Hip mineral density in females with a recent hip fracture.

To evaluate the role of local bone mineral density (BMD) in the etiology of hip fractures, we measured the hip BMD using dual photon absorptiometry in 29 females who had recently suffered a hip fracture associated with minimal or moderate, but not major, trauma and compared their BMD to those of 14 young normal females, 58 early postmenopausal normal females, 13 age-matched normal females, and 114 spinal osteoporotic females without a hip fracture. Hip-fractured patients had a BMD significantly lower (P less than 0.001) than that of all other studied groups, suggesting that a low hip BMD is associated with hip fracture risk. A femoral neck BMD below 0.75 g/cm2 suggests an increased likelihood for developing a hip fracture. Peak BMD was measured at 1.03 g/cm2, a value comparable to published normative data. Thus, a loss in hip BMD of approximately 30% from peak mineral density appears necessary before a hip fracture may occur after moderate trauma.

CSF beta-endorphin and dynorphin in bulimia nervosa.

OBJECTIVE: Preclinical and clinical evidence suggests that central opioid dysfunction may play a role in the pathophysiology of the eating disorders. In particular, endogenous opioids are known to regulate feeding behavior, mood, perception, and neuroendocrine function, all of which are disturbed in patients with eating disorders. Although low concentrations of CSF beta-endorphin have been reported in low-weight patients with anorexia nervosa, central opioid activity in normal-weight patients with bulimia nervosa has not been reported. The authors therefore measured CSF concentrations of beta-endorphin and dynorphin in drug-free female patients with DSM-III-R-defined bulimia nervosa and normal comparison subjects. METHOD: After 4 days of a low monoamine diet and overnight bed rest, CSF was obtained (12-26 cc) from 11 women with bulimia and 17 normal comparison subjects (eight women and nine men). RESULTS: The women with bulimia had significantly lower CSF concentrations of beta-endorphin than did the female comparison subjects. However, CSF concentrations of dynorphin were not significantly different in patients and female or male comparison subjects. beta-Endorphin concentrations were inversely correlated with Beck Depression Inventory scores and the depression subscale of the Eating Disorders Inventory. CONCLUSIONS: These data support a role for central opiates in the mediation of the pathophysiology of the signs and symptoms of bulimia nervosa, although it is impossible to rule out the effects of depression on the results.

Synthesis of highly mu and delta opioid receptor selective peptides containing a photoaffinity group.

A series of cyclic, conformationally constrained photolabile peptides related to the enkephalins and to somatostatin were designed and synthesized in an effort to develop highly selective and potent peptides for the delta and mu opioid receptors. The following new peptides were prepared and tested for their delta opioid receptor potency and selectivity in the guinea pig ileum assay, the mouse vas deferens assay, and the rat brain binding assay: H-Tyr-D-Pen-Gly-p-NH2Phe-D-Pen-OH (1, [p-NH2Phe4]DPDPE) and H-Tyr-D-Pen-Gly-p-N3Phe-D-Pen-OH (2, [p-N3Phe4]-DPDPE). The following new peptides were prepared and tested for their mu opioid receptor potency and selectivity in the same assays: H-D-Phe-Cys-p-NH2Phe-D-Trp-Lys-Thr-Pen-Thr-NH2 (3, [p-NH2Phe3]CTP) and D-Phe-Cys-p-N3Phe-D-Trp-Lys-Thr-Pen-Thr-NH2 (4, [p-N3Phe3]CTP). The delta selective photoaffinity peptide 2 displayed both high affinity (IC50 = 9.5 nM) and good selectivity (IC50 mu/IC50 delta = 1053) as an agonist at delta opioid receptors in bioassays, and 2 also displayed moderate affinity (33 nM) and excellent selectivity (IC50 mu/IC50 delta = 110) for rat brain delta opioid receptors. The mu selective photoaffinity peptide 4 displayed very weak affinity (8% contraction at 300 nM) at mu opioid receptors in bioassays, but good affinity (IC50 = 48.6 nM) and excellent selectivity (IC50 delta/IC50 mu = 412) for the rat brain mu opioid receptors. These conformationally constrained cyclic photoaffinity peptides may be useful tools to investigate the pharmacology of delta and mu opioid receptors.

