ABSTRACTDespite their ubiquitous presence, placebos and placebo effects retain an ambiguous and unsettling presence in biomedicine. Specifically focused on chronic pain, this review examines the ...effect of placebo treatment under three distinct frameworks: double blind, deception, and open label honestly prescribed. These specific conditions do not necessarily differentially modify placebo outcomes. Psychological, clinical, and neurological theories of placebo effects are scrutinized. In chronic pain, conscious expectation does not reliably predict placebo effects. A supportive patient-physician relationship may enhance placebo effects. This review highlights “predictive coding” and “bayesian brain” as emerging models derived from computational neurobiology that offer a unified framework to explain the heterogeneous evidence on placebos. These models invert the dogma of the brain as a stimulus driven organ to one in which perception relies heavily on learnt, top down, cortical predictions to infer the source of incoming sensory data. In predictive coding/bayesian brain, both chronic pain (significantly modulated by central sensitization) and its alleviation with placebo treatment are explicated as centrally encoded, mostly non-conscious, bayesian biases. The review then evaluates seven ways in which placebos are used in clinical practice and research and their bioethical implications. In this way, it shows that placebo effects are evidence based, clinically relevant, and potentially ethical tools for relieving chronic pain.
The glutathione (GSH) biosynthetic pathway in brain tumors. (A) Most brain tumors arise from 3 main cell types or their progenitors: neurons (green), oligodendrocytes (cyan), and astrocytes ...(magenta). (B) GSH biosynthesis consists of two ATP-dependent reactions: (1) glutamate cysteine ligase (GCL)-mediated formation of γ-glutamyl-cysteine (γGluCys) from glutamate (Glu) and cysteine (Cys) and (2) GSH synthetase (GS)-catalyzed formation of GSH from γGluCys and glycine (Gly). Buthionine sulfoximine (BSO) is an irreversible inhibitor of GCL. Detoxification of chemotherapeutic agents proceeds via the GSH-S-transferase (GST)-mediated formation of GSH-drug conjugates (GSH-X) followed by efflux by multidrug resistance protein (Mrp) transporters. γ-Glutamyl transpeptidase (γGT) can break GSH down into Glu and cysteinylglycine (CysGly). CysGly is further hydrolyzed by cellular dipeptidases (DP) followed by the transporter-mediated uptake of the constituent amino acids that can serve as substrates for either cellular GSH production or protein synthesis. Additional Cys may also be obtained via the glutamate-cystine antiporter (Xc-)-mediated uptake of extracellular cystine (CysCys).
Chemotherapy is central to the current treatment modality for primary human brain tumors, but despite high-dose and intensive treatment regimens there has been little improvement in patient outcome. The development of tumor chemoresistance has been proposed as a major contributor to this lack of response. While there have been some improvements in our understanding of the molecular mechanisms underlying brain tumor drug resistance over the past decade, the contribution of glutathione (GSH) and the GSH-related enzymes to drug resistance in brain tumors have been largely overlooked. GSH constitutes a major antioxidant defense system in the brain and together with the GSH-related enzymes plays an important role in protecting cells against free radical damage and dictating tumor cell response to adjuvant cancer therapies, including irradiation and chemotherapy. Glutamate cysteine ligase (GCL), glutathione synthetase (GS), glutathione peroxidase (GPx), glutathione reductase (GR), glutathione-S-transferases (GST), and GSH complex export transporters (GS-X pumps) are major components of the GSH-dependent enzyme system that function in a dynamic cascade to maintain redox homeostasis. In many tumors, the GSH system is often dysregulated, resulting in a more drug resistant phenotype. This is commonly associated with GST-mediated GSH conjugation of various anticancer agents leading to the formation of less toxic GSH–drug complexes, which can be readily exported from the cell. Advances in our understanding of the mechanisms of drug resistance and patient selection based on biomarker profiles will be crucial to adapt therapeutic strategies and improve outcomes for patients with primary malignant brain tumors.
