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Fibrosis around the smooth muscle of asthmatic airway walls leads to irreversible airway obstruction. Bronchial epithelial cells release granulocyte/macrophage colony-stimulating factor (GM-CSF) in asthmatics and are in close proximity to airway smooth muscle cells (ASMC). The findings in this study demonstrate that GM-CSF induces confluent, prolonged, serum-deprived cultures of ASMC to increase expression of collagen I and fibronectin. GM-CSF also induced ASMC to increase the expression of transforming growth factor (TGF)-beta receptors type I, II, and III (TbetaR-I, TbetaR-II, TbetaR-III), but had no detectable effect on the release of TGF-beta1 by the same ASMC. The presence of GM-CSF also induced the association of TGF-beta1 with TbetaR-III, which enhances binding of TGF-beta1 to TbetaR-II. The induction of TbetaRs was parallel to the increased induction of phosphorylated Smad2 (pSmad2) and connective tissue growth factor (CTGF), indicative of TGF-beta-mediated connective tissue synthesis. Dexamethasone decreased GM-CSF-induced TbetaR-I, TbetaR-II, TbetaR-III, pSmad2, CTGF, collagen I, and fibronectin. In conclusion, GM-CSF increases the responsiveness of ASMC to TGF-beta1-mediated connective tissue expression by induction of TbetaRs, which is inhibited by corticosteroids.

Melanoma is highly resistant to conventional chemotherapy. We have demonstrated that redox regulation in melanoma cells is aberrant, and redox-modulating agents can induce cell apoptosis. We have currently explored the effect of disulfiram (DSF), a member of the dithiocarbamate family, on apoptosis of melanoma cells in vitro. Human metastatic melanoma cells c81-46A, c81-61, and c83-2C were treated with DSF and apoptosis measured. DSF, at a dose of 25-50 ng/ml, consistently caused a 4-6-fold increase in apoptosis. The same dose of DSF did not significantly affect apoptosis in melanocytes. Coincubation of N-acetyl-cysteine reversed the DSF-induced apoptosis. Buthionine sulfoximine (BSO), an inhibitor of gamma-glutamyl-cysteine synthetase, as a single agent caused a approximately 2-fold increase in apoptosis when incubated with melanoma cells for 4 days. BSO slightly enhanced the level of apoptosis induced by DSF (4-10% higher than DSF alone). Intracellular glutathione was remarkably depleted with BSO treatment. DSF did not cause glutathione depletion; however, the ratio of reduced and oxidized glutathione was significantly decreased (14% of control), and N-acetyl-cysteine partially restored the ratio to 30% of control. There was a transient (2-fold) elevation of intracellular superoxide level after 24 h of DSF treatment (before the overt apoptosis). The intracellular H2O2 level progressively decreased with time. DSF decreased the mitochondrial membrane polarization in a time-dependent manner, and there was a significant inverse correlation between apoptosis and mitochondrial membrane polarization. We propose that DSF-induced apoptosis is redox related but involves a different mechanism from BSO-induced apoptosis in tumor cells. Our findings have provided new data for additional understanding of drug-induced apoptosis in melanoma cells and suggests an alternative therapeutic approach to melanoma.

Abstract Given the current opioid crisis around the world, harm reduction agencies are seeking to help people who use drugs to do so more safely. Many harm reduction agencies are exploring techniques to test illicit drugs to identify and, where possible, quantify their constituents allowing their users to make informed decisions. While these technologies have been used for years in Europe (Nightlife Empowerment & Well-being Implementation Project, Drug Checking Service: Good Practice Standards; Trans European Drugs Information (TEDI) Workgroup, Factsheet on Drug Checking in Europe, 2011; European Monitoring Centre for Drugs and Drug Addiction, An Inventory of On-site Pill-Testing Interventions in the EU: Fact Files, 2001), they are only now starting to be utilized in this context in North America. The goal of this paper is to describe the most common methods for testing illicit substances and then, based on this broad, encompassing review, recommend the most appropriate methods for testing at point of care. Based on our review, the best methods for point-of-care drug testing are handheld infrared spectroscopy, Raman spectroscopy, and ion mobility spectrometry; mass spectrometry is the current gold standard in forensic drug analysis. It would be prudent for agencies or clinics that can obtain the funding to contact the companies who produce these devices to discuss possible usage in a harm reduction setting. Lower tech options, such as spot/color tests and immunoassays, are limited in their use but affordable and easy to use.

Introduction: The widespread use of drugs in patients with different nutritional status, dietary habits, diet and dietary supplements creates an opportunity for the potentially unlimited numbers of interactions between medicines and food. Consequently, clinically significant manifestations of those interactions should not be ignored. Corresponding section headings: Many drugs contain ingredients that react with the human organism in different ways. Dietary habits and lifestyle can sometimes significantly affect pharmacological properties of drugs. Interactions of drugs and dietary supplements can have a significant impact on the success of the therapy. Conclusion: This kind of interaction is often forgotten when medication is prescribed, so the patient is usually not aware that eating habits, with given medication, can harm health. The result of these interactions in relation to the effects of drugs can be positive or negative, but it is often very significant.

In severe or chronic asthma, there is an increase in airway smooth muscle cell (ASMC) mass as well as an increase in connective tissue proteins in the smooth muscle layer of airways. Transforming growth factor-beta (TGF-beta) exists in three isoforms in mammals and is a potent regulator of connective tissue protein synthesis. Using immunohistochemistry, we had previously demonstrated that ASMCs contain large quantities of TGF-beta1-3. In this study, we demonstrate that bovine ASMC-derived TGF-beta associates with the TGF-beta latency binding protein-1 (LTBP-1) expressed by the same cells. The TGF-beta associated with LTBP-1 localizes TGF-beta extracellularly. Furthermore, plasmin, a serine protease, regulates the secretion of a biologically active form of TGF-beta by ASMCs as well as the release of extracellular TGF-beta. The biologically active TGF-beta released by plasmin induces ASMCs to synthesize collagen I in an autocrine manner. The autocrine induction of collagen expression by ASMCs may contribute to the irreversible fibrosis and remodeling seen in the airways of some asthmatics.

