The NAD
+-dependent deacetylase SIRT1 is an evolutionarily conserved metabolic sensor of the Sirtuin family that mediates homeostatic responses to certain physiological stresses such as nutrient ...restriction. Previous reports have implicated fluctuations in intracellular NAD
+ concentrations as the principal regulator of SIRT1 activity. However, here we have identified a cAMP-induced phosphorylation of a highly conserved serine (S434) located in the SIRT1 catalytic domain that rapidly enhanced intrinsic deacetylase activity independently of changes in NAD
+ levels. Attenuation of SIRT1 expression or the use of a nonphosphorylatable SIRT1 mutant prevented cAMP-mediated stimulation of fatty acid oxidation and gene expression linked to this pathway. Overexpression of SIRT1 in mice significantly potentiated the increases in fatty acid oxidation and energy expenditure caused by either pharmacological β-adrenergic agonism or cold exposure. These studies support a mechanism of Sirtuin enzymatic control through the cAMP/PKA pathway with important implications for stress responses and maintenance of energy homeostasis.
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► Stimulation of the cAMP/PKA pathway results in phosphorylation of SIRT1 serine 434 ► SIRT1 S434 phosphorylation increases intrinsic deacetylase activity ► SIRT1 activation by S434 phosphorylation is rapid and independent of changes in NAD
+ ► S434 phosphorylation induces PGC-1α deacetylation and increased fatty acid oxidation
We present an analysis of the mid-infrared (MIR) and optical properties of type 1 (broad-line) quasars detected by the Spitzer Space Telescope. The MIR color-redshift relation is characterized to z ...63, with predictions to z = 7. We demonstrate how combining MIR and optical colors can yield even more efficient selection of active galactic nuclei (AGNs)than MIR or optical colors alone. Composite spectral energy distributions (SEDs) are constructed for 259 quasars with both Sloan Digital Sky Survey and Spitzer photometry, supplemented by near-IR, GALEX, VLA, and ROSAT data, where available. We discuss how the spectral diversity of quasars influences the determination of bolometric luminosities and accretion rates; assuming the mean SED can lead to errors as large as 50% for individual quasars when inferring a bolometric luminosity from an optical luminosity. Finally, we show that careful consideration of the shape of the mean quasar SED and its redshift dependence leads to a lower estimate of the fraction of reddened/obscured AGNs missed by optical surveys as compared to estimates derived from a single mean MIR to optical flux ratio.
The prognosis of patients diagnosed with melanoma is highly dependent on staging, early detection, and early intervention. In this systematic review, the authors aimed to investigate the impact of ...surgical delay (time between diagnostic biopsy and definitive surgical excision) on melanoma-specific outcomes.
A systematic review was conducted from Embase (1974-present), MEDLINE (1946-present), Cochrane Central Register of Controlled Trials (2005-present), Scopus, and Web of Science. A total of 977 studies were included for review after removal of duplicates. A total of 10 studies were included for final analysis.
In total, 70% (7/10) of the studies found that longer wait times between initial biopsy and surgical intervention are correlated with lower overall survival. Among the 9 studies that reported overall survival as a percentage, the median and SD overall survival was 82% ± 5.87.
There is evidence that prolonged surgical delay in patients diagnosed with Stage I cutaneous melanoma is associated with worsened overall mortality, whereas the effect of surgical delay on overall mortality in Stages II and III melanomas is uncertain. Future prospective studies and randomized clinical trials are needed to better define the appropriate surgical wait times between biopsy and surgical treatment.
To retrospectively identify patients with VEXAS syndrome (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic syndrome) among male patients with bone marrow vacuolization using a clinically ...applicable, targeted-screening approach.
Bone marrow reports from 1 May 2014 through 18 February 2022 were reviewed for documentation of cytoplasmic vacuolization. Patients with acute leukaemia, lymphoma, metastatic solid tumour, amyloidosis or POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes) syndrome were excluded, as were those without clinical records available for direct chart review. Cases were rated for suspicion of VEXAS syndrome using a 5-point scale based on the presence of laboratory findings, clinical features and treatment response. Patients with available DNA material and moderate (three patients) or high (four to five patients) suspicion were tested for somatic UBA1 variants associated with VEXAS syndrome.
A total of 315 reports from 292 unique patients included documentation of vacuolization. Following exclusion criteria, 64 patients underwent direct medical chart review to assess likelihood of VEXAS syndrome, for which 21 patients met moderate to high suspicion. Available DNA was present in eight patients, seven (87.5%) of whom had a pathogenic somatic UBA1 variant consistent with VEXAS syndrome. The distribution of cytoplasmic vacuolization in the bone marrow biopsy reports among patients with VEXAS syndrome were erythroid and myeloid precursors (6/7), erythroid precursors only (1/7) and myeloid precursors only (0/7).
In this study, the utilization of a clinically applicable targeted-screening approach to test bone marrow specimens (with vacuolization) for the presence of previously undiagnosed VEXAS syndrome resulted in a positive detection rate of 87.5%.
Pulmonary manifestations in VEXAS syndrome Casal Moura, Marta; Baqir, Misbah; Tandon, Yasmeen K. ...
Respiratory medicine,
July 2023, 2023-07-00, 20230701, Letnik:
213
Journal Article
Recenzirano
Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome is a recently recognized multisystem disorder caused by somatic mutations in the UBA1 gene.
A retrospective cohort study was ...conducted on all patients with VEXAS syndrome evaluated at our institution from June 2020 through May 2022. Medical records and chest imaging studies were reviewed.
