EphrinA2 receptor (EphA2) is an invasion and intracellular signaling receptor for Chlamydia trachomatis.

The obligate intracellular bacterium Chlamydia trachomatis invades into host cells to replicate inside a membrane-bound vacuole called inclusion. Multiple different host proteins are recruited to the inclusion and are functionally modulated to support chlamydial development. Invaded and replicating Chlamydia induces a long-lasting activation of the PI3 kinase signaling pathway that is required for efficient replication. We identified the cell surface tyrosine kinase EphrinA2 receptor (EphA2) as a chlamydial adherence and invasion receptor that induces PI3 kinase (PI3K) activation, promoting chlamydial replication. Interfering with binding of C. trachomatis serovar L2 (Ctr) to EphA2, downregulation of EphA2 expression or inhibition of EphA2 activity significantly reduced Ctr infection. Ctr interacts with and activates EphA2 on the cell surface resulting in Ctr and receptor internalization. During chlamydial replication, EphA2 remains active accumulating around the inclusion and interacts with the p85 regulatory subunit of PI3K to support the activation of the PI3K/Akt signaling pathway that is required for normal chlamydial development. Overexpression of full length EphA2, but not the mutant form lacking the intracellular cytoplasmic domain, enhanced PI3K activation and Ctr infection. Despite the depletion of EphA2 from the cell surface, Ctr infection induces upregulation of EphA2 through the activation of the ERK pathway, which keeps the infected cell in an apoptosis-resistant state. The significance of EphA2 as an entry and intracellular signaling receptor was also observed with the urogenital C. trachomatis-serovar D. Our findings provide the first evidence for a host cell surface receptor that is exploited for invasion as well as for receptor-mediated intracellular signaling to facilitate chlamydial replication. In addition, the engagement of a cell surface receptor at the inclusion membrane is a new mechanism by which Chlamydia subverts the host cell and induces apoptosis resistance.

Dynamin-mediated lipid acquisition is essential for Chlamydia trachomatis development.

Chlamydia trachomatis is an obligate intracellular pathogen responsible for a high burden of human disease. Here, a loss-of-function screen using a set of lentivirally transduced shRNAs identified 14 human host cell factors that modulate C. trachomatis infectivity. Notably, knockdown of dynamin, a host GTPase, decreased C. trachomatis infectivity. Dynamin functions in multiple cytoplasmic locations, including vesicle formation at the plasma membrane and the trans-Golgi network. However, its role in C. trachomatis infection remains unclear. Here we report that dynamin is essential for homotypic fusion of C. trachomatis inclusions but not for C. trachomatis internalization into the host cell. Further, dynamin activity is necessary for lipid transport into C. trachomatis inclusions and for normal re-differentiation from reticulate to elementary bodies. Fragmentation of the Golgi apparatus is proposed to be an important strategy used by C. trachomatis for efficient lipid acquisition and replication within the host. Here we show that a subset of C. trachomatis-infected cells displayed Golgi fragmentation, which was concurrent with increased mitotic accumulation. Golgi fragmentation was dispensable for dynamin-mediated lipid acquisition into C. trachomatis inclusions, irrespective of the cell cycle phase. Thus, our study reveals a critical role of dynamin in host-derived lipid acquisition for C. trachomatis development.

Chlamydia trachomatis remodels stable microtubules to coordinate Golgi stack recruitment to the chlamydial inclusion surface.

Chlamydia trachomatis (Ctr), an obligate intracellular bacterium, survives and replicates within a membrane-bound vacuole, termed the inclusion, which intercepts host exocytic pathways to acquire nutrients. Ctr subverts cellular trafficking pathways from the Golgi by targeting small GTPases, including Rab proteins, to sustain intracellular bacterial replication; however, the precise mechanisms involved remain incompletely understood. Here, we show that Chlamydia infection in human epithelial cells induces microtubule remodeling, in particular the formation of detyrosinated stable MTs, to recruit Golgi ministacks, but not recycling endosomes, to the inclusion. These stable microtubules show increased resistance to chemically induced depolymerization, and their selective depletion results in reduced bacterial infectivity. Rab6 knockdown reversibly prevented not only Golgi ministack formation but also detyrosinated microtubule association with the inclusion. Our data demonstrate that Chlamydia co-opts the function of stable microtubules to support its development.

