Matrix metalloproteinase-9 and cell kinetics during the collection of peripheral blood stem cells by leukapheresis.

The plasma levels of matrix metalloproteinase-9 (MMP-9) were determined during 41 collections of peripheral blood stem cells (PBSC) by standard volume (two blood volumes) leukaphereses (SVL) in 29 donors (7 allogeneic and 22 autologous) mobilized with the granulocyte-colony stimulating factor (G-CSF). The association between MMP-9 levels and cell counts in donor's blood was explored. During the processing of the first blood volume (BV), MMP-9 levels declined on average by 31% and persisted at the same level during the processing of the second BV. During the collection, a slight decline of white blood cells (WBC), polymorphonuclear neutrophils (PMN) and platelets (PLT) in donor's blood was accompanied by a significant drop of CD34+ cells by 37% after 1 BV and by 44% after 2 BV had been processed (p=0.001). The drop of MMP-9 plasma levels showed a loose correlation with the decrease of WBC (r=0.68, p=0.002) and PMN counts (r=0.67, p=0.001). We conclude that the levels of MMP-9 that have been elevated by the mobilization of donors with G-CSF, decrease during the collection of PBSC by 4h SVL. The observed decrease was indirectly related to the drop of WBC and PMN counts, suggesting that certain other factors have an influence on MMP-9 kinetics during PBSC collection.     

Muscimol prevents long-lasting potentiation of dorsal horn field potentials in rats with chronic constriction injury exhibiting decreased levels of the GABA transporter GAT-1

The inhibitory activity of gamma-aminobutyric acid (GABA) is considered critical in setting the conditions for synaptic plasticity, and many studies support an important role of GABA in the suppression of nociceptive transmission in the dorsal horn. Consequently, any injury-induced modification of the GABA action has the potential to critically modify spinal synaptic plasticity. We have previously reported that chronic constriction injury of the sciatic nerve was accompanied by long-lasting potentiation of superficial spinal dorsal horn field potentials following high-frequency tetanus. In this study we examined whether the GABA-A receptor agonist muscimol would modify post-tetanic responses in rats with chronic constriction injury. In animals exhibiting maximal thermal hyperalgesia as one sign of neuropathic pain 7 days after loose ligation of the sciatic nerve, spinal application of muscimol (5, 10 or 20 microg) before the high-frequency (50 Hz) tetanus produced a long-lasting depression (rather than potentiation) of spinal dorsal horn field potentials. In separate but related Western immunoblot experiments, we also established that the chronic constriction injury was accompanied by significant decreases in the content of the GABA transporter GAT-1. These data demonstrated that GABA-A receptor agonists may effectively influence the expression of long-lasting synaptic plasticity in the spinal dorsal horn, and that an injury-induced loss in GABA transporter content may have contributed to a depletion of GABA from its terminals within the spinal dorsal horn. These data lent further support to the notion that the loss of GABA inhibition may have important consequences for the development of neuropathic pain.     

Prothrombogenic factors and reduced antioxidative defense in children and adolescents with pre-metabolic and metabolic syndrome.

BACKGROUND: The aim of this study was to examine prothrombogenic factors and antioxidative defense in obese children and adolescents with pre-metabolic and metabolic syndrome, and to analyze insulin secretion and resistance, early glycoregulation disorders and lipid status. METHODS: Insulin sensitivity was determined using the homeostasis model assessment for insulin resistance (HOMA-IR), while insulin secretion was determined using the homeostasis model assessment beta (HOMA-beta). Prothrombogenic factors analyzed were plasma plasminogen activator inhibitor-1 (PAI-1) and fibrinogen. Superoxide dismutase and glutathione peroxidase were measured as markers of antioxidative defense. RESULTS: Patients with metabolic syndrome were characterized with increased body mass index (BMI), waist circumference, and HOMA-IR and HOMA-beta levels, and all had increased blood pressure and triglyceride levels, low high-density lipoprotein cholesterol levels, increased PAI-1 levels and reduced antioxidative defense levels. Patients with pre-metabolic syndrome had higher levels of basal and mean insulinemia during an oral glucose tolerance test, higher levels of HOMA-beta and lower levels of antioxidative defense compared to patients with metabolic syndrome. CONCLUSIONS: Negative correlations between antioxidative defense parameters and BMI, abdominal obesity, insulin secretion, systolic blood pressure and atherogenic lipid factors, as well as correlations between PAI-1 and insulin resistance and basal glycemia in the metabolic syndrome group contribute to accelerated atherosclerosis. Positive correlations between PAI-1 and waist circumference and BMI, and negative correlations between BMI and antioxidative defense in the pre-metabolic syndrome patients show that this early stage preceding the metabolic syndrome is also characterized by atherosclerotic complication risks and evident hyperinsulinism and insulin resistance.     

