A 12-month follow-up study of patients with systemic lupus erythematosus after immunization against SARS-CoV-2.

OBJECTIVE: To identify all post-BNT162b2 vaccination (BioNTech and Pfizer) events during the ensuing 12 months in patients with systemic lupus erythematosus (SLE) from the Immuno-Rheumatology Department at Cayetano Heredia Hospital's cohort, Lima, Perú. METHODS: A 12-month follow-up study was conducted from the first dose of immunization with the BNT162b2 vaccine, which was given between May and June 2021, to SLE patients from this cohort. RESULTS: The initial population was constituted by 100 patients (100 patients received the 1st dose, 90 the 2nd dose, and 85 the 3rd dose of this vaccine); 33 patients presented a SLE reactivation (flare), 9% (9/100) post 1st dose, 26.6% (24/90) post 2nd dose, and 16.4% (14/85) post 3rd dose. The most common types of flare were articular (26) and renal (14) with 5/33 (15.1%) requiring hospitalization for flare management. A negative association with flare occurrence was found between the use of hydroxychloroquine RR 0.43 (0.21-0.85) and the opposite was the case for azathioprine RR 2.70 (1.39-5.25). During follow-up, 26 patients developed SARS-CoV-2 infection of whom three required hospitalization, one of whom died. CONCLUSIONS: 33 of 100 SLE patients immunized with BNT162b2 vaccine against SARS-CoV-2, presented SLE flares (47 episodes in total); 5 of these patients required in-hospital management and all fully recovered; 26 patients had SARS-CoV-2 infection; three required hospitalization, one died.

Front instabilities in the presence of convection due to thermal and compositional gradients.

Reaction fronts separate fluids of different densities due to thermal and compositional gradients that may lead to convection. The stability of convectionless flat fronts propagating in the vertical direction depends not only on fluid properties but also in the dynamics of a front evolution equation. In this work, we analyze fronts described by the Kuramoto-Sivashinsky (KS) equation coupled to hydrodynamics. Without density gradients, the KS equation has a flat front solution that is unstable to perturbations of long wavelengths. Buoyancy enhances this instability if a fluid of lower density is underneath a denser fluid. In the reverse situation, with the denser fluid underneath, the front can be stabilized with appropriate thermal and compositional gradients. However, in this situation, a different instability develops for large enough thermal gradients. We also solve numerically the nonlinear KS equation coupled to the Navier-Stokes equations to analyze the front propagation in two-dimensional rectangular domains. As convection takes place, the reaction front curves, increasing its velocity.

Biomarkers of Inflammation in Obesity-Psoriatic Patients.

Psoriasis is a common chronic inflammatory multisystemic disease with a complex pathogenesis consisting of genetic, immunological, and environmental components. It is associated with a number of comorbidities, including diabetes, metabolic syndrome, obesity, and myocardial infarction. In addition, the severity of psoriasis seems to be related to the severity of obesity. Patients with higher levels of obesity show poorer response to systemic treatments of psoriasis. Several studies have demonstrated that white adipose tissue is a crucial site of the formation of proinflammatory adipokines such as leptin, adiponectin, and resistin and classical cytokines such as interleukin- (IL-) 6 and tumour necrosis factor-α. In psoriasis, due to the proliferation of Th1, Th17, and Th22 cells, IL-22, among others, is produced in addition to the abovementioned cytokines. With respect to leptin and resistin, both of these adipokines are present in high levels in obese persons with psoriasis. Further, the plasma levels of leptin and resistin are related to the severity of psoriasis. These results strongly suggest that obesity, through proinflammatory pathways, is a predisposing factor to the development of psoriasis and that obesity aggravates existing psoriasis. Different inflammatory biomarkers link psoriasis and obesity. In this paper, the most important ones are described.

Identification of a new small ubiquitin-like modifier (SUMO)-interacting motif in the E3 ligase PIASy.

