Reliability of Magseed® marking before neoadjuvant systemic therapy with subsequent contrast-enhanced mammography in patients with non-palpable breast cancer lesions after treatment: the MAGMA study.

PURPOSE: To assess the reliability of excising residual breast cancer lesions after neoadjuvant systemic therapy (NAST) using a previously localized paramagnetic seed (Magseed®) and the subsequent use of contrast-enhanced spectral mammography (CESM) to evaluate response. METHODS: Observational, prospective, multicenter study including adult women (> 18 years) with invasive breast carcinoma undergoing NAST between January 2022 and February 2023 with non-palpable tumor lesions at surgery. Radiologists marked tumors with Magseed® during biopsy before NAST, and surgeons excised tumors guided by the Sentimag® magnetometer. CESMs were performed before and after NAST to evaluate tumor response (Response Evaluation Criteria for Solid Tumors [RECIST]). We considered intraoperative, surgical, and CESM-related variables and histological response. RESULTS: We analyzed 109 patients (median [IQR] age of 55.0 [46.0, 65.0] years). Magseed® was retrieved from breast tumors in all surgeries (100%; 95% CI 95.47-100.0%) with no displacement and was identified by radiology in 106 patients (97.24%), a median (IQR) of 176.5 (150.0, 216.3) days after marking. Most surgeries (94.49%) were conservative; they lasted a median (IQR) of 22.5 (14.75, 40.0) min (95% CI 23.59-30.11 min). Most dissected tumor margins (93.57%) were negative, and few patients (5.51%) needed reintervention. Magseed® was identified using CESM in all patients (100%); RECIST responses correlated with histopathological evaluations of dissected tumors using the Miller-Payne response grade (p < 0.0001) and residual lesion diameter (p < 0.0001). Also 69 patients (63.3%) answered a patient's satisfaction survey and 98.8% of them felt very satisfied with the entire procedure. CONCLUSION: Long-term marking of breast cancer lesions with Magseed® is a reliable and feasible method in patients undergoing NAST and may be used with subsequent CESM.

Methadone Requires the Co-Activation of µ-Opioid and Toll-Like-4 Receptors to Produce Extracellular DNA Traps in Bone-Marrow-Derived Mast Cells.

Methadone is an effective and long-lasting analgesic drug that is also used in medication-assisted treatment for people with opioid use disorders. Although there is evidence that methadone activates µ-opioid and Toll-like-4 receptors (TLR-4s), its effects on distinct immune cells, including mast cells (MCs), are not well characterized. MCs express µ-opioid and Toll-like receptors (TLRs) and constitute an important cell lineage involved in allergy and effective innate immunity responses. In the present study, murine bone-marrow-derived mast cells (BMMCs) were treated with methadone to evaluate cell viability by flow cytometry, cell morphology with immunofluorescence and scanning electron microscopy, reactive oxygen species (ROS) production, and intracellular calcium concentration ([Ca2+]i) increase. We found that exposure of BMMCs to 0.5 mM or 1 mM methadone rapidly induced cell death by forming extracellular DNA traps (ETosis). Methadone-induced cell death depended on ROS formation and [Ca2+]i. Using pharmacological approaches and TLR4-defective BMMC cultures, we found that µ-opioid receptors were necessary for both methadone-induced ROS production and intracellular calcium increase. Remarkably, TLR4 receptors were also involved in methadone-induced ROS production as it did not occur in BMMCs obtained from TLR4-deficient mice. Finally, confocal microscopy images showed a significant co-localization of µ-opioid and TLR4 receptors that increased after methadone treatment. Our results suggest that methadone produces MCETosis by a mechanism requiring a novel crosstalk pathway between µ-opioid and TLR4 receptors.

Semisynthesis of Betaxanthins from Purified Betacyanin of Opuntia dillenii sp.: Color Stability and Antiradical Capacity.

