Toxicity of oxidized phospholipids in cultured macrophages

ABSTRACT: BACKGROUND: The interactions of oxidized low-density lipoprotein (LDL) and macrophages are hallmarks in the development of atherosclerosis. The biological activities of the modified particle in these cells are due to the content of lipid oxidation products and apolipoprotein modification by oxidized phospholipids. RESULTS: It was the aim of this study to determine the role of short-chain oxidized phospholipids as compounds of modified LDL in cultured macrophages. For this purpose we investigated the effects of the following oxidized phospholipids on cell viability and apoptosis: 1-palmitoyl-2-glutaroyl-sn-glycero-3-phosphocholine (PGPC), 1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphocholine (POVPC) and oxidized dialkyl phospholipids including 1-O-hexadecyl-2-glutaroyl-sn-glycero-3-phosphocholine (E-PGPC) and 1-O-hexadecyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphocholine (E-POVPC). We found that these compounds induced apoptosis in RAW264.7 and bone marrow-derived macrophages. The sn-2 carboxyacyl lipid PGPC was more toxic than POVPC, which carries a reactive aldehyde function in position sn-2 of glycerol. The alkyl phospholipids (E-PGPC and E-POVPC) and the respective diacyl analogs show similar activities. Apoptosis induced by POVPC and its alkylether derivative could be causally linked to the fast activation of an acid sphingomyelinase, generating the apoptotic second messenger ceramide. In contrast, PGPC and its ether analog only neglegibly affected this enzyme pointing to an entirely different mechanism of lipid toxicity. The higher toxicity of PGPC is underscored by more efficient membrane blebbing from apoptotic cells. In addition, the protein pattern of PGPC-induced microparticles is different from the vesicles generated by POPVC. CONCLUSIONS: In summary our data reveal that oxidized phospholipids induce apoptosis in cultured macrophages. The mechanism of lipid toxicity, however, largely depends on the structural features of the oxidized sn-2 chain.     

Diffuse alveolar hemorrhage temporally related to cocaine smoking

Previous reports of respiratory complications from cocaine abuse have focused on pulmonary barotrauma or a reduction in carbon monoxide diffusing capacity. We report a patient who developed life-threatening alveolar hemorrhage following repeated inhalation of alkaloid cocaine.     

Über Häufigkeit und Ursache menschlicher Tuberkulose auf Grund von ca. 1400 Sektionen

Ohne ZusammenfassungUnter Zugrundelegung eines Vortrages, gehalten in der Gesellschaft für Natur-und Heilkunde in Dresden am 18. April 1903. (Erscheint aus äußeren Gründen verspätet.)     

Pharmacokinetics of intravenous and intraperitoneal ceftriaxone in chronic ambulatory peritoneal dialysis

Summary The kinetics of ceftriaxone was investigated in 8 patients without infection, who were receiving continuous ambulatory peritoneal dialysis (CAPD). Ceftriaxone 1 g was injected i.v. and 1 g was given intraperitoneally in the CAPD fluid during a 4-h dwell time. Ceftriaxone was assayed by HPLC. After intravenous administration, the kinetic parameters of ceftriaxone were: plasma t_1/2, 12.3 h, total plasma clearance, 14.0 ml/min, volume of distribution at steady state 0.18 l/kg, and peritoneal clearance 0.59 ml/min. Over 72 hours only 5.5% of the dose was eliminated by the peritoneal route. After intraperitoneal administration, ceftriaxone rapidly appeared in serum; the absorption t_1/2 was 1.1 h and the mean peak concentration was 38.8 µg/ml. The absorption of ceftriaxone from the peritoneal space was 39%. A single 1.0 g IP dose led to serum and dialysate concentrations of ceftriaxone above the minimum inhibitory concentration for susceptible pathogens for 24 hours.     

