Differential dependency of cutaneous mechanoreceptors on neurotrophins, trk receptors, and P75 LNGFR

The impact of null mutations of the genes for the NGF family of neurotrophins and their receptors was examined among the wide variety of medium to large caliber myelinated mechanoreceptors which have a highly specific predictable organization in the mystacial pad of mice. Immunofluorescence with anti-protein gene product 9.5, anti-200-kDa neurofilament protein (RT97), and anti-calcitonin gene-related product was used to label innervation in mystacial pads from mice with homozygous null mutations for nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), neurotrophin-4 (NT-4), the three tyrosine kinase receptors (trkA, trkB, trkC), and the low-affinity nerve growth factor receptor p75. Specimens were sacrificed at birth and at 1, 2, and 4 weeks for each type of mutation as well as at 11 weeks and 1 year for p75 and trkC mutations, respectively. Our results demonstrate several major concepts about the role of neurotrophins in the development of cutaneous mechanoreceptors that are supplied by medium to large caliber myelinated afferents. First, each of the high-affinity tyrosine kinase receptors, trkA, trkB, and trkC, as well as the low-affinity p75 receptor has an impact on at least one type of mechanoreceptor. Second, consistent with the various affinities for particular trk receptors, the elimination of NGF, BDNF, and NT-3 has an impact comparable to or more complex than the absence of their most specific high-affinity receptors: trkA, trkB, and trkC, respectively. These complexities include potential NT-3 signaling through trkA and trkB to support some neuronal survival. Third, most types of afferents are dependent on a different combination of neurotrophins and receptors for their survival: reticular and transverse lanceolate afferents are dependent upon NT-3, NGF, and trkA; Ruffini afferents upon BDNF and trkB; longitudinal lanceolate afferents upon NGF, trkA, BDNF, and trkB; and Merkel afferents on NGF, trkA, NT-3, trkC, and p75. NT-4 has no obvious detrimental impact on the mechanoreceptor development in the presence of BDNF. Fourth, NT-4 and BDNF signaling through trkB may suppress Merkel innervation and NT-3 signaling through trkC may suppress Ruffini innervation. Finally, regardless of the neurotrophin/receptor dependency for afferent survival and neurite outgrowth, NT-3 has an impact on the formation of all the sensory endings. In the context of these findings, indications of competitive and suppressive interactions that appear to regulate the balance of innervation density among the various sets of innervation were evident.     

Treatment of complex anterior urethral stricture disease with mesh graft urethroplasty

In this report we describe the toxicokinetics of the Tylenol Extended Relief (TER) preparation of acetaminophen in human overdose. We collected 41 cases of TER overdose from five regional poison centers. Patients who met the following criteria were studied: a single ingestion of TER alone; confirmed time of ingestion; at least four acetaminophen determinations; and normal concentrations of liver function enzymes. With the exception of standard decontamination measures, treatment with N-acetylcysteine (NAC) if any acetaminophen level was above the treatment line of the Rumack-Matthew nomogram, and additional acetaminophen determinations, no interventions were recommended. Our study group comprised 13 patients, 12 female and 1 male, with single overdoses of 10.4 to 65 g TER. The acetaminophen elimination half-life was 3.1 +/- .8 hours (mean +/- SD; range, 1.3 to 4.0 hours; n = 12). The elimination phase for patients 2, 3, 4, 6, 8, 9, 11, 13 was delayed until 8.0 +/- 2.8 hours (range, 5 to 14 hours) after ingestion. Patients 3, 8, and 11--who had initial acetaminophen levels below the "possible toxicity" line of the Rumack-Matthew nomogram--later had acetaminophen levels above this line. No patient demonstrated a late or second acetaminophen peak. We conclude that the elimination half-life of TER acetaminophen is similar to that reported in overdose of immediate-release acetaminophen overdose. In a subgroup of patients, drug absorption continued beyond the 2 to 4 hours previously reported in immediate-release acetaminophen overdose. On the basis of our data, the use of a single 4-hour acetaminophen determination may lead to failure to recognize patients with potentially toxic TER ingestion. Until more toxicokinetic data are available, a reasonable approach would be to obtain at least one additional acetaminophen determination at least 4 to 6 hours after the first, if the first is obtained 4 to 8 hours after ingestion. NAC treatment should be initiated if either level is above the nomogram line but not if both levels fall below the nomogram line.     