The availability of pure individual betalains in sufficient quantities which permit deeper understanding is still a challenge. This study investigates the high-yielding semisynthesis of betaxanthins using betalamic acid from a natural source (Opuntia dillenii), followed by condensation with ʟ-amino acids and further purification. Moreover, the color stability of the four synthesized individual betaxanthins, namely proline (ʟ-ProBX), alanine (ʟ-AlaBX), leucine (ʟ-LeuBX), and phenylalanine (ʟ-PheBX) betaxanthins, was investigated at different pHs. Their relative contribution to free radical scavenging was also scrutinized by TEAC and DPPH. ʟ-AlaBX and ʟ-LeuBx showed a significantly (p < 0.05) higher antioxidant activity, whereas ʟ-ProBX was the most resistant to the hydrolysis of betaxanthin and hence the least susceptible to color change. The color stability was strongly influenced by pH, with the color of ʟ-ProBX, ʟ-LeuBX, and ʟ-AlaBX at pH 6 being more stable, probably due to the easier hydrolysis under acid conditions. The semisynthesis and purification allowed us to have available remarkable quantities of pure individual betaxanthins of Opuntia dillenii for the first time, and to establish their color properties and antioxidant capacity. This study could be a step forward in the development of the best natural food colorant formulation, based on the betalain structure, which is of special interest in food technology.

Detection of SARS-CoV-2 in a cat owned by a COVID-19-affected patient in Spain.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiological agent of COVID-19, is considered a zoonotic pathogen mainly transmitted human to human. Few reports indicate that pets may be exposed to the virus. The present report describes a cat suffering from severe respiratory distress and thrombocytopenia living with a family with several members affected by COVID-19. Clinical signs of the cat prompted humanitarian euthanasia and a detailed postmortem investigation to assess whether a COVID-19-like disease was causing the condition. Necropsy results showed the animal suffered from feline hypertrophic cardiomyopathy and severe pulmonary edema and thrombosis. SARS-CoV-2 RNA was only detected in nasal swab, nasal turbinates, and mesenteric lymph node, but no evidence of histopathological lesions compatible with a viral infection were detected. The cat seroconverted against SARS-CoV-2, further evidencing a productive infection in this animal. We conclude that the animal had a subclinical SARS-CoV-2 infection concomitant to an unrelated cardiomyopathy that led to euthanasia.

First drug-checking study at an electronic festival and fentanyl detection in the central region of Mexico.

BACKGROUND: Perception of drug adulteration has increased in Mexico, but there is little research on adulterants and toxicity. The aim of this study was to identify drug composition in an electronic music outdoor festival nearby Mexico City. METHODS: The participants completed a questionnaire with demographic data, harm reduction strategies, drug-use patterns, history, and the drug they expected to find. We took a small sample of each substance and prepared it for drug checking. A two-section drug testing station was placed within the grounds of the festival. Interaction with participants occurred at the front part. Drug checking was conducted at the rear part. The service was free of charge, voluntary and confidential. Forty persons aged 22 to 48 years participated (mode = 28), of which 92.5% were male, most (82.5%) were single. Through the Substance Analysis Program of "ReverdeSer Collective," we conducted the testing with the attendants that provided 51 drug samples, following ethical and biosafety protocols. We used colorimetry, Fourier Transform Infrared Spectroscopy, and fentanyl immunoassay strips for sample analysis. RESULTS: Substances of choice among attendants were psychostimulants (MDMA and other amphetamine-like drugs) and hallucinogens. Most samples contained what the users expected plus adulterants. Main adulterants were methylene-dioxy-ethyl-amphetamine, methylene-dioxy-propyl-amphetamine, hydroxyamphetamine, and the selective serotonin reuptake inhibitor venlafaxine. Fentanyl was present in 2 out of 4 cocaine samples and in 14 of the 22 confirmed MDMA samples. CONCLUSIONS: Some of the adulterants found pose serious health risks, especially fentanyl, amphetamine-like substances, and venlafaxine. Therefore, it is urgent to monitor these adulterants at electronic music festivals and to implement prevention, treatment, and harm reduction public policies. Naloxone distribution and drug-assisted therapies should be part of government programs in Mexico.

Fentanyl and other New Psychoactive Synthetic Opioids. Challenges to Prevention and Treatment.

