Life-long vitamin C supplementation in combination with cold exposure does not affect oxidative damage or lifespan in mice, but decreases expression of antioxidant protection genes

Oxidative stress is suggested to be central to the ageing process, with endogenous antioxidant defence and repair mechanisms in place to minimize damage. Theoretically, supplementation with exogenous antioxidants might support the endogenous antioxidant system, thereby reducing oxidative damage, ageing-related functional decline and prolonging life- and health-span. Yet supplementation trials with antioxidants in animal models have had minimal success. Human epidemiological data are similarly unimpressive, leading some to question whether vitamin C, for example, might have pro-oxidant properties in vivo. We supplemented cold exposed (7 ± 2 °C) female C57BL/6 mice over their lifespan with vitamin C (ascorbyl-2-polyphosphate), widely advocated and self administered to reduce oxidative stress, retard ageing and increase healthy lifespan. No effect on mean or maximum lifespan following vitamin C treatment or any significant impact on body mass, or on parameters of energy metabolism was observed. Moreover, no differences in hepatocyte and lymphocyte DNA oxidative damage or hepatic lipid peroxidation was seen between supplemented and control mice. Using a DNA macroarray specific for oxidative stress-related genes, we found that after 18 months of supplementation, mice exhibited a significantly reduced expression of several genes in the liver linked to free-radical scavenging, including Mn-superoxide dismutase. We confirmed these effects by Northern blotting and found additional down-regulation of glutathione peroxidase (not present on macroarray) in the vitamin C treated group. We suggest that high dietary doses of vitamin C are ineffective at prolonging lifespan in mice because any positive benefits derived as an antioxidant are offset by compensatory reductions in endogenous protection mechanisms, leading to no net reduction in accumulated oxidative damage.     

Chard (Beta vulgaris L. var. cicla) extract ameliorates hyperglycemia by increasing GLUT2 through Akt2 and antioxidant defense in the liver of rats

Chard is a plant used as an alternative hypoglycemic agent by diabetic people in Turkey. The aim of this study was to examine the molecular mechanism of hypoglycemic effects of chard extract. Male Sprague-Dawley rats (6–7 months old) were divided into five groups for this investigation: (1) control, (2) hyperglycemic, (3) hyperglycemic + chard, (4) hyperglycemic + insulin, (5) hyperglycemic + chard + insulin. Fourteen days after animals were rendered hyperglycemic by intraperitoneal injection of 60 mg/kg streptozotocin, the chard water extract (2 g/kg/day) or/and insulin (6 U/kg/day) was administered for 45 days. Hypoglycemic effect of chard extract was demonstrated by a significant reduction in the fasting blood glucose and increased glycogen levels in liver of chard extract-treated hyperglycemic rats. Moreover, activity of adenosine deaminase, which is suggested as an important enzyme for modulating the bioactivity of insulin, was decreased by chard treatment. Immunostaining analysis showed increased nuclear translocation of Akt2 and synthesis of GLUT2 in the hepatocytes of chard or/and insulin-treated hyperglycemic rats. The oxidative stress was decreased and antioxidant defense was increased by chard extract or/and insulin treatment to hyperglycemic rats according to the decreased malondialdehyde formation, the activities of catalase, superoxide dismutase, myeloperoxidase and increased glutathione levels. These findings suggest that chard extract might improve glucose response by increasing GLUT2 through Akt2 and antioxidant defense in the liver.     

Effect of vitamin E administration on response to ischaemia-reperfusion of hearts from cold-exposed rats