High-dose therapy and autologous hematopoietic progenitor cell transplantation for recurrent or refractory Hodgkin's disease: analysis of the Stanford University results and prognostic indices

One hundred nineteen patients with relapsed or refractory Hodgkin's disease (HD) received high-dose therapy followed by autologous hematopoietic progenitor cell transplantation. Three preparatory regimens, selected on the basis of prior therapy and pulmonary status, were employed. Twenty-six patients without a history of prior chest or pelvic irradiation were treated with fractionated total body irradiation, etoposide (VP) 60 mg/kg and cyclophosphamide (Cy) 100 mg/kg. Seventy-four patients received BCNU 15 mg/kg with identical doses of VP and Cy. A group of 19 patients with a limited diffusing capacity or history of pneumonitis received a novel high-dose regimen consisting of CCNU 15 mg/kg, VP 60 mg/kg and Cy 100 mg/kg. Twenty-nine patients (24%) had failed induction therapy and 35 (29%) had progressive HD within 1 year of initial chemotherapy. At 4 years actuarial survival was 52%, event-free survival was 48% and freedom from progression (FFP) was 62%. No significant differences were seen in survival data with the three preparatory regimens. Six patients died within 100 days of transplantation and 5 died at a later date of transplant-related complications. Secondary malignancies have developed in 6 patients, including myelodysplasia/leukemia in four patients and solid tumors in two patients. Regression analysis identified systemic symptoms at relapse, disseminated pulmonary or bone marrow disease at relapse and more than minimal disease at the time of transplantation as significant prognostic factors for overall and event-free survival and FFP. Patients with none of these factors enjoyed an 85% FFP at 4 years compared with 41% for patients with one or more unfavorable prognostic factors (P = .0001). Our results confirm the efficacy of high-dose therapy and autografting in recurrent or refractory HD. Although longer follow-up is necessary to address ultimate cure rates and toxicity, our data indicate that a desire to reduce late effects should drive future research efforts in favorable patients whereas new initiatives are needed for those with less favorable prognoses.     

Prognostic importance of left ventricular diastolic filling velocity profiles in dilated cardiomyopathy

To determine the prognostic importance of pulsed Doppler-derived left ventricular diastolic filling velocity profiles and the relationship between Doppler variables and clinical functional status, the follow-up outcome of 58 patients with dilated cardiomyopathy and symptoms of left ventricular dysfunction was analysed. During a mean follow-up period of 31.2 +/- 12.8 months, 23 died of either progressive pump failure or sudden death. Peak early filling velocity (E) was higher and late atrial filling velocity (A) lower in nonsurvivors than in survivors. The E/A ratio was higher and the deceleration time (DT) of early diastole shorter in nonsurvivors. The mortality was significantly higher in patients with an E/A ratio > 2 or a DT < 150 ms than in those without. Repeated Doppler echocardiographic examinations in 31 of 35 survivors after intense treatment showed decreased E, increased A, reduced E/A ratio and prolonged DT in 18 patients with clinical functional improvement, whereas these measurements were unaltered in the remaining 13 patients whose functional status was unchanged or deteriorated. This study suggests that pulsed Doppler-derived left ventricular diastolic filling variables may be important predictors of outcome in dilated cardiomyopathy and provide useful measures in observing the effects of therapy during long-term follow-up of the patients.     