Synthetic opioids have played a significant role in the current opioid crisis in the United States (U.S.) and Canada and are a matter of concern worldwide. New psychoactive opioids (NPOs) are classified in the internationally recognized new psychoactive substances (NPSs) category. This group comprises compounds that may have been synthesized decades ago but appeared only recently in the illicit drug market. Such is the case of fentanyl, fentanyl analogs, and non-fentanyl opioids. Most NPOs have effects similar to morphine, including euphoria and analgesia, and can produce fatal respiratory depression. Here, we present an overview of the systemic and molecular effects of main NPOs, their classification, and their pharmacological properties. We first review the fentanyl group of NPOs, including the four compounds of clinical use (fentanyl, alfentanil, sufentanil, and remifentanil) and the veterinary drug carfentanil. We also provide essential information on non-medical fentanyl analogs and other synthetic opioids such as brorphine, etonitazene, and MT-45, used as adulterants in commonly misused drugs. This paper also summarizes the scarce literature on the use of NPOs in Mexico. It concludes with a brief review of the challenges to prevention and treatment posed by NPOs and some recommendations to face them.

The Resurgence of Hallucinogen Drugs in Clinical Research.

Since the dawn of civilization, ancient cultures have utilized hallucinogens from plants and fungi in the context of religious and healing practices. Recently, their use has expanded to other cultures. Hallucinogens are natural or synthetic substances that alter the perception of reality at nontoxic doses, producing intense psychological and physiological effects. The initial research on hallucinogens began in the 1950s. However, their non-medical use, studies without proper controls, and negative social opinion resulted in legal restrictions that limited their use for clinical and preclinical research for more than two decades. A renewed interest in studying hallucinogens as potential therapeutic agents for treating different psychiatric conditions has recently re-emerged. This review summarizes the effects of main hallucinogen drugs and their therapeutic potential. Classic hallucinogens such as LSD, dimethyltryptamine, psilocin, and mescaline have chemical structures similar to serotonin and directly activate 5-hydroxy-tryptamine (5-HT2A) receptors. Ketamine is a dissociative anesthetic with antagonist effects at the glutamatergic N-methyl-D-aspartate receptor, indirectly activating 5-HT2A receptors. Ketamine has rapid antidepressant effects and reduces suicidal ideation, but its effects are short-lasting. Other hallucinogens are under study. It is necessary to continue this research with a more rigorous methodology and include studying the long-term effects of psychedelics use.

Amphetamine-type Stimulants: Novel Insights into their Actions and use Patterns.

This review focuses on the effects and mechanisms of action of amphetamine-type stimulants (ATS) and their adverse effects on the cardiovascular, nervous, and immune systems. ATS include amphetamine (AMPH), methamphetamine (METH, "crystalmeth," or "ice"), methylenedioxymethamphetamine (MDMA, "ecstasy," or "Molly"), MDMA derivatives (e.g., methylenedioxyamphetamine [MDA] and methylenedioxy-N-ethylamphetamine [MDEA]), khat, and synthetic cathinones. The first section of this paper presents an overview of the historical aspects of ATS use, their initial clinical use, and regulations. The second part reviews the acute and chronic impact and the most salient clinical effects of ATS on the central nervous and cardiovascular systems, skin, and mouth. The chemical structure, pharmacokinetics, and classic and non-canonical pharmacological actions are covered in the third section, briefly explaining the mechanisms involved. In addition, the interactions of ATS with the central and peripheral immune systems are reviewed. The last section presents data about the syndemic of ATS and opioid use in the North American region, focusing on the increasing adulteration of METH with fentanyl.

Brain-Derived Neurotrophic Factor (BDNF) and First-Episode Psychosis. A longitudinal one-year prognosis study.

The brain-derived neurotrophic factor (BDNF) is a neurotrophin that has been linked to the schizophrenia neurodevelopmental hypothesis.

Morphine and Fentanyl Repeated Administration Induces Different Levels of NLRP3-Dependent Pyroptosis in the Dorsal Raphe Nucleus of Male Rats via Cell-Specific Activation of TLR4 and Opioid Receptors.

