The glutamate/aspartate transporter EAAT1 is crucial for T-cell acute lymphoblastic leukemia proliferation and survival.

T-cell acute lymphoblastic leukemia (T-ALL) is a cancer of the immune system. Approximately 20% of paediatric and 50% of adult T-ALL patients have refractory disease or relapse and die from the disease. To improve patient outcome new therapeutics are needed. With the aim to identify new therapeutic targets, we combined the analysis of T-ALL gene expression and metabolism to identify the metabolic adaptations that T-ALL cells exhibit. We found that glutamine uptake is essential for T-ALL proliferation. Isotope tracing experiments showed that glutamine fuels aspartate synthesis through the TCA cycle and that glutamine and glutamine-derived aspartate together supply three nitrogen atoms in purines and all but one atom in pyrimidine rings. We show that the glutamate-aspartate transporter EAAT1 (SLC1A3), which is normally expressed in the central nervous system, is crucial for glutamine conversion to aspartate and nucleotides and that T-ALL cell proliferation depends on EAAT1 function. Through this work, we identify EAAT1 as a novel therapeutic target for T-ALL treatment.

Safety outcomes of bariatric surgery in patients with advanced organ disease: the ONWARD study: a prospective cohort study.

INTRODUCTION: Increasing numbers of patients with advanced organ disease are being considered for bariatric and metabolic surgery (BMS). There is no prospective study on the safety of BMS in these patients. This study aimed to capture outcomes for patients with advanced cardiac, renal, or liver disease undergoing BMS. MATERIALS AND METHODS: This was a multinational, prospective cohort study on the safety of elective BMS in adults (≥18 years) with advanced disease of the heart, liver, or kidney. RESULTS: Data on 177 patients with advanced diseases of heart, liver, or kidney were submitted by 75 centres in 33 countries. Mean age and BMI was 48.56±11.23 years and 45.55±7.35 kg/m 2 , respectively. Laparoscopic sleeve gastrectomy was performed in 124 patients (70%). The 30-day morbidity and mortality were 15.9% ( n =28) and 1.1% ( n =2), respectively. Thirty-day morbidity was 16.4%, 11.7%, 20.5%, and 50.0% in patients with advanced heart ( n =11/61), liver ( n =8/68), kidney ( n =9/44), and multi-organ disease ( n =2/4), respectively. Cardiac patients with left ventricular ejection fraction less than or equal to 35% and New York Heart Association classification 3 or 4, liver patients with model for end-stage liver disease score greater than or equal to 12, and patients with advanced renal disease not on dialysis were at increased risk of complications. Comparison with a propensity score-matched cohort found advanced disease of the heart, liver, or kidney to be significantly associated with higher 30-day morbidity. CONCLUSION: Patients with advanced organ disease are at increased risk of 30-day morbidity following BMS. This prospective study quantifies that risk and identifies patients at the highest risk.

Global trends in BMS research using publication as a surrogate marker: A 30 year review.

Obesity is a global pandemic with increasing prevalence and long-term negative health outcomes. Bariatric metabolic surgery (BMS) is the most effective treatment option for achieving long-term weight loss. A systematic search was performed from 1990 to 2020 of BMS procedures using standardised groups. Data were collected on operation type reported, country and continent of publication. North America and Europe were the leading contributors to global publications in BMS, producing 41.3 % (n = 4931) and 37.1 % (n = 4436) of publications respectively, with increasing publications from Asia. Roux-en-Y Gastric Bypass (RYGB) and Sleeve Gastrectomy (SG) were the most studied procedure types with number of publications continuing to increase over time. A plateau and downward trend was seen for Laparoscopic Adjustable Gastric Band (LAGB) publication from 2015 to 2019. An increase in emerging/experimental techniques over the past decade is observed.

Aerosol-into-liquid capture and detection of atmospheric soluble metals across the gas-liquid interface using Janus-membrane electrodes.

The soluble fraction of atmospheric transition metals is particularly associated with health effects such as reactive oxygen species compared to total metals. However, direct measurements of the soluble fraction are restricted to sampling and detection units in sequence burdened with a compromise between time resolution and system bulkiness. Here, we propose the concept of aerosol-into-liquid capture and detection, which allowed one-step particle capture and detection via the Janus-membrane electrode at the gas-liquid interface, enabling active enrichment and enhanced mass transport of metal ions. The integrated aerodynamic/electrochemical system was capable of capturing airborne particles with a cutoff size down to 50 nm and detecting Pb(II) with a limit of detection of 95.7 ng. The proposed concept can pave the way for cost-effective and miniaturized systems, for the capture and detection of airborne soluble metals in air quality monitoring, especially for abrupt air pollution events with high airborne metal concentrations (e.g., wildfires and fireworks).

