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"Friedman, Richard"
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Antidepressants' Black-Box Warning — 10 Years Later
In 2004, the FDA issued a black-box warning linking antidepressants to an increased risk of suicidal thinking, feeling, and behavior in young people. But some worrisome trends suggest that the warning may inadvertently discourage appropriate treatment of depression.
In 2004, the Food and Drug Administration (FDA) issued a black-box warning on antidepressants indicating that they were associated with an increased risk of suicidal thinking, feeling, and behavior in young people. The agency's decision was immediately controversial: many members of the medical community worried that this warning would do more harm than good because it would discourage depressed patients from seeking help and discourage doctors from prescribing antidepressants when they were clinically indicated. Now, 10 years later, there are substantial epidemiologic data to address these important concerns. What effect has the FDA warning had on the rates of detection . . .
Journal Article
Opposing roles of hepatic stellate cell subpopulations in hepatocarcinogenesis
Hepatocellular carcinoma (HCC), the fourth leading cause of cancer mortality worldwide, develops almost exclusively in patients with chronic liver disease and advanced fibrosis
1
,
2
. Here we interrogated functions of hepatic stellate cells (HSCs), the main source of liver fibroblasts
3
, during hepatocarcinogenesis. Genetic depletion, activation or inhibition of HSCs in mouse models of HCC revealed their overall tumour-promoting role. HSCs were enriched in the preneoplastic environment, where they closely interacted with hepatocytes and modulated hepatocarcinogenesis by regulating hepatocyte proliferation and death. Analyses of mouse and human HSC subpopulations by single-cell RNA sequencing together with genetic ablation of subpopulation-enriched mediators revealed dual functions of HSCs in hepatocarcinogenesis. Hepatocyte growth factor, enriched in quiescent and cytokine-producing HSCs, protected against hepatocyte death and HCC development. By contrast, type I collagen, enriched in activated myofibroblastic HSCs, promoted proliferation and tumour development through increased stiffness and TAZ activation in pretumoural hepatocytes and through activation of discoidin domain receptor 1 in established tumours. An increased HSC imbalance between cytokine-producing HSCs and myofibroblastic HSCs during liver disease progression was associated with increased HCC risk in patients. In summary, the dynamic shift in HSC subpopulations and their mediators during chronic liver disease is associated with a switch from HCC protection to HCC promotion.
Subpopulations of cytokine-producing and myofibroblastic hepatic stellate cells, identified by single-cell RNA sequencing, protect against or promote the development of hepatocellular carcinoma via high expression of hepatocyte growth factor or type I collagen, respectively..
Journal Article
Mycobacterium tuberculosis Eis Regulates Autophagy, Inflammation, and Cell Death through Redox-dependent Signaling
The \"enhanced intracellular survival\" (eis) gene of Mycobacterium tuberculosis (Mtb) is involved in the intracellular survival of M. smegmatis. However, its exact effects on host cell function remain elusive. We herein report that Mtb Eis plays essential roles in modulating macrophage autophagy, inflammatory responses, and cell death via a reactive oxygen species (ROS)-dependent pathway. Macrophages infected with an Mtb eis-deletion mutant H37Rv (Mtb-Δeis) displayed markedly increased accumulation of massive autophagic vacuoles and formation of autophagosomes in vitro and in vivo. Infection of macrophages with Mtb-Δeis increased the production of tumor necrosis factor-α and interleukin-6 over the levels produced by infection with wild-type or complemented strains. Elevated ROS generation in macrophages infected with Mtb-Δeis (for which NADPH oxidase and mitochondria were largely responsible) rendered the cells highly sensitive to autophagy activation and cytokine production. Despite considerable activation of autophagy and proinflammatory responses, macrophages infected with Mtb-Δeis underwent caspase-independent cell death. This cell death was significantly inhibited by blockade of autophagy and c-Jun N-terminal kinase-ROS signaling, suggesting that excessive autophagy and oxidative stress are detrimental to cell survival. Finally, artificial over-expression of Eis or pretreatment with recombinant Eis abrogated production of both ROS and proinflammatory cytokines, which depends on the N-acetyltransferase domain of the Eis protein. Collectively, these data indicate that Mtb Eis suppresses host innate immune defenses by modulating autophagy, inflammation, and cell death in a redox-dependent manner.
Journal Article
Complication Rates After Hip or Knee Arthroplasty in Morbidly Obese Patients
Background
Morbid obesity has been shown to be a risk factor for increased complications after THA and TKA; however, large studies that would determine the effect size are lacking.
Questions/purposes
The purposes of this study were to determine whether morbid obesity increased the risk of: (1) venous thromboembolism (VTE), (2) bleeding, (3) other adverse events, and (4) infections during the early postoperative period (up to 6 to 8 weeks) after THA or TKA?
