UCP1: The Original Uncoupling Protein—and Perhaps the Only One? New Perspectives on UCP1, UCP2, and UCP3 in the Light of the Bioenergetics of the UCP1-Ablated Mice

The availability of a UCP1-ablated mouse has enabled critical studies of the function of UCP1,UCP2, and UCP3. Concerning UCP1, its presence in brown-fat mitochondria is associatedwith innate uncoupling, high GDP-binding capacity, and GDP-inhibitable Cl^- permeabilityand uncoupling—but the high fatty acid sensitivity found in these mitochondria is observedeven in the absence of UCP1. The absence of UCP1 leads to low cold tolerance but not toobesity. UCP1 ablation also leads to an augmented expression of UCP2 and UCP3 in brownadipose tissue, making this tissue probably the one that boasts the highest expression ofthese UCPs. However, these very high expression levels are not associated with any inherentuncoupling, or with a specific GDP-binding capacity, or with a GDP-sensitive Cl^- permeability,or with any effect of GDP on mitochondrial membrane potential, or with an increased basalmetabolism of cells, or with the presence of norepinephrine- or fatty acid-induced thermogenesisin cells, and not with a cold-acclimation recruited, norepinephrine-induced thermogenicresponse in the intact animal. Therefore, it can be discussed whether any uncoupling effect isassociated with UCP2 or UCP3 when they are endogenously expressed and, consequently,whether (loss of) uncoupling (thermogenic) effects of UCP2 or UCP3 can be invoked toexplain metabolic phenomena, such as obesity.     

Uncoupling Protein 2 (UCP2) Function in the Brain as Revealed by the Cerebral Metabolism of (1–<Superscript>13</Superscript>C)-Glucose

The mitochondrial aspartate/glutamate transporter Aralar/AGC1/Slc25a12 is critically involved in brain aspartate synthesis, and AGC1 deficiency results in a drastic fall of brain aspartate levels in humans and mice. It has recently been described that the uncoupling protein UCP2 transports four carbon metabolites including aspartate. Since UCP2 is expressed in several brain cell types and AGC1 is mainly neuronal, we set to test whether UCP2 could be a mitochondrial aspartate carrier in the brain glial compartment. The study of the cerebral metabolism of (1–¹³C)-glucose in vivo in wild type and UCP2-knockout mice showed no differences in C3 or C2 labeling of aspartate, suggesting that UCP2 does not function as a mitochondrial aspartate carrier in brain. However, surprisingly, a clear decrease (of about 30–35?%) in the fractional enrichment of glutamate, glutamine and GABA was observed in the brains of UCP2-KO mice which was not associated with differences in either glucose or lactate enrichments. The results suggest that the dilution in the labeling of glutamate and its downstream metabolites could originate from the uptake of an unlabeled substrate that could not leave the matrix via UCP2 becoming trapped in the matrix. Understanding the nature of the unlabeled substrate and its precursor(s) as alternative substrates to glucose is of interest in the context of neurological diseases associated with UCP2.     

Women’s Satisfaction with Body Image before Pregnancy and Body Mass Index 4 Years after Delivery in the Mothers of Generation XXI

Background

Body image satisfaction (BIS) influences body weight regulation and may contribute to long-term healthier lifestyle after pregnancy. Thus, we aimed to assess the association between BIS before pregnancy and body mass index (BMI) 4 years after the index pregnancy.

Methods

As part of the follow-up of a birth cohort, 3612 women with prepregnancy BMI >18.5 kg/m² were reevaluated 4 years after the birth of a child. BIS was defined as the difference between perceived and ideal body size before pregnancy, assessed by Stunkard Silhouettes after birth. The associations of BIS with BMI change (continuous) and BMI classes at 4 years, based on measured weight and height, were estimated using linear and multinomial regression, respectively.

Results

Among women with normal prepregnancy BMI, those who felt too small, regarding their ideal, had a 0.25 kg/m² smaller increase in BMI within 4 years and a lower likelihood of becoming overweight or obese [multivariate-adjusted odds ratio (OR) = 0.63; 95% confidence interval (95%CI): 0.44–0.91 and OR = 0.21; 95%CI: 0.05–0.91, respectively) than those satisfied with body image. Feeling too large was associated with a 0.41 kg/m² larger increase in BMI and a higher risk of becoming overweight or obese (OR = 2.12; 95%CI:1.73–2.59 and OR = 3.42; 95%CI:2.02–5.79, respectively). A similar, non-significant, trend was observed for overweight women. Obese women who felt too large had a non-significant decrease in BMI.

