A review of advances in the use of the GnRH agonist deslorelin in control of reproduction.

The prevention of breeding in animals using GnRH analogues has been the object of research over many years. Recently, a new drug delivery formulation was developed which enabled the development of products that could be commercialised for veterinary use. The formulation has now been approved in certain countries for use in male dogs, and applications are being expanded to cover repeat usage, extended duration, use in females, other indications and other animal species. With respect to repeat usage, dogs have been re-implanted for four consecutive doses and monitored until they returned to normal steroidogenesis. All dogs returned to normal steroidogenesis following cessation of treatment. In females, it was previously shown that implanted bitches with progesterone < 5 ng/mL at the time of implantation had an induced estrus. In a new study at Chulalongkorn University, implanting female pups at around 4 mo prevented this occurrence, whereas implantation at 7 mo did not.

The gene ygdP, associated with the invasiveness of Escherichia coli K1, designates a Nudix hydrolase, Orf176, active on adenosine (5')-pentaphospho-(5')-adenosine (Ap5A).

ygdP, a gene associated with the invasion of brain microvascular endothelial cells by Escherichia coli K1 (Badger, J. L., Wass, C. A., and Kim, K. S. (2000) Mol. Microbiol. 36, 174-182), the primary Gram-negative bacterium causing meningitis in newborns, has been cloned and expressed in E. coli. The protein, YgdP, was purified to near homogeneity and identified as a member of the Nudix hydrolase subfamily of dinucleoside oligophosphate pyrophosphatases. It catalyzes the hydrolysis of diadenosine tetra-, penta-, and hexa-phosphates with a preference for diadenosine penta-phosphate, from which it forms ATP and ADP. The enzyme has a requirement for a divalent metal cation that can be met with Mg2+, Zn2+, or Mn2+ and, like most of the Nudix hydrolases, has an alkaline pH optimum between 8.5 and 9. This is the second identification of a gene associated with the invasiveness of a human pathogen as a member of the Nudix hydrolase subfamily of dinucleoside oligophosphate pyrophosphatases, and an examination of homologous proteins in other invasive bacteria suggests that this may be a common feature of cellular invasion.

The psychosocial effects of rheumatoid arthritis on the patient and the well partner.

Rheumatoid arthritis (RA) is a chronic disorder that can have a severe impact on patient's lives. This present study investigated four questions regarding the psychosocial effects on patients and their well partners. First we found that depression for both patients and partners were slightly elevated and 35.7% of patients and 23.3% of well partners had scores above the cut-off for possible clinical depression on the Center for Epidemiological Studies Depression Scale. Second, there was no significant difference between the patients' level of distress and that of the partners. Third, there were moderate positive correlations between patients' and partners' scores on measure of psychological functioning. Fourth, there were no differences in either the patients' or partners' well-being based on the gender of the patient. Finally, an exploratory analysis was conducted to examine the factors which influence the patients' and partners' depression and their view of the relationship.

Cisplatin-induced platelet activation requires mononuclear cells: role of GMP-140 and modulation of procoagulant activity.

Cytotoxic drugs may potentiate the thrombotic complications in patients with malignancies and platelet function abnormalities have been reported after initiation of cisplatin therapy. This report describes a prolonged activation of platelets over 6-24 h co-culture with peripheral blood mononuclear cells (PBM) by pharmacological doses of cisplatin. Cisplatin had no direct effect on platelets and depended on PBM to produce aggregation which was apparently not mediated by products of the cyclooxygenase or lipoxygenase pathways, by platelet activation factor (PAF) or by thrombin. Although platelet aggregation normally involves the binding of fibrinogen to the beta 3 integrin, GP IIb-IIIa, on activated platelets, the cisplatin-dependent platelet aggregation observed in the co-culture experiments was not inhibited by an anti-GP IIb-IIIa monoclonal antibody which blocks fibrinogen-dependent aggregation nor by an adhesive peptide containing the RGDS integrin recognition sequence. Rather, aggregation appeared to involve a novel 140 kD granule membrane protein (GMP-140) mediated mechanism since aggregation was almost completely blocked by Fab fragments of an antibody to GMP-140 and was inhibited by fluid-phase GMP-140. At concentrations of cisplatin, adriamycin, and LPS that induced equivalent levels of tissue factor of blood monocytes, prothrombinase activity was significantly greater in cultures containing cisplatin. Prothrombinase activity was dependent on the presence of platelets and the rate of thrombin formation was enhanced by factor Xa generated by the tissue factor-factor VIIa complex. These studies suggest that the vascular and thrombotic complications associated with cisplatin therapy are mediated, at least in part, by platelet activation and aggregation and monocyte procoagulant activity.

