Differential inhibition of rat and mouse microsome heme oxygenase by derivatives of imidazole and benzimidazole.

Metalloporphyrin heme oxygenase (HO) inhibitors have made an important contribution to elucidating the role of HO in physiological processes. Nevertheless, their off-target effects have drawn substantial criticism, which prompted us to develop non-porphyrin, azole-based inhibitors of HO. These second-generation HO inhibitors were evaluated using spleen and brain microsomes from rats as native sources of HO-1 and HO-2, respectively.

Mitoxantrone and Etoposide for the Treatment of Acute Myeloid Leukemia Patients in First Relapse.

Relapsed acute myeloid leukemia (AML) represents a major therapeutic challenge. Achieving complete remission (CR) with salvage chemotherapy is the first goal of therapy for relapsed AML. However, there is no standard salvage chemotherapy.

Are icons sense data?

We argue that Hoffman, Singh, and Prakash (Psychon Bull Rev, this issue) have not made the case that "the language of space-time and physical objects is the wrong language for describing the true structure of the objective world." Further, we contend that, contrary to what Hoffman et al. claim, the perceptual icons posited by interface theory seem best taken to be sense data.

Structural analysis and identification of PhuS as a heme-degrading enzyme from Pseudomonas aeruginosa.

Bacterial pathogens require iron for proliferation and pathogenesis. Pseudomonas aeruginosa is a prevalent Gram-negative opportunistic human pathogen that takes advantage of immunocompromised hosts and encodes a number of proteins for uptake and utilization of iron. Here we report the crystal structures of PhuS, previously known as the cytoplasmic heme-trafficking protein from P.

Phase I trial of carboplatin and etoposide in combination with panobinostat in patients with lung cancer.

Unlabelled: A phase I trial consisting of panobinostat (a HDAC inhibitor), carboplatin and etoposide was conducted in patients with lung cancer.

Patients And Methods: Patients received carboplatin AUC5 on day 1 and etoposide 100 mg/m(2) on days 1, 2 and 3, every 21 days. Concurrent oral panobinostat was given 3 times weekly on a 2-weeks-on and 1-week-off schedule during the 4-6 cycles of chemotherapy and then continued as maintenance therapy.

Fludarabine and cytarabine in patients with relapsed acute myeloid leukemia refractory to initial salvage therapy.

The most effective regimen for relapsed acute myeloid leukemia (AML) patients who do not achieve complete remission (CR) after a course of salvage therapy has not been established. We evaluated the efficacy and toxicity of fludarabine and cytarabine in patients with AML in first relapse who did not respond to a course of salvage chemotherapy with mitoxantrone and etoposide. CR was achieved in 39 % of treated patients, and in 47 % of patients with a favorable/intermediate-risk karyotype.

Prosthetic limb sockets from plant-based composite materials.

Background: There is a considerable demand for lower limb prostheses globally due to vascular disease, war, conflict, land mines and natural disasters. Conventional composite materials used for prosthetic limb sockets include acrylic resins, glass and carbon fibres, which produce harmful gasses and dust in their manufacture.

Objectives: To investigate the feasibility of using a renewable plant oil-based polycarbonate-polyurethane copolymer resin and plant fibre composite, instead of conventional materials, to improve safety and accessibility of prosthetic limb manufacture.

Selective activation of heme oxygenase-2 by menadione.

While substantial progress has been made in elucidating the roles of heme oxygenases-1 (HO-1) and -2 (HO-2) in mammals, our understanding of the functions of these enzymes in health and disease is still incomplete. A significant amount of our knowledge has been garnered through the use of nonselective inhibitors of HOs, and our laboratory has recently described more selective inhibitors for HO-1. In addition, our appreciation of HO-1 has benefitted from the availability of tools for increasing its activity through enzyme induction.

Recombinant truncated and microsomal heme oxygenase-1 and -2: differential sensitivity to inhibitors.

Recombinant truncated forms of heme oxygenase-1 and -2 (HO-1 and HO-2) were compared with their crude microsomal counterparts from brain and spleen tissue of adult male rats with respect to their inhibition by azole-based, nonporphyrin HO inhibitors. The drugs tested were an imidazole-alcohol, an imidazole-dioxolane, and a triazole-ketone. Both the recombinant and crude forms of HO-2 were similarly inhibited by the 3 drugs.

The effects of azole-based heme oxygenase inhibitors on rat cytochromes P450 2E1 and 3A1/2 and human cytochromes P450 3A4 and 2D6.

