Benzo
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1,2,4triazinyl, or Blatter radicals, are stable free radicals, first reported by Blatter in 1968. In contrast to their nitroxide counterparts, their properties can be modified more widely and ...more easily through simple substitution changes. This, together with recent developments in their synthesis, now places them at the forefront of developing applications in functional materials. Herein, we survey the various methods to synthesise and customise Blatter radicals, highlighting key developments in the last decade that have transformed their utility. We then outline their important spectroscopic, structural, electrochemical, magnetic and chemical properties and how these depend on their chemical structure and morphology. Finally, we review their growing list of applications including as sensors, spin labels, magnetic materials, liquid crystals and in polymer and small molecule synthesis.
Benzo
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1,2,4triazinyl, or Blatter radicals, are stable free radicals with customisable magnetic, spectroscopic and electrochemical properties, and wide-ranging applications in synthesis and functional materials.
To investigate why certain at-risk individuals develop celiac disease (CD), we examined the association of proton pump inhibitors (PPI), histamine-2 receptor antagonists (H2RAs), and antibiotic ...prescriptions in the first 6 months of life with an early childhood diagnosis of CD.
A retrospective cohort study was performed using the Military Healthcare System database. Children with a birth record from October 1, 2001, to September 30, 2013, were identified. Outpatient prescription records were queried for antibiotic, PPI, and H2RA prescriptions in the first 6 months of life. Cox proportional hazards regression was used to calculate the hazard ratio (HR) of developing CD based on medication exposure. International Classification of Diseases, Ninth Revision, Clinical Modification codes identified children with an outpatient visit for CD.
There were 968 524 children who met the inclusion criteria with 1704 cases of CD in this group. The median follow-up for the cohort was approximately 4.5 years. PPIs (HR, 2.23; 95% CI, 1.76-2.83), H2RAs (HR, 1.94; 95% CI, 1.67-2.26), and antibiotics (HR, 1.14; 95% CI, 1.02-1.28) were all associated with an increased hazard of CD.
There is an increased risk of developing CD if antibiotics, PPIs and H2RAs are prescribed in the first 6 months of life. Our study highlights modifiable factors, such as medication stewardship, that may change the childhood risk of CD.
Objective To assess the prognostic accuracy of early cumulative supplemental oxygen (CSO) exposure for prediction of bronchopulmonary dysplasia (BPD) or death, and to evaluate the independent ...association of CSO with BPD or death. Study design We performed a secondary analysis of the Trial of Late Surfactant, which enrolled 511 infants born at ≤28 weeks gestational age who were mechanically ventilated at 7-14 days of life. Our primary outcome was BPD or death at 36 weeks postmenstrual age, as determined by a physiological oxygen/flow challenge. Average daily supplemental oxygen (fraction of inspired oxygen - 0.21) was calculated. CSO was calculated as the sum of the average daily supplemental oxygen over time periods of interest up to 28 days of age. Area under the receiver operating curve (AUROC) values were generated to evaluate the accuracy of CSO for prediction of BPD or death. The independent relationship between CSO and BPD or death was assessed in multivariate modeling, while adjusting for mean airway pressure. Results In the study infants, mean gestational age at birth was 25.2 ± 1.2 weeks and mean birth weight was 700 ± 165 g. The AUROC value for CSO at 14 days was significantly better than that at earlier time points for outcome prediction (OR, 0.70; 95% CI, 0.65-0.74); it did not increase with the addition of later data. In multivariate modeling, a CSO increase of 1 at 14 days increased the odds of BPD or death (OR, 1.7; 95% CI, 1.3-2.2; P < .0001), which corresponds to a 7% higher daily supplemental oxygen value. Conclusion In high-risk extremely low gestational age newborns, the predictive accuracy of CSO plateaus at 14 days. CSO is independently associated with BPD or death. This index may identify infants who could benefit from early intervention to prevent BPD.
Therapeutic Targeting of the Respiratory Microbiome Chotirmall, Sanjay H; Bogaert, Debby; Chalmers, James D ...
