NAD+ prevents septic shock-induced death by non-canonical inflammasome blockade and IL-10 cytokine production in macrophages.

Septic shock is characterized by an excessive inflammatory response depicted in a cytokine storm that results from invasive bacterial, fungi, protozoa, and viral infections. Non-canonical inflammasome activation is crucial in the development of septic shock promoting pyroptosis and proinflammatory cytokine production via caspase-11 and gasdermin D (GSDMD). Here, we show that NAD+ treatment protected mice toward bacterial and lipopolysaccharide (LPS)-induced endotoxic shock by blocking the non-canonical inflammasome specifically. NAD+ administration impeded systemic IL-1ß and IL-18 production and GSDMD-mediated pyroptosis of macrophages via the IFN-ß/STAT-1 signaling machinery. More importantly, NAD+ administration not only improved casp-11 KO (knockout) survival but rendered wild type (WT) mice completely resistant to septic shock via the IL-10 signaling pathway that was independent from the non-canonical inflammasome. Here, we delineated a two-sided effect of NAD+ blocking septic shock through a specific inhibition of the non-canonical inflammasome and promoting immune homeostasis via IL-10, underscoring its unique therapeutic potential.

Inhibition of Toxic Shock Syndrome-Associated Staphylococcus aureus by Probiotic Lactobacilli.

Staphylococcus aureus is a human pathogen with many infections originating on mucosal surfaces. One common group of S. aureus is the USA200 (CC30) clonal group, which produces toxic shock syndrome toxin-1 (TSST-1). Many USA200 infections occur on mucosal surfaces, particularly in the vagina and gastrointestinal tract. This allows these organisms to cause cases of menstrual TSS and enterocolitis. The current study examined the ability of two lactobacilli, Lactobacillus acidophilus strain LA-14 and Lacticaseibacillus rhamnosus strain HN001, for their ability to inhibit the growth of TSST-1 positive S. aureus, the production of TSST-1, and the ability of TSST-1 to induce pro-inflammatory chemokines from human vaginal epithelial cells (HVECs). In competition growth experiments, L. rhamnosus did not affect the growth of TSS S. aureus but did inhibit the production of TSST-1; this effect was partially due to acidification of the growth medium. L. acidophilus was both bactericidal and prevented the production of TSST-1 by S. aureus. This effect appeared to be partially due to acidification of the growth medium, production of H2O2, and production of other antibacterial molecules. When both organisms were incubated with S. aureus, the effect of L. acidophilus LA-14 dominated. In in vitro experiments with HVECs, neither lactobacillus induced significant production of the chemokine interleukin-8, whereas TSST-1 did induce production of the chemokine. When the lactobacilli were incubated with HVECs in the presence of TSST-1, the lactobacilli reduced chemokine production. These data suggest that these two bacteria in probiotics could reduce the incidence of menstrual and enterocolitis-associated TSS. IMPORTANCE Toxic shock syndrome (TSS) Staphylococcus aureus commonly colonize mucosal surfaces, giving them the ability to cause TSS through the action of TSS toxin-1 (TSST-1). This study examined the ability of two probiotic lactobacilli to inhibit S. aureus growth and TSST-1 production, and the reduction of pro-inflammatory chemokine production by TSST-1. Lacticaseibacillus rhamnosus strain HN001 inhibited TSST-1 production due to acid production but did not affect S. aureus growth. Lactobacillus acidophilus strain LA-14 was bactericidal against S. aureus, partially due to acid and H2O2 production, and consequently also inhibited TSST-1 production. Neither lactobacillus induced the production of pro-inflammatory chemokines by human vaginal epithelial cells, and both inhibited chemokine production by TSST-1. These data suggest that the two probiotics could reduce the incidence of mucosa-associated TSS, including menstrual TSS and cases originating as enterocolitis.

Angiotensin II for treating vasosuppressor-resistant hypotension caused by septic or distributive shock (terminated appraisal)

NICE is unable to make a recommendation on angiotensin II for treating vasosuppressor-resistant hypotension caused by septic or distributive shock. This is because Paion AG did not provide an evidence submission. We will review this decision if the company decides to make a submission.

Activation of GPR75 Signaling Pathway Contributes to the Effect of a 20-HETE Mimetic, 5,14-HEDGE, to Prevent Hypotensive and Tachycardic Responses to Lipopolysaccharide in a Rat Model of Septic Shock.

