The innervation of the medial humeral epicondyle: implications for medial epicondylar pain.

The purpose of this study was identification of the innervation of the medial humeral epicondyle which has not been described before. In 20 patients, the medial intermuscular septum was evaluated histopathologically: the nerve was identified in 15 specimens without S-100 staining, and in the remaining 5 with S-100 staining. In six fresh cadavers, bilateral dissections identified the source of this nerve as the radial nerve in the axilla, coursing adjacent to the ulnar nerve in the upper arm, then moving laterally to be superficial to, or within, the medial intermuscular septum, until the nerve terminated in the periosteum of the medial humeral epicondyle, at the origin of the flexor-pronator muscle mass. In one specimen, a branch from the ulnar nerve in the axilla contributed to this nerve to the medial humeral epicondyle.

Reconstruction of the spinal accessory nerve with autograft or neurotube? Two case reports.

Injury to the spinal accessory nerve is most commonly iatrogenic, but can be related to cervical trauma or resection of tumor. Of the two most recent publications related to injury of the spinal accessory nerve, one describes transfer of the levator scapulae muscle to restore shoulder function, while the other reports on the results of six surgical repairs, three of which used a sural nerve graft to reconstruct a short neural defect. The present report describes the results obtained in two patients when an iatrogenic injury to the XIth nerve was reconstructed at 3 months after the loss of shoulder function. Denervation of the XIth nerve was confirmed by a first EMG at 6 weeks, and a second one at 12 weeks. At surgery, each XIth nerve was found to have an in-continuity neuroma, most probably related to electrocoagulation. Intraoperative electrical stimulation did not pass the region of nerve injury. In the first patient, the XIth nerve was reconstructed with an autograft from the greater auricular nerve. In the second patient, the XIth nerve was reconstructed with a bioabsorbable conduit, the Neurotube. The patient with the Neurotube reconstruction reached M5 trapezius function by 3 months after surgery, and had no nerve graft donor-site morbidity, while the patient with the autograft reached M4 function by 6 months after reconstruction, and has persistent numbness of the ear lobe. This is the first reported case of a cranial motor nerve being reconstructed with a bioabsorbable conduit.

The use of local muscle flaps in foot and ankle reconstruction.

Pedicled muscle flaps always should be considered as a reconstructive option when evaluating possible options to filling a defect around the foot and ankle. To gain confidence in using this option, multiple anatomic dissections with special attention to the vascular anatomy are necessary. These dissections also should give the surgeon a feel for the reach of the various flaps and their applicability in various circumstances. For optimal results, the interoperative dissections should be performed with loupes and the Doppler. This allows the surgeon to identify and protect the dominant pedicle. When insetting the flap, special attention is directed to avoid placing excessive torsion or tension on the pedicle so that the blood flow is not compromised. The flow, both arterial and venous, should be assessed after insetting the muscle with a Doppler. Pedicled muscle flaps offer a rapid and easy solution to difficult soft tissue problems around the foot and ankle. The operation can be performed with a regional block in under two hours. The postoperative stay is short, and the donor defect is minimal. Pedicled muscle flaps offer a great alternative to microsurgical free flaps, especially in the sick patient. They should be considered more often when looking at how to fill small defects with exposed bone or osteomyelitis around the foot and ankle.

Gender difference in the cycle length-dependent QT and potassium currents in rabbits.

Women are known to have a longer electrocardiographic Q-T than men, which may contribute to their being at greater risk of developing drug-induced polymorphic ventricular arrhythmias. However, little is known about the underlying mechanisms. In the present study, we evaluated potential gender differences in Q-T interval in isolated perfused rabbit hearts using the Langendorff technique and evaluated the density of outward potassium currents in single ventricular myocytes using the whole-cell patch-clamp technique. We found that female hearts demonstrated a greater Q-T lengthening (delta Q-T%) upon an increase in cycle length (CL), resulting in a significantly longer Q-T (301 +/- 4.8 ms, CL = 2.3 s) at a long CL in female hearts compared with male hearts (267 +/- 4.0 ms, P < .01). Ventricular myocytes isolated from female hearts showed a smaller IK(tail) and peak IKI outward current density. A 50% reduction in extracellular K+ and Mg++ shifted the I-V relationship of IKI and Ito and reduced their amplitude. However, neither the I-V relationship of IKr nor the gender difference in the Q-T-CL relationship was significantly altered. We conclude that 1) female rabbit ventricular myocytes have significantly lower IKr and IKl outward current densities than do male cells, which may contribute to the gender difference in Q-T, and 2) a lower base-line IKr density may contribute to the steeper Q-T-CL relationship in female hearts.

