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Background and Aims: Carotid endarterectomy (CEA) is a common procedure conducted under regional anaesthesia, providing real-time cerebral function monitoring. Many different combinations of regional cervical blocks exist, and most offer adequate analgesia in intraoperative and postoperative recovery. This research compares a superficial cervical plexus block (SCB) alone and combined with an ultrasound (US)-guided carotid sheath block (CSB). The primary objective was to explore the length of the sensory block after combining SCB and CSB. Methods: Patients scheduled for nonemergency CEA surgery were randomised into two cohorts. The Subject group (28 participants) received US-guided CSB and SCB. The Control group (31 participants) received only an SCB. Both groups received 0.5% levobupivacaine (2 mg/kg) along with 2% lidocaine (2 mg/kg). The sensory block time and its initiation, analgesia and neutrophil-to-lymphocyte ratio (NLR) were recorded before and after the block. The numeric pain rating scale (NPRS) was used to evaluate analgesia every 2 h for 12 h post block. Analysis of variance, Mann–Whitney U or log-rank test was used to analyse the distinction of selected variables. Results: The demographic characteristics were comparable across the cohorts. The Subject group demonstrated a significantly accelerated onset of sensory block (P = 0.029) and an extended time to first analgesia (P = 0.003). The sensory block was also substantially extended in the Subject group (P = 0.040). Postoperative pain (NPRS ≥1) within the first 12 h was more recurrent in the Control group (P = 0.048). NLR showed minimal disparity between the groups (P = 0.125). Conclusion: Combining SCB and US-guided CSB effectively and safely extends postoperative analgesia for CEA surgery.

Abstract Osteoporosis is a common skeletal disease affecting millions of individuals world-wide, with an increased risk of fracture, and a decreased quality of life. Despite its well-known consequences, the etiology of osteoporosis and optimal treatment methods are not fully understood. Human genetic studies have identified genetic variants within the FMN2/GREM2 locus to be associated with trabecular volumetric bone mineral density (vBMD) and vertebral and forearm fractures, but not with cortical bone parameters. GREM2 is a bone morphogenetic protein (BMP) antagonist. In this study, we employed Grem2-deficient mice to investigate whether GREM2 serves as the plausible causal gene for the fracture signal at the FMN2/GREM2 locus. We observed that Grem2 is moderately expressed in bone tissue and particularly in osteoblasts. Complete Grem2 gene deletion impacted mouse survival and body growth. Partial Grem2 inactivation in Grem2 +/− female mice led to increased trabecular BMD of femur and increased trabecular bone mass in tibia due to increased trabecular thickness, with an unchanged cortical thickness, as compared with wildtype littermates. Furthermore, Grem2 inactivation stimulated osteoblast differentiation, as evidenced by higher alkaline phosphatase (Alp), osteocalcin (Bglap), and osterix (Sp7) mRNA expression after BMP-2 stimulation in calvarial osteoblasts and osteoblasts from the long bones of Grem2 −/− mice compared to wildtype littermates. These findings suggest that GREM2 is a possible target for novel osteoporotic treatments, to increase trabecular bone mass and prevent osteoporotic fractures.

Estradiol (E2) affects both reproductive and non-reproductive tissues, and the sensitivity to different doses of E2 varies between tissues. Membrane estrogen receptor α (mERα)-initiated signaling plays a tissue-specific role in mediating E2 effects, however, it is unclear if mERα signaling modulates E2 sensitivity. To determine this, we treated ovariectomized C451A females, lacking mERα signaling, and wildtype (WT) littermates with physiological (0.05 μg/mouse/day (low); 0.6 μg/mouse/day (medium)) or supraphysiological (6 μg/mouse/day (high)) doses of E2 (17β-estradiol-3-benzoate) for three weeks. Low-dose treatment increased uterus weight in WT, but not C451A mice, while non-reproductive tissues (gonadal fat, thymus, trabecular and cortical bone) were unaffected in both genotypes. Medium-dose treatment increased uterus weight and bone mass and decreased thymus and gonadal fat weights in WT mice. Uterus weight was also increased in C451A mice, but the response was significantly attenuated (- 85%) compared to WT mice, and no effects were triggered in non-reproductive tissues. High-dose treatment effects in thymus and trabecular bone were significantly blunted (- 34% and - 64%, respectively) in C451A compared to WT mice, and responses in cortical bone and gonadal fat were similar between genotypes. Interestingly, the high dose effect in uterus was enhanced (+ 26%) in C451A compared to WT mice. In conclusion, loss of mERα signaling reduces the sensitivity to physiological E2 treatment in both non-reproductive tissues and uterus. Furthermore, the E2 effect after high-dose treatment in uterus is enhanced in the absence of mERα, suggesting a protective effect of mERα signaling in this tissue against supraphysiological E2 levels.

