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It is a widespread misconception that infants with congenital heart disease (CHD) are not able to breastfeed. The purpose of this study was to describe breastfeeding duration and outcomes among a high-risk group of infants with CHD. Mothers of 68 infants at least 6 months of age, who had experienced cardiac surgery during the neonatal period, were surveyed regarding breastfeeding and milk expression habits. Results for this sample of infants were compared to a benchmark study conducted in 1993 at the same institution that described breastfeeding outcomes for 45 infants with CHD. Improved outcomes for the 1998-2000 sample are attributed to an active lactation consultation program instituted in 1998. These findings suggest that given support and education necessary to initiate and maintain lactation, mothers can successfully breastfeed their infants with CHD for durations recommended by the Healthy People 2010 initiative. [ABSTRACT FROM AUTHOR]

Purpose: The neurohormones melatonin and dopamine mediate clock-dependent/circadian regulation of inner retinal neurons and photoreceptor cells and in this way promote their functional adaptation to time of day and their survival. To fulfill this function they act on melatonin receptor type 1 (MT1 receptors) and dopamine D4 receptors (D4 receptors), respectively. The aim of the present study was to screen transcriptional regulators important for retinal physiology and/or pathology (Dbp, Egr-1, Fos, Nr1d1, Nr2e3, Nr4a1, Pgc-1α, Rorβ) for circadian regulation and dependence on melatonin signaling/MT1 receptors or dopamine signaling/D4 receptors., Methods: This was done by gene profiling using quantitative polymerase chain reaction in mice deficient in MT1 or D4 receptors., Results: The data obtained determined Pgc-1α and Nr4a1 as transcriptional targets of circadian melatonin and dopamine signaling, respectively., Conclusions: The results suggest that Pgc-1α and Nr4a1 represent candidate genes for linking circadian neurohormone release with functional adaptation and healthiness of retina and photoreceptor cells.

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.

The expression and activity of P-glycoprotein (pGP) play a role in the multidrug resistance of tumors. Because solid-growing tumors often show pronounced hypoxia or extracellular acidosis, this study attempted to analyze the impact of an acidic environment on the expression and activity of pGP and on the cytotoxicity of chemotherapeutic agents. For this, prostate carcinoma cells were exposed to an acidic extracellular environment (pH 6.6) for up to 24 hours. pGP activity was more than doubled after 3 to 6 hours of incubation in acidic medium, whereas cellular pGP expression remained constant, indicating that increased transport rate is the result of functional modulation. In parallel, the cytotoxic efficacy of daunorubicin showed pronounced reduction at low pH, an effect that was reversible on coincubation with a pGP inhibitor. A reduction of intracellular Ca2+ concentration by 35% under acidic conditions induced a higher transport rate of pGP, an effect comparable to that found on inhibition of protein kinase C (PKC). These data indicate that pGP activity is increased by low extracellular pH presumably as a result of lowered intracellular calcium levels and inhibition of PKC. These findings may explain the reduced cytotoxicity of chemotherapeutic agents in hypoxic/acidic tumors.

Objective: To assess the effects of dietary supplementation using two isomeric blends of conjugated linoleic acid (CLA) on immune function in healthy human volunteers., Design: Double-blind, randomised, placebo-controlled intervention trial., Subjects and Intervention: A total of 55 healthy volunteers (n=20 males, n=35 females) were randomised into one of three study groups who received 3 g/day of a fatty acid blend containing a 50:50 cis-9, trans-11: trans-10, cis-12 CLA isomer blend (2 g CLA), and 80:20 cis-9, trans-11: trans-10, cis-12 (80:20) CLA isomer blend (1.76 g CLA) or linoleic acid (control, 2 g linoleic acid) for 8 weeks., Results: Supplementation with the 80:20 CLA isomer blend significantly (P< or =0.05) enhanced PHA-induced lymphocyte proliferation. CLA decreased basal interleukin (IL)-2 secretion (P< or =0.01) and increased PHA-induced IL-2 and tumor necrosis factor alpha (TNF(alpha)) production (P< or =0.01). However, these effects were not solely attributable to CLA as similar results were observed with linoleic acid. CLA supplementation had no significant effect on peripheral blood mononuclear cells IL-4 production, or on serum-soluble intercellular adhesion molecule-1 (sICAM-1) or plasma prostaglandin E2 (PGE2) or leukotreine B4 (LTB4) concentrations., Conclusions: This study shows that CLA supplementation had a minimal effect on the markers of human immune function. Furthermore, supplementation with CLA had no immunological benefit compared with linoleic acid.