Semaglutide is an anti-diabetes and weight loss drug that decreases food intake, slows gastric emptying, and increases insulin secretion. Patients begin treatment with low-dose semaglutide and increase dosage over time as efficacy plateaus. With increasing dosage, there is also greater incidence of gastrointestinal side effects. One reason for the plateau in semaglutide efficacy despite continued low food intake is due to compensatory actions whereby the body becomes more metabolically efficient to defend against further weight loss. Mitochondrial uncoupler drugs decrease metabolic efficiency, therefore we sought to investigate the combination therapy of semaglutide with the mitochondrial uncoupler BAM15 in diet-induced obese mice. Mice were fed high-fat western diet (WD) and stratified into six treatment groups including WD control, BAM15, low-dose semaglutide without or with BAM15, and high-dose semaglutide without or with BAM15. Combining BAM15 with either semaglutide dose decreased body fat and liver triglycerides, which was not achieved by any monotherapy, while high-dose semaglutide with BAM15 had the greatest effect on glucose homeostasis. This study demonstrates a novel approach to improve weight loss without loss of lean mass and improve glucose control by simultaneously targeting energy intake and energy efficiency. Such a combination may decrease the need for semaglutide dose escalation and hence minimize potential gastrointestinal side effects., (© 2024 The Author(s).)

Contributions of brain glutamate (Glu) to conscious emotion are not well understood. Here, we evaluate the relationship of experimentally induced change in neocortical Glu (ΔGlu) and subjective states in well individuals, using combined application of pharmacological challenge, magnetic resonance spectroscopy (MRS), and comprehensive affective assessment. Drug challenge with d-amphetamine (AMP) (20 mg oral), methamphetamine (MA) (Desoxyn, 20 mg oral), and placebo (PBO) was conducted on three separate test days in a within-subjects double blind design. Proton MRS quantified neurometabolites in the right dorsal anterior cingulate cortex 140-150 min post-drug and PBO. Subjective states were assessed at half hour intervals over 5.5 h on each session, yielding 3792 responses per participant (91,008 responses overall, N = 24 participants), with self-reports reduced by principal components analysis (PCA). PCA produced a primary factor score of AMP- and MA-induced positive agency (ΔPA). MRS indicated drug-induced ΔGlu related positively to ΔPA (ΔGlu MA r = +0.44, p < 0.05, N = 21), with large effects in females (ΔGlu MA r = +0.52, p < 0.05; ΔGlu AMP r = +0.61, p < 0.05, N = 11). Subjective states related to ΔGlu included rise in subjective stimulation, vigor, friendliness, elation, positive mood, positive affect ( r 's = +0.51 to +0.74, p < 0.05), and alleviation of anxiety in females ( r = -0.61, p < 0.05, N = 11). These self-reports correlated with ΔGlu to the extent they loaded on ΔPA ( r = 0.95 AMP, p = 5 × 10 -10 ; r = 0.63 MA, p = 0.0015, N = 11), indicating the coherence of ΔGlu effects on emotional states. Timing data indicated Glu shaped positive emotion both concurrently and prospectively, with no relationship with pre-MRS emotion (ΔGlu AMP r = +0.59 to +0.65, p 's < 0.05; ΔGlu MA r = +0.53, p < 0.05, N = 11). Together these findings indicate substantive, mechanistic contributions of neocortical Glu to positive agentic states in healthy individuals, which are most readily observed in women. The findings illustrate the promise of combined application of pharmacological challenge, comprehensive affective assessment, and MRS neuroimaging techniques in basic and clinical studies.

It is well known that cAMP signaling plays a role in regulating functional plasticity at central glutamatergic synapses. However, in the Drosophila CNS, where acetylcholine is thought to be a primary excitatory neurotransmitter, cellular changes in neuronal communication mediated by cAMP remain unexplored. In this study we examined the effects of elevated cAMP levels on fast excitatory cholinergic synaptic transmission in cultured embryonic Drosophila neurons. We report that chronic elevation in neuronal cAMP (in dunce neurons or wild-type neurons grown in db-cAMP) results in an increase in the frequency of cholinergic miniature EPSCs (mEPSCs). The absence of alterations in mEPSC amplitude or kinetics suggests that the locus of action is presynaptic. Furthermore, a brief exposure to db-cAMP induces two distinct changes in transmission at established cholinergic synapses in wild-type neurons: a short-term increase in the frequency of spontaneous action potential-dependent synaptic currents and a long-lasting, protein synthesis-dependent increase in the mEPSC frequency. A more persistent increase in cholinergic mEPSC frequency induced by repetitive, spaced db-cAMP exposure in wild-type neurons is absent in neurons from the memory mutant dunce. These data demonstrate that interneuronal excitatory cholinergic synapses in Drosophila, like central excitatory glutamatergic synapses in other species, are sites of cAMP-dependent plasticity. In addition, the alterations in dunce neurons suggest that cAMP-dependent plasticity at cholinergic synapses could mediate changes in neuronal communication that contribute to memory formation.