Design and synthesis of somatostatin analogues with topographical properties that lead to highly potent and specific mu opioid receptor antagonists with greatly reduced binding at somatostatin receptors.

A series of conformationally restricted, cyclic octapeptides containing a conformationally stable tetrapeptide sequence related to somatostatin, -Tyr-D-Trp-Lys-Thr-, as a template, were designed and synthesized with the goal of developing highly potent and selective mu opioid antagonists with minimal or no somatostatin-like activity. Three distinct structures of the peptide became targets of chemical modifications and constraints; the N- and C-terminal amino acids and the cyclic 20-membered ring moiety. Based on the conformational analysis of active and inactive analogues of the parent peptide D-Phe1-Cys2-Tyr3-D-Trp4-Lys5-Thr6-Pen7+ ++-Thr8-NH2, CTP (Kazmierski, W.; Hruby, V. J. Tetrahedron 1988, 44, 697-710), we designed analogues to include the tetrahydroisoquinolinecarboxylate (Tic) moiety as the N-terminal amino acid instead of D-Phe, since Tic can exist only as a gauche (-) or a gauche (+) conformer. In this series, the following peptides were synthesized and pharmacologically evaluated: D-Tic-Cys-Tyr-D-Trp-Lys-Thr-Pen-Thr-NH2 (TCTP), D-Tic-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (TCTOP), and D-Tic-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 (TCTAP). In rat brain membrane opioid radioligand binding assays, all three peptides displayed high affinity for mu opioid receptors (IC50 = 1.2, 1.4, 1.2 nM, respectively), and exceptional mu vs delta opioid receptor selectivity: 7770, 11,396, and 1060, respectively. TCTOP and TCTAP also possess exceptional mu vs somatostatin receptor selectivity: 14,574 and 28,613, respectively. In the peripheral in vitro GPI bioassay, TCTP, TCTOP, and TCTAP were highly effective antagonists of the potent mu opioid receptor agonist PL017, with pA2 = 8.69 for TCTAP, 8.10 for TCTP, and 7.38 for TCTOP. Our results show that a 10-fold higher affinity and selectivity for mu opioid receptors (in both central and peripheral studies) over delta and somatostatin receptor was gained as a result of the D-Tic1 substitution. These three peptides, TCTP, TCTOP, and TCTAP, are the most potent and selective mu opioid antagonists known. CTP has been shown to possess prolonged biological action, much longer than that of naloxone. This renders these analogues potentially useful ligands for investigating the physiological functions of the mu opioid receptor. Analogues of TCTP in which the 20-membered disulfide ring was contracted by deletion of D-Trp4, and/or Lys5, and/or Thr6 led to compounds with greatly reduced potency at the mu opioid receptor.(ABSTRACT TRUNCATED AT 400 WORDS)

Cerebral oxygen availability by NIR spectroscopy during transient hypoxia in humans.

The effects of mild hypoxia on brain oxyhemoglobin, cytochrome a,a3 redox status, and cerebral blood volume were studied using near-infrared spectroscopy in eight healthy volunteers. Incremental hypoxia reaching 70% arterial O2 saturation was produced in normocapnia [end-tidal PCO2 (PETCO2) 36.9 +/- 2.6 to 34.9 +/- 3.4 Torr] or hypocapnia (PETCO2 32.8 +/- 0.6 to 23.7 +/- 0.6 Torr) by an 8-min rebreathing technique and regulation of inspired CO2. Normocapnic hypoxia was characterized by progressive reductions in arterial PO2 (PaO2, 89.1 +/- 3.5 to 34.1 +/- 0.1 Torr) with stable PETCO2, arterial PCO2 (PaCO2), and arterial pH and resulted in increases in heart rate (35%) systolic blood pressure (14%), and minute ventilation (5-fold). Hypocapnic hypoxia resulted in progressively decreasing PaO2 (100.2 +/- 3.6 to 28.9 +/- 0.1 Torr), with progressive reduction in PaCO2 (39.0 +/- 1.6 to 27.3 +/- 1.9 Torr), and an increase in arterial pH (7.41 +/- 0.02 to 7.53 +/- 0.03), heart rate (61%), and ventilation (3-fold). In the brain, hypoxia resulted in a steady decline of cerebral oxyhemoglobin content and a decrease in oxidized cytochrome a,a3. Significantly greater loss of oxidized cytochrome a,a3 occurred for a given decrease in oxyhemoglobin during hypocapnic hypoxia relative to normocapnic hypoxia. Total blood volume response during hypoxia also was significantly attenuated by hypocapnia, because the increase in volume was only half that of normocapnic subjects. We conclude that cytochrome a,a3 oxidation level in vivo decreases at mild levels of hypoxia. PaCO is an important determinant of brain oxygenation, because it modulates ventilatory, cardiovascular, and cerebral O2 delivery responses to hypoxia.