American journal of respiratory and critical care medicine,
09/2022, Letnik:
206, Številka:
5
Journal Article
Recenzirano
Odprti dostop
Our understanding of the microbiome in health and illness has changed as a result of culture-independent microbiology. We can now understand the intricacy of microbial communities within the ...respiratory tract, along with their metabolic, immunologic, and pathophysiologic effects, thanks to advancements in next-generation sequencing and other technologies. Respiratory microbiota are detectable, viable, and variable across patients across the spectrum of acute and chronic respiratory disease; correlated with disease status and seventy (I); linked to airway and alveolar inflammation; metabolically active and immunologically consequential; predictive of clinical outcomes; influenced by environment and geography; and causally involved in disease pathogenesis in animal models. Given these revelations, we think it wise to view the respiratory microbiome as an untapped, understudied therapeutic target and a biologically relevant therapeutic target.
l-Asparaginase (l-ASP) is a key component of therapy for acute lymphoblastic leukemia. Its mechanism of action, however, is still poorly understood, in part because of its dual asparaginase and ...glutaminase activities. Here, we show that l-ASP’s glutaminase activity is not always required for the enzyme’s anticancer effect. We first used molecular dynamics simulations of the clinically standard Escherichia colil-ASP to predict what mutated forms could be engineered to retain activity against asparagine but not glutamine. Dynamic mapping of enzyme substrate contacts identified Q59 as a promising mutagenesis target for that purpose. Saturation mutagenesis followed by enzymatic screening identified Q59L as a variant that retains asparaginase activity but shows undetectable glutaminase activity. Unlike wild-type l-ASP, Q59L is inactive against cancer cells that express measurable asparagine synthetase (ASNS). Q59L is potently active, however, against ASNS-negative cells. Those observations indicate that the glutaminase activity of l-ASP is necessary for anticancer activity against ASNS-positive cell types but not ASNS-negative cell types. Because the clinical toxicity of l-ASP is thought to stem from its glutaminase activity, these findings suggest the hypothesis that glutaminase-negative variants of l-ASP would provide larger therapeutic indices than wild-type l-ASP for ASNS-negative cancers.
•We used molecular dynamics, saturation mutagenesis, and enzymologic screening to develop a glutaminase-free mutant (Q59L) l-ASP.•We then used Q59L to show that glutaminase activity is not required for l-ASP activity against ASNS-negative cancer cells.
Type 1 diabetes mellitus (T1DM) is a lifelong diagnosis that involves immune-mediated damage of pancreatic beta cells and subsequent hyperglycemia, manifesting as: polyuria, polydipsia, polyphagia, ...and weight loss. Treatment of type 1 diabetes centers on insulin administration to replace or supplement the body's own insulin with the goal of achieving euglycemia and preventing or minimizing complications. Patients with T1DM are at risk for developing other autoimmune conditions, most commonly thyroid or celiac disease.
A 20-year-old African American female with T1DM was referred by her endocrinologist to pediatric gastroenterology for 2 months of nocturnal, non-bloody diarrhea, left lower quadrant pain, and nausea; she was also being followed by neurology for complaints of lower extremity paresthesias and pain. The patient's initial lab-workup was remarkable for a low total Immunoglobulin A (IgA) level of < 6.7 mg/dL. As IgA deficiency is associated with an increased risk of celiac disease, the patient underwent upper and lower endoscopy, which was grossly unremarkable; however, histology revealed a pattern consistent with autoimmune gastritis. Subsequent serum evaluation was remarkable for an elevated fasting gastrin level and an elevated parietal cell antibody level without macrocytic anemia, iron deficiency, or vitamin B12 depletion. The patient was diagnosed with autoimmune gastritis (AIG) and subsequently initiated on parenteral B12 supplementation therapy with improvement in her neurologic and gastrointestinal symptoms.
This case illustrates the importance of recognition of red flag findings in a patient with known autoimmune disease. Following well-established health maintenance recommendations for individuals with T1DM ensures that common comorbidities will be detected. Autoimmune gastritis, while a rarer pathology in the pediatric population, deserves consideration in patients with pre-existing autoimmune conditions and new gastrointestinal or neurologic symptoms, as AIG can be associated with poor outcomes and risk of malignancy. Initial lab findings associated with an eventual diagnosis of AIG typically include anemia, iron deficiency, or Vitamin B12 deficiency. However, as demonstrated in this case, symptoms of AIG can rarely present before anemia or Vitamin B12 deficiency develops. To prevent permanent neurological damage, parenteral Vitamin B12 therapy must be considered even in the absence of Vitamin B12 deficiency, especially in those patients already experiencing neurological symptoms.
The purpose of this study was to evaluate the effects of ambulance driving distance and transport time on mortality among trauma incidents occurring in the City of Chicago, a large metropolitan area.
