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Purpose of Review: Galactose - a key source of energy and a crucial structural element in complex molecules - is particularly important for early human development. However, galactose metabolism might be important not only for fetal and neonatal development but also for adulthood, as evidenced by the inherited disorders of galactose metabolism. The purpose of this review is to summarize the current evidence of galactose metabolism in health and disease., Recent Findings: The biological importance of galactose goes beyond its importance as a nutrient and a metabolite. Galactose has been selected by evolutionary pressure to exert also a crucial structural role in macromolecules. Additionally, galactose has recently been reported as beneficial in a number of diseases, particularly in those affecting the brain., Summary: Galactose is crucial for human metabolism, with an established role in energy delivery and galactosylation of complex molecules, and evidence for other roles is emerging.

Purpose: This study determined the effect of ingesting galactose and glucose 30 min before exercise on exogenous and endogenous fuel use during exercise., Methods: Nine trained male cyclists completed three bouts of cycling at 60% W(max) for 120 min after an overnight fast. Thirty minutes before exercise, the cyclists ingested a fluid formulation containing placebo, 75 g of galactose (Gal), or 75 g of glucose (Glu) to which (13)C tracers had been added, in a double-blind randomized manner. Indirect calorimetry and isotope ratio mass spectrometry were used to calculate fat oxidation, total carbohydrate (CHO) oxidation, exogenous CHO oxidation, plasma glucose oxidation, and endogenous liver and muscle CHO oxidation rates., Results: Peak exogenous CHO oxidation was significantly higher after Glu (0.68 ± 0.08 g.min(-1), P < 0.05) compared with Gal (0.44 ± 0.02 g.min(-1)); however, mean rates were not significantly different (0.40 ± 0.03 vs. 0.36 ± 0.02 g.min(-1), respectively). Glu produced significantly higher exogenous CHO oxidation rates during the initial hour of exercise (P < 0.01), whereas glucose rates derived from Gal were significantly higher during the last hour (P < 0.01). Plasma glucose and liver glucose oxidation at 60 min of exercise were significantly higher for Glu (1.07 ± 0.1 g.min(-1), P < 0.05, and 0.57 ± 0.08 g.min(-1), P < 0.01) compared with Gal (0.64 ± 0.05 and 0.29 ± 0.03 g.min(-1), respectively). There were no significant differences in total CHO, whole body endogenous CHO, muscle glycogen, or fat oxidation between conditions., Conclusion: The preexercise consumption of Glu provides a higher exogenous source of CHO during the initial stages of exercise, but Gal provides the predominant exogenous source of fuel during the latter stages of exercise and reduces the reliance on liver glucose.

Purpose: Both liver and muscle glycogen stores play a fundamental role in exercise and fatigue, but the effect of different CHO sources on liver glycogen synthesis in humans is unclear. The aim was to compare the effect of maltodextrin (MD) drinks containing galactose, fructose, or glucose on postexercise liver glycogen synthesis., Methods: In this double-blind, triple crossover, randomized clinical trial, 10 well-trained male cyclists performed three experimental exercise sessions separated by at least 1 wk. After performing a standard exercise protocol to exhaustion, subjects ingested one of three 15% CHO solutions, namely, FRU (MD + fructose, 2:1), GAL (MD + galactose, 2:1), or GLU (MD + glucose, 2:1), each providing 69 g CHO·h(-1) during 6.5 h of recovery. Liver glycogen changes were followed using (13)C magnetic resonance spectroscopy., Results: Liver glycogen concentration increased at faster rates with FRU (24 ± 2 mmol·L(-1)·h(-1), P < 0.001) and with GAL (28 ± 3 mmol·L(-1)·h(-1), P < 0.001) than with GLU (13 ± 2 mmol·L(-1)·h(-1)). Liver volumes increased (P < 0.001) with FRU (9% ± 2%) and with GAL (10% ± 2%) but not with GLU (2% ± 1%, NS). Net glycogen synthesis appeared linear and was faster with FRU (8.1 ± 0.6 g·h(-1), P < 0.001) and with GAL (8.6 ± 0.9 g·h(-1), P < 0.001) than with GLU (3.7 ± 0.5 g·h(-1))., Conclusions: When ingested at a rate designed to saturate intestinal CHO transport systems, MD drinks with added fructose or galactose were twice as effective as MD + glucose in restoring liver glycogen during short-term postexercise recovery.

