The Effect of Melatonin Upon Post-Acute Withdrawal Among Males in a Residential Treatment Program (M-Paws): A Randomized, Double-Blind, Placebo Controlled Trial

The study goal was to assess melatonin as an adjuvant treatment along with current pharmaco- and behavioral therapy for 28 days on weekly self-reported severity of anxiety, depression, stress, and sleep complaints as well as how sleep is affecting daily life in a sample of males in recovery from chemical dependency at a single, residential treatment site, Salvation Army Harbor Light Center in Pittsburgh, PA. This study was a single-center, randomized, double-blind, placebo-controlled, parallel group trial of 28 days. Participants were randomized to melatonin (5 mg) or placebo and instructed to administer the intervention nightly at bedtime. Primary self-reported outcome measures of severity of anxiety, depression, stress, as well as sleep complaints and how sleep is affecting daily life were assessed on a weekly basis with the Generalized Anxiety Disorder Scale (GAD-7), Personal Health Questionnaire Depression Scale (PHQ-8), Perceived Stress Scale (PSS-14), and Pittsburgh Sleep Symptom Questionnaire – Insomnia (PSSQ-1). Secondary outcome measures were to acquire participant histories, determine adherence as well as adverse events. Seventy participants (age 21 – 65, mean 40.4 ± 11 years) were enrolled with 24 completing the study in each group. Demographically, the sample consisted of those who identified as white (70%), single (74.3%), and with an education level of high school/G.E.D. or less (77.1%). Intention-to-treat analysis for all outcome measures revealed statistically significant within-groups differences over time for both groups. The study failed to demonstrate statistically between-group differences for these measures. Also, complete case analysis for each week revealed no between-group differences. Additionally, the change from Baseline and Day 28 as determined by a response of an improvement of 50% or higher in scores for each scale revealed no significant strength of association between the groups when considering worst case for the loss to follow-up. Melatonin appeared to be well tolerated with similar adverse events reported as placebo; however, there was a tendency to report more vivid dreams/nightmares as well as next day tiredness/grogginess/sleepiness. Clinical investigations into the use of melatonin as a treatment for depression, anxiety, stress, and sleep difficulties in those recovering from illicit and non-illicit drug dependency are limited and larger studies are warranted. Possible future directions include a study design that is multicenter, the inclusion of a therapy only arm, assessing various doses and timelines, assessing effects in adolescents or females, or limiting inclusion based on prescribed medications, mental health status, medical conditions, prior melatonin use, and/or a specific chemical dependency. Overall, this is the first and largest randomized, double-blind, placebo-controlled, parallel group trial assessing the effects of melatonin upon post-acute withdrawal among males in a residential treatment program. However, the various analyses indicated insufficient evidence to suggest that melatonin and placebo were significantly different, and it may be concluded, based upon the study sample, design, and its limitations, the effect of melatonin on the assessed measures was no different than placebo. Due to the heterogeneity of the participants as evidenced by the participant histories, there exists a possibility of a Type II error that must be considered and not overlooked

On Component Forces in Physics: A Pragmatic View

Do component forces exist? I argue that the answer lies in the affirmative, on historical and operational grounds

Suppression of NRF2 Activity by HIF-1α Promotes Fibrosis after Ischemic Acute Kidney Injury

Acute kidney injury (AKI) is a rapid decline in renal function and can occur after ischemia/reperfusion injury (IRI) to the tubular epithelia. The nuclear factor erythroid-2-related factor 2 (NRF2) pathway protects against AKI and AKI-to-chronic kidney disease (CKD) progression, but we previously demonstrated that severe IRI maladaptively reduced NRF2 activity in mice. To understand the mechanism of this response, we subjected C57BL/6J mice to unilateral kidney IRI with ischemia times that were titrated to induce mild to severe injury. Mild IRI increased NRF2 activity and was associated with renal recovery, whereas severe IRI decreased NRF2 activity and led to progressive CKD. Due to these effects of ischemia, we tested the hypothesis that hypoxia-inducible factor-1α (HIF-1α) mediates NRF2 activity. To mimic mild and severe ischemia, we activated HIF-1α in HK-2 cells in nutrient-replete or nutrient-deficient conditions. HIF-1α activation in nutrient-replete conditions enhanced NRF2 nuclear localization and activity. However, in nutrient-deficient conditions, HIF-1α activation suppressed NRF2 nuclear localization and activity. Nuclear localization was rescued with HIF-1α siRNA knockdown. Our results suggest that severe ischemic AKI leads to HIF-1α-mediated suppression of NRF2, leading to AKI-to-CKD progression

Co-administering Melatonin With an Estradiol-Progesterone Menopausal Hormone Therapy Represses Mammary Cancer Development in a Mouse Model of HER2-Positive Breast Cancer.