Small ubiquitin-like modifier (SUMO) conjugation is a reversible post-translational modification process implicated in the regulation of gene transcription, DNA repair, and cell cycle. SUMOylation depends on the sequential activities of E1 activating, E2 conjugating, and E3 ligating enzymes. SUMO E3 ligases enhance transfer of SUMO from the charged E2 enzyme to the substrate. We have previously identified PIASy, a member of the Siz/protein inhibitor of activated STAT (PIAS) RING family of SUMO E3 ligases, as essential for mitotic chromosomal SUMOylation in frog egg extracts and demonstrated that it can mediate effective SUMOylation. To address how PIASy catalyzes SUMOylation, we examined various truncations of PIASy for their ability to mediate SUMOylation. Using NMR chemical shift mapping and mutagenesis, we identified a new SUMO-interacting motif (SIM) in PIASy. The new SIM and the currently known SIM are both located at the C terminus of PIASy, and both are required for the full ligase activity of PIASy. Our results provide novel insights into the mechanism of PIASy-mediated SUMOylation. PIASy adds to the growing list of SUMO E3 ligases containing multiple SIMs that play important roles in the E3 ligase activity.

Natural product derivative Gossypolone inhibits Musashi family of RNA-binding proteins.

BACKGROUND: The Musashi (MSI) family of RNA-binding proteins is best known for the role in post-transcriptional regulation of target mRNAs. Elevated MSI1 levels in a variety of human cancer are associated with up-regulation of Notch/Wnt signaling. MSI1 binds to and negatively regulates translation of Numb and APC (adenomatous polyposis coli), negative regulators of Notch and Wnt signaling respectively. METHODS: Previously, we have shown that the natural product (-)-gossypol as the first known small molecule inhibitor of MSI1 that down-regulates Notch/Wnt signaling and inhibits tumor xenograft growth in vivo. Using a fluorescence polarization (FP) competition assay, we identified gossypolone (Gn) with a > 20-fold increase in Ki value compared to (-)-gossypol. We validated Gn binding to MSI1 using surface plasmon resonance, nuclear magnetic resonance, and cellular thermal shift assay, and tested the effects of Gn on colon cancer cells and colon cancer DLD-1 xenografts in nude mice. RESULTS: In colon cancer cells, Gn reduced Notch/Wnt signaling and induced apoptosis. Compared to (-)-gossypol, the same concentration of Gn is less active in all the cell assays tested. To increase Gn bioavailability, we used PEGylated liposomes in our in vivo studies. Gn-lip via tail vein injection inhibited the growth of human colon cancer DLD-1 xenografts in nude mice, as compared to the untreated control (P < 0.01, n = 10). CONCLUSION: Our data suggest that PEGylation improved the bioavailability of Gn as well as achieved tumor-targeted delivery and controlled release of Gn, which enhanced its overall biocompatibility and drug efficacy in vivo. This provides proof of concept for the development of Gn-lip as a molecular therapy for colon cancer with MSI1/MSI2 overexpression.

Dermatologists happiness and satisfaction / Estudio sobre la satisfacción laboral y la felicidad en médicos dermatólogos.

Objective: To assess the level of happiness and satisfaction in the life and medical practice of dermatologists in Mexico. Method: A descriptive study (online survey) was conducted focused on practicing dermatologists in our country. Questions included demographic characteristics, the Pemberton happiness index (with local validation) and questions that assessed the degree of personal satisfaction. Descriptive statistics were used to obtain the central tendency and dispersion. Measures of central tendency and dispersion were performed; to compare categorical variables, contingency tables for chi-square test were used and when comparing quantitative variables with normal distribution, Student's t t-test was used. Results: 219 surveys were included, 72.6% female and 27.4% male, with an average age of 45.6 and an average of 16 years of medical practice. Most of them (64.8%) graduate from Mexico City; 93% were very satisfied with the specialty and 98.6% of them would choose the same once again, the most important reason is to encompass medical and surgical areas. The level of happiness by using the Pemberton scale was "high" (mode: 9.11; standard deviation: 1.73). Conclusions: This first study in Latin America on this subject in dermatologists showed high levels of satisfaction and happiness in both professional and personal areas.

