Internal validity of inter‐digital web pinching as a model for perceptual diffuse noxious inhibitory controls‐induced hypoalgesia in healthy humans

Hot and ice‐water immersions are commonly used for heterotopic noxious counter‐stimulation (HNCS) in investigations on endogenous pain modulation. However, coincident sympathetic thermoregulatory activity does not allow to differentiate between perceptual hypoalgesia related to baroreflex sensitivity (BRS) or diffuse noxious inhibitory controls (DNIC). The present study analysed the internal validity of another supposedly less confounded tonic pain model (inter‐digital web pinching; IWP) regarding its potential as DNIC trigger. We performed a randomized controlled study in 24 healthy gender‐matched drug‐free volunteers aged 21–54 (median 25) years. The study protocol comprised the assessment of mechanical and thermal perceptual wind‐up before and after an IWP (15N) or hot water immersion trial (HIT; 47.5°C) of 2min duration. Wind‐up was induced either by 10 repetitive (1Hz) contact heat (max. 49°C; 5×5mm thermode) or ballistic impact stimuli (0.5g at 9m/s) on the phalanges of the non‐dominant hand. Cardiovascular activity, pain experience and corrugator muscle activity were continuously monitored. Although both HNCS forms produced a similar pain experience (45% of scale), a more pronounced cardiovascular activity was observable for the HIT (P<0.01). This indicates a higher baroreceptor activity and stronger contamination of painful water immersion by BRS‐related hypoalgesia. Regardless of pain modality, wind‐up was significantly reduced by HNCS, although this was stronger for painful water immersion than for noxious pinching (P<0.01). The HNCS types allow a differentiation between BRS‐related and DNIC‐like hypoalgesia. IWP proved its validity for DNIC induction, being practically non‐confounded by BRS.     

DHEA and its transformation into androgens and estrogens in peripheral target tissues: intracrinology.

A new understanding of the endocrinology of menopause is that women, at menopause, are not only lacking estrogens resulting from cessation of ovarian activity but have also been progressively deprived for a few years of androgens and some estrogens originating from adrenal DHEA and androstenedione (4-dione). In fact, serum DHEA decreases by about 60% between the maximal levels seen at 30 years of age to the age of menopause. This decreased secretion of DHEA and DHEA-S by the adrenals is responsible for a parallel decrease in androgen and estrogen formation in peripheral tissues by the steroidogenic enzymes specifically expressed in each cell type in individual target tissues. This new field of endocrinology, called intracrinology, describes the local synthesis of androgens and estrogens made locally in each cell of each peripheral tissue from the adrenal precursors DHEA and 4-dione. These androgens and estrogens exert their action in the same cells where their synthesis takes place and they are released from these target cells only after being inactivated. To further understand the effect of DHEA in women, DHEA has been administered in postmenopausal women for 12 months. Such treatment resulted in increased bone formation and higher bone mineral density accompanied by elevated levels of osteocalcin, a marker of bone formation. Vaginal maturation was stimulated, while no effect was observed on the endometrium. Preclinical studies, on the other hand, have shown that, due to its predominant conversion into androgens, DHEA prevents the development and inhibits the growth of dimethylbenz(a)anthracene-induced mammary carcinoma in the rat, a model of breast cancer. DHEA also inhibits the growth of human breast cancer ZR-75-1 xenografts in nude mice. The inhibitory effect of DHEA on breast cancer is due to an androgenic effect of testosterone and dihydrotestosterone made locally from DHEA. When used as replacement therapy, DHEA is free of the potential risk of breast and uterine cancer, while it stimulates bone formation and vaginal maturation and decreases insulin resistance. The combination of DHEA with a fourth generation SERM, such as EM-652 (SCH 57068), a compound having pure and potent antiestrogenic activity in the mammary gland and endometrium, could provide major benefits for women at menopause (inhibition of bone loss and serum cholesterol levels) with the associated major advantages of preventing breast and uterine cancer. A widely used application of intracrinology is the treatment of prostate cancer where the testicles are blocked by an LHRH agonist while the androgens made locally in the prostate from DHEA are blocked by a pure antiandrogen. Such treatment, called combined androgen blockade, has led to the first demonstration of a prolongation of life in prostate cancer.     