...We studied individuals 16 years or older who suffered a Level I or II injury and were taken to a Level I trauma center. The outcome was in-hospital mortality, including those dead on arrival but excluding those deemed dead on scene. Driving distance was calculated from the scene of injury to the trauma center where the patient was taken. Transport time was defined as the time from scene departure to arrival at the trauma center. Covariates included injury severity measures recorded at the scene. Logistic regression and instrumental variable probit regression models were used to examine the association between driving distance, transport time, and mortality, adjusting for injury severity.
A total of 24,834 incidents were analyzed, including 1,464 deaths. Median driving distance was 3.9 miles, and median transport time was 13 minutes. Our findings indicate that increased driving distance is associated with a modest increase in mortality, with a covariate-adjusted odds ratio of 1.12 per 2-mile increase in distance (95% confidence interval CI, 1.05-1.20). This corresponds to an increase in overall mortality of 0.26 percentage points per 2 miles (95% CI, 0.11-0.40). Using distance as an instrumental variable, we estimate a 0.51 percentage point increase in mortality per 5-minute increase in transport time (95% CI, 0.14-0.89).
We find a modest effect of distance on mortality that is approximately linear over a range of 0 to 12 miles. Instrumental variables analysis indicated a corresponding increase in mortality with increasing transport time. Limitations of the study include the possibility of unmeasured confounders and the assumption that distance affects mortality only through its effect on transport time.
Prognostic study, level III.
The plasticity of a preexisting regulatory circuit compromises the effectiveness of targeted therapies, and leveraging genetic vulnerabilities in cancer cells may overcome such adaptations. ...Hereditary leiomyomatosis renal cell carcinoma (HLRCC) is characterized by oxidative phosphorylation (OXPHOS) deficiency caused by fumarate hydratase (FH) nullizyogosity. To identify metabolic genes that are synthetically lethal with OXPHOS deficiency, we conducted a genetic loss-of-function screen and found that phosphogluconate dehydrogenase (PGD) inhibition robustly blocks the proliferation of FH mutant cancer cells both in vitro and in vivo. Mechanistically, PGD inhibition blocks glycolysis, suppresses reductive carboxylation of glutamine, and increases the NADP+/NADPH ratio to disrupt redox homeostasis. Furthermore, in the OXPHOS-proficient context, blocking OXPHOS using the small-molecule inhibitor IACS-010759 enhances sensitivity to PGD inhibition in vitro and in vivo. Together, our study reveals a dependency on PGD in OXPHOS-deficient tumors that might inform therapeutic intervention in specific patient populations.
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•PGD is a top hit in a loss-of-function genetics screen in OXPHOS-deficient cancer•OXPHOS-deficient cells depend on PGD in vitro and in vivo•PGD inhibition affects glycolysis, reductive carboxylation, and redox homeostasis•Pharmacological inhibition of OXPHOS renders PGD dependent
Loss-of-function genetics screen reveals a synthetically lethal interaction between OXPHOS inhibition and phosphogluconate dehydrogenase (PGD) inactivation. Sun et al. provide an example of targeting tumor metabolism in a genetically predefined context to maximize therapeutic impact and propose PGD as a therapeutic target for fumarate hydratase-deficient HLRCC.
To implement and to evaluate the effectiveness of the Uniformed Services Constipation Action Plan (USCAP) in our gastroenterology clinic for children with functional constipation.
This implementation ...science study included toilet-trained subjects aged 4 years and older who met the Rome IV criteria for functional constipation. Children were block randomized to receive either the USCAP or control. All clinic functional constipation plans recommended subjects continue pharmacotherapy for 4 months. Endpoints measured were clinical outcomes (resolution of functional constipation and achievement of a Pediatric Bristol Stool Form Scale PBSFS score of 3 or 4), patient-related outcomes (health-related quality of life HRQoL total scale score), and health confidence outcomes (Health Confidence Score HCS).
Fifty-seven treatment group subjects (44%) received a USCAP (52% male; mean age, 10.9 4.9 years) compared with 73 controls (56%; 48% male; mean age,10.9 5.3 years). A PBSFS score of 3 or 4 was achieved by 77% of the treatment group compared with 59% of controls (P = .03). Subjects from the treatment group were more likely than the controls to endorse adherence to the 4-month course of pharmacotherapy (P < .001). Subjects who received a USCAP had greater improvements in HRQoL total scale score by the end of the project (P = .04).
The USCAP is a simple, inexpensive tool that has the potential to improve global outcomes for functional constipation in children and should be recommended as standard clinical practice.
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