequently, the difference between the position of the virtual reamer and the Perspex bar was measured with a dedicated computer program. Drill-channel lengths measured with the system were compared with measurements obtained with a digital ruler. The mean difference in position of the Perspex bar and reamer at a predefined point was 0.90 mm (range: 0.00-3.21 mm) in 360 images. The mean difference in length measurements between the medivision system and the digital ruler was 1.00 mm (p = 0.01, SD =1.33). Reaming and measuring the screw channel of a DHS with a medivision fluoroscopy-based navigation system can be performed with an acceptable error margin.

[Results of 25-year pheochromocytoma treatment in the Groningen Academic Hospital]. / Resultaten van 25 jaar feochromocytoombehandeling in het Academisch Ziekenhuis Groningen.

OBJECTIVE: To evaluate 25 years' experience with the localisation techniques, operative management and results of treatment for phaeochromocytoma. DESIGN: Retrospective SETTING: Groningen University Hospital, the Netherlands. METHOD: Localisation results, per- and postoperative morbidity, mortality and treatment results were evaluated in all 59 patients treated for phaeochromocytoma in the period 1970-1995; 41 patients underwent unilateral adrenalectomy, 18 underwent bilateral adrenalectomy. RESULTS: From the introduction of MIBG scintigraphy all tumour sites were correctly diagnosed preoperatively. The transabdominal operation lead to considerable morbidity and minimal mortality. All MEN type 2 patients (n = 5) treated with unilateral adrenalectomy developed phaeochromocytoma in the contralateral gland and needed total adrenalectomy 7 to 14 years after the initial operation. CONCLUSION: A retroperitoneal approach in surgical treatment of phaeochromocytoma is to be preferred. In MEN type 2 patients bilateral adrenalectomy is still mandatory.

[Comparison of iodine scintigraphy and computerized tomography in the localization of pheochromocytoma]. / Vergelijking van jodium-scintigrafie en computertomografie bij de lokalisatie van het feochromocytoom.

A comparison is made of the results of CT scanning and MIBG scintigraphy in the localization of phaeochromocytoma. In 21 out of 24 patients with clinically diagnosed phaeochromocytoma in the University Medical Hospital, Groningen in 1983-1990, MIBG scintigraphy provided accurate localization, while in 16 out of 18 patients with phaeochromocytoma who underwent CT scanning a correct localization was obtained. False negative results were mainly present when lesions were smaller than 2 cm. There were no false positive results. It is concluded that the sensitivity of the two methods in the localization of phaeochromocytoma is about equal. The use of one of the methods rather than of both is advised.

The use of elastic intramedullary nailing in the stabilisation of paediatric fractures.

UNLABELLED: The treatment of paediatric long-bone fractures remains controversial. Elastic intramedullary nailing has been proposed as an alternative for the treatment of paediatric long-bone fractures. PATIENTS: We treated 68 children in a time span of 9 years with 32 fractures of the forearm, 27 fractures of the femur and nine fractures of the tibia. The mean age was 8.3 years and the mean admission time 2.6 days. RESULTS: Mean consolidation time was 7.9 weeks for the forearm fractures, 11.9 weeks for the femur fractures and 10.6 weeks for the tibial fractures. Full weight bearing for the latter two fracture types was allowed within the first week. There were no major complications. The complications encountered were three hydrops of the knee, four low-grade infections and one delayed union. Leg length discrepancy was only seen in five patients (18%) and was less than 2 cm. DISCUSSION: In femur fractures, we let the parents decide between skeletal traction and intramedullary rods. When confronted with the possible complications (operation-related complications and infection) compared to the advantages (early weight bearing and short admission time), they almost always choose the operative approach. In our opinion, elastic intramedullary nailing is an excellent treatment option for diaphyseal fractures in children with skeletal immaturity, especially of the femur.

Primary small bowel anastomosis in generalised peritonitis.