Ruptured abdominal aortic aneurysm: Impact of comorbidity and postoperative complications on outcome

Ruptured abdominal aortic aneurysm (AAA) remains a common and highly lethal problem. This study evaluates the morbidity and mortality rates and aims to identify which clinical variables could predict the outcome. We reviewed the records of 112 patients (97 men and 15 women) operated on for ruptured infrarenal AAA within the past 12 years (April 1, 1980, to March 31, 1992). Forty-seven clinical variables were collected and correlated with outcome by univariate and multivariate analysis. Mean age was 72.4 years (range 51 to 89 years). Only 12.5% were known to have an AAA before rupture. Preoperative systolic pressure <90 mm Hg was present in 84 patients (75%) and 11 patients (9.8%) experienced cardiac arrest before surgery. The in-hospital mortality rate was 49.1% (55/112). Two preoperative variables were associated with increased mortality: systolic pressure <90 mm Hg and cardiac arrest (p = 0.04 andp= 0.009, respectively). Preoperative comorbidity had no impact on outcome. Massive blood loss (5000 ml) was an intraoperative factor predictive of increased mortality (p = 0.0007). After multivariate analysis, only the following five postoperative variables were associated with increased mortality: cardiac event, renal failure requiring dialysis, coagulopathy, bleeding, and multisystem organ failure (allp <0.05). We did not identify a preoperative factor that predicts certain death and allows us to deny a patient a chance at survival. The occurrence of multisystem organ failure is associated with no survivors and raises the ethical issue of withholding treatment for these patients in the postoperative course. We favor selective screening and aggressive elective repair to improve survival by operating before rupture occurs.Presented at the Fifteenth Annual Meeting of the Canadian Society for Vascular Surgery, Vancouver, B.C., September 10–12, 1993, and at the Fourth Annual Winter Meeting of the Peripheral Vascular Surgery Society, Breckenridge, Colo., January 21–23, 1994.     

Is dehydroepiandrosterone a hormone?

Dehydroepiandrosterone (DHEA) is not a hormone but it is a very important prohormone secreted in large amounts by the adrenals in humans and other primates, but not in lower species. It is secreted in larger quantities than cortisol and is present in the blood at concentrations only second to cholesterol. All the enzymes required to transform DHEA into androgens and/or estrogens are expressed in a cell-specific manner in a large series of peripheral target tissues, thus permitting all androgen-sensitive and estrogen-sensitive tissues to make locally and control the intracellular levels of sex steroids according to local needs. This new field of endocrinology has been called intracrinology. In women, after menopause, all estrogens and almost all androgens are made locally in peripheral tissues from DHEA which indirectly exerts effects, among others, on bone formation, adiposity, muscle, insulin and glucose metabolism, skin, libido and well-being. In men, where the secretion of androgens by the testicles continues for life, the contribution of DHEA to androgens has been best evaluated in the prostate where about 50% of androgens are made locally from DHEA. Such knowledge has led to the development of combined androgen blockade (CAB), a treatment which adds a pure anti-androgen to medical (GnRH agonist) or surgical castration in order to block the access of the androgens made locally to the androgen receptor. In fact, CAB has been the first treatment demonstrated to prolong life in advanced prostate cancer while recent data indicate that it can permit long-term control and probably cure in at least 90% of cases of localized prostate cancer. The new field of intracrinology or local formation of sex steroids from DHEA in target tissues has permitted major advances in the treatment of the two most frequent cancers, namely breast and prostate cancer, while its potential use as a physiological HRT could well provide a physiological balance of androgens and estrogens, thus offering exciting possibilities for women's health at menopause.     

