Serum amyloid A proteins reduce bone mass during mycobacterial infections.

Introduction: Osteopenia has been associated to several inflammatory conditions, including mycobacterial infections. How mycobacteria cause bone loss remains elusive, but direct bone infection may not be required. Methods: Genetically engineered mice and morphometric, transcriptomic, and functional analyses were used. Additionally, inflammatory mediators and bone turnover markers were measured in the serum of healthy controls, individuals with latent tuberculosis and patients with active tuberculosis. Results and discussion: We found that infection with Mycobacterium avium impacts bone turnover by decreasing bone formation and increasing bone resorption, in an IFNγ- and TNFα-dependent manner. IFNγ produced during infection enhanced macrophage TNFα secretion, which in turn increased the production of serum amyloid A (SAA) 3. Saa3 expression was upregulated in the bone of both M. avium- and M. tuberculosis-infected mice and SAA1 and 2 proteins (that share a high homology with murine SAA3 protein) were increased in the serum of patients with active tuberculosis. Furthermore, the increased SAA levels seen in active tuberculosis patients correlated with altered serum bone turnover markers. Additionally, human SAA proteins impaired bone matrix deposition and increased osteoclastogenesis in vitro. Overall, we report a novel crosstalk between the cytokine-SAA network operating in macrophages and bone homeostasis. These findings contribute to a better understanding of the mechanisms of bone loss during infection and open the way to pharmacological intervention. Additionally, our data and disclose SAA proteins as potential biomarkers of bone loss during infection by mycobacteria.

SARS-CoV-2 variants induce distinct disease and impact in the bone marrow and thymus of mice.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has evolved to variants associated with milder disease. We employed the k18-hACE2 mouse model to study how differences in the course of infection by SARS-CoV-2 variants alpha, delta, and omicron relate to tissue pathology and the immune response triggered. We documented a variant-specific pattern of infection severity, inducing discrete lung and blood immune responses and differentially impacting primary lymphoid organs. Infections with variants alpha and delta promoted bone marrow (BM) emergency myelopoiesis, with blood and lung neutrophilia. The defects in the BM hematopoietic compartment extended to the thymus, with the infection by the alpha variant provoking a marked thymic atrophy. Importantly, the changes in the immune responses correlated with the severity of infection. Our study provides a comprehensive platform to investigate the modulation of disease by SARS-CoV-2 variants and underscores the impact of this infection on the function of primary lymphoid organs.

Is There an Early Morphological Decomposition during L2 Lexical Access? A Meta-Analysis on the Morphological Priming Effect.

A considerable body of experimental data currently exists on the representation and processing of derived words. However, no theoretical account has led to a consensus so far, due in part to inconsistencies in empirical results which show either the presence or the absence of signs of early morphological decomposition during lexical access. In this paper, we present the results of a meta-analysis that sought to examine the robustness of the masked morphological priming effect (MMP) in native and non-native speakers. This effect is indexed by faster responses to targets preceded by morphologically related primes vs. unrelated primes (e.g., fighter-FIGHT < needle-FIGHT), and is perhaps the most widespread effect used to test whether speakers of a given language are sensitive to the morphological components of words at early stages of lexical access. To this end, we selected 10 masked priming lexical decision studies (16 experiments) conducted with native and non-native speakers. Variables such as prime duration and level of L2 proficiency were considered in the analyses to assess their impact on the MMP effect. Results showed significant MMP effects, which were restricted to native speakers. No modulations were found for the prime duration. Results are interpreted in light of prevalent models of complex word processing.

Polymer Selection for Hot-Melt Extrusion Coupled to Fused Deposition Modelling in Pharmaceutics.

Three-dimensional (3D) printing offers the greatest potential to revolutionize the future of pharmaceutical manufacturing by overcoming challenges of conventional pharmaceutical operations and focusing design and production of dosage forms on the patient's needs. Of the many technologies available, fusion deposition modelling (FDM) is considered of the lowest cost and higher reproducibility and accessibility, offering clear advantages in drug delivery. FDM requires in-house production of filaments of drug-containing thermoplastic polymers by hot-melt extrusion (HME), and the prospect of connecting the two technologies has been under investigation. The ability to integrate HME and FDM and predict and tailor the filaments' properties will extend the range of printable polymers/formulations. Hence, this work revises the properties of the most common pharmaceutical-grade polymers used and their effect on extrudability, printability, and printing outcome, providing suitable processing windows for different raw materials. As a result, formulation selection will be more straightforward (considering the characteristics of drug and desired dosage form or release profile) and the processes setup will be more expedite (avoiding or mitigating typical processing issues), thus guaranteeing the success of both HME and FDM. Relevant techniques used to characterize filaments and 3D-printed dosage forms as an essential component for the evaluation of the quality output are also presented.