Nuclear Magnetic Resonance Spectroscopy Metabolomics in Idiopathic Intracranial Hypertension to Identify Markers of Disease and Headache.

BACKGROUND AND OBJECTIVE: We evaluated the metabolomic profile in CSF, serum and urine of participants with idiopathic intracranial hypertension (IIH) compared to controls and measured changes in metabolism associated with clinical markers of disease activity and treatment. METHODS: A case-control study compared women aged 18-55 years with active IIH (Friedman diagnostic criteria), to a sex, age and body mass index matched control group. IIH participants were identified from neurology and ophthalmology clinics from National Health Service hospitals and underwent a prospective intervention to induce disease remission through weight loss with re-evaluation at 12 months. Clinical assessments included lumbar puncture, headache, papilledema and visual measurements. Spectra of CSF, serum and urine metabolites were acquired utilizing proton nuclear magnetic resonance spectroscopy. RESULTS: Urea was lower in IIH (CSF; controls median ±IQR 0.196 ±0.008, IIH 0.058 ±0.059, p<0.001, urine; controls 5971.370 ±3021.831, IIH 4691.363 ±1955.774, p=0.009), correlated with ICP (urine p=0.019) and headache severity (CSF p=0.031) and increased by 12 months (CSF 12 months; 0.175 ±0.043, p=0.004, urine; 5210.874 ±1825.302, p=0.043). The lactate:pyruvate ratio was increased compared to controls (CSF; controls 49.739 ±19.523, IIH 113.114 ±117.298, p=0.023, serum; controls 38.187 ±13.392, IIH 54.547 ±18.471, p=0.004) and decreased at 12 months (CSF; 113.114 ±117.298, p<0.001). Baseline acetate was higher in IIH (CSF; controls 0.128 ±0.041, IIH 0.192 ±0.151, p=0.008), correlated with headache severity (p = 0.030) and headache disability (p = 0.003) and was reduced at 12 months (0.160 ±0.060, p = 0.007). Ketones 3-hydroxybutyrate and acetoacetate were altered in CSF at baseline in IIH (3-hydroxybutyrate; controls 0.074 ±0.063, IIH 0.049 ±0.055, p = 0.019, acetoacetate; controls 0.013 ±0.007, IIH 0.017 ±0.010, p = 0.013) and normalized at 12 months (0.112 ±0.114, p = 0.019, 0.029 ±0.017, p = 0.015 respectively). DISCUSSION: We observed metabolic disturbances that are evident in CSF, serum and urine of IIH participants, suggesting global metabolic dysregulation. Altered ketone body metabolites normalized following therapeutic weight loss. CSF:serum urea ratio was altered which may influence ICP dynamics and headache. Elevated CSF acetate, known to stimulate trigeminal sensitization, was associated with headache morbidity. These alterations of metabolic pathways specific to IIH provide biological insight and warrants mechanistic evaluation.

Handling of the Covid-19 Pandemic and Its Effects on Bariatric Surgical Practice: Analysis of GENEVA Study Database.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic led to a worldwide suspension of bariatric and metabolic surgery (BMS) services. The current study analyses data on patterns of service delivery, recovery of practices, and protective measures taken during the COVID-19 pandemic by bariatric teams. MATERIALS AND METHODS: The current study is a subset analysis of the GENEVA study which was an international cohort study between 01/05/2020 and 31/10/2020. Data were specifically analysed regarding the timing of BMS suspension, patterns of service recovery, and precautionary measures deployed. RESULTS: A total of 527 surgeons from 439 hospitals in 64 countries submitted data regarding their practices and handling of the pandemic. Smaller hospitals (with less than 200 beds) were able to restart BMS programmes more rapidly (time to BMS restart 60.8 ± 38.9 days) than larger institutions (over 2000 beds) (81.3 ± 30.5 days) (p = 0.032). There was a significant difference in the time interval between cessation/reduction and restart of bariatric services between government-funded practices (97.1 ± 76.2 days), combination practices (84.4 ± 47.9 days), and private practices (58.5 ± 38.3 days) (p < 0.001). Precautionary measures adopted included patient segregation, utilisation of personal protective equipment, and preoperative testing. Following service recovery, 40% of the surgeons operated with a reduced capacity. Twenty-two percent gave priority to long waiters, 15.4% gave priority to uncontrolled diabetics, and 7.6% prioritised patients requiring organ transplantation. CONCLUSION: This study provides global, real-world data regarding the recovery of BMS services following the COVID-19 pandemic.