Multi-Tiered System of Support (MTSS), as a fully integrated set of practices and interventions directed to academics and behavior, with emerging applications to social and emotional learning in the teaching/learning process, is very much in its ascendency in schools across the United States and elsewhere. As a result, there is an emerging need to prepare teacher and administrator educators to enter the rapidly expanding number of implementing schools and districts. Requisite dispositions, skills, and knowledge germane to ensuring successful applications, sustainability, and resultant student outcomes from MTSS introduction into systems praxis are increasingly required. In this position paper, we discuss the origins of MTSS, its expansion into various areas of education in the United States, and its emerging contribution to the thorny issue of inclusion. We conclude with examination of Innovation Configuration, a heuristic to assist teacher and administrator educators in the development of course syllabi and other professional learning vehicles addressed to MTSS.

It is well established that inflammatory processes in the vicinity of bone often induce osteoclast formation and bone resorption. Effects of inflammatory processes on bone formation are less studied. Therefore, we investigated the effect of locally induced inflammation on bone formation. Toll-like receptor (TLR) 2 agonists LPS from Porphyromonas gingivalis and PAM2 were injected once subcutaneously above mouse calvarial bones. After five days, both agonists induced bone formation mainly at endocranial surfaces. The injection resulted in progressively increased calvarial thickness during 21 days. Excessive new bone formation was mainly observed separated from bone resorption cavities. Anti-RANKL did not affect the increase of bone formation. Inflammation caused increased bone formation rate due to increased mineralizing surfaces as assessed by dynamic histomorphometry. In areas close to new bone formation, an abundance of proliferating cells was observed as well as cells robustly stained for Runx2 and alkaline phosphatase. PAM2 increased the mRNA expression of Lrp5, Lrp6 and Wnt7b, and decreased the expression of Sost and Dkk1. In situ hybridization demonstrated decreased Sost mRNA expression in osteocytes present in old bone. An abundance of cells expressed Wnt7b in Runx2-positive osteoblasts and ß-catenin in areas with new bone formation. These data demonstrate that inflammation, not only induces osteoclastogenesis, but also locally activates canonical WNT signaling and stimulates new bone formation independent on bone resorption.

Selective estrogen receptor modulators (SERMs) act as estrogen receptor (ER) agonists or antagonists in a tissue-specific manner. ERs exert effects via nuclear actions but can also utilize membrane-initiated signaling pathways. To determine if membrane-initiated ERα (mERα) signaling affects SERM action in a tissue-specific manner, C451A mice, lacking mERα signaling due to a mutation at palmitoylation site C451, were treated with Lasofoxifene (Las), Bazedoxifene (Bza), or estradiol (E2), and various tissues were evaluated. Las and Bza treatment increased uterine weight to a similar extent in C451A and control mice, demonstrating mERα-independent uterine SERM effects, while the E2 effect on the uterus was predominantly mERα-dependent. Las and Bza treatment increased both trabecular and cortical bone mass in controls to a similar degree as E2, while both SERM and E2 treatment effects were absent in C451A mice. This demonstrates that SERM effects, similar to E2 effects, in the skeleton are mERα-dependent. Both Las and E2 treatment decreased thymus weight in controls, while neither treatment affected the thymus in C451A mice, demonstrating mERα-dependent SERM and E2 effects in this tissue. Interestingly, both SERM and E2 treatments decreased the total body fat percent in C451A mice, demonstrating the ability of these treatments to affect fat tissue in the absence of functional mERα signaling. In conclusion, mERα signaling can modulate SERM responses in a tissue-specific manner. This novel knowledge increases the understanding of the mechanisms behind SERM effects and may thereby facilitate the development of new improved SERMs.

By introducing the healing of many distinctive anastomoses by BPC 157 therapy, this review practically deals with the concept of the resection and reconnection of the hollow parts of the gastrointestinal tract as one of the cornerstones of visceral surgery. In principle, the healing of quite distinctive anastomoses itself speaks for applied BPC 157 therapy, in particular, as a way in which the therapy of anastomoses can be successfully approached and carried out. Some of the anastomoses implicated were esophagogastric, colocolonic, jejunoileal, and ileoileal anastomoses, along with concomitant disturbances, such as esophagitis, sphincter dysfunction, failed intestinal adaptation, colitis, short bowel syndrome, major vessel occlusion, NO-system, and prostaglandins-system dysfunction, which were accordingly counteracted as well, and, finally, findings concerning other anastomoses healing (i.e., nerve and vessel). Moreover, the healing of fistulas, both external and internal, colocutaneous, gastrocutaneous, esophagocutaneous, duodenocutaneous, vesicovaginal, colovesical, and rectovaginal in rats, perceived as anastomoses made between two different tissues which are normally not connected, may also be indicative. This may be a particular reconnection of the parts of the gastrointestinal tract to re-establish adequate integrity depending on the tissue involved, given that both various intestinal anastomoses and various fistulas (intestinal and skin were accordingly healed simultaneously as the fistulas disappeared) were all healed.