Objetivo: Conocer la felicidad y la satisfacción laboral de los dermatólogos en México. Método: Estudio descriptivo, mediante encuesta en línea dirigida a dermatólogos especialistas, graduados y con ejercicio en México. Se incluyeron elementos demográficos, el Índice de Felicidad de Pemberton (con validación local) y preguntas para evaluar la satisfacción personal. Se realizaron medidas de tendencia central y dispersión; para comparar las variables categóricas, se utilizaron tablas de contingencia para ji al cuadrado, y al comparar variables cuantitativas con distribución normal se utilizó la prueba t de Student. Resultados: Se incluyeron 219 encuestados, el 72.6% mujeres y el 27.4% hombres, con una media de edad de 45.6 años y un promedio de 16 años de ejercicio profesional. La mayoría (64.8%) eran egresados de la Ciudad de México y el 75.3% estaban muy satisfechos con su escuela de formación. Un 93% se manifestó muy satisfecho con su especialidad y el 98.6% volvería a escogerla; el mayor motivo sería abarcar ámbitos médicos y quirúrgicos. El grado de felicidad según el Índice de Pemberton fue «alto¼ (media: 9.11; desviación estándar: 1.73). Conclusión: Este primer estudio en América Latina sobre este aspecto en dermatólogos, muestra unos altos índices de satisfacción y felicidad, tanto en el área profesional como en la personal.

Advances in Immunotherapy for Melanoma: A Comprehensive Review.

Melanomas are tumors originating from melanocytes and tend to show early metastasis secondary to the loss of cellular adhesion in the primary tumor, resulting in high mortality rates. Cancer-specific active immunotherapy is an experimental form of treatment that stimulates the immune system to recognize antigens on the surface of cancer cells. Current experimental approaches in immunotherapy include vaccines, biochemotherapy, and the transfer of adoptive T cells and dendritic cells. Several types of vaccines, including peptide, viral, and dendritic cell vaccines, are currently under investigation for the treatment of melanoma. These treatments have the same goal as drugs that are already used to stimulate the proliferation of T lymphocytes in order to destroy tumor cells; however, immunotherapies aim to selectively attack the tumor cells of each patient. In this comprehensive review, we describe recent advancements in the development of immunotherapies for melanoma, with a specific focus on the identification of neoantigens for the prediction of their elicited immune responses. This review is expected to provide important insights into the future of immunotherapy for melanoma.

Marangoni flow traveling with reaction fronts: Eikonal approximation.

Chemical reaction fronts traveling in liquids generate gradients of surface tension leading to fluid motion. This surface tension driven flow, known as Marangoni flow, modifies the shape and the speed of the reaction front. We model the front propagation using the Eikonal relation between curvature and normal speed of the front, resulting in a front evolution equation that couples to the fluid velocity. The sharp discontinuity between the reactants and products leads to a surface tension gradient proportional to a delta function. The Stokes equations with the surface tension gradient as part of the boundary conditions provide the corresponding fluid velocity field. Considering stress free boundaries at the bottom of the liquid layer, we find an analytical solution for the fluid vorticity leading to the velocity field. Solving numerically the appropriate no-slip boundary condition, we gain insights into the role of the boundary condition at the bottom layer. We compare our results with results from two other models for front propagation: the deterministic Kardar-Parisi-Zhang equation and a reaction-diffusion equation with cubic autocatalysis, finding good agreement for small differences in surface tension.

NMR identification of the binding surfaces involved in the Salmonella and Shigella Type III secretion tip-translocon protein-protein interactions.

The type III secretion system (T3SS) is essential for the pathogenesis of many bacteria including Salmonella and Shigella, which together are responsible for millions of deaths worldwide each year. The structural component of the T3SS consists of the needle apparatus, which is assembled in part by the protein-protein interaction between the tip and the translocon. The atomic detail of the interaction between the tip and the translocon proteins is currently unknown. Here, we used NMR methods to identify that the N-terminal domain of the Salmonella SipB translocon protein interacts with the SipD tip protein at a surface at the distal region of the tip formed by the mixed α/ß domain and a portion of its coiled-coil domain. Likewise, the Shigella IpaB translocon protein and the IpaD tip protein interact with each other using similar surfaces identified for the Salmonella homologs. Furthermore, removal of the extreme N-terminal residues of the translocon protein, previously thought to be important for the interaction, had little change on the binding surface. Finally, mutations at the binding surface of SipD reduced invasion of Salmonella into human intestinal epithelial cells. Together, these results reveal the binding surfaces involved in the tip-translocon protein-protein interaction and advance our understanding of the assembly of the T3SS needle apparatus. Proteins 2016; 84:1097-1107. © 2016 Wiley Periodicals, Inc.

