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Tumor hypoxia is an important factor limiting the efficiency of sparsely ionizing ra-diation and O2-dependent chemotherapy. Since the tumor pO2 is the result of a dynamic steady state between oxygen supply and O2 consumption of the tumor tissue, hypoxia could be reduced either by increasing the O2-supply or by reducing the O2 demand of the tumor cells. The O2 supply can be improved for instance by (i) increasing the arterial oxy-gen partial pressure, (ii) improving (and homogenizing) the tumor perfusion, or (iii) en-hancing the O2 release from blood into the tissue by right-shifting the HbO2 dissociation curve. Theoretically, it should also be possible to improve tumor oxygenation by a rela-tively small decrease in O2 consumption rate of the tumor cells. However, at present in-creasing the arterial pO2 by breathing hyperoxic gas mixtures seems to be the most effective method to improve tumor oxygenation and, thus, to enhance the efficiency of standard radio- and chemotherapy in experimental malignancies [1,7,10,11,15,24] as well as in human tumors [3,9,12,14,22,29,30]. However, since in some tumor entities oxygena-tion is inadequate and anisotropic [27], normobaric hyperoxia is often not sufficient to completely eradicate tumor hypoxia [6,16,18,26]. In these cases only breathing of hyper-oxic gases under hyperbaric conditions may be sufficient to lead to therapeutic results. On the other hand, studies on experimental tumors in animals as well as clinical trials in pa-tients showed non-uniform results concerning the therapeutic benefit of inspiratory hyper-oxia ranging from clear improvement of radiosensitivity [3,4,20,30] to no effect on therapeutic outcome [3,4]. Finally, enhancement of tumor growth by hyperbaric oxygenation has been discussed [13,23].

In 2003, arising from the unusual occurrence of two cases of lung cancer in a non-smoking household in a karstic limestone region of Ireland, a medical specialist suggested that radon in the dwelling be measured. The whole-house average radon concentration was found to be 49 kBq/m 3 , which is the highest radon level detected to date in an Irish dwelling. After remediation had taken place, measurements of surface alpha-recoil implanted 210 Po activities were made on glass objects throughout the dwelling by means of a standard passive alpha-track method. Surface activities of 210 Po on glass ranging up to 2500 Bq/m 2 were found. Using a modified Jacobi room model, it was estimated that the mean radon concentrations in different parts of the dwelling over the past 8–22 years ranged from 59 kBq/m 3 to as high as 212 kBq/m 3 . Samples of dust were also taken for analysis from the surface of a 70-year-old mirror covered in a thick layer of dust. Using gamma and alpha spectrometry, it was found that the dust contained between 0.88 and 1.10 MBq/kg of 210 Po/ 210 Pb.

Growth, blood flow, oxygenation, and bioenergetic status of experimental tumors were investigated in normal (control) and anemic animals after administration of recombinant human erythropoietin (rhEPO). DS sarcomas were implanted s.c. onto the hind foot dorsum of Sprague-Dawley rats. Tumor-associated anemia was induced by the development of an i.p. hemorrhagic ascites. rhEPO (1000 IU/kg) was administered s.c. three times per week over 14 days, after which it was found to have significantly increased hematocrit values in both normal and anemic animals. Tumor growth in anemic animals was slower than in normal animals, and rhEPO administration did not influence tumor growth in either group. Tumor blood flow in anemic animals was lower than in control animals and was only increased in larger tumors in animals in which anemia was prevented by prophylactic rhEPO application. Tumor oxygenation, determined using polarographic needle electrodes and oxygen partial pressure histography, was poorer in anemic animals than in normal animals. This reduction could be reversed partially, but not compensated fully by rhEPO treatment in smaller tumors (or = 1.4 ml). These changes suggest that rhEPO, by improving tumor oxygenation, may increase the efficacy of standard radiotherapy in anemic animals and may be of use in anemic tumor patients in whom the success of radiotherapy or O2-dependent chemotherapy might be limited by tumor hypoxia.

Metabolic physiologists often introduce stable isotopes, atoms containing additional neutrons, into molecules during biosynthesis. This tags the newly synthesized material by altering its mass. Monte Carlo analysis is implemented on a popular spreadsheet to analyze this process. An example is provided where acetoacetate is synthesized by condensation of two acetate moieties. The precursor acetate is present as a mixture of natural, and 13C enriched, acetate. Monte Carlo spreadsheet modeling captures the complexity of the multi-species isotope biosynthesis by repetitively performing multiple simultaneous Boolean calculations. The effects of increasing the number of molecules synthesized on the goodness of fit of between model and an exact analytical solution is illustrated.

