Metformin modulates corticosteroids hormones in adrenals cells promoting Mycobacterium tuberculosis elimination in human macrophages.

Research suggests that both tuberculosis (TB) and type 2 diabetes mellitus (T2DM) have an immuno-endocrine imbalance characterized by dysregulated proinflammatory molecules and hormone levels (high cortisol/DHEA ratio), impeding an effective immune response against Mycobacterium tuberculosis (Mtb) driven by cytokines, antimicrobial peptides (AMPs), and androgens like DHEA. Insulin, sulfonylurea derivatives, and metformin are commonly used glucose-lowering drugs in patients suffering from TB and T2DM. For this comorbidity, metformin is an attractive target to restore the immunoendocrine mechanisms dysregulated against Mtb. This study aimed to assess whether metformin influences cortisol and DHEA synthesis in adrenal cells and if these hormones influence the expression of proinflammatory cytokines and AMPs in Mtb-infected macrophages. Our results suggest that metformin may enhance DHEA synthesis while maintaining cortisol homeostasis. In addition, supernatants from metformin-treated adrenal cells decreased mycobacterial loads in macrophages, which related to rising proinflammatory cytokines and AMP expression (HBD-2 and 3). Intriguingly, we find that HBD-3 and LL-37 can modulate steroid synthesis in adrenal cells with diminished levels of cortisol and DHEA, highlighting the importance of crosstalk communication between adrenal hormones and these effectors of innate immunity. We suggest that metformin's effects can promote innate immunity against Mtb straight or through modulation of corticosteroid hormones.

Drug repositioning identifies histone deacetylase inhibitors that promote innate immunity in non-tuberculous mycobacterial infection.

Non-tuberculosis infections in immunocompromised patients represent a cause for concern, given the increased risks of infection, and limited treatments available. Herein, we report that molecules for binding to the catalytic site of histone deacetylase (HDAC) inhibit its activity, thus increasing the innate immune response against environmental mycobacteria. The action of HDAC inhibitors (iHDACs) was explored in a model of type II pneumocytes and macrophages infection by Mycobacterium aurum. The results show that the use of 1,3-diphenylurea increases the expression of the TLR-4 in M. aurum infected MDMs, as well as the production of defb4, IL-1ß, IL-12, and IL-6. Moreover, we observed that aminoacetanilide upregulates the expression of TLR-4 together with TLR-9, defb4, CAMP, RNase 6, RNase 7, IL-1ß, IL-12, and IL-6 in T2P. Results conclude that the tested iHDACs selectively modulate the expression of cytokines and antimicrobial peptides that are associated with reduction of non-tuberculous mycobacteria infection.

Therapeutic outcomes and survival analysis of Extramammary Paget's disease: A multicentre retrospective study of 249 patients.

BACKGROUND: Evidence regarding long-term therapeutic outcomes and disease-specific survival (DSS) in Extramammary Paget's disease (EMPD) is limited. OBJECTIVES: To assess the DSS and outcomes of surgical and nonsurgical therapeutic modalities in a large cohort of EMPD patients. METHODS: Retrospective chart review of EMPD patients from 20 Spanish tertiary care hospitals. RESULTS: Data on 249 patients with a median follow-up of 60 months were analyzed. The estimated 5-, 10-, and 15-year DSS was 95.9%, 92.9%, and 88.5%, respectively. A significantly lower DSS was observed in patients showing deep dermal invasion (≥1 mm) or metastatic disease (P < .05). A ≥50% reduction in EMPD lesion size was achieved in 100% and 75.3% of patients treated with surgery and topical therapies, respectively. Tumor-free resection margins were obtained in 42.4% of the patients after wide local excision (WLE). The 5-year recurrence-free survival after Mohs micrographic surgery (MMS), WLE with tumor-free margins, WLE with positive margins, radiotherapy, and topical treatments was 63.0%, 51.4%, 20.4%, 30.1%, and 20.8%, respectively. LIMITATIONS: Retrospective design. CONCLUSIONS: EMPD is usually a chronic condition with favorable prognosis. MMS represents the therapeutic alternative with the greatest efficacy for the disease. Recurrence rates in patients with positive margins after WLE are similar to the ones observed in patients treated with topical agents.