General practitioners' fear-avoidance beliefs influence their management of patients with low back pain

The objectives of this cross-sectional study conducted in primary care practice in France were to describe general practitioners' (GPs) fear-avoidance beliefs about low back pain (LBP), investigate the impact of these beliefs on their following guidelines for bed rest, physical activities, and sick leave, and uncover factors associated with GPs' fear-avoidance beliefs. A total of 864 GPs completed a 5-part self-administered questionnaire. Parts 1, 2, and 3 concerned demographic, professional data, and personal history of back pain, respectively. Part 4 dealt with GPs' education about LBP and practice for LBP. Part 5 assessed GPs' fear-avoidance beliefs on the Fear-Avoidance Beliefs Questionnaire (FABQ). GPs' mean age was 48.2+/-7.0 years, 80% were male, 88% had been practicing for more than 10 years, and 52% reported a previous personal episode of acute LBP. Forty-six percent had participated in an educational session on LBP during the last 3 years. Mean scores for the FABQ Phys and Work were 9.6+/-4.8 and 17.5+/-6.7, respectively. Sixteen percent of participants had high rating on the FABQ Phys (FABQ Phys score>14). FABQ Phys score was associated with recommendation of bed rest or rest during sick leave (p<0.0001) for acute LBP and less advice to maintain maximum bearable physical activities (p<0.001) for chronic LBP. FABQ Work score was associated with prescribing sick leave during painful periods (p<0.005) for acute LBP and less advice to maintain maximum bearable physical activities (p<0.001) for chronic LBP. GPs' fear-avoidance beliefs about LBP negatively influence their following guidelines concerning physical and occupational activities for patients with LBP.     

Estrogen receptor alpha-mediated adiposity-lowering and hypocholesterolemic actions of the selective estrogen receptor modulator acolbifene

OBJECTIVE: The selective estrogen receptor (ER) modulator (SERM) acolbifene (ACOL), a potent and pure antiestrogen in the mammary gland and uterus, exerts beneficial pro-estrogenic actions on energy balance, insulin sensitivity and lipid metabolism. ACOL binds ERs alpha and beta, both of which have been involved in the metabolic actions of estrogen. This study aimed at determining the identity of the ER involved in the beneficial metabolic actions of ACOL. DESIGN AND MEASUREMENTS: ACOL was administered for 4 weeks to male and female wild-type and ERalpha knockout (KO) mice, and indices of energy balance as well as plasma and liver lipid concentrations were determined. RESULTS: ERalpha KO mice were heavier, gained more fat mass and had larger adipose depots than their wild-type counterparts. In both genders, ACOL decreased fat gain (50%) and white adipose tissue mass in male and female wild-type, but not in ERalpha KO mice. ACOL reduced plasma cholesterol in female wild-type mice (-27%), whereas the compound remained ineffective in their ERalpha KO counterparts. Plasma triglycerides were unaffected by ACOL. Finally, ACOL decreased liver cholesterol and triglyceride concentrations only in wild-type female animals. CONCLUSION: The beneficial metabolic actions of the SERM ACOL on adiposity and on plasma and liver lipids are entirely due to its interaction with the ERalpha.     

Drug insight: breast cancer prevention and tissue-targeted hormone replacement therapy

The first-generation selective estrogen receptor modulator (SERM) tamoxifen has been the mainstream hormone therapy in breast cancer. Tamoxifen benefits all stages of the disease, but its use increases the risk of uterine cancer and thromboembolic events and it can only be administered for 5 years. Aromatase inhibitors are superior to tamoxifen at advanced stages of disease and as adjuvants; however, because they increase fractures, aromatase inhibitors are unlikely to be used to prevent disease. Raloxifene, a second-generation SERM, leads, like tamoxifen, to approximately 50% fewer cases of invasive breast cancer in high risk women, with a lower incidence of thromboembolic events. Several other SERMs are in development to improve tissue specificity, efficacy and tolerance. Raloxifene shows protection against vertebral fractures similar to bisphosphonates; however, no significant effect has been observed on nonvertebral fractures. Many SERMs are in development for prevention and treatment of osteoporosis. As breast cancer metastasizes early and advanced disease cannot be cured, prevention is essential. To avoid the concerns about the use of traditional hormone replacement therapy, dehydroepiandrosterone--a tissue-targeted precursor of sex steroid formation--offers hope of a physiological tissue-targeted hormone replacement that, combined with a SERM, would simultaneously prevent breast and uterine cancer.     

