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Hyperglycemia due to relative hypoinsulinism is common in extremely preterm infants and is associated with hippocampus-mediated long-term cognitive impairment. In neonatal rats, hypoinsulinemic hyperglycemia leads to oxidative stress, altered neurochemistry, microgliosis, and abnormal synaptogenesis in the hippocampus. Intranasal insulin (INS) bypasses the blood-brain barrier, targets the brain, and improves synaptogenesis in rodent models, and memory in adult humans with Alzheimer's disease or type 2 diabetes, without altering the blood levels of insulin or glucose. To test whether INS improves hippocampal development in neonatal hyperglycemia, rat pups were subjected to hypoinsulinemic hyperglycemia by injecting streptozotocin (STZ) at a dose of 80 mg/kg i.p. on postnatal day (P) 2 and randomized to INS, 0.3U twice daily from P3-P6 (STZ + INS group), or no treatment (STZ group). The acute effects on hippocampal neurochemical profile and transcript mRNA expression of insulin receptor (Insr), glucose transporters (Glut1, Glut4, and Glut8), and poly(ADP-ribose) polymerase-1 (Parp1, a marker of oxidative stress) were determined on P7 using in vivo 1H MR spectroscopy (MRS) and qPCR. The long-term effects on the neurochemical profile, microgliosis, and synaptogenesis were determined at adulthood using 1H MRS and histochemical analysis. Relative to the control (CONT) group, mean blood glucose concentration was higher from P3 to P6 in the STZ and STZ + INS groups. On P7, MRS showed 10% higher taurine concentration in both STZ groups. qPCR showed 3-folds higher Insr and 5-folds higher Glut8 expression in the two STZ groups. Parp1 expression was 18% higher in the STZ group and normal in the STZ + INS group. At adulthood, blood glucose concentration in the fed state was higher in the STZ and STZ + INS groups. MRS showed 59% higher brain glucose concentration and histochemistry showed microgliosis in the hippocampal subareas in the STZ group. Brain glucose was normal in the STZ + INS group. Compared with the STZ group, phosphocreatine and phosphocreatine/creatine ratio were higher, and microglia in the hippocampal subareas fewer in the STZ + INS group (p < 0.05 for all). Neonatal hyperglycemia was associated with abnormal glucose metabolism and microgliosis in the adult hippocampus. INS administration during hyperglycemia attenuated these adverse effects and improved energy metabolism in the hippocampus., (© 2022 S. Karger AG, Basel.)

Background: Genome-wide association studies identified several gene variants associated with peripheral arterial disease (PAD). Among them, rs6584389 A>C was significantly associated with PAD defined by decreased ankle-brachial index (ABI). The aim of this study was to investigate whether the rs6584389 variant is also associated with the earlier stages of atherosclerosis assessed by intima-media thickness (IMT) or pulse-wave velocity (PWV) in clinically asymptomatic subjects with type 2 diabetes (T2DM), a group of patients with a high cardiovascular risk., Patients and Methods: In total, 111 patients with T2DM (56 females, 55 males) with a mean age 63.0 ± 9.1 years were consecutively included in the study. IMT was measured by ultrasound using 7 MHz linear transducer. PWV was measured using a piezoelectric method. Genotyping for rs6584389 was performed by PCR-HRMA method., Results: The carriers of the risk C-allele of rs6584389 variant had significantly higher mean left-side IMT (AA: 0.67 ± 0.12, AC 0.77 ± 0.21, CC 0.78 ± 0.22 mm; p = 0.04). In multiple linear regression analysis, rs6586389 genotype was significantly associated with all measured IMT parameters. The presence of each risk C-allele predicted an increase in left-side IMT by 0.056 mm (p = 0.017), right-side IMT by 0.053 mm (p = 0.039), average IMT by 0.054 mm (p = 0.023), and maximal IMT by 0.058 mm (p = 0.021). Age and HbA1c levels were also significantly associated with increased IMT in all multivariate models., Conclusions: Gene variant rs6584389 A>C near to PAX2 gene was associated with increased carotid IMT in patients with type 2 diabetes independently of the other main risk factors for atherosclerosis.

Hyperglycemia (blood glucose concentration >150 mg/dL) is common in extremely low gestational age newborns (ELGANs; birth at <28 week gestation). Hyperglycemia increases the risk of brain injury in the neonatal period. The long-term effects are not well understood. In adult rats, hyperglycemia alters hippocampal energy metabolism. The effects of hyperglycemia on the developing hippocampus were studied in rat pups. In Experiment 1, recurrent hyperglycemia of graded severity (moderate hyperglycemia (moderate-HG), mean blood glucose 214.6 ± 11.6 mg/dL; severe hyperglycemia (severe-HG), 338.9 ± 21.7 mg/dL; control, 137.7 ± 2.6 mg/dL) was induced from postnatal day (P) 3 to P12. On P30, the hippocampal neurochemical profile was determined using in vivo 1 H MR spectroscopy. Dendritic arborization in the hippocampal CA1 region was determined using microtubule-associated protein (MAP)-2 immunohistochemistry. In Experiment 2, continuous hyperglycemia (mean blood glucose 275.3 ± 25.8 mg/dL; control, 142.3 ± 2.6 mg/dL) was induced from P2 to P6 by injecting streptozotocin (STZ) on P2. The mRNA expression of glycogen synthase 1 (Gys1), lactate dehydrogenase (Ldh), glucose transporters 1 (Glut1) and 3 (Glut3) and monocarboxylate transporters 1 (Mct1), 2 (Mct2) and 4 (Mct4) in the hippocampus was determined on P6. In Experiment 1, MRS demonstrated lower lactate concentration and glutamate/glutamine (Glu/Gln) ratio in the severe-HG group, compared with the control group (p < 0.05). Phosphocreatine/creatine ratio was higher in both hyperglycemia groups (p < 0.05). MAP-2 histochemistry demonstrated longer apical segment length, indicating abnormal synaptic efficacy in both hyperglycemia groups (p < 0.05). Experiment 2 showed lower Glut1, Gys1 and Mct4 expression and higher Mct1 expression in the hyperglycemia group, relative to the control group (p < 0.05). These results suggest that hyperglycemia alters substrate transport, lactate homeostasis, dendritogenesis and Glu-Gln cycling in the developing hippocampus. Abnormal neurochemical profile and dendritic structure due to hyperglycemia may partially explain the long-term hippocampus-mediated cognitive deficits in human ELGANs., (Copyright © 2018 John Wiley & Sons, Ltd.)

