Role of COX-2 specific inhibitors in oncogenesis

Cyclooxygenase-2 (COX-2) is over expressed in a variety of premalignant and malignant conditions. It may contribute to carcinogenesis by modulating xenobiotic metabolism, apoptosis, immune surveillance, and angiogenesis. Selective COX-2 inhibitors suppress the formation of tumors in experimental models. Selective COX-2 inhibitors also suppress the growth and metastases of established tumors and enhance the anticancer activity of both radiotherapy and chemotherapy in experimental animals. This review aims at discussing evidence that inhibition of COX-2 represents a promising strategy to treat, prevent or possibly prevent human malignancies. Importantly, selective COX-2 inhibitors do not inhibit platelet function and cause fewer gastrointestinal side effects (peptic ulcer disease) than traditional nonsteroidal anti-inflammatory drugs (NSAIDS). More clinical trials are warranted to define the role of selective COX-2 inhibitors in the prevention and treatment of cancer along with their assessment of toxicity.     

Reference intervals of biochemical bone turnover markers for Saudi Arabian women: A cross-sectional study

Biochemical bone turnover markers (BTMs) provide important information on the diagnosis, therapy and monitoring of metabolic bone diseases including osteoporosis. One goal of antiresorptive therapy in women is to decrease biochemical BTMs to the lower half of reference intervals for healthy pre-menopausal counterparts, using newly developed automated assays of such markers. The main objectives of the present study were to: (1) establish reference interval values for the following biochemical BTMs: serum osteocalcine (s-OC), bone alkaline phosphatase (s-bone ALP), procollagen type 1 N-terminal propeptide (s-PINP), crosslinked C-terminal telopeptide of Type 1 collagen (s-CTX), tartarate-resistant acid phosphatase isoform 5b (s-TRACP-5b) and urinary: CTX (u-CTX), N-telopeptides of type 1 collagen (u-NTX), pyridinoline (u-PYD) and deoxypyridinoline (u-DPD) in randomly selected Saudi healthy pre-menopausal women; (2) study the changes in biochemical BTMs in relation to age in pre- and post-menopausal women and the factors reported to influence bone turnover and (3) determine the effect of menopausal status on BTMs. A total of 2125 women were studied [including (n = 1557) pre-, and (n = 568) post-menopausal women, respectively, aged 20–79 years]. A total of 765 healthy pre-menopausal women (aged 35–45 years) were used to establish reference intervals for biochemical BTMs. All women studied were medically examined and had their bone mineral density (BMD) values obtained for the lumbar spine (L₁–L₄) and femoral neck according to detailed inclusion criteria. In all women, values of biochemical BTMs, decreased with increasing age up to the age of 45 years, increased steeply among women in their 50s and remained increased in post-menopausal women. Significant increases were evident in all biochemical BTMs in post-menopausal women with > 5 years since menopause with the exception of s-OC, u-DPD, and u-PYD. Using stepwise multiple linear regression analysis, several variables were identified (depending on the BTM) as determinants of BTMs including age, BMI, parity, FSH, LH, PTH, s-Ca, s-Mg, s-PO₄ and 25(OH)D. In the reference intervals group, there are no significant correlations between any of the biochemical BTMs and age of menarche, day of menstrual cycle, physical activity, total daily dietary calcium and caffeine intakes and parity. It is recommended that the age range 35–45 years should be used when establishing biochemical BTMs reference intervals in Saudi Arabian pre-menopausal women.     

Use of low-frequency ultrasound in preoperative care of the conjunctival cavity]

Experimental and clinical studies of the efficacy of preoperative treatment of the conjunctival cavity with low-frequency ultrasound were carried out. Ultrasound parameters employed were as follows: 20-70 kHz frequency, 25-35 microns oscillation amplitude, length of exposure 60-120 sec. Such treatment was found to reduce bacterial contamination of the conjunctival cavity. Clinical studies were carried out on 20 eyes of 14 patients operated on for cataracts and glaucomas at the department for ocular diseases of the Moscow municipal clinical hospital No. 15. Low-frequency ultrasound treatment of the conjunctival cavity was carried out before surgery in all these patients. In the reference patients (n = 15, 15 eyes) the conjunctival cavity was washed with 1:5000 furacilin solution and 30% sodium sulfacil solution or kanamycin solution (10,000 U in 1 ml) on the operation table. The bacterial contamination of the conjunctival cavity prior to surgery in 24 eyes has made up 84.1 bacterial colonies per Petri dish on an average. Preoperative treatment of the conjunctival cavity with low-frequency ultrasound has reduced the bacterial contamination to 6.3 colonies per Petri dish, i.e. by 13.3 times.     

New therapeutic approaches to autoimmune disease

Conclusion Autoimmune diseases represent robust and inappropriate immune reactions arising out of a background of immunodefectiveness and immune dysregulation. For too many years our only approach to therapy has been generalized and nonspecific immunosuppression with powerful and highly toxic drugs.This chapter summarizes the first few attempts of an infant field attempting to use more specific immunomodulation as a new treatment to restore immune balance and turn off autoreactivity. Whether this immunopharmacologic approach will ultimately be successful is unknown. One must be optimistic and hope for success since current therapy falls far short of the mark.     

Suppression or enhancement of natural killing does not alter tolerance to bovine gamma globulin

NZB/NZW F1 (B/W) mice have high levels of natural killing (NK), are resistant to the induction of tolerance to bovine gamma globulin (BGG), and spontaneously develop a disease resembling systemic lupus erythematosus. In vivo administration of 89Strontium (89Sr) to B/W mice reduces NK and improves their autoimmune disease. We tested the hypothesis that the high levels of NK exert an immunoregulatory influence and are responsible for the resistance to BGG tolerance. 89Sr was administered at 4 and 8 weeks, and tolerogen was injected at 10 weeks. Despite a marked suppression of NK, 89Sr-treated B/W mice remained resistant to the induction of tolerance. NK was stimulated in weanling B/W male and female mice, and in adult A/J females, by the injection of Poly I . C one day prior to the administration of tolerogen. Poly I . C induced an acute rise in NK but did not inhibit the induction of tolerance. We conclude that natural killer cells are not involved in the regulation of immune tolerance to BGG and, they do not appear to play a role in the resistance to tolerance in adult B/W mice.     

Targeted inactivation of the IL-4 receptor alpha chain I4R motif promotes allergic airway inflammation

The insulin/interleukin-4 (IL-4) receptor (I4R) motif mediates the association of insulin receptor substrate (IRS)-2 with the interleukin-4 (IL-4)Ralpha chain and transduces mitogenic signals in response to IL-4. Its physiological functions were analyzed in mice with a germline point mutation that changed the motif's effector tyrosine residue into phenylalanine (Y500F). The Y500F mutation abrogated IRS-2 phosphorylation and impaired IL-4-induced CD4+ T lymphocyte proliferation but left unperturbed Stat6 activation, up-regulation of IL-4-responsive gene products, and Th cell differentiation under Th2 polarizing conditions. However, in vivo the Y500F mutation was associated with increased allergen-induced IgE production, airway responsiveness, tissue eosinophilia, and mucus production. These results define an important role for the I4R motif in regulating allergic inflammation.