Observations on the direction of wear in Charnley sockets retrieved at revision

The direction of wear in the acetabular socket has implications for the amount of debris that is generated during movement, for the magnitude of eccentric loading and for the incidence of impingement of the neck. We observed the direction of penetration with respect to a global co-ordinate system in 84 acetabular components retrieved at reoperation. The mean direction of wear relative to the open face of the sockets was found to be 37 degrees with a range from 0 degrees to 87 degrees. For those values determined using the inclination of the socket on the prerevision radiograph, the mean direction of penetration in the coronal plane had a lateral, rather than a medial, component. The mean angle was 84 degrees (SD 17 degrees) with respect to the horizontal. The angle of penetration was found to correlate significantly with the depth, in that the lateral component became larger as the wear progressed. There was also a significant correlation between the rate of penetration and the direction of wear. Despite the theoretical advantage of penetration in the superolateral direction, i.e., along the margin of the socket, in reducing the probability of impingement of the neck, no significant correlation was seen between the angle of penetration and the period of use in vivo. This may suggest that impingement of the femoral neck on the rim of the socket may not be the dominant factor in loosening of the socket but can still be important in a few cases.     

Stereospecific effect of bupivacaine isomers on atrioventricular conduction in the isolated perfused guinea pig heart

BACKGROUND: The local anesthetic bupivacaine is an equal mixture of two optically active isomers known to exert different cardiotoxic profiles in vivo. Enantiomer-specific forms of bupivacaine may have differential effects on cardiovascular function, specifically on cardiac electrophysiology. The authors' aim was to determine if there were any direct functional differences in the cardiac effects of bupivacaine isomers. The isolated heart was used to avoid possible indirect cardiac effects of bupivacaine, such as autonomic nervous and hormonal influences, as well as preload and afterload factors. METHODS: The hearts of 12 ketamine-anesthetized guinea pigs were perfused with Krebs-Ringer's solution (97% oxygen, 3% carbon dioxide) at constant perfusion pressure using the Langendorff technique. Atrial and ventricular bipolar electrodes were placed to measure heart rate (HR) and atrioventricular (AV) conduction time. Left ventricular pressure (LVP), coronary flow, and inflow and outflow oxygen tensions were also measured. Oxygen delivery, oxygen consumption (MVO2), and percentage of oxygen extraction were calculated. Each heart was perfused with increasing randomized concentrations (0.5, 1, 5, 10 microM) of both isomers and the racemate of bupivacaine. RESULTS: Racemic and isomeric bupivacaine equally and dose dependently decreased cardiac function. At 10 microM bupivacaine these changes were HR, -17 +/- 2%; LVP, -50 +/- 3%; coronary flow, -20 +/- 4%; and MVO2, -46 +/- 4%. The (+) isomer significantly prolonged AV conduction compared with the racemate and the (-) isomer at all concentrations. At 10 microM, AV time was 54 +/- 6% longer with the (+) isomer and 30 +/- 4% longer with the (+/-) racemate than with the (-) isomer. The greater delay in AV time with the (+) than the racemate or (-) isomer led to a second-degree AV dissociation in 10 of 12 of hearts treated with (+) bupivacaine. CONCLUSIONS: This study shows that bupivacaine has an enatiomer-specific effect to delay AV conduction and to produce second-degree AV dissociation in the isolated perfused heart. This suggests that bupivacaine isomers probably have differential effects on one or more ion-specific channels regulating AV conduction. Other measured direct cardiac effects of bupivacaine appear to be independent of the isomeric form.     

Baroreflex impairment by low sodium diet in mild or moderate essential hypertension

Low sodium intake is the most widely used nonpharmacological approach to the treatment of hypertension. Although nonpharmacological treatment is by definition regarded as safe, the suggestion has been made that low sodium intake is not totally devoid of inconveniences, and animal data have shown it to be accompanied by an impairment of reflex blood pressure control and homeostasis. However, no data exist on this issue in humans. In mild essential hypertensive patients (age, 34.1+/-3.3 years [mean+/-SEM]), we measured beat-to-beat arterial blood pressure (finger photoplethysmographic device), heart rate (electrocardiogram), and efferent postganglionic muscle sympathetic nerve activity (microneurography) at rest and during baroreceptor stimulation and deactivation, induced by stepwise intravenous infusions of phenylephrine and nitroprusside, respectively. Measurements were performed at the end of three dietary periods, ie, after 8 days of regular sodium intake (210 mmol NaCl/d), low sodium intake (20 mmol NaCl/d) with unchanged potassium intake, and again regular sodium intake. Compared with the initial regular sodium diet, low sodium intake reduced urinary sodium excretion, whereas urinary potassium excretion was unchanged. Systolic blood pressure was significantly (P<.05), although slightly, reduced, whereas diastolic blood pressure was unaffected. Muscle sympathetic nerve activity was increased by 23.1+/-5.2% (P<.05). The increase was accompanied by a clear-cut impairment of the baroreceptor ability to modulate muscle sympathetic nerve activity, ie, by a 43.9+/-5.7% (P<.01) reduction in the sensitivity of the baroreceptor-muscle sympathetic nerve activity reflex compared with the control condition. Baroreceptor modulation of heart rate was also impaired, although to a smaller and less consistent extent. When regular sodium intake was restored, all the above-mentioned parameters and baroreflex responses returned to the values observed at the initial regular sodium diet. These data raise evidence that in humans sodium restriction may impair the arterial baroreflex. This may be responsible for the sympathetic activation occurring in this condition and for the impairment of blood pressure homeostasis.     