Background: Phlebotomy-induced anemia (PIA) is common in preterm infants. The hippocampus undergoes rapid differentiation during late fetal/early neonatal life and relies on adequate oxygen and iron to support oxidative metabolism necessary for development. Anemia shortchanges these two critical substrates, potentially altering hippocampal development and function., Methods: PIA (hematocrit <25%) was induced in neonatal mice pups from postnatal day (P)3 to P14. Neurochemical concentrations in the hippocampus were determined using in vivo (1)H NMR spectroscopy at 9.4T and compared with control animals at P14. Gene expression was assessed using quantitative real-time polymerase chain reaction (qRT-PCR)., Results: PIA decreased brain iron concentration, increased hippocampal lactate and creatine concentrations, and decreased phosphoethanolamine (PE) concentration and the phosphocreatine/creatine ratio. Hippocampal transferrin receptor (Tfrc) gene expression was increased, while the expression of calcium/calmodulin-dependent protein kinase type IIα (CamKIIα) was decreased in PIA mice., Conclusion: This clinically relevant model of neonatal anemia alters hippocampal energy and phospholipid metabolism and gene expression during a critical developmental period. Low target hematocrits for preterm neonates in the neonatal intensive care unit (NICU) may have potential adverse neural implications.

There is increasing evidence that intermittent hypoxia resulting from obstructive sleep apnoea (OSA) is independently associated with dyslipidaemia. Currently, no data exist on potential links between OSA-related dyslipidaemia and susceptibility genes for dyslipidaemia in such patients. Our aim was to study the effects of the apolipoprotein E (APOE) genotype and sleep apnoea severity on atherogenic dyslipidaemia in patients with OSA. 519 clinically stable subjects prospectively recruited at a tertiary referral teaching hospital underwent full polysomnography. APOE gene polymorphisms were assessed using real-time PCR. In all APOE genotype groups, serum triglycerides increased while high-density lipoprotein (HDL) cholesterol was reduced with increasing severity of OSA in each APOE genotype group, whereas the deleterious effects of OSA on serum apolipoprotein (Apo)B levels were observed in ε2 carriers and the ε3/ε3 genotype only. Nevertheless, the ε4 allele carriers had ApoB levels within the risk range, irrespective of nocturnal hypoxia. In addition, among patients with the high-risk ε4 genotype, those with the most severe nocturnal hypoxia had significantly higher triglyceride and lower HDL cholesterol levels compared with nonhypoxic ε4 subjects. APOE genotype and the oxygen desaturation index were both independent predictors of serum triglyceride levels (p=0.009 and p<0.001, respectively; R(2)=0.148) and ApoB levels (p=0.001 and p=0.003, respectively; R(2)=0.104). Our findings suggest that OSA has adverse effects on several lipid parameters over and above the effects carried by APOE genotype. Further st1udies are needed to analyse the effects of high-risk genotypes on metabolic and cardiovascular outcomes in patients with OSA.

Background: Long-term prefrontal cortex (PFC)- and hippocampus-based cognitive deficits are the sequelae of perinatal iron deficiency, despite iron supplementation starting in the newborn period. Whether high-dose iron supplementation prevents these deficits is yet to be determined., Methods: Perinatal iron deficiency was induced in rat pups using a low-iron (3 mg/kg diet) diet during gestation until postnatal day (P)8. Iron was supplemented using a standard (40 mg/kg diet) or a 10-fold higher (400 mg/kg diet) iron-containing diet until P21. PFC and hippocampal neurochemistry was determined using in vivo (1)H nuclear magnetic resonance (NMR) spectroscopy at 9.4 Tesla on P90., Results: Both standard and 10-fold higher iron supplementation doses corrected anemia and brain iron deficiency by P21. The neurochemical profile of the PFC in both supplementation groups was comparable with the control group. In the hippocampus, standard-dose iron supplementation resulted in lower concentrations of N-acetylaspartate (NAA) and phosphoethanolamine (PE) and higher concentrations of N-acetylaspartylglutamate (NAAG) and glycerophosphocholine + phosphocholine (GPC + PC). High-dose iron supplementation resulted in lower PE and higher GPC + PC concentrations., Conclusion: The iron supplementation dose for perinatal iron deficiency differentially alters the neurochemical profile of the PFC and hippocampus in adults. The neurochemical changes suggest altered glutamatergic neurotransmission, hypomyelination, and abnormal phospholipid metabolism in the formerly iron-deficient (FID) hippocampus.

Impairment of energy metabolism is a key feature of Huntington disease (HD). Recently, we reported longitudinal neurochemical changes in R6/2 mice measured by in-vivo proton magnetic resonance spectroscopy ((1)H MRS; Zacharoff et al, 2012). Here, we present similar (1)H MRS measurements at an early stage in the milder Q111 mouse model. In addition, we measured the concentration of ATP and inorganic phosphate (P(i)), key energy metabolites not accessible with (1)H MRS, using (31)P MRS both in Q111 and in R6/2 mice. Significant changes in striatal creatine and phosphocreatine were observed in Q111 mice at 6 weeks relative to control, and these changes were largely reversed at 13 weeks. No significant change was detected in ATP concentration, in either HD mouse, compared with control. Calculated values of [ADP], phosphorylation potential, relative rate of ATP synthase (v/V(max)(ATP)), and relative rate of creatine kinase (v/V(max)(CK)) were calculated from the measured data. ADP concentration and v/V(max)(ATP) were increased in Q111 mice at 6 weeks, and returned close to normal at 13 weeks. In contrast, these parameters were normal in R6/2 mice. These results suggest that early changes in brain energy metabolism are followed by compensatory shifts to maintain energetic homeostasis from early ages through manifest disease.

Aims: Potassium inwardly rectifier 6.2 subunit (Kir6.2) of the ATP-sensitive potassium (K(ATP)) channel encoded by KCNJ11 gene is a therapeutical target for sulfonylureas. KCNJ11 E23K polymorphism was associated with type 2 diabetes in genetic association studies. The aim of the present pharmacogenetic study was to examine the effect of sulfonylurea treatment on glycemic control in relationship to KCNJ11 E23K variant., Patients and Methods: One hundred and one patients with type 2 diabetes who failed to achieve HbA1c<7% on previous metformin monotherapy were included to the study. Sulfonylurea drug was given in addition to metformin. The main outcome of the study was reduction in HbA1c level (ΔHbA1c) after 6-month sulfonylurea therapy. KCNJ11 genotypes were determined by real-time PCR with melting curve analysis., Results: After 6-month treatment, KCNJ11 K-allele carriers had higher decrease in HbA1c compared with EE homozygotes in the dominant genetic model (1.04±0.10 vs. 0.79±0.12%, p=0.036). In the log-additive model, greater mean reduction in HbA1c by 0.16% (95% CI 0.01-0.32, p=0.038) per each K-allele was observed. The relationship of treatment response with KCNJ11 genotype was also significant in the biggest subgroup of patients treated with gliclazide (n=55)., Conclusions: Carriers of the KCNJ11 K-allele have better therapeutic response to gliclazide. This observation might help to identify patients who will have the highest benefit from sulfonylurea treatment., (Copyright © 2011 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.)