Stimulation of Adenosine 3′:5′-Cyclic Monophosphate Accumulation in Anterior Pituitary Gland In Vitro by Synthetic Luteinizing Hormone-Releasing Hormone

A near-maximal dose (20 ng/ml) of synthetic luteinizing hormone(LH)-releasing hormone/follicle-stimulating hormone(FSH)-releasing hormone added to incubated anterior pituitary tissue of male rats leads to concomitant increases of intracellular concentrations of adenosine 3':5'-monophosphate and of release of both LH and FSH. The stimulatory effect of LH-releasing hormone/FSH-releasing hormone is observed after a lag period of about 90 min and is progressive at later time intervals; a 3-fold stimulation of cAMP accumulation over control is seen after 210 min of incubation. Half-maximal stimulation of cAMP accumulation is observed between 0.1 and 1.0 ng/ml (0.1-1 nM) of LH-releasing hormone/FSH-releasing hormone. In the presence of 10 mM theophylline, the stimulatory effect of LH-releasing hormone/FSH-releasing hormone on cAMP accumulation is similar to that observed in the absence of the inhibitor of cyclic nucleotide phosphodiesterase, indicating that the releasing hormone exerts its effect by specific activation of adenylate cyclase in LH- and FSH-secreting cells rather than by inhibition of cyclic nucleotide phosphodiesterase. Since the release of growth hormone, thyrotropin, prolactin, and adrenocorticotropic hormone is not affected by LH-releasing hormone/FSH-releasing hormone, and since cAMP stimulates the release of all six adenohypophyseal hormones. the observed changes of cAMP concentrations indicate specific stimulation of adenylate cyclase activity in LH-and FSH-secreting cells of the adenohypophysis.     

Post-curing in dental resin-based composites

Objective

To determine the post-curing in six commercial contemporary resin-based composites (RBCs) using axial shrinkage, the degree of conversion, and Vickers hardness.

Future perspectives of selective estrogen receptor modulators used alone and in combination with DHEA

Breast cancer is the most frequently diagnosed and the second cause of cancer death in women, thus making breast cancer a most feared disease. Since breast cancer metastasizes early and it is unlikely that improvements in the treatment of metastatic disease could permit a cure in most cases in the foreseeable future, it is clear that prevention is essential in order practically to eliminate deaths from breast cancer. Tamoxifen is the only selective estrogen receptor modulator (SERM) currently registered for use in breast cancer prevention; the tamoxifen versus raloxifene study should indicate the efficacy of this compound compared with raloxifene. The recent benefits of aromatase inhibitors over tamoxifen indicate the advantages of a blockade of estrogens more complete than the one achieved with tamoxifen, a SERM having some estrogenic activity in the mammary gland and an even higher estrogenic action in the uterus. However, it is unlikely that the general estrogen ablation achieved with aromatase inhibitors will be acceptable for the long-term use required for prevention. It is thus important to develop SERMs with highly potent and pure antagonistic activity in the mammary gland and uterus while possessing estrogen-like activity in tissues of particular importance for women's health, namely the bones and the cardiovascular system. However, it is expected that a SERM alone will not meet all the requirements of women's health at the postmenopause when ovarian estrogen secretion has ceased and peripheral formation of androgens and estrogens from DHEA by intracrine mechanisms is decreased by 60% or more. One possibility is to combine a SERM with DHEA, a precursor of sex steroids that permits, somewhat like SERMs, tissue-specific formation of androgens and/or estrogens according to the level of expression of the steroidogenic and steroid-inactivating enzymes. DHEA could thus compensate for the important loss of androgens that accompanies aging and could also permit sex steroid formation and action in the brain while breast cancer prevention would be achieved by the SERM.