In both 3,5,3-triiodothyronine (T(3))-induced hyperthyroidism and cold-induced functional hyperthyroidism, the heart displays an increased susceptibility to oxidative challenge in vitro. Hearts from T(3)-treated rats also exhibit an increased susceptibility to ischaemia-reperfusion, a condition that raises free radical production. The present study was designed to establish whether cold-exposed rats exhibit an increased cardiac susceptibility to ischaemia-reperfusion which can be attenuated by vitamin E. The following four groups of animals were used: C, control rats (n = 8, temperature 24°C); C+VE, vitamin E-treated rats (n = 8, temperature 24°C); CE, cold-exposed rats (n = 8, temperature 4°C); and CE+VE, cold-exposed vitamin E-treated rats (n = 8, temperature 4°C). Langendorff preparations from these animals were submitted to 20 min ischaemia followed by 25 min reperfusion. At the end of the ischaemia-reperfusion protocol, homogenates and mitochondria were prepared and used for analytical procedures. With respect to control hearts, cold hearts showed a lower inotropic recovery and a higher oxidative stress, as inferred by higher levels of oxidized proteins and lipids and lower reduced glutathione levels. These changes were prevented when cold rats were treated with vitamin E. Evidence was also obtained that mitochondria are involved in the tissue derangement of cold hearts. Indeed, they display a faster production of reactive oxygen species, which causes mitochondrial oxidative damage and functional decline that parallel the tissue dysfunction. Moreover, vitamin E-linked improvement of tissue function was associated with a lower oxidative damage and a restored function of mitochondria. Finally, the mitochondrial population composition and Ca(2+)-induced swelling data indicate that the decline in mitochondrial function is in part due to a decrease in the amount of the highly functional heavy mitochondria linked to their higher susceptibility to oxidative damage and swelling. In conclusion, our work shows that vitamin E treatment attenuates harmful side-effects of the cardiac response to cold, such as oxidative damage and susceptibility to oxidants, thus preserving mitochondrial function and tissue recovery from ischaemia-reperfusion.     

Reduced serum non-enzymatic antioxidant defense and increased lipid peroxidation in schizophrenic patients on a hypocaloric diet

Introduction

Growing evidence suggests that oxidative stress (OS) may be associated with the pathophysiology underlying schizophrenia (SZ). Some studies indicate that nutritional supplements offer protection from OS, but there is no data about the effect of a hypocaloric diet on OS in this population. Therefore, we aimed to study the effect of a hypocaloric dietary intervention on OS in subjects with SZ.

Methods

A cross-sectional study of 96 participants in outpatient treatment for SZ comprised patients separated into two groups: one group of subjects followed a hypocaloric diet (HD) program (n = 42), while the other group followed a regular diet (RD) with no nutritional restrictions (n = 54). The serum total radical-trapping antioxidant parameter (TRAP), total antioxidant reactivity (TAR) and thiobarbituric acid reactive species (TBARS) levels were assessed.

Results

TRAP levels were lower and TBARS levels were higher in the HD group than in the RD group (p = 0.022 and p = 0.023, respectively). There were no differences in TAR levels between the groups. Additionally, there was a positive correlation between TRAP and TBARS levels after adjusting for BMI and clozapine dose (partial correlation = 0.42, p < 0.001). There were no correlations among the length of illness or diet and the levels of TRAP, TBARS, and TAR.

Conclusions

Subjects with SZ on a hypocaloric diet displayed different OS parameters than those not following a HD. Serum TRAP levels were lower and TBARS levels were higher among SZ subjects with HD compared to SZ subjects without HD. Lower TRAP levels may reflect decreased oxidative stress, whereas higher TBARS levels most likely reflect a biochemical reaction to the decreased TRAP levels. Additionally, TAR levels were similar between groups, suggesting a similar quality of antioxidant defenses, despite quantitative differences between the two dietary protocols in SZ patients under outpatient care.     

Effect of magnesium supplementation on oxidative stress in alloxanic diabetic rats.

Magnesium deficit and oxidative stress are common features of the diabetic state. This concept supported by another observation that magnesium deficiency is also a state of increased oxidative stress prompted us to study the effect of magnesium supplementation on magnesium status and oxidative stress in diabetic rats. For this purpose, male Wistar rats were made diabetic with a single intraperitoneal injection of Alloxan. Experimental diabetes caused a significant decrease in serum and red blood cell magnesium levels and increased urinary excretion of magnesium. Marked increase in plasma malondialdehyde and corresponding decrease in vitamins C & E, uric acid and total thiols was observed in the diabetic rats as compared to control group. In liver, MDA levels were increased significantly with concomitant decrease in vitamin C, non-protein thiols and antioxidant enzymes (SOD & GST). Magnesium supplementation for four weeks restored serum and RBC magnesium levels to near normal levels with marginal but significant decrease in blood glucose levels. Plasma and liver MDA levels were reduced significantly and vitamin C and total thiols were increased significantly with magnesium supplementation. Antioxidant enzyme activity was also increased significantly with magnesium supplementation in diabetic rats. Our data clearly demonstrates that alloxanic diabetes is associated with decreased magnesium status and increased oxidative stress and that magnesium supplementation can in part restore the antioxidant parameters and decrease the oxidative stress in experimental diabetic rats.     