To improve the ability to move from preclinical trials in mouse models of Huntington's disease (HD) to clinical trials in humans, biomarkers are needed that can track similar aspects of disease progression across species. Brain metabolites, detectable by magnetic resonance spectroscopy (MRS), have been suggested as potential biomarkers in HD. In this study, the R6/2 transgenic mouse model of HD was used to investigate the relative sensitivity of the metabolite profiling and the brain volumetry to anticipate the disease progression. Magnetic resonance imaging (MRI) and (1)H MRS data were acquired at 9.4 T from the R6/2 mice and wild-type littermates at 4, 8, 12, and 15 weeks. Brain shrinkage was detectable in striatum, cortex, thalamus, and hypothalamus by 12 weeks. Metabolite changes in cortex paralleled and sometimes preceded those in striatum. The entire set of metabolite changes was compressed into principal components (PCs) using Partial Least Squares-Discriminant Analysis (PLS-DA) to increase the sensitivity for monitoring disease progression. In comparing the efficacy of volume and metabolite measurements, the cortical PC1 emerged as the most sensitive single biomarker, distinguishing R6/2 mice from littermates at all time points. Thus, neurochemical changes precede volume shrinkage and become potential biomarkers for HD mouse models.

Morphine is frequently used as an analgesic and sedative in preterm infants. Adult rats exposed to morphine have an altered hippocampal neurochemical profile and decreased neurogenesis in the dentate gyrus of the hippocampus. To evaluate whether neonatal rats are similarly affected, rat pups were injected twice daily with 2 mg/kg morphine or normal saline from postnatal days 3 to 7. On postnatal day 8, the hippocampal neurochemical profile was determined using in vivo (1)H NMR spectroscopy. The mRNA and protein concentrations of specific analytes were measured in hippocampus, and cell division in dentate gyrus was assessed using bromodeoxyuridine. The concentrations of γ-aminobutyric acid (GABA), taurine, and myo-insotol were decreased, whereas concentrations of glutathione, phosphoethanolamine, and choline-containing compounds were increased in morphine-exposed rats relative to control rats. Morphine decreased glutamic acid decarboxylase enzyme levels and myelin basic protein mRNA expression in the hippocampus. Bromodeoxyuridine labeling in the dentate gyrus was decreased by 60-70% in morphine-exposed rats. These results suggest that recurrent morphine administration during brain development alters hippocampal structure., (Copyright © 2011 Wiley Periodicals, Inc.)

Determination of oxidative metabolism in the brain using in vivo ¹³C NMR spectroscopy (¹³C MRS) typically requires repeated blood sampling throughout the study to measure blood glucose concentration and fractional enrichment (input function). However, drawing blood from small animals, such as young rats, placed deep inside the magnet is technically difficult due to their small total blood volume. In the present study, a custom-built animal holder enabled temporary removal of the animal from the magnet for blood collection, followed by accurate repositioning in the exact presampling position without degradation of B₀ shimming. ¹³C label incorporation into glutamate C4 and C3 positions during a 120 min [1,6-¹³C₂] glucose infusion was determined in 28-day-old rats (n = 4) under α-chloralose sedation using localized, direct-detected in vivo ¹³C MRS at 9.4T. The tricarboxylic acid cycle activity rate (V(TCA)) determined using a one-compartment metabolic modeling was 0.67 ± 0.13 μmol/g/min, a value comparable to previous ex vivo studies. This methodology opens the avenue for in vivo measurements of brain metabolic rates using ¹³C MRS in small animals.

In this work, we investigated the frequency-offset dependence of the rotating frame longitudinal (R(1ρ)) and transverse (R(2ρ)) relaxation rate constants when using hyperbolic-secant adiabatic full passage pulses or continuous-wave spin-lock irradiation. Phantom and in vivo measurements were performed to validate theoretical predictions of the dominant relaxation mechanisms existing during adiabatic full passage pulses when using different settings of the frequency offset relative to the carrier. In addition, adiabatic R(1ρ) and R(2ρ) values of total creatine and N-acetylaspartate were measured in vivo from the human brain at 4 T. When the continuous-wave pulse power was limited to safe specific absorption rates for humans, simulations revealed a strong dependence of R(1ρ) and R(2ρ) values on the frequency offset for both dipolar interactions and anisochronous exchange mechanisms. By contrast, theoretical and experimental results showed adiabatic R(1ρ) and R(2ρ) values to be practically invariant within the large subregion of the bandwidth of the hyperbolic-secant pulse where complete inversion was achieved. However, adiabatic R(1ρ) and R(2ρ) values of the methyl protons of total creatine (at 3.03 ppm) were almost doubled when compared with those of the methyl protons of N-acetylaspartate (at 2.01 ppm) in spite of the fact that these resonances were in the flat region of the inversion band of the adiabatic full passage pulses. We conclude that differences in adiabatic R(1ρ) and R(2ρ) values of human brain metabolites are not a result of their chemical shifts, but instead reflect differences in dynamics., (Copyright © 2011 John Wiley & Sons, Ltd.)

Background: We aimed to analyse quantitative effects of treatment with sulphonylurea in addition to metformin on parameters of glycemic control in relation to KCNQ1 genotypes, and to identify factors predictive for the response to sulphonylurea treatment., Material/methods: Effect of 6-month sulphonylurea therapy in addition to metformin on glycemic control according to KCNQ1 genotypes was evaluated in 87 patients with type 2 diabetes who failed to achieve glycemic control on metformin monotherapy. KCNQ1 rs163184 (T>G) polymorphism was determined by real-time PCR with melting analysis of unlabeled probe., Results: The reduction in fasting plasma glucose (ΔFPG) after 6-month sulphonylurea therapy significantly differed among 3 KCNQ1 genotype groups (ANOVA, p=0.017). In a recessive genetic model, carriers of the T-allele (TT+TG) achieved significantly lower FPG levels in comparison with patients with the GG genotype (6.95 ± 0.13 vs. 7.50 ± 0.21 mmol/L, p=0.033). Consequently, ΔFPG was significantly higher in the TT+TG group compared to the GG group (1.58 ± 0.13 vs. 1.04 ± 0.18 mmol/L, p=0.016). In multiple linear regression analysis KCNQ1 genotype (p=0.016) and baseline FPG (p<0.001) were the only significant independent predictors of ΔFPG (R2=0.48)., Conclusions: Our results suggest that the magnitude of FPG reduction after 6-month sulphonylurea treatment in addition to metformin in patients with type 2 diabetes is related to the variation in KCNQ1. The FPG response to sulphonylureas was significantly lower in carriers of the risk GG genotype.