This study investigated long-term microenvironmental responses (oxygenation, perfusion, metabolic status, proliferation, vascular endothelial growth factor (VEGF) expression and vascularisation) to chronic hypoxia in experimental tumours. Experiments were performed using s.c.-implanted DS-sarcomas in rats. In order to induce more pronounced tumour hypoxia, one group of animals was housed in a hypoxic atmosphere (8% O(2)) for the whole period of tumour growth (chronic hypoxia). A second group was acutely exposed to inspiratory hypoxia for only 20 min prior to the measurements (acute hypoxia), whereas animals housed under normal atmospheric conditions served as controls. Acute hypoxia reduced the median oxygen partial pressure (pO(2)) dramatically (1 vs 10 mmHg in controls), whereas in chronically hypoxic tumours the pO(2) was significantly improved (median pO(2)=4 mmHg), however not reaching the control level. These findings reflect the changes in tumour perfusion where acutely hypoxic tumours show a dramatic reduction of perfused tumour vessels (maybe the result of a simultaneous reduction in arterial blood pressure). In animals under chronic inspiratory hypoxia, the number of perfused vessels increased (compared to acute hypoxia), although the perfusion pattern found in control tumours was not reached. In the chronically hypoxic animals, tumour cell proliferation and tumour growth were significantly reduced, whereas no differences in VEGF expression and vascular density between these groups were observed. These results suggest that long-term adaptation of tumours to chronic hypoxia in vivo, while not affecting vascularity, does influence the functional status of the microvessels in favour of a more homogeneous perfusion.

The effects of combined and simultaneously applied localised 43 degrees C hyperthermia (HT) and an antivascular bacteriochlorophyll-serine-based photodynamic therapy (Bchl-ser-PDT) on tumour growth and several microenvironmental parameters were examined. Rats bearing DS-sarcomas were allocated to treatment groups: (i) sham-treatment (control), (ii) Bchl-ser-PDT (20 mg kg(-1) i.v.), (iii) localised HT, (iv) Bchl-ser-PDT+HT. The light source used was an infrared-A irradiator, which, by use of appropriate filters, delivered the different ranges of wavelengths required. Following treatment, tumour volume was monitored. The greatest tumour growth inhibition was seen with Bchl-ser-PDT+HT, and subsequent experiments identified the pathophysiological basis for this effect. Red blood cell flux in tumour microvessels declined rapidly upon Bchl-ser-PDT+HT, reaching approximately 10% of initial values by the end of treatment. Similarly, tumour oxygenation worsened, reaching almost anoxic levels by the end of the treatment period. Assessment of metabolic parameters showed a pronounced increase in lactate levels and a decrease in ATP concentrations after combined treatment. The results presented suggest that vascular collapse and flow stasis resulting in a deterioration of tumour oxygenation and a switch from oxidative to glycolytic glucose turnover are key elements in the tumour eradication seen with this novel approach in which an antivascular PDT and HT are combined and simultaneously applied.

The possibility of enhancing aminolaevulinic acid (ALA)-based photodynamic therapy (PDT) by simultaneous application of localised hyperthermia (HT) was evaluated. Treatments of rat DS-sarcomas included: (i) control, (ii) ALA administration (375 mg kg(-1), i.p.), no illumination, (iii) 'nonthermal' illumination, (iv) ALA-PDT: that is, ALA administration, 'nonthermal' illumination, (v) localised HT, 43 degrees C, 60 min (vi) ALA-PDT+HT: ALA administration with full spectrum irradiation resulting in ALA-PDT and HT. Tumour volume was monitored for 90 days or until a target volume (3.5 ml) was reached. No differences were seen between the first three groups, with all tumours reaching the target volume by 8-11 days. A total of 13 and 15% of tumours did not reach the target volume by day 90 following HT or ALA-PDT treatment, respectively. ALA-PDT+HT showed the greatest antitumour effect (P=0.0001), with 61% of the tumours not reaching the target volume. Viability and in vitro growth were also assessed in cells from tumours excised after treatment. ALA-PDT+HT reduced the fraction of viable tumour cells by 85%, and in vitro culture showed pronounced growth delay compared to control cells. These results demonstrate an enhanced antitumour effect upon ALA+HT, which appears to involve direct cell toxicity rather than solely vascular damage.

Isolated limb perfusion allows the direct application of therapeutic agents to a tumour-bearing extremity. The present study investigated whether the dihydropyridine-type Ca(2+)-channel blocker nifedipine could improve blood flow and oxygenation status of experimental tumours during isolated limb perfusion. Perfusion was performed by cannulation of the femoral artery and vein in rats bearing DS-sarcoma on the hind foot dorsum. Perfusion rate was adjusted to maintain a perfusion pressure of 100-140 mmHg throughout the experiment. Following equilibration, nifedipine was continuously infused for 30 min (8.3 microg min(-1) kg(-1) BW). During constant-pressure isolated limb perfusion, nifedipine can significantly increase perfusion rate (+100%) and RBC flux (+60%) through experimental leg tumours. "Steal phenomena" in favour of the surrounding normal tissue and oedema formation were not observed. Despite the increased oxygen availability (+63%) seen upon application of this calcium channel blocker, nifedipine does not result in a substantial reduction of tumour hypoxia, most probably due to an increase in O(2) uptake with rising O(2) supply to the tumour-bearing hind limb. Nifedipine application during isolated limb perfusion can enhance tumour microcirculation and may therefore promote the delivery (pharmacokinetics) of anti-cancer drugs to the tumour and by this improve the efficacy of pressure-controlled isolated limb perfusion., (Copyright 2002 Cancer Research UK)