Targeting the proteasome: partial inhibition of the proteasome by bortezomib or deletion of the immunosubunit LMP7 attenuates experimental colitis.

BACKGROUND AND AIMS: Inflammatory bowel disease (IBD), comprising Crohn s disease and ulcerative colitis, is characterised by chronic relapsing inflammation of the gut. Increased proteasome activity, associated with the expression of immunoproteasomes, was found to enhance proinflammatory signalling and thus promotes inflammation in patients with IBD. The aim of this study was to explore whether modulation of the proteasomal activity is a suitable therapeutic approach to limit inflammation in colitis. METHODS: This concept was assessed in two different experimental set-ups. Development of dextran sodium sulfate (DSS)-induced colitis was tested (1) in lmp7(-/-) mice lacking the immunoproteasome subunit LMP7 and (2) in wild-type (WT) mice treated with the proteasome inhibitor bortezomib. RESULTS: Compared with WT mice, lmp7(-/-) mice develop significantly attenuated colitis due to reduced nuclear factor-kappaB (NF-kappaB) signalling in the absence of LMP7. Further, treatment with bortezomib revealed dose-dependent amelioration of DSS-induced inflammation. In both approaches modulation of the proteasome activity limited the secretion of proinflammatory cytokines and chemokines. Consequently, infiltration of the colon by neutrophils and expansion of inflammatory T helper 1 (Th1) and Th17 T cells was diminished and thus prevented excessive tissue damage. CONCLUSIONS: It was demonstrated that modulation of the proteasome activity is effective in attenuating experimental colitis. The results reveal that reduction of the proteasome activity either by partial inhibition with bortezomib or by specifically targeting the immunoproteasome subunit LMP7 is a suitable treatment of intestinal inflammation.

[Results and complications following the placement of the transobturator tension free tape for the treatment of stress urinary incontinence]. / Resultados y complicaciones posteriores a la colocación de la cinta transobturadora libre de tensión en el tratamiento de pacientes con incontinencia urinaria de esfuerzo.

OBJECTIVE: Evaluate the complications and short term sucess rate of the transobturator tape for the treatment of stress urinary incontinence. MATERIAL AND METHODS: It is a retrospective study of the transobturator tapes perform in 2005 and 2006. All the procedures were done with epidural anesthesia. The success rate, the immediate, short-term and long term complications were recorded at the first, second and third year. RESULTS: 28 women were included in the study, 54% of them with stress urinary incontinence. 25% were solely transobturator procedures. mong the complications were 2 vesical puntures, 1 periurethral fascia trauma and 5 urinary retention during the first 24 hours. In the 1 and 2 year follow-up were 2 cases of overactive detrusor. Objective sucess was 90% and subjective sucess was 92%. CONCLUSIONS: Transobturator tape is a highly successful and a low morbility procedure.

Neuropharmacological effects of d-pinitol and its possible mechanisms of action.

The aim was to evaluate the diuretic and neuropharmacological actions of d-pinitol and describe a possible mechanism of action. The diuretic effects of d-pinitol were evaluated using mice placed in metabolic cages. The sedative, anxiolytic-like, antidepressant-like, and anticonvulsant effects of 1-100 mg/kg d-pinitol were assessed. The possible mechanisms of action of the anxiolytic-like, antidepressant-like, and anticonvulsant effects of d-pinitol were evaluated using inhibitors. d-pinitol lacked diuretic effects. However, d-pinitol showed the highest anxiolytic-like actions (ED50  = 70 mg/kg p.o. in mice) in the cylinder exploratory test and the highest antidepressant-like activity in the forced swimming test (ED50  = 26 mg/kg p.o. in mice). d-pinitol (100 mg/kg) exerted anticonvulsant actions in the pentylenetetrazole-induced seizures test. The pre-treatment with 2 mg/kg flumazenil reverted the anxiolytic-like actions and the anticonvulsant effects of d-pinitol, whereas the pre-treatment with 1 mg/kg yohimbine and 0.05 mg/kg prazosin abolished the antidepressant effects of d-pinitol. PRACTICAL APPLICATIONS: d-pinitol (3-O-methyl-d-chiro-inositol) is a polyol found in many fruits, as well as in many members of the Leguminosae and Fabaceae families. The results propose that this compound could contribute in the treatment of anxiety, depression, and convulsions. The findings suggest the possible participation of the GABAergic system in the anxiolytic-like and anticonvulsant actions of d-pinitol, whereas the noradrenergic system is probably involved in the antidepressant effects of d-pinitol. This study provides new information about other pharmacological uses for d-pinitol.