IgG against Plasmodium falciparum variant surface antigens and growth inhibitory antibodies in Mozambican children receiving intermittent preventive treatment with sulfadoxine-pyrimethamine

This study aimed to evaluate whether intermittent preventive treatment in infants with sulfadoxine-pyrimethamine (IPTi-SP) had an effect on the acquisition of IgG against Plasmodium falciparum variant surface antigens (VSA) and growth-inhibitory antibodies in Manhiça, Mozambique. In addition, we assessed factors affecting the magnitude of these responses and the association between antibody levels and protection against malaria.IgG to VSA expressed by MOZ2, R29 and E8B parasite isolates were measured in plasma samples collected at 5, 9, 12 and 24 months of age by flow cytometry. Growth-inhibitory antibodies in dialyzed plasmas using GFP-D10 parasites were measured by flow cytometry at 12 and 24 months.IPTi-SP did not significantly modify the levels of IgG against VSA nor the growth-inhibitory capacity of antibodies up to 2 years of age. Age but not previous episodes of malaria influenced the magnitude of these responses. In addition, anti-VSA IgG levels were 7% higher in children with current P. falciparum infection and were associated with neighborhood of residence. Children aged 24 months had 10% less parasite growth than those aged 12 months (95% CI 0.88-0.93, P < 0.0001). Growth-inhibitory antibodies correlated with levels of IgG against AMA-1, when evaluating the 10% (R² = 0.444, P = 0.049) and 20% (R² = 0.230, P = 0.037) highest inhibitory samples. None of the responses were associated with subsequent risk of malaria.In conclusion, IPTi-SP does not negatively affect the development of antibody responses thought to be major contributors to the acquisition of immunity to malaria in infancy.     

Aging and antioxidants modulate rat brain levels of homocysteine and dehydroepiandrosterone sulphate (DHEA-S): Implications in the pathogenesis of Alzheimer's disease

The study has shown that in aged (22–24 months) rat brains an elevation of homocysteine level (42%) and a decrease in dehydroepiandrosterone sulphate (DHEA-S) content (32%) occur compared to those in the brains of young rats (4–6 months). Such changes in the brain levels of homocysteine and DHEA-S in aged rats are prevented, when the diet daily of the rats is supplemented with a combination of antioxidants (N-acetyl cysteine 50 mg, α-lipoic acid 3 mg and α-tocopherol 1.5 mg – each per 100 g of body weight) starting from 18 months until these are sacrificed between 22 and 24 months. The brain content of reduced glutathione is also decreased in aged rats as compared to that in young ones and the phenomenon can again be prevented completely by the same regimen of antioxidant supplementation. The changes in the levels of homocysteine and DHEA-S in aged rat brain have been related to associated glutathione depletion and oxidative stress and the implications of the results highlighted in the pathogenesis of Alzheimer's disease.     

Role of myeloid-derived suppressor cells in mouse pre-sensitized cardiac transplant model

Harness of sensitized transplantation remains a clinical challenge particularly in parallel with prolonged cold ischemia time (PCI)-mediated injury. Our present study was to test the role of myeloid-derived suppressor cells (MDSCs) in mouse pre-sensitized transplantation. Our findings revealed that CD11b + Gr1^low MDSC was shown to have strong suppressive activity. MDSCs subsets from the tolerated mice exhibited higher suppressive capacities compared with counterparts from naive (untreated) mice. Depletion of Tregs could not affect splenic CD11b + Gr1^-low MDSC frequency, but increase peripheral and intragraft CD11b + Gr1^-low frequency. Intriguingly, boost of Tregs remarkably caused an increase of CD11b + Gr1^-low frequency in the graft, peripheral blood, and spleen. Furthermore, peripheral CD11b + Gr1^-low cells were massively accumulated at the early stage when allogeneic immune response was enhanced. Taken together, MDSCs could prevent grafts from PCI-mediated injury independent on Tregs in the pre-sensitized transplant recipients. Utilization of MDSC subset particularly CD11b + Gr1^-low might provide a novel insight into improving graft outcome under such clinical scenarios.     

