Pioneering new frontiers in circadian medicine chronotherapies for cardiovascular health.

Cardiovascular disease (CVD) is a global health concern. Circadian medicine improves cardiovascular care by aligning treatments with our body's daily rhythms and their underlying cellular circadian mechanisms. Time-based therapies, or chronotherapies, show special promise in clinical cardiology. They optimize treatment schedules for better outcomes with fewer side effects by recognizing the profound influence of rhythmic body cycles. In this review, we focus on three chronotherapy areas (medication, light, and meal timing) with potential to enhance cardiovascular care. We also highlight pioneering research in the new field of rest, the gut microbiome, novel chronotherapies for hypertension, pain management, and small molecules that targeting the circadian mechanism.

Stroke in the Time of Circadian Medicine.

Time-of-day significantly influences the severity and incidence of stroke. Evidence has emerged not only for circadian governance over stroke risk factors, but also for important determinants of clinical outcome. In this review, we provide a comprehensive overview of the interplay between chronobiology and cerebrovascular disease. We discuss circadian regulation of pathophysiological mechanisms underlying stroke onset or tolerance as well as in vascular dementia. This includes cell death mechanisms, metabolism, mitochondrial function, and inflammation/immunity. Furthermore, we present clinical evidence supporting the link between disrupted circadian rhythms and increased susceptibility to stroke and dementia. We propose that circadian regulation of biochemical and physiological pathways in the brain increase susceptibility to damage after stroke in sleep and attenuate treatment effectiveness during the active phase. This review underscores the importance of considering circadian biology for understanding the pathology and treatment choice for stroke and vascular dementia and speculates that considering a patient's chronotype may be an important factor in developing precision treatment following stroke.

Crystallographic fragment screening in academic cancer drug discovery.

Fragment-based drug discovery (FBDD) has brought several drugs to the clinic, notably to target proteins once considered to be challenging, or even undruggable. Screening in FBDD relies upon observing and/or measuring weak (millimolar-scale) binding events using biophysical techniques or crystallographic fragment screening. This latter structural approach provides no information about binding affinity but can reveal binding mode and atomic detail on protein-fragment interactions to accelerate hit-to-lead development. In recent years, high-throughput platforms have been developed at synchrotron facilities to screen thousands of fragment-soaked crystals. However, using accessible manual techniques it is possible to run informative, smaller-scale screens within an academic lab setting. This chapter describes general protocols for home laboratory-scale fragment screening, from fragment soaking through to structure solution and, where appropriate, signposts to background, protocols or alternatives elsewhere.

Integrated care in patients with atrial fibrillation- a predictive heterogeneous treatment effect analysis of the ALL-IN trial.

INTRODUCTION: Integrated care is effective in reducing all-cause mortality in patients with atrial fibrillation (AF) in primary care, though time and resource intensive. The aim of the current study was to assess whether integrated care should be directed at all AF patients equally. METHODS: The ALL-IN trial (n = 1,240 patients, median age 77 years) was a cluster-randomized trial in which primary care practices were randomized to provide integrated care or usual care to AF patients aged 65 years and older. Integrated care comprised of (i) anticoagulation monitoring, (ii) quarterly checkups and (iii) easy-access consultation with cardiologists. For the current analysis, cox proportional hazard analysis with all clinical variables from the CHA2DS2-VASc score was used to predict all-cause mortality in the ALL-IN trial. Subsequently, the hazard ratio and absolute risk reduction were plotted as a function of this predicted mortality risk to explore treatment heterogeneity. RESULTS: Under usual care, after a median of 2 years follow-up the absolute risk of all-cause mortality in the highest-risk quarter was 31.0%, compared to 4.6% in the lowest-risk quarter. On the relative scale, there was no evidence of treatment heterogeneity (p for interaction = 0.90). However, there was substantial treatment heterogeneity on the absolute scale: risk reduction in the lowest risk- quarter of risk 3.3% (95% CI -0.4% - 7.0) compared to 12.0% (95% CI 2.7% - 22.0) in the highest risk quarter. CONCLUSION: While the relative degree of benefit from integrated AF care is similar in all patients, patients with a high all-cause mortality risk have a greater benefit on an absolute scale and should therefore be prioritized when implementing integrated care.

Preserving and enhancing mitochondrial function after stroke to protect and repair the neurovascular unit: novel opportunities for nanoparticle-based drug delivery.