Galactosyl-terminated drug carriers are known to enhance drug accumulation in the liver, while possible accompanying hepatic toxicity is usually not clarified. This study developed a galactosyl-α,β-poly[(2-hydroxyethyl)-L-aspartamide]-doxorubicin conjugate (Gal-PHEA-DOX) and investigated its therapeutic efficacy and safety in orthotopic hepatocellular carcinoma-bearing mice. Gal-PHEA-DOX had a galactosylation degree of 7.5 mol% and a DOX content of 8.9 wt%. A biodistribution study showed that Gal-PHEA-DOX sustainedly circulated in the plasma and highly accumulated in hepatocarcinoma. Free drug liberated from Gal-PHEA-DOX was relatively low in the liver and heart as compared with that of the DOX administration. The Gal-PHEA-DOX conjugate showed superior cytotoxicity against the hepatocellular carcinoma cell line HepG2 as compared with the nongalactosylated PHEA-DOX conjugate. Gal-PHEA-DOX exhibited comparable antitumor activity with PHEA-DOX in the S180-bearing mice, but more effective than PHEA-DOX or DOX in the Heps-bearing mice with negligible detrimental effect in the liver remnant. A systemic toxicity study showed that this conjugate did not show either cytotoxicity or hepatotoxicity at a relatively high dose, which would be harmful for free DOX. These results suggest that the Gal-PHEA-DOX conjugate has great potential for use in hepatocellular carcinoma chemotherapy because of its enhanced antitumor effect with reduced systemic toxicity including hepatotoxicity.

Accumulated evidence indicates chronic systemic injection of D-galactose mimics aging progress induced by oxidative stress. We addressed whether memory impairment in this model was associated with the cholinergic septohippocampal degeneration. Rats injected with D-galactose for 6 weeks showed impairment of spatial learning and memory as measured by the water maze test. Correspondingly, anti-choline acetyltransferase immunohistochemistry demonstrated a severe loss of cholinergic terminals in the hippocampus accompanied by a mild cholinergic neuronal atrophy and loss in the medial septum and the nucleus of the vertical limb of the diagonal band of Broca. A major synaptic degeneration in the hippocampus was confirmed by ultrastructural analysis. These findings provide neuropathological evidence for rodents with chronic injection of D-galactose as a promising model for brain aging and age-related neurodegeneration.

Background: Anti-Galalpha 1-3Gal (Gal) antibodies (Ab) play a key role in the rejection of pig cells or organs transplanted into primates. A course of extracorporeal immunoadsorption (EIA) of anti-Gal Ab using an immunoaffinity column of a Gal type 6 oligosaccharide depletes Ab successfully, but Ab returns during the next few days. Although therapy with an anti-CD154 monoclonal antibody (mAb) prevents an induced Ab response to Gal or non-Gal epitopes, T cell-independent natural anti-Gal IgM and IgG return to baseline (pretransplant) levels. We have investigated the capacity of continuous i.v. infusion of bovine serum albumin conjugated to Gal type 6 oligosaccharide (BSA-Gal) to deplete or maintain depletion of circulating anti-Gal Ab., Methods: Porcine peripheral blood mobilized progenitor cells (PBPC) obtained by leukapheresis from MHC-inbred miniature swine (n=6) were transplanted into baboons. Group 1 baboons (n=4) underwent whole body (300 cGy) and thymic (700 cGy) irradiation, T cell depletion with antithymocyte globulin, complement depletion with cobra venom factor, short courses of anti-CD154 mAb therapy (20 mg/kg i.v. on alternate days), cyclosporine (CyA) (in two baboons only), mycophenolate mofetil, and porcine hematopoietic growth factors. Anti-Gal Ab depletion by EIA was carried out before transplantation of high doses (2-4x 1010 cells/kg) of PBPC. Group 2 baboons (n=3) received the group 1 regimen (including CyA) plus a continuous i.v. infusion of BSA-Gal. To prevent sensitization to BSA, anti-CD154 mAb therapy was continued until BSA-Gal administration was discontinued., Results: In group 1, Gal-reactive Ab returned to pre-PBPC transplant levels within 15-21 days, but no induced Ab to Gal or non-Gal determinants developed while anti-CD154 mAb therapy was being administered. In group 2, anti-Gal Ab was either not measurable or minimally measurable while BSA-Gal was being administered. After discontinuation of BSA-Gal, Ab did not return to pre-PBPC transplant level for more than 40-60 days, and no sensitization developed even when all therapy was discontinued. In one baboon, however, Ab to Gal type 2, but not type 6, returned during BSA-Gal therapy., Conclusions: Prevention of the induced humoral response to Gal and non-Gal epitopes by anti-CD154 mAb therapy has been reported previously by our group, but our studies are the first to demonstrate a therapy that resulted in an absence of natural anti-Gal Ab for a prolonged period. The combination of BSA-Gal and T cell costimulatory blockade may facilitate survival of pig cells and organs transplanted into primates. The return in one baboon of Ab reactive with the Gal type 2 oligosaccharide, but not type 6, indicates some polymorphism of anti-Gal Ab and suggests that, to be effective in all cases, the infusion of a combination of type 6 and type 2 BSA-Gal may be required.