The present study was undertaken to exploit pathophysiological properties of solid tumours for a tumour-specific therapy. Experiments were carried out on DS-sarcomas implanted s.c. in the hind foot dorsum of Sprague Dawley rats. Treatment strategies included tumour acidification, lactate accumulation and disturbance of the microcirculation by induced systemic hyperglycaemia/hyperlact-acidaemia (15-25/10 mmol/L; for 60 min) as well as localized hyperthermia (water-bath; 43 degrees C, 30 min.). A special infusion solution was developed for the systemic treatment containing glucose, lactic acid and organic buffer without inorganic ions. Growth kinetics of tumour volume and animal survival were taken as endpoints in order to quantify therapeutic efficiency. After a single treatment with combined modalities, i.e., with hyperglycaemia/hyperlactacidaemia and hyperthermia, approximately 50% of the tumours showed complete remission in three independent series of experiments; around 40% of the animals survived more than two months. In the untreated control group, all animals died from the disease within 10-15 days after tumour implantation. The overall effect on tumour volume changes of the combined therapy was supra-additive compared to that of treatment with hyperthermia or hyperglycaemia/hyperlactacidaemia alone. However, treated animals either showed a dramatic response to the combination of treatments with complete tumour remission or hardly responded at all, justifying a subdivision into responders and non-responders. Pathophysiological mechanisms responsible for this behaviour have to be elucidated in future studies. Nevertheless, the present study represents an approach to an efficient tumour therapy with a potential application in clinical oncology in the not too distant future.

The effect of inhibiting DNA synthesis on the cellular O2 consumption rate of tumor cells (DS sarcoma) in vivo was analyzed using a photometric technique. Five days after DS-sarcoma ascites was induced in SD rats, animals were treated either with fludarabine (400 mg/kg i.p., 6 h prior to measurements) or lovastatin (3 x 20 mg/kg i.p., 24, 15, and 3 h prior to measurements), drugs that can inhibit tumor cell proliferation. In addition to cellular O2 consumption, the cell cycle distribution and the fraction of DNA-synthesizing cells in the tumor ascites were measured. Both drugs lowered DNA synthesis significantly, an effect that was more pronounced with fludarabine. The cellular O2 consumption rate following lovastatin application was significantly impaired (approximately 33%), whereas fludarabine had practically no effect on the respiration rate of tumor cells. From these data, it is concluded that a reduction in DNA synthesis does not necessarily result in a decrease in the O2 consumption rate of tumor cells in vivo.

A study was undertaken to assess the role of a physiological concentration of glutamine in AS-30D cell metabolism. Flux of 14C-glutamine to 14CO2 and of 14C-acetate to glutamate was detected indicating reversible flux between glutamate and TCA cycle alpha-ketoglutarate. These fluxes were transaminase dependent. A flux analysis was compared using data from three tracers that label alpha-ketoglutarate carbon 5, [2-14C]glucose, [1-14C]acetate and [5-14C]glutamine. The analysis indicated that the probability of flux of TCA cycle alpha-ketoglutarate to glutamate was, at minimum, only slightly less than the probability of flux of alpha-ketoglutarate through alpha-ketoglutarate dehydrogenase. The apparent Km for oxidative flux of [14C]glutamine to 14CO2, 0.07 mM, indicated that this flux was at a maximal rate at physiological, 0.75 mM, glutamine. Although oxidative flux through alpha-ketoglutrate dehydrogenase was the major fate of glutamine, flux of glutamine to lipid via reductive carboxylation of alpha-ketoglutarate was demonstrated by measuring incorporation of [5-14C]glutamine into 14C-lipid. In media containing glucose (6 mM), and glutamine (0.75 mM) 47 per cent of the lipid synthesized from substrates in the media was derived from glutamine via reductive carboxylation and 49 per cent from glucose. These findings of nearly equal fluxes suggest that lipogenesis via reductive carboxylation may be an important role of glutamine in hepatoma cells.