Design and evaluation of a mobile-based intervention for Maya adults during the COVID-19 pandemic

Introduction: The COVID-19 pandemic has had a direct impact on mental health. Inter national organisations have emphasised the vulnerability of indigenous people. Digital Mental Health approaches deliver online therapy as an evidence-based, effective, and accessible treat ment option for common mental health problems. However, the evidence regarding these ap proaches is limited in indigenous populations. The objective of this study is to describe the design, development, and evaluation of the efficacy of a self-applied online intervention regarding the psychological symptoms of depression, anxiety, and fear of COVID-19 in a sample of the Maya population. Method: A prospective longitudinal quantitative study was designed, where a single group was measured before and after receiving the online intervention. This study took place from April to September 2021 and consisted of six sessions delivered via WhatsApp in Spanish and Mayan. Results: The initial assessment was implemented with 82 participants who were evaluated using the Patient Health Questionnaire, Scale for Generalised Anxiety Disorder and the Fear of COVID-19 Scale; 18 participants remained in the intervention for the post-as sessment. Statistical differences were observed in PRE and POST measures of depression and anxiety, but not in fear of COVID-19. Conclusions: This study produced positive results for the first online mental health intervention implemented in the Latin American indigenous pop ulation. Future studies might consider developing similar interventions for other indigenous communities in Latin America.

Introducción: La pandemia de COVID-19 tuvo impacto directo en la salud mental. Organizaciones internacionales han enfatizado la vulnerabilidad de los pueblos indígenas. Los enfoques de salud mental digital brindan terapia en línea como una opción de tratamiento basada en evidencia, efectiva y accesible; sin embargo, los datos son limitados en población indígena. El objetivo de este estudio fue describir el diseño, desarrollo y evaluación de la eficacia de una intervención en línea autoaplicada sobre síntomas psicológicos de depresión, ansiedad y miedo al COVID-19 en una muestra de población maya. Método: Se diseñó un es tudio cuantitativo longitudinal prospectivo, donde se midió a un solo grupo antes y después de recibir la intervención en línea, implementada de abril a septiembre de 2021, que constó de seis sesiones impartidas vía WhatsApp, en español y maya. Resultados: La evaluación inicial se implementó con 82 participantes que fueron evaluados mediante el Cuestionario de Salud del Paciente, Escala para el Trastorno de Ansiedad Generalizada y Escala de Miedo al COVID-19; 18 participantes permanecieron para la evaluación posterior. Se observaron di ferencias estadísticas en las medidas pre- y post- de depresión y ansiedad, pero no miedo al COVID-19. Conclusiones: Este estudio arrojó resultados positivos de la primera intervención de salud mental en línea implementada en la población indígena latinoamericana. Estudios futuros podrían considerar el desarrollo de intervenciones similares para otras comunidades indígenas en América Latina.

Histone deacetylase (HDAC) inhibitors- based drugs are effective to control Mycobacterium tuberculosis infection and promote the sensibility for rifampicin in MDR strain

BACKGROUND Tuberculosis (TB) is a major public health problem, which has been aggravated by the alarming growth of drug-resistant tuberculosis. Therefore, the development of a safer and more effective treatment is needed. OBJECTIVES The aim of this work was repositioning and evaluate histone deacetylases (HDAC) inhibitors- based drugs with potential antimycobacterial activity. METHODS Using an in silico pharmacological repositioning strategy, three molecules that bind to the catalytic site of histone deacetylase were selected. Pneumocytes type II and macrophages were infected with Mycobacterium tuberculosis and treated with pre-selected HDAC inhibitors (HDACi). Subsequently, the ability of each of these molecules to directly promote the elimination of M. tuberculosis was evaluated by colony-forming unit (CFU)/mL. We assessed the expression of antimicrobial peptides and respiratory burst using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) FINDINGS Aminoacetanilide (ACE), N-Boc-1,2-phenylenediamine (N-BOC), 1,3-Diphenylurea (DFU), reduce bacillary loads in macrophages and increase the production of β-defensin-2, LL-37, superoxide dismutase (SOD) 3 and inducible nitric oxide synthase (iNOS). While only the use of ACE in type II pneumocytes decreases the bacterial load through increasing LL-37 expression. Furthermore, the use of ACE and rifampicin inhibited the survival of intracellular multi-drug resistance M. tuberculosis. MAIN CONCLUSIONS Our data support the usefulness of in silico approaches for drug repositioning to provide a potential adjunctive therapy for TB.

Nicotine associates to intracellular Mycobacterium tuberculosis inducing genes related with resistance to antimicrobial peptides.