ABSTRACT: The orphan receptor, G protein-coupled receptor (GPR) 75, which has been shown to mediate various effects of 20-hydroxyeicosatetraenoic acid (20-HETE), is considered as a therapeutic target in the treatment of cardiovascular diseases in which changes in the production of 20-HETE play a key role in their pathogenesis. Our previous studies showed that 20-HETE mimetic, N -(20-hydroxyeicosa-5[Z],14[Z]-dienoyl)glycine (5,14-HEDGE), protects against vascular hyporeactivity, hypotension, tachycardia, and arterial inflammation induced by lipopolysaccharide (LPS) in rats. This study tested the hypothesis that the GPR75 signaling pathway mediates these effects of 5,14-HEDGE in response to systemic exposure to LPS. Mean arterial pressure reduced by 33 mm Hg, and heart rate increased by 102 beats/min at 4 hours following LPS injection. Coimmunoprecipitation studies demonstrated that (1) the dissociation of GPR75/Gα q/11 and GPR kinase interactor 1 (GIT1)/protein kinase C (PKC) α, the association of GPR75/GIT1, large conductance voltage and calcium-activated potassium subunit ß (MaxiKß)/PKCα, MaxiKß/proto-oncogene tyrosine-protein kinase (c-Src), and epidermal growth factor receptor (EGFR)/c-Src, MaxiKß, and EGFR tyrosine phosphorylation were decreased, and (2) the association of GIT1/c-Src was increased in the arterial tissues of rats treated with LPS. The LPS-induced changes were prevented by 5,14-HEDGE. N -[20-Hydroxyeicosa-6( Z ),15( Z )-dienoyl]glycine, a 20-HETE antagonist, reversed the effects of 5,14-HEDGE in the arterial tissues of LPS-treated rats. Thus, similar to 20-HETE, by binding to GPR75 and activating the Gα q/11 /PKCα/MaxiKß, GIT1/PKCα/MaxiKß, GIT1/c-Src/MaxiKß, and GIT1/c-Src/EGFR signaling pathways, 5,14-HEDGE may exert its protective effects against LPS-induced hypotension and tachycardia associated with vascular hyporeactivity and arterial inflammation.

Centrally administered butyrate improves gut barrier function, visceral sensation and septic lethality in rats.

Short chain fatty acids readily crosses the gut-blood and blood-brain barrier and acts centrally to influence neuronal signaling. We hypothesized that butyrate, a short-chain fatty acid produced by bacterial fermentation, in the central nervous system may play a role in the regulation of intestinal functions. Colonic permeability and visceral sensation was evaluated in rats. Septic lethality was evaluated in a sepsis model induced by subcutaneous administration of both lipopolysaccharide and colchicine. Intracisternal butyrate dose-dependently improved colonic hyperpermeability and visceral nociception. In contrast, subcutaneous injection of butyrate failed to change it. Intracisternal orexin 1 receptor antagonist or surgical vagotomy blocked the central butyrate-induced improvement of colonic hyperpermeability. The improvement of intestinal hyperpermeability by central butyrate or intracisternal orexin-A was blocked by cannabinoid 1 or 2 receptor antagonist. Intracisternal butyrate significantly improved survival period in septic rats. These results suggest that butyrate acts in the central nervous system to improve gut permeability and visceral nociception through cannabinoid signaling. Endogenous orexin in the brain may mediate the reduction of intestinal hyperpermeability by central butyrate through the vagus nerve. We would suggest that improvement of leaky gut by central butyrate may induce visceral antinociception and protection from septic lethality.

The reduced risk of septic shock/sepsis with laparoscopic surgery among ulcerative colitis patients with preoperative chronic steroid use.