Short-term reduction in egg production in laying hens treated with an agonist of GnRH.

1. In two experiments laying hens were treated with an agonist of gonadotrophin releasing hormone (GnRH) to induce a reduction in the secretion of luteinising hormone (LH) and a pause in egg production. 2. In experiment 1, 70-week-old laying hens were either given daily subcutaneous injections of saline for 7 d, offered whole oats for 7 d (nutrient restriction), given daily injections of the GnRH agonist [D-Trp6-Pro9 N-ethyl amide]GnRH for 7 d at 50 micrograms/kg or 100 micrograms/kg or administered 4 biocompatible implants each containing 120 micrograms of the GnRH agonist. 3. Weekly egg production was monitored for 7 weeks and blood samples were taken at weekly intervals and assayed for plasma LH and oestradiol. Egg production was reduced in the birds treated with the agonist (28 to 46% reduction) but not to the same extent as in the birds offered whole oats (92.3% reduction). 4. The treatments also reduced plasma LH and oestradiol in treated hens but again to a greater extent in the birds offered whole oats than the birds treated with the agonist. Egg production and plasma LH and oestradiol increased following the termination of the treatments. 5. The birds fed whole oats suffered a reduction in weight of 16.7% over the treatment period whereas there were increases in the weights of the birds treated with saline, 50 micrograms of GnRH agonist and the implants of GnRH agonist, but no change in birds treated with 100 micrograms of GnRH agonist. 6. The birds fed oats lost feathers over the treatment period but the birds in the other treatment groups suffered no loss. 7. In experiment 2 laying hens were either injected daily with saline or 200 micrograms GnRH agonist and weekly egg production and plasma LH and oestradiol were measured. As egg production was reduced by almost 60% in the birds treated with the agonist but did not completely cease. Reductions in plasma LH and oestradiol were also observed. All variables increased to pretreatment levels once treatment ceased. 8. These data confirm the effects of severely depriving hens of nutrients on egg production and the secretion of LH and oestradiol.(ABSTRACT TRUNCATED AT 400 WORDS)

Discordant expression of tissue factor antigen and procoagulant activity on human monocytes activated with LPS and low dose cycloheximide.

The mechanisms underlying the superinduction of procoagulant activity by cycloheximide (CHX) on LPS-activated human monocytes have been investigated. Tissue factor (TF) activity of intact, viable cells was quantitated with a plasma recalcification assay and assays using chromogenic substrates specific for thrombin and factor Xa (FXa). TF antigen was measured simultaneously by immunocytochemical staining and immunoblotting with an anti-TF monoclonal antibody (MAb). Peripheral blood mononuclear cells (PBMC) activated with LPS in the presence of low dose CHX expressed more TF activity (approx. 100% increase) than cells activated with LPS alone. However, TF antigen levels were decreased approximately 70% by CHX. This discordant relationship was due primarily to differences in rates of activation of factor X (FX); LPS/CHX-treated PBMC activated nearly twice as much FX as LPS-treated cells (2.19 +/- 0.37 versus 1.10 +/- 0.21 ng FXa/10(6) PBMC/min, respectively). These studies indicate that TF cofactor activity on LPS/CHX-treated monocytes was approximately 7 times greater than that present on LPS-treated cells. Increased TF functional activity may be due to CHX-induced alterations in the type and content of phospholipids (PL) in the cell membrane. Results showed that exogenous mixed PL markedly increased TF activity on LPS-activated monocytes, but not on LPS/CHX-activated cells, without increasing TF antigen levels or altering cell viability. Membrane alterations may occur on monocytes in certain pathological or iatrogenic conditions resulting in a highly active form of TF in vivo.