Methods
Data from the REgulation of Coagulation in ORthopaedic surgery to prevent Deep vein thrombosis and pulmonary embolism (RECORD) clinical trial program of rivaroxaban for prevention of VTE after THA or TKA were analyzed retrospectively. Data for 12,355 patients were reviewed to identify complication rates in morbidly obese patients (BMI ≥ 40 kg/m
2
) compared with patients with a BMI less than 40 kg/m
2
. Explorative analyses compared the rates of asymptomatic deep vein thrombosis (DVT), symptomatic DVT, symptomatic pulmonary embolism, bleeding, and other adverse events by BMI group.
Results
There were no significant differences in asymptomatic DVT, symptomatic DVT, symptomatic pulmonary embolism, or bleeding, but there were increases in other adverse events (including receipt of blood transfusion, erythema, peripheral edema, diarrhea, gastrointestinal or abdominal pain) and infections (including respiratory tract or lung infections, wound inflammation or infection, and extrasurgical-site infections), in patients with a BMI of 40 kg/m
2
or greater compared with patients with a BMI less than 40 kg/m
2
.
Conclusions
After THA or TKA, morbid obesity is not associated with an increased risk of VTE or bleeding but is associated with increased early postoperative complications, including erythema, peripheral edema, diarrhea and gastrointestinal or abdominal pain, wound inflammation or infection, extrasurgical-site infections, and respiratory tract or lung infections.
Level of Evidence
Level III, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.
Journal Article
Grief, Depression, and the DSM-5
Though bereaved persons often have depressive symptoms, grief typically runs its course within 2 to 6 months and requires no treatment. But the new edition of the
Diagnostic and Statistical Manual of Mental Disorders
may define bereavement as a depressive disorder.
Nearly 2.5 million Americans die each year, leaving behind an even larger group of grief-stricken people.
1
Such a universal human experience as grief is recognized by the lay public and medical professionals alike as an entirely normal and expected emotional response to loss. Clinicians and researchers have long known that, for the vast majority of people, grief typically runs its course within 2 to 6 months and requires no treatment.
In a common clinical scenario, a patient who has just lost a loved one presents to a physician with mild depressive symptoms, such as sadness, tearfulness, and insomnia. Under the . . .
Journal Article
Evidence for rapid weathering response to climatic warming during the Toarcian Oceanic Anoxic Event
Chemical weathering consumes atmospheric carbon dioxide through the breakdown of silicate minerals and is thought to stabilize Earth’s long-term climate. However, the potential influence of silicate weathering on atmospheric
p
CO
2
levels on geologically short timescales (10
3
–10
5
years) remains poorly constrained. Here we focus on the record of a transient interval of severe climatic warming across the Toarcian Oceanic Anoxic Event or T-OAE from an open ocean sedimentary succession from western North America. Paired osmium isotope data and numerical modelling results suggest that weathering rates may have increased by 215% and potentially up to 530% compared to the pre-event baseline, which would have resulted in the sequestration of significant amounts of atmospheric CO
2
. This process would have also led to increased delivery of nutrients to the oceans and lakes stimulating bioproductivity and leading to the subsequent development of shallow-water anoxia, the hallmark of the T-OAE. This enhanced bioproductivity and anoxia would have resulted in elevated rates of organic matter burial that would have acted as an additional negative feedback on atmospheric
p
CO
2
levels. Therefore, the enhanced weathering modulated by initially increased
p
CO
2
levels would have operated as both a direct and indirect negative feedback to end the T-OAE.
Journal Article
Collective Trauma and Commemoration — A Moment of Silence, Please
Collective Trauma and CommemorationThe Covid-19 pandemic had characteristics of a collective traumatic event. A moment of silence could help people reflect on this catastrophe and lessen its continued emotional effect.
Journal Article
HMGB1 links chronic liver injury to progenitor responses and hepatocarcinogenesis
Cell death is a key driver of disease progression and carcinogenesis in chronic liver disease (CLD), highlighted by the well-established clinical correlation between hepatocellular death and risk for the development of cirrhosis and hepatocellular carcinoma (HCC). Moreover, hepatocellular death is sufficient to trigger fibrosis and HCC in mice. However, the pathways through which cell death drives CLD progression remain elusive. Here, we tested the hypothesis that high-mobility group box 1 (HMGB1), a damage-associated molecular pattern (DAMP) with key roles in acute liver injury, may link cell death to injury responses and hepatocarcinogenesis in CLD. While liver-specific HMGB1 deficiency did not significantly affect chronic injury responses such as fibrosis, regeneration, and inflammation, it inhibited ductular/progenitor cell expansion and hepatocyte metaplasia. HMGB1 promoted ductular expansion independently of active secretion in a nonautonomous fashion, consistent with its role as a DAMP. Liver-specific HMGB1 deficiency reduced HCC development in 3 mouse models of chronic injury but not in a model lacking chronic liver injury. As with CLD, HMGB1 ablation reduced the expression of progenitor and oncofetal markers, a key determinant of HCC aggressiveness, in tumors. In summary, HMGB1 links hepatocyte death to ductular reaction, progenitor signature, and hepatocarcinogenesis in CLD.
Journal Article