BACKGROUND: Preoperative steroid use has been associated with worse surgical outcomes. The purpose of this study was to determine whether laparoscopic surgery reduces the risk of septic shock/sepsis among ulcerative colitis patients with preoperative chronic steroid use. METHODS: Patients with ulcerative colitis undergoing a total abdominal colectomy were identified from the American College of Surgeons National Surgical Quality Improvement Program (NSQIP) database (2005-2019). Patients were stratified based on preoperative chronic steroid use and operative approach (open versus laparoscopic). The primary outcome was septic shock/sepsis. Multivariable regression models were used to assess the association between laparoscopic surgery and rates of septic shock/sepsis among steroid users and non-steroid users in both the elective and emergent settings. RESULTS: Among 8,644 patients undergoing a total abdominal colectomy, 67.1% were steroid users and 32.9% were non-steroid users. Compared with an open approach, elective laparoscopic surgery was associated with lower rates of septic shock/sepsis, albeit with higher readmission rates for both steroid users (15.1% [laparoscopic] vs 12.0% [open], P = .005) and non-steroid users (12.6% [laparoscopic] vs 9.4% [open], P = .019). On adjusted analysis, ulcerative colitis patients with chronic steroid use undergoing an elective laparoscopic total abdominal colectomy demonstrated a reduced risk of septic shock/sepsis compared to open surgery (odds ratio 0.61, 95% confidence interval 0.49-0.76, P < .001). Similar findings were seen among chronic steroid users undergoing emergent laparoscopic procedures (odds ratio 0.54, 95% confidence interval 0.31-0.95, P = .031). CONCLUSION: Laparoscopic surgery was associated with a reduced risk of septic shock/sepsis among ulcerative colitis patients with preoperative chronic steroid use, suggesting that minimally invasive surgery may be a promising option among this unique patient population.

Stevioside Activates AMPK to Suppress Inflammation in Macrophages and Protects Mice from LPS-Induced Lethal Shock.

Stevioside, a diterpenoid glycoside, is widely used as a natural sweetener; meanwhile, it has been proven to possess various pharmacological properties as well. However, until now there were no comprehensive evaluations focused on the anti-inflammatory activity of stevioside. Thus, the anti-inflammatory activities of stevioside, both in macrophages (RAW 264.7 cells, THP-1 cells, and mouse peritoneal macrophages) and in mice, were extensively investigated for the potential application of stevioside as a novel anti-inflammatory agent. The results showed that stevioside was capable of down-regulating lipopolysaccharide (LPS)-induced expression and production of pro-inflammatory cytokines and mediators in macrophages from different sources, such as IL-6, TNF-α, IL-1ß, iNOS/NO, COX2, and HMGB1, whereas it up-regulated the anti-inflammatory cytokines IL-10 and TGF-ß1. Further investigation showed that stevioside could activate the AMPK -mediated inhibition of IRF5 and NF-κB pathways. Similarly, in mice with LPS-induced lethal shock, stevioside inhibited release of pro-inflammatory factors, enhanced production of IL-10, and increased the survival rate of mice. More importantly, stevioside was also shown to activate AMPK in the periphery blood mononuclear cells of mice. Together, these results indicated that stevioside could significantly attenuate LPS-induced inflammatory responses both in vitro and in vivo through regulating several signaling pathways. These findings further strengthened the evidence that stevioside may be developed into a therapeutic agent against inflammatory diseases.

A Clinical Decision Analysis for Use of Antibiotic Prophylaxis for Nonabsorbable Nasal Packing.

OBJECTIVE: Nonabsorbable nasal packing is often placed for the treatment of epistaxis or after sinonasal or skull base surgery. Antibiotics are often prescribed to prevent toxic shock syndrome (TSS), a rare, potentially fatal occurrence. However, the risk of TSS must be balanced against the major risk of antibiotic use, specifically Clostridium difficile colitis (CDC). The purpose of this study is to evaluate in terms of cost-effectiveness whether antibiotics should be prescribed when nasal packing is placed. STUDY DESIGN: A clinical decision analysis was performed using a Markov model to evaluate whether antibiotics should be given. SETTING: Patients with nonabsorbable nasal packing placed. METHODS: Utility scores, probabilities, and costs were obtained from the literature. We assess the cost-effectiveness of antibiotic use when the risk of community-acquired CDC is balanced against the risk of TSS from nasal packing. Sensitivity analysis was performed for assumptions used in the model. RESULTS: The incremental cost-effectiveness ratio for antibiotic use was 334,493 US dollars (USD)/quality-adjusted life year (QALY). Probabilistic sensitivity analysis showed that not prescribing antibiotics was cost-effective in 98.0% of iterations at a willingness to pay of 50,000 USD/QALY. Sensitivity analysis showed that when the risk of CDC from antibiotics was greater than 910/100,000 or when the incidence of TSS after nasal packing was less than 49/100,000 cases, the decision to withhold antibiotics was cost-effective. CONCLUSIONS: Routine antibiotic prophylaxis in the setting of nasal packing is not cost-effective and should be reconsidered. Even if antibiotics are assumed to prevent TSS, the risk of complications from antibiotic use is of greater consequence. LEVEL OF EVIDENCE: 3a.