Heme oxygenases (HOs) catalyze the degradation of heme to biliverdin, carbon monoxide (CO), and free iron. The two major isoforms, HO-1 (inducible) and HO-2 (constitutive), are involved in a variety of physiological functions, including inflammation, apoptosis, neuromodulation, and vascular regulation. Major tools used in exploring these actions have been metalloporphyrin analogs of heme that inhibit the HOs.

Management of patients treated with chemoradiotherapy for head and neck cancer without prophylactic feeding tubes: the University of Pittsburgh experience.

Objectives/hypothesis: Mucositis and dysphagia are common complications of chemoradiotherapy (CRT) for head and neck cancer that may necessitate nutritional support with a gastrostomy tube (G-tube).

Methods: We reviewed records of patients who underwent and completed CRT, which included at least one traditional chemotherapeutic, for previously untreated head and neck cancer. G-tubes were placed as needed.

Extravascular lung water indexed to predicted body weight is a novel predictor of intensive care unit mortality in patients with acute lung injury.

Objectives: Acute lung injury and the acute respiratory distress syndrome are characterized by noncardiogenic pulmonary edema, which can be assessed by measurement of extravascular lung water. Traditionally, extravascular lung water has been indexed to actual body weight (mL/kg). Because lung size is dependent on height rather than weight, we hypothesized indexing to predicted body weight may be a better predictor of mortality in acute lung injury/acute respiratory distress syndrome.

Dialysis disequilibrium syndrome: a consideration in patients with hydrocephalus.

Dialysis disequilibrium syndrome is a rare neurological manifestation of intermittent hemodialysis. Urea removal occurs more slowly across the blood-brain barrier than from the plasma, generating an osmotic gradient that promotes water movement into the brain and cerebral edema. The authors report the development of dialysis disequilibrium syndrome in a patient with spina bifida and an adequately functioning shunt.

Chronic prenatal ethanol exposure and increased concentration of fatty acid ethyl esters in meconium of term fetal Guinea pig.

In humans, the occurrence of prenatal exposure to ethanol is difficult to validate objectively. Increased concentration of fatty acid ethyl esters (FAEE) in the meconium of the newborn may be a biomarker of prenatal ethanol exposure. The validity of this proposed biomarker was tested in pregnant guinea pigs that received chronic oral administration of 4 g ethanol/kg maternal body weight/day (n=8), isocaloric-sucrose/pair-feeding (n=8) or water (n=2) throughout gestation.

The source of heme for vascular heme oxygenase II: de novo heme biosynthesis in rat aorta.

Heme is an essential prosthetic group or substrate for many proteins, including hemoglobin, and hemo enzymes such as nitric oxide synthase, soluble guanylyl cyclase, and heme oxygenase (HO). HO is responsible for the breakdown of heme into equimolar amounts of biliverdin, iron, and carbon monoxide, the latter of which is thought to play a role in the regulation of vascular tone. It is not clear whether the source of heme for cardiovascular functions is derived from uptake from the extracellular milieu or synthesis.

The source of heme for vascular heme oxygenase I: heme uptake in rat aorta.

During the last decade, heme oxygenase (HO) and carbon monoxide (CO) have garnered substantial research interest in terms of cell and organ regulation, especially as they bear on the central nervous system, organ transplantation, and the cardiovascular system. While the enzymatic mechanism, substrates, and products of HO are well known, it is not clear whether the cardiovascular system derives its supply of the heme substrate through de novo synthesis or uptake from the extracellular milieu. The objective of the present study was to test the latter possibility in rat aorta and to determine the influence of plasma proteins that bind heme in vivo, viz.

Heme oxygenase expression in selected regions of term human placenta.

Carbon monoxide (CO), formed during heme oxygenase (HO)-catalyzed oxidation of heme, has been proposed to play a complementary role with nitric oxide in the regulation of placental hemodynamics. The objective of this study was to elucidate HO enzymatic activity and HO-1 (inducible) and HO-2 (constitutive) protein content in the microsomal subcellular fraction of homogenate of selected regions of placenta from normotensive and mild pre-eclamptic pregnancies. HO enzymatic activity was measured under optimized conditions by gas chromatography using CO formation as an index of activity, and HO-1 and HO-2 protein content were determined by Western immunoblot analysis.

Measurement of endogenous carbon monoxide formation in biological systems.

Endogenous carbon monoxide (CO) formation has been measured in different biological systems using a variety of analytical procedures. The methods include gas chromatography-reduction gas detection, gas chromatography-mass spectroscopic detection, laser sensor-infrared absorption, UV-visible spectrophotometric measurement of CO-hemoglobin or CO-myoglobin complex, and formation of (14)CO from (14)C-heme formed following [2-(14)C]glycine administration. CO formation ranged from a low of 0.