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Mitochondrial function as a determinant of life span.

Average human life expectancy has progressively increased over many decades largely due to improvements in nutrition, vaccination, antimicrobial agents, and effective treatment/prevention of cardiovascular disease, cancer, etc. Maximal life span, in contrast, has changed very little. Caloric restriction (CR) increases maximal life span in many species, in concert with improvements in mitochondrial function. These effects have yet to be demonstrated in humans, and the duration and level of CR required to extend life span in animals is not realistic in humans. Physical activity (voluntary exercise) continues to hold much promise for increasing healthy life expectancy in humans, but remains to show any impact to increase maximal life span. However, longevity in Caenorhabditis elegans is related to activity levels, possibly through maintenance of mitochondrial function throughout the life span. In humans, we reported a progressive decline in muscle mitochondrial DNA abundance and protein synthesis with age. Other investigators also noted age-related declines in muscle mitochondrial function, which are related to peak oxygen uptake. Long-term aerobic exercise largely prevented age-related declines in mitochondrial DNA abundance and function in humans and may increase spontaneous activity levels in mice. Notwithstanding, the impact of aerobic exercise and activity levels on maximal life span is uncertain. It is proposed that age-related declines in mitochondrial content and function not only affect physical function, but also play a major role in regulation of life span. Regular aerobic exercise and prevention of adiposity by healthy diet may increase healthy life expectancy and prolong life span through beneficial effects at the level of the mitochondrion.

Pflugers Arch. 2010 Jan;459(2):277-89

Coenzyme Q10 decreases amyloid pathology and improves behavior in a transgenic mouse model of Alzheimer’s disease.

Increased oxidative stress is implicated in the pathogenesis of Alzheimer’s disease (AD). A large body of evidence suggests that mitochondrial dysfunction and increased reactive oxygen species occur prior to amyloid-β (Aβ) deposition. Coenzyme Q10 (CoQ10), a component of the mitochondrial electron transport chain, is well characterized as a neuroprotective antioxidant in animal models and human trials of Huntington’s disease and Parkinson’s disease, and reduces plaque burden in AβPP/PS1 mice. We now show that CoQ10 reduces oxidative stress and amyloid pathology and improves behavioral performance in the Tg19959 mouse model of AD. CoQ10 treatment decreased brain levels of protein carbonyls, a marker of oxidative stress. CoQ10 treatment resulted in decreased plaque area and number in hippocampus and in overlying cortex immunostained with an Aβ42-specific antibody. Brain Aβ42 levels were also decreased by CoQ10 supplementation. Levels of amyloid-β protein precursor (AβPP) β-carboxyterminal fragments were decreased. Importantly, CoQ10-treated mice showed improved cognitive performance during Morris water maze testing. Our results show decreased pathology and improved behavior in transgenic AD mice treated with the naturally occurring antioxidant compound CoQ10. CoQ10 is well tolerated in humans and may
be promising for therapeutic trials in AD.

J Alzheimers Dis. 2011;27(1):211-23

Reversal of mitochondrial dysfunction by coenzyme Q10 supplement improves endothelial function in patients with ischaemic left ventricular systolic dysfunction: a randomized controlled trial.

AIMS: Coronary artery disease (CAD) is associated with endothelial dysfunction and mitochondrial dysfunction (MD). The aim of this study was to investigate whether co-enzyme Q10 (CoQ) supplementation, which is an obligatory coenzyme in the mitochondrial respiratory transport chain, can reverse MD and improve endothelial function in patients with ischaemic left ventricular systolic dysfunction (LVSD). METHODS AND RESULTS: We performed a randomized, double-blind, placebo-controlled trial to determine the effects of CoQ supplement (300 mg/day, n=28) vs. placebo (controls, n=28) for 8 weeks on brachial flow-mediated dilation (FMD) in patients with ischaemic LVSD(left ventricular ejection fraction <45%). Mitochondrial function was determined by plasma lactate/pyruvate ratio (LP ratio). After 8 weeks, CoQ-treated patients had significant increases in plasma CoQ concentration (treatment effect 2.20 µg/mL, P<0.001) and FMD (treatment effect 1.51%, P=0.03); and decrease in LP ratio (treatment effect -2.46, P=0.03) compared with controls. However, CoQ treatment did not alter nitroglycerin-mediated dilation, blood pressure, blood levels of fasting glucose, haemoglobin A1c, lipid profile, high-sensitivity C-reactive protein and oxidative stress as determined by serum superoxide dismutase and 8-isoprostane (all P>0.05). Furthermore, the reduction in LP ratio significantly correlated with improvement in FMD (r=-0.29, P=0.047). CONCLUSION: In patients with ischaemic LVSD, 8 weeks supplement of CoQ improved mitochondrial function and FMD; and the improvement of FMD correlated with the change in mitochondrial function, suggesting that CoQ improved endothelial function via reversal of mitochondrial dysfunction in patients with ischaemic LVSD.

Atherosclerosis. 2011 Jun;216(2):395-401

Cardiovascular mortality and N-terminal-proBNP reduced after combined selenium and coenzyme Q10 supplementation: A 5-year prospective randomized double-blind placebo-controlled trial among elderly Swedish citizens.

BACKGROUND: Selenium and coenzyme Q10 are essential for the cell. Low cardiac contents of selenium and coenzyme Q10 have been shown in patients with cardiomyopathy, but inconsistent results are published on the effect of supplementation of the two components separately. A vital relationship exists between the two substances to obtain optimal function of the cell. However, reports on combined supplements are lacking. METHODS: A 5-year prospective randomized double-blind placebo-controlled trial among Swedish citizens aged 70 to 88 was performed in 443 participants given combined supplementation of selenium and coenzyme Q10 or a placebo. Clinical examinations, echocardiography and biomarker measurements were performed. Participants were monitored every 6th month throughout the intervention. The cardiac biomarker N-terminal proBNP (NT-proBNP) and echocardiographic changes were monitored and mortalities were registered. End-points of mortality were evaluated by Kaplan-Meier plots and Cox proportional hazard ratios were adjusted for potential confounding factors. Intention-to-treat and per-protocol analyses were applied. RESULTS: During a follow up time of 5.2 years a significant reduction of cardiovascular mortality was found in the active treatment group vs. the placebo group (5.9% vs. 12.6%; P=0.015). NT-proBNP levels were significantly lower in the active group compared with the placebo group (mean values: 214 ng/L vs. 302 ng/L at 48 months; P=0.014). In echocardiography a significant better cardiac function score was found in the active supplementation compared to the placebo group (P=0.03). CONCLUSION: Long-term supplementation of selenium/coenzyme Q10 reduces cardiovascular mortality. The positive effects could also be seen in NT-proBNP levels and on echocardiography.