Imaging of the liver with helical CT: a survey of scanning techniques.

OBJECTIVE: We conducted a survey of the members of the Society of Computed Body Tomography/Magnetic Resonance to assess current techniques in liver imaging using helical CT. MATERIALS AND METHODS: The survey, which was designed to update earlier surveys from 1987 and 1993, included a questionnaire distributed to 77 members of the Society of Computed Body Tomography/Magnetic Resonance. RESULTS: Forty-nine members responded, representing 28 institutions. In 1993, 19% (5/26) of institutions used helical scanners, compared with 82% (23/28) in 1996. The group of institutions with helical CT served as the focus of this survey. In 1993, 58% of institutions used 1-cm collimation: in 1996, 78% (18/23) used thinner, 7- to 8-mm collimation. In 1987, 41% used power injectors compared with 85% in 1993 and 100% in 1996. In 1996, monophasic injections were used by 96% (22/23) of institutions. In 1993, most institutions used a contrast material injection rate of 1.5-2.0 ml/sec; in 1996, most used a 2.5-3.0 ml/sec injection rate. In 1993, 96% of institutions used 125-150 ml of contrast material; in 1996, 57% (13/23) of institutions used 125-150 ml and 30% of institutions used less than 125 ml of contrast material. A delay time of 21-45 see was used by 83% of institutions in 1993, whereas in 1996, 83% (19/23) of institutions used a longer delay time of 50-80 sec. In 1996, 13% of institutions used an individual scan delay technology and all institutions performed multiphasic scanning of hypervascular lesions. CONCLUSION: The availability of helical CT has changed radiologists' approach to liver imaging. The greatest effects of which are a more widespread use of power injectors, longer delay times, thinner collimation, increased contrast material injection rates, decreased contrast material volumes, and multiphasic scanning.

Comparative effects of loratadine and terfenadine on cardiac K+ channels.

Nonsedating H1-receptor antagonists appear to have wide and variable effects on the QT interval, mediated through modulation of cardiac K+ channels. By using the whole-cell patch-clamp technique, we examined the effects of terfenadine, loratadine, and descarboethoxyloratadine on a large family of K+ channels in ventricular myocytes and in Xenopus oocytes expressing the HERG delayed rectifier. The channels studied included the inward rectifier (I(Kl)) of rat and guinea pig, the transient outward K+ current (I(to)) of rat, the maintained K+ current (I(ped)) of rat, and the delayed rectifier K+ channels (I(Ks) and I(Kr)) of guinea pig myocytes. Loratadine and descarboethoxyloratadine, at therapeutic concentrations (30 to 100 nM), had no measurable effect on any one of the five types of K+ channels studied. At higher concentrations, 0.3 to 1.0 microM, only terfenadine had a significant suppressive effect on I(Kl) and delayed rectifier K+ channels, I(Kr) and I(Ks). At higher concentrations (1 to 2.5 microM), there were marked differences in the ability of the three drugs to suppress the five K+ channels. Generally, terfenadine was the most and loratadine, the least effective blocker of all K+ channels examined. The most susceptible K+ channels were the delayed rectifier channels (I(Ks) and I(Kr)) in guinea pig and I(ped) in rat myocytes. Comparative effects of loratadine and terfenadine examined on the I(Kr) channel (HERG) expressed in Xenopus oocytes suggest much higher affinity of this channel to terfenadine, such that 1 microM terfenadine completely suppressed the current, whereas loratadine had little or no effect. The preferential suppressive effect of terfenadine on the expressed HERG channel was consistent with data obtained on I(Kr) in isolated guinea pig ventricular myocytes. The strong suppressive effect of terfenadine, noted particularly on the I(Kr) and to a lesser extent on I(to), I(Kl), and I(Ks), may be the cause of the reported incidence of QT prolongation and arrhythmogenesis. The absence of significant effect of loratadine and descarboethoxyloratadine, especially on I(Kr), I(to), I(ped), and I(Kl), even at 100 x highest plasma concentrations achieved, may explain the absence of significant reports of QT prolongation and arrhythmogenesis by the latter drugs.

Suppression of mammalian K+ channel family by ebastine.