Apoptosis a programmed cell death, is an essential mechanism of eliminating damaged or aged cells and thus to maintain tissue integrity. There are two central pathways that lead to apoptosis: a) the positive induction by ligands (death factors) binding to plasma membrane receptors (death factor receptors) and b) negative induction by the loss of suppressor activity. The common execution mechanisms of apoptosis consist of the activation of cytosolic aspartate-specific proteases (ICE-proteases) termed caspases, which can be activated via various intracellular pathways. In the stomach, mucosal surface epithelial cells are constantly exfoliating to the gastric lumen and completely replaced within 3-5 days under physiological conditions. Apoptosis has been reported to take place in all regions of the stomach with apoptotic cells occurring predominantly in the superficial parts of the gastric glands, at a rate of 2-3% for all cells. Following mucosal injury (e.g. ulcer development), apoptosis rapidly increases and remains elevated for 2-3 months. In a 3-month old ulcer scar, the apoptosis rate of mucous, parietal, chief and endocrine cells was found to be similar to that of normal gastric mucosa. Helicobacter pylori (H. pylori) infection induces apoptosis in the gastric mucosa and this action appears to be independent of VacA cytotoxin of H. pylori strains. Nonsteroidal anti-inflammatory drugs (NSAIDs), especially cyclooxygenase-2 (COX-2) inhibitors are potent inductors of gastric epithelial cell apoptosis. However, they can abrogate apoptosis or proliferation effects induced by H. pylori. Many details of the exact intracellular and molecular mechanisms regulating apoptosis in gastric mucosa remain to be elucidated.

As part of systemic inflammatory reactions, interleukin 6 (IL-6) induces acute phase protein (APP) genes through the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway. Epidermal growth factor (EGF), which contributes to the regenerative process after liver injury and also activates STATs, does not induce but attenuates IL-6-stimulated expression of several APP genes in primary mouse hepatocytes. The APP-modifying action of EGF receptor (EGFR) was characterized in HepG2 cells. Although EGF less effectively engages STAT proteins in these cells, it reduces expression of fibrinogen and haptoglobin, but stimulates production of alpha(1)-antichymotrypsin and induces transcription through the alpha(1)-antichymotrypsin and C-reactive protein promoter. The stimulatory EGFR signal is insensitive to inhibition of JAKs and appears to involve Src kinases and STAT proteins as shown by inhibition through overexpression of C-terminal Src kinase (Csk) and transdominant negative STAT3, respectively. A mediator role of Src is supported by the ability of c-Src and v-Src to activate STATs and induce transcription through APP promoters. Src kinases have been observed in association with the IL-6 receptor; however, inhibition of Src kinases by Csk enhances IL-6-induced transcription. The Csk effect is attributed to prevention of Src kinases from phosphorylating gp130 at the docking site for the signal-moderating protein tyrosine phosphatase SHP-2. The inhibitory EGFR signal on APP expression correlates with the activation of Erk1 and Erk2. The study shows a dual signaling function for EGFR and suggests that the ratio of receptor-activated STATs and Erks influence the level of stimulated or inhibited expression of individual APPs.

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Objective: The objective of this study is to compare the uterine activity response between women administered dinoprostone (prostaglandin E2) and misoprostol (prostaglandin E1) for induction of labour (IOL) by analysing not only the traditional obstetric data but also the parameters extracted from uterine electrohysterogram (EHG).Methods: Two cohorts were defined: misoprostol (25-µg vaginal tablets; 251 women) and dinoprostone cohort (10 mg vaginal inserts; 249 women). All the mothers were induced by a medical indication of a Bishop Score < = 6.Results: The misoprostol cohort was associated with a shorter time to achieve active labour (p = .017) and vaginal delivery (p = .009) and with a higher percentage of vaginal delivery in less than 24 h in mothers with a very unfavourable cervix score (risk ratio (RR): 1.41, IC95% 1.17-1.69, p = .002). Successful inductions with misoprostol showed EHG parameter values significantly higher than basal state for amplitude and pseudo Montevideo units (PMU) 60' after drug administration, while spectral parameters significantly increased after 150'. This response was not observed in failed inductions. In the successful dinoprostone group, the duration and number of contractions increased significantly after 120', PMU did so after 180', and no significant differences were found for spectral parameters, possibly due to the slower pharmacokinetics of this drug.Conclusion: Successful inductions of labour by misoprostol are associated with earlier effective contractions than in labours induced by dinoprostone. [ABSTRACT FROM AUTHOR]

Vitamin K antagonists (VKAs) cannot be administered without regular monitoring in order to assure their efficacy and safety. Indeed, if well managed, the VKAs appear to be no less efficacious or safe than the newer direct oral anticoagulants (DOACs). Although it is claimed that no regular monitoring of the DOACs is needed, their levels are increasingly being measured under a variety of circumstances, for example, prior to surgery, in suspected overdose, to confirm effective reversal, in patients with malabsorption and to assess patient compliance. Although no therapeutic range has been identified for the DOACs, it has been demonstrated for dabigatran and edoxaban that their antithrombotic effect increases gradually with increasing concentrations and that the risk of major bleeding also gradually increases. Furthermore, it has been determined that almost all dabigatran‐related thrombotic events occur in patients with the lowest quartile concentration of the drug. This suggests that to assure an ideal effect of DOACs in all patients taking them, some form of regular monitoring and dose tailoring should be performed. For the vitamin K antagonists, the best outcome is obtained using formal algorithms and centralized management. Furthermore, data suggest that replacing the standard prothrombin time as a monitoring test may increase the stability of VKA anticoagulation with consequent reduction in thromboembolism without an increase in bleeding. Thus, it is likely that the outcome of all current oral anticoagulants can be improved in the coming years by improving monitoring and tailoring their effect. [ABSTRACT FROM AUTHOR]

