Noradrenergic depletion causes sex specific alterations in the endocannabinoid system in the Murine prefrontal cortex.

Brain endocannabinoids (eCB), acting primarily via the cannabinoid type 1 receptor (CB1r), are involved in the regulation of many physiological processes, including behavioral responses to stress. A significant neural target of eCB action is the stress-responsive norepinephrine (NE) system, whose dysregulation is implicated in myriad psychiatric and neurodegenerative disorders. Using Western blot analysis, the protein expression levels of a key enzyme in the biosynthesis of the eCB 2-arachidonoylglycerol (2-AG), diacylglycerol lipase-α (DGL-α), and two eCB degrading enzymes monoacylglycerol lipase (MGL) and fatty acid amide hydrolase (FAAH) were examined in a mouse model that lacks the NE-synthesizing enzyme, dopamine ß-hydroxylase (DßH-knockout, KO) and in rats treated with N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride (DSP-4). In the prefrontal cortex (PFC), DGL-α protein expression was significantly increased in male and female DßH-KO mice (P < 0.05) compared to wild-type (WT) mice. DßH-KO male mice showed significant decreases in FAAH protein expression compared to WT male mice. Consistent with the DßH-KO results, DGL-α protein expression was significantly increased in male DSP-4-treated rats (P < 0.05) when compared to saline-treated controls. MGL and FAAH protein expression levels were significantly increased in male DSP-4 treated rats compared to male saline controls. Finally, we investigated the anatomical distribution of MGL and FAAH in the NE containing axon terminals of the PFC using immunoelectron microscopy. MGL was predominantly within presynaptic terminals while FAAH was localized to postsynaptic sites. These results suggest that the eCB system may be more responsive in males than females under conditions of NE perturbation, thus having potential implications for sex-specific treatment strategies of stress-related psychiatric disorders.

Chronic eccentric exercise: improvements in muscle strength can occur with little demand for oxygen.

Eccentric contractions, the lengthening of muscle while producing force, are a common part of our everyday movements. This study presents a challenge to the accepted notion that eccentric work causes obligatory muscle injury while demonstrating that an increase in muscle strength, via eccentric work, can occur with little demand for oxygen. Nine healthy subjects, ages 18-34, were randomly placed in either an eccentric or a concentric training group. Both groups trained for 6 wk while progressively increasing training frequency and duration. Significant gains in isometric leg strength were seen in the eccentrically trained subjects only. While training, the oxygen consumption required to do the eccentric work was equal to or less than that required to do the concentric work. The results demonstrate that by progressively increasing the eccentric work rate, significant isometric strength gains can be made without muscle injury and with minimal increase in metabolic demand for oxygen. The potential clinical implications of an eccentric training program that uncouples skeletal muscle strength improvements from the demand for oxygen are alluring.

Shoulder immobilizers. Shoulder immobilization devices.

Currently a myriad of devices are available for immobilization of the injured or postsurgical upper extremity. Some of these devices are straightforward and easily used, but some are more complicated and require more familiarity for their successful application. However, even simple devices have the potential for misapplication and thus prevent their benefit to the patient. This article is the second in a 3-part series. The goals of the series are (1) to present and review several devices on the market used by shoulder surgeons to immobilize the upper extremity, and (2) to discuss proper application and precautions of their use. It is intended that this series will benefit nurses, therapists, and trainers involved in the use of these devices.

The sling. Shoulder immobilization devices.

Currently a myriad of devices are available for immobilization of the injured or postsurgical upper extremity. Some of these devices are straightforward and easily used, but some are more complicated and require more familiarity for their successful application. However, even simple devices have the potential for misapplication and thus prevent their benefit to the patient. This article is the first in a 3-part series. The goals of the series are (1) to present and review several devices on the market used by shoulder surgeons to immobilize the upper extremity, and (2) to discuss proper application and precautions of their use. It is intended that this series will benefit nurses, therapists, and trainers involved in the use of these devices.

Intramedullary goniometer can improve alignment in knee arthroplasty surgery.

Fifty total knee arthroplasties were performed using an intraoperative intramedullary goniometer to measure the angle of the distal femoral cut. When deviations of 1 degree or more were found, angled cutting blocks ranging from 1 degree to 5 degrees were used to recut the distal femur. Revised femoral cuts were made it 25 knees (50%). Postoperative evaluation from weight-bearing long-standing anteroposterior radiographs revealed an average distal femoral angle deviation from preoperative planning of 0.64 degree (range, 0 degree-3 degrees). This was statistically significantly different from the value for a comparison group of 50 knees on which arthroplasties were performed without the intraoperative goniometer with an average femoral angle deviation of 1.44 degrees (range, 0 degree-4 degrees) (P < .05). In the control group, there were 7 knees (14%) that deviated by 3 degrees or more versus only 2 knees in the study group. The authors conclude that an intramedullary goniometer is fast, is simple to use, and leads to more accurate preparation of the distal femur in total knee arthroplasty.

Pharmacokinetics and kinetic-dynamic modelling of aminophenones as methaemoglobin formers.