Conclusions

BIS plays a role in maternal body weight after delivery. Realistic body size goals may promote the motivation to lose weight and contribute to higher success in attaining them.     

Association of Six Well-Characterized Polymorphisms in TNF-α and TNF-β Genes with Sarcoidosis: A Meta-Analysis

Backgrounds

In this study, we aimed to investigate the association of six well-characterized polymorphisms in tumor necrosis factor alpha and beta (TNF-α and TNF-β) genes with the risk for sarcoidosis via a comprehensive meta-analysis.

Methods And Findings

The electronic MEDLINE (Ovid) and PubMed databases covering the period from the earliest possible year to June 2013 were searched. Total 13 qualified articles including 1584 patients with sarcoidosis and 2636 controls were recruited. The data were analyzed by RevMan software, and risk estimates were expressed as odds ratios (ORs) and 95% confidence intervals (95% CIs). Analyses of the full data set failed to identify any significant association of TNF-α gene -307A (OR=1.25; 95% CI: 0.98-1.59), -1031C (OR=0.88; 95% CI: 0.71-1.1), -863A (OR=0.89; 95% CI: 0.72-1.11), -238A (OR=0.97; 95% CI: 0.71-1.32), and -857T (OR=1.14; 95% CI: 0.74-1.77) alleles, but a significant association for TNF-β 252A allele (OR=1.65; 95%CI = 1.33-2.04; P<0.00001). Under a random-effects allelic model, there was marginally significant increased risk of sarcoidosis for -307A allele among Caucasians (OR=1.25; 95% CI: 0.96-1.62; P=0.09) but not among Asians (OR=2.12; 95% CI: 0.31-14.27; P=0.44). There was a low probability of publication bias as reflected by the fail-safe number.

Conclusions

This meta-analysis extended previous findings on the association between the TNF-α and TNF-β genetic polymorphisms and sarcoidosis, by showing that the TNF-β gene A252G polymorphism might be a potential risk factor for the development of sarcoidosis.     

Polymorphic Variants of the Renin–Angiotensin System Genes in the Polymetabolic Syndrome and Non-Insulin-Dependent Diabetes Mellitus

Polymorphisms of the genes for angiotensin-converting enzyme (ACE) and angiotensinogen, the proteins of the renin–angiotensin system (RAS), were tested for association with the polymetabolic syndrome (PMS) and non-insulin-dependent diabetes mellitus (NIDDM) in the Moscow population. The insertional (I) allele and the IIgenotypeof the ACE gene proved to be associated with PMS. A significant difference in allele and genotype frequency distributions of the (CA) _n microsatellite of the 3"-untranslated exon of the angiotensinogen gene was revealed between randomly sampled individuals and patients with PMS and IDDM from the Moscow population.     

Uncoupling proteins (UCP) in unicellular eukaryotes: True UCPs or UCP1-like acting proteins?

Uncoupling proteins belong to the superfamily of mitochondrial anion carriers. They are apparently present throughout the Eukarya domain in which only some members have an established physiological function, i.e. UCP1 from brown adipose tissue is involved in non-shivering thermogenesis. However, the proteins responsible for the phenotype observed in unicellular organisms have not been characterized. In this report we analyzed functional evidence concerning unicellular UCPs and found that true UCPs are restricted to some taxonomical groups while proteins conferring a UCP1-like phenotype to fungi and most protists are the result of a promiscuous activity exerted by other mitochondrial anion carriers. We describe a possible evolutionary route followed by these proteins by which they acquire this promiscuous mechanism.     

Influence of Body Mass Index on the Prognostic Value of Tumor 1?F-FDG Uptake in Stage I Non-Small Cell Lung Cancer

Background

The impact of host energy balance status on outcome of lung cancer has not been fully explored. It is also unknown if there is a potential modifying effect of body mass index (BMI) on tumor cell behavior in patients with early-stage non-small cell lung cancer (NSCLC). We therefore investigated the interactive effects of tumor [¹⁸F]-fluorodeoxyglucose (FDG) avidity and BMI.