The neurovascular unit (NVU) is composed of vascular cells, glia, and neurons that form the basic component of the blood brain barrier. This intricate structure rapidly adjusts cerebral blood flow to match the metabolic needs of brain activity. However, the NVU is exquisitely sensitive to damage and displays limited repair after a stroke. To effectively treat stroke, it is therefore considered crucial to both protect and repair the NVU. Mitochondrial calcium (Ca2+) uptake supports NVU function by buffering Ca2+ and stimulating energy production. However, excessive mitochondrial Ca2+ uptake causes toxic mitochondrial Ca2+ overloading that triggers numerous cell death pathways which destroy the NVU. Mitochondrial damage is one of the earliest pathological events in stroke. Drugs that preserve mitochondrial integrity and function should therefore confer profound NVU protection by blocking the initiation of numerous injury events. We have shown that mitochondrial Ca2+ uptake and efflux in the brain are mediated by the mitochondrial Ca2+ uniporter complex (MCUcx) and sodium/Ca2+/lithium exchanger (NCLX), respectively. Moreover, our recent pharmacological studies have demonstrated that MCUcx inhibition and NCLX activation suppress ischemic and excitotoxic neuronal cell death by blocking mitochondrial Ca2+ overloading. These findings suggest that combining MCUcx inhibition with NCLX activation should markedly protect the NVU. In terms of promoting NVU repair, nuclear hormone receptor activation is a promising approach. Retinoid X receptor (RXR) and thyroid hormone receptor (TR) agonists activate complementary transcriptional programs that stimulate mitochondrial biogenesis, suppress inflammation, and enhance the production of new vascular cells, glia, and neurons. RXR and TR agonism should thus further improve the clinical benefits of MCUcx inhibition and NCLX activation by increasing NVU repair. However, drugs that either inhibit the MCUcx, or stimulate the NCLX, or activate the RXR or TR, suffer from adverse effects caused by undesired actions on healthy tissues. To overcome this problem, we describe the use of nanoparticle drug formulations that preferentially target metabolically compromised and damaged NVUs after an ischemic or hemorrhagic stroke. These nanoparticle-based approaches have the potential to improve clinical safety and efficacy by maximizing drug delivery to diseased NVUs and minimizing drug exposure in healthy brain and peripheral tissues.

Development of an Online Mind-Body Physical Activity Intervention for Young Adults during COVID-19: A Pilot Study.

The purpose of this study was to examine the association between the implementation of an online mind-body physical activity (MBPA) intervention and physical activity (PA), stress, and well-being in young adults during COVID-19. The participants were a sample of college students (N = 21; 81% female). The MBPA intervention was organized in four online modules that were administered asynchronously for 8 weeks with three separate 10 min sessions per week. The intervention components consisted of traditional deep breathing, diaphragm mindful breathing, yoga poses, and walking meditation. Objective PA behaviors were assessed using wrist-worn ActiGraph accelerometers, and stress and well-being data were collected using validated self-report instruments. A 2 (sex) × 3 (time) doubly multivariate analysis of variance test with a univariate follow-up showed that the % of wear time in light (LPA) and moderate-to-vigorous physical activity (MVPA) was significantly higher at the end of the intervention compared to baseline (LPA mean difference = 11.3%, p = 0.003, d = 0.70; MVPA mean difference = 2.9%, p < 0.001, d = 0.56). No significant differences were observed for perceived stress and well-being, and there was no moderating effect of sex. The MBPA intervention showed promise, as it was associated with higher PA in young adults during COVID-19. No improvements were observed for stress and well-being. These results warrant further testing of the intervention's effectiveness using larger samples.

A postbiotic fermented oat gruel may have a beneficial effect on the colonic mucosal barrier in patients with irritable bowel syndrome.