Methaemoglobin, the oxidized form of haemoglobin, can be formed by a variety of agents, most of which act to oxidize haemoglobin directly or indirectly. Cyanide has a higher affinity for methaemoglobin than for mitochondrial cytochromes, making methaemoglobin formation a basis for the treatment of cyanide poisoning. We used the beagle dog model to investigate the relationship between drug concentration and methaemoglobin levels for two candidate anti-cyanide compounds. The compounds studied were the aminophenones p-aminopropiophenone (PAPP) and p-aminoheptylphenone (PAHP). Both PAPP and PAHP were given as intravenous boluses and as two different oral formulations. The kinetics of both compounds appeared to follow a three-compartment open model for intravenous bolus administration and a two-compartment open model for oral administration. The first distribution phase seen with the intravenous administration was obscured by the absorption phase during oral administration. Bioavailability for all formulations varied between 20 and 47%. For both compounds there was a delay between the appearance of drug in the plasma and the appearance of methaemoglobin (counter-clockwise hysteresis) which is suggestive of an active metabolite causing methaemoglobin formation. The pharmacodynamics were fit with an effect-compartment kinetic-dynamic model linked to a sigmoid Emax pharmacodynamic model. Maximum amounts of methaemoglobin occurred between 2 and 4 h for PAHP and between 1 and 3 h for PAPP. When administered intravenously estimates of EC50 were lower than the estimates of EC50 from oral administration for both compounds. This might be because of oral first-pass inactivation or a 'first-pass' activation through the lungs contributing to the formation of an active metabolite. The phenones as a class appear to have the drug cleared and methaemoglobin return to near baseline within 12 h. Both compounds seem to produce sufficient methaemoglobin to treat acute cyanide poisoning and to serve as prophylactic agents against acute cyanide poisoning in a military setting.

Shoulder immobilization devices.

Currently a myriad of devices are available for immobilization of the injured or postsurgical upper extremity. Some of these devices are straightforward and easily used, but some are more complicated and require more familiarity for their successful application. However, even simple devices have the potential for misapplication and thus prevent their benefit to the patient. This article is the third in a 3-part series. The goals of the series are (1) to present and review several devices on the market used by shoulder surgeons to immobilize the upper extremity, and (2) to discuss proper application and precautions of their use. It is intended that this series will benefit nurses, therapists, and trainers involved in the use of these devices.

Osteonecrosis of the talus: treatment by hindfoot fusion.

The results were reviewed for 11 ankles (10 patients) that had been treated with various hindfoot arthrodeses because of symptomatic osteonecrosis of the talus. Follow-up averaged 6.5 years (range, 2-15 years). A functional assessment using a modified Mazur grading system was performed both before surgery and at final follow-up. Data were also collected on the duration of the procedure, intraoperative findings, and the patient's assessment of postoperative cosmesis (excellent, good, fair, or poor). Radiographs were analyzed to determine the interval from the procedure until bony union. Nine of the 11 arthrodeses (82%) fused with the primary procedure and achieved excellent Mazur ratings (mean, 86 points; range, 81-90 points). The average interval until radiographic fusion was 7 months (range, 4-13 months). All eight patients (nine fusions) with successful fusions graded their cosmetic outcomes as excellent or good. The average length of the procedure was 148 minutes (range, 130-300 minutes), compared with an average of 92 minutes (range, 62-151 minutes) for ankle arthrodeses performed by the same surgeons in rheumatoid or osteoarthritic ankles (P < 0.001) and 102 minutes (range, 75-164 minutes) from a report in the literature. Two of the procedures were complicated by nonunions secondary to infections. In one patient, after treatment by debridement and intravenous antibiotics, reinfection and chronic osteomyelitis developed with a subsequent below-knee amputation. The other patient was treated successfully with debridement, antibiotics, and subsequent revision arthrodesis, which fused solidly at 9 months with an excellent result. We conclude that hindfoot arthrodeses for osteonecrosis can be technically demanding, but, despite having a long time to bony union, they can have an excellent clinical outcome.

Pharmacokinetics and kinetic-dynamic modeling of an 8-aminoquinoline candidate anticyanide and antimalarial drug (WR242511).

Malaria is a major cause of health problems in a large portion of the world. The 8-aminoquinoline compound, primaquine, is one of the only compounds useful for relapses of Plasmodium vivax and Plasmodium ovale malaria. Primaquine has several toxicities that include methemoglobinemia and hemolytic anemia. The induction of methemoglobinemia is a treatment for cyanide poisoning. We studied the pharmacokinetics and pharmacodynamics (percentage methemoglobin) for WR242511, an 8-aminoquinoline primaquine replacement and potential anticyanide compound. The drug's pharmacokinetics and pharmacodynamics are described for oral and intravenous dosing, and two kinetic-pharmacodynamic models are shown to describe the single dose data. A significant lag occurs between the onset of appearance of drug in the plasma and the onset of methemoglobinemia. Peak drug concentrations occurred within 4 hr for oral dosing, and peak effect (percentage methemoglobin) did not occur for 72-96 hrs for both the oral and intravenous routes. Elimination half-life for the drug was 30 +/- 14 hr. Two kinetic-dynamic models, one with an effect compartment relating drug concentration to effect and one with metabolite causing a first-order conversion of hemoglobin to methemoglobin, are compared as to their ability to predict multiple dose pharmacokinetics and pharmacodynamics. Both models were useful in predicting drug concentrations and methemoglobin levels for multiple-dose experiments.