Morphine promotes neuroinflammation after NOD-like receptor protein 3 (NLRP3) oligomerization in glial cells, but the capacity of other opioids to induce neuroinflammation and its relationship to the development of analgesic tolerance is unknown. We studied the effects of morphine and fentanyl on NLRP3 inflammasome activation in glial and neuronal cells in the dorsal raphe nucleus (DRN), a region involved in pain regulation. Male Wistar rats received i.p. injections of morphine (10 mg/kg) or fentanyl (0.1 mg/kg) 3 × daily for 7 days and were tested for nociception. Two hours after the last (19th) administration, we analyzed NLRP3 oligomerization, caspase-1 activation and gasdermin D-N (GSDMD-N) expression in microglia (CD11b positive cells), astrocytes (GFAP-positive cells) and neurons (NeuN-positive cells). Tolerance developed to both opioids, but only fentanyl produced hyperalgesia. Morphine and fentanyl activated NLRP3 inflammasome in astrocytes and serotonergic (TPH-2-positive) neurons, but fentanyl effects were more pronounced. Both opioids increased GFAP and CD11b immunoreactivity, caspase-1 and GSDMD activation, indicating pyroptotic cell death. The opioid receptor antagonist (-)-naloxone, but not the TLR4 receptor antagonist (+)-naloxone, prevented microglia activation and NLRP3 oligomerization. Only (+)-naloxone prevented astrocytes' activation. The anti-inflammatory agent minocycline and the NLRP3 inhibitor MCC950 delayed tolerance to morphine and fentanyl antinociception and prevented fentanyl-induced hyperalgesia. MCC950 also prevented opioid-induced NLRP3 oligomerization. In conclusion, morphine and fentanyl differentially induce cell-specific activation of NLRP3 inflammasome and pyroptosis in the DRN through TLR4 receptors in astrocytes and through opioid receptors in neurons, indicating that neuroinflammation is involved in opioid-induced analgesia and fentanyl-induced hyperalgesia after repeated administrations.

Co-administration of morphine and levamisole increases death risk, produces neutropenia and modifies antinociception in mice.

Levamisole is a veterinary anthelmintic drug and a common adulterant of misused drugs. This study analyses the lethal, antinociceptive and haematological effects produced by acute or repeated levamisole administration by itself or combined with morphine. Independent groups of male Swiss Webster mice were i.p. injected with 100 mg/kg morphine, 31.6 mg/kg levamisole (lethal doses at 10%, LD10 ) or the same doses combined. Naloxone pretreatment (10 mg/kg, i.p.) prevented morphine-induced death, as did 2.5 mg/kg, i.p. mecamylamine with levamisole. Co-administration of levamisole and morphine (Lvm + Mor) increased lethality from 10% to 80%. This augmented effect was prevented by 30 mg/kg, i.p. naloxone and reduced with 10 mg/kg naloxone plus 2.5 mg/kg, i.p. mecamylamine. In independent groups of mice, 17.7 mg/kg, i.p. levamisole antagonized the acute morphine's antinociceptive effect evaluated in the tail-flick test. Repeated 17.7 mg/kg levamisole administration (2×/day/3 weeks) did not affect tolerance development to morphine (10 mg/kg, 3×/day/1 week). Blood samples obtained from mice repeatedly treated with levamisole showed leukopenia and neutropenia. Morphine also produced neutropenia, increased erythrocyte count and other related parameters (e.g. haemoglobin). Lvm + Mor had similar effects on leukocyte and neutrophil counts to those seen with levamisole only, but no erythrocyte-related alterations were evident. Blood chemistry analysis did not indicate liver damage but suggested some degree of electrolyte balance impairment. In conclusion, Lvm + Mor increased death risk, altered morphine-induced antinociceptive effects and produced haematologic abnormalities. The importance of studying combinations of drugs of abuse lies in the fact that drug users frequently combine drugs, which are commonly adulterated.

Atypical purpura and other features associated with unfavorable outcomes of IgA vasculitis (Henoch-Schönlein purpura) in children: A retrospective study.

The prognosis of IgA vasculitis (also known as Henoch-Schönlein purpura) is determined by renal or other organ involvement. We conducted a retrospective study to identify the initial features of 106 children with IgA vasculitis and their association with unfavorable outcomes. Location of purpura above the waist and an altered urinalysis at diagnosis predicted a more aggressive course of disease.

Cutaneous Rosai-Dorfman disease in a 3-year-old boy.

The cutaneous form of Rosai-Dorfman disease is very rare in childhood. The clinical spectrum is highly variable and histopathological study with immunohistochemistry is essential for the diagnosis. We present the case of a 3-year-old boy with the diagnosis of cutaneous Rosai-Dorfman disease and review the pediatric cases published in the literature.

