[Primary care management of sexually transmitted infections (I). Epidemiology. Secreting syndrome]. / Manejo en atención primaria de las infecciones de transmisión sexual (I). Epidemiología. Síndrome secretor.

These days sexually transmitted infections (STIs) are important public health problems not only due to their high prevalence, but also because they require early diagnosis and treatment to avoid complications. In recent years, there has been an exponential increase in cases of infections caused by Chlamydia trachomatis and gonococcus in the population under 25years of age. In addition, an increase in the incidence of syphilis and hepatitisC (HCV) has also been detected, especially in men who have sex with other men (MSM). Genital herpes continues to be the second most frequent STI in the world, behind condyloma acuminata, and the first cause of genital ulcer among Spain in the sexually active population. A decrease in reported HIV cases was observed during 2020, but almost half of these new cases had a late diagnosis (<350CD4cell/µL). Current guidelines recommend offering STI annual screening to populations at risk or more often depending on the risk. STIs can appear in the form of syndromes, such as secretory syndrome (urethritis, proctitis, and cervicitis) or ulcerated syndrome (ulcers). The STIs that can cause secretory syndrome are mainly caused by Neisseria gonorrhoeae and C.trachomatis, which co-infect up to 40% of cases, and also cause urethritis, cervicitis or proctitis depending on where they are located. Gonococcus has an incubation period of 2-7days and Chlamydia 2-6weeks, and they are diagnosed using PCR and/or culture (the last one only valid for gonococcus) of samples collected according to sexual activities. Empirical treatment to cover both germs will be accomplished with ceftriaxone, 1g single intramuscular dose plus doxycycline 100mg every 12h orally for 7days, or azithromycin 1g single dose orally (we will use azithromycin only if we suspect a poor compliance with treatment, difficulty in going to the control or in pregnancy). Likewise, whenever we diagnose an STI firstly, we must offer advice and health education in order to promote the adoption of safe sexual behaviours and the correct use of barrier methods. Secondly, we must also screen for other STIs (HIV, syphilis, hepatitisB, and hepatitisA andC depending on the risk), offer HBV and HAV vaccination if it is appropriate, and finally study and treat all sexual partners from the previous 3months.

Failures of nerve regeneration caused by aging or chronic denervation are rescued by restoring Schwann cell c-Jun.

After nerve injury, myelin and Remak Schwann cells reprogram to repair cells specialized for regeneration. Normally providing strong regenerative support, these cells fail in aging animals, and during chronic denervation that results from slow axon growth. This impairs axonal regeneration and causes significant clinical problems. In mice, we find that repair cells express reduced c-Jun protein as regenerative support provided by these cells declines during aging and chronic denervation. In both cases, genetically restoring Schwann cell c-Jun levels restores regeneration to control levels. We identify potential gene candidates mediating this effect and implicate Shh in the control of Schwann cell c-Jun levels. This establishes that a common mechanism, reduced c-Jun in Schwann cells, regulates success and failure of nerve repair both during aging and chronic denervation. This provides a molecular framework for addressing important clinical problems, suggesting molecular pathways that can be targeted to promote repair in the PNS.

Neural crest Notch/Rbpj signaling regulates olfactory gliogenesis and neuronal migration.

The neural crest-derived ensheathing glial cells of the olfactory nerve (OECs) are unique in spanning both the peripheral and central nervous systems: they ensheathe bundles of axons projecting from olfactory receptor neurons in the nasal epithelium to their targets in the olfactory bulb. OECs are clinically relevant as a promising autologous cell transplantation therapy for promoting central nervous system repair. They are also important for fertility, being required for the migration of embryonic gonadotropin-releasing hormone (GnRH) neurons from the olfactory placode along terminal nerve axons to the medial forebrain, which they enter caudal to the olfactory bulbs. Like Schwann cell precursors, OEC precursors associated with the developing olfactory nerve express the glial marker myelin protein zero and the key peripheral glial transcription factor Sox10. The transition from Schwann cell precursors to immature Schwann cells is accelerated by canonical Notch signaling via the Rbpj transcription factor. Here, we aimed to test the role of Notch/Rbpj signaling in developing OECs by blocking the pathway in both chicken and mouse. Our results suggest that Notch/Rbpj signaling prevents the cranial neural crest cells that colonize the olfactory nerve from differentiating as neurons, and at later stages contributes to the guidance of GnRH neurons.