OBJECTIVE: To find out if primary small bowel anastomosis of the bowel is safe in patients with generalised peritonitis who are treated by planned relaparotomies. DESIGN: Retrospective study. SETTING: University hospital, The Netherlands. SUBJECTS: 10 Patients with generalised purulent peritonitis caused by perforation of the bowel. INTERVENTIONS: Resection or wedge resection of the bowel and primary intestinal anastomosis followed by planned relaparotomies every 24-48 hours. MAIN OUTCOME MEASURES: Mortality and morbidity with special reference to anastomotic leaks. RESULTS: Two patients died. Four of 20 wedge excisions in one patient leaked. All 19 end-to-end anastomoses in 10 patients healed without complications. Two patients developed small bowel fistulas which were not related to the anastomoses. CONCLUSION: Primary end-to-end anastomosis of the small bowel followed by planned relaparotomies seems a safe alternative to the creation of an enterostomy in patients with generalised purulent peritonitis and perforation of the bowel.

Fully automated experiments with isolated organs in vitro.

A fully automated system for pharmacological in vitro experiments with isolated tissues is described. The apparatus consists of an organ bath equipped with a) a gradient pump supplying a logarithmic concentration/time gradient of agonist; b) pumps and valves for dispensing bath fluid, antagonist solutions, and an oxygenation gas mixture; and c) a transducer with automatic baseline adjustment. The information coming from the preparation (i.e., changes in length or tension) is fed into a DEC PDP-11 mini-computer (MINC). This computer controls the test procedure either directly (e.g., when to break off the logarithmic gradient) or indirectly after processing the information in the form of log-concentration response curves (e.g., when to repeat a given procedure, or when to stop the experiment). At the end of the experiment, the results are presented both alpha-numerically and graphically. The data of various experiments can be accumulated and Schild-plots obtained. The example given demonstrates that this automated method offers considerable advantages over the classical manual method in that it has far greater precision. By careful planning, using several set-ups simultaneously with different isolated organs from the same animal, the investigator can carry out various experiments 24 hr a day and also reduce the number of sacrificed animals.

Subtotal adrenalectomy for phaeochromocytoma in multiple endocrine neoplasia type 2A.

OBJECTIVE: To describe our surgical technique for, and results of, subtotal adrenalectomy for phaeochromocytoma in multiple endocrine neoplasia (MEN) type 2. DESIGN: Retrospective study. SETTING: Teaching hospital, The Netherlands. SUBJECTS: 6 patients (four women and 2 men, mean age 35 years, range 31-46) with MEN type 2 who presented between 1993 and 1996. INTERVENTIONS: Cortical sparing adrenalectomy (n =4) together with contralateral total adrenalectomy in bilateral disease (n = 2). MAIN OUTCOME MEASURES: Morbidity, mortality, adrenal function postoperatively, and recurrence. RESULTS: Cortical sparing adrenalectomy leaving adequate adrenal reserve was possible in all cases. There was no operative morbidity or mortality. Mean follow-up was 40 months (range 1347). One patient developed a recurrent phaeochromocytoma 24 months after subtotal adrenalectomy. CONCLUSIONS: Subtotal adrenalectomy with preservation of adequate adrenal cortical reserve was feasible in all cases. Long term follow-up is necessary to establish its definitive place in the treatment of familial phaeochromocytoma.

Complications after bilateral adrenalectomy for phaeochromocytoma in multiple endocrine neoplasia type 2--a plea to conserve adrenal function.

OBJECTIVE: To evaluate the complications of the adrenocortical supplementation that is needed after bilateral adrenalectomy for phaeochromocytoma in patients with multiple endocrine neoplasia (MEN) type 2 syndrome. DESIGN: Retrospective study. SETTING: University hospital, The Netherlands. MATERIALS: 28 patients with MEN 2 who underwent total adrenalectomy for phaeochromocytoma between 1972 and 1996. MAIN OUTCOME MEASURES: Perioperative morbidity and mortality, histopathological findings, complications of adrenocortical supplementation therapy. RESULTS: 22 patients had bilateral phaeochromocytomas on histopathological examination (79%) and 6 patients had initially unilateral phaeochromocytomas There was no operative mortality or substantial morbidity except for one splenic injury that necessitated splenectomy. During a mean follow-up period of 14 years (range 1-26) nine patients (32%) had a total of 19 Addisonian crises that necessitated admission to hospital. One patient died of an unrecognised Addisonian crisis. CONCLUSION: Complications of adrenocortical supplementation therapy are considerable, but they can be reduced when unilateral adrenalectomy is done for a unilateral phaeochromocytoma in patients with MEN 2 syndrome, provided that they are carefully followed up.