Background: Impaired intestinal permeability and microbial dysbiosis are important pathophysiological mechanisms underlying irritable bowel syndrome (IBS). ReFerm®, also called Profermin®, is a postbiotic product of oat gruel fermented with Lactobacillus plantarum 299v. In this study, we investigated whether ReFerm® has a beneficial effect on the intestinal epithelial barrier function in patients with IBS. Materials and methods: Thirty patients with moderate to severe IBS-diarrhoea (IBS-D) or IBS-mixed (IBS-M) were treated with enema containing ReFerm® or placebo. The patients underwent sigmoidoscopy with biopsies obtained from the distal colon at baseline and after 14 days of treatment with ReFerm® or placebo twice daily. The biopsies were mounted in Ussing chambers, and paracellular and transcellular permeabilities were measured for 120 min. In addition, the effects of ReFerm® or placebo on the epithelial barrier were investigated in vitro using Caco-2 cells. Results: ReFerm® reduced paracellular permeability (p < 0.05) and increased transepithelial resistance (TER) over time (p < 0.01), whereas the placebo had no significant effect in patients. In ReFerm®-treated Caco-2 cells, paracellular and transcellular permeabilities were decreased compared to the control (p < 0.05) and placebo (p < 0.01). TER was increased in Caco-2 ReFerm®-treated cells, and normalised TER was increased in ReFerm®-treated Caco-2 cells compared to control (p < 0.05) and placebo-treated (p < 0.05) cells. Conclusion: ReFerm® significantly reduced paracellular permeability and improved TER in colonic biopsies collected from patients with IBS and in a Caco-2 cell model. Our results offer new insights into the potential benefits of ReFerm® in IBS management. Further studies are needed to identify the molecular mechanisms underlying the barrier-protective properties of ReFerm®. Clinical trial registration: [https://clinicaltrials.gov/], identifier [NCT05475314].

Implementation of Indigenous Food Tax Policies in Stores on Navajo Nation.

In 2014, the Navajo Nation Healthy Diné Nation Act (HDNA) was enacted and permanently approved in 2020; HDNA places a 2% surtax on unhealthy foods and beverages, while other 2014 legislation exempted healthy food items from the 6% regular sales tax. Little is known about Navajo Nation store manager/owner perspectives toward the HDNA and how best to support stores to implement the legislation. Purposive sampling was used to ensure a balanced sample of correct HDNA implementers, incorrect HDNA implementers, and stores which made healthy store changes over the past 6 years. Three community-based interviewers collected surveys by phone or in-person. Frequency of closed-ended questions was quantified, and open-ended responses were coded using thematic analysis. Of 29 identified sample stores, 20 were interviewed to reach saturation. Eleven of 20 stores made changes improving their healthy food environments. Barriers included lack of equipment (6/20) and low consumer demand (5/20). Facilitators included consumer awareness and increased produce supply options (5/20). Sixteen of 20 stores supported HDNA continuation. Facilitators to HDNA implementation included orientation and informational materials (6/20) and promotion of tax-free items (5/20). Barriers included confusion about the tax (6/20) and tax exemption (5/20). Suggestions for support included printed materials (6/20) and store training (5/20). HDNA benefits included greater awareness of healthy choices among staff (7/20) and customer-community members (2/20). Most managers and owners expressed receiving support for healthy store changes and HDNA, but also identified a need for added resources and support. Findings inform legislative action to promote timely and appropriate uptake of HDNA, and support equitable, healthy food systems.

Acceptance-enhanced behavior therapy for trichotillomania in adults: A randomized clinical trial.

Given the limited treatment options for trichotillomania (TTM), or Hair Pulling Disorder, this large randomized clinical trial evaluated the efficacy of acceptance-enhanced behavior therapy for TTM (AEBT-TTM) in reducing TTM severity relative to psychoeducation and supportive therapy (PST). Eighty-five adults (78 women) with TTM received 10 sessions (over 12 weeks) of either AEBT-TTM or PST. Independent evaluators masked to treatment assignment assessed participants at baseline (week 0), midpoint (week 6), and endpoint (week 12). Consistent with a priori hypotheses, 64% of the adults treated with AEBT-TTM were classified as clinical responders at post-treatment relative to 38% treated with PST. Clinical responders were identified by a score of 1 or 2 on the Clinical Global Impressions-Improvement (CGI-I) scale. Relative to the PST group, the AEBT-TTM group demonstrated significantly greater pre-to post-treatment reductions on the self-report Massachusetts General Hospital-Hairpulling Scale (MGH-HS) and the evaluator-rated National Institute of Mental Health Trichotillomania Severity Scale (NIMH-TSS). There were no significant post-treatment group differences on the Clinical Global Impressions-Severity (CGI-S) scale, or rate of TTM diagnoses. Results suggest AEBT-TTM provides greater treatment benefit than PST. Future research should continue to investigate AEBT-TTM along with mediators and moderators of its efficacy.