Abstract Estradiol (E2) affects both reproductive and non-reproductive tissues, and the sensitivity to different doses of E2 varies between tissues. Membrane estrogen receptor α (mERα)-initiated signaling plays a tissue-specific role in mediating E2 effects, however, it is unclear if mERα signaling modulates E2 sensitivity. To determine this, we treated ovariectomized C451A females, lacking mERα signaling, and wildtype (WT) littermates with physiological (0.05 μg/mouse/day (low); 0.6 μg/mouse/day (medium)) or supraphysiological (6 μg/mouse/day (high)) doses of E2 (17β-estradiol-3-benzoate) for three weeks. Low-dose treatment increased uterus weight in WT, but not C451A mice, while non-reproductive tissues (gonadal fat, thymus, trabecular and cortical bone) were unaffected in both genotypes. Medium-dose treatment increased uterus weight and bone mass and decreased thymus and gonadal fat weights in WT mice. Uterus weight was also increased in C451A mice, but the response was significantly attenuated (− 85%) compared to WT mice, and no effects were triggered in non-reproductive tissues. High-dose treatment effects in thymus and trabecular bone were significantly blunted (− 34% and − 64%, respectively) in C451A compared to WT mice, and responses in cortical bone and gonadal fat were similar between genotypes. Interestingly, the high dose effect in uterus was enhanced (+ 26%) in C451A compared to WT mice. In conclusion, loss of mERα signaling reduces the sensitivity to physiological E2 treatment in both non-reproductive tissues and uterus. Furthermore, the E2 effect after high-dose treatment in uterus is enhanced in the absence of mERα, suggesting a protective effect of mERα signaling in this tissue against supraphysiological E2 levels.

We highlight the particular aspects of the stable gastric pentadecapeptide BPC 157 pleiotropic beneficial activity (not destroyed in human gastric juice, native and stable in human gastric juice, as a cytoprotection mediator holds a response specifically related to preventing or recovering damage as such) and its possible relations with neurotransmitter activity. We attempt to resolve the shortage of the pleiotropic beneficial effects of BPC 157, given the general standard neurotransmitter criteria, in classic terms. We substitute the lack of direct conclusive evidence (i.e., production within the neuron or present in it as a precursor molecule, released eliciting a response on the receptor on the target cells on neurons and being removed from the site of action once its signaling role is complete). This can be a network of interconnected evidence, previously envisaged in the implementation of the cytoprotection effects, consistent beneficial particular evidence that BPC 157 therapy counteracts dopamine, serotonin, glutamate, GABA, adrenalin/noradrenalin, acetylcholine, and NO-system disturbances. This specifically includes counteraction of those disturbances related to their receptors, both blockade and over-activity, destruction, depletion, tolerance, sensitization, and channel disturbances counteraction. Likewise, BPC 157 activates particular receptors (i.e., VGEF and growth hormone). Furthermore, close BPC 157/NO-system relations with the gasotransmitters crossing the cell membrane and acting directly on molecules inside the cell may envisage particular interactions with receptors on the plasma membrane of their target cells. Finally, there is nerve-muscle relation in various muscle disturbance counteractions, and nerve-nerve relation in various encephalopathies counteraction, which is also exemplified specifically by the BPC 157 therapy application.

Abstract Estrogen receptor alpha (ERα) signaling has beneficial skeletal effects in males. ERα signaling also affects other tissues, and to find bone-specific treatments, more knowledge regarding tissue-specific ERα signaling is needed. ERα is subjected to posttranslational modifications, including phosphorylation, which can influence ERα function in a tissue-specific manner. To determine the importance of phosphorylation site S122 (corresponding to human ERα site S118) for the skeleton and other tissues, male mice with a S122A mutation were used. Total areal bone mineral density was similar between gonadal intact S122A and WT littermates followed up to 12 months of age, and weights of estrogen-responsive organs normalized for body weight were unchanged between S122A and WT males at both 3 and 12 months of age. Interestingly, 12-month-old S122A males had decreased body weight compared to WT. To investigate if site S122 affects the estrogen response in bone and other tissues, 12-week-old S122A and WT males were orchidectomized (orx) and treated with estradiol (E2) or placebo pellets for four weeks. E2 increased cortical thickness in tibia in both orx WT (+ 60%, p

Schools devote substantial resources to teacher professional development each year. Yet studies show much of this investment is directed toward ineffective short-term workshops that have little impact on instructional change or student outcomes. At the same time, more intensive job-embedded forms of professional learning, such as instructional coaching, require substantially more resources than traditional professional development. We report the results of a two-year study assessing the cost-effectiveness of instructional coaching through a design-based, continuous improvement research model. We study iterative, inquiry cycles in which educators collect data and make changes to the coaching model based on multiple rounds of implementation. We determined the effectiveness of coaching during each iteration by tracking the number of times teachers and coaches reached student-outcome based goals set during the coaching cycle. We assess the cost of implementing the coaching model for each of the three iterations by monitoring staff time allocations and other resource use. Results show that across five schools, the cost of the coaching intervention decreased substantially from the first iteration to the second iteration but increased moderately during the third iteration. Our findings suggest that coaching programs can become more cost-effective over time, as coaches and teachers refine their work together. While specific design features of the study limit generalizability of our findings, the study demonstrates how improvement science or design-based research can be combined with cost-effectiveness research to improve practice in local settings.