Methods

We investigated 1,197 patients with stage I NSCLC who underwent preoperative FDG positron emission tomography followed by curative resection. The primary outcome measure was disease-free survival (DFS). A multivariable Cox proportional hazards model was used to assess the potential independent effects of the prognostic variables. A stratified Cox regression analysis was also performed to assess the potential modifying effects of BMI on the relationship between tumor FDG uptake and patient survival.

Results

There were 145 tumor recurrences and 19 deaths during a median follow-up of 30 months. Tumor-related variables, including tumor size, maximum standardized uptake value (SUVmax), histologic cell type, differentiation, lymphovascular invasion, and visceral pleural invasion, did not differ significantly according to BMI status. In multivariable Cox regression analysis, overweight or obesity [hazard ratio (HR), 0.59; 95% CI, 0.43–0.81; P = 0.001] and tumor SUVmax (HR, 1.72; 95% CI, 1.43–2.07; P < 0.001) were significantly associated with DFS. There was a significant modifying effect of BMI (P for interaction < 0.001 in multivariable analysis). High tumor SUVmax was more strongly associated with worse DFS in normal weight patients (HR, 4.72; 95% CI, 2.77–8.06; P < 0.001) than in overweight or obese patients (HR, 2.61; 95% CI, 1.58–4.31; P < 0.001).

Conclusions

Tumor FDG avidity is an independent predictor of DFS in patients with early-stage NSCLC and this prognostic value was strengthened in normal weight patients than in overweight or obese patients. These results suggest that the host-tumor interaction between host energy balance status and tumor glucose metabolism plays an important role in the outcome of early-stage NSCLC.     

Association of eNOS and MCP-1 Genetic Variants with Type 2 Diabetes and Diabetic Nephropathy Susceptibility: A Case–Control and Meta-Analysis Study

Type 2 diabetes (T2D) and its secondary complications result from the complex interplay of genetic and environmental factors. To understand the role of these factors on disease susceptibility, the present study was conducted to assess the association of eNOS and MCP-1 variants with T2D and diabetic nephropathy (DN) in two ethnically and geographically different cohorts from North India. A total of 1313 subjects from two cohorts were genotyped for eNOS (rs2070744, rs869109213 and rs1799983) and MCP-1 (rs1024611 and rs3917887) variants. Cohort-I (Punjab) comprised 461 T2D cases (204 T2D with DN and 257 T2D without DN) and 315 healthy controls. Cohort-II (Jammu and Kashmir) included 337 T2D (150 T2D with DN and 187 T2D without DN) and 200 controls. Allele, genotype and haplotype frequencies were compared among the studied participants, and phenotype–genotype interactions were determined. Meta-analysis was performed to investigate the association between the selected variants and disease susceptibility. All three eNOS variants were associated with 1.5–4.0-fold risk of DN in both cohorts. MCP-1 rs1024611 conferred twofold risk towards DN progression in cohort-II, while rs3917887 provided twofold risk for both T2D and DN in both cohorts. eNOS and MCP-1 haplotypes conferred risk for T2D and DN susceptibility. Phenotype–genotype interactions showed significant associations between the studied variants and anthropometric and biochemical parameters. In meta-analysis, all eNOS variants conferred risk towards DN progression, whereas no significant association was observed for MCP-1 rs1024611. We show evidences for an association of eNOS and MCP-1 variants with T2D and DN susceptibility.

     

Association of the UCP polymorphisms with susceptibility to obesity: case–control study and meta-analysis