"I Felt Grounded and Clear-Headed": Qualitative Exploration of a Mind-Body Physical Activity Intervention on Stress Among College Students During COVID-19.

The COVID-19 pandemic affected college students' overall health. The aims of this qualitative inquiry were to provide a more comprehensive understanding of the effectiveness of the mind-body physical activity (MBPA) intervention and to explore the MBPA intervention experiences through the use of journals and photographs (photovoice) of a purposeful sample of 21 college students during the COVID-19 pandemic. An inductive qualitative process was used to explore the data that emerged from photovoice images and journals. Students' experiences were encapsulated in 6 key themes: (1) holistic individual well-being; (2) physical activity as a matter of necessity; (3) mind-body physical activity intervention impacts; (4) broadening strategies for adapting and reacting; (5) systemic effect of stress management changes; and (6) perceiving causes of stress. Participants reflected collective intellectual, physical, and emotional fatigue as obstacles and perceived stress. The quality of COVID-19 related perspectives and stressful experiences are defined from traumatic and overwhelming to higher than normal. Findings from this study contribute to our understanding of the distinctive factors of the COVID-19 era among college students. Health educators should consider the implementation of multilevel and multicomponent MBPA interventions, and our findings highlight the utility of supporting higher education students in a meaningful way.

Targeting the Retinoid X Receptor Pathway Prevents and Ameliorates Murine Chronic Graft-Versus-Host Disease.

Most allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients receive peripheral blood stem cell grafts resulting in a 30%-70% incidence of chronic graft-versus-host disease (cGVHD), a major cause of mortality and morbidity in long-term survivors. While systemic steroids remain the standard of care for first-line therapy, patients may require long-term administration, and those with steroid-resistant or refractory cGVHD have a worse prognosis. Although durable and deep responses with second-line therapies can be achieved in some patients, there remains an urgent need for new therapies. In this study, we evaluated the efficacy of IRX4204, a novel agonist that activates RXRs and is in clinical trials for cancer treatment to prevent and treat cGVHD in two complementary murine models. In a major histocompatibility complex mismatched, non-sclerodermatous multiorgan system model with bronchiolitis obliterans, IRX4204 prevented and reversed cGVHD including associated pulmonary dysfunction with restoration of germinal center T-follicular helper: T-follicular regulatory cell balance. In a minor histocompatibility antigen disparate sclerodermatous model, IRX4204 treatment significantly prevented and ameliorated skin cGVHD by reducing Th1 and Th17 differentiation due to anti-inflammatory properties. Together, these results indicate that IRX4204 is a promising therapeutic option to treat cGVHD with bronchiolitis obliterans or sclerodermatous manifestations.

Prostate cancer brachytherapy: SFRO guidelines 2021.

Prostate brachytherapy techniques are described, concerning both permanent seed implant and high dose rate brachytherapy. The following guidelines are presented: brachytherapy indications, implant procedure for permanent low dose rate implants and high dose rate with source projector, as well as dose and dose-constraints objectives, immediate postoperative management, post-treatment evaluation, and long-term follow-up.

Cytoreductive Thoracic Surgery Combined with Hyperthermic Chemoperfusion for Pleural Malignancies: A Single-Center Experience.

BACKGROUND: Lung-sparing cytoreductive surgery by extended pleurectomy and decortication (EPD) in combination with hyperthermic intrathoracic chemoperfusion (HITOC) forms a promising treatment strategy for malignant pleural mesothelioma and recurrent pleural thymic malignancies. OBJECTIVES: The objective of this study was to scrutinize the surgical procedure and perioperative patient management with emphasis on perioperative morbidity and local tumor control. METHODS: In 2014, a standardized EPD and HITOC procedure was implemented at the Thoraxklinik Heidelberg. This retrospective analysis included clinical data of consecutive patients with pleural mesothelioma and pleural metastasized malignancies treated by EPD and HITOC. The surgical procedure, perioperative management, lung function data, and progression-free survival (PFS) were analyzed. RESULTS: In the time range between April 2, 2014 and July 2018, 76 patients with pleural malignancies have been treated with EPD and HITOC, and were analyzed retrospectively. It included 61 patients with pleural mesothelioma and 15 patients with pleural metastases of thymic malignancies (12), non-small cell lung cancer (1), colorectal carcinoma (1), and sarcoma (1). Perioperative morbidity following EPD and HITOC treatments represented 23.7% of overall malignancies, while 30- and 90-day mortality were 0 and 1.3%, respectively. Median PFS lasted 18.4 months for mesothelioma and 72.2 months for thymic malignancies. CONCLUSION: Combining EPD with HITOC can be performed in patients with either pleural mesothelioma or pleural metastases resulting in low perioperative morbidity and mortality as well as remarkable local tumor control.