We reviewed gastric ulcer healing by dopamine considering several distinctive duodenal key points. Selye and Szabo describe the cysteamine-induced duodenal ulcer in rats as a duodenal stress ulcer in patients. Szabo’s cysteamine duodenal ulcer as the dopamine duodenal healing and cysteamine as a dopamine antagonist signifies the dopamine agonists anti-ulcer effect and dopamine antagonists ulcerogenic effect. From these viewpoints, we focused on dopamine and gastric ulcer healing. We mentioned antecedent studies on the dopamine presence in the stomach and gastric juice. Then we reviewed, in the timeline, therapy significance arising from the anti-ulcer potency of the various dopamine agonists, which is highly prevailing over the quite persistent beneficial evidence arising from the various dopamine antagonists. Meanwhile, the beneficial effects of several peptides (i.e., amylin, cholecystokinin, leptin, and stable gastric pentadecapeptide BPC 157, suggested as an acting mediator of the dopamine brain-gut axis) were included in the dopamine gastric ulcer story. We attempt to resolve dopamine agonists/antagonists issue with the dopamine significance in the stress (cysteamine as a prototype of the duodenal stress ulcer), and cytoprotection (cysteamine in small dose as a prototype of the cytoprotective agents; cysteamine duodenal ulcer in gastrectomized rats). Thereby, along with dopamine agonists’ beneficial effects, in special circumstances, dopamine antagonists having their own ulcerogenic effect may act as “mild stress (or)” or “small irritant” counteracting subsequent strong alcohol or stress procedure-induced severe lesions in this particular tissue. Finally, in the conclusion, as a new improvement in further therapy, we emphasized the advantages of the dopamine agents’ application in lower gastrointestinal tract therapy.

Summary: Background: Global sclerostin inhibition reduces fracture risk efficiently but has been associated with cardiovascular side effects. The strongest genetic signal for circulating sclerostin is in the B4GALNT3 gene region, but the causal gene is unknown. B4GALNT3 expresses the enzyme beta-1,4-N-acetylgalactosaminyltransferase 3 that transfers N-acetylgalactosamine onto N-acetylglucosaminebeta-benzyl on protein epitopes (LDN-glycosylation). Methods: To determine if B4GALNT3 is the causal gene, B4galnt3−/− mice were developed and serum levels of total sclerostin and LDN-glycosylated sclerostin were analysed and mechanistic studies were performed in osteoblast-like cells. Mendelian randomization was used to determine causal associations. Findings: B4galnt3−/− mice had higher circulating sclerostin levels, establishing B4GALNT3 as a causal gene for circulating sclerostin levels, and lower bone mass. However, serum levels of LDN-glycosylated sclerostin were lower in B4galnt3−/− mice. B4galnt3 and Sost were co-expressed in osteoblast-lineage cells. Overexpression of B4GALNT3 increased while silencing of B4GALNT3 decreased the levels of LDN-glycosylated sclerostin in osteoblast-like cells. Mendelian randomization demonstrated that higher circulating sclerostin levels, genetically predicted by variants in the B4GALNT3 gene, were causally associated with lower BMD and higher risk of fractures but not with higher risk of myocardial infarction or stroke. Glucocorticoid treatment reduced B4galnt3 expression in bone and increased circulating sclerostin levels and this may contribute to the observed glucocorticoid-induced bone loss. Interpretation: B4GALNT3 is a key factor for bone physiology via regulation of LDN-glycosylation of sclerostin. We propose that B4GALNT3-mediated LDN-glycosylation of sclerostin may be a bone-specific osteoporosis target, separating the anti-fracture effect of global sclerostin inhibition, from indicated cardiovascular side effects. Funding: Found in acknowledgements.

Recently, marked therapeutic effects pertaining to the recovery of injured rat spinal cords (1 min compression injury of the sacrocaudal spinal cord (S2-Co1) resulting in tail paralysis) appeared after a single intraperitoneal administration of the stable gastric pentadecapeptide BPC 157 at 10 min post-injury. Besides the demonstrated rapid and sustained recovery (1 year), we showed the particular points of the immediate effect of the BPC 157 therapy that began rapidly after its administration, (i) soon after injury (10 min), or (ii) later (4 days), in the rats with a definitive spinal cord injury. Specifically, in counteracting spinal cord hematoma and swelling, (i) in rats that had undergone acute spinal cord injury, followed by intraperitoneal BPC 157 application at 10 min, we focused on the first 10–30 min post-injury period (assessment of gross, microscopic, and gene expression changes). Taking day 4 post-injury as the definitive injury, (ii) we focused on the immediate effects after the BPC 157 intragastric application over 20 min of the post-therapy period. Comparable long-time recovery was noted in treated rats which had definitive tail paralysis: (iii) the therapy was continuously given per orally in drinking water, beginning at day 4 after injury and lasting one month after injury. BPC 157 rats presented only discrete edema and minimal hemorrhage and increased Nos1, Nos2, and Nos3 values (30 min post-injury, (i)) or only mild hemorrhage, and only discrete vacuolation of tissue (day 4, (ii)). In the day 4–30 post-injury study (iii), BPC 157 rats rapidly presented tail function recovery, and no demyelination process (Luxol fast blue staining).