Early Hemoperfusion for Cytokine Removal May Contribute to Prevention of Intubation in Patients Infected with COVID-19.

Hemoperfusion (HP) was helpful to prevent the development and progression of acute respiratory distress syndrome (ARDS), acute kidney injury (AKI), liver failure, and septic shock by removing cytokines and other inflammatory mediators and ultimately preventing progression toward multiple organ failure. A 54-year-old man diagnosed with COVID-19 was hospitalized in the intensive care unit. The patient's O2 saturation was 80% using an oxygen mask, which was gradually declining. After 4 sessions of HP/continuous renal replacement therapies (CRRT), O2 saturation reached to 95%, and the patient was transferred to the general ward. Performing HP/CRRT at the early stages of ARDS can obviate the need for intubating patients with COVID-19. Punctual and early use of HP and CRRT in the treatment of ARDS in patients with COVID-19 prevented the progression of ARDS and patient intubation, reduced respiratory distress and the patient's dependence on oxygen, prevented other complications such as AKI and septic shock in the patient, and reduced mortality and hospital length of stay.

Echinatin effectively protects against NLRP3 inflammasome-driven diseases by targeting HSP90.

Aberrant activation of NLRP3 inflammasome has been implicated in a variety of human inflammatory diseases, but currently, no pharmacological NLRP3 inhibitor has been approved. In this study, we showed that echinatin, the ingredient of the traditional herbal medicine licorice, effectively suppresses the activation of NLRP3 inflammasome in vitro and in vivo. Further investigation revealed that echinatin exerts its inhibitory effect on NLRP3 inflammasome by binding to heat-shock protein 90 (HSP90), inhibiting its ATPase activity and disrupting the association between the cochaperone SGT1 and HSP90-NLRP3. Importantly, in vivo experiments demonstrated that administration of echinatin obviously inhibits NLRP3 inflammasome activation and ameliorates LPS-induced septic shock and dextran sodium sulfate-induced (DSS-induced) colitis in mice. Moreover, echinatin exerted favorable pharmacological effects on liver inflammation and fibrosis in a mouse model of nonalcoholic steatohepatitis (NASH). Collectively, our study identifies echinatin as a potentially novel inhibitor of NLRP3 inflammasome, and its use may be developed as a therapeutic approach for the treatment of NLRP3-driven diseases.

High Titer Persistent Neutralizing Antibodies Induced by TSST-1 Variant Vaccine Against Toxic Shock Cytokine Storm.

Staphylococcal superantigen toxins lead to a devastating cytokine storm resulting in shock and multi-organ failure. We have previously assessed the safety and immunogenicity of a recombinant toxic shock syndrome toxin 1 variant vaccine (rTSST-1v) in clinical trials (NCT02971670 and NCT02340338). The current study assessed neutralizing antibody titers after repeated vaccination with escalating doses of rTSST-1v. At study entry, 23 out of 34 subjects (67.6%) had neutralizing antibody titers inhibiting T cell activation as determined by 3H-thymidine incorporation at a serum dilution of ≤1:100 with similar figures for inhibition of IL-2 activation (19 of 34 subjects, 55.9%) as assessed by quantitative PCR. After the first vaccination, numbers of subjects with neutralization titers inhibiting T cell activation (61.7% ≥ 1:1000) and inhibiting IL-2 gene induction (88.2% ≥ 1:1000) increased. The immune response was augmented after the second vaccination (inhibiting T cell activation: 78.8% ≥ 1:1000; inhibiting IL-2 induction: 93.9% ≥ 1:1000) corroborated with a third immunization months later in a small subgroup of subjects. Assessment of IFNγ, TNFα and IL-6 inhibition revealed similar results, whereas neutralization titers did not change in placebo participants. Antibody titer studies show that vaccination with rTSST-1v in subjects with no/low neutralizing antibodies can rapidly induce high titer neutralizing antibodies persisting over months.