Int J Cardiol. 2012 May 22

Exercise training increases mitochondrial biogenesis in the brain.

Increased muscle mitochondria are largely responsible for the increased resistance to fatigue and health benefits ascribed to exercise training. However, very little attention has been given to the likely benefits of increased brain mitochondria in this regard. We examined the effects of exercise training on markers of both brain and muscle mitochondrial biogenesis in relation to endurance capacity assessed by a treadmill run to fatigue (RTF) in mice. Male ICR mice were assigned to exercise (EX) or sedentary (SED) conditions (n = 16-19/group). EX mice performed 8 wk of treadmill running for 1 h/day, 6 days/wk at 25 m/min and a 5% incline. Twenty-four hours after the last training bout a subgroup of mice (n = 9-11/group) were euthanized, and brain (brain stem, cerebellum, cortex, frontal lobe, hippocampus, hypothalamus, and midbrain) and muscle (soleus) tissues were isolated for analysis of mRNA expression of peroxisome proliferator-activated receptor-gamma coactivator-1-alpha (PGC-1α), Silent Information Regulator T1 (SIRT1), citrate synthase (CS), and mitochondrial DNA (mtDNA) using RT-PCR. A different subgroup of EX and SED mice (n = 7-8/group) performed a treadmill RTF test. Exercise training increased PGC-1α, SIRT1, and CS mRNA and mtDNA in most brain regions in addition to the soleus (P < 0.05). Mean treadmill RTF increased from 74.0 ± 9.6 min to 126.5 ± 16.1 min following training (P < 0.05). These findings suggest that exercise training increases brain mitochondrial biogenesis, which may have important implications, not only with regard to fatigue, but also with respect to various central nervous system diseases and age-related dementia that are often characterized by mitochondrial dysfunction.

J Appl Physiol. 2011 Oct;111(4):1066-71

Pyrroloquinoline quinone stimulates mitochondrial biogenesis through cAMP response element-binding protein phosphorylation and increased PGC-1alpha expression.

Bioactive compounds reported to stimulate mitochondrial biogenesis are linked to many health benefits such increased longevity, improved energy utilization, and protection from reactive oxygen species. Previously studies have shown that mice and rats fed diets lacking in pyrroloquinoline quinone (PQQ) have reduced
mitochondrial content. Therefore, we hypothesized that PQQ can induce mitochondrial biogenesis in mouse hepatocytes. Exposure of mouse Hepa1-6 cells to 10-30 microm PQQ for 24-48 h resulted in increased citrate synthase and cytochrome c oxidase activity, Mitotracker staining, mitochondrial DNA content, and cellular oxygen respiration. The induction of this process occurred through the activation of cAMP response element-binding protein (CREB) and peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha), a pathway known to regulate mitochondrial biogenesis. PQQ exposure stimulated phosphorylation of CREB at serine 133, activated the promoter of PGC-1alpha, and increased PGC-1alpha mRNA and protein expression. PQQ did not stimulate mitochondrial biogenesis after small interfering RNA-mediated reduction in either PGC-1alpha or CREB expression. Consistent with activation of the PGC-1alpha pathway, PQQ increased nuclear respiratory factor activation (NRF-1 and NRF-2) and Tfam, TFB1M, and TFB2M mRNA expression. Moreover, PQQ protected cells from mitochondrial inhibition by rotenone, 3-nitropropionic acid, antimycin A, and sodium azide. The ability of PQQ to stimulate mitochondrial biogenesis accounts in part for action of this compound and suggests that PQQ may be beneficial in diseases associated with mitochondrial dysfunction.

J Biol Chem. 2010 Jan 1;285(1):142-52

Potential physiological importance of pyrroloquinoline quinone.

Pyrroloquinoline quinone (PQQ) is a novel biofactor for which a proposition can be made for physiological importance. PQQ was first recognized as an enzyme cofactor in bacteria. It has recently been tentatively identified as a component of interstellar dust. Thus, PQQ may have been present throughout early biological conception and evolution. PQQ is also a potent plant growth factor. Consequently, for animals and humans, there has been constant exposure to PQQ. In animals, PQQ is reported to participate in a range of biological functions with apparent survival benefits (e.g., improved neonatal growth and reproductive performance). There are also benefits from PQQ supplementation related to cognitive, immune, and antioxidant functions, as well as protection from cardiac and neurological ischemic events. Although PQQ is not currently viewed as a vitamin, its involvement in cell signaling pathways, particularly those important to mitochondriogenesis in experimental animal models, may eventually provide a rationale for defining PQQ as vital to life. For humans, such evidence suggests there may be similar parallels or benefits from improving PQQ status.

Altern Med Rev. 2009 Sep;14(3):268-77

Identification of transcriptional networks responding to pyrroloquinoline quinone dietary supplementation and their influence on thioredoxin expression, and the JAK/STAT and MAPK pathways.

PQQ (pyrroloquinoline quinone) improves energy utilization and reproductive performance when added to rodent diets devoid of PQQ. In the present paper we describe changes in gene expression patterns and transcriptional networks that respond to dietary PQQ restriction or pharmacological administration. Rats were fed diets either deficient in PQQ (PQQ-) or supplemented with PQQ (approx. 6 nmol of PQQ/g of food; PQQ+). In addition, groups of rats were either repleted by administering PQQ to PQQ- rats (1.5 mg of PQQ intraperitoneal/kg of body weight at 12 h intervals for 36 h; PQQ-/+) or partially depleted by feeding the PQQ- diet to PQQ+ rats for 48 h (PQQ+/-). RNA extracted from liver and a Codelink(R) UniSet Rat I Bioarray system were used to assess gene transcript expression. Of the approx. 10000 rat sequences and control probes analysed, 238 were altered at the P<0.01 level by feeding on the PQQ- diet for 10 weeks. Short-term PQQ depletion resulted in changes in 438 transcripts (P<0.01). PQQ repletion reversed the changes in transcript expression caused by PQQ deficiency and resulted in an alteration of 847 of the total transcripts examined (P<0.01). Genes important for cellular stress (e.g. thioredoxin), mitochondriogenesis, cell signalling [JAK (Janus kinase)/STAT (signal transducer and activator of transcription) and MAPK (mitogen-activated protein kinase) pathways] and transport were most affected. qRT-PCR (quantitative real-time PCR) and functional assays aided in validating such processes as principal targets. Collectively, the results provide a mechanistic basis for previous functional observations associated with PQQ deficiency or PQQ administered in pharmacological amounts.

Biochem J. 2010 Aug 1;429(3):515-26

Mitochondrial dysfunction, proteotoxicity, and aging: causes or effects, and the possible impact of NAD+-controlled protein glycation.

