The LKB1-salt-inducible kinase pathway functions as a key gluconeogenic suppressor in the liver

LKB1 is a master kinase that regulates metabolism and growth through adenosine monophosphate-activated protein kinase (AMPK) and 12 other closely related kinases. Liver-specific ablation of LKB1 causes increased glucose production in hepatocytes in vitro and hyperglycaemia in fasting mice in vivo. Here we report that the salt-inducible kinases (SIK1, 2 and 3), members of the AMPK-related kinase family, play a key role as gluconeogenic suppressors downstream of LKB1 in the liver. The selective SIK inhibitor HG-9-91-01 promotes dephosphorylation of transcriptional co-activators CRTC2/3 resulting in enhanced gluconeogenic gene expression and glucose production in hepatocytes, an effect that is abolished when an HG-9-91-01-insensitive mutant SIK is introduced or LKB1 is ablated. Although SIK2 was proposed as a key regulator of insulin-mediated suppression of gluconeogenesis, we provide genetic evidence that liver-specific ablation of SIK2 alone has no effect on gluconeogenesis and insulin does not modulate SIK2 phosphorylation or activity. Collectively, we demonstrate that the LKB1-SIK pathway functions as a key gluconeogenic gatekeeper in the liver

IL-4-secreting CD4+ T cells are crucial to the development of CD8+ T-cell responses against malaria liver stages.

CD4+ T cells are crucial to the development of CD8+ T cell responses against hepatocytes infected with malaria parasites. In the absence of CD4+ T cells, CD8+ T cells initiate a seemingly normal differentiation and proliferation during the first few days after immunization. However, this response fails to develop further and is reduced by more than 90%, compared to that observed in the presence of CD4+ T cells. We report here that interleukin-4 (IL-4) secreted by CD4+ T cells is essential to the full development of this CD8+ T cell response. This is the first demonstration that IL-4 is a mediator of CD4/CD8 cross-talk leading to the development of immunity against an infectious pathogen

Fatal stroke after completion pneumonectomy for torsion of left upper lobe following left lower lobectomy

BACKGROUND: The lobar torsion after lung surgery is a rare complication with an incidence of 0.09 to 0.4 %. It may occur after twisting of the bronchovascular pedicle of the remaining lobe after lobectomy, usually on the right side. The 180-degree rotation of the pedicle produces an acute obstruction of the lobar bronchus (atelectasis) and of the lobar vessels as well. Without prompt treatment it progresses to lobar ischemia, pulmonary infarction and finally fatal gangrene. CASE PRESENTATION: A 62 years old female patient was admitted for surgical treatment of lung cancer. She underwent elective left lower lobectomy for squamous cell carcinoma (pT2 N0). The operation was unremarkable, and the patient was extubated in the operating room. After eight hours the patient established decrease of pO(2 )and chest x-ray showed atelectasis of the lower lobe. To establish diagnosis, bronchoscopy was performed, demonstrating obstructed left lobar bronchus. The patient was re-intubated, and admitted to the operating room where reopening of the thoracotomy was performed. Lobar torsion was diagnosed, with the diaphragmatic surface of the upper lobe facing in an anterosuperior orientation. A completion pneumonectomy was performed. At the end of the procedure the patient developed a right pupil dilatation, presumably due to a cerebral embolism. A subsequent brain angio-CT scan established the diagnosis. She died at the intensive care unit 26 days later. CONCLUSION: The thoracic surgeon should suspect this rare early postoperative complication after any thoracic operation in every patient with atelectasis of the neighboring lobe. High index of suspicion and prompt diagnosis may prevent catastrophic consequences, such as, infarction or gangrene of the pulmonary lobe. During thoracic operations, especially whenever the lung or lobe hilum is full mobilized, fixation of the remaining lobe may prevent this life threatening complication

Performance and outcomes of transvenous rotational lead extraction: Results from a prospective, monitored, international clinical study.