Introduction: Direct oral anticoagulants (DOACs) require no laboratory monitoring, but they interfere with almost all clotting tests to a varying degree, depending on the DOAC, assay principles and reagents used. DOAC Stop (Haematex Research, Sydney, Australia) has recently been shown to adsorb DOACs from spiked and patient plasmas. The aim of our work was to investigate the DOAC Stop effect on a range of haemostasis assays on plasmas collected from patients on rivaroxaban or apixaban, to see whether it removes the effect of these drugs to enable more accurate interpretation of coagulation assays. Methods: Samples from patients anticoagulated with either rivaroxaban, apixaban or no anticoagulant were tested for prothrombin time (PT), activated partial thromboplastin time (APTT), DOAC‐specific anti‐Xa assay, factor VIII (one‐stage and chromogenic assay) and DRVVT (low and high phospholipid) before and after sample treatment with DOAC‐Stop. Results: DOAC Stop significantly removed the effects of rivaroxaban and apixaban on PT, APTT, anti‐Xa activity, factor VIII (one‐stage and chromogenic assays), and DRVVT (low and high phospholipid reagents), and reduced the number of false positive of lupus anticoagulant interpretations in patients on rivaroxaban. There was no effect on the results from patients that were not anticoagulated. Conclusion: This small study suggests that it is likely that DOAC Stop can be used in laboratories to screen for coagulopathy or lupus anticoagulants in samples containing rivaroxaban or apixaban. Care should be taken in the interpretation of results since complete reversal of the anti‐Xa effect did not occur in every sample. [ABSTRACT FROM AUTHOR]

Introduction: Monoclonal antibodies against proprotein‐convertase subtilisin/kexin type 9 (PCSK9) inhibitors are a newly‐introduced therapeutic approach against hypercholesterolemia. Clinical trials have reported few adverse effects of PCSK9 inhibitors and there are no reports of oral adverse effects. We present the case of a patient that showed gingival discomfort on eating and toothbrushing, coupled with the presence of gingival ischemia and petechiae, 3 days after a subcutaneous abdominal injection of 75‐mg alirocumab for hypercholesterolemia, and contemplate on their possible pathogenesis. Case Presentation: Αn 81‐year‐old male presented with gingival discomfort during eating and toothbrushing, 3 days after receiving a subcutaneous abdominal injection of alirocumab. Intraoral examination revealed that the anterior free and attached gingiva of both jaws appeared pale and the surrounding mucosa showed confluent petechiae that were more evident on the anterior palatal gingiva. The patient was asked to brush his teeth with a soft toothbrush and use a mouthwash containing hydrogen peroxide three times daily. At the 8‐day re‐examination he was symptom‐free, and the mucosa appeared totally normal. At the 5‐month follow‐up visit he reported having the same symptoms after each one of the 12 doses of alirocumab he received. Conclusions: Adverse dugs effects associated with subcutaneous injection of alirocumab may manifest in the gingiva. Therefore, oral and periodontal examination should be included in the regular follow‐up of patients medicated with this drug. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is a complex disease involving numerous genetic abnormalities. One of the major characteristics of CRC is enhanced Wnt signaling caused by loss-of-function mutations in the adenomatous polyposis coli (APC) gene. Previously, it has been demonstrated that the majority of malignant phenotypes following APC deletion in adult murine small intestines could be rescued when Myc, a downstream target of the Wnt pathway, was deleted. This indicated that Myc is a critical regulator of CRC development following APC loss. Previous studies reported that cyclic adenosine 3′,5′-monophosphate (cAMP) can influence the AKT/mammalian target of rapamycin (mTOR) survival pathway in cancer and Myc is a critical downstream molecule of AKT/mTOR signaling. Phosphodiesterase 4D (PDE4D), a member of the cAMP-specific PDE4 family, has been associated with drug resistance in CRC. However, the association between PDE4D and Myc remains unclear. To investigate the potential role of PDE4D in Myc regulation in CRC, the present study evaluated the expression levels of PDE4 subtypes in DLD-1 CRC cells. Additionally, the effects of PDE4 inhibitors on Myc expression and oncogenic properties were analyzed by western blot analysis, reverse transcription-quantitative polymerase chain reaction, colony formation and soft agar assays. It was demonstrated that cAMP/PDE4D signals serve a critical role in regulating Myc expression in DLD-1 CRC cells. Furthermore, PDE4D was identified to be a main hydrolyzer of cAMP and suppression of PDE4D using selective inhibitors of PDE4 increased intracellular cAMP levels, which resulted in a marked decrease in the oncogenic properties of DLD-1 cells, including colony formation, cell proliferation and anchorage-independent growth. Notably, the current data imply that cAMP represses Myc expression via the downregulation of AKT/mTOR signaling, which was abolished by high PDE4D activities in DLD-1 cells. Additionally, a natural polyphenol resveratrol in combination with forskolin elevated the concentration of cAMP and enhanced the expression of Myc and the malignant phenotype of DLD-1 cells, reproducing the effect of known chemical inhibitors of PDE4. In conclusion, the present study identified that cAMP/PDE4D signaling is a critical regulator of Myc expression in DLD-1 and possibly other CRC cells. [ABSTRACT FROM AUTHOR]

The knowledge and consumption of drugs are not issues emerged in the contemporary world, are recent phenomena that suddenly appeared and experienced an explosive development. Drug use appeared with the existence of mankind as a rational being. Although these substances still have a scientific attraction for scientists, they also claim a scheme of measures to combat their illicit traffic, measures that only reach their intended purpose to a small extent. At first, mankind as a rational being, has seen the properties and effects of drugs and toxic substances extracted from various plants and minerals. This knowledge came from his desire - which allowed the evolution of mankind - to know the surrounding world and, implicitly, himself. [ABSTRACT FROM AUTHOR]