Imprinted expression of the murine Angelman syndrome gene, Ube3a, in hippocampal and Purkinje neurons

BACKGROUND: Edatrexate and carboplatin are each active single agents in the treatment of non-small-cell lung cancer (NSCLC). Preclinical studies in NSCLC lines have demonstrated schedule-dependent synergy of edatrexate followed by carboplatin. In a phase I trial, we demonstrated the tolerability of this combination, the ability of ice-chip cryotherapy to ameliorate dose-limiting mucositis, and promising activity in NSCLC. This phase II trial (SWOG 9207) was undertaken to investigate the efficacy of this regimen in stage IV NSCLC. METHODS: A total of 24 patients with stage IV disease were accrued to this Southwest Oncology Group (SWOG) multicenter study. Treatment consisted of edatrexate 80 mg/m2 (50% dose on day 8) intravenously weekly for 5 weeks, then every other week, and carboplatin 350 mg/m2 every 28 days. RESULTS: Of the 24 patients, 23 were assessable for toxicity and response; one was ineligible for study entry. Myelosuppression was the most significant toxicity; grade 3-4 neutropenia was seen in 8/23 patients. Two patients died of neutropenic sepsis during the first cycle of therapy, in both instances associated with the presence of pleural effusions. Although mild mucositis was common, it was dose-limiting (grade 3) in only three patients. Objective response was observed in 3/23 patients (13%). The median survival time was 7 months, and 30% of patients remained alive at one year. CONCLUSIONS: This study suggests that ice-chip cryotherapy is effective in reducing the severity of mucositis typically associated with this edatrexate schedule of administration. However, unexpectedly severe myelosuppression resulted in death from neutropenic sepsis in two patients with third space fluid collections, leading to a protocol amendment to exclude such patients from study entry. Furthermore, response and median survival with this dose schedule of edatrexate and carboplatin do not appear to be improved compared to other chemotherapeutic regimens tested by SWOG in this patient population.     

Skeletal muscle regeneration during aging and after long-term denervation

Data accumulated in recent years strongly suggest that the basis for at least part of the muscle atrophy seen in old age is related to the diminution of motor innervation in normal muscle and a decreased effectiveness of reinnervation of regenerating muscle fibers. Thus, attempts to stabilize reverse the decline of the skeletal musculature during aging must take into account both the effects of aging on the peripheral nervous system and the presence of populations of denervated muscle fibers in the aging muscles. Of considerable importance is the question of how long muscle fibers in old animals can remain denervated before they begin to lose their capacity for restoration if they ultimately become reinnervated. The experimental studies reviewed here have shown that normal muscles in old animals are capable of a high degree of restoration as long as their motor nerve supply remains undamaged. After a certain period of time, denervated muscle in young animals steadily loses the capacity to restore or repair itself. To date, so little information is available on the properties of denervated muscle in old animals that meaningful comparisons cannot be made. Ultimately, ensuring that normal or injured muscle in old individuals is supplied by an effective motor innervation may be a real key to the problems of muscle loss in old age, but if such could be provided, it will be important that the old musculature, whether normal or injured, is capable of adequately responding to the innervation.     