Spinally mediated opioid antidiarrheal effects.

To assess the role of opioid receptors in the spinal cord in regulation of functions of the intestinal mucosa in a secretory model, we evaluated the ability of i.t. administered mu (PL017), delta (DPDPE) and kappa (U50,488H) selective opioid agonists to inhibit diarrhea produced in mice by an injection of prostaglandin E2 (PGE2) (200 micrograms/mouse, i.p.). I.t. PL017 and DPDPE inhibited diarrhea in a dose-related fashion. U50,488H had only minimal antidiarrheal effects. The i.t. doses of PL017 and DPDPE required to inhibit diarrhea were higher than the doses required to produce antinociception and inhibit gastrointestinal transit. Spinally administered PL017 and DPDPE were considerably less potent in the diarrhea model than after i.c.v. administration but far more effective than after peripheral (s.c.) dosing. The antidiarrheal effects of spinally administered opioids were antagonized by concurrently administered naloxone. These data indicate that opioid chemosensitive sites in the spinal cord can modulate diarrhea produced by PGE2, and that the receptor specific opioids, PL017 and DPDPE, and to a lesser extent U50,488H, all possess antidiarrheal activity when administered i.t.

A novel bioassay for the NK-2 neurokinin receptor: the guinea pig gallbladder.

Although three neurokinin receptors (NK-1, NK-2, NK-3) have been identified by radioligand binding assays, only the NK-1 and NK-3 types have been found in smooth muscle bioassays. In this study, evidence is presented demonstrating functional NK-2 type receptors in the guinea pig gallbladder (GPGB). The potencies of the following neurokinins were determined in the GPGB and the guinea pig ileum (GPI): substance P (SP), physalaemin (PH), eledoisin (EL), substance K (SK) and kassinin (KA). ED50 values were determined by linear regression analysis of the dose-related increases in the force generated by each peptide. In the GPI, the rank order of potency was SP = PH = EL greater than SK = KA, indicating NK-1 selectivity. In the GPGB, the relative potencies were SK greater than KA greater than EL much greater than PH greater than SP, which is similar to that reported for the NK-2 receptor in radioligand binding assays. These findings demonstrate the NK-2 receptor tissue selectivity of the GPGB.

Regulation of gastrointestinal function by multiple opioid receptors.

Agonist and antagonist drugs possessing selectivity for individual types of opioid receptors have been employed in vitro and in vivo to determine the mechanisms by which opioids regulate gastrointestinal functions. Selective mu opioid agonists given by intracerebroventricular (i.c.v.) injection, by intrathecal (i.t.) injection, or by peripheral (s.c. or i.v.) injection in rats or mice decreased gastrointestinal transit and motility, inhibited gastric secretion, and suppressed experimentally-induced diarrhea. Selective delta agonists, by contrast, inhibited gastrointestinal transit after i.t., but not after i.c.v. or s.c. administration. Delta agonists also did not alter gastric secretion after i.c.v. or s.c. injection. However, delta agonists exhibited antidiarrheal effects after i.c.v., i.t., or s.c. administration. Kappa agonists given i.c.v. had no effect on gastrointestinal transit in rats or mice or on gastric secretion in rats, but exhibited antidiarrheal effects in mice. The kappa agonist U-50, 488H given peripherally increased gastric acid secretion. Different types of opioid receptors in different anatomical sites influence differently gastrointestinal motility and propulsion, gastric secretion, and mucosal transport. Brain, spinal cord, enteric neural and smooth muscle opioid receptors represent chemosensitive sites for regulation of gastrointestinal function.

