Mechanism of the plasma cholesterol lowering effect of tazasubrate in rats: accelerated plasma cholesterol transport with increased liver lipoprotein receptor activity

Tazasubrate (30 mg/kg/day) a new lipid lowering agent, chemically unrelated to fibrates, reduces plasma cholesterol in rats within 2-3 days to 50% of controls. During the early rapid decrease of plasma cholesterol, increased liver cholesterol concentrations are observed. These return to normal, once the new steady state of plasma cholesterol (at 50% of controls) has been reached. Radiotracer studies with 3H-cholesterol labelled plasma very low density lipoproteins are consistent with an accelerated plasma cholesterol turnover. Analysis of the binding to liver membranes of 125I labelled cholesterol rich very low density lipoproteins (beta-VLDL) shows a marked increase in the total binding (Bmax rising from 106 ng/mg of protein 378 ng/mg), without significant alterations in the receptor affinity.     

Biochemical modulation of cytarabine triphosphate by clofarabine

Purpose Clofarabine has proven to be effective in the treatment of adult and pediatric acute myelogenous leukemia (AML). To investigate if clofarabine could be used with success in biochemical modulation strategies, we investigated the biochemical modulation of cytarabine triphosphate (ara-CTP) by clofarabine in a myeloid leukemia cell line and the effect of this combination on cytotoxicity.Experimental design K562 cells were incubated with clofarabine and ara-C either sequentially or simultaneously to evaluate the combination effect on their phosphorylated metabolites. Clonogenic assays were used to determine the cytotoxicity of each agent alone and in combination. Deoxynucleotide analysis was performed to assess the effect of clofarabine on dNTPs.Results Clofarabine added either simultaneously or in sequence increased ara-CTP accumulation. The maximal modulation of ara-CTP accumulation occurred with 1 M clofarabine. This level was achieved at the maximum tolerated dose for adult and pediatric patients with AML. With 10 M ara-C alone, 86 M ara-CTP had accumulated after 3 h. The optimal sequence for the drug combination, i.e., clofarabine followed 4 h later by ara-C, resulted in 248 M ara-CTP at 3 h. Clofarabine accumulated maximally in the monophosphate form. Preincubation with ara-C did not affect the triphosphate form, but it lowered clofarabine monophosphate. Clofarabine resulted in the intracellular decrease of dATP and dGTP levels. Clonogenic assays revealed that the combination of clofarabine and ara-C produced synergistic killing of myeloid leukemia cells.Conclusions These findings demonstrate that combination of clofarabine followed by ara-C results in a biochemical modulation of ara-CTP and synergistic cell kill. These studies provide a compelling rationale for clinical trials using this combination regimen for adult and pediatric patients with AML.     

Arachnoid cysts of the middle cranial fossa presented as subdural hematomas

The aim of the study was to present the authors' own experience and discuss the treatment method of arachnoid cysts of the middle cranial fossa disclosed as subdural hematoma. Three cases of male patients operated on because of chronic subdural hematoma are presented. Control CT studies after evacuation of hematomas revealed arachnoid cysts of the middle cranial fossa and all patients were qualified for delayed cystocisternostomy by open craniotomy. Indirect signs of presence of arachnoid cysts in the form of bony abnormalities and expanded the middle cranial fossa in the first CT were seen in all patients. Cysts were asymptomatic until the injury in all cases. The volumes of cysts in MRI scans were: 17.8 ml, 52.9 ml and 92.4 ml, respectively. All cysts were type II according to Galassi classification. After control MRI described above made to evaluate cyst appearance, delayed cystocisternostomy to basal cisterns was undertaken in two cases with full success. No complications were observed. The third patient refused surgery. During surgery the thick and non-transparent medial cyst wall and arachnoidea of tentorial notch cisterns were observed impeding the exact identification of neurovascular structures. In our opinion arachnoid cysts of the middle cranial fossa revealed as subdural hematoma should be operated on in two stages: in the first step subdural hematoma should be evacuated and in the second step cystocisternostomy should be performed. With regard to observed morphological changes of arachnoidea and cyst walls we think that open cystocisternostomy is treatment of choice in these cases.     

Pulmonary sequestration with haemoptysis and an unsuspected carcinoid tumour

We report the case of a fit and healthy 41-year-old man, who presented with significant haemoptysis without a history of recurrent infections. His computed tomography scan showed a dense lesion in the left lower lobe with a feeding vessel arising from the abdominal aorta, characteristic for an intra-pulmonary sequestration. To prevent possible further haemoptysis or infections, a left lower lobectomy was performed. The histological examination showed the typical features of a sequestration. However, within the sequestration, a carcinoid tumour without atypical features was found. There was no lymph node involvement. Sequestrations are congenital lesions without communication with the bronchial tree and with a systemic blood supply. They commonly cause recurrent infection. Fatal haemoptysis has also been described, but is rare. There are very few reports of neoplastic lesions in sequestrations. This case illustrates two unusual aspects of sequestrations. Surgery offers definitive treatment for both pathologies, as opposed to embolisation.