Abstract Many diseases, such as inflammatory and central nervous system disorders, currently have a limited number of effective side-effect free treatments. Citronellol (CT) is a monoterpene alcohol present in the essential oil of several plants used in cooking and traditional medicine, such as those of the genus Cymbopogon and Citrus , with pharmacological activities already described in the literature. The aim of this review was to summarize the pharmacological activities already attributed to CT that could be used in treatments for humans. The databases PubMed, MedLine, Scopus, Lilacs and Scielo were searched using the terms "Citronellol" and "Drug effect". 32 articles were identified and used in the study. Twenty-one articles demonstrated CT activities, including antibiotic and antifungal effects in vitro , and 11 properties including analgesic and anticonvulsant effects in vivo , besides presenting low toxicity. In view of the need to discover new drugs and the activities reported for CT, it can be stated that CT is a promising molecule to target in future pharmacological studies. Graphical abstract Image 1 Highlights • Several diseases do not yet have effective treatment without side effects, demonstrating the need for new drug discovery. • Natural products, especially terpenes, have been presented as promising alternatives for the discovery of new drugs. • Citronellol is a monoterpene present in the essential oil of several medicinal plants used in food. • Citronellol has several pharmacological activities, such as anti-inflammatory and analgesic that can be better investigated. • Citronellol presents low toxicological activity, making it an alternative in the search for new drugs. [ABSTRACT FROM AUTHOR]

Objective: A pilot study was conducted to establish a human placental xenograft, which could serve as a model to evaluate the effect of toxic exposures during pregnancy. Study Design: The protocol consisted of engraftment of third-trimester human placental tissue in immunocompromised mice, after induction of a pseudo-pregnancy state by ovariectomy and progesterone supplementation. To validate the model, the placental tissue before and after engraftment was examined by immunohistochemistry, fluorescence-activated cell sorting (FACS), single-nucleotide polymorphism (SNP) genotyping, and whole transcriptome sequencing (WTSS). The human chorion gonadotropin (hCG) production in serum and urine was examined by enzyme-linked immunosorbent assay. Results: Microscopic evaluation of the placental tissue before and after engraftment revealed a stable morphology and preserved histological structure of the human tissue. Viable trophoblast was present after engraftment and remained stable over time. Vascularization and hormonal secretion (hCG) were present till 3 weeks after engraftment. Thirty-one SNPs were equally present, and there was a stable expression level for 56 451 genes evaluated by whole transcriptome sequencing. Conclusion: Although this human placental xenograft model cannot copy the unique uterine environment in which the placenta develops and interacts between the mother and the fetus, it could be a suitable tool to evaluate the acute impact and adaptive processes of the placental tissue to environmental changes. [ABSTRACT FROM AUTHOR]

Agrin is an extracellular matrix protein involved in the formation of the postsynaptic apparatus of the neuromuscular junction. In addition to spinal motor neurons, agrin is expressed by many other neuronal populations throughout the nervous system. Agrin's role outside of the neuromuscular junction, however, is poorly understood. Here we use the polymerase chain reaction to examine expression and alternative splicing of agrin in mouse somatosensory cortex during early postnatal development in vivo and in dissociated cell culture. Peak levels of agrin gene expression in developing cortex coincide with ingrowth of thalamic afferent fibres and formation of thalamocortical and intracortical synapses. Analysis of alternatively spliced agrin messenger RNA variants shows that greater than 95% of all agrin in developing and adult somatosensory cortex originates in neurons, including isoforms that have little or no activity in acetylcholine receptor aggregation assays. The levels of expression of "active" and "inactive" isoforms, however, are regulated during development. A similar pattern of agrin gene expression is also observed during a period when new synapses are being formed between somatosensory neurons growing in dissociated cell culture. Changes in agrin gene expression, observed both in vivo and in vitro, are consistent with a role for agrin in synapse formation in the central nervous system.

Dysbiotic states of gut ecology can be altered directly by transplantation of fecal preparation from healthy donors to patients with therapeutic intent. This paper assesses this fecal microbiota transplantation (FMT) in two respects: (1) the bacterial shifts in patient microbiomes with FMT and (2) clinical outcomes and variables of FMT. The PubMed database was searched using the MeSH terms “Feces/microbiology,” “Microbiota,” and “Transplantation.” Thirteen papers found examined clinical outcomes and variables of FMT, and eight assessed metagenomic data and bacterial composition in the peri-FMT period. FMT was reported to have high cure rates in Clostridium difficile infection (CDI), generally increased levels of members of the phyla Bacteriodetes and Firmicutes, and decreased levels of members of Proteobacteria. Therapeutic FMT alters bacterial composition from a dysbiotic state pre-FMT to a healthy commensal state post-FMT in CDI patients, but further studies are necessary to understand its role in the treatment of other diseases

Haemophilus influenzae type b polysaccharide-conjugate vaccines elicit protective antibody responses in young infants. One of these conjugates, polysaccharide linked to outer membrane protein complex (PRP-OMPC), is produced by linking the capsular polysaccharide to an outer membrane protein complex derived from group B Neisseria meningitidis. The outer membrane protein complex contains T cell carrier epitopes that elicit T cell-dependent antibody responses. OMPC also has been shown to increase the antibody response to other proteins administered concurrently that are not covalently linked (i.e., acts as an adjuvant). In this study PRP-OMPC immunized mice demonstrated significant increases in spleen size as well as in splenocyte number as compared to saline controls (p < 0.01, p < 0.001, respectively). No such increase was noted after immunization with another H. influenzae type b-conjugate vaccine, oligosaccharide linked to a variant of diphtheria toxin. By analytic flow cytometry, the mice immunized with PRP-OMPC demonstrated an increase in large splenocytes expressing the Ag Mac-1 (CD11b, CR3). Furthermore, the spleens on histologic examination were characterized by an increase in the red pulp area consisting predominantly of cells of macrophage morphology. By immunohistochemical staining, the cells were identified as macrophages due to expression of Mac-1 and p150,95 (CD11C) Ag. After PRP-OMPC immunization, severe combined immunodeficient mice also demonstrated significant splenomegaly with an increase in macrophages identified by expression of Mac-1 and MHC class II Ag. Thus PRP-OMPC vaccine resulted in T cell-independent splenomegaly with an increase number of macrophages. We propose that this unique property may confer increased immunogenicity to PRP-OMPC through macrophage activation and cytokine release. Furthermore, the effect on macrophages may explain the "adjuvant" capacity of OMPC.

