Granzyme D Is a Novel Murine Mast Cell Protease That Is Highly Induced by Multiple Pathways of Mast Cell Activation

Granzymes are serine proteases known mostly for their role in the induction of apoptosis. Granzymes A and B have been extensively studied, but relatively little is known about granzymes C to G and K to M. T cells, lymphohematopoietic stromal cells, and granulated metrial gland cells express granzyme D, but the function of granzyme D is unknown. Here we show that granzyme D is expressed by murine mast cells and that its level of expression correlates positively with the extent of mast cell maturation. Coculture of mast cells with live, Gram-positive bacteria caused a profound, Toll-like receptor 2 (TLR2)-dependent induction of granzyme D expression. Granzyme D expression was also induced by isolated bacterial cell wall components, including lipopolysaccharide (LPS) and peptidoglycan, and by stem cell factor, IgE receptor cross-linking, and calcium ionophore stimulation. Granzyme D was released into the medium in response to mast cell activation. Granzyme D induction was dependent on protein kinase C and nuclear factor of activated T cells (NFAT). Together, these findings identify granzyme D as a novel murine mast cell protease and implicate granzyme D in settings where mast cells are activated, such as bacterial infection and allergy.     

Indian Hospitals and Government in the?Colonial?Andes

This article examines the reception of the early modern hospital among the indigenous people of the Andes under Spanish colonial rule. During the period covered by this study (sixteenth to mid-eighteenth centuries), the hospital was conceived primarily as a manifestation of the sovereign’s paternalistic concern for his subjects’ spiritual well being. Hospitals in the Spanish American colonies were organised along racial lines, and those catering to Indians were meant to complement the missionary endeavour. Besides establishing hospitals in the main urban centres, Spanish colonial legislation instituted hospitals for Indians in provincial towns and in small rural jurisdictions throughout the Peruvian viceroyalty. Indian hospitals often met with the suspicion and even hostility of their supposed beneficiaries, especially indigenous rulers. By conceptualising the Indian hospital as a tool of colonial government, this article investigates the reasons behind its negative reception, the work of adaptation that allowed a few of them to thrive, and the eventual failure of most of these institutions. Keywords and phrases : Hospital, Andes, Peru, Colonial, Government, PoorIn 1567, during his inspection visit to the province of Chucuito, the Spanish official Garci Diez de San Miguel questioned the local ethnic authorities about the conditions of the population under their oversight. The responses repeatedly referred to the numerous and growing payments of tribute and labour that the indigenous people of the province were obliged to provide to the Church, the colonial authorities, and the Spaniards who had settled in the region. The purpose of the inspection visit was to assess the resources of the province, compile the information necessary to set the rate of tribute, and facilitate the speedier and more abundant flow of its population’s contributions in labour, silver, and products to the benefit of the Crown. The voracious colonial extractive programme would be accompanied by measures that would assert the position of the king as protector of the Indians and patron of their evangelisation. Diez de San Miguel asked the curacas (chieftains of indigenous lineage groups) if they thought that a hospital where poor Indians could be treated should be established in the province. While some expressed their agreement, others replied that ‘there was no need for a hospital’. ¹ How should the curacas’ refusal be understood? The rejection of an institution that at least in theory should benefit them seems baffling, although it could be interpreted as a sign of opposition to the colonial order that was attempting to take root. Since in subsequent years hospitals were established not only in this province but also in the rest of the viceroyalty, this article proposes to examine why and how this policy came about and how it was received.As an extensive literature shows, the institution of the hospital was not originally created to address the problem of health, but rather that of poverty. ² Its point of departure and ultimate objectives were fundamentally concerned with spiritual affairs. ³ The hospital offered hospitality to pilgrims and the homeless, and sheltered those who, ill or near death, had urgent need of assistance and guidance to save their souls. The hospital was not a homogeneous institution; under this name were grouped establishments and collective actions that had a number of distinct purposes and rationales for assistance. ⁴ Their motivation was not disinterested, since it began with the premise that good works would receive divine recompense. Exported to the New World, the institution conserved some of these features, but changed its character, inasmuch as its promoters sought to express a bond between the Crown and its subjects as firm as the one between God and his faithful. In their objectives and operation, urban hospitals sought to foreground the role of health, and even that of doctors. I argue that, due to the political implications of these measures as well as for practical reasons, these objectives were difficult to attain. Because it had political and religious ends, and was, moreover, a space where distinct levels of authority and different, even discrepant visions of assistance to the poor and of the form in which it should be administered were articulated, the Indian hospital offers a privileged vantage point from which to observe the methods and institutions of government. Studying the conditions in which hospitals for Indians were established and administered allows us to approach a field of conflict and negotiation where matters of religion, subsistence, and governance overlapped. Using judicial and administrative sources produced by civil and church governments, I focus on hospitals located outside of the viceregal capital between the sixteenth and eighteenth centuries. ⁵      