Abnormalities of hormones affecting gastrointestinal motility have been found in "functional" disorders of the gastrointestinal system in adults. One such disorder of childhood, encopresis, is frequently associated with constipation, the treatment of which often eliminates the soiling. We hypothesized that hormones affecting gastrointestinal motility were different between encopretic patients and matched controls.Ten encopretic patients were matched by age, race, and sex with controls who had no history of encopresis or constipation. After an overnight fast, each child consumed a meal of Ensure, the amount of which was based on body weight. Plasma levels of gastrin, pancreatic polypeptide, cholecystokinin, motilin, thyroxine, estrogen, and insulin were measured 20 and 5 minutes before the meal, and 5, 10, 15, 30, 45, 60, 90, 120, 150, and 180 minutes after the meal.Postprandial levels of pancreatic polypeptide remained consistently higher and peaked earlier (P.05) for encopretic patients. The motilin response was lower (P.03) for encopretic children than for controls.We conclude that pancreatic polypeptide and motilin responses to a meal are different in encopretic children than in children in the control group. These gastrointestinal hormone findings may in part explain and/or be the result of the severe constipation that frequently underlies the fecal soiling found in these patients. These findings also suggest the motility of the stomach and small intestine may be abnormal in encopresis.

The occurrence of differential heating and differential thermal sensitivity between malignant tumors and normal tissues is thought to be due to limited heat dissipation and energy depletion in many solid tumors which in turn results from an inadequately functioning tumor microcirculation (Jain and Ward-Hartley 1984; Song 1984, 1991; Vaupel and Kallinowski 1987; Reinhold 1988; Vaupel et al. 1988a; Vaupel 1990). As a consequence of the latter pathophysiological condition, supply and drainage function are restricted in many solid tumors or, at least, in some tumor areas, thus creating a hostile metabolic microenvironment characterized by tissue hypoxia, acidosis, and energy depletion. Thermal sensitivity has been shown to depend greatly on tumor pH, and on energy and nutritional status of the tumors treated. Although no conclusive evidence is so far available concerning the ranking of these pivotal factors, there is no doubt that the rate and homogeneity of blood perfusion plays a paramount role in determining the metabolic and energy status.

PURPOSE The gene Kcnv2 codes for the voltage-gated potassium channel subunit Kv8.2, which can coassemble with Kv2.1 subfamily members to constitute functional voltage-gated potassium channels. Mutations in the Kcnv2 gene result in a retinal disorder designated "cone dystrophy with supernormal rod response (CDSRR)," revealing that Kcnv2 is essential for visual processing and cone survival. The aim of this study was to determine whether expression of Kcnv2 and Kv2.1 is under circadian regulation and may thus contribute to the clock-driven adjustment of photoreceptor function. METHODS Expression of the genes was recorded in preparations of the whole retina and microdissected retinal neurons by using quantitative polymerase chain reaction and Western blot. RESULTS The transcript levels of Kcnv2 and Kv2.1 in preparations of whole retina and photoreceptor cells were found to display daily rhythms, with elevated values during the night. For Kcnv2 this rhythm was shown to evoke a corresponding rhythm in Kv8.2, the protein product of this gene. The daily changes in retinal Kcnv2 and Kv2.1 mRNA levels persisted under constant darkness and are therefore driven by the endogenous retinal clock system, which itself is entrained by light. CONCLUSIONS The present data provide evidence that the transcriptional regulation of Kcnv2 and Kv2.1 is a way through which the retinal clock system drives the functional adaptation of visual function to the marked daily changes in environmental lighting conditions.

Despite continued interest in the administration of nicotinamide (NA) as a tumor-specific radiosensitizer (an effect thought to be related to increases in tumor blood flow and oxygenation), little is known about the underlying mechanism(s) of this effect. The aim of this study was to investigate metabolic changes following NA application in both tumor and normal tissues. Increased concentrations of NAD+ were measured in DS-sarcomas, liver, and kidney tissue, with no changes in concentrations in resting skeletal muscle. Further investigations also examined the concentrations of glucose, lactate, ATP, ADP and AMP in tumor and resting skeletal muscle tissue following NA application. Here, the only change detected was an increase in lactate levels in tumor tissue. The changes in NAD+ concentrations described correlate well with reported changes in tissue blood flow measured following NA. On the basis of changes in tumor blood flow, oxygenation and metabolite concentrations found in this and other recent studies, possible mechanisms for tumor radiosensitization following nicotinamide administration are considered.