An experimental study of craniocerebral trauma during ethanol intoxication

This study evaluates the effects of ethanol (blood levels of 200 mg/dl for one hour) and dimethyl sulfoxide (DMSO) on cerebral lesion volumes after pressure-induced focal ischemia during normotension and induced hypotension in the canine. This experimental design simulates the situation where an individual imbibes two to four alcoholic drinks over a one-hour period, then drives a motor vehicle, and suffers a head injury either without significant blood loss or where the cerebral perfusion pressure is reduced to the lower limits of autoregulation (mean arterial pressure of 50 mm Hg). Ethanol was shown to increase brain lesion volumes in both the normotensive (4.5 +/- 0.7 cm3) and hypotensive (14.9 +/- 2.2 cm3) groups when compared to controls (0.8 +/- 0.3 and 2.9 +/- 0.4 cm3, respectively). DMSO markedly attenuated this response in the normotensive and hypotensive ethanol groups. It is thought that the intermediate metabolites of ethanol provide a large source of hydroxyl-free radicals in the presence of neuronal tissue damage and that these free radicals are effectively scavenged by DMSO.     

In vitro study of the transplacental passage of chloroquine sulfate

The authors, by performing in vitro perfusion on six human placentas, have studied the passage of chloroquine sulphate into the placenta. The drug levels were recorded by high performance liquid chromatography (HPLC). The placental perfusions lasted one hour and drug passage into placental tissue was low (14.21%) which seems to be due to the high degree of fixation of chloroquine on placental tissue.     

Ferruginous bodies and pulmonary fibrosis in dead low to moderately exposed asbestos cement workers: histological examination

Histological slides from the lungs of 89 dead asbestos cement workers have been examined with respect to ferruginous bodies and fibrosis. The results have been compared with individually matched controls with no known exposure to asbestos, and related to asbestos exposure, expressed as duration of exposure and cumulative asbestos dose, and smoking habits. The asbestos cement workers studied had been employed for on average 15 years, with a mean cumulative dose of 26 fibre-years per ml (f-y/ml). Clear dose-response relations between exposure (duration of exposure and cumulative asbestos dose) and level of ferruginous bodies were found. An association was evident already at a low cumulative dose (1-10 f-y/ml). Fibrosis was more common and more pronounced among the exposed workers than among controls. An association between ferruginous bodies and fibrosis was also found. Among the controls, but not among exposed workers, there was an association between smoking history and fibrosis.     

Striatal and nigral neuron subpopulations in rigid Huntington's disease: implications for the functional anatomy of chorea and rigidity-akinesia

Neuropeptide immunohistochemistry was used to test several hypotheses of the anatomical bases of chorea and rigidity-akinesia. To test the hypothesis that elevated concentration of striatal somatostatin causes chorea, we visually compared the density of striatal neurons containing somatostatin and neuropeptide Y in brains affected by choreic or rigid-akinetic Huntington's disease (HD). The density of these neurons was elevated in both rigid-akinetic and choreic HD specimens with an apparently normal total number of these neurons, indicating that elevated somatostatin concentration, by itself, does not lead to chorea. We tested the hypothesis that rigid-akinetic HD results from deficient dopaminergic nigrostriatal neurotransmission by examining tyrosine hydroxylase-immunoreactive (TH-IR) neurons in the substantia nigra. In rigid-akinetic HD brains, there was no obvious reduction of nigral TH-IR neurons, indicating that rigid-akinetic HD is probably not due to loss of nigral dopaminergic neurons. Finally, we also examined the status of striatal projection neurons and found near total loss of all striatal neurons projecting to the lateral globus pallidus, medial globus pallidus, and substantia nigra in brains affected by rigid-akinetic HD in contrast to the preservation of neurons projecting to the medial globus pallidus in choreic HD. These results are consistent with the hypothesis that chorea results from preferential loss of striatal neurons projecting to the lateral globus pallidus and that rigid-akinetic HD is a consequence of the additional loss of striatal neurons projecting to the medial segment of the pallidum.