Guidelines for the design and conduct of human clinical trials on ingestion-time differences - chronopharmacology and chronotherapy - of hypertension medications.

Current hypertension guidelines fail to provide a recommendation on when-to-treat, thus disregarding relevant circadian rhythms that regulate blood pressure (BP) level and 24 h patterning and medication pharmacokinetics and pharmacodynamics. The ideal purpose of ingestion-time (chronopharmacology, i.e. biological rhythm-dependent effects on the kinetics and dynamics of medications, and chronotherapy, i.e. the timing of pharmaceutical and other treatments to optimize efficacy and safety) trials should be to explore the potential impact of endogenous circadian rhythms on the effects of medications. Such investigations and outcome trials mandate adherence to the basic standards of human chronobiology research. In-depth review of the more than 150 human hypertension pharmacology and therapeutic trials published since 1974 that address the differential impact of upon-waking/morning versus at-bedtime/evening schedule of treatment reveals diverse protocols of sometimes suboptimal or defective design and conduct. Many have been "time-of-day," i.e. morning versus evening, rather than circadian-time-based, and some relied on wake-time office BP rather than around-the-clock ambulatory BP measurements (ABPM). Additionally, most past studies have been of too small sample size and thus statistically underpowered. As of yet, there has been no consensual agreement on the proper design, methods and conduct of such trials. This Position Statement recommends ingestion-time hypertension trials to follow minimum guidelines: (i) Recruitment of participants should be restricted to hypertensive individuals diagnosed according to ABPM diagnostic thresholds and of a comparable activity/sleep routine. (ii) Tested treatment-times should be selected according to internal biological time, expressed by the awakening and bed times of the sleep/wake cycle. (iii) ABPM should be the primary or sole method of BP assessment. (iv) The minimum-required features for analysis of the ABPM-determined 24 h BP pattern ought to be the asleep (not "nighttime") BP mean and sleep-time relative BP decline, calculated in reference to the activity/rest cycle per individual. (v) ABPM-obtained BP means should be derived by the so-called adjusted calculation procedure, not by inaccurate arithmetic averages. (vi) ABPM should be performed with validated and calibrated devices at least hourly throughout two or more consecutive 24 h periods (48 h in total) to achieve the highest reproducibility of mean wake-time, sleep-time and 48 h BP values plus the reliable classification of dipping status. (vii) Calculation of minimum required sample size in adherence with proper statistical methods must be provided. (viii) Hypertension chronopharmacology and chronotherapy trials should preferably be randomized double-blind, randomized open-label with blinded-endpoint, or crossover in design, the latter with sufficient washout period between tested treatment-time regimens.

The Effects of Silymarin on Acetaminophen-Induced Acute Hepatic and Renal Toxicities in Domestic Pigeons (Columba livia).

This study evaluated the effects of silymarin on acetaminophen-induced acute liver and kidney toxicities in domestic pigeons (Columba livia). Standard colorimetric methods with commercial kits were used to measure the serum activities or levels of biomarkers associated with liver and kidney damage, such as aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, urea, uric acid, total protein, albumin, and total cholesterol, in 21 pigeons randomly assigned into 3 groups (A, B, and C). Groups A and B were administered acetaminophen 3000 mg/ kg PO q24h at the beginning of the experiment (hour 0). Group B pigeons were further treated with silymarin 35 mg/kg, starting at 12 hours after acetaminophen exposure (post-AA), with the silymarin treatment continuing q12h for 3 days. Group C pigeons served as the control group and were given tap water as the placebo. Blood was collected from the pigeons at hours 0, 12, 24, 48, and 72 of the experiment for serum biochemistry analyses. The results showed that treatment of group B pigeons with silymarin decreased the serum levels of aspartate aminotransferase, alanine aminotransferase, urea, and uric acid compared with the untreated control (group A). It also prevented decreases in serum alkaline phosphatase, total protein, albumin, and cholesterol seen in Group A. Mortality, which was 86% in the untreated control (group A), was completely prevented in group B. It was concluded that silymarin remediated the effects of acetaminophen-induced acute toxic liver and kidney injuries, which may result in pigeon mortality.