The failure of many attempts to improve tumor oxygenation - and thus the outcome of standard radiotherapy - may be due to the fact that the occurrence of hypoxia in tumors is not solely a result of diffusion-limited “chronic” hypoxia but is also due to temporary flow cessations in microregional tumor perfusion which have been shown to occur in tumor tissue1. As a result, attempts have more recently been made to reduce hypoxia in tumors through the reduction of tumor perfusion fluctuations. The benzamide analog nicotinamide is an agent which has recently received attention in this respect. It has been reported to be an effective, tumor-specific radiosensitizer in several tumor models, an effect thought to be mediated through an increase in tumor blood perfusion2. To date, little is known about the mechanism by which nicotinamide brings about its radiosensitizing effect. The aim of this study therefore was to investigate nicotinamide-induced changes in tumor and muscle microcirculatory function, tumor oxygenation, and tumor and muscle metabolism in an attempt to try and elucidate possible mechanisms for nicotinamide’s actions.

An increasing number of investigations carried out in recent years provide evidence suggesting that “chronic” decreases in tumor blood flow and/or tissue oxygenation (e.g., during tumor growth) or acute declines in the tissue perfusion (e.g., following therapeutic measures) might be accompanied by significant reductions in the energy status. In several instances, positive correlations between energy status and tumor blood flow or oxygenation have been reported (Lilly et al., 1985; Evelhoch et al., 1986; Tozer et al., 1989; Vaupel et al., 1989a, 1989b; Steen and Graham, 1991), and these investigations have led to the conclusion that blood flow may be the limiting factor in determining the bioenergetic status of tumors during growth. Manipulations of tumor blood flow by vasodilators, hyperthermia, tumor necrosis factor-α (TNF-α), lymphotoxin, interleukin-1, x-irradiation or after i.p. mannitol administration were accompanied by parallel changes in tumor energy status. Only in studies where i.p. or i.v. glucose was administered was energy status found to be stable or even slightly improved despite significant reductions in tumor perfusion (Okunieff et al., 1989; Kruger et al., 1991; Mayer et al., 1992; Schaefer et al., 1993). Similar observations of a dissociation between changes in tumor blood flow, oxygenation and energetic status have been observed in normoglycemic mice during photodynamic therapy (Bremner et al., 1993) or following hydralazine administration in xenografted human and isotransplanted murine tumors (Bremner et al., 1991; Adams et al., 1992).

Anemia associated with malignancy is a common clinical problem. Its etiology is varied and includes nutritional causes, hemorrhage, hemolysis, bone marrow metastasis and hypoplasia, paraneoplastic syndromes, and chemotherapy1, with many patients presenting with anemia even before they receive cytotoxic therapy and even if their bone marrow is not invaded by tumor cells2. The response of tumors to standard radiotherapy and oxygen-dependent chemotherapy in these patients is often less satisfactory than in subjects with normal hemoglobin levels3. This is presumed to be due to the worsening of tumor oxygenation as a result of the decreased oxygen-carrying capacity of the blood in these anemic tumor patients. Blood transfusions for anemic patients undergoing radiotherapy have not been universally accepted on the ground of infection risks and non-specific immunosuppression, although beneficial effects of transfusions on radiotherapy in anemic patients have been reported4. As a result, interest has recently focused on the possible use of erythropoietin - a glycoprotein hormone regulating the differentiation and maturation of red blood cells - in the correction of malignancy-associated anemia. The aim of this study was to investigate the effects of recombinant human erythropoietin (rhEPO) on red blood cell-related parameters, tumor blood flow and tumor oxygenation, in anemic and non-anemic rats, in order to ascertain whether this more “physiological” approach could have implications for improving tumor oxygenation and subsequently radiotherapy outcome in anemic tumor patients.

Cell reprogramming from a quiescent to proliferative state requires coordinate activation of multiple -omic networks. These networks activate histones, increase cellular bioenergetics and the synthesis of macromolecules required for cell proliferation. However, mechanisms that coordinate the regulation of these interconnected networks are not fully understood. The oncogene c-Myc (Myc) activates cellular metabolism and global chromatin remodeling. Here we tested for an interconnection between Myc regulation of metabolism and acetylation of histones. Using [(13)C(6)]glucose and a combination of GC/MS and LC/ESI tandem mass spectrometry, we determined the fractional incorporation of (13)C-labeled 2-carbon fragments into the fatty acid palmitate, and acetyl-lysines at the N-terminal tail of histone H4 in myc(-/-) and myc(+/+) Rat1A fibroblasts. Our data demonstrate that Myc increases mitochondrial synthesis of acetyl-CoA, as the de novo synthesis of (13)C-labeled palmitate was increased 2-fold in Myc-expressing cells. Additionally, Myc induced a forty percent increase in (13)C-labeled acetyl-CoA on H4-K16. This is linked to the capacity of Myc to increase mitochondrial production of acetyl-CoA, as we show that mitochondria provide 50% of the acetyl groups on H4-K16. These data point to a key role for Myc in directing the interconnection of -omic networks, and in particular, epigenetic modification of proteins in response to proliferative signals.