Aging is frequently characterized by the accumulation of altered proteins and dysfunctional mitochondria. This review discusses possible causes of these effects, their interdependence and the impact of energy metabolism on proteostasis, especially formation and elimination of altered proteins. It is suggested NAD+ to some degree regulates formation of aberrant proteins and generation of oxygen free-radicals and reactive oxygen species (ROS), because when NAD+ is limiting, glycolytic triose phosphates spontaneously decompose into methylglyoxal (MG), a highly deleterious glycating agent and ROS inducer. That NAD+ has stimulatory effects on stress protein expression and autophagy, while mitochondria regenerate NAD+ from NADH, further integrates energy metabolism into proteostasis. It is suggested that, as altered proteins can deleteriously interact with mitochondria, changes in synthesis, or elimination, of cytosolic error-proteins will affect mitochondrial activity. It is also suggested that functional mitochondria are essentially antiaging agents, while their dysfunction or inactivity accelerate ROS formation and aging. These proposals may also help explain the oxygen paradox that while ROS may be causal to aging, increased mitochondrial activity (i.e., oxygen utilization) suppresses aging and much associated pathology. Increased synthesis of glutathione, humanin, and mitochondrial chaperone proteins are other additional consequences of increased mitogenesis and which would help ensure proteostasis.

Adv Clin Chem. 2010;50:123-50

Coenzyme Q10 deficiency in mitochondrial DNA depletion syndromes.

We evaluated coenzyme Q₁₀ (CoQ) levels in patients studied under suspicion of mitochondrial DNA depletion syndromes (MDS) (n=39). CoQ levels were quantified by HPLC, and the percentage of mtDNA depletion by quantitative real-time PCR. A high percentage of MDS patients presented with CoQ deficiency as compared to other mitochondrial patients (Mann-Whitney-U test: p=0.001). Our findings suggest that MDS are frequently associated with CoQ deficiency, as a possible secondary consequence of disease pathophysiology. Assessment of muscle CoQ status seems advisable in MDS patients since the possibility of CoQ supplementation may then be considered as a candidate therapy.

Mitochondrion. 2013 Apr 11;13(4):337-341

Comparison of the administration of progesterone versus progesterone and vitamin D in improvement of outcomes in patients with traumatic brain injury: A randomized clinical trial with placebo group.

BACKGROUND: Due to the heterogeneity of traumatic brain injury (TBI), many of single treatments have not been successful in prevention and cure of these kinds of injuries. The neuroprotective effect of progesterone drug on severe brain injuries has been identified, and recently, the neuroprotective effect of vitamin D has also been studied as the combination of these two drugs has shown better effects on animal samples in some studies. This study was conducted to examine the effect of vitamin D and progesterone on brain injury treatment after brain trauma. MATERIALS AND METHODS: This study was performed on patients with severe brain trauma (Glasgow Coma Scale (GCS) ≤ 8) from April to September, 2011. The patients were divided to 3 groups (placebo, progesterone, progesterone-vitamin D), each with 20 people. Upon the patients’ admission, their GCS and demographic information were recorded. After 3 months, they were reassessed, and their GCS and GOS (Glasgow outcome scale) were recorded. The collected data were analyzed using SPSS 18 software (SPSS Inc., Chicago IL, USA). RESULTS: Before intervention, GCS mean of the placebo, progesterone, and progesterone-vitamin D groups were 6.3 ± 0.88, 6.31 ± 0.87, and 6 ± 0.88, respectively. They increased to 9.16 ± 1.11, 10.25 ± 1.34, and 11.27 ± 2.27, respectively 3 months after intervention. There was a significant difference among GCS means of the 3 groups (P-value = 0.001). GOS was classified to 2 main categories of favorable and unfavorable recovery, of which, favorable recovery in placebo, progesterone, and progesterone-vitamin D was 25%, 45%, and 60%, respectively which showed a statistical significant difference among the groups (P-value = 0.03). CONCLUSION: The results showed that recovery rate in patients with severe brain trauma in the group receiving progesterone and vitamin D together was significantly higher than that of progesterone group, which was in turn higher than that of placebo group.

Adv Biomed Res. 2012;1:58

Bone mineral density and vitamin D status among African American children with forearm fractures.

OBJECTIVE: To determine whether African American children with forearm fractures have decreased bone mineral density and an increased prevalence of vitamin D deficiency (serum 25-hydroxyvitamin D level ≤ 20 ng/mL) compared with fracture-free control patients. METHODS: This case-control study in African American children, aged 5 to 9 years, included case patients with forearm fracture and control patients without fracture. Evaluation included measurement of bone mineral density and serum 25-hydroxyvitamin D level. Univariable and multivariable analyses were used to test for associations between fracture status and 2 measures of bone health (bone mineral density and 25-hydroxyvitamin D level) while controlling for other potential confounders. RESULTS: The final sample included 76 case and 74 control patients. There were no significant differences between case and control patients in age, gender, parental education level, enrollment season, outdoor play time, height, or mean dietary calcium nutrient density. Cases were more likely than control patients to be overweight (49.3% vs 31.4%, P = .03). Compared with control patients, case patients had lower whole body z scores for bone mineral density (0.62 ± 0.96 vs 0.98 ± 1.09; adjusted odds ratio 0.38 [0.20-0.72]) and were more likely to be vitamin D deficient (47.1% vs 40.8%; adjusted odds ratio 3.46 [1.09-10.94]). CONCLUSIONS: These data support an association of lower bone mineral density and vitamin D deficiency with increased odds of forearm fracture among African American children. Because suboptimal childhood bone health also negatively impacts adult bone health, interventions to increase bone mineral density and correct vitamin D deficiency are indicated in this population to provide short-term and long-term benefits.

Pediatrics. 2012 Sep;130(3):e553-60

Dietary intake and stress fractures among

BACKGROUND: Appropriate and sufficient dietary intake is one of the main requirements for maintaining fitness and health. Inadequate energy intake may have a negative impact on physical performance which may result in injuries among physically active populations. The purpose of this research was to evaluate a possible relationship between dietary intake and stress fracture occurrence among combat recruits during basic training (BT). METHODS: Data was collected from 74 combat recruits (18.2 ± 0.6 yrs) in the Israeli Defense Forces. Data analyses included changes in anthropometric measures, dietary intake, blood iron and calcium levels. Measurements were taken on entry to 4-month BT and at the end of BT. The occurrence of stress reaction injury was followed prospectively during the entire 6-month training period. RESULTS: Twelve recruits were diagnosed with stress fracture in the tibia or femur (SF group). Sixty two recruits completed BT without stress fractures (NSF). Calcium and vitamin D intakes reported on induction day were lower in the SF group compared to the NSF group-38.9% for calcium (589 ± 92 and 964 ± 373 mg·d-1, respectively, p < 0.001), and-25.1% for vitamin D (117.9 ± 34.3 and 157.4 ± 93.3 IU·d-1, respectively, p < 0.001). During BT calcium and vitamin D intake continued to be at the same low values for the SF group but decreased for the NSF group and no significant differences were found between these two groups. CONCLUSIONS: The development of stress fractures in young recruits during combat BT was associated with dietary deficiency before induction and during BT of mainly vitamin D and calcium. For the purpose of intervention, the fact that the main deficiency is before induction will need special consideration.