Evaluación de los parámetros de desempeño de un contador hematológico / Evaluation of performance parameters of an automated hematology analyzer / Avaliação dos parâmetros de desempenho de um analisador da hematologia

El primer paso para obtener seguridad en los resultados emitidos por el laboratorio clínico es confirmar que los procedimientos de medida utilizados tienen un desempeño analítico aceptable. Para conseguirlo se verificó el contador hematológico Beckman Coulter LH 750 de acuerdo con las especificaciones del fabricante y con los requisitos de calidad de este laboratorio. Los parámetros de desempeño evaluados, tanto en modo manual como automático, fueron: porcentaje de arrastre, según protocolo CLSI H26-A2, precisión en condiciones de repetibilidad, precisión en condiciones de precisión intermedia y veracidad, según protocolo CLSI EP15-A2 utilizando controles BIO-RAD, intervalo de medición, según protocolo CLSI EP6-A, límite de cuantificación, según protocolo CLSI EP17-A2 e intervalos de referencia, según protocolo CLSI EP28-A3C. Los datos se analizaron mediante LinChecker y GraphPad 5. En los ensayos realizados se cumplió con las especificaciones estipuladas por el fabricante, como así también con el requisito de calidad de este laboratorio que es variabilidad biológica mínima. También se verificaron los intervalos de referencia para individuos adultos. De esta manera, se logró realizar la verificación del contador hematológico, evidenciando que los parámetros analíticos evaluados tienen un desempeño aceptable.

The first step for safety in the results issued by the clinical laboratory is to confirm that all analytical measurement procedures have shown an acceptable analytical performance. A quality performance evaluation of automated hematology analyzer Beckman Coulter LH 750 was performed according to the quality requirements of our laboratory and manufacturer's specifications. The performance parameters evaluated by both manual and automatic mode were: carryover according to CLSI H26-A2 protocol; repeatability, intermediate precision and trueness according to CLSI EP15-A2 protocol and using BIO-RAD controls; linearity according to CLSI EP6-A protocol; quantification limits according to CLSI EP17-A2 protocol; and reference intervals according to CLSI EP28-A3C protocol. Data were analyzed using LinChecker and GraphPad5 programs. The tests performed complied with the requirements stipulated by the manufacturer and the quality requirements of our laboratory like minimal biological variability. Reference intervals for adult individuals were also checked. Consequently, performance evaluation of the automated hematology analyzer showed that the assessed laboratory parameters have acceptable performance.

O primeiro passo para obter segurança nos resultados emitidos pelo laboratório clínico é confirmar que os processos de medição utilizados tenham um desempenho analítico aceitável. Para obtê-los foi verificado o analisador hematológico Beckman Coulter LH 750 de acordo com as especificações do fabricante e os requisitos de qualidade deste laboratório. Os parâmetros de desempenho avaliados, tanto em modo manual quanto automático, foram: percentual de arrastamento, de acordo com o protocolo CLSI H26-A2, em condições de repetitibidade, precisão em condições de precisão intermediária e veracidade, conforme o protocolo CLSI EP15-A2 usando controles Bio-Rad, intervalo de medição segundo o protocolo CLSI EP6-A, limite de quantificação, de acordo com CLSI EP- 17-A2 e intervalos de referência, de acordo com o protocolo CLSI EP28-A3C. Os dados foram analisados através de LinChecker e GraphPad 5. Nos ensaios realizados foram obsevadas as especificações estabelecidas pelo fabricante, bem como a exigência de qualidade deste laboratório que é variabilidade biológica mínima. Os intervalos de referência para indivíduos adultos também foram verificados. Desta forma, foi possível realizar a verificação do analisador hematológico, que demonstra que os parâmetros analíticos avaliados têm um desempenho aceitável.

Cannabidiol reduces lipopolysaccharide-induced vascular changes and inflammation in the mouse brain: an intravital microscopy study.

BACKGROUND: The phytocannabinoid cannabidiol (CBD) exhibits antioxidant and antiinflammatory properties. The present study was designed to explore its effects in a mouse model of sepsis-related encephalitis by intravenous administration of lipopolysaccharide (LPS). METHODS: Vascular responses of pial vessels were analyzed by intravital microscopy and inflammatory parameters measured by qRT-PCR. RESULTS: CBD prevented LPS-induced arteriolar and venular vasodilation as well as leukocyte margination. In addition, CBD abolished LPS-induced increases in tumor necrosis factor-alpha and cyclooxygenase-2 expression as measured by quantitative real time PCR. The expression of the inducible-nitric oxide synthase was also reduced by CBD. Finally, preservation of Blood Brain Barrier integrity was also associated to the treatment with CBD. CONCLUSIONS: These data highlight the antiinflammatory and vascular-stabilizing effects of CBD in endotoxic shock and suggest a possible beneficial effect of this natural cannabinoid.

The activation of cannabinoid CB2 receptors stimulates in situ and in vitro beta-amyloid removal by human macrophages.

The endocannabinoid system is a promising therapeutic target in a wide variety of diseases. However, the non-desirable psychotropic effects of natural and synthetic cannabinoids have largely counteracted their clinical usefulness. These effects are mostly mediated by cannabinoid receptors of the CB(1) type, that exhibit a wide distribution in neuronal elements of the CNS. Thus, the presence of other elements of this system in the CNS, such as CB(2) receptors, may open new possibilities for the development of cannabinoid-based therapies. These receptors are almost absent from the CNS in normal conditions but are up-regulated in glial cells under chronic neuroinflammatory stimuli, as has been described in Alzheimer's disease. To understand the functional role of these receptors, we tested their role in the process of beta-amyloid removal, that is currently considered as one of the most promising experimental approaches for the treatment of this disease. Our results show that a CB(2) agonist (JWH-015) is capable of inducing the removal of native beta-amyloid removal from human frozen tissue sections as well as of synthetic pathogenic peptide by a human macrophage cell line (THP-1). Remarkably, this effect was achieved at low doses (maximum effect at 10 nM) and was specific for this type of cells, as U373MG astrocytoma cells did not respond to the treatment. The effect was CB(2)-mediated, at least partially, as the selective CB(2) antagonist SR144528 prevented the JWH-015-induced plaque removal in situ. These data corroborate the possible therapeutic interest of CB(2) cannabinoid specific chemicals in the treatment of Alzheimer's disease.