Melatonin has numerous anti-cancer properties reported to influence cancer initiation, promotion, and metastasis. With the need for effective hormone therapies (HT) to treat menopausal symptoms without increasing breast cancer risk, co-administration of nocturnal melatonin with a natural, low-dose HT was evaluated in mice that develop primary and metastatic mammary cancer. Individually, melatonin (MEL) and estradiol-progesterone therapy (EPT) did not significantly affect mammary cancer development through age 14 months, but, when combined, the melatonin-estradiol-progesterone therapy (MEPT) significantly repressed tumor formation. This repression was due to effects on tumor incidence, but not latency. These results demonstrate that melatonin and the HT cooperate to decrease the mammary cancer risk. Melatonin and EPT also cooperate to alter the balance of the progesterone receptor (PR) isoforms by significantly increasing PRA protein expression only in MEPT mammary glands. Melatonin significantly suppressed amphiregulin transcripts in MEL and MEPT mammary glands, suggesting that amphiregulin together with the higher PRA:PRB balance and other factors may contribute to reducing cancer development in MEPT mice. Melatonin supplementation influenced mammary morphology by increasing tertiary branching in the mouse mammary glands and differentiation in human mammary epithelial cell cultures. Uterine weight in the luteal phase was elevated after long-term exposure to EPT, but not to MEPT, indicating that melatonin supplementation may reduce estrogen-induced uterine stimulation. Melatonin supplementation significantly decreased the incidence of grossly-detected lung metastases in MEL mice, suggesting that melatonin delays the formation of metastatic lesions and/or decreases aggressiveness in this model of HER

Co-administering melatonin with an estradiol-progesterone menopausal hormone therapy represses mammary cancer development in a mouse model of her2-positive breast cancer

Melatonin has numerous anti-cancer properties reported to influence cancer initiation, promotion, and metastasis. With the need for effective hormone therapies (HT) to treat menopausal symptoms without increasing breast cancer risk, co-administration of nocturnal melatonin with a natural, low-dose HT was evaluated in mice that develop primary and metastatic mammary cancer. Individually, melatonin (MEL) and estradiol-progesterone therapy (EPT) did not significantly affect mammary cancer development through age 14 months, but, when combined, the melatonin-estradiol-progesterone therapy (MEPT) significantly repressed tumor formation. This repression was due to effects on tumor incidence, but not latency. These results demonstrate that melatonin and the HT cooperate to decrease the mammary cancer risk. Melatonin and EPT also cooperate to alter the balance of the progesterone receptor (PR) isoforms by significantly increasing PRA protein expression only in MEPT mammary glands. Melatonin significantly suppressed amphiregulin transcripts in MEL and MEPT mammary glands, suggesting that amphiregulin together with the higher PRA:PRB balance and other factors may contribute to reducing cancer development in MEPT mice. Melatonin supplementation influenced mammary morphology by increasing tertiary branching in the mouse mammary glands and differentiation in human mammary epithelial cell cultures. Uterine weight in the luteal phase was elevated after long-term exposure to EPT, but not toMEPT, indicating thatmelatonin supplementationmay reduce estrogen-induced uterine stimulation. Melatonin supplementation significantly decreased the incidence of grossly-detected lung metastases in MEL mice, suggesting that melatonin delays the formation of metastatic lesions and/or decreases aggressiveness in this model of HER2+ breast cancer. Mammary tumor development was similar in EPT and MEPT mice until age 8.6 months, but after 8.6 months, only MEPT continued to suppress cancer development. These data suggest that melatonin supplementation has a negligible effect in young MEPT mice, but is required in older mice to inhibit tumor formation. Sincemelatonin binding was significantly decreased in oldermammary glands, irrespective of treatment, melatonin supplementation may overcome reduced melatonin responsiveness in the agedMEPTmice. Sincemelatonin levels are known to decline near menopause, nocturnal melatonin supplementation may also be needed in aging women to cooperate with HT to decrease breast cancer risk