J Int Soc Sports Nutr. 2012 Mar 13;9(1):6

Epidemiology of metatarsal stress fractures versus tibial and femoral stress fractures during elite training.

BACKGROUND: The training of elite infantry recruits takes a year or more. Stress fractures are known to be endemic in their basic training and the clinical presentation of tibial, femoral, and metatarsal stress fractures are different. Stress fracture incidence during the subsequent progressively more demanding training is not known. The study hypothesis was that after an adaptation period, the incidence of stress fractures during the course of 1 year of elite infantry training would fall in spite of the increasingly demanding training. MATERIALS AND METHODS: Seventy-six male elite infantry recruits were followed for the development of stress fractures during a progressively more difficult training program composed of basic training (1 to 14 weeks), advanced training (14 to 26 weeks), and unit training (26 to 52 weeks). Subjects were reviewed regularly and those with clinical suspicion of stress fracture were assessed using bone scan and X-rays. RESULTS: The incidence of stress fractures was 20% during basic training, 14% during advanced training and 23% during unit training. There was a statistically significant difference in the incidence of tibial and femoral stress fractures versus metatarsal stress fractures before and after the completion of phase II training at week 26 (p=0.0001). Seventy-eight percent of the stress fractures during phases I and II training were either tibial or femoral, while 91% of the stress fractures in phase III training were metatarsal. Prior participation in ball sports (p=0.02) and greater tibial length (p=0.05) were protective factors for stress fracture. CONCLUSION: The study hypothesis that after a period of soldier adaptation, the incidence of stress fractures would decrease in spite of the increasingly demanding elite infantry training was found to be true for tibial and femoral fractures after 6 months of training but not for metatarsal stress fractures. Further studies are required to understand the mechanism of this difference but physicians and others treating stress fractures should be aware of this pattern.

Foot Ankle Int. 2011 Jan;32(1):16-20

Plasma 25 hydroxyvitamin D level and blood gene expression profiles: a cross-sectional study of the Norwegian Women and Cancer Post-genome Cohort.

Background/Objectives: Vitamin D deficiency has been associated with increased risk of developing several diseases, but much is unknown about the molecular effects involved. Gene expression technology is increasingly being used to elucidate molecular mechanisms related to nutritional factors, and in this study of free-living, middle-aged Norwegian women, we aimed at identifying gene expression pathways in the blood associated with vitamin D status. Subjects/Methods: Blood samples and questionnaires were collected as a part of the Norwegian Women and Cancer Post-genome Cohort (500 invited subjects, 218 included). Plasma 25 hydroxyvitamin D (25(OH)D) concentrations were measured using high-performance liquid chromatography, and we compared groups with sufficient versus deficient vitamin D status (25(OH)D >50 nmol/l (n=66) versus <37.5 nmol/l (n=83)), to identify differences in gene expression profiles obtained using full-genome microarrays. Results: In a targeted pathway-level analysis, several immunological processes, immune cell functions and major signaling pathways were differentially regulated according to vitamin D status (P<0.01). To a certain degree, results from in vitro studies reported in the literature were reflected in this population setting. Conclusions: We conclude that vitamin D status measured as 25(OH)D was associated with molecular pathways that may ultimately affect the potential onset of diseases. The use of gene expression analysis in a population setting may give valuable input to the study of effects of nutritional factors.

Eur J Clin Nutr. 2013 Mar 6

Vitamin D deficiency and myocardial diseases.

Vitamin D deficiency is common among patients with myocardial diseases because sun-induced vitamin D production in the skin and dietary intake of vitamin D is often insufficient. Knockout mice for the vitamin D receptor develop myocardial hypertrophy and dysfunction. It has also been shown that children with rickets who suffered from severe heart failure could be successfully treated with supplementation of vitamin D plus calcium. In adults, almost all patients with heart failure exhibit reduced 25-hydroxyvitamin D levels, which are used to classify the vitamin D status. In prospective studies, vitamin D deficiency was an independent risk factor for mortality, deaths due to heart failure and sudden cardiac death. Several vitamin D effects on the electrophysiology, contractility, and structure of the heart suggest that vitamin D deficiency might be a causal factor for myocardial diseases. Data from interventional trials, however, are rare and urgently needed to elucidate whether vitamin D supplementation is useful for the treatment of myocardial diseases. In our opinion, the current knowledge of the beneficial effects of vitamin D on myocardial and overall health strongly argue for vitamin D supplementation in all vitamin D-deficient patients with or at high risk for myocardial diseases.

Mol Nutr Food Res. 2010 Aug;54(8):1103-13

Worsening severity of vitamin D deficiency is associated with increased length of stay, surgical intensive care unit cost, and mortality rate in surgical intensive care unit patients.

BACKGROUND: Vitamin D deficiency is the most common nutritional deficiency in the United States. It is seldom measured or recognized, and rarely is treated, particularly in critically ill patients. The purpose of this study was to investigate the prevalence and impact of vitamin D deficiency in surgical intensive care unit patients. We hypothesized that severe vitamin D deficiency increases the length of stay, mortality rate, and cost in critically ill patients admitted to surgical intensive care units. METHODS: We performed a prospective observational study of vitamin D status on 258 consecutive patients admitted to the Surgical Intensive Care Unit at Grady Memorial Hospital between August 2009 and January 2010. Vitamin D levels (25 [OH]2 vitamin-D3) were measured by high-pressure liquid chromatography and tandem mass spectrometry. Vitamin D deficiency was defined as follows: severe deficiency was categorized as less than 13 ng/mL; moderate deficiency was categorized as 14 to 26 ng/mL; mild deficiency was categorized as 27 to 39 ng/mL; and normal levels were categorized as greater than 40 ng/mL. RESULTS: Of the 258 patients evaluated, 70.2% (181) were men, and 29.8% (77) were women; 57.6% (148) were African American and 32.4% (109) were Caucasian. A total of 138 (53.5%) patients had severe vitamin D deficiency, 96 (37.2%) had moderate deficiency, 18 (7.0%) had mild deficiency, and 3 (1.2%) of the patients had normal vitamin D levels. The mean length of stay in the Surgical Intensive Care Unit for the severe vitamin D-deficient group was 13.33 ± 19.5 days versus 7.29 ± 15.3 days and 5.17 ± 6.5 days for the moderate and mild vitamin D-deficient groups, respectively, which was clinically significant (P = .002). The mean treatment cost during the patient stay in the surgical intensive care unit was $51,413.33 ± $75,123.00 for the severe vitamin D-deficient group, $28,123.65 ± $59,752.00 for the moderate group, and $20,414.11 ± $25,714.30 for the mild vitamin D-deficient group, which also was clinically significant (P = .027). More importantly, the mortality rate for the severe vitamin D-deficient group was 17 (12.3%) versus 11 (11.5%) in the moderate group (P = .125). Because no deaths occurred in the mildly or normal vitamin D-deficient groups, we compared the mortality rate between severe/moderate and mild/normal vitamin D groups (P = .047). CONCLUSIONS: In univariate analysis, severe and moderate vitamin D deficiency was related inversely to the length of stay in the surgical intensive care unit (r = .194; P = .001), related inversely to surgical intensive care unit treatment cost (r = .194; P = .001) and mortality (r = .125; P = .023), compared with the mild vitamin D-deficient group, after adjusting for age, sex, race, and comorbidities (myocardial infarctions, acute renal failure, and pneumonia); the length of stay, surgical intensive care unit cost, and mortality remained significantly associated with vitamin D deficiency.