Introduction: The role of fat-bone interactions in the pathogenesis of osteoporosis in chronic obstructive pulmonary disease (COPD) is poorly understood. Our aim was to investigate expressions of leptin and osteoprotegerin (OPG) in the adipose tissue, and their relationships to osteoporosis in patients with COPD., Methods: In 39 patients with stable COPD, bone mineral density (BMD) and body composition was assessed by Dual Energy X-Ray Absorptiometry. Serum leptin was determined by the enzyme-linked immunosorbent assay, and bone turnover markers osteocalcin and β-crosslaps by the electrochemiluminiscence immunoassays. Subcutaneous adipose tissue samples were analyzed using real-time PCR., Results: Twenty-one patients without, and 18 with osteoporosis were enrolled (35 men; age 62.2 ± 7.3years). Compared to patients without osteoporosis, those with the disease had significantly lower serum levels and adipose tissue expressions of leptin, in association with increased serum β-crosslaps (p=0.028, p=0.034, p=0.022, respectively). Log adipose tissue leptin was inversely related to serum β-crosslaps (p=0.015), and directly to serum leptin (p<0.001) and to the total, femoral, and lumbar BMD and T-score (p<0.02 for all relationships). Adipose tissue OPG expression was related to all variables of bone density except for lumbar BMD and T-score (p<0.05 for all relationships). Log adipose tissue leptin and OPG expressions predicted femoral T-score independently of age, gender and pulmonary function (p<0.001, adjusted R(2)=0.383; p=0.008, adjusted R(2)=0.301, respectively). Introducing body mass (or fat mass) index into these models eliminated independent predictive value of leptin and OPG expressions., Conclusion: Our results suggest that adipose tissue leptin and OPG expressions are related to osteoporosis in patients with COPD, and appear to act as mediators between fat mass and BMD., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Objective: Perinatal iron deficiency results in persistent hippocampus-based cognitive deficits in adulthood despite iron supplementation. The objective of the present study was to determine the long-term effects of perinatal iron deficiency and its treatment on hippocampal anatomy and neurochemistry in formerly iron-deficient young adult rats., Methods: Perinatal iron deficiency was induced using a low-iron diet during gestation and the first postnatal week in male rats. Hippocampal size was determined using volumetric magnetic resonance imaging at 8 weeks of age. Hippocampal neurochemical profile, consisting of 17 metabolites indexing neuronal and glial integrity, energy reserves, amino acids, and myelination, was quantified using high-field in vivo (1)H NMR spectroscopy at 9.4T (N = 11) and compared with iron-sufficient control group (N = 10)., Results: The brain iron concentration was 56% lower than the control group at 7 days of age in the iron-deficient group, but had recovered completely at 8 weeks. The cross-sectional area of the hippocampus was decreased by 12% in the formerly iron-deficient group (P = 0.0002). The hippocampal neurochemical profile was altered: relative to the control group, creatine, lactate, N-acetylaspartylglutamate, and taurine concentrations were 6-29% lower, and glutamine concentration 18% higher in the formerly iron-deficient hippocampus (P < 0.05)., Discussion: Perinatal iron deficiency was associated with reduced hippocampal size and altered neurochemistry in adulthood, despite correction of brain iron deficiency. The neurochemical changes suggest suppressed energy metabolism, neuronal activity, and plasticity in the formerly iron-deficient hippocampus. These anatomic and neurochemical changes are consistent with previous structural and behavioral studies demonstrating long-term hippocampal dysfunction following perinatal iron deficiency.

In the majority of patients with type 2 diabetes (T2D), oral antidiabetic drug (OAD) treatment is the first line treatment after lifestyle measures fail. Two major groups of OAD are used in clinical practice--insulin secretagogues and insulin sensitisers. Sulphonyluea (SU) derivatives are insulin secretagogues and stimulate insulin secretion by inhibiting ATP-sensitive potassium channels. Genes KCNJ11 and ABCC8 encode potassium channel proteins. KCNJ11 gene Glu23Lys polymorphism was associated with an increased risk of SU secondary failure, while Ser1369Ala polymorphism of ABCC8 gene had influence antidiabetic efficacy of SU drug gliclazide. In addition, the polymorphism of TCF7L2 gene, which has the strongest association with T2D, also influenced secondary SU drug failure. Insulin sensitisers include both metformin and glitazones. Some drug-genotype associations were observed for metformin in patients with T2D. Several genes influenced the effect of glitazone treatment. Rosiglitazone was more effective in diabetes control in carriers of Prol2Ala polymorphism of PPARG gene encoding the PPARg-receptor--the target of this drug. Rosiglitazone treatment had less effect on glycemic control and adiponectin increase in T2D patients with GG-genotypes of adiponectin (APM1) polymorphism. Pioglitazone treatment had smaller effect on glycemic control in patients with LPL Ser447X polymorphism. Identification of drug-genotype interactions in pharmacogenetic studies of the OAD treatment might have clinical implications in the near future resulting in selection of more specific "patient-tailored therapy" in T2D (Tab. 1, Ref. 58).

Objective: Chronic obstructive pulmonary disease (COPD) is associated with increased cardiovascular morbidity and mortality. Several large population-based cohort studies identified an association between reduced lung function and increased intima-media thickness (IMT). Nevertheless, a vast majority of subjects in these studies did not suffer from COPD and thus it remains unclear whether IMT differs among various stages of COPD severity. The aim of the present pilot study was to evaluate IMT in central European patients with moderate, severe and very severe COPD., Methods: In forty-nine patients (34 men, 15 women; mean age 66.1 +/- 10.9 years) with COPD, the combined thickness of intima and media layers of the common carotid arteries was measured using B-mode ultrasound imaging., Results: Increased cardiovascular disease risk as evidenced by carotid IMT values greater or equal to 75th percentile were present in 14 (28.6%), whereas IMT hypertrophy (IMT values greater or equal 0.80 mm) was present in 24 (49.0%) of patients. Average IMT in the entire cohort was 0.85 +/- 0.21 mm, with no significant differences from stage II to stages III and IV of COPD., Conclusion: Present results indicate a high prevalence of IMT hypertrophy and increased cardiovascular disease risk as assessed by carotid ultrasonography in COPD patients with a broad spectrum of airway obstruction severity. The lack of differences in carotid IMT between various stages of lung impairment severity suggests that atherosclerosis starts early in the course of COPD. Therefore, the need to screen patients for the presence of concomitant atherosclerosis in early stages of COPD severity may be warranted (Tab. 2, Ref. 33).

Background: CD40, a transmembrane receptor of the tumor necrosis factor gene superfamily, is activated in response to cellular stress, including hypoxia, and orchestrates the process of inflammation via secondary messengers such as mitogen-activated protein kinase kinase 4 (MKK4) and c-Jun NH(2)-terminal kinases (JNK)., Objectives: We hypothesized that CD40, MKK4 and JNK expression is increased in the adipose tissue of patients with very severe chronic obstructive pulmonary disease (COPD)., Methods: In 20 patients with stable COPD, lung function was assessed using body plethysmography, and samples of subcutaneous adipose tissue were analyzed using real-time PCR. Body composition, including fat mass index (FMI), was assessed by bioelectrical impedance., Results: 12 patients in GOLD stage I-III (age 61.6 ± 8.6 years, 4 females, mean partial pressure of oxygen in arterial blood, PaO(2), 9.38 ± 0.21 kPa) were compared to 8 patients in GOLD stage IV (age 62.6 ± 6.3 years, all male, mean PaO(2) 7.70 ± 0.37 kPa). Compared to patients in GOLD stage I-III, patients in GOLD stage IV had lower FMI (p = 0.004), being associated with significantly higher adipose tissue expression of CD40, MKK4 and JNK [ΔΔCt: 2.55 (1.99, 4.40) vs. 1.87 (1.63, 2.23), p = 0.013; 5.19 (3.13, 5.96) vs. 2.98 (2.82, 3.86), p = 0.002; 9.01 (5.12, 11.41) vs. 4.65 (4.42, 6.26), p = 0.001, respectively]. Log-transformed CD40, MKK4 and JNK expression was significantly inversely related to PaO(2), respectively., Conclusions: Upregulation of proinflammatory CD40, MKK4 and JNK gene expression in adipose tissue in very severe COPD raises the possibility of a role of chronic systemic hypoxia in the pathogenesis of adipose tissue inflammation in COPD., (Copyright © 2010 S. Karger AG, Basel.)

