Gastrointestinal permeability in ovarian cancer and breast cancer patients treated with paclitaxel and platinum

Background  

Combination of platinum derivatives with paclitaxel is currently the standard front line regimen for patients with epithelial ovarian carcinoma, and represents also an active regimen in patients with metastatic breast or unknown primary carcinomas. Measurement of intestinal permeability represents one of the potential methods of noninvasive laboratory assessment of gastrointestinal mucositis induced by chemotherapy, but little is known about intestinal permeability in patients treated with paclitaxel or platinum.     

Metabolism of carcinogenic N-nitroso-N-methylaniline by purified cytochromes P450 2B1 and P450 2B2

N-Nitroso-N-methylaniline (NMA) is an esophageal carcinogen in the rat. The in vitro enzymatic metabolism of NMA was investigated using cytochromes P450 2B1 and P450 2B2, isolated from liver microsomes of rats pretreated with phenobarbital (PB), reconstituted with NADPH-cytochrome P450 reductase and dilauroylphosphatidylcholine. Formaldehyde is produced by both cytochromes P450 (P450). NMA is a better substrate for P450 2B1 than for P450 2B2. The maximal velocity (V_max) values are 3.3 and 1.6 nmol HCHO/min per nmol P450 for P450 2B1 and P450 2B2, respectively. Beside formation of formaldehyde, aniline and p-aminophenol (p-AP) are found to be metabolites formed from NMA by both P450 isoenzymes. P450 2B1 also affords phenol, while none was found with the P450 2B2 isoenzyme. Phenol formation presumably arose from direct alpha-C-hydroxylation of NMA via a benzenediazonium ion (BDI) intermediate. The results suggest strongly that P450 2B1 catalyzes both alpha-C-hydroxylation and denitrosation of NMA while P450 2B2 catalyzes only denitrosation. Therefore, the P450 2B1 isoenzyme participates in the activation of NMA to the ultimate carcinogenic BDI.     

Caspase activation and amyloid precursor protein cleavage in rat ocular hypertension

PURPOSE: Retinal ganglion cell (RGC) death in glaucoma involves apoptosis. Activation of caspases and abnormal processing of amyloid precursor protein (APP) are important events in other chronic neurodegenerations, such as Alzheimer's disease (AD). The retinal expression and activation of caspases and the patterns of caspase-3-mediated APP processing in ocular hypertensive models of rat glaucoma were investigated. METHODS: RGC death was produced in one eye by chronic exposure to increased intraocular pressure (IOP) or by optic nerve transection. Elevated IOP was produced by obstruction of aqueous humor outflow with laser coagulation or limbal hypertonic saline injection. Caspase activity and APP processing in the retina were examined by RNase protection assay (RPA), immunocytochemistry, immunoblot assay, and colorimetric assay. RESULTS: RPA revealed elevations of caspase-3 mRNA, as well as other apoptosis-related mRNAs. Immunocytochemistry showed caspase-3 activation in RGCs damaged by ocular hypertension. The generation of the caspase-3-mediated APP cleavage product (DeltaC-APP) was also increased in ocular hypertensive RGCs. Western immunoblot assay and colorimetry revealed significantly more activated caspase-3 in ocular hypertensive retinas than in control retinas. The activated form of caspase-8, an initiator caspase, and amyloid-beta, a product of APP proteolysis and a component of senile plaques in AD, were detected in RGCs by immunohistochemistry significantly more often in ocular hypertensive than in control retinas. The amounts of full-length APP were reduced and amyloid-beta-containing fragments were increased in ocular hypertensive retinas by Western immunoblot assay. CONCLUSIONS: Rat RGCs subjected to chronic ocular hypertension demonstrate caspase activation and abnormal processing of APP, which may contribute to the pathophysiology of glaucoma.     