Mycobacterium tuberculosis associated with severe tuberculosis evades cytosolic surveillance systems and modulates IL-1ß production.

Genetic diversity of Mycobacterium tuberculosis affects immune responses and clinical outcomes of tuberculosis (TB). However, how bacterial diversity orchestrates immune responses to direct distinct TB severities is unknown. Here we study 681 patients with pulmonary TB and show that M. tuberculosis isolates from cases with mild disease consistently induce robust cytokine responses in macrophages across multiple donors. By contrast, bacteria from patients with severe TB do not do so. Secretion of IL-1ß is a good surrogate of the differences observed, and thus to classify strains as probable drivers of different TB severities. Furthermore, we demonstrate that M. tuberculosis isolates that induce low levels of IL-1ß production can evade macrophage cytosolic surveillance systems, including cGAS and the inflammasome. Isolates exhibiting this evasion strategy carry candidate mutations, generating sigA recognition boxes or affecting components of the ESX-1 secretion system. Therefore, we provide evidence that M. tuberculosis strains manipulate host-pathogen interactions to drive variable TB severities.

Deficiency in the glycosyltransferase Gcnt1 increases susceptibility to tuberculosis through a mechanism involving neutrophils.

Modulation of immunity and disease by glycans is increasingly recognized. However, how host glycosylation shapes and is shaped by tuberculosis remains poorly understood. We show that deficiency in the glucosaminyl (N-acetyl) transferase 1 (Gcnt1), a key enzyme for core-2 O-glycans biosynthesis, drives susceptibility to Mycobacterium tuberculosis infection. The increased susceptibility of Gcnt1 deficient mice was characterized by extensive lung immune pathology, mechanistically related to neutrophils. Uninfected Gcnt1 deficient mice presented bone marrow, blood and lung neutrophilia, which further increased with infection. Blood neutrophilia required Gcnt1 deficiency in the hematopoietic compartment, relating with enhanced granulopoiesis, but normal cellular egress from the bone marrow. Interestingly, for the blood neutrophilia to translate into susceptibility to M. tuberculosis infection, Gnct1 deficiency in the stroma was also necessary. Complete Gcnt1 deficiency associated with increased lung expression of the neutrophil chemoattractant CXCL2. Lastly, we demonstrate that the transcript levels of various glycosyltransferase-encoding genes were altered in whole blood of active tuberculosis patients and that sialyl Lewis x, a glycan widely present in human neutrophils, was detected in the lung of tuberculosis patients. Our findings reveal a previously unappreciated link between Gcnt1, neutrophilia and susceptibility to M. tuberculosis infection, uncovering new players balancing the immune response in tuberculosis.

A rare and reversible case of heart failure-Hypocalcemia due to hypoparathyroidism.

Physicians should look more carefully for the potential reversible causes of acute heart failure, namely hypoparathyroidism. The recovery of left ventricular function with the treatment of hypoparathyroidism underlines the importance of calcium and the reversibility of this type of cardiomyopathy.

Immunoglobulin Therapy in a Patient With Severe Chikungunya Fever and Vesiculobullous Lesions.

Chikungunya virus (CHIKV) is an emerging arbovirus whose transmission has already been reported in several countries. Although the majority of individuals acutely infected with CHIKV appear to become asymptomatic, reports showing the occurrence of atypical and severe forms of the disease are increasing. Among them, the neurological and skin manifestations require medical attention. Treatment of CHIKV infection is almost symptomatic. In this sense, we report the case of a 56-years-old man who presented fever, headaches, paresthesia and pain in the right arm with visible red spots on the skin starting 30 days before Hospital admission. Tests determined Chikungunya infection and excluded other co-morbidities. Disease evolved with edema in hands and feet and extensive hemorrhagic bullous lesions on the skin of upper and lower limbs. Variations in hematological counts associated with liver dysfunction determined this patient's admission to the Intensive Care Unit. Then, he received intravenous antibiotic and immunoglobulin therapy (400 mg/Kg/day for the period of 5 days) with total recovery from the lesions after 10 days of follow-up. A general improvement in blood cell count and successful wound healing was observed. After discharge, no other clinical sign of the disease was reported until nowadays. This case reports for the first time the successful administration of intravenous immunoglobulin therapy to a patient with severe atypical dermatological form of Chikungunya Fever without any associated comorbidity.

