Modulation of IgG effector functions by a monovalent fragment of staphylococcal protein A

The monovalent V-1 fragment of protein A (fSpA) with a mol. wt of 13,000 obtained from an u.v. mutant of Staphylococcus aureus Cowan I strain was proved to be able to modulate significantly some of the effector functions of IgG, such as complement fixation, catabolism, attachment to Fc receptors and antibody-dependent cell-mediated cytotoxicity. Moreover fSpA-like protein A obtained from the A676 strain is mitogenic and enhances NK activity of human peripheral lymphocytes. The efficiency of fSpA was found to be lower than that of protein A with regard to its ability to inhibit complement fixation, EA rosette formation and antibody-dependent cell-mediated cytotoxicity. Both protein A and fSpA had the same efficiency in activation of the complement system after reaction with human or guinea pig IgG, and in increasing the IgG catabolism. Unlike fSpA the monovalent B fragment of protein A (with mol. wt of 7000) was not able to inhibit EA rosette formation and antibody-dependent cell-mediated cytotoxicity. The results recommend fSpA, substituting for protein A, as a molecular probe for the investigation of IgG antibody and lymphocyte effector functions.     

Increased apical enlargement contributes to excessive dentin removal in curved root canals: a stepwise microcomputed tomography study

Introduction

To determine whether increased apical enlargement would result in a complete preparation of curved canals and to progressively assess shaping quality using multiple microcomputed tomography (MCT) scans.

Methods

Ninety root canals with a curvature of 25° to 50° were selected. Five MCT scans, 1 preoperative and 4 postoperative, were acquired from each canal. Canal preparation was performed up to size 50 using 3 techniques, nickel-titanium (NiTi) hand files, Mtwo (VDW, Munich, Germany), and ProTaper (Maillefer, Ballaigue, Switzerland), by experienced operators in a dental mannequin so as to simulate the clinical conditions. At a level of 1 mm short of the working length, 2 parameters were evaluated in each of the 4 postoperative acquisitions: the percentage of the prepared outline and the amount of dentin removed (the prepared area).

Results

Statistically, there was no significant difference between the 3 systems used regarding the prepared outline. The maximum prepared outline was achieved by the use of NiTi hand files (63%; confidence interval [CI], 54%–73%), whereas Mtwo and ProTaper amounted to 58% (CI, 50%–66%) and 60% (CI, 51%–70%), respectively. In contrast, the dentin area removed by ProTaper was significantly higher than that of Mtwo and NiTi hand files.

Conclusions

Increased apical enlargement of curved canals did not result in a complete apical preparation, whereas it did lead to the unnecessary removal of dentin.     

Consistency of Apex Locator Function: A Clinical Study

The consistency of apex locators was determined by calculating the dysfunction frequency. Electronic working length (EWL) was determined in 507 patients requiring endodontic treatment. Different clinical parameters were recorded including tooth vitality, presence of obliteration, and metallic restoration. Two apex locators were used (Root ZX [Morita, Tokyo, Japan] and Raypex5 [VDW, Munich, Germany]). Apex locator performance was considered “consistent” when the scale bars were stable and moved only in correspondence to the movement of file in the root canal. A working length radiograph with files set to the EWL was performed. EWL were considered “acceptable” when the file tip was located 0 to 2 mm short of the radiographic apex. The function of apex locators was consistent in 85% of the patients (429/507 [99% confidence interval, 80-88]). The inconsistent measurements were strongly associated with partially or totally obliterated root canals (p < 0.0001). Radiographically, 97% of consistent measurements were “acceptable.”     

Cardiovascular risk factors for physician-diagnosed lumbar disc herniation

BACKGROUND CONTEXT: Despite the high prevalence of lumbar disc disease among the general population, the determinants of this condition remain poorly understood. A recent hypothesis suggests that atherosclerotic vascular disease may play an important role in the etiology of this disorder. PURPOSE: To explore the relationship between cardiovascular risk factors and the incidence of lumbar disc herniation. STUDY DESIGN/SETTING: We prospectively examined the association between smoking, high cholesterol, high blood pressure, obesity, and diabetes and self-reported lumbar disc herniation. The study was conducted among 98,407 female nurses who in 1976 were ages 30-55 years, free of cancer (except non-melanoma skin cancer), lumbar disc disease, and who responded to the 1992 questionnaire regarding whether or not a physician diagnosis of lumbar disc herniation had been made. RESULTS: During 16 years of follow-up (438,662 person-years), 2,727 nurses who were free of cancer reported a physician-diagnosed lumbar disc herniation that was confirmed either by computed tomography or magnetic resonance imaging. After adjusting for age, body mass index, smoking, vigorous or moderate exercise, employment status, having seen a physician in the last year, and each of the following other factors, the multivariate relative risk for diabetes was 1.52 (95% confidence interval [95% CI], 1.17 to 1.98); for hypertension it was 1.25 (95% CI, 1.11 to 1.41); for high cholesterol it was 1.26 (95% CI, 1.10 to 1.44), and for having a parent who had suffered a myocardial infarction before age 60 it was 1.13 (95% CI, 1.02 to 1.26). In these models, compared with never smokers, the relative risk for past smokers was 1.10 (95% CI, 1.00 to 1.20), for current smokers the risk increased with the number of cigarettes smoked per day. A decrease in risk occurred after cessation. Also in these models, we noted a significant trend of increasing risk with higher body mass index (p=.01). CONCLUSIONS: Cardiovascular risk factors are significantly and independently associated with symptomatic lumbar disc herniation. These findings provide further confirmation that atherosclerosis may be involved in spinal disc degeneration. Modification of risk factors, particularly smoking, may also prove to be beneficial.     