Am J Surg. 2012 Jul;204(1):37-43

The ubiquitin-proteasome system at the crossroads of stress-response and ageing pathways: a handle for skin care?

The regulation of gene expression at the transcriptional level has been considered for long as the main mechanism of cellular adaptive responses. Since the turn of the century, however, it is becoming clear that higher organisms developed a complex, sensitive and maybe equally important network of regulatory pathways, relying largely on protein interactions, post-translational modifications and proteolysis. Here we review the involvement of the ubiquitin-proteasome pathway of protein degradation at different levels of cellular life in relation with ageing, and with a special focus on skin. It comes out that the ubiquitin system plays a major role in signal transduction associated with stress and ageing, in skin in particular through the control of retinoid and NF-kappaB pathways. The understanding of specific proteolytic targeting by E3 ubiquitin-ligases paves the way for a new generation of active molecules that may control particular steps of normal and pathological ageing.

Ageing Res Rev. 2006 Feb;5(1):60-90

Human studies related to protein oxidation: protein carbonyl content as a marker of damage.

Proteins constitute the major ‘working force’ for all forms of biological work. Their exact conformation and pattern of folding are tightly connected to their activity and function. Reactive oxygen and nitrogen species (ROS and RNS) are formed during normal metabolism and in higher fluxes under pathological conditions. They cause cellular damage, an important part of which is the oxidation of amino acid residues on proteins, forming protein carbonyls. Other direct modifications of protein side chains, such as o-tyrosine, chloro-, nitrotyrosine, and dityrosine, have been identified. In addition, carbohydrate and lipid derivatives can react with proteins to form adducts that can be analyzed. Protein carbonyl content (PCC) is the most widely used marker of oxidative modification of proteins. There are several methodologies for the quantitation of PCC; in all of them 2,4-dinitrophenyl hydrazine is allowed to react with the protein carbonyls to form the corresponding hydrazone, which can be analyzed optically by radioactive counting or immunohistochemically. Using PCC as a marker, it could be demonstrated that oxidative damage to proteins correlates well with aging and the severity of some diseases. A critical evaluation of PCC and other markers of protein oxidation is presented, together with examples of protein oxidation in diabetes, neurodegenerative diseases, and aging.

Free Radic Res. 2000 Nov;33 Suppl:S99-108

Age-associated decrease in proteasome content and activities in human dermal fibroblasts: restoration of normal level of proteasome subunits reduces aging markers in fibroblasts from elderly persons.

We measured proteasome activities and the levels of proteasome subunits in dermal fibroblasts from individuals aged 20-82 years. Proteasome activities changed with age in a biphasic manner, decreasing significantly up to 50 years of age and showing no significant change between 50 and 78 years of age. Similarly, proteasome activities in replicatively senescent dermal fibroblasts showed a passage-dependent biphasic change. We confirmed that the decreases in proteasome activities were accompanied by the accumulation of oxidized and ubiquitinated proteins. The decline in proteasome activities in aging fibroblasts was associated with a decrease in the expression of proteasome subunits. We found that the restoration of the normal level of proteasome catalytic subunits, using a lentivirus gene-delivery system, decreased the severity of the aging markers in dermal fibroblasts from elderly donors. These findings suggest that proteasome malfunction may contribute to the aging process in human skin and that the maintenance of normal proteasome activities could delay skin aging.

J Gerontol A Biol Sci Med Sci. 2007 May;62(5):490-9

Proteasomal dysfunction and endoplasmic reticulum stress enhance trafficking of prion protein aggregates through the secretory pathway and increase accumulation of pathologic prion protein.

A conformational change of the cellular prion protein (PrP(c)) underlies formation of PrP(Sc), which is closely associated with pathogenesis and transmission of prion diseases. The precise conformational prerequisites and the cellular environment necessary for this post-translational process remain to be completely elucidated. At steady state, glycosylated PrP(c) is found primarily at the cell surface, whereas a minor fraction of the population is disposed of by the ER-associated degradation-proteasome pathway. However, chronic ER stress conditions and proteasomal dysfunctions lead to accumulation of aggregation-prone PrP molecules in the cytosol and to neurodegeneration. In this study, we challenged different cell lines by inducing ER stress or inhibiting proteasomal activity and analyzed the subsequent repercussion on PrP metabolism, focusing on PrP in the secretory pathway. Both events led to enhanced detection of PrP aggregates and a significant increase of PrP(Sc) in persistently prion-infected cells, which could be reversed by overexpression of proteins of the cellular quality control. Remarkably, upon proteasomal impairment, an increased fraction of misfolded, fully glycosylated PrP molecules traveled through the secretory pathway and reached the plasma membrane. These findings suggest a novel pathway that possibly provides additional substrate and template necessary for prion formation when protein clearance by the proteasome is impaired.

J Biol Chem. 2011 Sep 30;286(39):33942-53

The Jujube (Ziziphus Jujuba Mill.) Fruit: A Review of Current Knowledge of Fruit Composition and Health Benefits.

The nutritional jujube (Ziziphus jujube Mill.) fruit belonging to the Rhamnaceous family grows mostly in Europe, southern and eastern Asia, and Australia, especially the inland region of north China. Jujube has a long history of usage as a fruit and remedy. The main biologically active components are vitamin C, phenolics, flavonoids, triterpenic acids and polysaccharides. Recent phytochemical studies of jujube fruits have shed some light on their biological effects, such as the anticancer-, antiinflammatory-, antiobesity-, immunostimulating-, antioxidant-, hepatoprotective-, gastrointestinal protective activities and inhibition of foam cell
formation in macrophages. A stronger focus on clinical studies and phytochemical definition of jujube fruits will be essential for future research efforts. This review may be useful for predicting other medicinal uses, potential drug or food interactions and may be beneficial for people living where the jujube fruits are prevalent and healthcare resources are scarce.