A Functional Network Driven by MicroRNA-125a Regulates Monocyte Trafficking in Acute Inflammation.

During the onset of acute inflammation, rapid trafficking of leukocytes is essential to mount appropriate immune responses towards an inflammatory insult. Monocytes are especially indispensable for counteracting the inflammatory stimulus, neutralising the noxa and reconstituting tissue homeostasis. Thus, monocyte trafficking to the inflammatory sites needs to be precisely orchestrated. In this study, we identify a regulatory network driven by miR-125a that affects monocyte adhesion and chemotaxis by the direct targeting of two adhesion molecules, i.e., junction adhesion molecule A (JAM-A), junction adhesion molecule-like (JAM-L) and the chemotaxis-mediating chemokine receptor CCR2. By investigating monocytes isolated from patients undergoing cardiac surgery, we found that acute yet sterile inflammation reduces miR-125a levels, concomitantly enhancing the expression of JAM-A, JAM-L and CCR2. In contrast, TLR-4-specific stimulation with the pathogen-associated molecular pattern (PAMP) LPS, usually present within the perivascular inflamed area, resulted in dramatically induced levels of miR-125a with concomitant repression of JAM-A, JAM-L and CCR2 as early as 3.5 h. Our study identifies miR-125a as an important regulator of monocyte trafficking and shows that the phenotype of human monocytes is strongly influenced by this miRNA, depending on the type of inflammatory stimulus.

Effect of BMI on safety of bariatric surgery during the COVID-19 pandemic, procedure choice, and safety protocols - An analysis from the GENEVA Study.

BACKGROUND: It has been suggested that patients with a Body Mass Index (BMI) of > 60 kg/m2 should be offered expedited Bariatric Surgery (BS) during the Coronavirus Disease-2019 (COVID-19) pandemic. The main objective of this study was to assess the safety of this approach. METHODS: We conducted a global study of patients who underwent BS between 1/05/2020 and 31/10/2020. Patients were divided into three groups according to their preoperative BMI - Group I (BMI<50 kg/m2), Group II (BMI 50-60 kg/m2), and Group III (BMI>60 kg/m2). The effect of preoperative BMI on 30-day morbidity and mortality, procedure choice, COVID-19 specific safety protocols, and comorbidities was assessed. RESULTS: This study included 7084 patients (5197;73.4 % females). The mean preoperative weight and BMI were 119.49 ± 24.4 Kgs and 43.03 ± 6.9 Kg/m2, respectively. Group I included 6024 (85 %) patients, whereas Groups II and III included 905 (13 %) and 155 (2 %) patients, respectively. The 30-day mortality rate was higher in Group III (p = 0.001). The complication rate and COVID-19 infection were not different. Comorbidities were significantly more likely in Group III (p = <0.001). A significantly higher proportion of patients in group III received Sleeve Gastrectomy or One Anastomosis Gastric Bypass compared to other groups. Patients with a BMI of > 70 kg/m2 had a 30-day mortality of 7.7 % (2/26). None of these patients underwent a Roux-en-Y Gastric Bypass. CONCLUSION: The 30-day mortality rate was significantly higher in patients with BMI > 60 kg/m2. There was, however, no significant difference in complications rates in different BMI groups, probably due to differences in procedure selection.

Safety of Bariatric Surgery in ≥ 65-Year-Old Patients During the COVID-19 Pandemic.