Characterization of the Shigella and Salmonella Type†III Secretion System Tip-Translocon Protein-Protein Interaction by Paramagnetic Relaxation Enhancement.

Many Gram-negative pathogens, such as Shigella and Salmonella, assemble the type III secretion system (T3SS) to inject virulence proteins directly into eukaryotic cells to initiate infectious diseases. The needle apparatus of the T3SS consists of a base, an extracellular needle, a tip protein complex, and a translocon. The atomic structure of the assembled tip complex and the translocon is unknown. Here, we show by NMR paramagnetic relaxation enhancement (PRE) that the mixed α-ß domain at the distal region of the Shigella and Salmonella tip proteins interacts with the N-terminal ectodomain of their major translocon proteins. Our results reveal the binding surfaces involved in the tip-translocon protein-protein interaction and provide insights about the assembly of the needle apparatus of the T3SS.

Update of phylogenetic and genetic diversity of Sporothrix schenckii sensu lato.

Sporothrix schenckii sensu lato causes subcutaneous mycosis. In this article we analysed its phylogeny and genetic diversity using calmodulin DNA sequences deposited in GenBank database. Population genetics indices were calculated, plus phylogenetic and haplotype network trees were built. Five clades with high values of posterior probability, 47 haplotypes and high diversity in the complex were found. Analysis of partial calmodulin sequences alignment revealed conserved and polymorphic regions that could be used as reference for taxonomic identification. The use of population genetics analysis allowed understanding the phylogenetic proximity of S. schenckii s. str. and S. brasiliensis; scarce genetic flow among them with low migration index and high ancestry coefficient was found. Similarly, S. globosa, S. mexicana and S. pallida sequences showed highly differentiated species with no genetic exchange. The phylogenetic tree suggests that S. mexicana shared a common ancestor with S. pallida; while S. globosa and S. brasiliensis are more related to S. schenckii s. str. and showed less haplotype diversity and restrictions in geographic distribution. In the haplotype network tree S. schenckii s. str. species displayed worldwide distribution without dispersion centres; while S. brasiliensis and S. globosa, exhibited Brazil and Euro-Asia as dispersion centres, respectively. Our data suggest that S. schenckii complex has been submitted to a divergent evolution process, probably due to the pressure of the environment and of the host. In contrast, S. brasiliensis could have been submitted to purifying selection or expansion process.

Maturity-related Variability of the Thymus in Cynomolgus Monkeys (Macaca fascicularis).

Terminal body weights (TBWs), thymus weight parameters, and thymus morphology were retrospectively evaluated in 453 cynomolgus monkeys assigned to control groups on nonclinical toxicity studies. Morphology of bone, ovary, and testis/epididymis were used to determine maturity status of individual animals. There was no correlation between TBW and thymus weight (absolute and/or relative to TBW or brain weight). Thymus weight parameters and grades of decreased lymphocytes in the thymus were highly variable in immature animals compared to mature animals. There was also high (up to 11-fold) variability of thymus weight parameters within a given control group on the same study (generally 3 or 4 animals per sex). Several parameters evaluated had more pronounced age-related changes in males when compared to females. Our results demonstrate the inherent variability of thymus weight parameters and morphologic observations for cynomolgus monkeys on toxicology studies. Changes in thymus parameters in cynomolgus monkeys are unreliable indicators of immunomodulation or immunotoxicity in the absence of other relevant findings. Therefore, the thymus parameters commonly evaluated in preclinical safety assessments should not be the primary data set used to determine the presence of a direct test article-related effect on the immune system.

[Presence of lactoferrin (LF) in lymphocutaneous sporotrichosis. Yeast-bound antimicrobial peptide]. / Presencia de lactoferrina (LF) en la esporotricosis linfocutánea. Péptido antimicrobiano unido a levaduras.

