Treatment of dysfunctional uterine bleeding in the perimenopause: the effects of adding combined estradiol/norethisterone acetate therapy to goserelin acetate treatment--a randomized, placebo-controlled, double-blind trial.

OBJECTIVE: To assess the effects of adding combined estradiol/norethisterone acetate therapy (CENT) to goserelin acetate treatment (GA) of dysfunctional uterine bleeding (DUB) in perimenopausal women. METHODS: In a randomized, placebo-controlled, double-blind trial followed by an open follow-up study, 31 perimenopausal women with DUB were recruited from gynecological outpatient departments of two Dutch hospitals and randomized for treatment with either GA/placebo or GA/CENT for 6 months followed by 18 months of GA/CENT for all. The main outcome measures were abdominal pain, number of bleeding days, double-layer endometrial thickness (DET), Greene climacteric score (GCS), visual analog scale for well-being, bone mineral density (BMD) and mammographic density (BI-RAD score). RESULTS: Abdominal pain, number of bleeding days and DET decreased in both groups, the between-group difference in decrease not being statistically significant. GCS initially showed significant improvement in the GA/CENT group. BMD decreased significantly in the GA/placebo group (-4.1%) compared with the GA/CENT group (-0.3%). Another 18 months of GA/CENT did not result in a lasting difference in BMD between groups. BI-RAD scores did not differ significantly between or within the two groups. CONCLUSIONS: Adding CENT to GA treatment for DUB in perimenopausal women initially prevented BMD loss and improved climacteric complaints, while having no negative impact on vaginal bleeding, abdominal pain or BI-RAD scores. However, prolonged treatment did not result in a lasting prevention of bone loss.     

Improved adhesion and proliferation of human endothelial cells on polyethylene precoated with monoclonal antibodies directed against cell membrane antigens and extracellular matrix proteins.

Endothelial cell seeding may improve the patency of synthetic vascular grafts provided that platelet reactivity of nonendothelialized sites is not increased. We have investigated if surface-adsorbed monoclonal antibodies directed against endothelial cell membrane proteins and against extracellular matrix proteins promote the adhesion and proliferation of cultured human endothelial cells, without causing platelet deposition at non-endothelialized sites. Adhesion of endothelial cells onto polyethylene coated with monoclonal antibodies directed against endothelial cell-specific membrane antigens, integrin receptors and glycoprotein CD31 was equal to or higher than adhesion onto fibronectin-coated polyethylene. Endothelial cells did not proliferate on these surface-adsorbed antibodies. However, pre-coating of polyethylene with mixtures of endothelial cell-specific monoclonal antibodies and monoclonal antibodies directed against fibronectin or von Willebrand factor, resulted in relatively high adhesion and optimal proliferation. Platelet reactivity of the polyethylene surface was found to significantly increase after adsorption of fibronectin, endothelial cell-specific monoclonal antibody or its Fc fragments. In contrast, adsorption of F(ab')2 fragments of endothelial cell-specific monoclonal antibody did not promote platelet deposition. Therefore, it is concluded that coating of vascular graft materials with mixtures of F(ab')2 fragments of monoclonal antibodies specifically directed against endothelial cells and against extracellular matrix proteins may be an effective way to both promote the growth of seeded endothelial cells and limit platelet-graft interaction.     

Tumor necrosis factor-alpha in whole blood cultures of preeclamptic patients and healthy pregnant and nonpregnant women.

OBJECTIVES: Tumor necrosis factor-alpha (TNF-alpha) is recognized as a likely mediator of the excessive endothelial activation and injury that is a key pathogenetic mechanism of preeclampsia. We used whole blood cell cultures from 12 patients with severe preeclampsia and from 12 healthy pregnant and nonpregnant women to determine the release of TNF-alpha by unstimulated leukocytes as a measure of their state of activation, and their response to stimulation with lipopolysaccharide (LPS) as an indicator of their state of priming. METHODS: Blood was cultivated without and with LPS, and TNF-alpha release was measured after six and 24 hours of cultivation by enzyme-linked immunoassays. Differential leukocyte counts were performed, and TNF-alpha values calculated per 10(5) monocytes. RESULTS: In unstimulated whole blood cultures, TNF-alpha release after six hours of cultivation was similar in all three groups; but after 24 hours, TNF-alpha concentrations in culture supernatants from preeclamptic patients were significantly higher than were values obtained in blood from normotensive pregnant women. In LPS-stimulated blood cultures with a maximum of TNF-alpha release at six hours cultivation time, TNF-alpha concentrations were significantly lower in preeclamptic women than they were in both control groups. We showed in an additional experiment that a strong LPS challenge following preactivation with high doses of LPS resulted in reduced release of TNF-alpha compared with release of TNF-alpha following preactivation with low doses of LPS. CONCLUSIONS: The observed high capacity for spontaneous TNF-alpha release by leukocytes in preeclampsia indicates activation of TNF-alpha producing leukocytes by the disease process. Preactivation and exhaustion of leukocytes by leakage of TNF-alpha could lead to the reduced response to TNF-alpha inducer LPS as observed in blood cultures from preeclamptic patients.     

Calcitonin gene-related peptide-like immunoreactivity, in botulinum toxin-paralysed rat muscles

Changes in calcitonin gene-related peptide-like immunoreactivity (CGRP-LI) at the motor endplates of botulinum toxin-paralysed rat muscles were investigated using immunohistochemistry. One day following toxin injection, a dramatic increase in CGRP-LI was detected at the motor endplates and within preterminal axons of the soleus and gastrocnemius muscles. The upregulation of CGRP-LI persisted throughout the period during which muscle fibres were paralysed and new neuromuscular junctions were being formed by the growing sprouts. Decline of CGRP-LI at the motor endplates coincided with clinical recovery. Both up- and down-regulation of CGRP-LI took place earlier in the soleus than in the gastrocnemius muscle. Up-regulation of CGRP-LI was also detected in a subpopulation of motor axons in the sciatic nerves and in the spinal motor neurons innervating the paralysed muscles. These results indicate that levels of CGRP are regulated, at least partly, by changes in the target innervation. They also suggest an important role for CGRP in the regenerative processes following muscle paralysis.     

Supratentorial ischemic stroke: more than an upper motor neuron disorder.

The primary goal of this study was to identify secondary functional changes in the peripheral motor units of the paretic upper extremity (UE) in patients with severe ischemic stroke and to determine how these changes develop during the first weeks after stroke. An inception cohort of 27 consecutive patients with an acute ischemic supratentorial stroke and an initial UE paralysis was compared with 10 healthy control subjects. The ulnar nerve was electrically stimulated proximal to the wrist and electromyographic recordings were obtained from the abductor digiti minimi muscle. Hemiparetic side mean values of the compound muscle action potential (CMAP) 1 and 3 weeks after stroke were compared with the nonparetic side and with CMAP values obtained from healthy control subjects. The mean CMAP amplitude in patients was significantly lower on the paretic side compared with the nonparetic side and with control subjects. Decrease in CMAP amplitude was observed in more than half of the stroke patients, sometimes as early as 4 days after stroke, and persisted in most cases. Whenever present, it was accompanied by absence of motor recovery at that specific time after stroke. Decreased CMAP amplitude in the abductor digiti minimi muscle can be seen already in the very acute phases after stroke unrelated to peripheral neuropathy, radiculopathy, or plexopathy, and it is accompanied by absence of UMN recovery. This knowledge is important for interpreting electrophysiological data in stroke patients.