An anti-perfringolysin O monoclonal antibody cross-reactive with streptolysin O protects against streptococcal toxic shock syndrome.

OBJECTIVE: Streptococcus pyogenes (Group A Streptococcus; GAS) causes a variety of infections that include life-threatening, severe invasive GAS infections, such as streptococcal toxic shock syndrome (STSS), with > 30% mortality rate, despite effective antibiotics and treatment options. STSS clinical isolates highly express streptolysin O (SLO), a member of a large family of pore-forming toxins called cholesterol-dependent cytolysins (CDCs). SLO is an important toxic factor for GAS and may be an effective therapeutic target for the treatment of STSS. Our aim was to identify a monoclonal antibody (mAb) that reacts with SLO and has therapeutic potential for STSS treatment. RESULTS: We focused on mAbs that had originally been established as neutralizing reagents to perfringolysin O (PFO), another member of the CDC family, as some cross-reactivity with SLO had been reported. Here, we confirmed cross-reactivity of an anti-PFO mAb named HS1 with SLO. In vitro analysis revealed that HS1 mAb sufficiently prevented human neutrophils from being killed by STSS clinical isolates. Furthermore, prophylactic and therapeutic injection of HS1 mAb into C57BL/6 mice significantly improved the survival rate following lethal infection with an STSS clinical isolate. These results highlight the therapeutic potential of HS1 mAb for STSS treatment.

Acceptability and safety of the menstrual cup: A systematic review of the literature / Aceptabilidad y seguridad de la copa menstrual: revisión sistemática de la literatura

Objectives: To conduct a systematic review of the literature and assess the acceptability and safety of the menstrual cup as a feminine hygiene product. Materials and methods: A search was conducted in the PubMed, Cochrane Library, Scopus, PopLine and Google Scholar databases for publications be- tween 1966 and July 2019. The terms ("Menstrual" AND "Cup") OR ("Copa" AND "Menstrual") were used. Quantitative, qualitative and mixed studies were included, as well as case series and case reports published in English and Spanish assessing the menstrual cup in women in childbearing age. The studies were selected and the data extracted by two reviewers working independently. Acceptability and safety were assessed as the primary result. The summary of the information is presented in narrative form. Results: Overall, 737 titles were found for initial review and, in the end, 38 studies were included in this work. The acceptability of the menstrual cup ranges between 35 % and 90 %. Between 10 to 45 % of women found it difficult to use. It was described as more comfortable when compared to tampons and pads. Continued use of the cup ranges between 48 and 94 %. In terms of safety, there was one case of toxic shock syndrome, one case of mechanical entrapment, and another case of allergy; and a higher risk of expulsion was found among intrauterine device users. Conclusion: The menstrual cup appears to be a comfortable, safe and efficient option for menstrual hygiene. Further randomized controlled studies and long-term prospective cohort studies are needed in order to determine the risk of complications due to excess bacterial colonization or retrograde menstruation.

TITULO: ACEPTABILIDAD Y SEGURIDAD DE LA COPA MENSTRUAL: REVISIÓN SISTEMÁTICA DE LA LITERATURA. OBJETIVO: Realizar una búsqueda sistemática de la literatura para evaluar la aceptabilidad y seguridad de la copa menstrual como producto de higiene genital femenina. METODOS: Se realizó búsqueda en las bases de datos PubMed, Cochrane Library, Scopus, PopLine y Google Scholar, desde 1966 hasta julio de 2019. Se utilizaron los términos: "Menstrual" AND "Cup" OR "Copa" AND "Menstrual". Se incluyeron estudios cuantitativos, cualitativos y mixtos, series y reportes de caso publicados en inglés y español que hubieran evaluado la copa menstrual en mujeres en edad reproductiva. Los estudios fueron selecciona- dos y los datos fueron extraídos por dos evaluadores de manera independiente. Como resultado primario se evaluó la aceptabilidad y seguridad. La síntesis de información se presenta de manera narrativa. RESULTADOS: Se encontraron 737 títulos para revisión inicial. Finalmente, se incluyeron 38 estudios. La copa menstrual tiene una aceptabilidad que varía entre el 35 y el 90 %. Del 10 al 45 % la encontraron difícil de usar. Fue descrita como más cómoda comparada con el tampón y la toalla higiénica de fabricación industrial. La continuidad de su uso está entre el 48 y el 94 %. En cuanto a la seguridad se presentó un caso de síndrome de choque tóxico, uno de atrapamiento mecánico, uno de alergia al producto y mayor riesgo de expulsión en usuarias del dispositivo intrauterino. CONCLUSIONES: La copa menstrual es una alternativa cómoda, segura y eficiente para la higiene mens- trual. Se requieren más estudios controlados alea- torizados y cohortes prospectivas a largo plazo para determinar el riesgo de complicaciones por una exagerada colonización bacteriana o menstruación retrógrada.

