Development and assessment of the Osteoporosis Index of Risk (OSIRIS) to facilitate selection of women for bone densitometry.

A simple questionnaire would be useful to identify individuals most in need of bone mineral density (BMD) testing. We designed a new predictive model and risk assessment instrument based on an extensive review of the literature evaluating risk factors for osteoporosis, and tested its performance in a large cohort of postmenopausal women in whom BMD was measured by dual x-ray absorptiometry. In total, 1303 postmenopausal women from an outpatient osteoporosis clinic participated in this study. The Osteoporosis Index of Risk (OSIRIS) is based on four variables: age, body weight, current hormone replacement therapy use and history of previous low impact fracture. The sensitivity and specificity for an OSIRIS value of +1 were respectively 78.5% and 51.4%. The AUC under the ROC curve of OSIRIS was 0.71. Three categories were arbitrarily created using OSIRIS, with cutoff of +1 and -3. The low risk category (OSIRIS > +1) represented 41% of all women; only 7% of the women in this category had osteoporosis. The prevalence of osteoporosis was very high (66%) among the group at high risk (OSIRIS < -3 representing 15% of all women). The prevalence of osteoporosis was 39% in the intermediate risk group (-3 < OSIRIS < +1, 44% of all women). In conclusion, OSIRIS is a simple index based on four easy-to-collect variables from postmenopausal women, it shows a high degree of accuracy, and performed well for classifying the degree of risk of osteoporosis in western European women of Caucasian lineage. Based on this instrument it is possible to propose a strategy that would initiate treatment in women with very high risk, postpone BMD measurement in women with low risk and limit BMD measurement to women with intermediate risk of osteoporosis, this would spare more than 55% of the densitometry bill compared with a mass screening scenario.     

Antiangiogenic and antitumor activity of IDN 5390, a new taxane derivative.

PURPOSE: We previously reported that paclitaxel, a microtubule-stabilizing drug, inhibited angiogenesis, mainly by inhibiting endothelial cell motility (D. Belotti et al., Clin. Cancer Res., 2: 1843-1849, 1996). The aim of this study was to select a taxane with little cytotoxicity but with antimotility and hence antiangiogenic activity. EXPERIMENTAL DESIGN: Different taxanes, seco derivatives, and 14-beta-hydroxy-10-deacetyl baccatin III derivatives were tested for their effects on the proliferation and motility of human umbilical vein endothelial cells. The antiangiogenic and antineoplastic activities of the compound selected from this screening were further investigated in experimental models in vitro and in vivo. RESULTS: From the screening of different taxanes, we selected IDN 5390, a seco derivative that showed potent antimotility activity and less cytotoxicity than paclitaxel. In comparable experimental conditions, IDN 5390 inhibited endothelial cell migration without affecting proliferation. This compound dose-dependently inhibited the capacity of human umbilical vein endothelial cells plated on Matrigel to organize into a network of cords. In vivo, IDN 5390 significantly inhibited fibroblast growth factor-2-induced angiogenesis in Matrigel implants. Daily treatment with IDN 5390 in mice bearing established lung micrometastases from the B16BL6 murine melanoma caused a reduction in the size of metastases. Finally, IDN 5390 slowed the s.c. growth of the paclitaxel-resistant human ovarian carcinoma, 1A9/PTX22, xenografted in nude mice. CONCLUSIONS: The seco derivative IDN 5390 might represent the prototype of a new class of taxane derivatives with antiangiogenic properties.     

Recurrent squamous cell carcinoma of the vulva: clinicopathologic determinants identifying low risk patients

BACKGROUND: The identification of prognostic factors in the recurrence of vulvar squamous cell carcinoma is crucial for less invasive treatments. METHODS: The authors studied 101 patients treated for primary invasive squamous cell carcinoma of the vulva. Selected pathologic variables were observed in a standardized manner during treatment, and their association with disease free survival was investigated using the Cox model. Independent prognostic factors were selected by a stepwise procedure. The absolute survival of patient groups determined on the basis of such factors was computed by the product limit method. RESULTS: The median follow-up was 3.1 years (range, 56 days to 15.5 years). Recurrences developed in 33 patients. The independent recurrence predictors were as follows: International Federation of Gynecology and Obstetrics (FIGO) Stage IVA (vs. IB, II, or III) (risk ratio [RR]adjusted for other independent factors, 7.39), tumor multifocality (RR, 4.10), lymphovascular space involvement (LVSI) (RR, 2.96), the presence of associated vulvar intraepithelial neoplasia (VIN) Grade 2 or 3 (RR, 3.34), and the involvement of resection margins (RR, 4.88). By ignoring the FIGO stage and lymph node status, the independent predictors were then as follows: greatest tumor dimension < 2.5 cm, 2.5-4 cm (RR, 2.86), or > 4 cm (RR, 5.98); tumor multifocality (RR, 3.36); LVSI (RR, 4.19); the presence of VIN 2 or 3 (RR, 3.06); and the involvement of surgical margins (RR, 2.78). No recurrences were observed in 119 at-risk years among patients with unifocal tumors < 2.5 cm in greatest dimension, free surgical margins, no LVSI, and no associated VIN 2 or 3. CONCLUSIONS: The presence of associated VIN 2 or 3 was revealed to be a previously unidentified independent prognostic factor for recurrence. Subjects at low risk of recurrence could be identified even without consideration of lymph node status.     