Cannabinoid CB2 receptor agonists protect the striatum against malonate toxicity: relevance for Huntington's disease.

Cannabinoid agonists might serve as neuroprotective agents in neurodegenerative disorders. Here, we examined this hypothesis in a rat model of Huntington's disease (HD) generated by intrastriatal injection of the mitochondrial complex II inhibitor malonate. Our results showed that only compounds able to activate CB2 receptors were capable of protecting striatal projection neurons from malonate-induced death. That CB2 receptor agonists are neuroprotective was confirmed by using the selective CB2 receptor antagonist, SR144528, and by the observation that mice deficient in CB2 receptor were more sensitive to malonate than wild-type animals. CB2 receptors are scarce in the striatum in healthy conditions, but they are markedly upregulated after the lesion with malonate. Studies of double immunostaining revealed a significant presence of CB2 receptors in cells labeled with the marker of reactive microglia OX-42, and also in cells labeled with GFAP (a marker of astrocytes). We further showed that the activation of CB2 receptors significantly reduced the levels of tumor necrosis factor-alpha (TNF-alpha) that had been increased by the lesion with malonate. In summary, our results demonstrate that stimulation of CB2 receptors protect the striatum against malonate toxicity, likely through a mechanism involving glial cells, in particular reactive microglial cells in which CB2 receptors would be upregulated in response to the lesion. Activation of these receptors would reduce the generation of proinflammatory molecules like TNF-alpha. Altogether, our results support the hypothesis that CB2 receptors could constitute a therapeutic target to slowdown neurodegeneration in HD.

The CB(2) cannabinoid receptor controls myeloid progenitor trafficking: involvement in the pathogenesis of an animal model of multiple sclerosis.

Cannabinoids are potential agents for the development of therapeutic strategies against multiple sclerosis. Here we analyzed the role of the peripheral CB(2) cannabinoid receptor in the control of myeloid progenitor cell trafficking toward the inflamed spinal cord and their contribution to microglial activation in an animal model of multiple sclerosis (experimental autoimmune encephalomyelitis, EAE). CB(2) receptor knock-out mice showed an exacerbated clinical score of the disease when compared with their wild-type littermates, and this occurred in concert with extended axonal loss, T-lymphocyte (CD4(+)) infiltration, and microglial (CD11b(+)) activation. Immature bone marrow-derived CD34(+) myeloid progenitor cells, which play a role in neuroinflammatory pathologies, were shown to express CB(2) receptors and to be abundantly recruited toward the spinal cords of CB(2) knock-out EAE mice. Bone marrow-derived cell transfer experiments further evidenced the increased contribution of these cells to microglial replenishment in the spinal cords of CB(2)-deficient animals. In line with these observations, selective pharmacological CB(2) activation markedly reduced EAE symptoms, axonal loss, and microglial activation. CB(2) receptor manipulation altered the expression pattern of different chemokines (CCL2, CCL3, CCL5) and their receptors (CCR1, CCR2), thus providing a mechanistic explanation for its role in myeloid progenitor recruitment during neuroinflammation. These findings demonstrate the protective role of CB(2) receptors in EAE pathology; provide evidence for a new site of CB(2) receptor action, namely the targeting of myeloid progenitor trafficking and its contribution to microglial activation; and support the potential use of non-psychoactive CB(2) agonists in therapeutic strategies for multiple sclerosis and other neuroinflammatory disorders.

Cannabinoid CB1 receptors are expressed by parietal cells of the human gastric mucosa.

Experimental data suggest that the endogenous cannabinoid system is involved in gastric function in different animal species. In most of them, CB(1) receptors have been localized on vagal terminals innervating the external wall of the stomach. We aimed at studying the putative presence and distribution of these receptors in the human gastric mucosa. To this end, we first performed Western blotting, RT-PCR, in situ hybridization, and immunohistochemical analysis of CB(1) protein distribution in biopsy samples of healthy individuals. To determine the precise cell populations expressing CB(1) receptors, we performed double immunofluorescence plus confocal microscopy analysis of the same samples. Our results show that CB(1) receptors are present in the gastric epithelium of the mucosa. Specifically, they are expressed by a subpopulation of mucosal cells, the acid-secreting parietal cells, as shown by double immunohistochemical staining and by their differential abundance in subregions of the gastric mucosa. These results reinforce the notion of a prominent role for the endocannabinoid system in the gastric function in humans and postulate the use of cannabinoid CB(1) receptors in parietal cells as new therapeutic targets for the regulation of gastric acid production.