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Objectives: For patients undergoing lobectomy for non-small cell lung cancer (NSCLC), a survival benefit exists with increased number of lymph nodes (LNs) resected. We sought to evaluate the associations of LN removal with outcomes in clinical stage I lung cancer patients undergoing wedge resection., Methods: We evaluated all patients undergoing wedge resection for peripheral, clinical stage IA NSCLC and grouped patients into those with and without LN assessment. Data were compared and survival analysed using Kaplan-Meier, with differences compared using log-rank. Propensity score matching controlling for age, gender, Charlson comorbidity index, patient tolerability of lobectomy, surgery year, tumour size and surgical approach was done (51 patients in each group, caliper 0.2)., Results: We identified196 patients undergoing wedge resection, of whom 138 patients (70%) had LNs resected (median = 4 nodes), while the remaining 58 patients (30%) had none. There were no significant differences in the clinical or pathologic characteristics between the two groups. There was no difference in terms of OR time, estimated blood loss, chest tube duration or length of stay. Median pT size was 1.5 cm in each group ( P  = 0.73). Among patients with LNs removed, 6 (4.3%) had positive nodes Patients in the LN assessed group had higher probability of freedom from loco-regional recurrence compared to the no lymph node (NLN) group (5-year: 92 vs 74%, P  = 0.025).In propensity matched groups, patients who underwent LN dissection also had higher probability of freedom from local recurrence ( P  = 0.024)., Conclusions: Accompanying wedge resection for lung cancer, LN sampling adds no morbidity and does not increase length of stay. Positive nodes are identified in 4.3% of patients thought eligible for wedge resection. LN removal appears to decrease locoregional recurrence and may be associated with a survival benefit., (© The Author 2016. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Context: Increased bone resorption predicts mortality and bone resorption heightens during critical illness. Bisphosphonates are potent inhibitors of bone resorption. Whether bisphosphonate impacts clinical outcome of intensive care unit (ICU) admission is unknown., Objective: We investigated the relationship between preadmission bisphosphonate use and clinical outcome in critically ill patients., Design: This was a retrospective hospital-based analysis., Setting: The study was conducted at a tertiary referral hospital ICU., Patients: A total of 7830 critically ill patients between 2003 and 2014 participated in the study., Interventions: The intervention included bisphosphonate treatment., Main Outcome Measures: In-hospital mortality in the main study (n = 7830) and bone density loss and biochemical and hematological changes in the mechanistic substudy (n = 111) were measured., Results: A total of 245 patients received preadmission bisphosphonate. Bisphosphonate users were older (66 ± 16 vs 58 ± 18 y, P < .01) and had greater comorbid disease burden (Charlson comorbidity index: 5.7 ± 3.6 vs 4.6 ± 3.8, P < .01), yet bisphosphonate use was associated with a lower in-hospital mortality (mortality rate ratio: 0.41, 95% confidence interval 0.24-0.71, P < .01), which remained significant after adjusting for age, sex, principal diagnosis, admitting unit, comorbidities and admission year. Bisphosphonate-associated survival benefit was independent of vitamin D, but bisphosphonate/vitamin D co-use was associated with additive reduction in mortality (mortality rate ratio 0.38, 95% confidence interval 0.20-0.71, P < .01). Bone density decreased during ICU admission (-13% ± 19% per week, P < .01) but was significantly attenuated among bisphosphonate users compared with nonusers (-3% ± 13% per week v. -15% ± 14% per week, P < .01), despite similar disease severity on admission. All bisphosphonate users in the substudy survived, whereas six nonusers died., Conclusions: Preadmission bisphosphonate use was associated with superior survival among critically ill patients. Prospective studies examining the effects of bisphosphonate in critical illness are required.