Palmitate (PA) is known to induce reactive oxygen species (ROS) formation and apoptosis in liver cells, whereas concurrent treatment of oleate (OA) with PA predominately induces steatosis without ROS in liver cells. We previously reported that PA treatment induces the decoupling of glycolysis and tricarboxylic acid cycle (TCA cycle) fluxes, but OA co-treatment restored most metabolic fluxes to their control levels. However, the mechanisms by which metabolites are linked to metabolic fluxes and subsequent lipoapoptotic or steatotic phenotypes remain unclear. To determine the link, we used GC-MS-based polar and non-polar metabolic profiling in lipoapoptosis- or steatosis-developing H4IIEC3 hepatoma cells, to examine the metabolome at different time points after treatment with either PA alone (PA cells) or both PA and OA (PA/OA cells). Metabolic profiles revealed various changes in metabolite levels for TCA cycle intermediates, pentose phosphate pathway (PPP) intermediates, and energy storage metabolites between PA and PA/OA cells. For example, adenosine was markedly increased only in PA cells, whereas gluconate was increased in PA/OA cells. To assess the interaction among these metabolites, the metabolite-to-metabolite correlations were calculated and correlation networks were visualized. These correlation networks demonstrate that a dissociation among PPP metabolites was introduced in PA-treated cells, and this dissociation was restored in PA/OA-treated cells. Thus, our data suggest that abnormal PPP fluxes, in addition to increased adenosine levels, might be related to the decoupling of glycolysis and the resulting lipoapoptotic phenotype.

A wide range of growth and differentiation processes are regulated by the signalling of receptor tyrosine kinases (RTKs). We have developed a nested polymerase chain reaction (PCR) procedure with degenerate primers, and used it to identify RTKs expressed in murine fetal thymus. A novel RTK, called FLT4, and the murine homologue of FLT were found, and their PCR fragment sequences were used to isolate larger cDNA clones spanning the complete coding regions of these receptors. FLT4 was found to contain an extracellular region similar to the corresponding sequences of FLT and Flk-1, containing seven immunoglobulin domains.

Engineering cells and microbes to make a commercially valuable product has been successfully accomplished by introducing foreign genes into target cells ( Zaslavskaia et al.). According to the Perspective by Stephanopoulos and Kelleher, successful gene modification may require intervention at multiple steps in a metabolic pathway to optimize the desired cellular properties. As the authors explain, this necessitates successive rounds of genetic modification and physiological evaluation, a strategy that forms the basis of metabolic engineering.

A novel device consisting of an infrared-A (= ultrared-A) radiation source equipped with a water filter in the radiation path is described which allows for the therapeutic heating of superficial experimental and human tumors. Preliminary studies with agar phantoms showed that heating in the presence of the water-cuvette avoids intolerable overheating in the very superficial layers. This effect can be further enhanced by surface cooling with room air such that a stratification of the temperature distribution can be achieved. In subsequent experiments, temperature distributions were recorded in the x-, y- and z-axis of superficial rodent tumors. The results obtained confirm those from the phantom experiments, showing that therapeutically relevant temperatures (Tor = 42 degrees C) could be achieved through the tumor mass to a depth of approximately 1.2 cm. Temperature homogeneity is comparable to that seen in superficial tumors undergoing water-bath hyperthermia. This novel technique has proved to be reliable, is well-tolerated, is easy to apply, and is easily accessible to a larger number of potential users for the local heating of superficial malignancies.

A growing body of evidence suggests that chronic medical illness is associated with an increased prevalence and incidence of psychiatric and psychological disturbances. The present literature review is based on two theses: first, that chronic illness is viewed as a stressor and is associated with increased psychological distress, and secondly, that interventions can minimize the distress. A review of the studies conducted with adult patients diagnosed either with coronary heart disease or cancer suggests that psychosocial interventions are, in general, efficacious in relieving self-reported psychological distress. The review also recommends psychosocial interventions for high-risk patients rather than all patients, and that researchers need to identify other outcomes such as health care costs, disability, days in hospital, morbidity, and mortality in order to convince policy makers that these interventions are worthwhile. Recommendations for future research are also discussed.