The skill of North American multimodel ensemble (NMME) seasonal forecasts in East Africa (EA), which encompasses one of the most food and water insecure areas of the world, is evaluated using ...deterministic, categorical, and probabilistic evaluation methods. The skill is estimated for all three primary growing seasons: March–May (MAM), July–September (JAS), and October–December (OND). It is found that the precipitation forecast skill in this region is generally limited and statistically significant over only a small part of the domain. In the case of MAM (JAS) OND season it exceeds the skill of climatological forecasts in parts of equatorial EA (Northern Ethiopia) equatorial EA for up to 2 (5) 5 months lead. Temperature forecast skill is generally much higher than precipitation forecast skill (in terms of deterministic and probabilistic skill scores) and statistically significant over a majority of the region. Over the region as a whole, temperature forecasts also exhibit greater reliability than the precipitation forecasts. The NMME ensemble forecasts are found to be more skillful and reliable than the forecast from any individual model. The results also demonstrate that for some seasons (e.g. JAS), the predictability of precipitation signals varies and is higher during certain climate events (e.g. ENSO). Finally, potential room for improvement in forecast skill is identified in some models by comparing homogeneous predictability in individual NMME models with their respective forecast skill.
Glutathione (GSH) is a tripeptide composed of glutamate, cysteine, and glycine. The first and rate-limiting step in GSH synthesis is catalyzed by glutamate cysteine ligase (GCL, previously known as ...γ-glutamylcysteine synthetase). GCL is a heterodimeric protein composed of catalytic (GCLC) and modifier (GCLM) subunits that are expressed from different genes. GCLC catalyzes a unique γ-carboxyl linkage from glutamate to cysteine and requires ATP and Mg
++ as cofactors in this reaction. GCLM increases the
V
max and
K
cat of GCLC, decreases the
K
m for glutamate and ATP, and increases the
K
i for GSH-mediated feedback inhibition of GCL. While post-translational modifications of GCLC (e.g. phosphorylation, myristoylation, caspase-mediated cleavage) have modest effects on GCL activity, oxidative stress dramatically affects GCL holoenzyme formation and activity. Pyridine nucleotides can also modulate GCL activity in some species. Variability in GCL expression is associated with several disease phenotypes and transgenic mouse and rat models promise to be highly useful for investigating the relationships between GCL activity, GSH synthesis, and disease in humans.
Abstract Background Perioperative hypotension and bradycardia in the surgical patient are associated with adverse outcomes, including stroke. We developed and evaluated a new preoperative risk model ...in predicting intraoperative hypotension or bradycardia in patients undergoing elective noncardiac surgery. Methods Prospective data were collected in 193 patients undergoing elective, noncardiac surgery. Intraoperative hypotension was defined as systolic blood pressure <90 mm Hg for >5 minutes or a 35% decrease in the mean arterial blood pressure. Intraoperative bradycardia was defined as a heart rate of <60 beats/min for >5 minutes. A logistic regression model was developed for predicting intraoperative hypotension or bradycardia with bootstrap validation. Model performance was assessed using area under the receiver operating curves and Hosmer-Lemeshow tests. Results A total of 127 patients developed hypotension or bradycardia. The average age of participants was 67.6 ± 11.3 years, and 59.1% underwent major surgery. A final 5-item score was developed, including preoperative Heart rate (<60 beats/min), preoperative hypotension (<110/60 mm Hg), Elderly age (>65 years), preoperative renin-Angiotensin blockade (angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, or beta-blockers), Revised cardiac risk index (≥3 points), and Type of surgery (major surgery), entitled the “HEART” score. The HEART score was moderately predictive of intraoperative bradycardia or hypotension (odds ratio, 2.51; 95% confidence interval, 1.79-3.53; C-statistic, 0.75). Maximum points on the HEART score were associated with an increased likelihood ratio for intraoperative bradycardia or hypotension (likelihood ratio, +3.64). Conclusions The 5-point HEART score was predictive of intraoperative hypotension or bradycardia. These findings suggest a role for using the HEART score to better risk-stratify patients preoperatively and may help guide decisions on perioperative management of blood pressure and heart rate-lowering medications and anesthetic agents.
Biochemical combinatorial techniques such as phage display, RNA display and oligonucleotide aptamers have proven to be reliable methods for generation of ligands to protein targets. Adapting these ...techniques to small synthetic molecules has been a long-sought goal. We report the synthesis and interrogation of an 800-million-member DNA-encoded library in which small molecules are covalently attached to an encoding oligonucleotide. The library was assembled by a combination of chemical and enzymatic synthesis, and interrogated by affinity selection. We describe methods for the selection and deconvolution of the chemical display library, and the discovery of inhibitors for two enzymes: Aurora A kinase and p38 MAP kinase.