Pathways and efficiency of nitrogen attenuation in wastewater effluent through soil aquifer treatment.

Soil Aquifer Treatment (SAT) is used to increase groundwater resources and enhance the water quality of wastewater treatment plant (WWTP) effluents. The resulting water quality needs to be assessed. In this study, we investigate attenuation pathways of nitrogen (N) compounds (predominantly NH4+) from a secondary treatment effluent in pilot SAT systems: both a conventional one (SAT-Control system) and one operating with a permeable reactive barrier (PRB) to provide extra dissolved organic carbon to the recharged water. The goal is to evaluate the effectiveness of the two systems regarding N compounds by means of chemical and isotopic tools. Water chemistry (NO3-, NH4+, Non-Purgeable Dissolved Organic Carbon (NPDOC), and O2) and isotopic composition of NO3- (ẟ15N-NO3- and ẟ18O-NO3-) and NH4+ (ẟ15N-NH4+) were monitored in the inflow and at three different sections and depths along the aquifer flow path. Chemical and isotopic results suggest that coupled nitrification-denitrification were the principal mechanisms responsible for the migration and distribution of inorganic N in the systems and that nitrification rate decreased with depth. At the end of the study period, 66% of the total N in the solution was removed in the SAT-PRB system and 69% in the SAT-Control system, measured at the outlet of the systems. The residual N in solution in the SAT-PRB system had an approximately equal proportion of N-NH4+ and N-NO3- while in the SAT-Control system, the residual N in solution was primarily N-NO3-. Isotopic data also confirmed complete NO3- degradation in the systems from July to September with the possibility of mixing newly generated NO3- with the residual NO3- in the substrate pool.

DELAYED NEUROPSYCHIATRIC SYNDROME AFTER CARBON MONOXIDE POISONING.

arbon monoxide (CO) is an odorless, tasteless, colorless and nonirritating gas 1. In Spain, most of the accidents due to CO poisoning are caused by water heaters2,3,4. CO binds to hemoglobin with much greater affinity than oxygen, for- ming carboxyhemoglobin (COHb) and resulting in impaired oxygen transport and utilization.XS In up to 40 percent of patients with significant CO exposure, a delayed neuropsy- chiatric syndrome (DNS) can arise 3 to 240 days after appa- rent recovery, characterized by cognitive deficits, personality changes, movement disorders, and focal neurologic deficits, which may persist for a year or longer.

Minocycline prevents neuronal hyperexcitability and neuroinflammation in medial prefrontal cortex, as well as memory impairment caused by repeated toluene inhalation in adolescent rats.

Toluene can be intentionally misused by adolescents to experience psychoactive effects. Toluene has a complex mechanism of action and broad behavioral effects, among which memory impairment is reported consistently. We have previously reported that repeated toluene inhalation (8000 ppm) increases layer 5 prelimbic pyramidal cells' excitability in the medial prefrontal cortex (mPFC) of adolescent rats. Toluene also produces reactive oxygen species (ROS), which activate glial cells. Here, we tested the hypothesis that the anti-inflammatory agent minocycline would decrease toluene's effects because it inhibits NF-κB (nuclear factor enhancer of the kappa light chains of activated B cells) and reduces pro-inflammatory cytokine and ROS production. Our results show that minocycline (50 mg/kg, ip, for 10 days) prevents the hyperexcitability of mPFC neurons observed after repeated 8000 ppm toluene exposure (30 min/day, 2×/day for 10 days). Minocycline prevents toluene-induced hyperexcitability by a mechanism that averts the loss of the slow calcium-dependent potassium current, and normalizes mPFC neurons' firing frequency. These effects are accompanied by significant decreased expression of astrocytes and activated microglia in the mPFC, reduced NLRP3 inflammasome activation and mRNA expression levels of the pro-inflammatory cytokine interleukin 1ß (IL-1ß), as well as increased mRNA expression of the anti-inflammatory cytokine transforming growth factor ß (TGF-ß). Minocycline also prevents toluene-induced memory impairment in adolescent rats in the passive avoidance task and the temporal order memory test in which the mPFC plays a central role. These results show that neuroinflammation produces several effects of repeated toluene administration at high concentrations, and minocycline can significantly prevent them.