This paper describes a case–control study and a meta-analysis performed to evaluate if the following polymorphisms are associated with presence of obesity: ?3826A/G (UCP1); ?866G/A, Ala55Val and Ins/Del (UCP2) and ?55C/T (UCP3). The case–control study enrolled 282 obese and 483 non-obese patients with type 2 diabetes. A literature search was made to identify all studies that evaluated associations between UCP1–3 polymorphisms and obesity. In the case–control study the distributions of the UCP variants did not differ between obese and non-obese groups (P > 0.05). Forty-seven studies were eligible for the meta-analysis and the results showed that the UCP2 ?866G/A and UCP3 ?55C/T polymorphisms were associated with protection to obesity in Europeans (OR = 0.89, 95 % CI 0.82–0.97 and OR = 0.88, 95 % CI 0.80–0.97, respectively). The UCP2 Ala55 val polymorphism was associated with obesity in Asians (OR = 1.61, 95 % CI 1.13–2.30). The UCP2 Ins/Del polymorphism was associated with obesity mainly in Europeans (OR = 1.19, 95 % CI 1.00–1.42). There was no significant association of the UCP1 ?3826A/G polymorphism with obesity. In our case–control study we were not able to demonstrate any association between UCP polymorphisms and obesity in T2DM patients; however, in the meta-analysis we detected a significant association of UCP2 ?866G/A, Ins/Del, Ala55Val and UCP3 ?55C/T polymorphisms with obesity.     

Independent Effects of Sleep Duration and Body Mass Index on the Risk of a Work-Related Injury: Evidence From the US National Health Interview Survey (2004–2010)

Fatigue has been linked to adverse safety outcomes, and poor quality or decreased sleep has been associated with obesity (higher body mass index, BMI). Additionally, higher BMI is related to an increased risk for injury; however, it is unclear whether BMI modifies the effect of short sleep or has an independent effect on work-related injury risk. To answer this question, the authors examined the risk of a work-related injury as a function of total daily sleep time and BMI using the US National Health Interview Survey (NHIS). The NHIS is an in-person household survey using a multistage, stratified, clustered sample design representing the US civilian population. Data were pooled for the 7-yr survey period from 2004 to 2010 for 101 891 “employed” adult subjects (51.7%; 41.1?±?yrs of age [mean?±?SEM]) with data on both sleep and BMI. Weighted annualized work-related injury rates were estimated across a priori defined categories of BMI: healthy weight (BMI: <25), overweight (BMI: 25–29.99), and obese (BMI: ≥30) and also categories of usual daily sleep duration: <6, 6–6.99, 7–7.99, 8–8.99, and ≥9?h. To account for the complex sampling design, including stratification, clustering, and unequal weighting, weighted multiple logistic regression was used to estimate the risk of a work-related injury. The initial model examined the interaction among daily sleep duration and BMI, controlling for weekly working hours, age, sex, race/ethnicity, education, type of pay, industry, and occupation. No significant interaction was found between usual daily sleep duration and BMI (p?=?.72); thus, the interaction term of the final logistic model included these two variables as independent predictors of injury, along with the aforementioned covariates. Statistically significant covariates (p?≤?.05) included age, sex, weekly work hours, occupation, and if the worker was paid hourly. The lowest categories of usual sleep duration (<6 and 6–6.9?h) showed significantly (p?≤?.05) elevated injury risks than the referent category (7–8?h sleep), whereas sleeping >7–8?h did not significantly elevate risk. The adjusted injury risk odds ratio (OR) for a worker with a usual daily sleep of <6?h was 1.86 (95% confidence interval [CI]: 1.37–2.52), and for 6–6.9?h it was 1.46 (95% CI: 1.18–1.80). With regards to BMI, the adjusted injury risk OR comparing workers who were obese (BMI: ≥30) to healthy weight workers (BMI: <25) was 1.34 (95% CI: 1.09–1.66), whereas the risk in comparing overweight workers (BMI: 25–29.99) to healthy weight risk was elevated, but not statistically significant (OR?=?1.08; 95% CI: .88–1.33). These results from a large representative sample of US workers suggest increase in work-related injury risk for reduced sleep regardless of worker's body mass. However, being an overweight worker also increases work-injury risk regardless of usual daily sleep duration. The independent additive risk of these factors on work-related injury suggests a substantial, but at least partially preventable, risk. (Author correspondence: david.lombardi@libertymutual.com)     

Quantitative Proteomics Reveals Protein–Protein Interactions with Fibroblast Growth Factor 12 as a Component of the Voltage-Gated Sodium Channel 1.2 (Nav1.2) Macromolecular Complex in Mammalian Brain