A new analysis of stable isotope data for biosynthesis reaction, isotopomer spectral analysis (ISA), is demonstrated. ISA is theoretically applicable for polymerization biosynthesis where data are collected using selected ion-monitoring gas chromatography-mass spectrometry. ISA utilizes the discrete spectrum of isotopomer abundances and the multinomial distribution to estimate two key parameters related to the biosynthesis. These parameters are 1) the dilution of the precursor immediately before biosynthesis and 2) the dilution of the newly synthesized product in the sampled compartment. Differentiated 3T3-L1 cells incorporated 2 mM [1,2-13C]acetate into triglyceride palmitate, yielding a spectrum of mass isotopomers of palmitate. The set of equations for the first nine isotopomers were solved for the two parameters using nonlinear regression. We found that precursor dilutions for acetate and glucose were constant over time, whereas the product dilution parameter increased with time, as expected for cells accumulating triglyceride palmitate. Mathematical procedures are presented for calculating 1) the predicted isotopomer fractional abundance values and 2) the correction for atoms other than the tracer atom in the mass ion.

IL12 (formerly NKSF or CLMF) is a unique cytokine composed of two unrelated disulfide-linked subunits. The larger 40-kDa subunit (p40) is a member of the cytokine receptor family, and the smaller 35-kDa subunit (p35) is related to IL6 and GCSF. The chromosomal localization of these two subunits was determined by PCR analysis of DNA from rodent-human hybrids. More refined mapping was obtained by PCR analysis of hybrids containing translocation chromosomes and for p40, by analysis of radiation hybrids. The subunits map to different chromosomes: p40 (IL12B) to 5q31–q33 and p35 (IL12A) to 3p12–3q13.2.

Answers on p245. A 59 year old insulin dependent diabetic male presented with an eight week history of lower thoracic back pain and a two to three week history of progressive exertional dyspnoea, limiting his exercise tolerance to around 100 yards, associated with mild ankle oedema. He did not complain of cough or chest pain. He had been discharged from another hospital four weeks earlier after a prolonged admission with pneumonia and renal failure. There was no other past medical history of note. In particular, there …

We report here the nucleotide sequence of a full-length Chinese hamster genomic proviral element, CHIAP34. CHIAP34 is 6,403 bp long with long terminal repeats of 311 bp at each end. The genetic organization of CHIAP34 was determined by comparison with intracisternal A particle (IAP) genetic elements from the mouse and Syrian hamster. Extensive homology at the nucleotide and deduced amino acid sequence levels was observed between CHIAP34 and the mouse and Syrian hamster IAP elements. CHIAP34 may represent a defective Chinese hamster IAP genetic element. The gag gene consists of 837 codons, of which 558 codons are in a single long open reading frame followed by several frameshifts. The pol gene begins with a -1 frameshift and consists of a long open reading frame of 753 codons followed by a short open reading frame of 103 codons. The putative env region contains multiple termination codons in all reading frames. CHIAP34 is representative of the predominant retroviral elements in the Chinese hamster ovary cell genome present at around 80 copies per haploid genome.

Exercise is a useful tool in the management of diabetes, contributing to cardiovascular and psychosocial well-being, weight control, and, in noninsulin-dependent diabetes, improvement of blood glucose levels. An optimal exercise program should be based on a comprehensive assessment and include a written prescription for the type, frequency, duration, and intensity of exercise. This article includes guidelines for writing exercise prescriptions as well as techniques for monitoring its effects. A discussion of risks related to diabetes provides safety guidelines.

We have isolated the genomic sequence of human interleukin-9 (IL-9) based on its sequence homology with a human IL-9 cDNA isolated from human T-cell leukemia virus (HTLV)-I-transformed T cells by expression cloning. The entire genomic sequence has been determined and the gene consists of five exons and four introns. The human IL-9 gene is mapped to the long arm of human chromosome 5 at band 5q31–32, a region found to be deleted in a number of patients with acquired 5q- abnormalities and hematologic disorders. Several blocks of transcriptional control sequences have been identified at the 5′-flanking region of the human IL-9 gene that may play an important role in the control of IL-9 gene expression. The 5′-regulatory region of the human IL-9 gene also contains sequences identified in the 5′-flanking regions of other cytokine genes mapped to the long arm of human chromosome 5, including IL-3, IL-4, IL-5, and granulocyte-macrophage colony-stimulating factor and other T-cell growth factor genes including IL-2 and IL-6. The IL-9 gene is constitutively expressed in the HTLV-I-transformed human T cells and the expression of IL-9 in these cells can be further induced by 12-O-tetradecanoyl phorbol 13-acetate. Transient transfection analysis using the plasmid containing the 5′-flanking region of IL-9 gene upstream from the firefly luciferase ciferase report gene indicated that the 0.9-kb Smal-Sacl fragment of the IL-9 gene contains sequences required for the constitutive and activated expression of IL- 9 gene in HTLV-I-transformed cells. These results will now allow us to study the regulatory mechanism of IL-9 gene expression in normal and leukemic human T cells.