Ascorbate (vitamin C, Asc) was quantified in vivo using short-TE (1)H NMR spectra from a previously published study on regional and developmental changes in the neurochemical profile of the rat brain (Tkac I, Rao R, Georgieff MK, Gruetter R. Magn Reson Med. 2003; 50: 24-32). Asc concentration was quantified on postnatal days P7-P28 from three regions that are of interest in the study of neurocognitive development, i.e. the hippocampus, striatum and cerebral cortex. The previously measured (1)H NMR spectra were re-analyzed using LCModel with the Asc spectrum included in the basis set. The Asc concentration was consistently quantified from all 110 re-analyzed spectra with an estimated fitting error of 7% (i.e. the average Cramer-Rao lower bound). The sensitivity of Asc quantification was sufficiently high to detect regional and developmental changes in Asc concentration. The concentration of Asc was highest on P7, and decreased with age in all three brain regions (p < 0.001) in agreement with previous in vitro studies. At P10 and older postnatal ages, an inhomogeneous distribution of Asc among brain regions was detected. In addition to facilitating the quantification of this important antioxidant concentration, the inclusion of the Asc spectrum in the LCModel basis set improved the quantification accuracy of other brain metabolite concentrations in the neurochemical profile.

Unlabelled: Iron deficiency (ID) is the most common gestational micronutrient deficiency in the world, targets the fetal hippocampus and striatum and results in long-term behavioral abnormalities. These structures primarily mediate spatial and procedural memory, respectively, in the rodent but have interconnections that result in competition or cooperation during cognitive tasks. We determined whether ID-induced impairment of one alters the function of the other by genetically inducing a 40% reduction of hippocampus iron content in late fetal life in mice and measuring dorsal striatal gene expression and metabolism and the behavioral balance between the two memory systems in adulthood. Slc11a2(hipp/hipp) mice had similar striatum iron content, but 18% lower glucose and 44% lower lactate levels, a 30% higher phosphocreatine:creatine ratio, and reduced iron transporter gene expression compared to wild type (WT) littermates, implying reduced striatal metabolic function. Slc11a2(hipp/hipp) mice had longer mean escape times on a cued task paradigm implying impaired procedural memory. Nevertheless, when hippocampal and striatal memory systems were placed in competition using a Morris Water Maze task that alternates spatial navigation and visual cued responses during training, and forces a choice between hippocampal and striatal strategies during probe trials, Slc11a2(hipp/hipp) mice used the hippocampus-dependent response less often (25%) and the visual cued response more often (75%) compared to WT littermates that used both strategies approximately equally. Hippocampal ID not only reduces spatial recognition memory performance but also affects systems that support procedural memory, suggesting an altered balance between memory systems., Electronic Supplementary Material: The online version of this article (doi:10.1007/s11689-010-9049-0) contains supplementary material, which is available to authorized users.

Hypoglycemia is common during development and is associated with the risk of neurodevelopmental deficits in human infants. The effects of hypoglycemia on the developing hippocampus are poorly understood. The sequential changes in energy substrates, amino acids and phosphocreatine were measured from the hippocampus during 180 min of insulin-induced hypoglycemia (blood glucose < 2.5 mmol/L) in 14-day-old rats using in vivo(1)H NMR spectroscopy. Hypoglycemia resulted in neuroglycopenia (brain glucose < 0.5 micromol/g). However, the phosphocreatine/creatine (PCr/Cr) ratio was maintained in the physiological range until approximately 150 min of hypoglycemia, indicating that energy supply was sufficient to meet the energy demands. Lactate concentration decreased soon after the onset of neuroglycopenia. Beyond 60 min, glutamine and glutamate became the major energy substrates. A precipitous decrease in the PCr/Cr ratio, indicative of impending energy failure occurred only after significant depletion of these amino acids. Once glutamate and glutamine were significantly exhausted, aspartate became the final energy source. N-acetylaspartate concentration remained unaltered, suggesting preservation of neuronal/mitochondrial integrity during hypoglycemia. Correction of hypoglycemia normalized the PCr/Cr ratio and partially restored the amino acids to pre-hypoglycemia levels. Compensatory neurochemical changes maintain energy homeostasis during prolonged hypoglycemia in the developing hippocampus.

Ascorbate (Asc, vitamin C) was quantified in the human brain noninvasively using two different (1)H NMR spectroscopy methods: short-echo time STEAM and MEGA-PRESS homonuclear editing. Taking advantage of increased sensitivity and chemical shift dispersion at 7 T, Asc was quantified with increased reliability relative to our previous study accomplished at 4 T. Asc concentration quantified from short-echo time spectra measured from the occipital lobe of eight healthy subjects ([Asc] = 1.1 +/- 0.3 micromol/g, mean +/- SD) was in excellent agreement with Asc concentration quantified from the same volume of interest using homonuclear editing ([Asc] = 1.2 +/- 0.2 micromol/g). This agreement indicates that at 7 T, Asc can be reliably quantified in the human brain simultaneously with 15 other metabolites. Additional advantages of the short-echo time approach were: shorter measurement time than homonuclear editing and minimal effect of T(2) relaxation on Asc quantification. High magnetic field was also beneficial for Asc quantification with MEGA-PRESS because increased chemical shift dispersion enabled editing with full efficiency, which resulted in a supra-linear gain in signal-to-noise ratio relative to 4 T., (2009 John Wiley & Sons, Ltd.)

Potential links between metabolic derangements and adipose tissue (AT) inflammation in patients with chronic obstructive pulmonary disease (COPD) are unexplored. We investigated AT expressions of interleukin (IL)-6, tumor necrosis factor (TNF)-α, CD68 (macrophage cell surface receptor), caspase-3, and Bax, and their relationships to the metabolic phenotype in nine cachectic, 12 normal-weight, 12 overweight, and 11 obese patients with COPD (age 62.3 ± 7.2 years). With increasing body mass index, increases in AT expressions of IL-6, TNF-α, and CD68 were observed (P < .001; P = .005; P < .001, resp.), in association with reduced insulin sensitivity (P < .001). No differences were observed between cachectic and normal-weight patients in AT expressions of inflammatory or proapoptotic markers. Adipose tissue CD68 and TNF-α expressions predicted insulin sensitivity independently of known confounders (P = .005; P = .025; R(2) = 0.840). Our results suggest that AT inflammation in obese COPD patients relates to insulin resistance. Cachectic patients remain insulin sensitive, with no AT upregulation of inflammatory or proapoptotic markers.