J Agric Food Chem. 2013 Mar 12

Free radicals and extrinsic skin aging.

Human skin is constantly directly exposed to the air, solar radiation, environmental pollutants, or other mechanical and chemical insults, which are capable of inducing the generation of free radicals as well as reactive oxygen species (ROS) of our own metabolism. Extrinsic skin damage develops due to several factors: ionizing radiation, severe physical and psychological stress, alcohol intake, poor nutrition, overeating, environmental pollution, and exposure to UV radiation (UVR). It is estimated that among all these environmental factors, UVR contributes up to 80%. UV-induced generation of ROS in the skin develops oxidative stress, when their formation exceeds the antioxidant defence ability of the target cell. The primary mechanism by which UVR initiates molecular responses in human skin is via photochemical generation of ROS mainly formation of superoxide anion (O(2) (-) (·)), hydrogen peroxide (H(2)O(2)), hydroxyl radical (OH(·)), and singlet oxygen ((1)O(2)). The only protection of our skin is in its endogenous protection (melanin and enzymatic antioxidants) and antioxidants we consume from the food (vitamin A, C, E, etc.). The most important strategy to reduce the risk of sun UVR damage is to avoid the sun exposure and the use of sunscreens. The next step is the use of exogenous antioxidants orally or by topical application and interventions in preventing oxidative stress and in enhanced DNA repair.

Dermatol Res Pract. 2012;2012:135206

Oleuropein in olive and its pharmacological effects.

Olive from Olea europaea is native to the Mediterranean region and, both the oil and the fruit are some of the main components of the Mediterranean diet. The main active constituents of olive oil include oleic acid, phenolic constituents, and squalene. The main phenolic compounds, hydroxytyrosol and oleuropein, give extra-virgin olive oil its bitter, pungent taste. The present review focuses on recent works that have analyzed the relationship between the major phenolic compound oleuropein and its pharmacological activities including antioxidant, anti-inflammatory, anti-atherogenic, anti-cancer activities, antimicrobial activity, antiviral activity, hypolipidemic and hypoglycemic effect.

Sci Pharm. 2010;78(2):133-54

Sebaceous gland carcinoma of the eyelid.

Sebaceous gland carcinoma, commonly arises in the periocular area, is an uncommon condition. It represents 1-5.5% of eyelid malignancies and is considered to be the third most common eyelid malignancy after basal cell and squamous cell carcinomas, although few reports placed this tumor as second most common after basal cell carcinoma. It usually affects elderly women and characterized by high rate of local recurrence, regional, and distant metastases. A delay in diagnosis, which can be attributed primarily to ability of this tumor to masquerade as more benign conditions, often leads to inappropriate management with increased morbidity and mortality rates. In this study, the authors discuss key elements of the primary disease and therapeutic options available to treat such devastating problem.

Oman J Ophthalmol. 2010 Sep;3(3):117-21

Influence of facial skin attributes on the perceived age of Caucasian women.

BACKGROUND AND OBJECTIVE: The facial appearance of a person does not always reflect the chronological age; some people look younger or older than they really are. Many studies have described the changes in skin properties (colour, wrinkles, sagging, micro relief, etc.) with age, but few of them have analysed their influence on the perceived age. The primary objective of this study was to assess the contribution of individual skin attributes of the face on the perceived age of Caucasian women. Secondary objectives were to assess the influence of age and gender of graders with regard to the age perception. SUBJECTS AND METHOD: A random sample of 173 subjects of 20 to 74 years of age was taken from a database of more than 5,000 healthy Caucasian women. A trained grader performed visual assessment of facial skin attributes (using a visual analogue scale), and a front face photograph was taken from each subject. Photographs were shown to 48 graders (20 men and 28 women, aged 22-64 years) who were asked to estimate the age of the subjects. Graders were classified as young (less than 35 years), middle age (35-50 years) and seniors (older than 50 years). Partial Least Square regression models were built to predict the chronological and the perceived age from the measured facial individual attributes. The contribution of each attribute within the regression model enabled to measure the relevance of this attribute with regards to age prediction. RESULTS: The eye area and the skin colour uniformity were the main attributes related to perceived age. For age prediction, older graders’ estimations were more driven by lips border definition shape and eyes opening, whereas younger graders’ (older than 50 years) estimations were more driven by dark circles, nasolabial fold and brown spots. There were statistically significant differences in graders’ age perception between gender and among age ranges. Our findings suggest that female graders are more accurate than male, and younger graders (under 35 years) are more accurate than older (over 50 years) to predict Caucasian women age from facial photographs. CONCLUSIONS: Different skin attributes influence the estimation of age. These attributes have a different weight in the evaluation of the perceived age, depending on the age and of the observer. The most important attributes to estimate age are eyes, lips and skin colour uniformity.

J Eur Acad Dermatol Venereol. 2008 Aug;22(8):982-91

Consumption of a boiled Greek type of coffee is associated with improved endothelial function: The Ikaria Study.

Objective: The association of coffee consumption with cardiovascular disease remains controversial. Endothelial function is associated with cardiovascular risk. We examined the association between chronic coffee consumption and endothelium function in elderly inhabitants of the island of Ikaria. Methods: The analysis was conducted on 142 elderly subjects (aged 66-91 years) of the Ikaria Study. Endothelial function was evaluated by ultrasound measurement of flow-mediated dilation (FMD). Coffee consumption was evaluated based on a food frequency questionnaire and was categorized as ‘low’ (< 200 ml/day), ‘moderate’ (200-450 ml/day), or ‘high’ (> 450 ml/day). Results: From the subjects included in the study, 87% consumed a boiled Greek type of coffee. Moreover, 40% had a ‘low’, 48% a ‘moderate’ and 13% a ‘high’ daily coffee consumption. There was a linear increase in FMD according to coffee consumption (‘low’: 4.33 ± 2.51% vs ‘moderate’: 5.39 ± 3.09% vs ‘high’: 6.47 ± 2.72%; p = 0.032). Moreover, subjects consuming mainly a boiled Greek type of coffee had a significantly higher FMD compared with those consuming other types of coffee beverages
(p = 0.035). Conclusions: Chronic coffee consumption is associated with improved endothelial function in elderly subjects, providing a new connection between nutrition and vascular health.

Vasc Med. 2013 Mar 18

Coffee and its consumption: benefits and risks.