The electromigration drift velocity of Al in Al(3wt.% Si), Al(2wt.%Cu), and Al(2wt.%Cu,3wt.%Si) was measured in a temperature range 133 to 220 °C with current densities of 1.0 to 1.5×106A/cm2. In Al(3wt.% Si), a significant Al depletion at the cathode end and accumulation at the anode end of stripe were observed within a few hours at 1.5×106A/cm2 and 200°C. In addition, local hillocks and voids along the metal lines were observed. For Al(Cu,Si), the Al drift velocity was slowed down by Cu addition. The majority of hillocks started to grow at a distance about 6 μm away from the cathode end with current density of 1.5×106 A/cm2. The drift velocity of Al in Al(Cu,Si) was found to be a function of time starting with an initial low value and increasing to a an final steady-state value. The behavior was attributed to the migration of Cu and dissolution of Al2Cu precipitates. The activation energies of the depletion 3 Aμm of Al(2%,Cu, 3%Si) was determined to be 0.90±02 eV. The dissolution and growth of A12Cu in the tested samples of Ti/Al(2%Cu)/Ti/TiN were observed using the scanning electron microscope and an electron microprobe.

Eukaryotic protein synthesis initiation factor 4B (eIF-4B) is an 80,000 dalton polypeptide which is essential for the binding of mRNA to ribosomes. A highly purified preparation of eIF-4B from HeLa cells was subjected to enzymatic cleavage and amino-terminal amino acid sequence analysis. Degenerate oligonucleotide probes were used to isolate a 3851 bp cDNA encoding eIF-4B from a human cDNA library. The DNA encodes a protein comprising 611 residues with a mass of 69,843 daltons. The amino-terminal domain of eIF-4B contains a consensus RNA binding domain present in a number of other RNA binding proteins. Expression of eIF-4B in transfected COS-1 cells yielded a polypeptide which reacted with anti-eIF-4B antiserum and comigrated with purified eIF-4B. Expression of eIF-4B in COS-1 cells resulted in a general inhibition of translation, possibly due to a 50-fold eIF-4B overproduction.

The stimulation of 2-oxoglutarate and NAD(+)-isocitrate dehydrogenase by Ca2+ in mitochondria from normal tissues has been proposed to mediate partially the activation of oxidative energy metabolism elicited by physiological elevations in cytosolic Ca2+. This mode of regulation may also occur in tumor cells in which several aspects of mitochondrial metabolism are known to be altered. This study provides a comparison of the stimulation by submicromolar concentrations of Ca2+ on the rates of ATP-generating (state 3) respiration under physiologically realistic conditions by mitochondria isolated from normal rat liver and from highly malignant rat AS-30D ascites hepatoma cells. The K0.5 for activation of glutamate-dependent state 3 respiration by Ca2+ in the presence of ATP at 37 degrees C was determined to be 0.70 +/- 0.05 (S.E.) microM for hepatoma mitochondria and 0.90 +/- 0.03 microM for rat liver mitochondria. This activation was also reflected by a Ca2(+)-induced shift in the oxidation-reduction state of hepatoma mitochondrial pyridine nucleotides to a more reduced level and Ca2+ stimulation of 14CO2 production from [1-14C]glutamate. Whereas the Ca2+ sensitivity of state 3 respiration by hepatoma mitochondria can be explained by the activation of 2-oxoglutarate and possibly NAD(+)-isocitrate dehydrogenases, the Ca2+ sensitivity of liver mitochondrial respiration appears to be predominantly mediated by activation of electron flow through ubiquinone and Complex III of the electron transport chain, as indicated by the specificity of the effects of Ca2+ on respiration with different oxidizable substrates. Although rat liver and hepatoma mitochondria employ different modes of Ca2(+)-activated ATP generation, these results support the hypothesis that changes in cytosolic Ca2+ play a significant role in the potentiation of energy production in tumor, as well as normal tissue.