Pharmacokinetics of cannabidiol in children with refractory epileptic encephalopathy

Growing interest in the clinical use of cannabidiol (CBD) as adjuvant therapy for pediatric refractory epileptic encephalopathy emphasizes the need for drug treatment optimization. The aim of this study was to characterize the pharmacokinetics of CBD in pediatric patients with refractory epileptic encephalopathy receiving an oil‐based oral solution. To evaluate CBD concentrations, six serial blood samples per patient were collected after the morning dose of CBD, at least 21 days after the beginning of treatment. Twelve patients who received a median (range) dose of 12.2 (5.3‐19.4) mg/kg/d (twice daily) were included in the analysis. Median (range) CBD time to maximum plasma concentration, maximum plasma concentration, and area under the concentration versus time curve up to 6 hours after dosing were 3.2 hours (1.9‐6.2), 49.6 ng/mL (14.4‐302.0), and 226.3 ng ? h/mL (70.5‐861.3), respectively. CBD systemic exposure parameters were in the lower range of previous reports in pediatric patients receiving doses in a similar range. Most of our patients (83%) showed little CBD plasma level fluctuation during a dosing interval, comparable to that encountered after oral administration of an extended release drug delivery system. CDB administration was generally safe and well tolerated, and a novel levothyroxine‐CBD interaction was recorded. Similar to other studies, large interindividual variability in CBD exposure was observed, encouraging the use of CBD therapeutic drug monitoring.     

Protective effect of γ‐tocopherol‐enriched diet on N‐methyl‐N‐nitrosourea‐induced epithelial dysplasia in rat ventral prostate

Despite recent advances in understanding the biological basis of prostate cancer (PCa), the management of this disease remains a challenge. Chemoprotective agents have been used to protect against or eradicate prostate malignancies. Here, we investigated the protective effect of γ‐tocopherol on N‐methyl‐N‐nitrosourea (MNU)‐induced epithelial dysplasia in the rat ventral prostate (VP). Thirty‐two male Wistar rats were divided into four groups (n = 8): control (CT): healthy control animals fed a standard diet; control+γ‐tocopherol (CT+γT): healthy control animals without intervention fed a γ‐tocopherol‐enriched diet (20 mg/kg); N‐methyl‐N‐nitrosourea (MNU): rats that received a single dose of MNU (30 mg/kg) plus testosterone propionate (100 mg/kg) and were fed a standard diet; and MNU+γ‐tocopherol (MNU+γT): rats that received the same treatment of MNU plus testosterone and were fed with a γ‐tocopherol‐enriched diet (20 mg/kg). After 4 months, the VPs were excised to evaluate morphology, cell proliferation and apoptosis, as well as cyclooxygenase‐2 (Cox‐2), glutathione‐S‐transferase‐pi (GST‐pi) and androgen receptor (AR) protein expression, and matrix metalloproteinase‐9 (MMP‐9) activity. An increase in the incidence of epithelial dysplasias, such as stratified epithelial hyperplasia and squamous metaplasia, in the MNU group was accompanied by augmented cell proliferation, GST‐pi and Cox‐2 immunoexpression and pro‐MMP‐9 activity. Stromal thickening and inflammatory foci were also observed. The administration of a γ‐tocopherol‐enriched diet significantly attenuated the adverse effects of MNU in the VP. The incidence of epithelial dysplasia decreased, along with the cell proliferation index, GST‐pi and Cox‐2 immunoexpression. The gelatinolytic activity of pro‐MMP‐9 returned to the levels observed for the CT group. These results suggest that γ‐tocopherol acts as a protective agent against MNU‐induced prostatic disorders in the rat ventral prostate.     