Avascular necrosis of the humeral head treated by core decompression. A retrospective review.

Thirty shoulders, in 20 patients, which had undergone core decompression for symptomatic avascular necrosis of the humeral head were reviewed 2 to 14 years later (average 5.6). Twenty-two showed good or excellent clinical results; the other eight shoulders had required arthroplasty. All 14 shoulders with stage I or II radiological changes (Ficat and Arlet 1980) at operation had good or excellent results. We advocate early core decompression for symptomatic avascular necrosis of the humeral head.

Tibiotalar contact and fibular malunion in ankle fractures. A cadaver study.

Six cadaveric ankles were dissected, preserving medial and lateral ligaments; an axial load of 455N was applied to the tibia supported by the foot and ankle. The unconstrained tibia was moved through 20 degrees of flexion and extension to simulate walking. The tibiotalar contact area was defined using carbon black suspension, recorded photographically, and measured using computerized area analysis. Osteotomy of the distal fibula was performed and fixed with a specially modified plate; a selection of plates provided fixation with 0 degrees or 30 degrees of external rotation in combination with 0 or 2 mm of shortening. The contact area was measured for each of the plates and after division of the deltoid ligament. There were greater than 30 percent decreases in tibiotalar contact with both fibular shortening and external rotation, doubled with a divided deltoid ligament. Anatomic restoration of both fibular length and rotation is essential for normal ankle mechanics. The deltoid ligament has crucial effects on the stability of the ankle mortise.

Outpatient premedication: use of midazolam and opioid analgesics.

The perioperative effects of administering sedative and analgesic drugs prior to outpatient surgery were evaluated. One hundred fifty adult outpatients were randomly assigned to one of six study groups according to a double-blind protocol design. Patients were given placebo (saline) or midazolam (5 mg im) 30-60 min prior to surgery, and then either placebo, oxymorphone (1 mg iv), or fentanyl (100 micrograms iv) 3-5 min prior to a standardized anesthetic technique. Preoperatively, midazolam premedication was associated with a significantly lower anxiety level (37 +/- 29 mm vs. 50 +/- 32 mm, P less than 0.05), higher sedation level (254 +/- 136 mm vs. 145 +/- 109 mm, P less than 0.01), worsening of psychomotor skill (5 +/- 5 vs. 2 +/- 2 dots missed, P less than 0.01; midazolam vs. placebo), and impaired recall abilities. In addition, use of midazolam did not prolong the discharge time. Compared to control patients, those who received fentanyl had a decreased incidence of intraoperative airway difficulties such as coughing (28% vs. 0%, P less than 0.01). Although use of opioids increased the incidence of postoperative nausea (42% vs. 18%, P less than 0.01) and vomiting (23% vs. 2%, P less than 0.01; opioid vs. no opioid), average recovery times were not affected by opioid administration. Oxymorphone use was associated with a lower incidence of pain at home compared with that following fentanyl (46% vs. 74%, P less than 0.05). Finally, preoperative administration of both midazolam and fentanyl or oxymorphone prior to a standardized methohexital-nitrous oxide anesthetic technique did not adversely affect recovery after outpatient surgery.

Comparison of sedative infusions during regional anesthesia--methohexital, etomidate, and midazolam.

Using a randomized, double-blind study design, the intra- and postoperative sedative effects of three intravenous central nervous system depressants were compared in 64 patients during regional anesthesia. After establishing regional anesthesia, methohexital 59 +/- 29 mg IV, etomidate 12.6 +/- 8 mg IV, or midazolam 3.7 +/- 1.5 mg IV (mean dose +/- SD) were infused in a titrated fashion over 5-15 minutes to achieve similar end points of sedation. This level of sedation was then maintained with a variable-rate infusion of either methohexital 180 +/- 65 mg/hr, etomidate 32 +/- 12 mg/hr, or midazolam 7.5 +/- 4 mg/hr (mean dose +/- SD) To maintain a stable level of sedation, changes in the maintenance infusion rate were required more frequently with methohexital (4.6 +/- 3 times) than with etomidate (2.6 +/- 2 times) or midazolam (2.7 +/- 3 times). Decreases in oxygen saturation below 95% were more frequent with midazolam than with methohexital and etomidate, while recall of intraoperative events was less frequent after midazolam. Observer evaluations found less sedation in the methohexital and etomidate groups than in the midazolam group during the early postoperative period. However, the patients' evaluation of residual sedative effects (e.g., postoperative sedation visual analogue scores) and discharge times from the recovery room were similar in all three groups. Nevertheless, patients given midazolam had significantly greater impairment of performance on the digit-symbol substitution test in the early postoperative period than did patients given either methohexital or etomidate.

The services industry: is it recession-proof?

Steady growth has led the services division to account for nearly 20 percent of total employment in 1980, linked mainly to business and health services; since 1948, it has been nearly immune to recessions and has displayed relative cyclical insensitivity.