Combined Human Genome-wide RNAi and Metabolite Analyses Identify IMPDH as a Host-Directed Target against Chlamydia Infection.

Chlamydia trachomatis (Ctr) accounts for >130 million human infections annually. Since chronic Ctr infections are extremely difficult to treat, there is an urgent need for more effective therapeutics. As an obligate intracellular bacterium, Ctr strictly depends on the functional contribution of the host cell. Here, we combined a human genome-wide RNA interference screen with metabolic profiling to obtain detailed understanding of changes in the infected cell and identify druggable pathways essential for Ctr growth. We demonstrate that Ctr shifts the host metabolism toward aerobic glycolysis, consistent with increased biomass requirement. We identify key regulator complexes of glucose and nucleotide metabolism that govern Ctr infection processes. Pharmacological targeting of inosine-5'-monophosphate dehydrogenase (IMPDH), the rate-limiting enzyme in guanine nucleotide biosynthesis, efficiently inhibits Ctr growth both in vitro and in vivo. These results highlight the potency of genome-scale functional screening for the discovery of drug targets against bacterial infections.

Niveles de presión arterial en adultos indígenas Yanomami del Estado Amazonas, Venezuela / Blood pressure levels in Yanomami indigenous adults from the State of Amazonas, Venezuela

Introducción: Existen poblaciones que por razones aún no completamente estudiadas y comprendidas presentan niveles de presión arterial óptimos que determinan la ausencia de morbilidad y mortalidad relacionada con las afecciones cardiovasculares. Objetivo: Determinar los niveles de presión arterial de adultos indígenas Yanomami ubicados en la serranía de Topirapecó en el Estado Amazonas en Venezuela. Métodos: Entre los meses de mayo a julio y diciembre de 2021, se realizó un estudio cuantitativo transversal en 271 adultos indígenas Yanomami de 20 años de edad o más. Se visitó en 2 ocasiones cada shabono con la finalidad de realizarle medición de la presión arterial. Las orientaciones para cumplir con el protocolo de medición de presión arterial fueron impartidas en el idioma original de los Yanomami con el apoyo de un Agente Comunitario Yanomami de Atención Primaria de Salud. El análisis estadístico incluyó promedios, porcentajes e intervalos de confianza para promedios y para porcentajes. Resultados: El 93% de los individuos presentaron valores de presión arterial óptimos (<120 y <80) y 5,5% PA normal (<130 y <85). Solo se presentaron 2 casos (0,7%) con HTA (Grado I). Los niveles promedios de PAS, PAD y PAM fueron 93,10 (±11,70); 60,66 (±9,87) y 71,48 (±9,77) mm Hg, respectivamente. Conclusiones: Los Yanomami que viven en comunidades del área geográfica de la serranía de Tapirapecó presentan niveles óptimos de presión arterial, lo que les previene de comorbilidad asociada a la HTA, lo que indica que no constituye un problema de salud emergente entre los Yanomami (AU)

Personal and professional use of menopausal hormone therapy among gynecologists: A multinational study (REDLINC VII).

BACKGROUND: Previously, the REDLINC VI study showed that the main reason for the low use of menopausal hormone therapy (MHT) was its low rate of prescription by doctors. OBJECTIVE: To determine the use of MHT and perceived related risks among gynecologists. METHODS: A self-administered and anonymous questionnaire was delivered to certified gynecologists in 11 Latin American countries. RESULTS: A total of 2154 gynecologists were contacted, of whom 85.3% responded to the survey (n = 1837). Mean age was 48.1 ± 11.4 years; 55.5% were male, 20.3% were faculty members and 85% had a partner. Overall, 85.4% of gynecologists responded that they would use MHT if they had menopausal symptoms (81.8% in the case of female gynecologists) or prescribe it to their partner (88.2% in the case of male gynecologists; p < 0.001). Perceived risk related to MHT use (on a scale from 0 to 10) was higher among female than among male gynecologists (4.06 ± 2.09 vs. 3.83 ± 2.11, p < 0.02). The top two perceived reported risks were thromboembolism (women 33.6% vs. men 41.4%, p < 0.009) and breast cancer (women 38.5% vs. men 33.9%, p < 0.03). Overall, gynecologists reported prescribing MHT to 48.9% of their symptomatic patients (women 47.3% vs. men 50.2%, p < 0.03) and 86.8% currently prescribed non-hormonal remedies and 83.8% alternative therapies for the management of the menopause. Gynecologists who were older and academic professionals prescribed MHT more often. CONCLUSION: Although this Latin American survey showed that gynecologists are mostly supporters of MHT use (for themselves or their partners), this is not necessarily reflected in their clinical practice.