PURPOSE: To investigate the possible protective effect of rutin on methotrexate induced hepatotoxicity in rats. METHODS: Twenty-two rats were divided into three experimental groups; Control-saline, Mtx, Mtx+Rutin. Hepatic tissue was taken for histological assessment and biochemical assays. Oxidative stress parameters malondialdehyde (MDA), glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) were investigated. Liver markers aspartate aminotransferase (AST), alanine aminotransferase (ALT) were analyzed in serum. RESULTS: Mtx+Rutin group showed lower histological injury compared to Mtx group, MDA and ALT levels were increased, while SOD and GSH-Px were decreased in Mtx group compared with Control-saline group. MDA and ALT levels were increased, while SOD and GSH-Px were decreased in Mtx group, compared with Mtx +Rutin group. Serum AST levels were similar among the groups. CONCLUSION: Rutin may be a potential adjuvant drug to reduce the hepatic side effects observed during Mtx therapy for various clinical conditions.

Background: Restless and violent behaviors are common in Emergency Departments (EDs), which need therapeutic interventions in most of the times. The first-generation anti-psychotic drugs are one of the most applicable therapeutic agents in the management of such patients, but their use has some limitations. Some studies suggest midazolam as an alternative medicine. Therefore, this study was performed with the aim of comparison of the efficacy and safety of haloperidol and midazolam in the restless management of referring patients to EDs. Materials and Methods: The present double-blinded trial was done on patients needed sedation and referred to the ED of Alzahra Hospital, Isfahan, Iran, in 2014. The patients were categorized into two random groups of haloperidol (5 mg) and midazolam receivers (2.5 mg for those weighing 50 kg), as intramuscular administration. The time to achieve sedation, need for rescue dose, need to resedation within the first 60 min, and adverse effects of drugs were compared among the groups. Results: Forty-eight patients were entered to the study. The mean age in the haloperidol and midazolam groups was 44.8 ± 4.1 years and 45.5 ± 4.7 years, respectively (P = 0.91). The mean time of sedation in the haloperidol and midazolam groups was 5.6 ± 0.3 min and 5.2 ± 0.1 min, respectively (P = 0.31). The mean time of full consciousness after sedation was 36.2 ± 4.5 min and 38.2 ± 3.4 min in the haloperidol and midazolam groups, respectively (P = 0.72). On average, time to arousal in the midazolam group was 10.33 min more than the haloperidol group, but it was not statistically significant. Conclusion: The results of the present study show that administration of midazolam and haloperidol have similar efficacy in the treatment of restless symptoms with the same recovery time from drug effects for referring patients to the ED. In addition, none of the adverse effects were observed in this study.

Objective: The objective was to evaluate the protective effects of dexmedetomidine (DEX), a selective agonist of α2-adrenergic receptor, on sepsis-induced diaphragm injury and the underlying molecular mechanisms. Data Sources: The data used in this review were mainly from PubMed articles published in English from 1990 to 2015. Study Selection: Clinical or basic research articles were selected mainly according to their level of relevance to this topic. Results: Sepsis could induce severe diaphragm dysfunction and exacerbate respiratory weakness. The mechanism of sepsis-induced diaphragm injury includes the increased inflammatory cytokines and excessive oxidative stress and superfluous production of nitric oxide (NO). DEX can reduce inflammatory cytokines, inhibit nuclear factor-kappaB signaling pathways, suppress the activation of caspase-3, furthermore decrease oxidative stress and inhibit NO synthase. On the basis of these mechanisms, DEX may result in a shorter period of mechanical ventilation in septic patients in clinical practice. Conclusions: Based on this current available evidence, DEX may produce extra protective effects on sepsis-induced diaphragm injury. Further direct evidence and more specific studies are still required to confirm these beneficial effects.

Introduction: The dipeptidyl peptidase-4 (DPP-4) enzyme significantly influences carcinogenic pathways in the skin. The objective of this study was to determine whether DPP-4 inhibitors are associated with the incidence of melanoma and nonmelanoma skin cancer, compared with sulfonylureas., Research Design and Methods: Using the United Kingdom Clinical Practice Research Datalink, we assembled two new-user active comparator cohorts for each skin cancer outcome from 2007 to 2019. For melanoma, the cohort included 96 739 DPP-4 inhibitor users and 209 341 sulfonylurea users, and 96 411 DPP-4 inhibitor users and 208 626 sulfonylurea users for non-melanoma skin cancer. Propensity score fine stratification weighted Cox proportional hazards models were used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs of melanoma and non-melanoma skin cancer, separately., Results: Overall, DPP-4 inhibitors were associated with a 23% decreased risk of melanoma compared with sulfonylureas (49.7 vs 65.3 per 100 000 person-years, respectively; HR 0.77, 95% CI 0.61 to 0.96). The HR progressively reduced with increasing cumulative duration of use (0-2 years HR 1.14, 95% CI 0.84 to 1.54; 2.1-5 years HR 0.44, 95% CI 0.29 to 0.66; >5 years HR 0.33, 95% CI 0.14 to 0.74). In contrast, these drugs were not associated with the incidence of non-melanoma skin cancer, compared with sulfonylureas (448.1 vs 426.1 per 100 000 person-years, respectively; HR 1.06, 95% CI 0.98 to 1.15)., Conclusions: In this large, population-based cohort study, DPP-4 inhibitors were associated with a reduced risk of melanoma but not non-melanoma skin cancer, compared with sulfonylureas., Competing Interests: Competing interests: RP received consulting fees from Biogen, Boehringer Ingelheim, Merck, Nant Pharma, Pfizer, and Reckitt Benckiser for work unrelated to this study. LA received consulting and speaker fees from Janssen, Pfizer, and Roche for work unrelated to this study. Other authors have no conflict of interest to declare., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Labor induction is a common practice to promote uterine contractions and labor onset. Uterine electrohysterogram (EHG) has proved its suitability for characterizing the uterus electrophysiological condition in women with spontaneous labor. The aim of this study was to characterize and compare uterine myoelectrical activity during the first 4 h in response to labor induction drugs, Misoprostol (G1) and Dinoprostone (G2), by analyzing the differences between women who achieved active phase of labor and those who did not (successful and failed inductions). A set of temporal, spectral and complexity parameters were computed from the EHG-bursts. As for successful inductions, statistical significant and sustained increases with respect to basal period were obtained for EHG amplitude, mean frequency, uterine activity index (UAI) and Teager, after 60′ for the G1 group; duration, amplitude, number of contractions and UAI for the G2 group, after 120′. Moreover, Teager showed statistical significant and sustained differences between successful and failed inductions (1.43 ± 1.45 µV 2. Hz 2. 10 5  vs. 0.40 ± 0.26 µV 2. Hz 2. 10 5 after 240′) for the G1 group, but not in the G2 group, probably due to the slower pharmacokinetics of this drug. These results revealed that EHG could be useful for successful induction prediction in the early stages of induction, especially when using Misoprostol. [ABSTRACT FROM AUTHOR]