Protective effects of 17β estradiol on altered age related neuronal parameters in female rat brain

Biological aging is a fundamental process observed in almost all living beings. During aging the brain experiences structural, molecular, and functional alterations. Aging in females and males is considered as the end of natural protection against age related diseases like osteoporosis, coronary heart disease, diabetes, Alzheimer's and Parkinson's disease. These changes increase during menopausal condition in females when the level of estradiol is decreased. The aim of the present study was to investigate the anti-aging and protective potential of 17β estradiol (E2) treatment on activities of membrane linked ATPases (Na⁺K⁺ ATPase, Ca²⁺ATPase), antioxidant enzymes (superoxide dismutases, glutathione-S-transferases), intrasynaptosomal calcium levels, membrane fluidity and neurolipofuscin in the brain of aging female rats of 3 months (young), 12 months (adult) and 24 months (old) age groups, and to see whether these changes are restored to normal levels after exogenous administration of E2 (0.1 μg/g body weight for one month).The results obtained in the present work revealed that normal aging was associated with significant decrease in the activities of membrane linked ATPases, antioxidant enzymes and an increase in neurolipofuscin, intrasynaptosomal calcium levels in brain of aging female rats. The present study showed that E2 treatment reversed the changes to near normal levels. E2 treatment appears to be beneficial in preventing some of the age related changes in the brain, an important anti-aging effect of the hormone.     

Morinda citrifolia fruit reduces stress-induced impairment of cognitive function accompanied by vasculature improvement in mice

The purpose of this study was to investigate effects of Morinda citrifolia fruit juice, which is locally called Noni, on stress-induced impairment of cognitive function. Male ICR mice were divided into four groups: Control (C mice), Restraint stress (RS mice), Restraint + Noni (Noni mice), and Restraint + vitamin E (VE mice). The RS, Noni, and VE mice were subjected to 8 h of chronic restraint stress (CRS) 6 days a week for 6 weeks. During this period, the Noni and VE mice were given a diet supplemented with either Noni or vitamin E, respectively. At Week 5, the mice were subjected to the Morris water maze (MWM) test to measure cognitive function. At Week 7, mouse brains were isolated for immunohistochemical analysis with BrdU or CD31 antibody to assess the proliferation of new cells and blood vessel density in the dentate gyrus of the hippocampus. The time taken to reach the platform in the MWM test was shorter in the Noni mice than in the RS mice on Day 16. Malondialdehyde (MDA ) level of the Noni mice was significantly higher than that of the C mice; however no difference was found in MDA levels between the VE and C mice. Blood vessel area was significantly lower in the R and VE mice than in the C mice; no difference was found between the C and Noni mice. These findings suggest that the administration of Noni fruit juice protects brains from stress-induced impairment of cognitive function and that this protective effect may be related to improvement in stress-induced decreases in blood vessel density in the hippocampal dentate gyrus.     

Symptomatic myositis-myalgia in hypercholesterolemic statin-treated patients with concurrent vitamin D deficiency leading to statin intolerance may reflect a reversible interaction between vitamin D deficiency and statins on skeletal muscle

Myositis-myalgia is the most common cause of statin intolerance, leading to cessation of statin use, with consequent failure to lower LDL cholesterol to target levels for primary and secondary prevention of cardiovascular disease (CVD). We hypothesize that symptomatic myositis-myalgia in hypercholesterolemic statin-treated patients with concurrent 25 (OH) vitamin D deficiency and statin intolerance may reflect a reversible interaction between vitamin D deficiency and statins on skeletal muscle. In hypercholesterolemic, vitamin D deficient patients, intolerant to statins because of myositis-myalgia, three non-blinded clinical case series have uniformly demonstrated that after supplementation with oral vitamin D2 which normalizes serum 25 (OH) vitamin D levels, statins can be successfully re-instituted in >90% of patients, without recurrent myositis-myalgia, with reduction of LDL cholesterol to target levels. Empirically, in 68 hypercholesterolemic patients, unable to tolerate ? 1 statin because of myositis-myalgia, selected by low (<32 ng/ml) serum 25 (OH) vitamin D, we have prospectively assessed whether resolution of vitamin D deficiency would result in statin tolerance, free of myositis-myalgia. On no statins, 50,000 units of vitamin D2 was given twice/week for 3 weeks, and was then continued once/week. After 3 weeks on vitamin D supplementation, statins were restarted, and patients were re-assessed after 3 months on statins while continuing vitamin D supplementation. At 3 months follow-up, on vitamin D supplementation and re-instituted statins, 62 of 68 (91%) previously statin-intolerant patients now tolerated statins well and were asymptomatic without myositis-myalgia. In these 68 patients, on vitamin D supplementation and statins, mean ± SD vitamin D rose from 22 ± 7 to 43 ± 13 ng/ml (p < 0.0001), and LDL cholesterol fell from 162 ± 55 to 101 ± 35 mg/dl (p < 0.0001). Despite published and new empirical evidence, the medical establishment has refused to accept the hypothesis, requiring placebo-controlled, double-blind studies, none having been reported to date. A placebo-controlled, double-blind study is needed to document that normalization of serum 25 (OH) vitamin D levels in vitamin D deficient, statin intolerant patients would facilitate re-introduction of statins with concurrent freedom from myositis-myalgia. The ability to reverse myositis-myalgia in vitamin D deficient, statin intolerant, hypercholesterolemic patients by vitamin D supplementation would be extraordinarily valuable, facilitating reinstitution of statins to lower LDL cholesterol to reduce risk of CVD events. We hypothesize that symptomatic myositis-myalgia in hypercholesterolemic statin-treated patients with concurrent vitamin D deficiency producing statin intolerance may reflect a reversible interaction between vitamin D deficiency and statins on skeletal muscle.     