Cardiac tamponade in a patient with severe dengue fever.

A 26-year-old postpartum female presented with symptoms characteristic of dengue fever on the 16th day of puerperium. On the third day of the illness, the patient presented a clinical picture consistent with shock. Tests determined primary infection with dengue virus serotype 2. Cardiac tamponade was confirmed by echocardiography. This rare manifestation is described in a patient without any associated comorbidity.

Cardiac tamponade in a patient with severe dengue fever

Abstract A 26-year-old postpartum female presented with symptoms characteristic of dengue fever on the 16th day of puerperium. On the third day of the illness, the patient presented a clinical picture consistent with shock. Tests determined primary infection with dengue virus serotype 2. Cardiac tamponade was confirmed by echocardiography. This rare manifestation is described in a patient without any associated comorbidity.

Chikungunya virus infection with severe neurologic manifestations: report of four fatal cases.

Here, we present four patients with confirmed Chikungunya virus infection showing atypical neurologic manifestations and death. This case series includes patients ranging in age from five to 92 years, with or without comorbidities. This report is important, as very few cases in the literature reporting death due to atypical Chikungunya virus infection are available.

Chikungunya virus infection with severe neurologic manifestations: report of four fatal cases

Abstract Here, we present four patients with confirmed Chikungunya virus infection showing atypical neurologic manifestations and death. This case series includes patients ranging in age from five to 92 years, with or without comorbidities. This report is important, as very few cases in the literature reporting death due to atypical Chikungunya virus infection are available.

Drug-Related Problems Identified in a Sample of Portuguese Institutionalised Elderly Patients and Pharmacists' Interventions to Improve Safety and Effectiveness of Medicines.

BACKGROUND: Currently, people live longer but often with poor quality of life. The decrease in healthy life-years is partly attributable to the institution of polypharmacy to treat various comorbidities. OBJECTIVES: The objectives of the study were to determine the prevalence and nature of drug-related problems (DRPs) in polypharmacy elderly patients residing in nursing homes and to test the acceptability of a pharmacist's intervention. METHODS: An exposure cohort was constituted in three Portuguese nursing homes, where all polypharmacy (five or more medicines) elderly patients (≥65 years of age) were analysed and then a random stratified sample was extracted to be subject to an intervention. Clinical and therapeutic data were collected and analysed for DRPs and classified according to the II Granada Consensus, by a pharmacist-led team. The intervention was the formulation of a pharmacist's recommendations to prescribers addressing clinically relevant DRPs, along with suggestions for therapy changes. RESULTS: The initial sample included 126 elderly patients taking 1332 medicines, where 2109 DRPs were identified. The exposure cohort included 63 patients, with comparable baseline data (p > 0.005). Manifest DRPs occurred in 31.7 % of the intervention group (mainly quantitative ineffectiveness-DRP 4), whereas potential DRPs were identified in 100 % of patients (mainly non-quantitative unsafe-DRP 5). Amongst the DRPs identified, 584 (56.7 %) were reported to prescribers (all types of DRPs) and 113 (11 %) to nurses (only non-quantitative ineffectiveness-DRP 3). A total of 539 pharmacist recommendations were presented to physicians, corresponding to 62 letters sent by mail, each including an average of 8.7 recommendations to solve DRPs present in intervention group (IG) patients. There was a high non-response rate (n = 34 letters; 54.8 %; containing 367 pharmacist recommendations; 68.1 %) and amongst recommendations receiving feedback, only 8.7 % of pharmacist recommendations made were accepted (n = 15). Positive responses were significantly associated with a lower number of recommendations made, whereas a higher number of recommendations increased the odds of no response (p < 0.001). CONCLUSION: A pharmacist-led medication review proved useful in identifying DRPs in elderly polypharmacy nursing home residents. Stronger bonds must be developed between healthcare professionals to increase patient safety in the vulnerable institutionalised elderly population.