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Objective To investigate the efficacy and drug related adverse reactions of sorafenib and sunitinib as first-line tyrosine-kinase inhibitors (TKIs) for patients with metastatic renal cell carcinoma (mRCC) and analyze the clinical prognostic factor for survival. Methods The data of 271 patients with metastatic renal cell carcinoma who had complete clinicopathological data were retrospectively analyzed, including 174 cases in sorafenib group and 97 cases in sunitinib group, to access patients' overall survival (OS) and progression-free survival (PFS). Prognostic values of all characteristics were determined by using univariate and multivariate Cox regression models. Results The objective response rates (ORR) of the sorafenib and sunitinib groups were 14.9% and 19.6%, respectively, and the disease control rates (DCR) were 85. 1% and 88.6%, respectively. No significant difference was found between the sorafenib and sunitinib group in ORR (P- 0.325) or DCR (P- 0.408). The most common grade 3 to 4 adverse events in the sorafenib group were hand-foot syndrome (6.7%), diarrhea (2.3%), and rash (2.3%). The most common grade 3 to 4 adverse events in the sunitinib group were neutropenia (6.2%), hand-foot syndrome (6. 2%), and thrombocytopenia (4. 6%). During the follow-up, 97 cases death occurred and 81 cases disease progression occurred in sorafenib group. The median PFS was 12 months (95% 67; 9-15 months), and the median OS was 25 months (95% CI: 21-29 months) in sorafenib group. While 74 cases death occurred and 40 cases disease progression occurred in sunitinib group, the median PFS was 12 months (95% CI: 10-12 months) and the median OS was 23 months (95% 67: 20-32 months) in sunitinib group. No significant difference was found between the sorafenib and the sunitinib group in PFS (P- 0.771) or OS (P= 0.548). Multivariate analysis showed Fuhrman grades (HR - 1.358, 95% CI: 1.004-1.835), number of metastatic sites (HR- 1.550, 95%CI; 1.143-2.101) and MSKCC risk grade (Intermediate risk group: HR = 1.621, 95% 67: 1.117-2.232; Poor risk group; HR= 2.890, 95% CI: 1.942-4.298) were independent prognostic factors for PFS. Fuhrman grades (HR-2.135, 95%67; 1.533-2.974), number of metastatic sites (HR- 1.774, 95%CI-. 1.279-2.461) and MSKCC risk grade (Intermediate risk group: HR- 1.415, 95% 67; 1.002-1.998;Poor risk group: HR-3A6X, 95%67; 2.065-4.838) were independent prognostic factors for OS. Conclusions The results of this study indicate that sorafenib and sunitinib are both effective as the first-line TKIs for mRCC patients and sorafenib has comparable efficacy to sunitinib. Rut they have differences in the incidence of adverse effects. Fuhrman grades, number of metastatic sites and MSKCC risk grade are independent prognostic factors for mRCC patients. [ABSTRACT FROM AUTHOR]

Background: Sleep disturbances, in particular insomnia, represent a common problem in children with neurodevelopmental disabilities (NDDs). Currently, there are no approved medications for insomnia in children by the US Food and Drug Administration or European Medicines Agency and therefore they are prescribed off‐label. We critically reviewed pediatric literature on drugs as well as nonpharmacological (behavioral) interventions used for sleep disturbances in children with NDDs. Methods: PubMed, Ovid (including PsycINFO, Ovid MEDLINE®, and Embase), and Web of Knowledge databases were searched through February 12, 2017, with no language restrictions. Two authors independently and blindly performed the screening. Results: Good sleep practices and behavioral interventions, supported by moderate‐to‐low level evidence, are the first recommended treatments for pediatric insomnia but they are often challenging to implement. Antihistamine agents, such as hydroxyzine or diphenhydramine, are the most widely prescribed sedatives in the pediatric practice but evidence supporting their use is still limited. An increasing body of evidence supports melatonin as the safest choice for children with NDDs. Benzodiazepines are not recommended in children and should only be used for transient insomnia, especially if daytime anxiety is present. Only few studies have been carried out in children's and adolescents’ zolpidem, zaleplon, and eszopiclone, with contrasting results. Limited evidence supports the use of alpha‐agonists such as clonidine to improve sleep onset latency, especially in attention deficit/hyperactivity disorder subjects. Tricyclic antidepressants, used in adults with insomnia, are not recommended in children because of their safety profile. Trazodone and mirtazapine hold promise but require further studies. Conclusions: Here, we provided a tentative guide for the use of drugs for insomnia in children with NDDs. Well‐controlled studies employing both objective polysomnography and subjective sleep measures are needed to determine the efficacy, effectiveness, and safety of the currently prescribed pediatric sleep medicines in children with NDDs. [ABSTRACT FROM AUTHOR]