The study evaluated pharmacist interventions in pediatric patients within an integrated health system specialty pharmacy, focusing on adherence, adverse drug reactions, and drug utilization reviews. The interventions had a high acceptance rate of 98% and positively impacted patient care. Another study found that pharmacist-led interventions significantly reduced A1C levels and total medication expenditures in patients with uncontrolled diabetes. Integrating electronic patient-reported outcomes (ePROs) into clinical practice, particularly in diseases like rheumatoid arthritis, can enhance patient-centered care and improve treatment outcomes. Research posters presented on specialty pharmacy services aim to optimize medication programs, improve patient engagement, and evaluate the impact of pharmacist interventions on disease management programs to enhance patient outcomes and reduce healthcare costs. [Extracted from the article]

Given in reperfusion, the use of stable gastric pentadecapeptide BPC 157 is an effective therapy in rats. It strongly counteracted, as a whole, decompression/reperfusion-induced occlusion/occlusion-like syndrome following the worst circumstances of acute abdominal compartment and intra-abdominal hypertension, grade III and grade IV, as well as compression/ischemia-occlusion/occlusion-like syndrome. Before decompression (calvariectomy, laparotomy), rats had long-lasting severe intra-abdominal hypertension, grade III (25 mmHg/60 min) (i) and grade IV (30 mmHg/30 min; 40 mmHg/30 min) (ii/iii), and severe occlusion/occlusion-like syndrome. Further worsening was caused by reperfusion for 60 min (i) or 30 min (ii/iii). Severe vascular and multiorgan failure (brain, heart, liver, kidney, and gastrointestinal lesions), widespread thrombosis (peripherally and centrally) severe arrhythmias, intracranial (superior sagittal sinus) hypertension, portal and caval hypertension, and aortal hypotension were aggravated. Contrarily, BPC 157 therapy (10 µg/kg, 10 ng/kg sc) given at 3 min reperfusion times eliminated/attenuated venous hypertension (intracranial (superior sagittal sinus), portal, and caval) and aortal hypotension and counteracted the increases in organ lesions and malondialdehyde values (blood ˃ heart, lungs, liver, kidney ˃ brain, gastrointestinal tract). Vascular recovery promptly occurred (i.e., congested inferior caval and superior mesenteric veins reversed to the normal vessel presentation, the collapsed azygos vein reversed to a fully functioning state, the inferior caval vein–superior caval vein shunt was recovered, and direct blood delivery returned). BPC 157 therapy almost annihilated thrombosis and hemorrhage (i.e., intracerebral hemorrhage) as proof of the counteracted general stasis and Virchow triad circumstances and reorganized blood flow. In conclusion, decompression/reperfusion-induced occlusion/occlusion-like syndrome counteracted by BPC 157 therapy in rats is likely for translation in patients. It is noteworthy that by rapidly counteracting the reperfusion course, it also reverses previous ischemia-course lesions, thus inducing complete recovery.

After inferior caval vein embolization therapy, post-embolization syndrome (sodium laurate 10 mg/kg, 0.1 mL into rat inferior caval vein, assessment at 15, 30, 60 min, prime lung lesions, thromboemboli occluding lung vessels), as a severe occlusion/occlusion-like syndrome, might be resolved as a whole by stable gastric pentadecapeptide BPC 157 therapy. At 5 min after laurate injection, stable gastric pentadecapeptide BPC 157 was implemented as therapy (10 µg/kg, 10 ng/kg intraperitoneally or intragastrically). As before, confronted with the occlusion of major vessel(s) or similar noxious procedures, such as rapidly acting Virchow triad circumstances, the particular effect of the therapy (i.e., collateral pathways activation, “bypassing vascular key”, i.e., direct blood flow delivery via activation of azygos vein) assisted in the recovery of the vessel/s and counteracted multiorgan failure due to occlusion/occlusion-like syndrome as a whole in the laurate-injected rats. Along with prime lung lesions and thromboemboli occluding lung vessels, post-embolization syndrome rapidly occurred peripherally and centrally as a shared multiorgan and vessel failure, brain, heart, lung, liver, kidney, and gastrointestinal tract lesions, venous hypertension (intracranial (superior sagittal sinus), portal, and caval), aortal hypotension, progressing thrombosis in veins and arteries and stasis, congested and/or failed major veins, and severe ECG disturbances. Whatever the cause, these were all counteracted, eliminated, or attenuated by the application of BPC 157 therapy. As recovery with BPC 157 therapy commonly and rapidly occurred, reversing the collapsed azygos vein to the rescuing collateral pathway might initiate rapid direct blood delivery and start blood flow reorganization. In conclusion, we suggest BPC 157 therapy to resolve further vascular and embolization injuries.

In this article, we build on the extant literature documenting efforts to reform teacher education for inclusive education in the United States to demonstrate the complexity of preparing teachers to enact inclusive education given their own educational trajectories. We draw on qualitative data from a larger study on the nature and impact of an undergraduate course in inclusive education, providing an empirical analysis of the mediating role of general education pre-service teachers' educational experiences in their constructions of inclusive education and its feasibility. Our data reveal how pre-service teachers' educational experiences within school organisations configured by professionalisation and specialisation, worked to perpetuate and legitimate the separation of general and special education. We conclude by suggesting possible efforts to prepare educators for inclusive education.