A prospective study evaluating the role of donor-specific anti-endothelial crossmatch (XM-ONE assay) in predicting living donor kidney transplant outcome

Anti-endothelial cell antibodies (AECAs) may play a role in allograft rejection. We prospectively tested 150 consecutive living donor kidney transplant recipients, with transplants performed at Northwestern Memorial Hospital between January and December 2010, using the donor-specific endothelial (XM-ONE) crossmatch. 88/150 Patients received standard of care (SOC) immunosuppression and analyzed separately, in addition to the complete study cohort. Patients were followed for one year and XM-ONE results were analyzed in relation to occurrence of acute rejection, proteinuria, serum creatinine levels, and biopsy proven fibrosis. No correlation was found between XM-ONE results and protocol or “for-cause” biopsy proven acute rejection or vasculopathy at 12 months. When IgG+ and IgM+ results of the XM-ONE assay were combined, a correlation with proteinuria at 12 months was observed (p = 0.047). Although IgG + XM-ONE results were associated with significantly higher creatinine at 6 months (p = 0.018), significance was lost at 12 months. Conversely, patients with an IgM + XM-ONE crossmatch had significantly lower creatinine at 1 month (p = 0.019), 3 months (p = 0.0045), and 6 months (p = 0.038) post-transplant, but lost statistical significance at 12 months (p = 0.67) post-transplant. In summary, the presence of AECAs as determined by a positive XM-ONE result was not predictive of overall poorer graft outcome after one year in our center.     

Does daily vitamin D 800 IU and calcium 1000 mg supplementation decrease the risk of falling in ambulatory women aged 65–71 years? A 3-year randomized population-based trial (OSTPRE-FPS)

Objective

The hypothesis was that the calcium and vitamin D supplementation prevents falls at the population level.Study design: The OSTPRE-FPS was a randomized population-based open-trial with 3-year follow-up. The supplementation group (n = 1566) received daily cholecalciferol 800 IU + calcium carbonate 1000 mg, while the control group (n = 1573) received no supplementation or placebo. A randomly selected subsample of 593 subjects underwent a detailed measurement program including serum 25(OH)D measurements.

Main outcome measure

The occurrence of falls was the primary outcome of the study. The participants in the subsample were telephoned at 4 months intervals and the rest of the trial population was interviewed by phone once a year.

Results

In the entire trial population (ETP), there were 812 women with 1832 falls in the intervention group and 833 women with 1944 falls in the control group (risk ratio was 0.98, 95% CI 0.92–1.05, P = 0.160). The supplementation was not associated with single or multiple falls in the ETP. However, in the subsample, multiple fall incidence decreased by 30% (odds ratio (OR) 0.70, 95% CI 0.50–0.97, P = 0.034) in the supplementation group. Further, the supplementation decreased the incidence of multiple falls requiring medical attention (OR 0.72, 95% CI 0.53–0.97, P = 0.031) in the ETP. The mean compliance in the entire trial population was 78% and in the subsample 79%.

Discussion

Overall, the primary analysis showed no association between calcium and vitamin D supplementation and risk of falls. However, the results of a post hoc analysis suggested that there was a decreased risk of multiple falls requiring medical attention: this finding requires confirmation.     