Abstract: Therapeutic antibodies targeting the programmed cell death protein 1 (PD‐1) pathway function as immune checkpoint inhibitors, allowing the immune system to recognize tumors which otherwise escape immune surveillance. However, these agents can also elicit an autoimmune response by inhibiting the ability of non‐neoplastic tissues and regulatory cells to suppress the immune system. Here we present a fatal case of active myocarditis in a 55‐year‐old man with non‐small‐cell lung cancer which occurred following monotherapy with the PD‐1 inhibitor nivolumab (Opdivo). He presented with acute right‐sided heart failure and died 1 day after admission. Postmortem examination revealed multiple gelatinous lesions in the myocardium of the interventricular septum and the bilateral atria and ventricles which had microscopic features diagnostic of myocarditis. Subsequent studies failed to identify an infectious cause. Immune checkpoint inhibitors are an increasingly common addition to anticancer regimens and they should be considered in the evaluation of acute myocarditis. [ABSTRACT FROM AUTHOR]

The reported proof of principle study demonstrated the feasibility of local delivery of a c-Met inhibitor (VXc-140) in a subcutaneous xenograft tumor model. VXc-140 was formulated in a wafer delivery system for direct implantation into the tumor. Systemic and local tumor exposure of VXc-140 was analyzed. High tumor exposures coupled with fast release of compound were associated with significant tumor regression and reduction in tumor levels of phosphorylated c-Met. High VXc-140 tumor-to-plasma ratios (∼42 at the tumor periphery) were achieved. The tumor response achieved (7/11 partial response) with VXc-140 with the local delivery in the wafer (4 mg over 15 days) was comparable to the regression observed (11/15 partial response) for VXc-140 in the oral delivery (∼8 mg total administered once a day for 2 weeks). Notably, the plasma levels in animals implanted with VXc-140 wafers ranged from 2 to 4 μM, which, although higher than trough levels achieved with oral administration, were well below oral Cmax levels (∼42 μM) suggesting that toxicities associated with Cmax exposure may be reduced or eliminated by local delivery. The high tumor to plasma exposure of VXc-140 and the efficacy observed with local wafer delivery warrants further exploration into the utility of local delivery. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to evaluate the impact of a reduction of the anticholinergic burden (AB) on the frequency and severity of behavioral and psychological symptoms of dementia (BPSD) and their repercussions on the care team (occupational disruptiveness).Methods: In this prospective, single-center study in an acute care unit for Alzheimer disease (AD) and related disorders, 125 elderly subjects (mean age: 84.4 years) with dementia presented with BPSD. The reduction of the AB was evaluated by the Anticholinergic Cognitive Burden Scale. BPSD were evaluated with the Neuropsychiatric Inventory-Nursing Home Version (NPI-NH). The effect of the reduction of the AB on the BPSD was studied using logistic regression adjusting for the variables of the comprehensive geriatric assessment.Results: Seventy-one subjects (56.8%) presenting with probable AD, 32 (25.6%) mixed dementia (AD and vascular), 17 (13.6%) vascular dementia, and 5 (4.0%) Lewy body dementia were included. Reducing the AB by at least 20% enabled a significant decrease in the frequency × severity scores of the NPI-NH (adjusted odds ratio: 3.5; 95% confidence interval: 1.6-7.9) and of the occupational disruptiveness score (adjusted odds ratio: 9.9; 95% confidence interval: 3.6-27.3).Conclusion: AB reduction in elderly subjects with dementia makes is possible to reduce BPSD and caregiver burden. Recourse to treatments involving an AB must be avoided as much as possible in these patients, and preferential use of nonpharmacologic treatment management plans is encouraged. [ABSTRACT FROM AUTHOR]

This narrative review aims to investigate the effects of drugs on implant osseointegration, analyzing their potential positive or negative impact on the direct structural and functional connection between bone and load-carrying implants. The review seeks to provide a comprehensive understanding of osseointegration, which refers to the successful integration of an implant with living bone, resulting in no progressive relative movement between them. Exploring the effects of drugs on implant osseointegration is crucial for optimizing outcomes and enhancing patient care in orthopedic implant procedures. Relevant studies on the effects of drugs on implant osseointegration were identified through a literature search. Electronic databases, including PubMed, Embase, and Google Scholar, were utilized, employing appropriate keywords and MeSH terms related to osseointegration, implants, and drug interventions. The search was limited to English studies. This overview presents a detailed analysis of the effects of drugs on implant osseointegration. It explores drugs such as bisphosphonates, teriparatide, statins, angiotensin-converting enzyme inhibitors, beta-blockers, nitrites, and thiazide diuretics as promoters of osseointegration. Conversely, loop diuretics, non-steroidal anti-inflammatory drugs, corticosteroids, cyclosporine A, cisplatin, methotrexate, antibiotics, proton pump inhibitors (PPIs), antiepileptics, selective serotonin reuptake inhibitors (SSRIs), and anticoagulants are discussed as inhibitors of the process. The role of vitamin D3 remains uncertain. The complex relationship between drugs and the biology of implant osseointegration is emphasized, underscoring the need for further in vitro and in vivo studies to validate their effects This narrative review contributes to the literature by providing an overview of the effects of drugs on implant osseointegration. It highlights the complexity of the subject and emphasizes the necessity for more extensive and sophisticated studies in the future. Based on the synthesis of the reviewed literature, certain drugs, such as bisphosphonates and teriparatide, show potential for promoting implant osseointegration, while others, including loop diuretics and certain antibiotics, may impede the process. However, additional research is required to solidify these conclusions and effectively inform clinical practice. [ABSTRACT FROM AUTHOR]