Vesícula en porcelana: un interesante hallazgo incidental. Presentación de un caso y revisión de la literatura / Porcelain gallbladder an interesting incidental finding. Case report and literature review / Vesícula em porcelana: um achado incidental interessante. Apresentação de caso e revisão de literatura

RESUMEN Se realizó la comunicación de un caso recientemente diagnosticado en el Hospital Docente Clínico Quirúrgico "Joaquín Albarrán" de La Habana. El caso que se presenta correspondió con un paciente masculino de 73 años de edad que en el estudio autópsico se reveló la presencia de vesícula en porcelana, la cual, según la literatura, su identificación es un diagnóstico incidental durante el estudio del paciente por otro padecimiento, en su mayoría neoplásico o en la autopsia. Su relación con el cáncer de vesícula presenta controversias. La vesícula en porcelana es una entidad caracterizada por la calcificación intramural de la vesícula, tiene una incidencia reportada de 0,06 a 0,8 % de las colecistectomías realizadas. Se realizó revisión de la literatura en bases de datos, MEDLINE, PubMed, ELSEVIER y SciELO, con un total de 26 publicaciones encontradas entre 1999 y 2018.

ABSTRACT The communication of a newly diagnosed case was carried out at the "Joaquín Albarrán" Surgical Clinical Teaching Hospital in Havana. The case presented corresponded with a 73-year-old male patient who in the autopsy study revealed the presence of a porcelain gallbladder, which, according to the literature, its identification is an incidental diagnosis during the study of the patient for another condition, mostly neoplastic or at autopsy. His relationship with gallbladder cancer is controversial. The porcelain gallbladder is an entity characterized by intramural gallbladder calcification, has a reported incidence of 0.06 to 0.8% of the cholecystectomies performed. We reviewed the literature in databases, MEDLINE, PubMed, ELSEVIER and SciELO, with a total of 26 publications found between 1999 and 2018.

RESUMO A comunicação de um caso recentemente diagnosticado foi realizada no Hospital de Ensino Clínico Cirúrgico "Joaquín Albarrán", em Havana. O caso apresentado correspondeu a um paciente do sexo masculino, 73 anos, que no estudo de autópsia revelou a presença de uma vesícula na porcelana, a qual, segundo a literatura, sua identificação é um diagnóstico incidental durante o estudo do paciente para outra condição, principalmente neoplásico ou na autópsia. Sua relação com o câncer de vesícula biliar é controversa. A vesícula biliar de porcelana é uma entidade caracterizada pela calcificação intramural da vesícula biliar, com incidência relatada de 0,06 a 0,8% das colecistectomias realizadas. Revisamos a literatura nas bases de dados MEDLINE, PubMed, ELSEVIER e SciELO, com um total de 26 publicações encontradas entre 1999 e 2018.

Recombinant bacteriophage-based multiepitope vaccine against Taenia solium pig cysticercosis.

The aim of this study was to test the capacity of recombinant phages to deliver antigens for vaccination against porcine cysticercosis. Thus, three peptides (KETc1, KETc12, GK1) and a recombinant antigen KETc7, previously proven to induce high levels of protection against pig cysticercosis, were expressed on the surface of the M13 bacteriophage at multiple copies. The pool of these four recombinant phages induced high levels of protection against an experimental murine cysticercosis. The immunogenicity of the phage vaccine preparation was therefore, tested in pigs, the natural host of Taenia solium. Subcutaneous or oral vaccination with these phages induced antigen-specific cellular immune responses in pigs. Preliminary data also points to the protective capacity of this recombinant phage vaccine against pig cysticercosis. The immunogenicity of these recombinant phages, together with the low cost of their production, make them a realistic candidate to be tested in pigs as an anti-cysticercus phage vaccine for field trials. This is the first report describing the application of a filamentous bacteriophage as a vaccine in large animals such as pigs, the only intermediate hosts of T. solium, a parasite of major medical importance in developing countries. The potential application of phages as a modern platform for vaccines for human and animal diseases is discussed.