Potential validity of conducting research on headache in internet populations

OBJECTIVE: While it is technically feasible to conduct migraine research on the Internet, can one be sure that the subjects who participate actually have the disorder? We examined this issue in 109 sequential subjects in an Internet study of migraineurs' symptoms. BACKGROUND: The increasing use of the Internet by the US population provides an opportunity for using this medium in clinical research, but, to be useful, the results of such research must be valid and generalizable. METHODS: Using postings to Internet newsgroups of migraineurs, we recruited subjects to a migraine research site. We examined reported symptoms by comparing them with the International Headache Society's criteria for diagnosis of migraine and by subjective review by a neurologist. We also attempted to contact the subject's primary care physicians to confirm their diagnosis. RESULTS: We found considerable evidence for the validity of the participants' self-reported diagnoses. Most subjects with professed migraine reported quality of pain (97%) and associated symptoms (92%) consistent with that diagnosis, and review of their symptoms and questionnaire responses by the neurologist suggested that almost all subjects (97%) had migraine. Personal physicians confirmed a diagnosis of migraine in 90% of consenting subjects (n=49). CONCLUSIONS: The validity of self-reported diagnosis of migraine does not appear to be an obstacle to conducting research in subject populations on the Internet.     

Quantitative sensory tests (perceptual thresholds) in patients with spinal cord injury

This article was presented at the Premeeting Workshop on Outcome Measures at the American Spinal Injury Association (ASIA) Annual Scientific Meeting in Dallas, Texas, in May 2005. The article summarizes preliminary findings of three quantitative sensory tests that were evaluated as part of the International Spinal Research Trust Clinical Initiative study: perceptual thresholds to electrical, vibration, and thermal stimulation. The results gathered so far suggest that the three tests are simple, reproducible, and applicable in a clinical setting. The tests seem to add resolution and sensitivity to the standard clinical testing and could be useful adjuncts in longitudinal monitoring of spinal cord injury for research purposes.     

Can utility-weighted health-related quality-of-life estimates capture health effects of quality improvement for depression?

BACKGROUND: Utility methods that are responsive to changes in desirable outcomes are needed for cost-effectiveness (CE) analyses and to help in decisions about resource allocation. OBJECTIVES: Evaluated is the responsiveness of different methods that assign utility weights to subsets of SF-36 items to average improvements in health resulting from quality improvement (QI) interventions for depression. DESIGN: A group level, randomized, control trial in 46 primary care clinics in six managed care organizations. Clinics were randomized to one of two QI interventions or usual care. SUBJECTS: One thousand one hundred thirty-six patients with current depressive symptoms and either 12-month, lifetime, or no depressive disorder identified through screening 27,332 consecutive patients. MEASURES: Utility weighted SF-12 or SF-36 measures, probable depression, and physical and mental health-related quality of life scores. RESULTS: Several utility-weighted measures showed increases in utility values for patients in one of the interventions, relative to usual care, that paralleled the improved health effects for depression and emotional well being. However, QALY gains were small. Directly elicited utility values showed a paradoxical result of lower utility during the first year of the study for intervention patients relative to controls. CONCLUSIONS: The results raise concerns about the use of direct single-item utility measures or utility measures derived from generic health status measures in effectiveness studies for depression. Choice of measure may lead to different conclusions about the benefit and CE of treatment. Utility measures that capture the mental health and non-health outcomes associated with treatment for depression are needed.     

Pharmacological evaluation of halogenated and non-halogenated arylpiperazin-1-yl-ethyl-benzimidazoles as D(2) and 5-HT(2A) receptor ligands

Five groups of previously synthesized and initially screened non-substituted and 4-halogenated arylpiperazin-1-yl-ethyl-benzimidazoles were estimated for their in-vitro binding affinities at the rat D(2) , 5-HT(2A) , and α(1) -adrenergic receptors. Among all these compounds, 2-methoxyphenyl and 2-chlorophenyl piperazines demonstrate the highest affinities for the tested receptors. The effects of 4-halogenation of benzimidazoles reveal that substitution with bromine may greatly increase the affinity of the compounds for the studied receptors, while the effect of substitution with chlorine is less remarkable. Most of the tested components show 5-HT(2A)/D(2) pK(i) binding ratios slightly above or less than 1, while only 4-chloro-6-(2-{4-[3-(trifluoromethyl)phenyl]piperazin-1-yl}ethyl)-1H-benzimidazole expresses an appropriate higher binding ratio (1.14), which was indicated for atypical neuroleptics. This compound exhibits a non-cataleptic action in rats and prevents d-amphetamine-induced hyperlocomotion in mice, which suggest its atypical antipsychotic potency.