Effect of centrifugation on the pressure resistance of exponential phase cells of Escherichia coli 8164

OBJECTIVE: To assess the efficacy of partial left ventriculectomy as a treatment for patients with end-stage heart failure. METHODS: From February to June 1995, 7 patients with end-stage heart failure underwent partial left ventriculectomy. Subsequently, patients underwent clinical evaluation every 2 months, and 2-dimensional echocardiography at the 6th and 12th months after cardiac surgery. All patients were given digitalis and diuretics at conventional doses, and captopril or enalapril at maximal tolerated doses. RESULTS: Two (28%) patients died; 1 from cardiac arrhythmia associated with gastrointestinal hemorrhage, and the other suddenly. One (14%) patient developed an embolic cerebrovascular accident. Four (57%) patients were hospitalized for congestive heart failure; all of them had either decreased the daily dose of captopril or enalapril or discontinued the drugs by themselves. Twelve months after ventriculectomy, left ventricular ejection fraction values were greater and left ventricular diastolic dimension and functional class values lower than those found before cardiac operation. CONCLUSION: Beneficial effects of partial left ventriculectomy are observed one year after the surgical procedure. This technique, therefore, can be useful for the treatment of patients with end-stage heart failure.     

Preserved catalytic activity in an engineered ribonucleotide reductase R2 protein with a nonphysiological radical transfer pathway. The importance of hydrogen bond connections between the participating residues

A hydrogen-bonded catalytic radical transfer pathway in Escherichia coli ribonucleotide reductase (RNR) is evident from the three-dimensional structures of the R1 and R2 proteins, phylogenetic studies, and site-directed mutagenesis experiments. Current knowledge of electron transfer processes is difficult to apply to the very long radical transfer pathway in RNR. To explore the importance of the hydrogen bonds between the participating residues, we converted the protein R2 residue Asp237, one of the conserved residues along the radical transfer route, to an asparagine and a glutamate residue in two separate mutant proteins. In this study, we show that the D237E mutant is catalytically active and has hydrogen bond connections similar to that of the wild type protein. This is the first reported mutant protein that affects the radical transfer pathway while catalytic activity is preserved. The D237N mutant is catalytically inactive, and its tyrosyl radical is unstable, although the mutant can form a diferric-oxo iron center and a R1-R2 complex. The data strongly support our hypothesis that an absolute requirement for radical transfer during catalysis in ribonucleotide reductase is an intact hydrogen-bonded pathway between the radical site in protein R2 and the substrate binding site in R1. Our data thus strongly favor the idea that the electron transfer mechanism in RNR is coupled with proton transfer, i.e. a radical transfer mechanism.     

Concurrent pharmacokinetic analysis of plasma cocaine and adrenocorticotropic hormone in men

The purpose of this study was to determine the covariance between plasma cocaine and ACTH pharmacokinetics. Twelve healthy male occasional cocaine users participated in a double blind study. Intravenous cocaine (0.2 mg/kg) or placebo was infused over 1 min, and samples for cocaine, ACTH and cortisol analysis were collected at 2, 4, 8, 12, 16, 20, 30, 40, 60, 80, 120, 180, and 240 min. Peak cocaine plasma levels averaged 101.2 +/- 14.6 ng/mL. ACTH increases were significantly correlated (P < 0.0001) with increases in plasma cocaine levels (r = 0.67; r2 = 0.44). Pharmacokinetic analysis showed that the t(max) (observed time to maximum concentration) values for cocaine (6.0 +/- 1.4 min) and ACTH (7.3 +/- 1.2 min) were almost identical. The area under the curve was calculated using the trapezoidal rule. The area under the curve for plasma cocaine was 6463 +/- 1070 ng/min x mL, and the area under the curve for ACTH was 1873 +/- 188 pmol/min x L. The mean half-life for plasma cocaine was 46.7 +/- 4.0 min, and that for ACTH was 35.8 +/- 5.1 min. Cardiovascular and subjective effect measures were correlated with concurrent increases in plasma cocaine and ACTH levels.     

The effect of dietary vitamin D3 on the intracellular calcium gradient in mammalian colonic crypts

A physiological gradient in intracellular calcium ([Ca2+]i) has been hypothesized to exist along the colonic crypt base-mouth axis, which may be involved in the regulation of colonocyte proliferation, differentiation and apoptosis. In addition [Ca2+]i may be modulated by dietary vitamin D3 which is thought to be protective against colorectal cancer. CF1 mice were maintained for 6 weeks on a defined diet containing either high or low vitamin D3. A colonic crypt base-mouth [Ca2+]i gradient of 201 +/- 79 nM (mean +/- SEM, P < 0.05) was observed in animals maintained on a high vitamin D3 diet and was abolished in mice maintained on a low vitamin D3 diet. The [Ca2+]i gradient was independent of extracellular calcium and elevated levels of [Ca2+]i observed in the basal regions of the crypt in animals maintained on low levels of vitamin D3 were also associated with an increase in intracellular calcium stores. Therefore, a [Ca2+]i gradient exists in colonic crypts and is dependent on dietary vitamin D3.