Sexual behaviour is impaired by the abused inhalant toluene in adolescent male rats.

Inhalant misuse is a worldwide problem, especially among adolescents. Toluene is the most widely misused inhalant. One hallmark of adolescence is the emergence of sexual behaviour, which can be affected by drug use. The aim of this study was to analyse the effects of toluene inhalation on different aspects of male rats' sexual behaviour using a binge pattern of exposure in adolescent rats. Male Wistar rats were individually exposed to air or 6,000 ppm toluene for 30 min (acute exposure; n = 8 each) or twice a day for 12 days (repeated exposure; n = 9 each) in static exposure chambers. Independent groups of sexually experienced, adolescent rats (postnatal day 63, PN63) were tested after acute toluene exposure for copulation, sexual incentive motivation or noncontact erections. Sexually naïve, adolescent rats (PN45-59) were repeatedly exposed to toluene and tested for sexual behaviour after completing the 1st, 3rd, 5th, 7th, 9th, 11th and 13th exposure sessions. Acute toluene exposure impaired copulatory performance, diminished sexual incentive motivation and delayed noncontact erection occurrence in sexually experienced rats. Repeated toluene exposure during adolescence completely inhibited the onset of copulatory behaviours in sexually naïve rats, at the time at which they should have appeared. However, once the inhalant exposure ended, copulatory responses appeared gradually, and animals attained a typical, stable copulatory pattern. In conclusion, acute toluene exposure impairs sexual behaviour in young, sexually experienced animals, while repeated toluene exposure during adolescence prevents the onset of copulatory behaviour, although this effect is transitory.

Structure-activity study of acute neurobehavioral effects of cyclohexane, benzene, m-xylene, and toluene in rats.

Toluene is a widely misused solvent that causes a variety of behavioral effects in both humans and animals. Preclinical and clinical research has provided evidence that toluene inhalation produces psychoactive effects similar to those caused by other Central Nervous System depressant drugs, but little is known about the consequences of inhaling solvents other than toluene that are also present in commercial products. As part of this research project, we studied the effects of hydrocarbon solvents chemically related to toluene on anxiety-like behavior, passive-avoidance learning, nociception, motor coordination and social interaction. We tested independent groups of adolescent male Wistar rats in the burying behavior task, step through avoidance learning task, hot plate test, shock threshold test, social interaction or rotarod tests after a 30 min exposure to either cyclohexane, benzene, toluene or m-xylene (2000 to 8000 ppm). Control animals breathed only air. Benzene, toluene and m-xylene produced anxiolytic-like actions, impaired learning, caused antinociception and decreased social interaction in a concentration-dependent manner. Locomotor coordination was impaired only with 8000 ppm m-xylene and 8000 ppm toluene. Cyclohexane had no effect on any of the behavioral tasks. Our data suggest that the aromatic ring is critical for solvents to produce a wide variety of behavioral effects.

Analysis of Phenolic Composition of Byproducts (Seeds and Peels) of Avocado (Persea americana Mill.) Cultivated in Colombia.

The byproducts (seeds and peels) of an avocado cultivated in the south of Colombia were extracted with aqueous acetone and their antioxidant properties were measured with ABTS (2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) and DPPH (2,2-diphenyl-1-picrylhydrazyl) assays, and total polyphenol content was determined by Folin-Ciocalteu method. A bioguided fractionation was performed, first by SPE (solid phase extraction) on Amberlite XAD-7, and then by size exclusion chromatography on Sephadex LH-20. The polyphenolic-rich extracts and their fractions were analyzed by ultra-performance liquid chromatography-electrospray ionization-mass spectrometry (UPLC-ESI-MS/MS), finding the presence of organic acids, hydroxycinnamic acids, catechins, free and glycosylated flavonoids, and dimeric and trimeric procyanidins. Catechin, epicatechin, six quercetin derivatives, four dimeric procyanidins (three type B and one type A), and three trimeric procyanidins (two type B and one type A) were detected in the most active fractions of avocado peel and seeds. The most antioxidant fractions contain the higher molecular weight phenolic compounds (condensed tannins).