BACKGROUND: Age ≥ 65 years is regarded as a relative contraindication for bariatric surgery. Advanced age is also a recognised risk factor for adverse outcomes with Coronavirus Disease-2019 (COVID-19) which continues to wreak havoc on global populations. This study aimed to assess the safety of bariatric surgery (BS) in this particular age group during the COVID-19 pandemic in comparison with the younger cohort. METHODS: We conducted a prospective international study of patients who underwent BS between 1/05/2020 and 31/10/2020. Patients were divided into two groups - patients ≥ 65-years-old (Group I) and patients < 65-years-old (Group II). The two groups were compared for 30-day morbidity and mortality. RESULTS: There were 149 patients in Group 1 and 6923 patients in Group II. The mean age, preoperative weight, and BMI were 67.6 ± 2.5 years, 119.5 ± 24.5 kg, and 43 ± 7 in Group I and 39.8 ± 11.3 years, 117.7±20.4 kg, and 43.7 ± 7 in Group II, respectively. Approximately, 95% of patients in Group 1 had at least one co-morbidity compared to 68% of patients in Group 2 (p = < 0.001). The 30-day morbidity was significantly higher in Group I (11.4%) compared to Group II (6.6%) (p = 0.022). However, the 30-day mortality and COVID-19 infection rates were not significantly different between the two groups. CONCLUSIONS: Bariatric surgery during the COVID-19 pandemic is associated with a higher complication rate in those ≥ 65 years of age compared to those < 65 years old. However, the mortality and postoperative COVID-19 infection rates are not significantly different between the two groups.

Early Use of Methylene Blue in Vasoplegic Syndrome: A 10-Year Propensity Score-Matched Cohort Study.

BACKGROUND: Vasoplegic syndrome is associated with increased morbidity and mortality in patients undergoing cardiac surgery. This retrospective, single-center study aimed to evaluate the effect of early use of methylene blue (MB) on hemodynamics after an intraoperative diagnosis of vasoplegic syndrome (VS). METHODS: Over a 10-year period, all patients diagnosed with intraoperative VS (hypotension despite treatment with norepinephrine ≥0.3 µg/kg/min and vasopressin ≥1 IE/h) while undergoing heart surgery and cardiopulmonary bypass were identified, and their data were examined. The intervention group received MB (2 mg/kg intravenous) within 15 min after the diagnosis of vasoplegia, while the control group received standard therapy. The two groups were matched using propensity scores. RESULTS: Of the 1022 patients identified with VS, 221 received MB intraoperatively, and among them, 60 patients received MB within 15 min after the diagnosis of VS. After early MB application, mean arterial pressure was significantly higher, and vasopressor support was significantly lower within the first hour (p = 0.015) after the diagnosis of vasoplegia, resulting in a lower cumulative amount of norepinephrine (p = 0.018) and vasopressin (p = 0.003). The intraoperative need of fresh frozen plasma in the intervention group was lower compared to the control group (p = 0.015). Additionally, the intervention group had higher creatinine values in the first three postoperative days (p = 0.036) without changes in dialysis incidence. The 90-day survival did not differ significantly (p = 0.270). CONCLUSION: Our results indicate the additive effects of MB use during VS compared to standard vasopressor therapy only. Early MB administration for VS may significantly improve the patients' hemodynamics with minor side effects.

Does powered stapler improve the mechanical integrity of gastrojejunal anastomosis compared to the current techniques? Experimental study in ex vivo porcine models.

BACKGROUND: Numerous techniques have been described for fashioning gastrojejunostomy (GJ) in a Roux-en-Y gastric bypass. These include hand-sewn anastomosis (HSA) and mechanical anastomosis; the latter includes circular stapled anastomosis (CSA) or manual linear stapled anastomosis (mLSA). More recently, this list also includes powered linear stapled anastomosis (pLSA). The aim of this study was to analyse if addition of power to stapling would improve the integrity of GJ anastomosis in ex vivo porcine models. SUBJECTS AND METHODS: The present study included five groups - mLSA1, mLSA2, HSA, CSA, and pLSA. Sequential infusions of methylene blue-coloured saline were performed into the GJ models. Pressure readings were recorded till the point of leak denoting burst pressure (BP). Total volume (TV) and site of leak were recorded. Compliance was calculated from the equation ΔTV/ΔBP. RESULTS: Differences in pouch and intestinal thickness were not statistically significant between the models. BPs were higher in the mechanical anastomosis groups, i.e., pLSA 21 ± 9.85 mmHg, CSA 20.33 ± 5.78 mmHg, mLSA1 18 ± 4.69 mmHg and mLSA2 11 ± 2.94 mmHg, when compared to HSA 9.67 ± 3.79 mm Hg, which was found to be statistically significant (Kruskal-Wallis test, P = 0.03). Overall, the highest BP was recorded for powered stapling followed by circular, and then, linear stapling; however, this difference was not statistically significant (P = 0.86). There was no statistically significant difference among groups with regard to compliance (Kruskal-Wallis test, P = 0.082). CONCLUSION: Despite the limited number of samples, mechanical anastomosis showed a statistically higher BP when compared to HSA, suggesting better anastomotic integrity. The pLSA group showed promising results with the highest BP recorded among all groups; however, this did not reach statistical significance.