Objectives: To examine the relationship between polymorphisms of five candidate genes for type 2 diabetes mellitus (T2DM) and the age at diagnosis of T2DM., Methods: 538 Slovakian patients with T2DM were included and their age at diagnosis of T2DM retrieved from their medical records. Polymorphisms of genes encoding peroxisome proliferator activated receptor gamma (PPARG), PPARG-coactivator-1 (PGC1), insulin-receptor substrate 1 (IRS1), the subunit Kir 6.2 of the ATP-dependent potassium-channel (KCNJ11) and transcription factor 7-like 2 (TCF7L2) were detected by PCR-RFLP methods., Results: No significant relationship between the risk alleles of the examined gene polymorphisms to the lower mean age at diagnosis of T2DM was observed. The carriers of the TT-genotype of TCF7L2 rs7903146 polymorphism had significantly increased odds ratio for diagnosis of diabetes before the age of 40 years [OR 3.02 (1.34, 6.81), p = 0.008], in comparison with the CC/CT genotype carriers., Conclusion: No significant association of PPARG, PGC1, IRS1, KCNJ11 and TCF7L2 gene polymorphisms and the age at diagnosis of T2DM was observed in the present study. Homozygotes for the risk allele of TCF7L2 had more frequently early onset of T2DM, before age of 40 years (Tab. 4, Ref. 15).

Copper deficiency is associated with impaired brain development and mitochondrial dysfunction. Perinatal copper deficiency was produced in Holtzman rats. In vivo proton NMR spectroscopy was used to quantify 18 cerebellar and hippocampal metabolites on postnatal day 21 (P21). Copper status was evaluated in male copper-adequate (CuA) and copper-deficient (CuD) brothers at P19 and at P23, 2 days following NMR experiments, by metal and in vitro metabolite data. Compared to CuA pups, CuD pups had lower ascorbate concentration in both brain regions, confirming prior HPLC data. Both regions of CuD rats also had lower N-acetylaspartate levels consistent with delayed development or impaired mitochondrial function similar to prior work demonstrating elevated lactate and citrate. For other metabolites, the P21 neurochemical profile of CuD rats was remarkably similar to CuA rats but uniquely different from iron-deficient or chronic hypoxia models. Further research is needed to determine the neurochemical consequences of copper deficiency.

Iron deficiency (ID) is the most prevalent micronutrient deficiency in the world and it affects neurobehavioral outcome. It is unclear whether the effect of dietary ID on the brain is due to the lack of neuronal iron or from other processes occurring in conjunction with ID (e.g. hypoxia due to anemia). We delineated the role of murine Slc11a2 [divalent metal ion transporter-1 (DMT-1)] in hippocampal neuronal iron uptake during development and memory formation. Camk2a gene promoter-driven cre recombinase (Cre) transgene (Camk2a-Cre) mice were mated with Slc11a2 flox/flox mice to obtain nonanemic Slc11a2(hipp/hipp) (double mutant, hippocampal neuron-specific knockout of Slc11a2(hipp/hipp)) mice, the first conditionally targeted model of iron uptake in the brain. Slc11a2(hipp/hipp) mice had lower hippocampal iron content; altered developmental expression of genes involved in iron homeostasis, energy metabolism, and dendrite morphogenesis; reductions in markers for energy metabolism and glutamatergic neurotransmission on magnetic resonance spectroscopy; and altered pyramidal neuron dendrite morphology in area 1 of Ammon's Horn in the hippocampus. Slc11a2(hipp/hipp) mice did not reach the criterion on a difficult spatial navigation test but were able to learn a spatial navigation task on an easier version of the Morris water maze (MWM). Learning of the visual cued task did not differ between the Slc11a2(WT/WT) and Slc11a2(hipp/hipp) mice. Slc11a2(WT/WT) mice had upregulation of genes involved in iron uptake and metabolism in response to MWM training, and Slc11a2(hipp/hipp) mice had differential expression of these genes compared with Slc11a2(WT/WT) mice. Neuronal iron uptake by DMT-1 is essential for normal hippocampal neuronal development and Slc11a2 expression is induced by spatial memory training. Deletion of Slc11a2 disrupts hippocampal neuronal development and spatial memory behavior.

Unlabelled: Objective of this study was to compare the distribution frequencies of gene polymorphisms of renin-angiotensin and serotonin system in patients with positive and negative head- up tilt test (HUT)., Methods: DNA from 191 patients (mean age 44+ 18 years, 61 men) was collected. HUT was positive in 117 and negative in 74 patients. Following gene polymorphisms were determined by the PCR method: ACE insertion/deletion (I/D ACE), angiotensinogen (AGT) (M 235), angiotensin II receptor (ATR1) (A 1166C) and serotonin transporter (SERT) polymorphism (5HTTLPR)., Results: No significant differences in the distribution of gene polymorphisms between syncopal patients with positive and negative HUT were dectected. Distribution of polymorphisms included: I/D ACE: II 19 vs 20%, ID 55 vs 52%, DD 26 vs 28%. Angiotensinogen gene polymorphism MM 27% vs 30%, MT 48% vs 46%, TT 25% vs 24%. ATR1 polymorphism AA 44 vs 32%, AC50 vs 60%, CC 6 vs 8%, 5HTTLPR serotonin transporter gene polymorphism LL 42 vs 43%, SL 41 vs 39%, SS 17 vs 18%., Conclusions: An association between polymorphisms of ACE, AGT, ATR1 and SERT gene, and predisposition to VVS was not proven by the present study (Tab. 2, Ref. 22). Full Text (Free, PDF) www.bmj.sk.

Background: Obstructive sleep apnea (OSA) has been linked to cardiovascular and cerebrovascular diseases in previous studies. However, it remains unclear whether OSA relates to cardiovascular outcomes independently of obesity and/or insulin resistance., Material/methods: At a tertiary referral teaching hospital, this cross-sectional analysis of 98 subjects (28 without, 39 with mild-moderate, and 31 with severe OSA) aimed to determine whether OSA relates to National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) cardiovascular risk independently of obesity and insulin resistance. OSA was diagnosed by attended polysomnography. The insulin resistance index (HOMA-IR) was based on a homeostasis model assessment method., Results: Of the patients without to those with mild-moderate to those with severe OSA, significant increases were observed in NCEP ATP III risk [median (25%, 75% quartiles) from 2.0 (1.0, 8.0) to 3.0 (1.0, 12.0) to 16.0 (5.3, 20.0)%, p <0.001 for the trend] in association with increases in HOMA-IR (p<0.001), diastolic (p=0.039) and mean blood pressure (p=0.016), serum triglycerides (p=0.047), apolipoprotein B (p=0.039), plasma fibrinogen (p=0.013), and fasting glucose levels (p=0.002). Compared with subjects without sleep apnea, patients with severe OSA had significantly higher odds for NCEP ATP III risk higher than 10% (moderately high and high cardiovascular risk) (odds ratio: 4.06, 95% confidence interval: 1.02-16.25, p=0.048) after adjustment for body mass index and HOMA-IR., Conclusions: These findings suggest that severe OSA is related to higher cardiovascular risk independently of obesity and insulin resistance.