Synthesis and biological evaluation of N alpha-hydroxysulfonyl-[Nle28,31]-CCK26-33.

Two analogues of [Nle28,31]-CCK26-33 containing an N-terminal acetyl or N-terminal hydroxysulfonyl moiety were prepared and characterized. Both analogues were equipotent to native CCK26-33 in four bioassays, demonstrating that N-terminal sulfation of CCK26-33 analogues is compatible with full biological activity.

Comparison of intravenous midazolam with pentobarbital for sedation for head computed tomography imaging.

OBJECTIVE: To compare the efficacy of intravenous (IV) midazolam with that of IV pentobarbital when used for sedation for head computed tomography (CT) imaging in emergency department (ED) pediatric patients. METHODS: Prospective, randomized clinical trial in an urban children's hospital. During a two-and-a-half-year period, 55 patients were enrolled: 34 males and 21 females. Measurements included induction time, recovery time, efficacy, side effects, complications, and failure with each drug. Success of sedation was graded as good (GS), adequate (AS), poor (PS), or unsuccessful (US). RESULTS: Sedation for CT was used for patients with the following problems: head trauma (21/55), central nervous system pathology (17/55), ventriculoperitoneal shunt evaluation (6/55), periorbital cellulitis (6/55), and retropharyngeal abscess (5/55). Twenty-nine (53%) patients received pentobarbital (mean +/- SD dose 3.75 +/- 1. 10 mg/kg) and 26 (47%) patients received midazolam (mean +/- SD dose 0.2 +/- 0.03 mg/kg). In the pentobarbital group, 28 (97%) patients were scanned and successfully sedated. Pentobarbital's mean induction time was 6 minutes and duration of sedation averaged 86 minutes. In the midazolam group, only five (19%) patients were successfully scanned with midazolam alone. Of the 21 (81%) patients given midazolam who were unsuccessfully sedated, 12 (61%) were subsequently sedated with the addition of pentobarbital for completion of CT imaging. Mild oxygen desaturation, O(2) sat >90% yet <94%, was seen in only four patients. All four patients responded to blow-by oxygen and required no other intervention. CONCLUSION: Intravenous pentobarbital is more effective than IV midazolam for sedation of children requiring CT imaging.

The discriminative stimulus properties of the R2 isomer of viminol.

Viminol is a pyrrylethanolamine derivative which exists naturally as a racemic mixture containing six different stereoisomers. Viminol has been reported to exert both potent analgesic activity and minimal dependence liability. The analgesic component of racemic viminol has been attributed to the R2 isomer, while the antagonistic S2 isomer appears to be responsible for minimizing the dependence liability of the racemate. We tested the R2 isomer of viminol in rats trained to discriminate 3 mg/kg morphine sulfate from saline on a VI-15 sec schedule for sweetened milk reinforcement. The R2 isomer resulted in dose dependent morphine-like responding, with complete generalization to the 2.5 mg/kg dose of R2 viminol. The morphine-like discriminative stimulus properties of R2 viminol were reversed by naloxone in a dose-dependent fashion, with total blockade by 0.1 mg/kg naloxone. R2 viminol, like morphine, also had a biphasic effect on response rate with low doses increasing and high doses suppressing response rates. R2 viminol had a overall shorter time course than that reported for morphine, and its different physiological and behavioral effects may not occur simultaneously. These data suggest that R2 viminol exerts a subjective effect similar to that of morphine and supports the hypothesis that R2 viminol has opiate activity despite its lack of structural relationship to the opiate series.

Characterization of the interaction of pentazocine and tripelennamine: drug discrimination and mu-receptor binding assay.