Sporotrichosis is a common subcutaneous mycosis in Latin America, produced by dimorphic fungi belong to Sporothrix schenckii complex of cryptic species. Infection is acquired by traumatic inoculation with contaminated organic material. Host immune response includes polymorphonuclear neutrophils chemotaxis and release of granular components. Lactoferrin is a protein member of the transferrin family of iron-binding proteins, present inside polymorphonuclear granular structure, and has been reported to affect growth and development of infectious agents, including fungal organisms. Nevertheless, lactoferrin expression in sporotrichosis infections has not been reported yet. OBJECTIVE: To determine the expression of lactoferrin using immunohistochemical staining in sporotrichosis human infection. MATERIAL AND METHODS: The dermatology department's files during a period of five years were reviewed; cases with a diagnosis of sporotrichosis were selected and lactoferrin immunostaining was performed when enough biological material was available. RESULTS: Three cases with a diagnosis of sporotrichosis and adequate biological material on paraffin block were identified. In all cases, lactoferrin immunostaining was positive around yeast cell.

Nuclear Magnetic Resonance Characterization of the Type III Secretion System Tip Chaperone Protein PcrG of Pseudomonas aeruginosa.

Lung infection with Pseudomonas aeruginosa is the leading cause of death among cystic fibrosis patients. To initiate infection, P. aeruginosa assembles a protein nanomachine, the type III secretion system (T3SS), to inject bacterial proteins directly into target host cells. An important regulator of the P. aeruginosa T3SS is the chaperone protein PcrG, which forms a complex with the tip protein, PcrV. In addition to its role as a chaperone to the tip protein, PcrG also regulates protein secretion. PcrG homologues are also important in the T3SS of other pathogens such as Yersinia pestis, the causative agent of bubonic plague. The atomic structure of PcrG or any member of the family of tip protein chaperones is currently unknown. Here, we show by circular dichroism and nuclear magnetic resonance (NMR) spectroscopy that PcrG lacks a tertiary structure. However, it is not completely disordered but contains secondary structures dominated by two long α-helices from residue 16 to 41 and from residue 55 to 76. The helices of PcrG are partially formed, have similar backbone dynamics, and are flexible. NMR titrations show that the entire length of PcrG residues from position 9 to 76 is involved in binding to PcrV. PcrG adds to the growing list of partially folded or unstructured proteins with important roles in type III secretion.

K88 Fimbrial Adhesin Targeting of Microspheres Containing Gentamicin Made with Albumin Glycated with Lactose.

The formulation and characterization of gentamicin-loaded microspheres as a delivery system targeting enterotoxigenic Escherichia coli K88 (E. coli K88) was investigated. Glycated albumin with lactose (BSA-glucose-ß (4-1) galactose) was used as the microsphere matrix (MS-Lac) and gentamicin included as the transported antibiotic. The proposed target strategy was that exposed galactoses of MS-Lac could be specifically recognized by E. coli K88 adhesins, and the delivery of gentamicin would inhibit bacterial growth. Lactosylated microspheres (MS-Lac1, MS-Lac2 and MS-Lac3) were obtained using a water-in-oil emulsion, containing gentamicin, followed by crosslinking with different concentrations of glutaraldehyde. Electron microscopy displayed spherical particles with a mean size of 10-17 µm. In vitro release of gentamicin from MS-Lac was best fitted to a first order model, and the antibacterial activity of encapsulated and free gentamicin was comparable. MS-Lac treatments were recognized by plant galactose-specific lectins from Ricinus communis and Sophora japonica and by E. coli K88 adhesins. Results indicate MS-Lac1, produced with 4.2 mg/mL of crosslinker, as the best treatment and that lactosylated microsphere are promising platforms to obtain an active, targeted system against E. coli K88 infections.

Morphological findings of deep cutaneous fungal infections.

Cutaneous fungal infections used to be rare in most developed countries. However, they have become more common due to immunosuppression and globalization. In this report, we summarize the histopathologic findings of the main cutaneous fungal infections that are commonly seen in daily practice, including eumycetoma, sporotrichosis, histoplasmosis, cryptococcosis, coccidioidomycosis, aspergillosis, zygomycosis, phaeohyphomycosis, alternariosis, blastomycosis, paracoccidioidomycosis, lobomycosis, and chromoblastomycosis. We also include protothecosis (despite the fact that the infectious agent of this disease is algal and not fungal) and rhinosporidiosis (despite being caused by mesomycetozoea, which are not fungi).