We identified 45 subjects with median age of 68 years (range, 57–89), all men. Prior to VEXAS diagnosis, most patients had been diagnosed with various hematologic, rheumatologic, and dermatologic disorders. Most patients (84%) demonstrated canonical UBA1 methionine-41 (p.Met41) somatic mutations in hematopoietic cells. Fever (82%), skin lesions (91%), and respiratory symptoms (93%) were common presenting features. Chest CT manifested abnormalities in 91% of patients including parenchymal opacities in 25 (74%), most commonly ground-glass opacities (47%), along with mediastinal lymphadenopathy (29%), airway abnormalities (29%), and pleural effusion (24%). Pulmonary function test results available in 18 (40%) patients demonstrated mild restrictive impairment or normal results. Bronchoalveolar lavage and lung biopsy performed in a minority of patients demonstrated neutrophilic alveolitis and parenchymal inflammation, respectively. All patients received glucocorticoid therapy with at least partial response, but relapses were common and other immunosuppressive agents were employed in most patients. Pulmonary involvement appeared to improve in patients who received tocilizumab and JAK inhibitors.
The pulmonary manifestations in VEXAS are relatively nonspecific and nonsevere, occur in the context of systemic inflammation and are responsive to escalation in glucocorticoid dosing.
•Respiratory symptoms are common in the clinical presentation of VEXAS syndrome.•Parenchymal opacities are seen on chest CT for ¾ of patients, most commonly GGOs.•Most patients respond to glucocorticoid therapy, but relapses occur at lower doses.•Respiratory manifestations are nonspecific and reflect multi-organ inflammation.
Background
VEXAS (vacuoles, E1 enzyme, X‐linked, autoinflammatory, somatic) syndrome is an autoinflammatory disease with frequent cutaneous manifestations.
Methods
We conducted a retrospective study ...of all patients with genetically confirmed VEXAS syndrome seen at our institution. Available clinical photographs and skin biopsy slides were reviewed.
Results
Cutaneous manifestations developed in 22/25 (88%) patients with VEXAS syndrome. From this group, 10/22 (45%) developed skin involvement before or at the time of other clinical features of VEXAS. Twenty distinct dermatologic presentations of VEXAS from 14 patients were reviewed, and histopathologic patterns were classified as follows: neutrophilic urticarial dermatosis (n = 5, 25%), leukocytoclastic/urticarial vasculitis (n = 4, 20%), urticarial tissue reaction (n = 4, 20%), neutrophilic dermatosis (n = 3, 15%), neutrophilic panniculitis (n = 2, 10%), and nonspecific chronic septal panniculitis (n = 2, 10%). Common systemic findings included macrocytic anemia (96%), fever (88%), thrombocytopenia (76%), weight loss (76%), ocular inflammation (64%), pulmonary infiltrates (56%), deep venous thrombosis or pulmonary embolism (52%), and inflammatory arthritis (52%).
Conclusions
Cutaneous involvement is a common feature of VEXAS syndrome, and histopathologic findings exist on a spectrum of neutrophilic inflammatory dermatoses.
Current guidelines recommend deferring liver transplantation (LT) in patients with severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection until clinical improvement occurs and two PCR ...tests collected at least 24 hours apart are negative. We report a case of an 18‐year‐old, previously healthy African‐American woman diagnosed with COVID‐19, who presents with acute liver failure (ALF) requiring urgent LT in the context of SARS‐CoV‐2 polymerase chain reaction (PCR) positivity. The patient was thought to have acute Wilsonian crisis on the basis of hemolytic anemia, alkaline phosphatase:bilirubin ratio <4, AST:ALT ratio >2.2, elevated serum copper, and low uric acid, although an unusual presentation of COVID‐19 causing ALF could not be excluded. After meeting criteria for status 1a listing, the patient underwent successful LT, despite ongoing SARS‐CoV‐2 PCR positivity. Remdesivir was given immediately posttransplant, and mycophenolate mofetil was withheld initially and the SARS‐CoV‐2 PCR test eventually became negative. Three months following transplantation, the patient has made a near‐complete recovery. This case highlights that COVID‐19 with SARS‐CoV‐2 PCR positivity may not be an absolute contraindication for transplantation in ALF. Criteria for patient selection and timing of LT amid the COVID‐19 pandemic need to be validated in future studies.
An 18‐year‐old, previously healthy African American woman presents with both acute COVID‐19 (known recent exposure; SARS‐CoV‐2 polymerase chain reaction positivity) and acute liver failure (previously undiagnosed Wilson's Disease), undergoes urgent liver transplantation 2 weeks after presentation and has a near‐complete recovery.
l-Glutamate is a major excitatory neurotransmitter that binds ionotropic and metabotropic glutamate receptors. Cerebral endothelial cells from many species have been shown to express several forms of ...glutamate receptors; however, human cerebral endothelial cells have not been shown to express either the N-methyl-D-aspartate (NMDA) receptor message or protein. This study provides evidence that human cerebral endothelial cells express the message and protein for NMDA receptors. Human cerebral endothelial cell monolayer electrical resistance changes in response to glutamate receptor agonists, antagonists, and second message blockers were tested. RT-PCR and Western blot analysis were used to demonstrate the presence of the NMDA receptor. Glutamate and NMDA (1 mM) caused a significant decrease in electrical resistance compared with sham control at 2 h postexposure; this response could be blocked significantly by MK-801 (an NMDA antagonist), 8-(N,N-diethylamino)-n-octyl-3,4,5-trimethyoxybenzoate (an intracellular Ca2+ antagonist), and N-acetyl-L-cystein (an antioxidant). Trans(+/-)-1-amino-1,3-cyclopentanedicarboxylic acid, a metabotropic receptor agonist (1 mM), did not significantly decrease electrical resistance. Our results are consistent with a model where glutamate, at excitotoxic levels, may lead to a breakdown in the blood brain barrier via activation of NMDA receptors.
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