Nonsedating H1 receptor (H1-R) antagonists exert variable effects on QT interval, most likely mediated through modulation of cardiac K+ channels. We examined the effects of a novel H1-R antagonist, ebastine, on a family of K+ currents in isolated rat and guinea pig ventricular cardiomyocytes as well as on HERG-induced rapidly delayed rectifier K+ current (I(Kr)) in Xenopus laevis oocytes. The effect of ebastine was compared with that of two other H1-R antagonists, terfenadine and loratadine, with and without reported cardiotoxicity, respectively. In guinea pig ventricular myocytes, ebastine at concentrations approximating those found in plasma under certain conditions suppressed in a voltage-independent manner the I(Kr) (Kd = 0.14 microM, maximum block 74%) more effectively than the slowly delayed rectifier K+ current (I(Ks)) (Kd = 0.8 microM, maximum block 60%). Ebastine also suppressed I(Kr) in HERG-expressing X. laevis oocytes with the Kd value of 0.3 microM and a maximal block of 46% at 3 microM. The block of the rapidly activating delayed rectifier channel in rat myocytes (Iped) (Kd = 1.7 microM, maximum block 58%) had a small voltage dependence. Ebastine only minimally suppressed rat transient K+ current (Ito) (Kd = 1.1 microM, maximum block 10%). The drug was also not a very potent blocker of the inwardly rectifier K+ current (I(K1)) of rat and guinea pig (15 +/- 3% block at 3 microM). At concentrations of <100 nM, ebastine produced negligible effect on all K+ currents. We conclude that ebastine blocks various cardiac K+ channels with different potencies. The group of delayed rectifier K+ currents appeared to be most susceptible to ebastine with the order of sensitivity of I(Kr) > I(Ks) > Iped. Ebastine-induced inhibition of all K+ current types was always weaker than that observed with similar concentrations of terfenadine.

Assessment of a technology that permits individualized scan delays on helical hepatic CT: a technique to improve efficiency in use of contrast material.

OBJECTIVE: We performed this study to assess the usefulness of a computer automated scan technology (CAST) for individualizing scan delay during helical CT to improve the efficiency of hepatic enhancement. SUBJECTS AND METHODS: We prospectively evaluated 183 patients who were randomized into five groups. Control patients received 100 or 150 ml of contrast material (320 mg I/ml) with a 60-sec delay between contrast injection at 3 ml/sec and scanning. CAST patients received 100, 125, or 150 ml. In our latter groups we used an hepatic enhancement threshold of 50 H over baseline to determine the optimum delay between contrast injection and scanning. For the intergroup comparisons, we measured the liver on baseline and enhanced helical CT scans at the upper, mid, and lower levels of the liver. RESULTS: The mean enhancement in patients who received 150 ml of contrast material was 70.7 +/- 19.4 H for the control group and 81.0 +/- 17.5 H for the CAST group (p < .05). Hepatic enhancement above 50 H was achieved in 84% of the control subjects compared with 100% of CAST subjects; more than 60 H hepatic enhancement was achieved in 73% of control subjects and in 89% of CAST subjects. The use of CAST software with 125-ml contrast doses provided enhancement equivalent to that of control subjects who received 150 ml of contrast material (mean enhancement in CAST subjects, 70.3 +/- 15.4 H). Enhancement above 50 H was reached in 98% of CAST and 84% of control patients. With 100 ml of contrast material, 24% of patients failed to initiate CAST, resulting in enhancement similar to control patients (CAST, 54.2 +/- 11.4 H; controls, 56.9 +/- 15.2 H). CONCLUSION: Using a contrast dose of 150 ml, CAST provided significantly increased hepatic enhancement than that achieved in control subjects with less variability. For equivalent hepatic enhancement, contrast doses could be decreased by 25 ml using CAST technology because it provides individualized scan delays.

gamma-Aminobutyric acid gating of Cl- channels in recombinant GABAA receptors.

We studied gamma-aminobutyric acid (GABA) gated whole-cell Cl- currents after rapid transmitter application (< 10 ms) to cells expressing structurally different recombinant GABAA receptors. A variety of recombinant receptors were transiently transfected in a human cell line with three cDNAs encoding for different molecular forms of alpha-, beta- and gamma-subunits of the GABAA receptors. The maximal current amplitude elicited by GABA on recombinant GABAA receptors was greater when the alpha-subunits were combined with beta 2 gamma 2-subunits than with beta 1 gamma 2-subunits, with the exception of receptors including the alpha 6-subunit. The maximal current amplitude elicited by GABA was greater when the beta-subunits were combined with gamma 2 alpha 1-subunits than with gamma 1 alpha 1 subunits, with the exception of receptors including the beta 3-subunit. Furthermore, receptors comprising the beta 3-subunit had a greater sensitivity to GABA than those including the beta 1-or beta 2-subunits. When the gamma-subunits were substituted in receptors including alpha- and beta-subunits, the greatest current amplitude elicited by GABA was obtained with the alpha 1 beta 2 gamma 2 combination, whereas the GABA potency was greater with alpha 1 beta 2 gamma 1 and alpha 1 beta 1 gamma 3 than with the alpha 1 beta 2 gamma 2 combination. In receptors including alpha 6 beta 2-subunits the rank order of GABA maximal current amplitude was gamma 1 > gamma 2 > delta subunits.