Tobacco consumption is related to an increased risk to develop tuberculosis. Antimicrobial peptides are essential molecules in the response to Mycobacterium tuberculosis (Mtb) because of their direct antimicrobial activity. The aim of this study was to demonstrate that nicotine enters into Mtb infected epithelial cells and associates with the mycobacteria inducing genes related to antimicrobial peptides resistance. Epithelial cells were infected with virulent Mtb, afterwards cells were stimulated with nicotine. The internalization of nicotine was followed using electron and confocal microscopy. The lysX expression was evaluated isolating mycobacterial RNA and submitted to RT-PCR analysis. Our results indicated that nicotine promotes Mtb growth in a dose-dependent manner in infected cells. We also reported that nicotine induces lysX expression. In conclusion, nicotine associates to intracellular mycobacteria promoting intracellular survival.

Retinoic acid induces antimicrobial peptides and cytokines leading to Mycobacterium tuberculosis elimination in airway epithelial cells.

Tuberculosis (TB) is the leading cause of death by a single infectious agent, Mycobacterium tuberculosis (Mtb). Alveolar macrophages and respiratory epithelial cells are the first cells exposed to Mtb during the primary infection, once these cells are activated, secrete cytokines and antimicrobial peptides that are associated with the Mtb contention and elimination. Vitamins are micronutrients that function as boosters on the innate immune system, however, is unclear whether they have any protective activity during Mtb infection. Thus, we investigated the role of vitamin A (retinoic acid), vitamin C (ascorbic acid), vitamin D (calcitriol), and vitamin E (alfa-tocopherol) as inductors of molecules related to mycobacterial infection in macrophages and epithelial cells. Our results showed that retinoic acid promotes the expression of pro- and anti-inflammatory molecules such as Thymic stromal lymphopoietin (TSLP), ß-defensin-2, IL-1ß, CCL20, ß-defensin-3, Cathelicidin LL-37, TGF-ß, and RNase 7, whereas calcitriol, ascorbic acid, and α-tocopherol lead to an anti-inflammatory response. Treatment of Mtb-infected epithelial cells and macrophage-like cells with the vitamins showed a differential response, where calcitriol reduced Mtb in macrophages, while retinoic acid reduced infection in epithelial cells. Thereby, we propose that a combination of calcitriol and retinoic acid supplementation can drive the immune response, and promotes the Mtb elimination by increasing the expression of antimicrobial peptides and cytokines, while simultaneously modulating inflammation.

Steroid hormone modulates the production of cathelicidin and human ß-defensins in lung epithelial cells and macrophages promoting Mycobacterium tuberculosis killing.

Several studies have documented the interaction between the immune and endocrine systems as an effective defense strategy against tuberculosis, involving the production of several molecules and immunological processes. In this study, we determined the effect of cortisol and dehydroepiandrosterone (DHEA) on the production of antimicrobial peptides such as cathelicidin and human ß-defensin (HBD) -2, and HBD-3 and their effect on intracellular growth of Mycobacterium tuberculosis (Mtb) in lung epithelial cells and macrophages. Our results showed that DHEA promotes the production of these antimicrobial peptides in infected cells, correlating with the decrease of Mtb bacilli loads. These results suggest the use of exogenous DHEA as an adjuvant for tuberculosis therapy.

Dolor torácico y shock secundarios a perforación espontánea de esófago: síndrome de Boerhaave.

La perforación esofágica es la más letal de todas las perforaciones del aparato digestivo. Se presenta el caso de un varón de 65 años que acude a urgencias por un cuadro clínico de dolor torácico, vómitos e hipotensión. Se le realizó tomografía computarizada por sospecha de síndrome aórtico agudo, con hallazgos sugerentes de perforación esofágica. El síndrome de Boerhaave consiste en la rotura longitudinal del esófago sobre una pared macroscópicamente sana. Su tratamiento definitivo se realiza con cirugía durante las primeras 24 horas. El síndrome de Boerhaave debe considerarse como complicación posible en los pacientes con dolor epigástrico y vómitos, ya que es una emergencia quirúrgica con alta morbimortalidad.Esophageal perforation is the most lethal of all perforations of the digestive system. 65-year-old male who goes to the emergency department due to clinical symptoms of chest pain, vomiting and hypotension, who underwent CT scan for suspected acute aortic syndrome, with suggestive findings of esophageal perforation. Boerhaave syndrome consists of the longitudinal rupture of the esophagus on a macroscopically healthy wall. Its definitive treatment is performed with surgery during the first 24 hours. Boerhaave syndrome should be considered as a possible complication in patients with epigastric pain and vomiting, as it is a surgical emergency with high morbidity and mortality.