Purpose: To study synthesis and transport of glutathione (GSH) in guinea-pig cornea and to determine the effect of galactose feeding and growth on transport., Methods: Steady-state level and maximal rate of synthesis of GSH (GSH-SR) were determined in guinea pigs fed 50% galactose diet for 10 days and in controls. By using a model of in situ eye perfusion, corneal transport of [35S]GSH (4 nM) and [14C]sucrose was measured as a function of time (1-10 min) in normal guinea pigs under gamma-glutamyltranspeptidase (GGT)-inhibited and uninhibited conditions. The unidirectional constant of GSH uptake was determined as a function of GSH concentration in the perfusate. The effect of galactose feeding on corneal uptake of tracer GSH was determined in control and 10-day galactose-fed guinea pigs. Levels of GSH and uptake of GSH also were measured in corneas from three different age groups: 10 days, 4 weeks, and 9 months., Results: The mean GSH level (nmol/ mg protein) in corneas of control guinea pigs was 47.6, which decreased to 36.4 (p<0.05) in 10-day galactose-fed animals. The GSH-SR was not significantly different in the two groups (1.98 vs. 2.27 nmol/min/mg protein, respectively; p = NS). Corneal uptake of tracer [35S]GSH (4 nM) was linear up to 10 min and was several-fold higher than that of the impermeable marker [14C]sucrose. The unidirectional rate constant (corrected for sucrose) for GSH was 4.03+/-0.21x10(-3)/min. GSH uptake in normal guinea pigs occurred by a saturable process with a Km of 24+/-4 microM and Vmax of 92+/-14 pmol/min/g and was significantly inhibited by GSH and GSH monoethyl ester at 60 microM concentrations. Corneal uptake of tracer GSH in galactose-fed guinea pigs showed a dramatic decrease (almost to that of sucrose) as compared with control guinea pigs. GSH uptake was similar in corneas of 10-day and 4-week-old guinea pigs, whereas that in 9-month-old guinea pigs showed a significant (approximately 80%) decrease in uptake., Conclusion: Cellular uptake of GSH by the cornea in the young, adult guinea pigs is carrier mediated via mechanism(s) that can be dissociated from the transpeptidation pathway. The reduced availability of circulating GSH may be an important factor in the development of corneal pathology associated with aging and corneal hydration due to relative GSH deficiency.

Rationale and Objectives: This study sought to evaluate prospectively the diagnostic potential of unenhanced and enhanced color Doppler and power Doppler for the differentiation of tumors and tumorlike lesions of the breast., Methods: Ninety-two patients with 110 tumors or tumorlike lesions of the breast were investigated by unenhanced and enhanced color and power Doppler ultrasound. The sonomorphologic aspects of vascularization were analyzed. In addition, maximal systolic frequency shift, resistance, and pulsatility indices were determined., Results: In 15 (24%) of 63 primary carcinomas, 15 (68%) of 22 fibroadenomas, and all (100%) of 14 postoperative lesions, the sonomorphologic analysis for the differential diagnosis of breast tumors was improved after contrast enhancement in color Doppler mode. In comparing unenhanced color Doppler to power Doppler, the latter was found to be slightly superior (sensitivity, 60% vs. 67%; specificity, 39% vs. 45%, respectively); after enhancement, both modes were equivalent (sensitivity, 100% vs. 100%; specificity, 95% vs. 95%, respectively). Signal enhancement resulted in a significant improvement in sensitivity and specificity (P < 0.01). Typical signs of malignancy were irregular vessel calibers, serpiginous courses, penetration of the tumor's margin, and irregular reticular vascularization. The quantitative parameters proved not to be helpful for the differential diagnosis of breast tumors., Conclusions: By improved analysis of the vascularization pattern, d-galactose-enhanced color Doppler sonography was found to provide more reliable differential diagnostic information than unenhanced Doppler ultrasound in tumors and tumorlike lesions of the breast.