Intravenous immunoglobulins (IVIg) have been widely used in clinical practice for more than 35 years. Their efficacy has been established in many clinical trials for the treatment of autoimmune rheumatic diseases including systemic lupus erythematosus, ANCA positive vasculitis and dermatomyositis, but these indications are classified as the "off label" treatment. For the diseases mentioned above there are no generally accepted therapeutic guidelines. The case reports (one patient with lupus erythematosus chorea, two patients with dermatomyositis and one with the Wegener's granulomatosis) present a treatment of systemic connective tissue diseases with IVIg following the failure of standard therapeutic regimens. A successful therapy has been realized using different doses of IVIg, which raises a question on an appropriate dose. Based on our experience, we conclude that intravenous immunoglobulins are effective in the treatment of many "off label" indications in rheumatology, particularly in cases when standard immunosuppressive therapy could be harmful. Despite the evidence of efficacy, the dosage and timing of IVIg therapy, and questions of costs/benefits ratio still remain insufficiently documented and multicentric controlled clinical trials with consecutive development of guidelines are necessary (Ref. 27).

The brain of a hibernating mammal withstands physiological extremes that would result in cerebral damage and death in a non-hibernating species such as humans. To examine the possibility that this neuroprotection results from alterations in cerebral metabolism, we used in vivo(1)H NMR spectroscopy at high field (9.4 T) to measure the concentration of 18 metabolites (neurochemical profile) in the brain of 13-lined ground squirrels (Spermophilus tridecemlineatus) before, during, and after hibernation. Resolved in vivo(1)H NMR spectra were obtained even at low temperature in torpid hibernators ( approximately 7 degrees C). The phosphocreatine-to-creatine ratio was increased during torpor (+143%) indicating energy storage, and remained increased to a lesser extent during interbout arousal (IBA) (+83%). The total gamma-aminobutyric acid concentration was increased during torpor (+135%) and quickly returned to baseline during IBA. Glutamine (Gln) was decreased (-54%) during torpor but quickly returned to normal levels during IBA and after terminal arousal in the spring. Glutamate (Glu) was also decreased during torpor (-17%), but remained decreased during IBA (-20% compared with fall), and returned to normal level in the spring. Our observation that Glu and Gln levels are depressed in the brain of hibernators suggests that the balance between anaplerosis and loss of Glu and Gln (because of glutamatergic neurotransmission or other mechanisms) is altered in hibernation.

Gestational and early postnatal iron deficiency occurs commonly in humans and results in altered behaviors suggestive of striatal dysfunction. We hypothesized that early iron deficiency alters the metabolome of the developing striatum and accounts for abnormalities in striatum-dependent behavior in rats. Sixteen metabolite concentrations from a 9-11 microL volume within the striatum were serially assessed in 10 iron-deficient and 10 iron-sufficient rats on postnatal days 8, 22 (peak anemia), and 37 (following recovery from anemia) using (1)H NMR spectroscopy at 9.4 tesla. Chin-elicited bilateral forelimb placing and vibrissae-elicited unilateral forelimb placing were also assessed on these days. Iron deficiency altered metabolites indexing energy metabolism, neurotransmission, glial integrity, and myelination over time (P < 0.05). Successful development of behaviors was delayed in the iron-deficient group (P < or = 0.01). Alterations in creatine, glucose, glutamine, glutamate, N-acetylaspartate, myo-inositol, and glycerophosphorylcholine + phosphorylcholine concentrations accounted for 77-83% of the behavioral variability during peak anemia on postnatal day 22 in the iron-deficient group. Correction of anemia normalized the striatal metabolome but not the behaviors on postnatal day 37. These novel data imply that alterations in the metabolite profile of the striatum likely influence later neural functioning in early iron deficiency.

The hippocampus is injured in both hypoxia-ischemia (HI) and perinatal iron deficiency that are co-morbidities in infants of diabetic mothers and intrauterine growth restricted infants. We hypothesized that preexisting perinatal iron deficiency predisposes the hippocampus to greater injury when exposed to a relatively mild HI injury. Iron-sufficient and iron-deficient rats (hematocrit 40% lower and brain iron concentration 55% lower) were subjected to unilateral HI injury of 15, 30, or 45 mins (n=12 to 13/HI duration) on postnatal day 14. Sixteen metabolite concentrations were measured from an 11 microL volume on the ipsilateral (HI) and contralateral (control) hippocampi 1 week later using in vivo 1H NMR spectroscopy. The concentrations of creatine, glutamate, myo-inositol, and N-acetylaspartate were lower on the control side in the iron-deficient group (P<0.02, each). Magnetic resonance imaging showed hippocampal injury in the majority of the iron-deficient rats (58% versus 11%, P<0.0001) with worsening severity with increasing durations of HI (P=0.0001). Glucose, glutamate, N-acetylaspartate, and taurine concentrations were decreased and glutamine, lactate and myo-inositol concentrations, and glutamine/glutamate ratio were increased on the HI side in the iron-deficient group (P<0.01, each), mainly in the 30 and 45 mins HI subgroups (P<0.02, each). These neurochemical changes likely reflect the histochemically detected neuronal injury and reactive astrocytosis in the iron-deficient group and suggest that perinatal iron deficiency predisposes the hippocampus to greater injury from exposure to a relatively mild HI insult.

The neurochemical profile of the striatum of R6/2 Huntington's disease mice was examined at different stages of pathogenesis using in vivo(1)H NMR spectroscopy at 9.4 T. Between 8 and 12 weeks, R6/2 mice exhibited distinct changes in a set of 17 quantifiable metabolites compared with littermate controls. Concentrations of creatine, glycerophosphorylcholine, glutamine and glutathione increased and N-acetylaspartate decreased at 8 weeks. By 12 weeks, concentrations of phosphocreatine, taurine, ascorbate, glutamate, and myo-inositol increased and phophorylethanolamine decreased. These metabolic changes probably reflected multiple processes, including compensatory processes to maintain homeostasis, active at different stages in the development of HD. The observed changes in concentrations suggested impairment of neurotransmission, neuronal integrity and energy demand, and increased membrane breakdown, gliosis, and osmotic and oxidative stress. Comparisons between metabolite concentrations from individual animals clearly distinguished HD transgenics from non-diseased littermates and identified possible markers of disease progression. Metabolic changes in R6/2 striata were distinctly different from those observed previously in the quinolinic acid and 3NP models of HD. Longitudinal monitoring of changes in these metabolites may provide quantifiable measures of disease progression and treatment effects in both mouse models of HD and patients.