In an investigation of the antitumor effects of 2-methoxyestradiol (2-ME) in combination with other reactive oxygen generating treatments, 2-ME (0.5 microM) was found to completely inhibit cell proliferation of rat DS-sarcoma cells in vitro, with 71% of cells dying after exposure to 5 microM 2-ME. Concentration-dependent increases in ROS-formation, lipid peroxidation and mitochondrial changes were also observed, and an elevation in caspase-3 activity resulted in DNA fragmentation and apoptosis. Combination of 2-ME with hypoxanthine and xanthine oxidase enhanced in vitro cytotoxicity. In vivo, 2-ME caused a slight inhibition of tumor growth, with no tumors cured. Combination of 2-ME treatment with localized 44 degrees C hyperthermia, respiratory hyperoxia and xanthine oxidase caused a tumor growth delay with 51% of tumors cured. These results suggest that amplifying the levels of reactive oxygen species within tumor tissue with substances such as 2-ME may prove to be a promising strategy for adjuvant treatment of solid tumors.

The aim of this study was to examine the impact of anemia prevention by recombinant human erythropoietin (rHuEPO) treatment on the cytotoxicity of cyclophosphamide in solid experimental tumors. Anemia was induced using a single dose of carboplatin (50 mg/kg i.v.) resulting in a long-lasting reduction (30%) of the hemoglobin concentration. In a second group, the development of anemia was prevented by rHuEPO (1000 IU/kg) administered s.c. three times/week starting 7 days before carboplatin application. Four days after carboplatin treatment, tumors (DS-sarcoma of the rat) were implanted s.c. onto the hind food dorsum. Neither carboplatin nor rHuEPO treatment influenced tumor growth rate per se. When tumors were treated with a single dose of cyclophosphamide (60 mg/kg i.p.) 5 days after implantation, a growth delay with a subsequent regrowth of the tumors was observed. In the anemia group, the growth delay was significantly shorter compared with nonanemic controls (13.3 days versus 8.6 days). In the group where anemia was prevented by rHuEPO treatment, growth delay was comparable with that of nonanemic controls (13.3 days). These results suggest that chemotherapy-induced anemia reduces cytotoxicity of cyclophosphamide in tumors, whereas correction of anemia by rHuEPO treatment (epoetin alpha) increases the sensitivity, probably as a result of an improved oxygen supply to tumor tissue.

Perfusion and oxygenation of experimental tumours were studied during angiotensin II (AT II) administration whereby the rate of the continuous AT II infusion was chosen to increase the mean arterial blood pressure (MABP) by 50-70 mmHg. In subcutaneous DS-sarcomas the red blood cell (RBC) flux was assessed using the laser Doppler technique and the mean tumour oxygen partial pressure (pO2) was measured polarographically using O2-sensitive catheter and needle electrodes. Changes in RBC flux with increasing MABP depended mainly on tumour size. In small tumours, RBC flux decreased with rising MABP whereas in larger tumours RBC flux increased parallel to the MABP. As a result of these volume-dependent effects on tumour blood flow, the impact of AT II on tumour pO2 was also mainly tumour volume-related. In small tumours oxygenation decreased with increasing MABP during AT II infusion, whereas in large tumours a positive relationship between blood pressure and O2 status was found. This disparate behaviour might be the result of the co-existence of two functionally distinct populations of tumour vessels. In small tumours, perfusion decreases presumably due to vasoconstriction of pre-existing host vessels feeding the tumour. In larger malignancies, newly formed tumour vessels predominate and seem not to have this vasoresponsive capability (lack of smooth muscle cells and/or AT receptors), resulting in an improvement of perfusion which is not tumour-related per se, but is due to the increased perfusion pressure.

The effects of respiratory hyperoxia (RH) and xanthine oxidase (XO) during localized hyperthermia (HT) were investigated by determining markers of oxidative damage to lipids and proteins and tumor growth. Anesthetized rats with s.c. DS-sarcomas underwent one of the following treatments: (a) localized saline-bath HT (60 min, 44 degrees C); (b) HT + RH (100% O2); and (c) HT + RH + XO (15 units/kg i.v.). Sham-treated animals served as controls. Tumors were investigated for: (a) thiobarbituric acid-reactive substance formation and protein-bound 4-hydroxynonenal, as indicators of lipid peroxidation; (b) reactive oxygen-mediated protein modifications; (c) apoptosis; and (d) tumor volume growth. Upon treatment, increases in thiobarbituric acid-reactive substances, protein-bound 4-hydroxynonenal, protein-associated carbonyl functions, and number of cells undergoing apoptosis were found in tumor tissue, together with an inhibition of tumor growth. When treatment groups were compared, effects in the group HT + RH + XO were generally most pronounced. These findings indicate that the antitumor effect of HT is at least partially mediated through the selective induction of lipid peroxidation and oxidative injury in tumor cells, leading to apoptosis. This effect was enhanced by adding RH or RH + XO, presumably due to enhanced tissue damage following an increased formation of reactive oxygen species, with higher levels of lipid peroxidation and protein oxidation.

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.

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.