Voltage-gated sodium channels (Nav1.1–Nav1.9) are responsible for the initiation and propagation of action potentials in neurons, controlling firing patterns, synaptic transmission and plasticity of the brain circuit. Yet, it is the protein–protein interactions of the macromolecular complex that exert diverse modulatory actions on the channel, dictating its ultimate functional outcome. Despite the fundamental role of Nav channels in the brain, information on its proteome is still lacking. Here we used affinity purification from crude membrane extracts of whole brain followed by quantitative high-resolution mass spectrometry to resolve the identity of Nav1.2 protein interactors. Of the identified putative protein interactors, fibroblast growth factor 12 (FGF12), a member of the nonsecreted intracellular FGF family, exhibited 30-fold enrichment in Nav1.2 purifications compared with other identified proteins. Using confocal microscopy, we visualized native FGF12 in the brain tissue and confirmed that FGF12 forms a complex with Nav1.2 channels at the axonal initial segment, the subcellular specialized domain of neurons required for action potential initiation. Co-immunoprecipitation studies in a heterologous expression system validate Nav1.2 and FGF12 as interactors, whereas patch-clamp electrophysiology reveals that FGF12 acts synergistically with CaMKII, a known kinase regulator of Nav channels, to modulate Nav1.2-encoded currents. In the presence of CaMKII inhibitors we found that FGF12 produces a bidirectional shift in the voltage-dependence of activation (more depolarized) and the steady-state inactivation (more hyperpolarized) of Nav1.2, increasing the channel availability. Although providing the first characterization of the Nav1.2 CNS proteome, we identify FGF12 as a new functionally relevant interactor. Our studies will provide invaluable information to parse out the molecular determinant underlying neuronal excitability and plasticity, and extending the relevance of iFGFs signaling in the normal and diseased brain.Voltage-gated sodium channels (Nav)¹ are transmembrane proteins consisting of a pore-forming α subunit (Nav1.1-Nav1.9) and one or more accessory β-subunits (β₁–β₄) (1–3). Predominately clustered at the axonal initial segment (AIS), the α subunit alone is necessary and sufficient for channel assembly and the initiation and propagation of action potentials following membrane depolarization (4). Although the α subunit is functional on its own, it is the transient and stable protein–protein interactions that modulate subcellular trafficking, compartmentalization, functional expression, and fine-tune the channel biophysical properties (5–9). Thus, the Nav channel and the protein constituents that comprise the protein–protein interaction network are all part of a macromolecular complex that modulates the spatiotemporal dynamics of neuronal input and output playing a critical role in synaptic transmission, signal integration, and neuronal plasticity. Perturbations in this protein–protein interaction network can lead to deficits in neuronal excitability, and eventually neurodegeneration and cell death (10–15).Given the relevance of these interactions for the native channel activity and its overall role in controlling brain circuits, it is increasingly important to uncover these associations. Antibody-based affinity purification (AP) combined with mass spectrometry (MS) is widely used for the enrichment and analysis of target proteins and constituents of their protein–protein interactions as it can be performed at near physiological conditions and preserves post-translational modifications relevant to protein complex organization (16–19). Differential mass spectrometry provides an unbiased method for the efficient, MS-based measurement of relative protein fold changes across multiple complex biological samples. This technology has been successfully applied to a number of ion channels (20–26), but—to the best of our knowledge—not to the study of any member of the Nav channel family. Using a target-directed AP approach combined with quantitative MS, we identified proteins constituting the putative interactome of Nav1.2, one of three dominant Nav channel isoforms in the mammalian brain, from native tissue (1, 2, 4, 8). Among these putative interactors, the fibroblast growth factor 12 (FGF12), a member of the intracellular FGF family (5, 13, 14), stood out as one of the most abundant coprecipitating proteins with ∼30-fold enrichment over other interactors. With a combination of confocal microscopy in brain tissue, reconstitution of the interactor in a heterologous systems and electrophysiological assays, we provide validation for FGF12 as a bona fide relevant component of the Nav1.2 proteome and a modulator of Nav1.2-encoded currents. Altogether, the identified channel/protein interaction between FGF12 and Nav1.2 provides new insights for structural and functional interpretation of neuronal excitability, synaptic transmission, and plasticity in the normal and diseased brain.     

The Dose–Response Decrease in Heart Rate Variability: Any Association with the Metabolites of Polycyclic Aromatic Hydrocarbons in Coke Oven Workers?