Components of carotid atherosclerotic plaque can be analysed preoperatively by non-invasive advanced imaging modalities such as magnetic resonance imaging (MRI). The expression of matrix metalloproteinase-9 protein (MMP-9), which has a potential role in remodelling of atherosclerotic plaques, can be analysed immunohistochemically. The aim of the present prospective pilot study is to analyse histological characteristics and expression of MMP-9 in carotid plaques of patients undergoing carotid endarterectomy (CEA) and to investigate the correlation with preoperative clinical symptoms and MRI features. Preoperative clinical assessment, MRI imaging, postoperative histological and immunohistochemical analyses were performed. Fifteen patients with symptomatic (7/15; 47%) and asymptomatic carotid artery stenosis undergoing CEA were included. Among symptomatic patients, 5 (71%) had recent stroke and 2 (29%) had recent transient ischaemic attack with a median timing of 6 weeks (IQR: 1, 18) before the surgery. Both groups did not significantly differ in respect to preoperative characteristics. Prevalence of unstable plaque was higher in symptomatic than asymptomatic patients, although it was not significant (63% vs. 37%, p = 0.077). The expression of MMP-9 in CD68 cells within the plaque by semiquantitative analysis was found to be significantly higher in symptomatic as compared to asymptomatic patients (86% vs. 25% with the highest expression, p = 0.014). The average microvascular density was found to be higher and lipid core area larger among both symptomatic patients and unstable carotid plaque specimens, although this did not reach statistical significance (p = 0.064 and p = 0.132, p = 0.360 and p = 0.569, respectively). Our results demonstrate that MRI is reliable in classifying carotid lesions and differentiating unstable from stable plaques. We have also shown that the expression of MMP-9 is significantly higher among symptomatic patients undergoing CEA.

Petra Henning,1 Sofia Movérare-Skrtic,1 Anna Westerlund,1 Pedro Paulo Chaves de Souza,2,3 Thais Floriano-Marcelino,3 Karin H Nilsson,1 Maha El Shahawy,1,4 Claes Ohlsson,1 Ulf H Lerner1 1Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Osteoporosis Centre and Centre for Bone and Arthritis Research at the Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; 2The Innovation in Biomaterials Laboratory, School of Dentistry, Federal University of Goiás, Goiânia, Brazil; 3Department of Physiology and Pathology, São Paulo State University (UNESP), School of Dentistry, Araraquara, Brazil; 4Department of Oral Biology, Faculty of Dentistry, Minia University, Minia, 61511, EgyptCorrespondence: Ulf H LernerUniversity of Gothenburg, Klin Farm Lab, Vita Straket 11, Gothenburg, 41345, SwedenTel +46 70 651 91 03Email ulf.lerner@gu.seBackground: Bone loss is often observed adjacent to inflammatory processes. The WNT signaling pathways have been implicated as novel regulators of both immune responses and bone metabolism. WNT16 is important for cortical bone mass by inhibiting osteoclast differentiation, and we have here investigated the regulation of WNT16 by several members of the pro-inflammatory gp130 cytokine family.Methods: The expression and regulation of Wnt16 in primary murine cells were studied by qPCR, scRNAseq and in situ hybridization. Signaling pathways were studied by siRNA silencing. The importance of oncostatin M (OSM)-induced WNT16 expression for osteoclastogenesis was studied in cells from Wnt16-deficient and wild-type mice.Results: We found that IL-6/sIL-6R and OSM induce the expression of Wnt16 in primary mouse calvarial osteoblasts, with OSM being the most robust stimulator. The induction of Wnt16 by OSM was dependent on gp130 and OSM receptor (OSMR), and downstream signaling by the SHC1/STAT3 pathway, but independent of ERK. Stimulation of the calvarial cells with OSM resulted in enhanced numbers of mature, oversized osteoclasts when cells were isolated from Wnt16 deficient mice compared to cells from wild-type mice. OSM did not affect Wnt16 mRNA expression in bone marrow cell cultures, explained by the finding that Wnt16 and Osmr are expressed in distinctly different cells in bone marrow, nor was osteoclast differentiation different in OSM-stimulated bone marrow cell cultures isolated from Wnt16−/- or wild-type mice. Furthermore, we found that Wnt16 expression is substantially lower in cells from bone marrow compared to calvarial osteoblasts.Conclusion: These findings demonstrate that OSM is a robust stimulator of Wnt16 mRNA in calvarial osteoblasts and that WNT16 acts as a negative feedback regulator of OSM-induced osteoclast formation in the calvarial bone cells, but not in the bone marrow.Keywords: oncostatin M, WNT16, osteoclast, osteoblast