Evaluation of novel compounds interacting with H2-histamine receptors: Effect on histamine-sensitive adenylate cyclase activity in guinea-pig gastric mucosa

The activity of a number of compounds belonging to the novel class ofN-imidazolylphenyl-N'-alkyl-formamidines on histamine-sensitive adenylate cyclase was evaluated. All substances inhibited histamine-dependent adenylate cyclase activation. The compounds which were investigated in a wider concentration range, i.e. DA 4360, DA 4577, and DA 4626, behaved as simple competitive antagonists, yielding apparentK _B values comparable with those estimated in conventional H₂-receptor assays. These results provide further evidence for the highly selective H₂-receptor antagonism of these new molecules, and confirm the suitability of the histamine-stimulated adenylate cyclase assay in guinea-pig gastric cells as a functionally reduced system for the study of H₂ antagonists.     

Pharmacological profile of mifentidine: a novel H2-receptor antagonist

Mifentidine, a representative compound of a novel class of H2-antagonists, has been investigated for its ability to interact with H2-receptors and to inhibit gastric acid secretion. Affinity estimates (KB) of mifentidine obtained from in vitro studies on cardiac and gastric mucosal histamine (H2) receptors were in the 20-50 nM range. Mifentidine appeared to be endowed with strong anti-secretory properties against histamine-stimulated secretion in the anaesthetized rat and in the conscious dog. Distinct features of mifentidine were considerable bioavailability and duration of anti-secretory effect.     

Occupational risk among orchard workers: a descriptive study

Orchard workers are exposed to an array of occupational health and safety hazards that result in injury, illness, and, in some cases, death. The purpose of this qualitative study was to identify and explore factors that contribute to occupational risks related to orchard work. Twenty-five Hispanic orchard workers were interviewed. They reported that the most common type of accident was falls, usually from a ladder; and the most common injuries were strains and sprains. Three broad categories of factors that contributed to the occurrence of such injuries were Knowledge, Attitudes and Behaviors; Work-Related Factors; and Factors External to Work.     

Markers of inflammation before and after renal transplantation

BACKGROUND: This study aims to compare serum C-reactive protein (CRP), interleukin (IL-6), and tumor necrosis factor (TNF)-alpha in end-stage renal disease (ESRD) patients before versus after receiving renal transplantation (RT) and versus donors. METHODS: Serum samples from 37 ESRD patients (24 male, age 34+/-13 years) were collected before and after RT; in addition, samples from 31 donors were obtained at transplantation. CRP concentrations were measured using nephelometry, and TNF-alpha and IL-6 were measured by enzyme-linked immunoadsorbent assay. RESULTS: Ninety-two percent of recipients had a living donor, 73% received cyclosporine A, 27% tacrolimus, and 70% induction with daclizumab. Thirteen percent had acute rejection and 16% chronic allograft nephropathy. All inflammation markers decreased 6 months after RT, but only CRP was below baseline values (baseline: 5.0+/-3.5; 6 months: 3.0+/-0; 12 months: 3.2+/-0.7; 18 months: 3.2+/-0.6; donors: 3.6+/-1.5 mg/L; P<0.05), whereas median TNF-alpha (baseline: 0.1 [0.03-0.2]; 6 months: 0 [0-0.1]; 12 months: 0.3 [0.1-2.6]; 18 months: 0.6 [0.1-1.9]; donors: 0 [0-0.1] pg/mL; P<0.05) and IL-6 (baseline: 1.9 [1.2-7.1]; 6 months: 1.2 [0.6-28.3]; 12 months: 2.6 [1.3-3.4]; 18 months: 2.7 [1.7-4.2]; donors: 1.1 [0.6-1.9] pg/mL; P<0.05) significantly increased up to the end of follow-up. Before RT, CRP correlated with age (r 0.45, P=0.006) and albumin (r -0.36, P=0.04). TNF-alpha and IL-6 were correlated before (r 0.34, P=0.04) and after (r 0.55, P=0.02) RT. Inflammation markers were not different in patients who had acute rejection episodes or chronic nephropathy. CONCLUSIONS: Compared with controls, patients displayed an inflammatory phenomenon before receiving RT. Serum CRP decreased significantly after RT, whereas TNFalpha and IL-6 increased.     

Abnormalities of cardiovascular neural control and reduced orthostatic tolerance in patients with primary fibromyalgia

OBJECTIVE: Fibromyalgia (FM) is a syndrome characterized by widespread musculoskeletal pain. Symptoms of orthostatic intolerance may also be present, suggesting underlying abnormalities of cardiovascular neural regulation. We tested the hypothesis that FM is characterized by sympathetic overactivity and alterations in cardiovascular autonomic response to gravitational stimulus. METHODS: Sixteen patients with primary FM and 16 healthy controls underwent electrocardiography examination, finger blood pressure, respiration, and muscle sympathetic nerve activity (MSNA) recordings at rest and during stepwise tilt test, up to 75 degrees . The autonomic profile was assessed by MSNA, plasma catecholamine, and spectral indices of cardiac sympathetic (LFRR in normalized units, NU) and vagal (HFRR both in absolute and NU) modulation and of sympathetic vasomotor control (LFSAP) computed by spectrum analysis of RR and systolic arterial pressure (SAP) variability. Arterial baroreflex function was evaluated by the SAP/RR spontaneous-sequences technique, the index a, and the gain of MSNA/diastolic pressure relationship during stepwise tilt test. RESULTS: At rest, patients showed higher values of heart rate, MSNA, LFRR NU, LF/HF, LFSAP, and reduced HFRR than controls. During tilt test, lack of increase of MSNA, less decrease of HFRR, and excessive rate (44%) of syncope were found in patients, suggesting reduced capability to enhance the sympathetic activity to vessels and withdraw the vagal modulation to sino-atrial node. Baroreflex function was similar in both groups. CONCLUSION: Patients with FM have an overall enhancement of cardiovascular sympathetic activity while recumbent. Lack of increased sympathetic discharge to vessels and decreased cardiac vagal activity characterize their autonomic profile during tilt test, and might account for the excessive rate of syncope.