Use of calcium supplements and the risk of coronary heart disease in 52–62-year-old women: The Kuopio Osteoporosis Risk Factor and Prevention Study

Background

To analyse prospectively the effect of calcium or calcium + D supplementation on coronary heart disease (CHD) in 52–62-year-old women.

Methods and results

10,555 52–62-year-old women from the population-based Kuopio Osteoporosis Risk Factor and Prevention Study (OSTPRE) who did not have CHD at baseline were followed for nearly 7 years in 1994–2001. Information about use of calcium supplements and health events was obtained from two repeated questionnaires in 1989 and 1994. Information about causes of death during the follow-up was obtained from the Statistics Finland. Information about CHD and other disease morbidity before and during the follow-up was obtained from the Registry of Specially Refunded Drugs of the Finnish Social Insurance Institution (SII). Cox's proportional-hazards models were used to estimate the risk of CHD morbidity related to the use of calcium supplements. At baseline, 2723 women reported current use of calcium or calcium + D supplementation. During the follow-up, CHD was diagnosed in 513 women. Compared to non-users of calcium/calcium + D supplements, the multivariate adjusted hazard ratio (HR) of CHD was 1.24 (95% CI 1.02–1.52) in women who used these supplements. The multivariate adjusted HR for CHD morbidity in postmenopausal women who used calcium/calcium + D supplements was 1.26 (95% CI 1.01–1.57).

Conclusions

Calcium or calcium + D supplementation appears to increase the risk of CHD among women before old age.     

Serum cathepsin K as a marker of bone metabolism in postmenopausal women treated with alendronate

Context

Cathepsin K is a member of the cysteine protease family that cleaves both helical and telopeptide regions of collagen I, the major type of collagen in bone. Measurement of circulating levels of cathepsin K may be useful to assay the number or function of osteoclasts.

Objective

The aim of the study was to evaluate the role of serum cathepsin K as a biochemical marker of bone metabolism in patients with postmenopausal osteoporosis before and after treatment with alendronate.

Design, setting and participants

The study was a case–control and prospective study with postmenopausal osteoporotic women including a total number of 86 subjects. Serum cathepsin K was determined in 46 women with postmenopausal osteoporosis before and after 3, 6 and 12 months of treatment with alendronate. Basal serum cathepsin K levels were also compared between premenopausal healthy women (n = 20), postmenopausal women without osteoporosis (n = 20) and osteoporotic women. In addition, serum carboxyterminal cross-linked telopeptide of type I collagen (CTX), osteocalcin (OC) and bone-specific alkaline phosphatase (bALP) were measured.

Main outcome measure

Changes in cathepsin K serum levels after alendronate treatment.

Results

Serum cathepsin K levels were higher in postmenopausal women with osteoporosis (9.4 ± 11 pmol/L) compared with healthy postmenopausal women (6.8 ± 8.1 pmol/L; p < 0.01) and premenopausal women (6.3 ± 5.0 pmol/L, p < 0.01). Serum cathepsin K decreases gradually after alendronate treatment (17% at 3 months, 22% at 6 months and 41% at 12 months, p < 0.01). In contrast, the treatment resulted in early and sustained reductions in serum CTX.

Conclusion

We conclude that serum cathepsin K seems to provide additional information on bone metabolism in postmenopausal women treated with alendronate.     

Circulating levels of GDNF in bipolar disorder

Neurotrophic factors regulate the survival and growth of neurons, and influence synaptic efficiency and plasticity. Several studies suggest the existence of a relationship between changes in neurotrophic levels and bipolar disorder (BD). The glial cell-line derived neurotrophic factor (GDNF) influences monoaminergic neurons and glial cells, but its role in BD patients is controversial. In order to elucidate it we evaluated plasma levels of GDNF in a sample of 70 BD patients (35 in mania and 35 in euthymia) and compared with 50 healthy controls matched for age, gender and educational levels. GDNF plasma levels were measured by enzyme-linked immunosorbent assay (ELISA). Patients were assessed by a Mini-International Neuropsychiatric Interview (MINI-plus), Young Mania and Hamilton Depression Rating Scales. Plasma GDNF levels were significantly increased in BD patients in euthymia compared with BD patients in mania and healthy controls (p < 0.05). GDNF plasma levels were correlated with age (ρ = 0.30, p < 0.05) and negatively correlated with manic symptoms in BD patients (ρ = −0.54, p < 0.05). Our results provide evidence that peripheral levels of GDNF are related with different mood states in BD, reinforcing the involvement of neurotrophic factors in its physiopathology.     