Background
Trichotillomania (TTM) is a psychiatric disorder that leads to significant hair loss, distress, and impairment. Few validated measures exist to assess TTM, and psychometric research ...examining these tools is sparse. This study evaluated the psychometric properties of commonly used TTM severity measures and extended prior research by including hair loss severity ratings in our analyses.
Methods
Participants included 91 adults (92.3% Female;
M
age = 35.0) with TTM who completed baseline assessments as part of a randomized clinical trial of psychotherapy for TTM. TTM measures included the Massachusetts General Hospital Hairpulling Scale (MGH-HS) and National Institute of Mental Health Trichotillomania Severity Scale (NIMH-TSS). Independent evaluators rated photos of participants’ most severely affected pulling sites using a one-item hair loss severity scale.
Results
Results showed mixed psychometric properties for TTM measures. The MGH-HS showed acceptable internal consistency (alpha = 0.83; omega = 0.89), while the NIMH-TSS had lower internal consistency (alpha = 0.52; omega = 0.73). Both the MGH-HS and NIMH-TSS demonstrated low test-retest reliability. Total scores on the MGH-HS and NIMH-TSS were not associated with hair loss severity.
Conclusions
Given these findings, it is imperative to develop new, psychometrically-sound TTM measures. These results also emphasize the importance of a multi-method approach to TTM assessment. In addition to self-report and clinician-administered measures, hair loss severity ratings may offer valuable information as part of a comprehensive assessment of TTM.
Hypertonic saline (HTS) has been used intravenously to reduce organ dysfunction following injury and as an inhaled therapy for cystic fibrosis lung disease. The role and mechanism of HTS inhibition ...was explored in the TNFα and IL-1β stimulation of pulmonary epithelial cells. Hyperosmolar (HOsm) media (400 mOsm) inhibited the production of select cytokines stimulated by TNFα and IL-1β at the level of mRNA translation, synthesis and release. In TNFα stimulated A549 cells, HOsm media inhibited I-κBα phosphorylation, NF-κB translocation into the nucleus and NF-κB nuclear binding. In IL-1β stimulated cells HOsm inhibited I-κBα phosphorylation without affecting NF-κB translocation or nuclear binding. Incubation in HOsm conditions inhibited both TNFα and IL-1β stimulated nuclear localization of interferon response factor 1 (IRF-1). Additional transcription factors such as AP-1, Erk-1/2, JNK and STAT-1 were unaffected by HOsm. HTS and sorbitol supplemented media produced comparable outcomes in all experiments, indicating that the effects of HTS were mediated by osmolarity, not by sodium. While not affecting MAPK modules discernibly in A549 cells, both HOsm conditions inhibit IRF-1 against TNFα or IL-1β, but inhibit p65 NF-kB translocation only against TNFα but not IL-1β. Thus, anti-inflammatory mechanisms of HTS/HOsm appear to disrupt cytokine signals at distinct intracellular steps.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Trichotillomania (TTM) is associated with impairments in response inhibition and cognitive flexibility, but it is unclear how such impairments relate to treatment outcome. The present study examined ...pre-treatment response inhibition and cognitive flexibility as predictors of treatment outcome, change in these domains from pre-to post-treatment, and associations with TTM severity. Participants were drawn from a randomized controlled trial comparing acceptance-enhanced behavior therapy (AEBT) to psychoeducation and supportive therapy (PST) for TTM. Adults completed assessments at pre-treatment (n = 88) and following 12 weeks of treatment (n = 68). Response inhibition and cognitive flexibility were assessed using the Stop Signal Task and Object Alternation Task, respectively. Participants completed the MGH-Hairpulling Scale. Independent evaluators administered the NIMH-Trichotillomania Severity Scale and Clinical Global Impressions-Improvement Scale. Higher pre-treatment TTM severity was associated with poorer pre-treatment cognitive flexibility, but not response inhibition. Better pre-treatment response inhibition performance predicted positive treatment response and lower post-treatment TTM symptom severity, irrespective of treatment assignment. Cognitive flexibility did not predict treatment response. After controlling for age, neither neurocognitive variable changed during treatment. Response inhibition and cognitive flexibility appear uniquely related to hair pulling severity and treatment response in adults with TTM. Implications for treatment delivery and development are discussed.
•Examined neurocognition in adults with trichotillomania in a treatment trial.•At baseline, higher TTM severity correlated with poorer cognitive flexibility.•Better baseline response inhibition predicted lower post-treatment TTM severity.•Response inhibition and cognitive flexibility did not improve pre-to post-treatment.
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