Enzymatic cross-linking of pectin in a high-pressure foaming process.

The enzyme laccase is a copper-containing oxidoreductase with the ability to oxidize a wide range of substrates, such as ferulic acid. Thus, the ferulic acid-containing sugar beet pectin (SBP) can be cross-linked through laccase-mediated oxidation. As cross-linking increases viscosity, it could be applied to stabilize SBP-containing foams. In this study, laccase-mediated cross-linking of SBP was investigated under conditions of a high-pressure foaming process. Shear, presence of CO2, and pressure were simulated in a rheometer equipped with a high-pressure cell. At rest, addition of laccase to SBP solution led to the formation of a stiff gel. Application of shear upon mixing of laccase and SBP solution decreased the storage modulus with increasing shear duration and shear rate. This can be attributed to the formation of a fluid gel. However, when shear was stopped before all available ferulic acid groups were cross-linked, a stronger and more coherent network was formed. Pressure exerted by CO2 did not affect cross-linking. Additionally, this approach was tested in a stirred high-pressure vessel where SBP was foamed through CO2 dissolution under pressure and shear followed by controlled pressure release. While pure SBP foam was highly unstable, addition of laccase decelerated collapse. Highest stability was reached when laccase and SBP were mixed prior to depressurization. At the point of foam formation, the continuous phase was thereby viscous enough to increase foam stability. At the same time, continuation of cross-linking at rest caused gel templating of the foam structure.

Peripheral Nerve Stimulation for Refractory Trigeminal Pain: Recent Single-Institution Case Series With Long-Term Follow-Up and Review of the Literature.

BACKGROUND: Peripheral neurostimulation (PNS) for medically refractory trigeminal pain is an emerging alternative to traditional surgical approaches, with safety and efficacy demonstrated in several retrospective series and a prospective trial currently in progress. Many existing studies suffer from relatively small numbers and short or inconsistent follow-up, making balanced treatment assessment difficult. MATERIALS AND METHODS: Consecutive cases of trial and permanent placement of trigeminal branch stimulation electrodes by a single surgeon from May 2014 through January 2019 were retrospectively reviewed from a prospectively collected database, following the PROCESS guidelines for surgical case series. Outcomes were assessed at six months and at last follow-up. RESULTS: Ninteen patients underwent trial electrode placement, with 15 patients undergoing permanent system placement. The most common diagnoses were idiopathic trigeminal neuralgia Type 2 (N = 8) and trigeminal neuropathic pain (N = 7). Median follow-up was 14 months (range 6-58 months). At last follow-up, 12 of 15 implanted patients (80%) were still receiving stimulation, with mean (median) pain reduction of 52.3% (47.5%). Infection and revision rates were high, although erosion and migration, which have typically plagued trigeminal PNS surgery, did not occur. Implanted systems were well-tolerated, with excellent cosmetic outcomes and high patient satisfaction that proved durable over long follow-up. CONCLUSIONS: We present a single-institution series of PNS for complex craniofacial pain involving the trigeminal nerve. The procedure is safe, effective and durable over at least one year in the large majority of a well-selected patient population.

Effect of the fixed combination of valerian, lemon balm, passionflower, and butterbur extracts (Ze 185) on the prescription pattern of benzodiazepines in hospitalized psychiatric patients-A retrospective case-control investigation.