Imidazenil: a new partial positive allosteric modulator of gamma-aminobutyric acid (GABA) action at GABAA receptors.

Positive allosteric modulators of gamma-aminobutyric acid (GABA)A receptors, including benzodiazepines and congeners, can be classified into three categories: 1) full allosteric modulators (i.e., triazolam and alprazolam) that act with high potency and efficacy at many GABAA receptors; 2) selective allosteric modulators (i.e., diazepam) that act with high potency and high efficacy at selected GABAA receptors; and 3) partial allosteric modulators (i.e., bretazenil) that act with high potency but low efficacy at many GABAA receptors. Imidazenil, an imidazobenzodiazepine carboxamide, has been characterized as a novel representative of the partial allosteric modulator class. When tested on a broad spectrum (native and recombinant) of GABAA receptors, imidazenil positively modulates the GABA-elicited Cl- currents with a 4- to 5-fold higher potency but an efficacy (30-50%) lower than that of diazepam, and it antagonizes the effects of the latter drug. Imidazenil in vitro (Ki = 5 x 10(-10) M) and in vivo (ID50 = 0.2 mumol/kg i.v.) displaces [3H]flumazenil from its brain binding sites and in vivo it possesses a marked anticonflict profile in the rat Vogel conflict-punishment test and is 10 times more potent than bretazenil and 100 times more potent than diazepam or alprazolam in antagonizing bicuculline- and pentylenetetrazol-induced seizures. Unlike diazepam and alprazolam, which induce sedation and ataxia and potentiate the effects of ethanol and thiopental at doses similar to those that produce anticonflict effects and occupy 50% of brain flumazenil binding sites, imidazenil does not produce ataxia or sedation in rats nor does it potentiate the effects of ethanol or thiopental in doses 30- to 50-fold higher than those required for the anticonflict effect and for 100% occupancy of brain flumazenil binding sites. Furthermore, when administered with diazepam, imidazenil blocks in a dose-related fashion the sedative, ataxic effects of this drug and thus acts on these unwanted responses as an antagonist (i.e., like flumazenil). In all tests, imidazenil has the pharmacological profile of a partial allosteric modulator, but is more potent than bretazenil, has a longer biological half-life and, in rodents, is virtually unable to cause sedation, ataxia or to potentiate ethanol toxicity.

Does neurosteroid modulatory efficacy depend on GABAA receptor subunit composition?

The modulation of GABA activity by 3 alpha-OH-DHP (allopregnanolone, 3 alpha-hydroxy-5 alpha-pregnan-20-one) and PS (pregnenolone sulfate) has been studied in native GABAA receptors of rat cortical neurons in primary cultures and in structurally different recombinant GABAA receptors of rat cortical neurons in primary cultures and in structurally different recombinant GABAA receptors expressed in the 293 human embryonic kidney cell line (HEK 293). In cortical neurons 3 alpha-OH-DHP positively modulates GABA elicited Cl- currents while PS at 10 microM negatively modulates (50% decrease) this GABA response, but at 10 nM PS positively modulates the GABA current (40% increase). Both neurosteroids are equally active on various types of recombinant GABAA receptors, except for alpha 6 beta 1 gamma 2 receptors which are less sensitive to the positive allosteric modulation by 3 alpha-OH-DHP. In contrast the presence of the gamma 1 subunit doubles the efficacy of 3 alpha-OH-DHP. The negative modulation of PS is similar in recombinant GABAA receptors including various molecular forms of alpha or gamma units. A direct activation of Cl- current by 3 alpha-OH-DHP was observed in native and recombinant receptors but its efficacy on the various molecular forms of GABAA receptor tested was always smaller than that of identical concentrations (10 microM) of GABA.

Triazolam is more efficacious than diazepam in a broad spectrum of recombinant GABAA receptors.