Background and Purpose: Transtemporal insonation in transcranial Doppler sonography is often impaired by an insufficient signal-to-noise ratio, especially in elderly patients. A transpulmonary stable air microbubble suspension was injected intravenously in humans as an intracranial ultrasonic contrast agent., Methods: In a clinical phase II study, 20 patients (15 women, 5 men; mean age, 65.5 +/- 11.5 years) presenting with clinical indications for transcranial Doppler investigation were examined. A total of 97 intravenous injections with different concentrations (200, 300, and 400 mg/mL of suspension) of air microbubbles bound to galactose microparticles as a carrier were performed. The signal enhancement of color-coded pulse curves of basal cerebral arteries was evaluated off-line in comparison to an integrated color-coded decibel scale, considering quality, quantity, and time course of enhancement requiring a 3-dB level above the native signal. The overall diagnostic information was assessed according to a reliability score., Results: The first acoustic signal increase was registered after an average of 21 seconds. Time intervals for a dose-dependent peak intensity and maximal duration were 41.3 +/- 17.1 seconds and 118.0 +/- 69.8 seconds (200 mg/mL); 55.5 +/- 27.7 seconds and 237.0 +/- 112.3 seconds (300 mg/mL); and 66.1 +/- 31.8 seconds and 293.0 +/- 122.0 seconds (400 mg/mL), respectively. Duration of signal enhancement increased significantly (P < .05) with higher concentrations. The extent of signal enhancement during the whole pulse curve reached an average of 9.1 +/- 5.0 dB for 200 mg/mL, 12.0 +/- 5.4 dB for 300 mg/mL (significant on P < .05 level), and 13.1 +/- 5.6 dB for 400 mg/mL concentration (P = NS). Respective maximal intensity spots reached 17.5 +/- 6.0, 20.7 +/- 5.5, and 22.7 +/- 5.9 dB for increasing concentrations, respectively. Overall visual assessment of enhanced pulse curves for diagnostic reliability showed a sufficient result in 38.1% of all injections with 200 mg/mL, in 88.6% with 300 mg/mL, and in 84.2% with 400 mg/mL concentration. Minimal side effects occurring in 12.4% of all injections were all reversible., Conclusions: Transpulmonary stable air microbubbles bound to a galactose carrier represent a useful and safe contrast agent in case of an insufficient native signal in transcranial Doppler investigation.

Objectives: To determine the effect of a body burn on effective or nutrient liver blood flow and the relationship between blood flow and oxidant-induced lipid peroxidation., Design: Anesthetized sheep were given a 40% of total body surface, third-degree burn, after which animals were fluid resuscitated to return ventricular filling pressures and cardiac output to baseline values. Animals, for the 6-hr study period, were resuscitated with lactated Ringer's solution alone or lactated Ringer's solution plus 1500 mL of 5% hydroxyethyl starch or lactated Ringer's solution plus hydroxyethyl starch on which was complexed the iron chelator deferoxamine to prevent oxidant release. Effective liver blood flow was measured using the galactose infusion technique. Liver tissue lipid peroxidation was monitored using malondialdehyde content., Results: We found that effective liver blood flow was decreased by 50% in the 4- to 5-hr postburn period, even when animals were resuscitated to baseline cardiac output values with lactated Ringer's solution. Tissue malondialdehyde content increased in the group treated with lactated Ringer's solution from a control value of 110 +/- 7 to 202 +/- 59 nmol/g of tissue. Resuscitation with hydroxyethyl starch restored postburn effective liver blood flow to control values, but malondialdehyde content was still increased two-fold. Resuscitation with hydroxyethyl starch and deferoxamine resulted in an increase in effective liver blood flow postburn to a value 80% above controls. In addition, lipid peroxidation was prevented., Conclusions: Effective liver blood flow is markedly decreased after burn injury, even with apparently adequate volume resuscitation, when using lactated Ringer's solution. Liver lipid peroxidation persists even when effective liver blood flow is maintained, indicating that the oxidant process is not solely related to blood flow. Infusion of the antioxidant deferoxamine during resuscitation not only prevents the lipid peroxidation, most likely by a nonblood-flow-related process, but also results in an increase in blood flow above normal rates, suggesting that postburn liver oxygen needs exceed normal values.