The Muller F element (4.2 Mb, ~80 protein-coding genes) is an unusual autosome of Drosophila melanogaster; it is mostly heterochromatic with a low recombination rate. To investigate how these properties impact the evolution of repeats and genes, we manually improved the sequence and annotated the genes on the D. erecta, D. mojavensis, and D. grimshawi F elements and euchromatic domains from the Muller D element. We find that F elements have greater transposon density (25-50%) than euchromatic reference regions (3-11%). Among the F elements, D. grimshawi has the lowest transposon density (particularly DINE-1: 2% vs. 11-27%). F element genes have larger coding spans, more coding exons, larger introns, and lower codon bias. Comparison of the Effective Number of Codons with the Codon Adaptation Index shows that, in contrast to the other species, codon bias in D. grimshawi F element genes can be attributed primarily to selection instead of mutational biases, suggesting that density and types of transposons affect the degree of local heterochromatin formation. F element genes have lower estimated DNA melting temperatures than D element genes, potentially facilitating transcription through heterochromatin. Most F element genes (~90%) have remained on that element, but the F element has smaller syntenic blocks than genome averages (3.4-3.6 vs. 8.4-8.8 genes per block), indicating greater rates of inversion despite lower rates of recombination. Overall, the F element has maintained characteristics that are distinct from other autosomes in the Drosophila lineage, illuminating the constraints imposed by a heterochromatic milieu., (Copyright © 2015 Leung et al.)

Context: The contribution of brown adipose tissue (BAT) to the energy balance in humans exposed to sustainable cold has not been completely established, partially because of measurement limitations of both BAT activity and energy expenditure (EE)., Objective: The objective of the study was to characterize the role of BAT activation in cold-induced thermogenesis (CIT)., Design: This study was a single-blind, randomized crossover intervention., Setting: The study was conducted at the National Institutes of Health Clinical Center., Study Participants: Thirty-one healthy volunteers participated in the study., Interventions: The intervention included mild cold exposure., Main Outcomes: CIT and BAT activation were the main outcomes in this study., Methods: Overnight EE measurement by whole-room indirect calorimeter at 24 °C or 19 °C was followed by 2-[18F]-fluoro-2-deoxy-D-glucose positron emission tomography (PET) scan. After 36 hours, volunteers crossed over to the alternate study temperature under identical conditions. BAT activity was measured in a 3-dimensional region of interest in the upper torso by comparing the uptake at the two temperatures., Results: Twenty-four volunteers (14 males, 10 females) had a complete data set. When compared with 24 °C, exposure at 19 °C resulted in increased EE (5.3 ± 5.9%, P < .001), indicating CIT response and mean BAT activity (10.5 ± 11.1%, P < .001). Multiple regression analysis indicated that a difference in BAT activity (P < .001), age (P = .01), and gender (P = .037) were independent contributors to individual variability of CIT., Conclusions: A small reduction in ambient temperature, within the range of climate-controlled buildings, is sufficient to increase human BAT activity, which correlates with individual CIT response. This study uncovers for the first time a spectrum of BAT activation among healthy adults during mild cold exposure not previously recognized by conventional PET and PET-computed tomography methods. The enhancement of cold-induced BAT stimulation may represent a novel environmental strategy in obesity treatment.

Brown adipose tissue (BAT) plays a key role in energy homeostasis and thermogenesis in animals, conferring protection against diet-induced obesity and hypothermia through the action of uncoupling protein 1 (UCP1). Recent metabolic imaging studies using positron emission tomography computerized tomography (PET-CT) scanning have serendipitously revealed significant depots of BAT in the cervical-supraclavicular regions, demonstrating persistence of BAT beyond infancy. Subsequent cold-stimulated PET-CT studies and direct histological examination of adipose tissues have demonstrated that BAT is highly prevalent in adult humans. BAT activity correlates positively with increment of energy expenditure during cold exposure and negatively with age, body mass index, and fasting glycemia, suggesting regulatory links between BAT, cold-induced thermogenesis, and energy metabolism. Human BAT tissue biopsies express UCP1 and harbor inducible precursors that differentiate into UCP1-expressing adipocytes in vitro. These recent discoveries represent a metabolic renaissance for human adipose biology, overturning previous belief that BAT had no relevance in adult humans. They also have implications for the understanding of the pathogenesis and treatment of obesity and its metabolic sequelae.