Potentially inappropriate medications in a sample of Portuguese nursing home residents: Does the choice of screening tools matter?

UNLABELLED: Background Potentially inappropriate medications (PIMs) are often found in high proportion among the elderly population. The STOPP criteria have been suggested to detect more PIMs in European elderly than the Beers criteria. Objective This study aimed to determine the prevalence of PIMs and potential prescribing omissions (PPOs) in a sample of Portuguese nursing homes residents. Setting Four elderly facilities in mainland Portugal Method A descriptive cross-sectional study was used. Elderly polypharmacy patients were included in the study and their medication (registered in patient clinical records) analysed using the Beers (2012 original version and 2008 version adapted to Portugal), STOPP (Screening Tool of Older Person's Prescriptions) and START (Screening Tool to Alert doctors to Right Treatment) criteria. Data were analysed using univariate and bivariate descriptive statistics, considering a confidence interval of 95 %. MAIN OUTCOME MEASURES: Prevalence of PIMs and PPOs. Results The sample included 161 individuals, with a mean age of 84.7 years (SD = 6.35), 68.9 % being female. A total of 807 PIMs and 90 PPOs were identified through the application of the three set of criteria. The prevalence of PIMs using the most recent version of the Beers criteria was 85.1 and 42.1 % for independent and dependent of diagnosis, respectively. The Portuguese adaptation of this same tool indicated a lower prevalence of PIMs, 60.3 and 16.7 %, respectively. The prevalence of PIMs using the STOPP criteria was 75.4 %, whilst the prevalence of PPOs, using START, was 42.9 %. There were significant differences in the mean number of PIMs detected depending on the tool used. (p < 0.001). Conclusions The application of the studied criteria in an elderly sample enabled the identification of a notable amount of PIMs and PPOs, indicating there is room for improving the quality of care. The variation in prevalence indicates careful choice of the tool is a prerequisite for engaging in medication review. Using START/STOPP criteria enabled a more holistic approach to the quality of prescribing in the elderly, highlighting low levels of cardiovascular risk prevention and abuse of psychotropic drugs, aside with system failures largely preventable by electronic prescribing and alert generation.

Childhood Adversity Among Institutionalized Male Juvenile Offenders and Other High-Risk Groups Without Offense Records in Portugal.

The literature has shown that delinquent adolescents report high rates of childhood adversity and family dysfunction. However, it is important to know both the degree of adversity among delinquent adolescents in comparison with other high-risk samples and the contribution of each single form of adversity to this comparison. The purpose of this study was to evaluate childhood adversity, psychopathology, and risk behaviors among 4 high-risk groups, including incarcerated delinquent youths. The participants were 120 male youths between 13 and 19 years old (M = 16.18, SD = 1.26), including 30 youths who were arrested and held in detention centers as a consequence of violent crimes; 30 youths who were identified by Child Protective Services (CPS) and remained with their families; 30 youths who were identified by CPS, removed from their homes, and placed in child and youth residential care; and 30 youths who were randomly selected from schools. The incarcerated youths reported significantly more adversity, global psychopathology, and global index of risk behaviors. When considering each risk behavior, the incarcerated youths reported higher percentages of alcohol abuse, drug use, early smoking initiation, physical assault, carrying weapons, early initiation of sexual intercourse, sexual intercourse under the influence of drugs, and sexual intercourse without condom use. The logistic regression analyses showed that only emotional neglect was significantly associated with delinquency. This study suggests that delinquent youths are exposed to a great magnitude of adversities in childhood, with emotional neglect as an independent risk factor for delinquency. In addition, these youths have higher rates of psychopathology and risk behaviors compared to other high-risk samples.

Reaçäo inflamatória local em acidente crotálico / Local inflamatory reaction in accident with Crotalus

Relatam-se dois casos de pacientes que desenvolveram intensa reaçao inflamatória no local da picada por Crotalus durissus. Ambos queixavam-se de fortes dores musculares e urina de coloraçao vinhosa, sugerindo diagnóstico clínico de rabdomiólise; apresentavam ainda ptose palpebral bilateral e alteraçoes visuais. Os exames laboratoriais nao evidenciaram alteraçao da funçao renal. A terapêutica instituída foi o soro anti-crotálico e antibiotecoterapia, com boa evoluçao, havendo total remissao da sintomatologia.