Anti-inflammatory action of dapsone: inhibition of neutrophil adherence is associated with inhibition of chemoattractant-induced signal transduction

Dapsone has clinical utility as an anti-inflammatory agent but the mechanism of this action remains unknown. We have previously reported that dapsone inhibits beta2 integrin (CD11b/CD18)-mediated adherence of human neutrophils in vitro and now describe studies designed to discover how dapsone-mediated inhibition of this neutrophil function occurs. Results indicate that dapsone interferes with the activation or function of the G-protein (Gi type) that initiates the signal transduction cascade common to chemotactic stimuli. They also show that dapsone-mediated suppression of this pathway inhibits the generation of second messengers essential to the activation of beta2 integrin molecules, as well as respiratory and secretory functions of neutrophils exposed to chemoattractants. We propose that the inhibition of chemoattractant-induced signal transduction by dapsone suppresses neutrophil recruitment and local production of toxic respiratory and secretory products in the affected skin of dermatitis herpetiformis and other neutrophilic dermatoses.     

Pathogenetic aspects of the L-arginine-NO metabolic pathway in arteriosclerosis and possible therapeutic aspects

A yearly pattern in the occurrence of uterine cervical cancer (UCC), obtained from cytological examinations reported as type V (cases concluding a malignant alteration), has been previously shown for data obtained in the Monterrey Metropolitan Area (state of Nuevo Leon, Mexico) for a span of 10 years (1978-1987), with a peak of relative incidence in the month of February being high stable for consecutive years. With the aim of extending and validating those results, we analyzed the monthly totals of positive detected cases of UCC in the states of Nuevo Leon, Chihuahua, Coahuila, and Tamaulipas (covering most of Northern Mexico) during the same period. To eliminate bias due to the seasonal variation in the number of screening smears, data were first expressed in relation to the number of cytological examinations done the same month. The least-squares fit of a 1-year cosine curve to the data of relative incidence in the four states reveals a statistically significant yearly pattern (p = .008), with a maximum of relative incidence in February almost double that during the rest of the year. Results indicate that the relative incidence of UCC is higher than the yearly average during the winter, with secondary peaks in May and October. In view of the nonsinusoidal waveform in the incidence of UCC, we undertook a multiple-component analysis, allowing several cosine functions to be simultaneously fitted to the data. Results indicate that the yearly pattern in the relative incidence of UCC can be represented by a model that includes two components with periods of 12 and 4 months (p = .004). The same model can be documented as statistically significant independently for each of the four states. These results, summarizing over 2200 positive cases of UCC detected in more than 1,100,000 screening smears, are in full agreement with those found previously for part of the state of Nuevo Leon and reveal a highly stable and predictable yearly pattern of variation in the relative incidence of UCC in Northern Mexico.     

Evaluation of serum gamma-glutamyltransferase activity as a predictor of passive transfer status in crias

OBJECTIVE: To determine the relationship between serum gamma-glutamyltransferase (GGT) activity and serum IgG concentration in neonatal crias. DESIGN: Prospective observational study. ANIMALS: 21 llama and 4 alpaca crias from 0 to 5 days old. PROCEDURE: Serum GGT activity was measured, using a commercially available kit. Serum IgG concentration was determined by use of radial immunodiffusion. With a serum IgG concentration of 1,000 mg/dl (considered adequate passive transfer), specificity and sensitivity of serum GGT activity in the detection of failure of passive transfer were determined. Regression models were developed to determine the relationship between serum GGT activity and serum IgG concentration. RESULTS: Sensitivity ranged from 0.56 to 0.89, and specificity ranged from 0.88 to 0.31, depending on the value of serum GGT activity chosen as a threshold. Proportion of crias correctly classified ranged from 0.76 to 0.52. Regression models failed to demonstrate a significant relationship between serum GGT activity and serum IgG concentration. CLINICAL IMPLICATIONS: Passive transfer status in crias cannot be accurately predicted on the basis of serum GGT activity.     

Becker muscular dystrophy with bundle branch reentry ventricular tachycardia

This report describes a case of Becker muscular dystrophy presenting with recurrent symptomatic wide complex tachycardia. Electrophysiologic testing demonstrated the mechanism to be bundle branch reentry ventricular tachycardia. It is important to consider this potential mechanism in patients with ventricular arrhythmias who have this particular clinical entity, since radiofrequency catheter ablation can represent a curative treatment.     

Amifostine (WR-2721) shortens the engraftment period of 4-hydroperoxycyclophosphamide-purged bone marrow in breast cancer patients receiving high-dose chemotherapy with autologous bone marrow support