Coffee is the leading worldwide beverage after water and its trade exceeds US $10 billion worldwide. Controversies regarding its benefits and risks still exist as reliable evidence is becoming available supporting its health promoting potential; however, some researchers have argued about the association of coffee consumption with cardiovascular complications and cancer insurgence. The health-promoting properties of coffee are often attributed to its rich phytochemistry, including caffeine, chlorogenic acid, caffeic acid, hydroxyhydroquinone (HHQ), etc. Many research investigations, epidemiological studies, and meta-analyses regarding coffee consumption revealed its inverse correlation with that of diabetes mellitus, various cancer lines, Parkinsonism, and Alzheimer’s disease. Moreover, it ameliorates oxidative stress because of its ability to induce mRNA and protein expression, and mediates Nrf2-ARE pathway stimulation. Furthermore, caffeine and its metabolites help in proper cognitive functionality. Coffee lipid fraction containing cafestol and kahweol act as a safeguard against some malignant cells by modulating the detoxifying enzymes. On the other hand, their higher levels raise serum cholesterol, posing a possible threat to coronary health, for example, myocardial and cerebral infarction, insomnia, and cardiovascular complications. Caffeine also affects adenosine receptors and its withdrawal is accompanied with muscle fatigue and allied problems in those addicted to coffee. An array of evidence showed that pregnant women or those with postmenopausal problems should avoid excessive consumption of coffee because of its interference with oral contraceptives or postmenopausal hormones. This review article is an attempt to disseminate general information, health claims, and obviously the risk factors associated with coffee consumption to scientists, allied stakeholders, and certainly readers.

Crit Rev Food Sci Nutr. 2011 Apr;51(4):363-73

Coffee consumption and risk of stroke in women.

BACKGROUND: Data on the association between coffee consumption and risk of stroke are sparse. We assessed the association between coffee consumption and the risk of stroke over 24 years of follow-up in women. METHODS AND RESULTS: We analyzed data from a prospective cohort of 83,076 women in the Nurses’ Health Study without history of stroke, coronary heart disease, diabetes, or cancer at baseline. Coffee consumption was assessed first in 1980 and then repeatedly every 2 to 4 years, with follow-up through 2004. We documented 2,280 strokes, of which 426 were hemorrhagic, 1,224 were ischemic, and 630 were undetermined. In multivariable Cox regression models with adjustment for age, smoking status, body mass index, physical activity, alcohol intake, menopausal status, hormone replacement therapy, aspirin use, and dietary factors, the relative risks (RRs) of stroke across categories of coffee consumption (<1 cup per month, 1 per month to 4 per week, 5 to 7 per week, 2 to 3 per day, and >or=4 per day) were 1, 0.98 (95% CI, 0.84 to 1.15), 0.88 (95% CI, 0.77 to 1.02), 0.81 (95% CI, 0.70 to 0.95), and 0.80 (95% CI, 0.64 to 0.98) (P for trend=0.003). After further adjustment for high blood pressure, hypercholesterolemia, and type 2 diabetes, the inverse association remained significant. The association was stronger among never and past smokers (RR for >or=4 cups a day versus <1 cup a month, 0.57; 95% CI, 0.39 to 0.84) than among current smokers (RR for >or=4 cups a day versus <1 cup a month, 0.97; 95% CI, 0.63 to 1.48). Other drinks containing caffeine such as tea and caffeinated soft drinks were not associated with stroke. Decaffeinated coffee was associated with a trend toward lower risk of stroke after adjustment for caffeinated coffee consumption (RR for >or=2 cups a day versus <1 cup a month, 0.89; 95% CI, 0.73 to 1.08; P for trend=0.05). CONCLUSIONS: Long-term coffee consumption was not associated with an increased risk of stroke in women. In contrast, our data suggest that coffee consumption may modestly reduce risk of stroke.

Circulation. 2009 Mar 3;119(8):1116-23

Coffee consumption and the risk of heart failure in Finnish men and women.

OBJECTIVES: To evaluate the association of coffee consumption with the risk of heart failure (HF) in the Finnish population. DESIGN: Prospective population-based cohort study. SETTING: This study, which is a part of FINRISK study, was carried out in Finland. SUBJECTS: Study cohorts included 59,490 Finnish participants aged 25-74 years who were free of HF at baseline. MAIN OUTCOME MEASURES: HF (2,020 men and 1,807 women) during a mean follow-up of 19.2 years. RESULTS: Multivariable-adjusted (age, study year, body mass index, smoking, education, alcohol consumption, tea consumption, physical activity, systolic blood pressure, history of myocardial infarction, history of valvular heart disease, history of diabetes and total cholesterol) HRs (with 95% CI) of HF associated with the amount of coffee consumption daily (0, 1-2, 3-4, 5-6, 7-9 and ≥10 cups) were 1.00, 0.91 (0.71 to 1.16), 0.88 (0.70 to 1.10), 0.91 (0.73 to 1.13), 0.96 (0.76 to 1.22) and 1.02 (0.80 to 1.30) (p(trend) = 0.485) for men and 1.00, 0.73 (0.56 to 0.97), 0.77 (0.60 to 0.98), 0.68 (0.53 to 0.88), 0.80 (0.61 to 1.04) and 0.88 (0.65 to 1.19) (p(trend) = 0.007) for women, respectively. Stratification by age, smoking status, alcohol consumption, history of type 2 diabetes mellitus and body mass index gave similar results. CONCLUSION: Coffee consumption does not increase the risk of HF in Finnish men and women. In women, an inverse association was observed between low to moderate coffee consumption and the risk of HF.

Heart. 2011 Jan;97(1):44-8

Habitual coffee consumption and risk of heart failure: a dose-response meta-analysis.

BACKGROUND: There have been discrepant findings on the association between coffee consumption and risk of incident heart failure. METHODS AND RESULTS: We conducted a systematic review and a dose-response meta-analysis of prospective studies that assessed the relationship between habitual coffee consumption and the risk of heart failure. We searched electronic databases (MEDLINE, Embase, and CINAHL) from January 1966 through December 2011, with the use of a standardized protocol. Eligible studies were prospective cohort studies that examined the association of coffee consumption with incident heart failure. Five independent prospective studies of coffee consumption and heart failure risk, including 6,522 heart failure events and 140,220 participants, were included in the meta-analysis. We observed a statistically significant J-shaped relationship between coffee and heart failure. Compared with no consumption, the strongest inverse association was seen for 4 servings/day and a potentially higher risk at higher levels of consumption. There was no evidence that the relationship between coffee and heart failure risk varied by sex or by baseline history of myocardial infarction or diabetes. CONCLUSIONS: Moderate coffee consumption is inversely associated with risk of heart failure, with the largest inverse association observed for consumption of 4 servings per day.

Circ Heart Fail. 2012 Jul 1;5(4):401-5

Possible mechanism of preventive effects of coffee intake on the formation of arterial occlusive thrombosis.