30-day morbidity and mortality of sleeve gastrectomy, Roux-en-Y gastric bypass and one anastomosis gastric bypass: a propensity score-matched analysis of the GENEVA data.

BACKGROUND: There is a paucity of data comparing 30-day morbidity and mortality of sleeve gastrectomy (SG), Roux-en-Y gastric bypass (RYGB), and one anastomosis gastric bypass (OAGB). This study aimed to compare the 30-day safety of SG, RYGB, and OAGB in propensity score-matched cohorts. MATERIALS AND METHODS: This analysis utilised data collected from the GENEVA study which was a multicentre observational cohort study of bariatric and metabolic surgery (BMS) in 185 centres across 42 countries between 01/05/2022 and 31/10/2020 during the Coronavirus Disease-2019 (COVID-19) pandemic. 30-day complications were categorised according to the Clavien-Dindo classification. Patients receiving SG, RYGB, or OAGB were propensity-matched according to baseline characteristics and 30-day complications were compared between groups. RESULTS: In total, 6770 patients (SG 3983; OAGB 702; RYGB 2085) were included in this analysis. Prior to matching, RYGB was associated with highest 30-day complication rate (SG 5.8%; OAGB 7.5%; RYGB 8.0% (p = 0.006)). On multivariate regression modelling, Insulin-dependent type 2 diabetes mellitus and hypercholesterolaemia were associated with increased 30-day complications. Being a non-smoker was associated with reduced complication rates. When compared to SG as a reference category, RYGB, but not OAGB, was associated with an increased rate of 30-day complications. A total of 702 pairs of SG and OAGB were propensity score-matched. The complication rate in the SG group was 7.3% (n = 51) as compared to 7.5% (n = 53) in the OAGB group (p = 0.68). Similarly, 2085 pairs of SG and RYGB were propensity score-matched. The complication rate in the SG group was 6.1% (n = 127) as compared to 7.9% (n = 166) in the RYGB group (p = 0.09). And, 702 pairs of OAGB and RYGB were matched. The complication rate in both groups was the same at 7.5 % (n = 53; p = 0.07). CONCLUSIONS: This global study found no significant difference in the 30-day morbidity and mortality of SG, RYGB, and OAGB in propensity score-matched cohorts.

30-Day morbidity and mortality of bariatric metabolic surgery in adolescence during the COVID-19 pandemic - The GENEVA study.

BACKGROUND: Metabolic and bariatric surgery (MBS) is an effective treatment for adolescents with severe obesity. OBJECTIVES: This study examined the safety of MBS in adolescents during the coronavirus disease 2019 (COVID-19) pandemic. METHODS: This was a global, multicentre and observational cohort study of MBS performed between May 01, 2020, and October 10,2020, in 68 centres from 24 countries. Data collection included in-hospital and 30-day COVID-19 and surgery-specific morbidity/mortality. RESULTS: One hundred and seventy adolescent patients (mean age: 17.75 ± 1.30 years), mostly females (n = 122, 71.8%), underwent MBS during the study period. The mean pre-operative weight and body mass index were 122.16 ± 15.92 kg and 43.7 ± 7.11 kg/m2 , respectively. Although majority of patients had pre-operative testing for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (n = 146; 85.9%), only 42.4% (n = 72) of the patients were asked to self-isolate pre-operatively. Two patients developed symptomatic SARS-CoV-2 infection post-operatively (1.2%). The overall complication rate was 5.3% (n = 9). There was no mortality in this cohort. CONCLUSIONS: MBS in adolescents with obesity is safe during the COVID-19 pandemic when performed within the context of local precautionary procedures (such as pre-operative testing). The 30-day morbidity rates were similar to those reported pre-pandemic. These data will help facilitate the safe re-introduction of MBS services for this group of patients.

30-Day Morbidity and Mortality of Bariatric Surgery During the COVID-19 Pandemic: a Multinational Cohort Study of 7704 Patients from 42 Countries.