In selective internal radiation (SIR) therapy of hepatic metastases, tumor vasculature is preferentially embolized with high-energy beta-emitting yttrium-90-labeled microspheres. To enable accurate estimation of the resultant absorbed radiation doses to tissues, an intraoperative beta detection probe is used to scan the liver surface. The validity of the response of this probe to Y-90 and its clinical application were assessed with a phantom containing varying activities and with biopsy samples obtained from patients being treated with SIR therapy. A linear relationship was found between the probe counts taken from the biopsy samples and the calculated tissue radiation doses from the specific activities of each sample. This relationship was repeated with probe counts determined against a water phantom containing various activities of Y-90. The probe was shown to respond minimally to bremsstrahlung. The use of the probe in measuring tissue radiation doses at laparotomy provides the opportunity to control dose administration during SIR therapy. In this way, subtherapeutic exposure of normal tissue can be assured while tumor tissue receives maximal radiation levels.

There are no reliable data documenting the tolerance of the human liver to ionizing radiation from a continuous Yttrium-90 source. As Yttrium-90 incorporated into microspheres is being used to treat patients with liver cancer, it is imperative that the tolerance of the human liver to this form of radiation damage be determined. Four patients with metastatic liver cancer were treated with Yttrium-90 to deliver radiation doses above that considered tolerable when given by conventional external sources. Patients were monitored with serial estimations of liver function tests and between 7 and 9 months after treatment liver biopsies were performed. Histological examination of the liver biopsies confirmed only minimal changes in the normal liver parenchyma. These data indicate that the human liver may tolerate relatively large radiation doses when delivered by Yttrium-90 microspheres embedded in the liver parenchyma as a number of discrete point sources.

The influence of regional liver hyperthermia in conjunction with systemic doxorubicin administration was examined in a rabbit VX2 tumour model. Hyperthermia was delivered by 2450MHz microwave generator to the exteriorised livers of the rabbits to provide a thermal dose equivalent of 43 degrees C for 30 minutes. Animals receiving doxorubicin infusion were treated with a total of 1.2 mg/kg over a 3 day protocol through an ear vein. Rabbits were divided into 4 groups; a no treatment control, hyperthermia alone, doxorubicin alone and hyperthermia immediately preceded by doxorubicin. The tumour mass, 10 days post treatment was significantly (P less than 0.0001) reduced in all treatment groups. However, the mean tumour mass in the combination treatment group was also significantly lower than both treatments alone (P less than 0.001). This increased response was not accompanied by any signs of increased systemic or local toxicity associated with any treatment.

Reduction in medical care utilization is one criteria for assessing the impact of mental health treatment for children with psychosocial problems. This reduction has been termed the "offset" effect. Almost all published research concerning offset after mental health treatment concerns adults, and the few studies in pediatric populations are limited by methodologic problems. A study of health care utilization after mental health treatment for children was conducted. Mental health treatment for psychosocial problems was significantly associated with decreased use of medical care only for older children, after potentially confounding variables were controlled for. Furthermore, this decreased use was found only for nonmental health specialty care visits. No reduction in primary care visits occurred. Other factors such as previous patterns of use and the presence of other morbidity were stronger predictors of subsequent primary health care use than was mental health treatment. Mental health treatment does not have a major impact on the high utilization of most children with psychosocial problems in pediatric settings. Because the reasons for this may be particular morbidity patterns in these children, future studies should include some measure of case mix as a potentially important variable in assessment of mental health treatment effects.

Nature 441, 709–713 (2006) In this Article, Fig. 2 was printed in reverse (bright areas appeared dark and vice versa). The correct figure is reprinted below.

The biology of human breast milk, and the policy of encouraging breastfeeding, continue to be the object of much scientific inquiry. The past year has seen several advances in these fields of nutrition, and this article reviews some of the most interesting and pertinent studies. Four general themes have been apparent in the recent literature: 1) the role of breastfeeding and breast milk in the incidence of infectious diseases; 2) the effect of breastfeeding on neurodevelopmental outcome; 3) the nutritional composition of breast milk; and 4) the determinants of breastfeeding among adolescents and ethnic minority mothers. Review of these studies will assist the office-based pediatrician in knowing the scientific rationale, and the best methodology, for the promotion of breastfeeding.