BACKGROUND: Prevalence and incidence of arterial occlusive thrombosis are influenced by life-style. Coffee consumption was shown with a lower incidence of myocardial infarction by Framingham Study. Yet, the mechanism is to be elucidated. METHODS: We examined the effects of coffee intake on the progression of occlusive thrombus formation in mouse cremasteric arteries. After 7 days of free intake of pure water, coffee containing water (5 mg/ml), or caffeine containing water (0.1 mg/ml), endothelial cell function was locally damaged by FeCl3. Circulating platelet and leukocytes were rendered fluorescently by rhodamine 6G. Process of occlusive thrombus growth was continuously visualized by 3-D imaging system equipped with ultra-fast confocal microscopy, and time to vascular occlusion was measured in each mouse. RESULTS: Platelet accumulation started immediately after FeCl3 exposure in all tested groups. However, arterial occlusion time in taking coffee containing water was significantly longer than those taking pure water. (46.0 ± 17.4 min (n = 5) vs. 12.3 ± 2.6 min (n = 31), p < 0.05) Arterial occlusion time in mice taking caffeine (13.8 ± 5.9 min (n = 4)) was not different from those taking pure water. CONCLUSION: Coffee, but not caffeine intake, may have preventive effect on arterial occlusive thrombus formation initiated by functional injury of arterial endothelium.

Tokai J Exp Clin Med. 2010 Dec 20;35(4):133-6

Coffee intake and risk of type 2 diabetes: the Multiethnic Cohort.

OBJECTIVE: We evaluated the influence of coffee consumption on diabetes incidence among the Hawaii component of the Multiethnic Cohort (MEC). DESIGN: Prospective cohort. SETTING: Population-based sample residing in Hawaii. SUBJECTS: After exclusions, 75,140 men and women of Caucasian, Japanese American and Native Hawaiian ancestry aged 45-75 years were part of the current analysis. All participants provided information on diet and lifestyle through an FFQ. After 14 years of follow-up 8,582 incident diabetes cases were identified using self-reports, medication questionnaires and health plan linkages. Hazard ratios (HR) and 95% confidence intervals were calculated using Cox regression while adjusting for known ovariates. RESULTS: The risk for diabetes associated with total coffee consumption differed by sex (P interaction < 0·0001). Women consuming ≥3 cups of any type of coffee daily had a significantly lower risk (HR = 0·66; 95% CI 0·58, 0·77; P trend < 0·0001) than those reporting <1 cup/d, whereas the relationship in men was borderline (HR = 0·89; 95% CI 0·80, 0·99; P trend = 0·09). The same difference by sex was seen for regular coffee consumption, with HR of 0·65 (95% CI 0·54, 0·78; P trend < 0·0001) and 0·86 (95% CI 0·75, 0·98; P trend = 0·09) in men and women, respectively. No significant association with diabetes was apparent for decaffeinated coffee in women (HR = 0·85; 95% CI 0·72, 1·01; P trend = 0·73) or men (HR = 1·07; 95% CI 0·93, 1·23; P trend = 0·71). Despite small differences by ethnicity, the interaction terms between coffee intake and ethnicity were not significant. CONCLUSIONS: In this multiethnic population, regular, but not decaffeinated, coffee intake was much more protective against diabetes in women of all ethnic groups than in men.

Public Health Nutr. 2013 Feb 27:1-9

Coffee prevents early events in tamoxifen-treated breast cancer patients and modulates hormone receptor status.

PURPOSE: Whether coffee modulates response to endocrine therapy in breast cancer patients is currently unknown. The CYP1A2 and CYP2C8 enzymes contribute to tamoxifen and caffeine metabolism. The purpose was to investigate the impact of coffee consumption on tumor characteristics and risk for early events in relation to breast cancer treatment and CYP1A2 and CYP2C8 genotypes. METHODS: Questionnaires regarding lifestyle were completed preoperatively by 634 patients in southern Sweden. CYP1A2*1F and CYP2C8*3 were genotyped. Clinical data and tumor characteristics were obtained from patients’ charts, population registries, and pathology reports. Coffee consumption was categorized as low (0-1 cups/day), moderate (2-4 cups/day), or high (5+ cups/day). RESULTS: The proportion of estrogen receptor negative (ER-) tumors increased with increasing coffee consumption (p (trend) = 0.042). Moderate to high consumption was associated with lower frequency of discordant receptor status (ER + PgR-) OR 0.38 (0.23-0.63) compared to low consumption. Median follow-up time was 4.92 (IQR 3.01-6.42) years. Tamoxifen-treated patients with ER+ tumors (n = 310) who consumed two or more cups/day had significantly decreased risk for early events compared to patients with low consumption, adjusted HR 0.40 (0.19-0.83). Low consumption combined with at least one CYP1A2*1F C-allele (n = 35) or CYP2C8*3 (n = 13) was associated with a high risk for early events in tamoxifen-treated patients compared to other tamoxifen-treated patients, adjusted HRs 3.49 (1.54-7.91) and 6.15 (2.46-15.36), respectively. CONCLUSION: Moderate to high coffee consumption was associated with significantly decreased risk for early events in tamoxifen-treated patients and modified hormone receptor status. If confirmed, new recommendations regarding coffee consumption during tamoxifen treatment may be warranted.

Cancer Causes Control. 2013 Feb 15

Caffeine intake is associated with a lower risk of cognitive decline: a cohort study from Portugal.

Alzheimer’s disease has emerged in recent decades as a major health problem and the role of lifestyles in the modulation of risk has been increasingly recognized. Recent epidemiological studies suggest a protective effect for caffeine intake in dementia. We aimed to quantify the association between caffeine dietary intake and cognitive decline, in a cohort of adults living in Porto. A cohort of 648 subjects aged > or =65 years was recruited between 1999-2003. Follow-up evaluation (2005-2008) was carried out on 58.2% of the eligible participants and 10.9% were deceased. Caffeine exposure in the year preceding baseline evaluation was assessed with a validated food frequency questionnaire. Cognitive evaluation consisted of baseline and follow-up Mini-Mental State Examination (MMSE). Cognitive decline was defined by a decrease > or =2 points in the MMSE score between evaluations. Relative risk (RR) and 95% confidence interval (95%CI) estimates adjusted for age, education, smoking, alcohol drinking, body mass index, hypertension, and diabetes were computed using Poisson regression. Caffeine intake (> 62 mg/day [3rd third] vs. < 22 mg/day [1st third]) was associated with a lower risk of cognitive decline in women (RR=0.49, 95%CI 0.24-0.97), but not significantly in men (RR=0.65, 95%CI 0.27-1.54). Our study confirms the negative association between caffeine and cognitive decline in women.

J Alzheimers Dis. 2010;20 Suppl 1:S175-85