BACKGROUND: There are data on the safety of cancer surgery and the efficacy of preventive strategies on the prevention of postoperative symptomatic COVID-19 in these patients. But there is little such data for any elective surgery. The main objectives of this study were to examine the safety of bariatric surgery (BS) during the coronavirus disease 2019 (COVID-19) pandemic and to determine the efficacy of perioperative COVID-19 protective strategies on postoperative symptomatic COVID-19 rates. METHODS: We conducted an international cohort study to determine all-cause and COVID-19-specific 30-day morbidity and mortality of BS performed between 01/05/2020 and 31/10/2020. RESULTS: Four hundred ninety-nine surgeons from 185 centres in 42 countries provided data on 7704 patients. Elective primary BS (n = 7084) was associated with a 30-day morbidity of 6.76% (n = 479) and a 30-day mortality of 0.14% (n = 10). Emergency BS, revisional BS, insulin-treated type 2 diabetes, and untreated obstructive sleep apnoea were associated with increased complications on multivariable analysis. Forty-three patients developed symptomatic COVID-19 postoperatively, with a higher risk in non-whites. Preoperative self-isolation, preoperative testing for SARS-CoV-2, and surgery in institutions not concurrently treating COVID-19 patients did not reduce the incidence of postoperative COVID-19. Postoperative symptomatic COVID-19 was more likely if the surgery was performed during a COVID-19 peak in that country. CONCLUSIONS: BS can be performed safely during the COVID-19 pandemic with appropriate perioperative protocols. There was no relationship between preoperative testing for COVID-19 and self-isolation with symptomatic postoperative COVID-19. The risk of postoperative COVID-19 risk was greater in non-whites or if BS was performed during a local peak.

Effect of COVID-19 pandemic on global Bariatric surgery PRActiceS - The COBRAS study.

INTRODUCTION: There is a paucity of data in scientific literature on the impact of Coronavirus Disease 2019 (COVID-19) pandemic on bariatric surgery. The aim of this study was to evaluate the impact of COVID-19 pandemic on Bariatric Surgery globally. METHODS: We conducted a global online survey of bariatric surgeons between 16/04/20 - 15/05/20. The survey was endorsed by five national bariatric surgery societies and circulated amongst their memberships. Authors also shared the link through their personal networks, email groups, and social media. RESULTS: 703 respondents from 77 countries completed the survey. Respondents reported a drop in elective bariatric activity from a median (IQR) of 130 (60-250) procedures in 2019 to a median of 0 (0-2) between16/03/2020 and 15/04/2020 during the pandemic. The corresponding figures for emergency activity were 5 (2-10) and 0 (0-1) respectively. 441 (63%) respondents did not perform any bariatric procedures during this time period. Surgeons reported outcomes of 61 elective bariatric surgical procedures during the pandemic with 13 (21%) needing ventilation and 2 (3.3%) deaths. Of the 13 emergency bariatric procedures reported, 5 (38%) needed ventilation and 4 (31%) died. 90 (13%) surgeons reported having had to perform a bariatric surgical or endoscopic procedure without adequate Personal Protective Equipment. CONCLUSIONS: COVID-19 pandemic led to a remarkable decline in global elective and emergency bariatric surgery activity at its beginning. Both elective and emergency procedures performed at this stage of the pandemic had considerable morbidity and mortality.

Systemic and adipocyte transcriptional and metabolic dysregulation in idiopathic intracranial hypertension.

BACKGROUNDIdiopathic intracranial hypertension (IIH) is a condition predominantly affecting obese women of reproductive age. Recent evidence suggests that IIH is a disease of metabolic dysregulation, androgen excess, and an increased risk of cardiovascular morbidity. Here we evaluate systemic and adipose specific metabolic determinants of the IIH phenotype.METHODSIn fasted, matched IIH (n = 97) and control (n = 43) patients, we assessed glucose and insulin homeostasis and leptin levels. Body composition was assessed along with an interrogation of adipose tissue function via nuclear magnetic resonance metabolomics and RNA sequencing in paired omental and subcutaneous biopsies in a case-control study.RESULTSWe demonstrate an insulin- and leptin-resistant phenotype in IIH in excess of that driven by obesity. Adiposity in IIH is preferentially centripetal and is associated with increased disease activity and insulin resistance. IIH adipocytes appear transcriptionally and metabolically primed toward depot-specific lipogenesis.CONCLUSIONThese data show that IIH is a metabolic disorder in which adipose tissue dysfunction is a feature of the disease. Managing IIH as a metabolic disease could reduce disease morbidity and improve cardiovascular outcomes.FUNDINGThis study was supported by the UK NIHR (NIHR-CS-011-028), the UK Medical Research Council (MR/K015184/1), Diabetes UK, Wellcome Trust (104612/Z/14/Z), the Sir Jules Thorn Award, and the Midlands Neuroscience Teaching and Research Fund.