Stress is an increasing problem that can result in various psychiatric and somatoform symptoms. Among others, benzodiazepines and valerian preparations are used to treat stress symptoms. The aim of this study was to investigate whether the prescription of a fixed herbal extract combination of valerian, lemon balm, passionflower, and butterbur (Ze 185) changes the prescription pattern of benzodiazepines in hospitalized psychiatric patients. In a retrospective case-control study, anonymized medical record data from 3,252 psychiatric in-house patients were analysed over a 3.5-year period. Cases (n = 1,548) with a prescription of Ze 185 and controls (n = 1,704) were matched by age, gender, hospitalization interval, and main International Classification of Diseases, Version 10 F-diagnoses. The primary objective was to investigate the effect of Ze 185 on the prescription pattern of benzodiazepines. Secondary objectives investigated the prescriptions of concomitant drugs and effectiveness of the hospital stay. Distribution of drug classes was analysed using the WHO's anatomic-therapeutic-chemical code. Data showed that both treatment modalities had a comparable clinical effectiveness but with significantly less prescriptions of benzodiazepines in the Ze 185 group (p = .006). This is of clinical importance because suitable alternatives to benzodiazepines are desirable. To obtain more support for this hypothesis, a dedicated randomized, controlled clinical trial monitoring drug safety is required.

Protective effects of alpha stone on monosodium glutamate-induced uterine hyperplasia in female wistar rats.

BACKGROUND: Uterine leiomyomas (fibroids), a menace of the reproductive age, is characterized by proliferation of smooth muscle cells (hyperplasia) of the uterus. Alpha Stone Decoction is a poly-herbal formulation that is used for the shrinkage and prevention of uterine fibroids in folkore medicine. OBJECTIVE: We investigated the efficacy and safety of Alpha Stone Decoction (ASD), on monosodium glutamate (MSG) induced uterine hyperplasia. MATERIALS AND METHODS: Twenty-eight mature virgin female rats were randomly divided into four study groups: A-control B- MSG (200 mg/kgbw), C- MSG + ASD (100 mg/kgbw) and D- ASD 100 mg/kgbw alone. The administration was carried out by as a single daily dose via intraperitoneal route for 14 days. Total protein, triglycerides, estradiol (estrogen), progesterone, and total cholesterol levels in sera were determined using appropriate kits. Uterine hyperplasia was assessed via histomorphometric method using the mitotic image plus software to compute the fibroblast cell count density while the uteri and ovaries of animals were stained with mason-tricon stain for histological examination. RESULTS: Administration of MSG for 14 days resulted heavy deposits of collagen connective tissue within the myometrium layers of the uteri. ASD significantly (p < 0.05) reduced fibroblast cell count in MSG-treated animals and also protected against MSG-induced damage observed in the myometrium of the uteri and ovaries of the animals. Significant increases (p < 0.05) in levels of total protein; triglycerides, progesterone, cholesterol and estrogen in the MSG-treated animals were ameliorated following administration of ASD. CONCLUSION: These findings suggest that ASD contains bioactive agents which reversed MSG-induced uterine hyperplasia. It may therefore be useful in reducing the proliferation of fibroblast cells and managing other symptoms associated with uterine myoma.

Mind-Body Physical Activity Interventions and Stress-Related Physiological Markers in Educational Settings: A Systematic Review and Meta-Analysis.

Mind-Body Physical Activity (MBPA) in educational settings is one possible preventive strategy for ameliorating stress-related physiological health parameters. The objectives of this study were to conduct a systematic review of the literature with meta-analyses on the effects of MBPA on stress-related physiological health markers in primary, secondary, and higher education students. In accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, the search for peer-reviewed articles published in English was conducted in PubMed, EBSCOhost, PsychInfo, Scopus, and Cochrane Library databases. Criteria for inclusion consisted of empirical studies targeting the student population (primary, secondary, higher education), studies examining the effectiveness of an MBPA intervention, studies including a control or comparison group (pre-test/post-test studies excluded), studies targeting physiological marker outcomes such as heart rate, blood glucose, cortisol, and blood pressure, and finally, studies examining interventions implemented within educational settings. Twenty-six interventions were eligible for the review and quantitative synthesis, which comprised a total of 1625 participants, with 783 students serving within the control/comparison group. There were statistically significant and large pooled effects for MBPA effectiveness for lowering heart rate (Hedges' g = -1.71, 95% Confidence Interval (CI): -2.43, -0.98), cortisol (Hedges' g = -1.32, 95% CI: -2.50, -0.16), and systolic and diastolic blood pressure (Hedges' g = -1.04, 95% CI: -1.53, -0.58). These effects tended to be stronger in older students compared to younger students. Most analyses were characterized as having high heterogeneity and only 10 of the 26 studies were characterized as good quality (38.4%). MBPA interventions may have a positive impact on specific physiological health markers in students, especially in students within higher education. However, higher-quality research is needed in this area.