Context: Cold exposure stimulates fibroblast growth factor 21 (FGF21) secretion in animals, enhancing the cold-induced thermogenesis (CIT) response through browning of white adipose tissue. In humans, the effects of cold exposure on circulating FGF21 levels are unknown., Objective: Our objective was to evaluate the effects of mild cold exposure on circulating FGF21 and its relationship with CIT and lipolysis in humans., Design and Setting: We conducted a randomized, single-blind, crossover intervention study at the National Institutes of Health Clinical Center., Participants: Participants were healthy adults., Intervention: Subjects were exposed to a 12-h exposure to 24 or 19 C in a whole-room indirect calorimeter., Outcome Measures: Energy expenditure, plasma FGF 21, nonesterified fatty acid, and adipose tissue microdialysis glycerol concentrations were evaluated., Results: At 24 C, plasma FGF21 exhibited a diurnal rhythm, peaking at 0800 h [110 (59-178) pg/ml], and progressively dropped to a nadir at 1700 h [41 (21-71) pg/ml, P < 0.0001] before rising at 1900 h [60 (11-81) pg/ml, P < 0.0001]. Exposure at 19 C lessened the diurnal reduction of FGF21 observed at 24 C from 0800-1700 h and augmented overall FGF21 levels by 37 ± 45% (P = 0.01). The change in area under the curve plasma FGF21 between 19 and 24 C correlated positively with the change in area under the curve adipose microdialysate glycerol (R(2) = 0.35, P = 0.04) but not with nonesterified fatty acid. Cold-induced increase in FGF21 predicted greater rise in energy expenditure during cold exposure (β = 0.66, P = 0.027), independent of age, gender, fat mass, and lean mass., Conclusions: Mild cold exposure increased circulating FGF21 levels, predicting greater lipolysis and CIT. A small reduction in environmental temperature is sufficient to modulate FGF21 diurnal rhythm in humans, which may mediate cold-induced metabolic changes similar to those in animals.

Background: Our previous studies have shown that broccoli sprouts high in the glucosinolate glucoraphanin decreases renal and vascular oxidative stress and inflammation as well as blood pressure in spontaneously hypertensive stroke-prone (SHRSP) rats. The objective of this study was to determine whether the metabolite of glucoraphanin, sulforaphane, was responsible for this improved blood pressure and whether this is associated with normalization of renal methylated DNA., Methods: Sulforaphane was given by gavage to SHRSP and Sprague Dawley (SD) rats over 4 months and blood pressure measured under anesthesia just before euthanasia. Renovascular morphology was determined by histology and methylated deoxycytosine levels analyzed using high-performance liquid chromatography., Results: Mean arterial pressure was 20% higher in vehicle-treated SHRSP when compared to SD. Sulforaphane administration to SHRSP improved blood pressure and lowered this difference to 11%. Vehicle-treated SHRSP had significantly increased wall:lumen ratios in renal arteries, increased numbers of vascular smooth muscle cells (VSMCs), increased renal protein nitration, and decreased (11%) renal DNA methylation compared to SD. Sulforaphane administration to SHRSP significantly lowered arterial wall:lumen ratio by 35%, reduced the number of VSMCs, reduced the level of protein nitration, and increased methylated deoxycytosine levels by 14%., Conclusions: Sulforaphane administration rectified pathological abnormalities in SHRSP kidneys and significantly improved blood pressure. This was associated with normalization of global kidney DNA methylation suggesting that DNA methylation could be associated with hypertension.