We focused on the first demonstration that antiarrhythmics, particularly class II and class III antiarrhythmic and beta-blocker sotalol can induce severe occlusion/occlusion-like syndrome in rats. In this syndrome, as in similar syndromes with permanent occlusion of major vessels, peripheral and central, and other similar noxious procedures that severely disable endothelium function, the stable gastric pentadecapeptide BPC 157-collateral pathways activation, was a resolving therapy. After a high dose of sotalol (80 mg/kg intragastrically) in 180 min study, there were cause-consequence lesions in the brain (swelling, intracerebral hemorrhage), congestion in the heart, lung, liver, kidney, and gastrointestinal tract, severe bradycardia, and intracranial (superior sagittal sinus), portal and caval hypertension, and aortal hypotension, and widespread thrombosis, peripherally and centrally. Major vessels failed (congested inferior caval and superior mesenteric vein, collapsed azygos vein). BPC 157 therapy (10 µg, 10 ng/kg given intragastrically at 5 min or 90 min sotalol-time) effectively counteracted sotalol-occlusion/occlusion-like syndrome. In particular, eliminated were heart dilatation, and myocardial congestion affecting coronary veins and arteries, as well as myocardial vessels; eliminated were portal and caval hypertension, lung parenchyma congestion, venous and arterial thrombosis, attenuated aortal hypotension, and centrally, attenuated intracranial (superior sagittal sinus) hypertension, brain lesions and pronounced intracerebral hemorrhage. Further, BPC 157 eliminated and/or markedly attenuated liver, kidney, and gastrointestinal tract congestion and major veins congestion. Therefore, azygos vein activation and direct blood delivery were essential for particular BPC 157 effects. Thus, preventing such and similar events, and responding adequately when that event is at risk, strongly advocates for further BPC 157 therapy.

Recently, stable gastric pentadecapeptide BPC 157 therapy by activation of collateral pathways counteracted various occlusion/occlusion-like syndromes, vascular, and multiorgan failure, and blood pressure disturbances in rats with permanent major vessel occlusion and similar procedures disabling endothelium function. Thereby, we revealed BPC 157 cytoprotective therapy with strong vascular rescuing capabilities in glaucoma therapy. With these capabilities, BPC 157 therapy can recover glaucomatous rats, normalize intraocular pressure, maintain retinal integrity, recover pupil function, recover retinal ischemia, and corneal injuries (i.e., maintained transparency after complete corneal abrasion, corneal ulceration, and counteracted dry eye after lacrimal gland removal or corneal insensitivity). The most important point is that in glaucomatous rats (three of four episcleral veins cauterized) with high intraocular pressure, all BPC 157 regimens immediately normalized intraocular pressure. BPC 157-treated rats exhibited normal pupil diameter, microscopically well-preserved ganglion cells and optic nerve presentation, normal fundus presentation, nor- mal retinal and choroidal blood vessel presentation, and normal optic nerve presentation. The one episcleral vein rapidly upgraded to accomplish all functions in glaucomatous rats may correspond with occlusion/occlusion-like syndromes of the activated rescuing collateral pathway (azygos vein direct blood flow delivery). Normalized intraocular pressure in glaucomatous rats corresponded to the counteracted intra-cranial (superior sagittal sinus), portal, and caval hypertension, and aortal hypotension in occlusion/occlusion-like syndromes, were all attenuated/eliminated by BPC 157 therapy. Furthermore, given in other eye disturbances (i.e., retinal ischemia), BPC 157 instantly breaks a noxious chain of events, both at an early stage and an already advanced stage. Thus, we further advocate BPC 157 as a therapeutic agent in ocular disease.

Genetic association signals for fractures have been reported at the RSPO3 locus, but the causal gene and the underlying mechanism are unknown. Here, the authors show that RSPO3 exerts an important role for vertebral trabecular bone mass and bone strength in mice and fracture risk in humans.

Even before behavioral disturbances, neuroleptics, amphetamine, and domperidone application rapidly emerged severe occlusion/occlusion-like syndrome, shared innate vascular and multiorgan failure in rats, comparable to occlusion/occlusion-like syndrome described with vessel(s) occlusion or similar noxious procedures application. As therapy, i.e., activation of the collateral pathways, “bypassing key” (activated azygos vein pathway, direct blood flow delivery), the stable gastric pentadecapeptide BPC 157 is a novel solution. Recently, BPC 157 therapy particularly counteracted neuroleptic- or L-NAME-induced catalepsy, lithium intoxication, and schizophrenia positive and negative symptoms (amphetamine/methamphetamine/apomorphine/ketamine). In rats with complete calvariectomy, medication (BPC 157 10 µg/kg, 10 ng/kg ip or ig) was given 5 min after distinctive dopamine agents (mg/kg ip) (haloperidol (5), fluphenazine (5), clozapine (10), risperidone (5), olanzapine (10), quetiapine (10), or aripiprazole (10), domperidone (25), amphetamine (10), and combined amphetamine and haloperidol) and assessed at 15 min thereafter. All neuroleptic-, domperidone-, and amphetamine-induced comparable vascular and multiorgan failure severe syndrome was alleviated with BPC 157 therapy as before major vessel(s) occlusion or other similar noxious procedures. Specifically, all severe lesions in the brain (i.e., immediate swelling, hemorrhage), heart (i.e., congestion, arrhythmias), and lung (i.e., congestion, hemorrhage), as well as congestion in the liver, kidney, and gastrointestinal (stomach) tract, were resolved. Intracranial (superior sagittal sinus), portal, and caval hypertension and aortal hypotension were attenuated or eliminated. BPC 157 therapy almost annihilated arterial and venous thrombosis, peripherally and centrally. Thus, rapidly acting Virchow triad circumstances that occur as dopamine central/peripheral antagonists and agonist essential class-points, fully reversed by BPC 157 therapy, might be overwhelming for both neuroleptics and amphetamine.