Drug-resistant and immune-escape hepatitis B virus mutants, occult hepatitis B infection and coinfections in public hospital patients from Argentina

Virus Genes - Argentina exhibits low serological prevalence for Hepatitis B virus (HBV); however, occult hepatitis B infection (OBI) has been reported in blood donors, Amerindians and individuals...     

Construction of an intercultural preventive strategy of alcohol use in rural Mapuche communities: A community‐based participatory research

The research presented in this paper consists of a case study that analyses the elements necessary for a culturally grounded methodological strategy for the prevention of problematic alcohol consumption in rural Mapuche communities in the Araucanía region. To do this, we proposed to answer the questions: what are the particularities that alcohol consumption adopts in the local space? And what are the elements that should be considered for an intercultural preventive strategy for alcohol consumption? Oriented to the perspective of community‐based participatory research, data were collected through group interviews with the local community, participant observation and in‐depth interviews with people who consumed alcohol, were recovering from consumption and nondrinkers. A total of 84 people participated and the information gathered was analysed using ATLAS.ti software. The results show key aspects that must be considered for the design, including: strengthening the cultural identity, providing spaces for shared reflection in places where the community converges (schools and rural health centres), and problematising alcohol consumption from their own conceptions of normal and problematic consumption. Therefore, there is a need to focus on strengthening intracultural processes in community spaces, with a preventive strategy within the logic of action research, with increasing degrees of community participation.     

Prognostic value of the immunohistochemical expression of vascular endothelial growth factors in malignant salivary gland neoplasms: a systematic review and meta-analysis

Background The immunohistochemical expression of vascular endothelial growth factor is a prognostic marker in several cancer types. In salivary gland tumors, the association between vascular endothelial growth factor and prognosis remains unclear. The purpose of this study was to perform a systematic review and meta-analysis to assess whether the immunohistochemical expression of vascular endothelial growth factor in patients with salivary gland neoplasms presents prognostic value. Material and Methods Immunohistochemical studies assessing the predictive value of vascular endothelial growth factor in salivary gland neoplasms were systematically reviewed using PubMed, Scopus, Embase, Cochrane Library, and Web of Science databases. It was assessed any survival rates. The fixed-effect model with an adjusted hazard ratio (HR) and 95% confidence intervals (95% CI) as effect measures were performed in the meta-analysis. The Quality in Prognosis Studies (QUIPS) tool was used to assess the quality of the included studies, and the evidence quality was assessed by the Grading of Recommendation, Assessment, Development, and Evaluation (GRADE) system. Results The immunohistochemical overexpression of vascular endothelial growth factor in patients with salivary gland neoplasms was associated with shortened survival (HR=5.37, 95% CI: 2.67-10.83, P = 0.00001). In addition, the presence of vascular endothelial growth factor was tightly associated with tumor size, lymph node metastasis, clinical stage, perineural invasion, vascular invasion, poor local control of the disease, and recurrence. Conclusions The immunohistochemical overexpression of vascular endothelial growth factor in patients with salivary gland neoplasms has prognostic value and was associated with decreased survival time. However, more primary well-designed studies are necessary to increase the level of evidence. Key words:Salivary gland neoplasms, salivary glands, head and neck neoplasms, vascular endothelial growth factors, prognosis.