Brown adipose tissue (BAT) plays key roles in thermogenesis and energy homeostasis in rodents. Metabolic imaging using positron emission tomography (PET)-computer tomography has identified significant depots of BAT in the supraclavicular fossa of adult humans. Whether supraclavicular fat contains precursor brown adipocytes is unknown. The aim of the present study was to determine the adipogenic potential of precursor cells in human supraclavicular fat. We obtained fat biopsies from the supraclavicular fossa of six individuals, as guided by PET-computer tomography, with paired sc fat biopsies as negative controls. Each piece of fat tissue was divided and processed for histology, gene analysis, and primary culture. Cells were examined for morphological changes in culture and harvested for RNA and protein upon full differentiation for analysis of UCP1 level. Histological/molecular analysis of supraclavicular fat revealed higher abundance of BAT in PET-positive than PET-negative individuals. In all subjects, fibroblast-like cells isolated from supraclavicular fat differentiated in vitro and uniformly into adipocytes containing multilobulated lipid droplets, expressing high level of UCP1. The total duration required from inoculation to emergence of fibroblast-like cells was 32-34 and 40-42 d for PET-positive- and PET-negative-derived samples, respectively, whereas the time required to achieve full differentiation was 7 d, regardless of PET status. Precursor cells from sc fat failed to proliferate or express UCP1. In summary, preadipocytes isolated from supraclavicular fat are capable of differentiating into brown adipocytes in vitro, regardless of PET status. This study provides the first evidence of inducible brown adipogenesis in the supraclavicular region in adult humans.

Context: Positron emission tomography (PET)-computed tomography (CT) has identified metabolically active supraclavicular fat in adult humans based on uptake of labeled glucose and confirmed to be brown adipose tissue (BAT) histologically. However, PET-CT has estimated a prevalence of BAT as low as 5% in adult humans, casting doubt on its significance. The true prevalence of BAT is unknown because of the suboptimal sensitivity of standard PET-CT., Objective: The objective of the study was to determine whether BAT is present in PET-negative supraclavicular fat., Design: This was a prospective cohort study., Setting: The study was conducted at a tertiary referral hospital., Patients: Seventeen patients who underwent preoperative PET-CT for staging of head and neck malignancy participated in the study., Main Outcome: The main outcome was signature BAT gene transcripts and protein in biopsies of supraclavicular fat with sc fat as negative control., Results: PET-CT was positive in three and negative in 14 patients. PET-positive fat harbored multilobulated lipid droplets and stained strongly for uncoupling protein 1 (UCP1). These features are absent in sc fat. By contrast, PET-negative fat contained a predominance of cells with unilobulated lipid droplets, with scattered cells containing multilobulated lipid droplets and variable UCP1 staining. Molecular analyses of fat biopsies showed lower but clear expression of UCP1, NDUFS3 (NADH dehydrogenase (ubiquinone) iron-sulfur protein 3), β₃-adrenoceptor, and PRDM16 (PR domain containing 16) transcripts., Conclusions: BAT is present in supraclavicular fat, regardless of PET status. BAT is highly prevalent in adult humans, and its abundance determines PET status.

Context: Adipose tissue is a major target of GH action. GH stimulates lipolysis and reduces fat mass. The molecular mechanism underlying cellular and metabolic effects of GH in adipose tissue is not well understood., Objective: The aim of this study is to identify GH-responsive genes that regulate lipid metabolism in adipose tissue., Design: Eight men with GH deficiency underwent measurement of plasma free fatty acid (FFA), whole-body lipid oxidation, and fat biopsies before and after 1 month of GH treatment (0.5 mg/d). Gene expression profiling was performed using Agilent 44K G4112F arrays using a two-color design. Differentially expressed genes were identified using an empirical Bayes, moderated t test, with a false discovery rate under 5%. Target genes were validated by quantitative RT-PCR., Results: GH increased circulating IGF-I and FFA and stimulated fat oxidation. A total of 246 genes were differentially expressed, of which 135 were up-regulated and 111 down-regulated. GH enhanced adipose tissue expression of IGF-I and SOCS3. GH increased expression of patatin-like phospholipase domain containing 3 (PNPLA3), a novel triglyceride (TG) hydrolase, but not hormone-sensitive lipase (HSL), a classical TG hydrolase. GH repressed cell death-inducing DFFA-like effector A (CIDEA), a novel lipid droplets-associated protein, promoting TG storage. GH differentially regulated genes promoting diacylglycerol synthesis. GH suppressed hydroxysteroid (11β) dehydrogenase 1, which activates local cortisol production and genes encoding components of extracellular matrix and TGF-β signaling pathway., Conclusion: GH stimulates the TG/FFA cycle by regulating the expression of novel genes that enhance TG hydrolysis, reduce TG storage, and promote diacylglycerol synthesis. GH represses adipocyte growth, differentiation and inflammation.