Susceptibility to pulmonary disease due to Mycobacterium avium–intracellulare complex may reflect low IL-17 and high IL-10 responses rather than Th1 deficiency

It remains unclear why some individuals and not others are susceptible to non-tuberculous mycobacterial lung disease (NTMLD). To determine whether NTMLD is associated with defects or biases in Th1/Th2/Th17 immunity, blood leukocytes from NTM patients with nodular bronchiectasis, their adult offspring, and healthy population controls were stimulated with staphylococcal enterotoxin B (SEB), tuberculin and sensitin to measure cytokine production. In response to SEB, NTM patients exhibited higher frequencies of IFNγ-producing CD4⁺ T cells than population controls (P < 0.001). In supernatant, levels of IL-17 were lower in patients than adult offspring. Sensitin elicited higher IFNγ responses from patients than controls (P < 0.05). Patients also produced more IL-10 in supernatant than controls after culture with tuberculin (P < 0.01) or sensitin (P < 0.05), but IL-10-producing CD4⁺ T cells were undetectable. NTMLD is not associated with deficient IFNγ production, but may be associated with reduced Th17 immunity and/or a predisposition towards IL-10 production from non-CD4⁺ T cells.     

Alterations in fear response and spatial memory in pre- and post-natal zinc supplemented rats: Remediation by copper

The role of zinc in the nervous system is receiving increased attention. At a time when dietary fortification and supplementation have increased the amount of zinc being consumed, little work has been done on the effects of enhanced zinc on behavior. Both zinc and copper are essential trace minerals that are acquired from the diet; under normal conditions the body protects against zinc overload, but at excessive dosages, copper deficiency has been seen. In order to examine the effect of enhanced metal administration on learning and memory, Sprague Dawley rats were given water supplemented with 10 ppm Zn, 10 ppm Zn + 0.25 ppm Cu, or normal lab water, during pre- and post-natal development. Fear conditioning tests at 4 months showed significantly higher freezing rates during contextual retention and extinction and cued extinction for rats drinking water supplemented with zinc, suggesting increased anxiety compared to controls raised on lab water. During the MWM task at 9 months, zinc-enhanced rats had significantly longer latencies to reach the platform compared to controls. The addition of copper to the zinc supplemented water brought freezing and latency levels closer to that of controls. These data demonstrate the importance of maintaining appropriate intake of both metals simultaneously, and show that long-term supplementation with zinc may cause alterations in memory.     

Coenzyme Q addition to an n-6 PUFA-rich diet resembles benefits on age-related mitochondrial DNA deletion and oxidative stress of a MUFA-rich diet in rat heart

Age-related changes in cardiomyocytes reduce the capacity to recover from acute injury or to adapt during chronic disease in advanced age. N-6 polyunsaturated fatty acids (n-6PUFA) lead to higher lipid peroxidation during aging than the less oxidizable monounsaturated fatty acids (MUFA); and coenzyme Q (CoQ)-supplemented n-6PUFA lengthens the lifespan and reduces peroxidation in comparison to non-supplemented n-6PUFA. Here, lifelong feeding on MUFA, n-6PUFA, and n-6 PUFA + CoQ was compared regarding age-related alterations in rat heart. Less mitochondrial area and perimeter were reported for aged n-6 PUFA-fed animals while MUFA led to a higher density of mitochondrial cristae. Mitochondrial complexes and cytochrome c oxidase activity decreased with aging (except complex I and cytochrome c oxidase in n-6 PUFA + CoQ), while increased apoptosis-inducing factor was found with aging. MUFA led to lower mitochondrial DNA-deletion frequency. The lowest hydroperoxide levels for aged animals were found for n-6 PUFA + CoQ, which also showed lower concentrations than did n-6 PUFA. For protein oxidation, specific carbonyl compounds were lower in aged animals; meanwhile lipoxidation-derived protein-oxidation markers were higher. The results suggest that MUFA can protect mitochondria from age-related changes, and that CoQ supplementation to n-6 PUFA partially resembles MUFA benefits. Moreover, under our experimental conditions, lipid-derived oxidative damage appears to be more important than the pure protein-derived oxidative damage during aging.