Mechanisms responsible for hypoglycemia unawareness remain unknown. Previously, we found that patients with type 1 diabetes and hypoglycemia unawareness had increased brain glucose concentrations as measured by (1)H-magnetic resonance spectroscopy (MRS) compared with controls measured under the same metabolic condition, suggesting that an alteration in brain glucose transport and/or metabolism may play a role in the pathogenesis of hypoglycemia unawareness. To determine whether the brain glucose concentration is altered in normal subjects subjected to recurrent hypoglycemia, we compared the brain glucose concentrations measured in healthy subjects after three episodes of hypoglycemia to blunt the counterregulatory response over 24 hr and compared this value with that measured at a time remote from the antecedent hypoglycemia protocol. Sixteen subjects (9 M/7 F, age 36 +/- 10 years, mean +/- SD) underwent three hypoglycemic clamps for 30 min at 8 AM (0 hr), 5 PM (9 hr), and 7 AM (24 hr). After the third hypoglycemic clamp, subjects underwent a hyperglycemic clamp during which brain glucose concentration was measured by MRS at 4 T. Brain glucose concentration after repeated hypoglycemia was not different from the brain glucose concentration measured in the same subjects during a control study (5.1 +/- 0.8 vs. 4.5 +/- 0.5 mumol/g wet weight, respectively, P = 0.05). These observations suggest that brain glucose transport or metabolism is not altered following short episodes of recurrent hypoglycemia in healthy human volunteers., (Copyright 2005 Wiley-Liss, Inc.)

Hyperglycemia and diabetes alter the function and metabolism of many tissues. The effect on the brain remains poorly defined, but some animal data suggest that chronic hyperglycemia reduces rates of brain glucose transport and/or metabolism. To address this question in human beings, we measured glucose in the occipital cortex of patients with poorly controlled diabetes and healthy volunteers at the same levels of plasma glucose using proton magnetic resonance spectroscopy. Fourteen patients with poorly controlled diabetes (hemoglobin A 1c = 9.8% +/- 1.7%, mean +/- SD) and 14 healthy volunteers similar with respect to age, sex, and body mass index were studied at a plasma glucose of 300 mg/dL. Brain glucose concentrations of patients with poorly controlled diabetes were lower but not statistically different from those of control subjects (4.7 +/- 0.9 vs 5.3 +/- 1.1 micromol/g wet wt; P = .1). Our sample size gave 80% power to detect a difference as small as 1.1 micromol/g wet wt. We conclude that chronic hyperglycemia in diabetes does not alter brain glucose concentrations in human subjects.

The cognitive deficits observed in children with cyanotic congenital heart disease suggest involvement of the developing hippocampus. Chronic postnatal hypoxia present during infancy in these children may play a role in these impairments. To understand the biochemical mechanisms of hippocampal injury in chronic hypoxia, a neurochemical profile consisting of 15 metabolite concentrations and 2 metabolite ratios in the hippocampus was evaluated in a rat model of chronic postnatal hypoxia using in vivo 1H NMR spectroscopy at 9.4 T. Chronic hypoxia was induced by continuously exposing rats (n = 23) to 10% O2 from postnatal day (P) 3 to P28. Fifteen metabolites were quantified from a volume of 9-11 microl centered on the left hippocampus on P14, P21, and P28 and were compared with normoxic controls (n = 14). The developmental trajectory of neurochemicals in chronic hypoxia was similar to that seen in normoxia. However, chronic hypoxia had an effect on the concentrations of the following neurochemicals: aspartate, creatine, phosphocreatine, GABA, glutamate, glutamine, glutathione, myoinositol, N-acetylaspartate (NAA), phosphorylethanolamine, and phosphocreatine/creatine (PCr/Cr) and glutamate/glutamine (Glu/Gln) ratios (P < 0.001 each, except glutamate, P = 0.04). The increased PCr/Cr ratio is consistent with decreased brain energy consumption. Given the well-established link between excitatory neurotransmission and brain energy metabolism, we postulate that elevated glutamate, Glu/Gln ratio, and GABA indicate suppressed excitatory neurotransmission in an energy-limited environment. Decreased NAA and phosphorylethanolamine suggest reduced neuronal integrity and phospholipid metabolism. The altered hippocampal neurochemistry during its development may underlie some of the cognitive deficits present in human infants at risk of chronic hypoxia.

Although it is well established that recurrent hypoglycemia leads to hypoglycemia unawareness, the mechanisms responsible for this are unknown. One hypothesis is that recurrent hypoglycemia alters brain glucose transport or metabolism. We measured steady-state brain glucose concentrations during a glucose clamp to determine whether subjects with type 1 diabetes and hypoglycemia unawareness may have altered cerebral glucose transport or metabolism after exposure to recurrent hypoglycemia. We compared 14 subjects with diabetes and hypoglycemia unawareness to 27 healthy control subjects. Brain glucose concentrations were measured under similar metabolic conditions using in vivo (1)H nuclear magnetic resonance (NMR) spectroscopy at 4 Tesla during a hyperglycemic clamp (plasma glucose = 16.7 mmol/l) with somatostatin and insulin. Subjects with type 1 diabetes and hypoglycemia unawareness had significantly higher brain glucose concentrations compared to that in controls under the same conditions (5.5 +/- 0.3 vs. 4.7 +/- 0.1 micromol/g wet weight, P = 0.016). These data suggest that changes in brain glucose transport or metabolism may occur as a result of recurrent hypoglycemia., ((c) 2004 Wiley-Liss, Inc.)

Cognitive deficits in human infants at risk for gestationally acquired perinatal iron deficiency suggest involvement of the developing hippocampus. To understand the plausible biological explanations for hippocampal injury in perinatal iron deficiency, a neurochemical profile of 16 metabolites in the iron-deficient rat hippocampus was evaluated longitudinally by 1H NMR spectroscopy at 9.4 T. Metabolites were quantified from an 11-24 microL volume centered in the hippocampus in 18 iron-deficient and 16 iron-sufficient rats on postnatal day (PD) 7, PD10, PD14, PD21 and PD28. Perinatal iron deficiency was induced by feeding the pregnant dam an iron-deficient diet from gestational d 3 to PD7. The brain iron concentration of the iron-deficient group was 60% lower on PD7 and 19% lower on PD28 (P < 0.001 each). The concentration of 12 of the 16 measured metabolites changed over time between PD7 and PD28 in both groups (P < 0.001 each). Compared with the iron-sufficient group, phosphocreatine, glutamate, N-acetylaspartate, aspartate, gamma-aminobutyric acid, phosphorylethanolamine and taurine concentrations, and the phosphocreatine/creatine ratio were elevated in the iron-deficient group (P < 0.02 each). These neurochemical alterations suggest persistent changes in resting energy status, neurotransmission and myelination in perinatal iron deficiency. An altered neurochemical profile of the developing hippocampus may underlie some of the cognitive deficits observed in human infants with perinatal iron deficiency.

1. The biological effects of carnosine, a natural hydrophilic neuropeptide, on the reactive oxygen species (ROS) pathological generation are reviewed. 2. We describe direct antioxidant action observed in the in vitro experiments. 3. Carnosine was found to effect metabolism indirectly. These effects are reflected in ROS turnover regulation and lipid peroxidation (LPO) processes. 4. During brain ischemia carnosine acts as a neuroprotector, contributing to better cerebral blood flow restoration, electroencephalography (EEG) normalization, decreased lactate accumulation, and enzymatic protection against ROS. 5. The data presented demonstrate that carnosine is a specific regulator of essential metabolic pathways in neurons supporting brain homeostasis under unfavorable conditions.