In vivo [U-13C]glucose labeling to assess heart metabolism in murine models of pressure and volume overload.

Alterations in the metabolism of substrates such as glucose are integrally linked to the structural and functional changes that occur in the remodeling heart. Assessment of such metabolic changes under in vivo conditions would provide important insights into this interrelationship. We aimed to investigate glucose carbon metabolism in pressure-overload and volume-overload cardiac hypertrophy by using an in vivo [U-13C]glucose labeling strategy to enable analyses of the metabolic fates of glucose carbons in the mouse heart. Therefore, [U-13C]glucose was administered in anesthetized mice by tail vein infusion, and the optimal duration of infusion was established. Hearts were then excised for 13C metabolite isotopomer analysis by NMR spectroscopy. [U-13C]glucose infusions were performed in mice 2 wk following transverse aortic constriction (TAC) or aortocaval fistula (Shunt) surgery. At this time point, there were similar increases in left ventricular (LV) mass in both groups, but TAC resulted in concentric hypertrophy with impaired LV function, whereas Shunt caused eccentric hypertrophy with preserved LV function. TAC was accompanied by significant changes in glycolysis, mitochondrial oxidative metabolism, glucose metabolism to anaplerotic substrates, and de novo glutamine synthesis. In contrast to TAC, hardly any metabolic changes could be observed in the Shunt group. Taken together, in vivo [U-13C]glucose labeling is a valuable method to investigate the fate of nutrients such as glucose in the remodeling heart. We find that concentric and eccentric cardiac remodeling are accompanied by distinct differences in glucose carbon metabolism.NEW & NOTEWORTHY This study implemented a method for assessing the fate of glucose carbons in the heart in vivo and used this to demonstrate that pressure and volume overload are associated with distinct changes. In contrast to volume overload, pressure overload-induced changes affect the tricarboxylic acid cycle, glycolytic pathways, and glutamine synthesis. A better understanding of cardiac glucose metabolism under pathological conditions in vivo may provide new therapeutic strategies specific for different types of hemodynamic overload.

Backbone resonance assignments of the catalytic and regulatory domains of Ca2+/calmodulin-dependent protein kinase 1D.

The CaMK subfamily of Ser/Thr kinases are regulated by calmodulin interactions with their C-terminal regions. They are exemplified by Ca2+/calmodulin dependent protein kinase 1δ which is known as CaMK1D, CaMKIδ or CKLiK. CaMK1D mediates intracellular signalling downstream of Ca2+ influx and thereby exhibits amplifications of Ca2+signals and polymorphisms that have been implicated in breast cancer and diabetes. Here we report the backbone 1H, 13C, 15N assignments of the 38 kDa human CaMK1D protein in its free state, including both the canonical bi-lobed kinase fold as well as the autoinhibitory and calmodulin binding domains.

Brief O2 uploading during continuous hypothermic machine perfusion is simple yet effective oxygenation method to improve initial kidney function in a porcine autotransplant model.

With oxygenation proposed as a resuscitative measure during hypothermic models of preservation, the aim of this study was to evaluate the optimal start time of oxygenation during continuous hypothermic machine perfusion (HMP). In this porcine ischemia-reperfusion autotransplant model, the left kidney of a ±40 kg pig was exposed to 30 minutes of warm ischemia prior to 22 hours of HMP and autotransplantation. Kidneys were randomized to receive 2 hours of oxygenation during HMP either at the start (n = 6), or end of the perfusion (n = 5) and outcomes were compared to standard, nonoxygenated HMP (n = 6) and continuous oxygenated HMP (n = 8). The brief initial and continuous oxygenated HMP groups were associated with superior graft recovery compared to either standard, nonoxygenated HMP or kidneys oxygenated at the end of HMP. This correlated with significant metabolic differences in perfusate (eg, lactate, succinate, flavin mononucleotide) and tissues (eg, succinate, adenosine triphosphate, hypoxia-inducible factor-1α, nuclear factor erythroid 2-related factor 2) suggesting superior mitochondrial preservation with initial oxygenation. Brief initial O2 uploading during HMP at procurement site might be an easy and effective preservation strategy to maintain aerobic metabolism, protect mitochondria, and achieve an improved early renal graft function compared with standard HMP or oxygen supply shortly at the end of HMP preservation.