Hepatic epithelioid angiomyolipoma: contribution of a new case.

In relation to the article published by Ortiz S et al. (1), we have recently seen a 37-year-old female who presented to the Emergency Department with pain in right hypochondrium and a mild increase in transaminase levels. An ultrasound was performed that showed a large 13-cm tumor in the right hepatic lobe, which was heterogeneous with hyperechogenic and anechoic areas.

Targeting miR-21 to treat psoriasis.

Psoriasis is a common inflammatory skin disease with limited treatment options that is characterized by a complex interplay between keratinocytes, immune cells, and inflammatory mediators. MicroRNAs (miRNAs) are regulators of gene expression and play critical roles in many human diseases. A number of miRNAs have been described to be up-regulated in psoriasis, but their causal contribution to disease development has not been demonstrated. We confirm that miR-21 expression is increased in epidermal lesions of patients with psoriasis and that this leads to reduced epidermal TIMP-3 (tissue inhibitor of matrix metalloproteinase 3) expression and activation of TACE (tumor necrosis factor-α-converting enzyme)/ADAM17 (a disintegrin and metalloproteinase 17). Using patient-derived skin samples and mouse models of psoriasis, we demonstrate that increased miR-21 may be a consequence of impaired transcriptional activity of Jun/activating protein 1 (AP-1), leading to activation of the interleukin-6 (IL-6)/signal transducer and activator of transcription 3 (Stat3) pathway. Inhibition of miR-21 by locked nucleic acid (LNA)-modified anti-miR-21 compounds ameliorated disease pathology in patient-derived psoriatic skin xenotransplants in mice and in a psoriasis-like mouse model. Targeting miR-21 may represent a potential therapeutic option for the treatment of psoriasis.

Prognostic factors of successful tympanoplasty in pediatric patients: a cohort study.

BACKGROUND: Tympanoplasty in children is a current and controversial theme. The success of tympanoplasty traditionally has been measured only by the post-operative integrity of the graft. Yet, there are other variables that may be used to determine success. The objectives of the present work were to analyze which factors are predictive of successful tympanoplasty in pediatric patients and to construct and validate a prognostic index that could be used as a tool to predict the success of tympanoplasty in children. SETTING: Department of Pediatric Otorhinolaryngology, tertiary-care hospital, Mexico City. PATIENTS: Forty-eight patients, who were older that five years of age, had persistent perforation of the tympanic membrane, and had undergone tympanoplasty (January 2005-June 2008), were followed for a year. MAIN OUTCOME MEASURES: The factors tested for their value as predictors were the following: age at time of surgery, state of contralateral ear, previous adenoidectomy, cause of perforation, size of perforation, infection at the time of surgery, state of mucosa, age at first occurrence of perforation, presence of craniofacial dysmorphia, and surgical technique. These factors were compared with the criterion, success, which was defined as attaining three positive outcomes: 1) integrity of the implant or membrane; 2) minimum of 10-dB gain in the auditory threshold or, in the case of normal hearing, conservation of same; and 3) air-filled space in the middle ear. The best model was obtained through logistic regression analysis; the model was validated. RESULTS: The most balanced prediction model was that in which the three success criteria were included, with age, surgical technique, and infection at surgery being excluded as variables. The additional 12 pediatric cases used in the validation had a probability of success >0.425 (best cut-off level); two patients (17%) had poor evolution. CONCLUSIONS: This is the first study that validated a predictive index of the result of tympanoplasty in children. This index predicted 81% of the successful outcomes.

Terapia de rehabilitación con entrenador mental en el adulto mayor con deterioro cognitivo / Rehabilitation therapy with mental trainer in the elderly with cognitive impairment

