Blood lipid profile in ischaemia reperfusion injury

BACKGROUND: Lipid components are considered to play an important role in ischaemia reperfusion injury although the mechanism of their action remains unknown. Accumulation of lipid metabolites in ischaemic tissues is a consistent observation, but exactly how these lipids are cleared from the tissues by the circulating blood during reperfusion is still open to speculation. In the present study, levels of blood lipids (fatty acids, phospholipids, triglycerides, cholesterol, lysolecithin and lysolecithin platelet activating factor (lyso PAF)) and the enzyme phospholipase A2 were determined in an experimental animal model (dogs) of ischaemic reperfusion injury. METHODS: The injury was induced by 4 h of aortic clamping followed by 2 h of reperfusion (unclamping). Blood samples were collected before clamping and at predetermined time intervals (0, 15, 60 and 120 min) after the release of clamp. The lipid contents were analysed and compared with sham-treated control dogs. RESULTS: The results showed significantly elevated levels of triglycerides and phospholipase A2, during ischaemia and reperfusion in experimental animals indicating tissue damage in the ischaemic phase continuing into the reperfusion phase and the risk of systemic damage from these toxic substances. Total fatty acid content in the circulating blood showed decreasing trends during the same time interval, which suggested possible reduced clearance of accumulated fatty acids from the affected tissues. Serum cholesterol, phospholipids, lyso PAF and lysolecithin did not show any significant variation compared with control dogs. CONCLUSIONS: It is possible that the delayed clearance of fatty acids may be due to the presence of fatty acids binding proteins in the ischaemic tissue, which trap these fatty acids in the tissues during ischaemic reperfusion injury. The prolonged retention of the accumulated fatty acids in the tissues in association with elevated triglycerides and phospholipase A2 activity may contribute to ischaemia reperfusion injury.     

Neuropsychologic status in multiple sclerosis after treatment with glatiramer

BACKGROUND: Glatiramer acetate (Copaxone) therapy reduces clinical disease activity in relapsing-remitting multiple sclerosis (MS). OBJECTIVE: To study the effect of glatiramer therapy on neuropsychologic function as part of a randomized, placebo-controlled, multicenter trial. METHODS: Two hundred forty-eight patients with relapsing-remitting MS and mild to moderate disability (Expanded Disability Status Scale score, <5.0) were tested before and 12 and 24 months after randomization to administration of glatiramer acetate, 20 mg/d, or matching placebo. Neuropsychologic tests examined 5 cognitive domains most often disrupted in patients with MS: sustained attention, perceptual processing, verbal and visuospatial memory, and semantic retrieval. RESULTS: Baseline neuropsychologic test performance was similar in both treatment groups and was within normal range, except for impaired semantic retrieval. Mean neuropsychologic test scores were higher at 12 and 24 months than at baseline, and no differences were detected between treatment groups over time. No significant interactions were detected between treatment and either time or baseline impairment. CONCLUSIONS: Our 2-year longitudinal study showed no effect of glatiramer therapy on cognitive function in relapsing-remitting MS. Although it is possible that glatiramer therapy has no effect on cognitive function, the lack of measurable decline in cognitive function in both patient groups for 2 years limits the opportunity for glatiramer to demonstrate a therapeutic effect by minimizing such decline. Emerging treatments for MS should continue to be examined for their effect on cognitive impairment because it can be a critical determinant of disability. A greater understanding of the natural history of cognitive decline in MS is essential for a rational design of these drug trials.     

Boron neutron capture therapy of brain tumors: an emerging therapeutic modality

Boron neutron capture therapy (BNCT) is based on the nuclear reaction that occurs when boron-10, a stable isotope, is irradiated with low-energy thermal neutrons to yield alpha particles and recoiling lithium-7 nuclei. For BNCT to be successful, a large number of 10B atoms must be localized on or preferably within neoplastic cells, and a sufficient number of thermal neutrons must be absorbed by the 10B atoms to sustain a lethal 10B (n, alpha) lithium-7 reaction. There is a growing interest in using BNCT in combination with surgery to treat patients with high-grade gliomas and possibly metastatic brain tumors. The present review covers the biological and radiobiological considerations on which BNCT is based, boron-containing low- and high-molecular weight delivery agents, neutron sources, clinical studies, and future areas of research. Two boron compounds currently are being used clinically, sodium borocaptate and boronophenylalanine, and a number of new delivery agents are under investigation, including boronated porphyrins, nucleosides, amino acids, polyamines, monoclonal and bispecific antibodies, liposomes, and epidermal growth factor. These are discussed, as is optimization of their delivery. Nuclear reactors currently are the only source of neutrons for BNCT, and the fission reaction within the core produces a mixture of lower energy thermal and epithermal neutrons, fast or high-energy neutrons, and gamma-rays. Although thermal neutron beams have been used clinically in Japan to treat patients with brain tumors and cutaneous melanomas, epithermal neutron beams now are being used in the United States and Europe because of their superior tissue-penetrating properties. Currently, there are clinical trials in progress in the United States, Europe, and Japan using a combination of debulking surgery and then BNCT to treat patients with glioblastomas. The American and European studies are Phase I trials using boronophenylalanine and sodium borocaptate, respectively, as capture agents, and the Japanese trial is a Phase II study. Boron compound and neutron dose escalation studies are planned, and these could lead to Phase II and possibly to randomized Phase III clinical trials that should provide data regarding therapeutic efficacy.     

Effects of TGFbeta on bone ingrowth in the presence of polyethylene particles

We implanted bone harvest chambers (BHCs) bilaterally in ten mature male New Zealand white rabbits. Polyethylene particles (0.3+/-0.1 microm in diameter, 6.4 x 10(12) particles/ml) were implanted for two, four or six weeks bilaterally in the BHCs, with subsequent removal of the ingrown tissue after each treatment. In addition to the particles, one side also received 1.5 microg of recombinant transforming growth factor beta1 (TGFbeta1). At two weeks, the bone area as a percentage of total area was less in chambers containing TGFbeta compared with those with particles alone (7.8+/-1.3% v 16.9+/-2.7% respectively; 95% confidence interval (CI) for difference -14.0 to -4.30; p = 0.002). At four weeks, the percentage area of bone was greater in chambers containing TGFbeta compared with those with particles alone (31.2+/-3.4% v 22.5+/-2.0% respectively; 95% CI for difference 1.0 to 16.4; p = 0.03). There were no statistical differences at six weeks, despite a higher mean value with TGFbeta treatment (38.2+/-3.9% v 28.8 +/-3.5%; 95% CI for difference -4.6 to 23.3; p = 0.16). The number of vitronectin-receptor-positive cells (osteoclast-like cells) was greater in the treatment group with TGFbeta compared with that with particles alone; most of these positive cells were located in the interstitium, rather than adjacent to bone. TGFbeta1 is a pleotropic growth factor which can modulate cellular events in the musculoskeletal system in a time- and concentration-dependent manner. Our data suggest that there is an early window at between two and six weeks, in which TGFbeta may favourably affect bone ingrowth in the BHC model. Exogenous growth factors such as TGFbeta may be a useful adjunct in obtaining osseointegration and bone ingrowth, especially in revisions when there is compromised bone stock and residual particulate debris.     

Dislodgement of Intracoronary Thrombus During Angiography in a Patient with Unstable Angina Pectoris

A patient with unstable angina pectoris in whom thrombus release from intracoronary lesion was seen during angiography is described. The event resulted in improvement of vessel patency and resolution of ischemic symptoms. To our knowledge, only two similar cases have been reported in English literature since 1966.