BackgroundAir pollution has been associated with an increased risk of cardiopulmonary mortality and decreased heart rate variability (HRV). However, it is unclear whether coke oven emissions (COEs) and polycyclic aromatic hydrocarbons (PAHs) are associated with HRV.ObjectivesOur goal in the present study was to investigate the association of exposure to COEs and the urinary metabolite profiles of PAHs with HRV of coke oven workers.MethodsWe measured benzene soluble matter, carbon monoxide, sulfur dioxide, particulate matters, and PAHs at different workplaces of a coke oven plant. We determined 10 urinary PAH metabolites and HRV indices of 1333 workers using gas chromatography–mass spectrometry and a 3-channel digital Holter monitor, respectively.ResultsOur results showed that there was a significant COEs-related dose-dependent decrease in HRV, and an inverse relationship between the quartiles of urinary 2-hydroxynaphthalene and five HRV indices (p_trend<0.01 for all). After adjustment for potential confounders, elevation per interquartile range (IQR) (1.81 µg/mmol creatinine) of urinary 2-hydroxynaphthalene was associated with a 5.46% (95% CI, 2.50–8.32) decrease in standard deviation of NN intervals (SDNN). As workers worked more years, SDNN gradually declined in the same quartiles of 2-hydroxynaphthalene levels (p_trend = 1.40×10⁻⁴), especially in workers with the highest levels of 2-hydroxynaphthalene.ConclusionsOccupational exposure to COEs is associated with a dose-response decrease in HRV. In particular, increased exposure to 2-hydroxynaphthalene is associated with significantly decreased HRV. Increase of working years and exposure levels has resulted in a gradual decline of HRV.     

Binding of α2ML1 to the Low Density Lipoprotein Receptor-Related Protein 1 (LRP1) Reveals a New Role for LRP1 in the Human Epidermis

Background

The multifunctional receptor LRP1 has been shown to bind and internalize a large number of protein ligands with biological importance such as the pan-protease inhibitor α2-macroglobulin (α2M). We recently identified Α2ML1, a new member of the α2M gene family, expressed in epidermis. α2ML1 might contribute to the regulation of desquamation through its inhibitory activity towards proteases of the chymotrypsin family, notably KLK7. The expression of LRP1 in epidermis as well as its ability to internalize α2ML1 was investigated.

Methods and Principal Findings

In human epidermis, LRP1 is mainly expressed within the granular layer of the epidermis, which gathers the most differentiated keratinocytes, as shown by immunohistochemistry and immunofluorescence using two different antibodies. By using various experimental approaches, we show that the receptor binding domain of α2ML1 (RBDl) is specifically internalized into the macrophage-like cell line RAW and colocalizes with LRP1 upon internalization. Coimmunoprecipitation assays demonstrate that RBDl binds LRP1 at the cell surface. Addition of RAP, a universal inhibitor of ligand binding to LRP1, prevents RBDl binding at the cell surface as well as internalization into RAW cells. Silencing Lrp1 expression with specific siRNA strongly reduces RBDl internalization.

Conclusions and Significance

Keratinocytes of the upper differentiated layers of epidermis express LRP1 as well as α2ML1. Our study also reveals that α2ML1 is a new ligand for LRP1. Our findings are consistent with endocytosis by LRP1 of complexes formed between α2ML1 and proteases. LRP1 may thus control desquamation by regulating the biodisponibility of extracellular proteases.     

Genetic Structure of Blastocerus dichotomus Populations in the Paraná River Basin (Brazil) Based on Protein Variability

The population structure of 147 marsh deer (Blastocerus dichotomus) from three areas in the Paraná River basin, Brazil, was studied by observing protein polymorphism at 17 loci. Six loci were polymorphic and 11 monomorphic. The proportion of polymorphic loci (P) was 35.29% and the average heterozygosity (H) was 6.31%. Wright's F_ST indicated that only 4.9% of the total variation in allelic frequencies was due to genetic differences between the three groups. The high value of F_IS (0.246) indicated inbreeding in the marsh deer. Genetic distance values (D = 0.014–0.051) showed little divergence between the three areas. We suggest that probable mechanisms accounting for the genetic structure are female phylopatry and polygyny and also that inbreeding has resulted from decreasing areas of wetland leading to isolation, overhunting, and diseases transmitted by cattle.     