Chlamydia infection depends on a functional MDM2-p53 axis.

Chlamydia, a major human bacterial pathogen, assumes effective strategies to protect infected cells against death-inducing stimuli, thereby ensuring completion of its developmental cycle. Paired with its capacity to cause extensive host DNA damage, this poses a potential risk of malignant transformation, consistent with circumstantial epidemiological evidence. Here we reveal a dramatic depletion of p53, a tumor suppressor deregulated in many cancers, during Chlamydia infection. Using biochemical approaches and live imaging of individual cells, we demonstrate that p53 diminution requires phosphorylation of Murine Double Minute 2 (MDM2; a ubiquitin ligase) and subsequent interaction of phospho-MDM2 with p53 before induced proteasomal degradation. Strikingly, inhibition of the p53-MDM2 interaction is sufficient to disrupt intracellular development of Chlamydia and interferes with the pathogen's anti-apoptotic effect on host cells. This highlights the dependency of the pathogen on a functional MDM2-p53 axis and lends support to a potentially pro-carcinogenic effect of chlamydial infection.

Limited English proficient HMO enrollees remain vulnerable to communication barriers despite language assistance regulations.

HMO enrollees with limited English proficiency, and particularly those in poorer health, face communication barriers despite language assistance regulations. More than 1.3 million California HMO enrollees ages 18 to 64 do not speak English well enough to communicate with medical providers and may experience reduced access to high-quality health care if they do not receive appropriate language assistance services. Based on analysis of the 2007 and 2009 California Health Interview Surveys (CHIS), commercial HMO enrollees with limited English proficiency (LEP) in poorer health are more likely to have difficulty understanding their doctors, placing this already vulnerable population at even greater risk. The analysis also uses CHIS to examine the potential impact of health plan monitoring starting in 2009 (due to a 2003 amendment to the Knox-Keene Health Care Services Act) requiring health plans to provide free qualified interpretation and translation services to HMO enrollees. The authors recommend that California's health plans continue to incorporate trained interpreters into their contracted networks and delivery systems, paying special attention to enrollees in poorer health. The results may serve as a planning tool for health plans, providing a detailed snapshot of enrollee characteristics that will help design effective programs now and prepare for a likely increase in insured LEP populations in the future, as full implementation of the Affordable Care Act takes place over the next decade.

Isolation of neurocysticercosis-related antigens from a genomic phage display library of Taenia solium.

In this study, the authors have generated a tapeworm Taenia solium genomic DNA expression library where foreign peptides/proteins were fused to N-termini of M13 cpVIII and expressed at a high copy number on the phage surface, and they showed that this library may be used in bioselection against antipathogen immune sera, allowing the identification of disease-related antigens recognizing antibodies present in clinical samples. They isolated 2 phage clones expressing T. solium-derived antigens specifically reacting with antibodies present in plasma and cerebrospinal fluid samples of neuroimaging-confirmed neurocysticercosis patients. The described antigen discovery strategy may be used for the direct identification of antigens useful for host-pathogen interaction studies as well as for the development of molecular vaccines and diagnostics.

Isolation of the Taenia crassiceps antigens from a phage display cDNA library and evaluation of their use for diagnosis of neurocysticercosis.

A novel cDNA cloning strategy consisting in elimination of non-coding DNA sequences from 3' regions of cDNAs was applied to construct the Taenia crassiceps phage displayed cDNA expression library. After biopanning using immune sera, three phage clones expressing T. crassiceps-derived antigens specifically recognizing antibodies present in cerebrospinal fluid and plasma samples from neuroimaging-confirmed neurocysticercosis patients were selected. This novel cloning strategy may be applied to other pathogens allowing rapid identification of peptides/proteins for immunodiagnostic tests.