4-Hydroperoxycyclophosphamide (4-HC), a commonly used marrow-purging agent, is active against many tumors, but is also toxic to normal marrow progenitors. Amifostine (WR-2721) is a sulfhydryl compound with chemoprotectant activity. Preclinical studies using suspensions of bone marrow and breast cancer cells demonstrated that ex vivo treatment with amifostine followed by 4-HC resulted in protection of marrow progenitors, with no compromise in the antitumor effect of 4-HC. This fact stimulated the development of a clinical trial. Bone marrow was harvested from 15 poor-prognosis breast cancer patients and randomly assigned to ex vivo treatment with amifostine followed by 4-HC (amifostine + 4-HC), or treatment with 4-HC alone. High-dose chemotherapy was then administered followed by infusion of the purged autologous bone marrow support (ABMS). Leukocyte engraftment, defined as a white blood cell count > or = 1 x 10(9)/L, was achieved in an average of 26 days for patients whose marrow was purged with amifostine + 4-HC versus 36 days for patients whose marrow was purged with 4-HC alone (P = .032). The average number of platelet transfusions (12 v 29; P = .017) and days of antibiotic therapy (28 v 40; P = .012) were significantly less for patients whose marrow was exposed to amifostine + 4-HC, compared with 4-HC alone. Unpurged backup marrow fractions were infused into three patients whose marrow was purged with 4-HC alone, because of inadequate marrow recovery. None of the patients who received amifostine + 4-HC-purged marrow required a backup marrow fraction. Complete remissions were achieved in 83% of patients with measurable disease, with no difference between the two cohorts. Forty-three percent of patients remained alive and progression-free at a mean of 13 months posttransplant. There was no significant difference in the rate or pattern of relapse for patients whose marrow was purged with amifostine + 4-HC compared with those whose marrow was purged with 4-HC alone. Ex vivo treatment of marrow with amifostine significantly shortens the time to marrow recovery, thereby reducing the risk of myelosuppressive complications in breast cancer patients receiving high-dose chemotherapy and 4-HC-purged ABMS. Since supportive care requirements are also significantly decreased, amifostine may reduce the cost of such therapy.     

Absorbability of Calcium From Common Beans

Absorption of calcium from white, red, and pinto beans, labeled with ⁴⁵Ca, was measured in 24 women in a three-way randomized design using a calcium load of 72 mg and milk as the referent. Fractional absorption for the three beans averaged 0.219 ± 0.047 and did not differ by type. Milk calcium absorption at the same load was more than two times higher, 0.451 ± 0.088 (P < 0.001). Oxalate content averaged 0.34%, and phytate averaged 1.7%, a stoichiometric excess relative to calcium. To evaluate the relation of phytate to reduced absorbability, labeled pinto beans were pre-treated with phytase and fed to 10 subjects. Fractional absorption rose, averaging 0.318 ± 0.071, (P <0.01 vs. untreated beans), but was significantly below that of milk. The difference was partly accounted for by phytate, with the remainder probably due to relatively high oxalate.     

An intrinsic guanine nucleotide exchange inhibitor in Gi2 alpha. Significance of G-protein self-suppression which antagonizes receptor signal

The alpha subunit of Gi2 (Gi2 alpha) is a member of the heterotrimeric G protein family, which transduces receptor signals as a proto-oncogene product. We have found a novel self-suppressive region in Gi2 alpha near its C terminus. A polypeptide consisting of residues 338-352 of Gi2 alpha (Gi2 alpha-339-352) antagonizes receptor- and receptor peptide-stimulated Gi2 alpha activation, without affecting basal activity. Antagonism by Gi2 alpha-338-352 is attributable to an interaction with activated Gi2 alpha, which is not competitive with receptor polypeptides. Combined with the reports suggesting the presence of self-suppressive domains in a juxta-C-terminal portion of Gi2 alpha and G(o) alpha, this study supports the hypothesis that Gi2 alpha-338-352 constitutes an intrinsic guanine nucleotide exchange inhibitor, which in turn antagonizes receptor stimulation, suggesting that G proteins are activated by receptors through relaxation of a self-suppressive conformation.     

Are max-specified infant facial expressions during face-to-face interaction consistent with differential emotions theory?

Differential emotions theory (DET) proposes that infant facial expressions of emotions are differentiated. To test this hypothesis, the authors examined infant facial expressions longitudinally at 2, 4, and 6 mo of age during face-to-face play and a "still-face" interaction with their mothers. Infant expressions were coded using the Maximally Discriminative Facial Movement Coding System (Max). Consistent with DET, discrete positive expressions occurred more of the time and were of longer duration than blended expressions of positive affect. Contrary to DET, at no age did the proportions or durations of discrete and blended negative expressions differ, and they showed different patterns of developmental change. One is led to either reject or revise DET or else question the adequacy of the Max system. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Lactate clearance and survival following injury

Previous reports cite optimization of O2 delivery (DO2) to 660 mL/min/m2, O2 consumption (VO2) to 170 mL/min/m2, and cardiac index (CI) of 4.5 L/min as predicting survival. We prospectively evaluated 76 consecutive patients with multiple trauma admitted directly to the ICU from the operating room or emergency department. Patients had serum lactate levels and oxygen transport measured on ICU admission and at 8, 16, 24, 36, and 48 hours. Patients were analyzed with respect to survival (S) versus nonsurvival (NS), lactate clearance to normal (< or = 2 mmol/L) by 24 and 48 hours, hemodynamic optimization as defined above, as well as Injury Severity Score (ISS), ICU stay (LOS), and admission blood pressure. All patients achieved non-flow-dependent VO2. There was no difference in CI, DO2, VO2, or ISS when S was compared with NS. All 27 patients whose lactate level normalized in 24 hours survived. If lactate levels cleared to normal between 24 and 48 hours, the survival rate was 75%. Only 3 of the 22 patients who did not clear their lactate level to normal by 48 hours survived. Ten of the 25 nonsurvivors (40%) achieved the above arbitrary optimization criteria. Fifteen of the survivors never achieved any of these criteria. Optimization alone does not predict survival. However, the time needed to normalize serum lactate levels is an important prognostic factor for survival in severely injured patients.