Association of the SOD2 Ala(–9)Val and SOD3 Arg213Gly Polymorphisms with Diabetic Polyneuropathy in Diabetes Mellitus Type 1

Single-nucleotide polymorphisms of the genes for mitochondrial (SOD2) and extracellular (SOD3) superoxide dismutases were tested for association with diabetic polyneuropathy (DPN) in diabetes mellitus (DM) type 1. Patients (N = 180) were divided into two groups with nonoverlapping (polar) phenotypes. Group DPN+ included 86 individuals with DPN and DM type 1 record of no more than 5 years. Group DPN– included 94 patients with DM type 1 record of more than 10 years but without clinical signs of DPN. Fisher's exact test revealed significant differences in allele and genotype frequencies for the two groups. Higher frequencies of SOD2 allele Val and genotype Val/Val and of SOD3 allele Arg and genotype Arg/Arg were established for group DPN+. On this evidence, SOD2 and SOD3 were associated with DPN in DM type 1.     

The Influence of Body Mass Index on Outcomes in Patients Undergoing Cardiac Surgery: Does the Obesity Paradox Really Exist?

Purpose

Obesity influences risk stratification in cardiac surgery in everyday practice. However, some studies have reported better outcomes in patients with a high body mass index (BMI): this is known as the obesity paradox. The aim of this study was to quantify the effect of diverse degrees of high BMI on clinical outcomes after cardiac surgery, and to assess the existence of an obesity paradox in our patients.

Methods

A total of 2,499 consecutive patients requiring all types of cardiac surgery with cardiopulmonary bypass between January 2004 and February 2009 were prospectively studied at our institution. Patients were divided into four groups based on BMI: normal weight (18.5–24.9 kg∙m⁻²; n = 523; 21.4%), overweight (25–29.9kg∙m⁻²; n = 1150; 47%), obese (≥30–≤34.9kg∙m⁻²; n = 624; 25.5%) and morbidly obese (≥35kg∙m⁻²; n = 152; 6.2%). Follow-up was performed in 2,379 patients during the first year.

Results

After adjusting for confounding factors, patients with higher BMI presented worse oxygenation and better nutritional status, reflected by lower PaO₂/FiO₂ at 24h and higher albumin levels 48h after admission respectively. Obese patients showed a higher risk for Perioperative Myocardial Infarction (OR: 1.768; 95% CI: 1.035–3.022; p = 0.037) and septicaemia (OR: 1.489; 95% CI: 1.282–1.997; p = 0.005). In-hospital mortality was 4.8% (n = 118) and 1-year mortality was 10.1% (n = 252). No differences were found regarding in-hospital mortality between BMI groups. The overweight group showed better 1-year survival than normal weight patients (91.2% vs. 87.6%; Log Rank: p = 0.029. HR: 1.496; 95% CI: 1.062–2.108; p = 0.021).

Conclusions

In our population, obesity increases Perioperative Myocardial Infarction and septicaemia after cardiac surgery, but does not influence in-hospital mortality. Although we found better 1-year survival in overweight patients, our results do not support any protective effect of obesity in patients undergoing cardiac surgery.     

The Changing Body Mass–Mortality Association in the United States: Evidence of Sex-Specific Cohort Trends from Three National Health and Nutrition Examination Surveys

The association between body mass index (BMI) categories and mortality remains uncertain. Using three National Health and Nutrition Examination Surveys covering the 1971–2006 period for cohorts born between 1896 and 1968, this study estimates separately for men and women models for year-of-birth (cohort) and year-of-observation (period) trends in how age-specific mortality rates differ across BMI categories. Among women, relative to the normal weight (BMI 18.5–24.9 kg/m²), there are increasing trends in mortality rates for the overweight (BMI 25–29.9) or obese (BMI ≥ 30). Among men, mortality rates relative to the normal weight decrease for the overweight, do not change for the moderately obese (BMI 30–34.9), and increase for the severely obese (BMI ≥ 35). Period and cohort trends are similar, but the cohort trends are more consistent. In the latest cohorts, compared with the normal weight, mortality rates are 50 percent lower for overweight men, not different for moderately obese men, and 100–200 percent higher for severely obese men and for overweight or obese women. For U.S. cohorts born after the 1920s, a lower overweight than normal weight mortality is confined to men. I speculate on possible reasons why the mortality association with overweight and obesity varies by sex and cohort.