Se realizó un estudio cuasi experimental de tipo antes después sin grupo control con 48 pacientes donde se aplicó rehabilitación cognitiva con entrenador mental en pacientes con Deterioro Cognitivo Ligero y estadios iniciales de demencia pertenecientes al municipio de Güines, provincia Mayabeque, durante el período comprendido entre abril del 2008 hasta abril del 2009, con el objetivo de mejorar sus funciones cognitivas y su estado afectivo, para lo cual se aplicaron técnicas para mejorar la orientación, memoria de fijación, lenguaje, atención y la esfera afectiva. En la muestra predominó el grupo de edad de 76 a 85 años en un 50 por ciento y el sexo femenino con un 56 por ciento, siendo el nivel de escolaridad bajo con un 90 por ciento. El Deterioro Cognitivo Ligero fue la afección cognitiva predominante con un 40 por ciento. El 77 por ciento mejoró el lenguaje y el 79 por ciento la orientación espacial. El puntaje del Minimental State Examination de Folstein mejoró posterior a la terapia donde 4 pacientes presentaron puntajes superiores a 23 puntos. En la esfera afectiva un 77 por ciento se mostró optimista y un 50 por ciento aumentó su satisfacción. Se concluyó que el proceso de estimulación mental demostró ser efectivo puesto que mejoró sus procesos cognitivos y afectivos indispensables para mejorar la calidad de vida de estos pacientes

It was conducted a quasi-experimental study of type before-after without control group with 48 patients where it was applied cognitive rehabilitation with mental trainer in patients with mild cognitive impairment and early stages of dementia belonging to the municipality of Güines, Mayabeque province, during the period from April 2008 until April 2009, with the aim of improving their cognitive function and affective state, for which it was applied techniques to improve orientation, fixation memory, language, attention and affective sphere. In the sample predominated the age group of 76-85 years in 50 per cent and female sex with 56 per cent, being low the educational level with 90 per cent. Mild cognitive impairment was the predominant cognitive condition with 40 per cent. 77 per cent improved language and 79 per cent spatial orientation. Folstein's Mini-Mental State Examination score improved after therapy in which 4 patients had scores above 23 points. In the affective sphere 77 per cent expressed optimism and 50 per cent increased their satisfaction. It was concluded that the process of mental stimulation was effective since it improved their cognitive and affective processes which are indispensable to improve the quality of life of these patients

Nodular herpes zoster with herpetic syringitis and no epidermal involvement in a patient with Burkitt lymphoma.

Herpes zoster (HZ) occurs with an increased incidence in immunosuppressed patients, in whom it frequently displays atypical clinical presentations. Herpetic syringitis, the involvement of the eccrine epithelium by herpes virus infection, is an infrequently described histologic pattern that has been rarely and almost exclusively reported in HIV-infected patients. We report the case of a woman with Burkitt lymphoma who developed 2 nodular, asymptomatic lesions while receiving treatment with chemotherapy and radiotherapy for her hematological disease. Histology showed viropathic changes in the epithelium of eccrine glands not in the epidermis. PCR was positive for varicella-zoster virus (VZV). Nodular herpes zoster seems to be an exceptional clinical presentation. We report another such case which is, as far as we know, the first report of herpetic syringitis with no concomitant epidermal involvement.

[Mycosis fungoides-type eruptions induced by carbamazepine]. / Erupciones de tipo micosis fungoide inducidas por carbamazepina.

Cutaneous pseudolymphomas are inflammatory diseases of the skin that simulate malignant lymphomas in their clinical and/or histological form. Those induced by drugs are infrequent and are characterized by their clinical and histological polymorphism. There is no consensus regarding the definition of these dermatoses, and they can be seen in different forms of presentation. There are two main groups of drug-induced pseudolymphomas: those that clinically and histologically simulate cutaneous lymphomas, and those known as hypersensitivity syndromes. Pseudolymphomas cannot be differentiated from true lymphomas through clinical, pathological or molecular findings. The definitive test for diagnosis is the resolution of the lesions after the medication involved is suspended. We present three cases of carbamazepine-induced cases of pseudolymphomas that histologically simulate mycosis fungoides, with different clinical presentations.

[Cutaneous marginal zone B-cell lymphoma treated with rituximab]. / Linfoma cutáneo de células B de la zona marginal tratado con rituximab.

Marginal zone B-cell lymphoma (MZL) is probably the most frequent of the primary cutaneous B-cell lymphomas, which are entities with indolent behavior. Clinically, it appears in middle-aged patients as papules, nodules or erythematous plaques, solitary or multiple, on the trunk and proximal part of the limbs. The prognosis is excellent despite frequent cutaneous recurrences. We present the case of a 40-year-old male who, after having several recurrences of MZL over a ten-year period, was treated with rituximab for multiple skin lesions. The patient showed full remission after four weeks of treatment, and developed cytokine-release syndrome after the first infusion of the drug.