Position Paper of the American Council on Science and Health on Risk Factors for Breast Cancer: Established, Speculated, and Unsupported

Abstract: This article provides the position of the American Council on Science and Health regarding how breast cancer is defined and classified; the magnitude of the public health problem of breast cancer among women; the implications of variation in incidence of breast cancer internationally and with migration; access to health care as a factor in slight differences in incidence and mortality rates among African-American and white women; and the evidence concerning various proposed human-breast-cancer risk factors. The article classifies risk factors as either established, speculated, or unsupported on the basis of available evidence. Specific genes have been identified that may explain as much as 5–10% of new breast cancer cases. Inherited predispositions may be characterized by family history of breast or ovarian cancer, young age at diagnosis, breast cancer diagnosed in both breasts, and male breast cancer. Benign breast disease (BBD), particularly the subtypes of BBD involving atypical hyperplasia, and exposure early in life to ionizing radiation is an established risk factor for breast cancer. Several reproductive characteristics are established as risk factors for breast cancer: early age at menarche, first full-term pregnancy after age 35 years of late age, and late age of menopause. Obesity and low physical activity are established as risk factors for breast cancer and are modifiable. Speculated risk factors for breast cancer that are gaining scientific support include nulliparity, oral contraceptive use, and postmenopausal estrogen replacement therapy. Speculated risk factors for which there is conflicting or preliminary support include not breast feeding, postmenopausal estrogen/progestogen replacement therapy, prescribed diethylstilbestrol, low consumption of phytoestrogens, specific dietary practices, alcohol consumption, not using nonsteroidal antinflammatory drugs, abortion, and breast augmentation. Unsupported risk factors include higher than average consumption of phytoestrogens, premenopausal obesity, electromagnetic fields, and low-dose ionizing radiation after 40 years of age. There is only limited support for xenoestrogens and large breast size as risk factors for breast cancer.     

Test–retest reliability and longitudinal analysis of automated hippocampal subregion volumes in healthy ageing and Alzheimer's disease populations

The hippocampal formation is a complex brain structure that is important in cognitive processes such as memory, mood, reward processing and other executive functions. Histological and neuroimaging studies have implicated the hippocampal region in neuropsychiatric disorders as well as in neurodegenerative diseases. This highly plastic limbic region is made up of several subregions that are believed to have different functional roles. Therefore, there is a growing interest in imaging the subregions of the hippocampal formation rather than modelling the hippocampus as a homogenous structure, driving the development of new automated analysis tools. Consequently, there is a pressing need to understand the stability of the measures derived from these new techniques. In this study, an automated hippocampal subregion segmentation pipeline, released as a developmental version of Freesurfer (v6.0), was applied to T1‐weighted magnetic resonance imaging (MRI) scans of 22 healthy older participants, scanned on 3 separate occasions and a separate longitudinal dataset of 40 Alzheimer's disease (AD) patients. Test–retest reliability of hippocampal subregion volumes was assessed using the intra‐class correlation coefficient (ICC), percentage volume difference and percentage volume overlap (Dice). Sensitivity of the regional estimates to longitudinal change was estimated using linear mixed effects (LME) modelling. The results show that out of the 24 hippocampal subregions, 20 had ICC scores of 0.9 or higher in both samples; these regions include the molecular layer, granule cell layer of the dentate gyrus, CA1, CA3 and the subiculum (ICC > 0.9), whilst the hippocampal fissure and fimbria had lower ICC scores (0.73–0.88). Furthermore, LME analysis of the independent AD dataset demonstrated sensitivity to group and individual differences in the rate of volume change over time in several hippocampal subregions (CA1, molecular layer, CA3, hippocampal tail, fissure and presubiculum). These results indicate that this automated segmentation method provides a robust method with which to measure hippocampal subregions, and may be useful in tracking disease progression and measuring the effects of pharmacological intervention.     

Antidepressants induce cellular insulin resistance by activation of IRS-1 kinases

Certain selective serotonin reuptake inhibitors (SSRIs) induce the clinical and biochemical manifestations of a metabolic syndrome by as yet unknown mechanism. Here we demonstrate that incubation (1 h) of rat hepatoma Fao cells with the SSRIs paroxetine and sertraline, but not with the atypical antipsychotic drug olanzapine, inhibited the insulin-stimulated Tyr phosphorylation of the insulin receptor substrate-1 (IRS-1) with half-maximal effects at approximately 10 microM. This inhibition correlated with a rapid phosphorylation and activation of a number of Ser/Thr IRS-1 kinases including JNK, S6K1, ERK and p38 MAPK, but not PKB (Akt). JNK appears as a key player activated by SSRIs because specific JNK inhibitors partially eliminated the effects of these drugs. The SSRIs induced the phosphorylation of IRS-1 on S307 and S408, which inhibits IRS-1 function and insulin signaling. These results implicate selected SSRIs as inhibitors of insulin signaling and as potential inducers of cellular insulin resistance.