BACKGROUND: Transvenous lead extraction (TLE) plays a critical role in managing patients with cardiovascular implantable electronic devices. Mechanical TLE tools, including rotational sheaths, are used to overcome fibrosis and calcification surrounding leads. Prospective clinical data are limited regarding the safety and effectiveness of use of mechanical TLE devices, especially rotational tools. OBJECTIVE: To prospectively investigate the safety and effectiveness of mechanical TLE in real-world usage. METHODS: Patients were enrolled at 10 sites in the United States and Europe to evaluate the use of mechanical TLE devices. Clinical success, complete procedural success, and complications were evaluated through follow-up (median, 29 days). Patient data were source verified and complications were adjudicated by an independent clinical events committee (CEC). RESULTS: Between October 2018 and January 2020, mechanical TLE tools, including rotational sheaths, were used to extract 460 leads with a median indwell time of 7.4 years from 230 patients (mean age 64.3 ± 14.4 years). Noninfectious indications for TLE were more common than infectious indications (61.5% vs 38.5%, respectively). The extracted leads included 305 pacemaker leads (66.3%) and 155 implantable cardioverter-defibrillator leads (33.7%), including 85 leads with passive fixation (18.5%). A bidirectional rotational sheath was needed for 368 leads (88.0%). Clinical success was obtained in 98.7% of procedures; complete procedural success was achieved for 96.3% of leads. CEC-adjudicated device-related major complications occurred in 6 of 230 (2.6%) procedures. No isolated superior vena cava injury or procedural death occurred. CONCLUSION: This prospective clinical study demonstrates that use of mechanical TLE tools, especially bidirectional rotational sheaths, are effective and safe

Genome wide in silico SNP-tumor association analysis

BACKGROUND: Carcinogenesis occurs, at least in part, due to the accumulation of mutations in critical genes that control the mechanisms of cell proliferation, differentiation and death. Publicly accessible databases contain millions of expressed sequence tag (EST) and single nucleotide polymorphism (SNP) records, which have the potential to assist in the identification of SNPs overrepresented in tumor tissue. METHODS: An in silico SNP-tumor association study was performed utilizing tissue library and SNP information available in NCBI's dbEST (release 092002) and dbSNP (build 106). RESULTS: A total of 4865 SNPs were identified which were present at higher allele frequencies in tumor compared to normal tissues. A subset of 327 (6.7%) SNPs induce amino acid changes to the protein coding sequences. This approach identified several SNPs which have been previously associated with carcinogenesis, as well as a number of SNPs that now warrant further investigation CONCLUSIONS: This novel in silico approach can assist in prioritization of genes and SNPs in the effort to elucidate the genetic mechanisms underlying the development of cancer

Jet energy measurement with the ATLAS detector in proton-proton collisions at root s=7 TeV

The jet energy scale and its systematic uncertainty are determined for jets measured with the ATLAS detector at the LHC in proton-proton collision data at a centre-of-mass energy of √s = 7TeV corresponding to an integrated luminosity of 38 pb-1. Jets are reconstructed with the anti-kt algorithm with distance parameters R=0. 4 or R=0. 6. Jet energy and angle corrections are determined from Monte Carlo simulations to calibrate jets with transverse momenta pT≥20 GeV and pseudorapidities {pipe}η{pipe}<4. 5. The jet energy systematic uncertainty is estimated using the single isolated hadron response measured in situ and in test-beams, exploiting the transverse momentum balance between central and forward jets in events with dijet topologies and studying systematic variations in Monte Carlo simulations. The jet energy uncertainty is less than 2. 5 % in the central calorimeter region ({pipe}η{pipe}<0. 8) for jets with 60≤pT<800 GeV, and is maximally 14 % for pT<30 GeV in the most forward region 3. 2≤{pipe}η{pipe}<4. 5. The jet energy is validated for jet transverse momenta up to 1 TeV to the level of a few percent using several in situ techniques by comparing a well-known reference such as the recoiling photon pT, the sum of the transverse momenta of tracks associated to the jet, or a system of low-pT jets recoiling against a high-pT jet. More sophisticated jet calibration schemes are presented based on calorimeter cell energy density weighting or hadronic properties of jets, aiming for an improved jet energy resolution and a reduced flavour dependence of the jet response. The systematic uncertainty of the jet energy determined from a combination of in situ techniques is consistent with the one derived from single hadron response measurements over a wide kinematic range. The nominal corrections and uncertainties are derived for isolated jets in an inclusive sample of high-pT jets. Special cases such as event topologies with close-by jets, or selections of samples with an enhanced content of jets originating from light quarks, heavy quarks or gluons are also discussed and the corresponding uncertainties are determined. © 2013 CERN for the benefit of the ATLAS collaboration