Benzodiazepine-induced modifications of GABA (gamma-aminobutyric acid) activated Cl- currents were studied in native GABAA receptors expressed in neonatal rat brain cortical neurons in primary cultures and in recombinant GABAA receptors expressed in transformed human embryonic kidney cells (293) after a transient transfection with cDNAs encoding for different molecular forms of alpha, beta, and gamma subunits of GABAA receptors. The efficacy of triazolam in cortical neurons was higher than that of diazepam. In transfected cells, triazolam showed a greater efficacy as a positive modulator of GABA-elicited Cl- currents in alpha 1 beta 1 gamma 1, alpha 1 beta 1 gamma 2, alpha 1 beta 1 gamma 3, alpha 6 beta 1 gamma 2 and alpha 1 beta 3 gamma 2 receptors than diazepam, except in alpha 3 beta 1 gamma 2 receptors where diazepam was more efficacious. When triazolam and diazepam were applied together to GABAA receptors assembled by transfecting cDNAs encoding for alpha 1 beta 1 gamma 1 subunits, the action of triazolam was curtailed in a manner related to the dose of diazepam. In recombinant receptors assembled with alpha 1 beta 1 gamma 1 receptors, maximally active doses of triazolam were more efficacious than those of clonazepam, alpidem, zolpidem, diazepam or bretazenil.

Molecular mechanisms of the partial allosteric modulatory effects of bretazenil at gamma-aminobutyric acid type A receptor.

In central nervous system gamma-aminobutyric acid (GABA) inhibits neuronal activity by acting on GABA type A (GABAA) receptors. These heterooligomeric integral membrane proteins include a GABA-gated Cl- channel and various allosteric modulatory sites where endogenous modulators and anxiolytic drugs act to regulate GABA action. In vivo, various anxiolytic drugs exhibit a wide range of variability in their modulatory efficacy and potency of GABA action. For instance, bretazenil modulatory efficacy is much lower than that of diazepam. Such low efficacy could be due either to a preferential modulation of specific GABAA receptor subtypes or to a low modulatory efficacy at every GABAA receptor subtype. To address these questions we studied drug-induced modifications of GABA-activated Cl- currents in native GABAA receptors of cortical neurons in primary cultures and in recombinant GABAA receptors transiently expressed in transformed human embryonic kidney cells (293) after transfection with cDNAs encoding different molecular forms of alpha, beta, and gamma subunits of GABAA receptors. In cortical neurons the efficacy of bretazenil was lower than that of diazepam, whereas the potency of the two drugs was similar. In cells transfected with gamma 2 subunits and various molecular forms of alpha and beta subunits bretazenil efficacy was always lower than that of diazepam. However, in cells transfected with gamma 1 or gamma 3 subunits and various forms of alpha and beta subunits the efficacy of both diazepam and bretazenil was lower and always of similar magnitude. When bretazenil and diazepam were applied together to GABAA receptors including a gamma 2 subunit, the action of diazepam was curtailed in a manner related to the dose of bretazenil.

Benzodiazepine antagonist flumazenil reduces bicuculline-induced enhancement of neuronal activity in the spinal cord.

The interaction between the GABAA receptor antagonist bicuculline and the benzodiazepine receptor (BR) antagonist flumazenil was studied in the lumbosacral cord of spinal cats. Bicuculline (0.8 mg/kg i.v.) evoked epileptiform bursting of motoneurons in parallel with a depression of peripherally elicited dorsal root potentials (DRP) and dorsal root reflexes (DDR). A low dose of flumazenil (0.03 mg/kg i.v.) reduced the bursting activity of motoneurons as well as partially reversed the depression of DRP and DRR induced by bicuculline. It is suggested that an endogenous BR ligand down-regulating GABAA receptors is released during the bicuculline-evoked enhancement of neuronal activity and may contribute to the epileptiform discharge of motoneurons in the spinal cord.

Afferent stimulation frequency modulates GABAergic phenomena in the spinal cord: reversal by benzodiazepine antagonists.

Switching from a low (0.5 Hz) to a higher (5 Hz) frequency repetitive stimulation of hindlimb muscle nerve afferents reduced GABA-mediated dorsal root potentials and dorsal root reflexes in the lumbosacral cord of spinal cats. Benzodiazepine receptor antagonists flumazenil and Ro 15-3505 in a very low dose (0.03 mg/kg i.v.) reversed this effect suggesting a stimulation-coupled release of an endogenous benzodiazepine receptor ligand down-regulating GABAA-receptors in the spinal cord.