Candida species isolation in peristomal skin in patients with abdominal stomas and correlation to clinical signs: a descriptive pilot study.

The reported prevalence of candidiasis in peristomal skin varies greatly. Very few studies exist that correlate the clinical findings around the peristomal skin to the mycology. In this study, the authors report on Candida species prevalence, clinical correlation, and mycology.

[Vaginal colonization by Candida spp. Frequency and description of the species isolated in asymptomatic women]. / Colonización vaginal por Candida spp. Frecuencia y descripción de las especies aisladas en mujeres asintomáticas.

BACKGROUND: During reproductive age 75% of women experience at least one episode of vulvovaginal candidiasis, approximately 6% to 55% of healthy women are asymptomatic carriers. In Mexico there are no current data of the frequency of vaginal colonization by Candida in the general population. OBJECTIVE: To determine the frequency of the colonization by Candida species in asymptomatic women. MATERIAL AND METHODS: A descriptive, open, observational, prospective, cross sectional study was carried out in adult women attending the cervical cytology department at Hospital General Dr. Manuel Gea González in Mexico City. The study was conducted from January to May 2013. RESULTS: There were a total of 150 samples of asymptomatic women between 15 and 77 years (mean 43 years). We obtained positive culture for Candida in 19 samples (12.6 %). 47% of the species corresponded to C. albicans, however, it was isolated other species such as C. krusei in 26%, C. glabrata (21%) and C. tropicalis by 15%. CONCLUSIONS: Our findings are consistent with data reported in the literature. It is relevant the isolation of non-albicans Candida species. These findings may be caused by an increase of inappropriate therapies.

[Atypical microbacteriosis: a report of two cases and review of the literature]. / Lipotransferencia complicada con micobacteriosis atípicas. Reporte de dos casos y revisión de la literatura.

Lipotransference is a technique that has evolved within the aesthetic and reconstructive surgery area to change body shape in the individual. However, it has been associated occasionally with infections of varying degrees of morbidity and mortality. We report two cases of patients who underwent abdominal and waist area lipotransference to buttocks, and who developed postoperative infection. Using polymerase chain reaction of DNA extracted from a tissue sample and from a culture, with subsequent sequencing, Mycobacterium chelonae and M. massiliense were identified as causative agents.

Assessment of Mechanically Induced Changes in Helical Fiber Microstructure Using Diffusion Tensor Imaging.

Noninvasive methods to detect microstructural changes in collagen-based fibrous tissues are necessary to differentiate healthy from damaged tissues in vivo but are sparse. Diffusion Tensor Imaging (DTI) is a noninvasive imaging technique used to quantitatively infer tissue microstructure with previous work primarily focused in neuroimaging applications. Yet, it is still unclear how DTI metrics relate to fiber microstructure and function in musculoskeletal tissues such as ligament and tendon, in part because of the high heterogeneity inherent to such tissues. To address this limitation, we assessed the ability of DTI to detect microstructural changes caused by mechanical loading in tissue-mimicking helical fiber constructs of known structure. Using high-resolution optical and micro-computed tomography imaging, we found that static and fatigue loading resulted in decreased sample diameter and a re-alignment of the macro-scale fiber twist angle similar with the direction of loading. However, DTI and micro-computed tomography measurements suggest microstructural differences in the effect of static versus fatigue loading that were not apparent at the bulk level. Specifically, static load resulted in an increase in diffusion anisotropy and a decrease in radial diffusivity suggesting radially uniform fiber compaction. In contrast, fatigue loads resulted in increased diffusivity in all directions and a change in the alignment of the principal diffusion direction away from the constructs' main axis suggesting fiber compaction and microstructural disruptions in fiber architecture. These results provide quantitative evidence of the ability of DTI to detect mechanically induced changes in tissue microstructure that are not apparent at the bulk level, thus confirming its potential as a noninvasive measure of microstructure in helically architected collagen-based tissues, such as ligaments and tendons.