Abuse of the combination of pentazocine (P) and tripelennamine (T) reputedly produces an opiate-like euphoria not obtainable from either drug alone. To determine if this effect is related to interactions at the behavioral or receptor levels we tested this combination in rats trained to discriminate morphine from saline and in mu-receptor binding assays. Displacement of 3H-DHM was compared in morphine-naive, dependent and withdrawn states to determine the importance of prior morphine exposure. The morphine training cue (3 mg/kg) generalized to P but not to T. Combinations of T (0.3 and 1.0 mg/kg) with "no effect" doses of P (1 and 3 mg/kg) resulted in greater than additive increases in morphine-like responding. 3H-DHM was displaced by P but not T in naive, dependent and withdrawn states. Specific dose combinations of T (1 nM) with P (1 nM, 10 nM, 100 nM) resulted in enhanced displacement of 3H-DHM and was not related to prior morphine exposure. We conclude that the addition of T to P increases the mu-like subjective effects of P and this effect may be due to enhanced affinity of P for the mu-receptor.

Common problems seen by the plastic surgery emergency room service.

This article covers many issues of particular interest to the care of the child who presents to the emergency department with a traumatic wound. General concepts regarding the staffing of an emergency department, staff qualifications, and their consultation patterns are reviewed. Issues pertaining to the management of children in the emergency setting, including an update on outpatient sedation and analgesia and some infectious disease considerations are also discussed.

Arthrodesis of the first metatarsophalangeal joint. Current recommendations.

Fusion of the first metatarsophalangeal joint is a time-honored, effective procedure for multiple conditions. Numerous fixation techniques have been described over the years. The authors provide an extensive overview of specific fixation techniques used throughout the past 6 years. Emphasis is placed on the potential advantages and disadvantages of the individual fixation techniques.

The effect of hallux abducto valgus surgery on the sesamoid apparatus position.

A new parameter, the tibial sesamoid-second metatarsal distance, was established to determine whether the sesamoids move in relation to the foot in hallux abducto valgus surgery. The reliability of the tibial sesamoid-second metatarsal distance was assessed and shown to be excellent. Seventy-five feet underwent surgical correction of hallux abducto valgus. Four radiographic parameters--the intermetatarsal angle, the hallux abductus angle, the tibial sesamoid position, and the tibial sesamoid-second metatarsal distance--were measured before and after surgery. The hallux abductus angle, intermetatarsal angle, and tibial sesamoid position were all significantly reduced following surgery. The tibial sesamoid-second metatarsal distance was not affected by hallux abducto valgus correction. Thus the correction in sesamoid position gained with hallux abducto valgus correction is a direct result of lateral translocation of the metatarsal head, with no contribution from change in position of the sesamoid apparatus relative to the foot.

Iatrogenic deformities of the first ray.

Surgical correction of a hallux valgus deformity is common among podiatric and orthopedic surgeons. Complications following hallux valgus surgery are not uncommon. Although many of these complications can be avoided by a comprehensive understanding of the pathomechanics of a hallux valgus deformity and continual honing o surgical skills, some are inevitable. This article provides a comprehensive overview and insight into the diagnosis and treatment of the more common complications encountered with hallux valgus surgery.

Morphine dependence and diabetes. I. The development of morphine dependence in streptozotocin-diabetic rats and spontaneously diabetic C57BL/KsJ mice.

Spontaneously diabetic (db/db) and nondiabetic (db/m+, m+/m+) C57BL/KsJ mice were made dependent by a 9-day exposure to increasing doses of morphine-admixed food. Radioimmunoassay for morphine demonstrated that diabetic mice had significantly greater brain accumulations of morphine than nondiabetic littermates after morphine-admixed food. Despite their greater brain levels of morphine, diabetic mice showed significantly fewer behavioral signs of withdrawal after naloxone, and lost significantly less weight at 60 min after naloxone than their nondiabetic littermates. Streptozotocin-diabetic and nondiabetic rats rendered dependent by a 6-day i.p. infusion of morphine had equal brain levels of morphine, but the diabetic rats showed significantly fewer behavioral signs of withdrawal than nondiabetic rats at 24 and 48 hr after the end of the infusion. These results indicate that spontaneously diabetic mice and streptozotocin-diabetic rats were both significantly less physically dependent upon morphine than their respective nondiabetic controls and support our conclusion that the development of physical dependence upon morphine is reduced in experimental models of diabetes.