PGE2 attenuates PGF2 alpha-induced increases in free intracellular calcium in ovine large luteal cells

When ovine large luteal cells are placed in culture and exposed to PGF2 alpha, there is a rapid and sustained increase in the concentration of free intracellular calcium which is believed to play a major role in the luteolytic and cytotoxic effects of PGF2 alpha. Since administration of exogenous PGE2 can prevent spontaneous and PGF2 alpha-induced luteolysis in vivo, and the cytotoxic effects of PGF2 alpha on large luteal cells in vitro, the objective of this study was to determine if one mechanism by which PGE2 acts is to attenuate increases in free intracellular calcium induced by PGF2 alpha. At concentrations of 10 nM or greater, PGF2 alpha caused a significant and sustained increase in free intracellular calcium in large luteal cells. Similarly, PGE2 also induced increases in free intracellular calcium but required doses 20-fold greater than PGF2 alpha. When PGE2 (1, 10 or 100 nM) was incubated with PGF2 alpha (100 nM) increases in free intracellular calcium induced by PGF2 alpha were attenuated (P < 0.05) when measured 5 min, but not at 30 min, after initiation of treatment. The observed decrease in the concentration of free intracellular calcium at 5 min in response to PGF2 alpha was the result of fewer cells responding to PGF2 alpha. In addition, the concentrations of free intracellular calcium attained in the cells that did respond was reduced 25% compared to cells treated with PGF2 alpha alone. Thus, part of the luteal protective actions of PGE2 appears to involve an inhibition of the early (5 min) increase in free intracellular calcium induced by PGF2 alpha.     

Using the bubble inclinometer to measure laryngeal tilt and predict difficulty of laryngoscopy

STUDY OBJECTIVE: To evaluate a simple device, the bubble inclinometer, to measure degrees of laryngeal tilt (LT) for predicting difficulty of direct laryngoscopy using a Macintosh #3 laryngoscope. DESIGN: Randomized, double-blind study. SETTING: Inpatient surgery center at a university medical center. PATIENTS: 50 renal lithotripter patients. INTERVENTIONS: Patients were measured with the bubble inclinometer and the laryngeal indices caliper. A sleep dose of thiopental sodium (4 mg/kg) and a muscle-relaxing dose of succinylcholine (1 mg/kg) were then given to each patient. MEASUREMENTS AND MAIN RESULTS: LT was measured by both methods (directly and indirectly). Difficulty of laryngoscopy was graded as follows: Grade 1 = all of vocal cords seen; Grade 2 = part of vocal cords seen; Grade 3 = no part of vocal cords seen. CONCLUSIONS: The bubble inclinometer accurately and reproducibly measures relative LT, and the anterior tilt of the larynx directly correlates with the ability to see the laryngeal opening during direct laryngoscopy with a Macintosh #3 laryngoscope.     

Dose-response relationship of atracurium besylate in the halothane-anaesthetised pig

The dose response relationship for the intermediate-acting non-depolarising muscle relaxant, atracurium besylate in the pig was determined using evoked electromyography. An incremental dose technique was used in seven Large White/Landrace crossbred pigs anaesthetised with nitrous oxide and halothane. ED50 and ED95 were 510 +/- 87 micrograms kg-1 and 1150 +/- 270 micrograms kg-1, respectively. Although these values may represent an overestimate, they provide a reasonable guideline for the use of atracurium by veterinary anaesthetists.     

Reproducibility of measurements of potential doubling time of tumour cells in the multicentre National Cancer Institute protocol T92-0045

We compared the flow cytometric measurement and analysis of the potential doubling time (Tpot) between three centres involved in the National Cancer Institute (NCI) protocol T92-0045. The primary purpose was to understand and minimize the variation within the measurement. A total of 102 specimens were selected at random from patients entered into the trial. Samples were prepared, stained, run and analysed in each centre and a single set of data analysed by all three centres. Analysis of the disc data set revealed that the measurement of labelling index (LI) was robust and reproducible. The estimation of duration of S-phase (T(S)) was subject to errors of profile interpretation, particularly DNA ploidy status, and analysis. The LI dominated the variation in Tpot such that the level of final agreement, after removal of outliers and ploidy agreement, reached correlation coefficients of 0.9. The sample data showed poor agreement within each of the components of the measurement. There was some improvement when ploidy was in agreement, but correlation coefficients failed to exceed values of 0.5 for Tpot. The data suggest that observer-associated analysis of T(S) and tissue processing and tumour heterogeneity were the major causes of variability in the Tpot measurement. The first two aspects can be standardized and minimized, but heterogeneity will remain a problem with biopsy techniques.