NAD(P)H Oxidase Mediates TGF-β1–Induced Activation of Kidney Myofibroblasts

TGF-β1 expression closely associates with activation and conversion of fibroblasts to a myofibroblast phenotype and synthesis of an alternatively spliced cellular fibronectin variant, Fn-ED-A. Reactive oxygen species (ROS), such as superoxide, which is a product of NAD(P)H oxidase, also promote the transition of fibroblasts to myofibroblasts, but whether these two pathways are interrelated is unknown. Here, we examined a role for NAD(P)H oxidase–derived ROS in TGF-β1–induced activation of rat kidney fibroblasts and expression of α-smooth muscle actin (α-SMA) and Fn-ED-A. In vitro, TGF-β1 stimulated formation of abundant stress fibers and increased expression of both α-SMA and Fn-ED-A. In addition, TGF-β1 increased both the activity of NADPH oxidase and expression of Nox2 and Nox4, homologs of the NAD(P)H oxidase family, indicating that this growth factor induces production of ROS. Small interfering RNA targeted against Nox4 markedly inhibited TGF-β1–induced stimulation of NADPH oxidase activity and reduced α-SMA and Fn-ED-A expression. Inhibition of TGF-β1 receptor 1 blocked Smad3 phosphorylation; reduced TGF-β1–enhanced NADPH oxidase activity; and decreased expression of Nox4, α-SMA, and Fn-ED-A. Diphenyleneiodonium, an inhibitor of flavin-containing enzymes such as the Nox oxidases, had no effect on TGF-β1–induced Smad3 but reduced both α-SMA and Fn-ED-A protein expression. The Smad3 inhibitor SIS3 reduced NADPH oxidase activity, Nox4 expression, and blocked α-SMA and Fn-ED-A, indicating that stimulation of myofibroblast activation by ROS is downstream of Smad3. In addition, TGF-β1 stimulated phosphorylation of extracellular signal–regulated kinase (ERK1/2), and this was inhibited by blocking TGF-β1 receptor 1, Smad3, or the Nox oxidases; ERK1/2 activation increased α-SMA and Fn-ED-A. Taken together, these results suggest that TGF-β1–induced conversion of fibroblasts to a myofibroblast phenotype involves a signaling cascade through Smad3, NAD(P)H oxidase, and ERK1/2

Selected solutions of Einstein's field equations: their role in general relativity and astrophysics

Contents: 1) Introduction and a few excursions [A word on the role of explicit solutions in other parts of physics and astrophysics. Einstein's field equations. "Just so" notes on the simplest solutions: The Minkowski, de Sitter and anti-de Sitter spacetimes. On the interpretation and characterization of metrics. The choice of solutions. The outline] 2) The Schwarzschild solution [Spherically symmetric spacetimes. The Schwarzschild metric and its role in the solar system. Schwarzschild metric outside a collapsing star. The Schwarzschild-Kruskal spacetime. The Schwarzschild metric as a case against Lorentz-covariant approaches. The Schwarzschild metric and astrophysics] 3) The Reissner- Nordstrom solution [Reissner-Nordstrom black holes and the question of cosmic censorship. On extreme black holes, d-dimensional black holes, string theory and "all that"] 4) The Kerr metric [Basic features. The physics and astrophysics around rotating black holes. Astrophysical evidence for a Kerr metric] 5) Black hole uniqueness and multi-black hole solutions 6) Stationary axisymmetric fields and relativistic disks [Static Weyl metrics. Relativistic disks as sources of the Kerr metric and other stationary spacetimes. Uniformly rotating disks] 7) Taub-NUT space [A new way to the NUT metric. Taub-NUT pathologies and applications] 8) Plane waves and their collisions [Plane-fronted waves. New developments and applications. Colliding plane waves] 9) Cylindrical waves [Cylindrical waves and the asymptotic structure of 3-dimensional general relativity. Cylindrical waves and quantum gravity. Cylindrical waves: a miscellany] 10) On the Robinson-Trautman solutions 11) The boost-rotation symmetric radiative spacetimes 12) The cosmological models [Spatially homogeneous cosmologies. Inhomogeneous models] 13) Concluding remark