Conceptually, a wide beneficial effect, both peripherally and centrally, might have been essential for the harmony of brain–gut and gut–brain axes’ function. Seen from the original viewpoint of the gut peptides’ significance and brain relation, the favorable stable gastric pentadecapeptide BPC 157 evidence in the brain–gut and gut–brain axes’ function might have been presented as a particular interconnected network. These were the behavioral findings (interaction with main systems, anxiolytic, anticonvulsive, antidepressant effect, counteracted catalepsy, and positive and negative schizophrenia symptoms models). Muscle healing and function recovery appeared as the therapeutic effects of BPC 157 on the various muscle disabilities of a multitude of causes, both peripheral and central. Heart failure was counteracted (including arrhythmias and thrombosis), and smooth muscle function recovered. These existed as a multimodal muscle axis impact on muscle function and healing as a function of the brain–gut axis and gut–brain axis as whole. Finally, encephalopathies, acting simultaneously in both the periphery and central nervous system, BPC 157 counteracted stomach and liver lesions and various encephalopathies in NSAIDs and insulin rats. BPC 157 therapy by rapidly activated collateral pathways counteracted the vascular and multiorgan failure concomitant to major vessel occlusion and, similar to noxious procedures, reversed initiated multicausal noxious circuit of the occlusion/occlusion-like syndrome. Severe intracranial (superior sagittal sinus) hypertension, portal and caval hypertensions, and aortal hypotension were attenuated/eliminated. Counteracted were the severe lesions in the brain, lungs, liver, kidney, and gastrointestinal tract. In particular, progressing thrombosis, both peripherally and centrally, and heart arrhythmias and infarction that would consistently occur were fully counteracted and/or almost annihilated. To conclude, we suggest further BPC 157 therapy applications.

By introducing the healing of many distinctive anastomoses by BPC 157 therapy, this review practically deals with the concept of the resection and reconnection of the hollow parts of the gastrointestinal tract as one of the cornerstones of visceral surgery. In principle, the healing of quite distinctive anastomoses itself speaks for applied BPC 157 therapy, in particular, as a way in which the therapy of anastomoses can be successfully approached and carried out. Some of the anastomoses implicated were esophagogastric, colocolonic, jejunoileal, and ileoileal anastomoses, along with concomitant disturbances, such as esophagitis, sphincter dysfunction, failed intestinal adaptation, colitis, short bowel syndrome, major vessel occlusion, NO-system, and prostaglandins-system dysfunction, which were accordingly counteracted as well, and, finally, findings concerning other anastomoses healing (i.e., nerve and vessel). Moreover, the healing of fistulas, both external and internal, colocutaneous, gastrocutaneous, esophagocutaneous, duodenocutaneous, vesicovaginal, colovesical, and rectovaginal in rats, perceived as anastomoses made between two different tissues which are normally not connected, may also be indicative. This may be a particular reconnection of the parts of the gastrointestinal tract to re-establish adequate integrity depending on the tissue involved, given that both various intestinal anastomoses and various fistulas (intestinal and skin were accordingly healed simultaneously as the fistulas disappeared) were all healed. [ABSTRACT FROM AUTHOR]

Abstract Atherosclerosis is characterized by retention of modified lipoproteins, especially oxidized low density lipoprotein (oxLDL) within the sub-endothelial space of affected blood vessels. Recruited monocyte-derived and tissue-resident macrophages subsequently ingest oxLDL by binding and internalizing oxLDL via scavenger receptors, particularly CD36. The secreted neurorepellent, Slit2, acting through its transmembrane receptor, Roundabout-1 (Robo-1), was previously shown to inhibit recruitment of monocytes into nascent atherosclerotic lesions. The effects of Slit2 on oxLDL uptake by macrophages have not been explored. We report here that Slit2 inhibits uptake of oxLDL by human and murine macrophages, and the resulting formation of foam cells, in a Rac1-dependent and CD36-dependent manner. Exposure of macrophages to Slit2 prevented binding of oxLDL to the surface of cells. Using super-resolution microscopy, we observed that exposure of macrophages to Slit2 induced profound cytoskeletal remodeling with formation of a thick ring of cortical actin within which clusters of CD36 could not aggregate, thereby attenuating binding of oxLDL to the surface of cells. By inhibiting recruitment of monocytes into early atherosclerotic lesions, and the subsequent binding and internalization of oxLDL by macrophages, Slit2 could represent a potent new tool to combat individual steps that collectively result in progression of atherosclerosis.

Estrogen receptor α (ERα) signaling leads to cellular responses in several tissues and in addition to nuclear ERα-mediated effects, membrane ERα (mERα) signaling may be of importance. To elucidate the significance, in vivo, of mERα signaling in multiple estrogen-responsive tissues, we have used female mice lacking the ability to localize ERα to the membrane due to a point mutation in the palmitoylation site (C451A), so called Nuclear-Only-ER (NOER) mice. Interestingly, the role of mERα signaling for the estrogen response was highly tissue-dependent, with trabecular bone in the axial skeleton being strongly dependent (>80% reduction in estrogen response in NOER mice), cortical and trabecular bone in long bones, as well as uterus and thymus being partly dependent (40-70% reduction in estrogen response in NOER mice) and effects on liver weight and total body fat mass being essentially independent of mERα (