Ocular perfusion abnormalities in diabetes

PURPOSE: To review the role of ocular perfusion in the pathophysiology of diabetic retinopathy, one of the leading causes of irreversible blindness in the industrialized world. METHODS: We carried out a Medline search of the literature published in English or with English abstracts from 1966 to 2000 using various combinations of relevant key words. RESULTS: Hyperglycaemia leads to a wide variety of vascular abnormalities at the microvascular and macrovascular levels, including abnormal autoregulation. CONCLUSION: Three major aspects of ocular perfusion in diabetic retinopathy require additional investigation. Firstly, the precise mechanisms that link elevated glucose to dysfunction of retinal vascular cells need to be identified. Secondly, those factors that lead to both capillary dropout and to angiogenesis, twin processes that are linked to tissue hypoxia and lead to excess perfusion, increased risk of extravascular leakage and frank haemorrhage, must be carefully delineated. Finally, once specific knowledge of disease fundamentals has been amassed, tests of therapies to reverse or prevent these pathological processes can move forward.     

Unequal development of thresholds for various phenomena induced by cortical stimulation in rats

Electrical stimulation of sensorimotor cortical area was performed in 9-, 12-, 18-, 25-, 35- and 90-day-old rats with implanted electrodes to establish threshold intensities of currents necessary to elicit four different motor or EEG phenomena. Two different stimulation frequencies (8 and 50 Hz) were used. Development of thresholds for stimulation-bound movements, spike-and-wave afterdischarges and clonic seizures accompanying these afterdischarges was similar: the lowest threshold was found in 18-, respectively, in 18- and 25-day-old rats with the 8 and 50 Hz frequencies. Younger as well as older animals exhibited higher threshold intensities. The fourth phenomenon, transition into another, 'limbic' type of afterdischarges appeared only exceptionally in the youngest rats and its incidence increased whereas the threshold decreased with age. Higher frequency was more efficient in elicitation of limbic afterdischarges than the 8 Hz stimulation in rats aged 18 and more days. Our data represent a background for pharmacological studies and indicate the development of cortical excitability and of connections between the thalamocortical system and limbic structures.     

Hypersensitivity reaction to cisplatin during chemoradiation therapy for gynecologic malignancy

Hypersensitivity reactions to intravenous cisplatin are rare. The appearance of hypersensitivity reactions in 4 of 25 consecutive patients treated with concomitant pelvic radiation and weekly intravenous cisplatin for gynecologic malignancies is reported. The reactions appeared within hours of cisplatin delivery and included primarily fever, rash, and pruritus. Infection was ruled out by blood cultures and other laboratory studies. Affected patients were treated prophylactically with an antihistamine before subsequent courses of cisplatin, with excellent results. The high rate of hypersensitivity reactions in our series may be attributable to tumor necrosis and cytokine release caused by the pelvic irradiation. Clinicians should be aware of this potential side effect so that early premedication regimens can be instituted to prevent unnecessary toxicity.     

Significant increase of colonic mutated crypts in ulcerative colitis correlatively with duration of illness

Mild periodic acid-Schiff (mPAS) staining can discriminate non-O-acetylated(mPAS positive) from O-acetylated (mPAS negative) epithelial sialoglycoproteins in human colonic mucosa, giving three haplotypes of expression of a single polymorphic autosomal gene (oat). Increase in mPAS-positive crypts in heterozygotes is an indication of mutations, and wholly mPAS-positive (stem cell mutated) crypts and clusters of two or more mPAS-positive crypts in heterozygotes of ulcerative colitis (P < 0.0001) were found to be increased significantly, compared with controls. The observed correlation with ulcerative colitis duration (r = 0.892 and 0.853, respectively) supports a chronic inflammation-carcinoma sequence.     

Findings from the Global Youth Tobacco Survey (GYTS) in Czech Republic, Hungary, Poland and Slovakia – smoking initiation, prevalence of tobacco use and cessation

Objectives  

To show selected findings from the Global Youth Tobacco Survey (GYTS) conducted in Czech Republic, Hungary, Poland and Slovakia.     

Giant bleeding renal angiomyolipoma: Diagnosis and management

A case of a giant bleeding renal angiomyolipoma is presented. The patient was a 40‐year‐old Egyptian male with no clinical or radiological evidence of tuberous sclerosis. The radiological features and management, including the role of angiography are briefly discussed and the medical reviews on this subject are briefly considered.