Controlling behavior, power relations within intimate relationships and intimate partner physical and sexual violence against women in Nigeria

<p>Abstract</p> <p>Background</p> <p>Controlling behavior is more common and can be equally or more threatening than physical or sexual violence. This study sought to determine the role of husband/partner controlling behavior and power relations within intimate relationships in the lifetime risk of physical and sexual violence in Nigeria.</p> <p>Methods</p> <p>This study used secondary data from a cross-sectional nationally-representative survey collected by face-to-face interviews from women aged 15 - 49 years in the 2008 Nigeria Demographic and Health Survey. Utilizing a stratified two-stage cluster sample design, data was collected frrm 19 216 eligible with the DHS domestic violence module, which is based on the Conflict Tactics Scale (CTS). Multivariate logistic regression analysis was used to determine the role of husband/partner controlling behavior in the risk of ever experiencing physical and sexual violence among 2877 women aged 15 - 49 years who were currently or formerly married or cohabiting with a male partner.</p> <p>Results</p> <p>Women who reported controlling behavior by husband/partner had a higher likelihood of experiencing physical violence (RR = 3.04; 95% CI: 2.50 - 3.69), and women resident in rural areas and working in low status occupations had increased likelihood of experiencing physical IPV. Controlling behavior by husband/partner was associated with higher likelihood of experiencing physical violence (RR = 4.01; 95% CI: 2.54 - 6.34). In addition, women who justified wife beating and earned more than their husband/partner were at higher likelihood of experiencing physical and sexual violence. In contrast, women who had decision-making autonomy had lower likelihood of experiencing physical and sexual violence.</p> <p>Conclusion</p> <p>Controlling behavior by husband/partner significantly increases the likelihood of physical and sexual IPV, thus acting as a precursor to violence. Findings emphasize the need to adopt a proactive integrated approach to controlling behavior and intimate partner violence within the society.</p

Survey of oxaliplatin-associated neurotoxicity using an interview-based questionnaire in patients with metastatic colorectal cancer

BACKGROUND: New chemotherapy regimens for patients with colorectal cancer have improved survival, but at the cost of clinical toxicity. Oxaliplatin, an agent used in first-line therapy for metastatic colorectal cancer, causes acute and chronic neurotoxicity. This study was performed to carefully assess the incidence, type and duration of oxaliplatin neurotoxicity. METHODS: A detailed questionnaire was completed after each chemotherapy cycle for patients with metastatic colorectal cancer enrolled in a phase I trial of oxaliplatin and capecitabine. An oxaliplatin specific neurotoxicity scale was used to grade toxicity. RESULTS: Eighty-six adult patients with colorectal cancer were evaluated. Acute neuropathy symptoms included voice changes, visual alterations, pharyngo-laryngeal dysesthesia (lack of awareness of breathing); peri-oral or oral numbness, pain and symptoms due to muscle contraction (spasm, cramps, tremors). When the worst neurotoxicity per patient was considered, grade 1/2/3/4 dysesthesias and paresthesias were seen in 71/12/5/0 and 66/20/7/1 percent of patients. By cycles 3, 6, 9, and 12, oxaliplatin dose reduction or discontinuation was needed in 2.7%, 20%, 37.5% and 62.5% of patients. CONCLUSION: Oxaliplatin-associated acute neuropathy causes a variety of distressing, but transient, symptoms due to peripheral sensory and motor nerve hyperexcitability. Chronic neuropathy may be debilitating and often necessitates dose reductions or discontinuation of oxaliplatin. Patients should be warned of the possible spectrum of symptoms and re-assured about the transient nature of acute neurotoxicity. Ongoing studies are addressing the treatment and prophylaxis of oxaliplatin neurotoxicity