Beta-Adrenergic Blockers as a Potential Treatment for COVID-19 Patients.

More than 15 million people have been affected by coronavirus disease 2019 (COVID-19) and it has caused 640 016 deaths as of July 26, 2020. Currently, no effective treatment option is available for COVID-19 patients. Though many drugs have been proposed, none of them has shown particular efficacy in clinical trials. In this article, the relationship between the Adrenergic system and the renin-angiotensin-aldosterone system (RAAS) is focused in COVID-19 and a vicious circle consisting of the Adrenergic system-RAAS-Angiotensin converting enzyme 2 (ACE2)-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (which is referred to as the "ARAS loop") is proposed. Hyperactivation of the ARAS loop may be the underlying pathophysiological mechanism in COVID-19, and beta-adrenergic blockers are proposed as a potential treatment option. Beta-adrenergic blockers may decrease the SARS-CoV-2 cellular entry by decreasing ACE2 receptors expression and cluster of differentiation 147 (CD147) in various cells in the body. Beta-adrenergic blockers may decrease the morbidity and mortality in COVID-19 patients by preventing or reducing acute respiratory distress syndrome (ARDS) and other complications. Retrospective and prospective clinical trials should be conducted to check the validity of the hypothesis. Also see the video abstract here https://youtu.be/uLoy7do5ROo.

Lista de medicamentos esenciales para el manejo de pacientes que ingresan a unidades de cuidados intensivos con sospecha o diagnóstico confirmado de COVID-19 / List of essential drugs for the management of patients admitted to intensive care units with suspected or confirmed diagnosis of COVID-19

En el transcurso de la pandemia de COVID-19, numerosos países, de ingresos bajos, medianos y alto, han visto agotadas sus reservas de medicamentos esenciales necesarios para el manejo de los pacientes con COVID-19 en las unidades de cuidados intensivos (UCI). El plan de preparación para emergencias sanitarias de los países requiere incluir una lista de medicamentos esenciales y otros dispositivos médicos necesarios en las UCI para afrontar emergencias sanitarias. La lista de medicamentos esenciales para el manejo de pacientes que ingresan a unidades de cuidados intensivos con sospecha o diagnóstico confirmado de COVID-19 es un documento de orientación fundamental que ayuda a los sistemas de salud de los países a priorizar los medicamentos esenciales que deben estar ampliamente disponibles y ser asequibles para manejar los pacientes en las UCI durante las situaciones de emergencia sanitaria, en este caso con sospecha o diagnóstico confirmado de COVID-19. Está dirigida a las autoridades sanitaras y a los encargados del manejo del sistema de salud de los países. Esta lista incluye fundamentalmente los medicamentos considerados esenciales para el manejo de los cuadros clínicos que con se observan con mayor frecuencia en pacientes hospitalizados en UCI a causa de una infección por SARS-CoV-2. No se incluyen la mayoría de los medicamentos que comúnmente se encuentran en las UCI para el manejo de otras patologías, comorbilidades o la estabilización del paciente (p. ej., insulina o antihipertensivos), salvo aquellos que pueden requerirse para el tratamiento o apoyo (p. ej., bloqueantes neuromusculares o anestésicos) de las dolencias generadas por la infección. Tampoco se incluyen medicamentos específicos para el tratamiento de la infección por SARS-CoV-2, puesto que no existe, por el momento, evidencia científica de alta calidad que avale su uso, salvo en el contexto de ensayos clínicos controlados. Un equipo de expertos en el tema realizó una búsqueda de información sobre la atención de pacientes en UCI durante la pandemia de COVID-19, en Medline (a través de PubMed), Cochrane, Tripdatabase, Epistemonikos y en buscadores generales de internet (Google). Se identificaron también revisiones o guías generadas por ministerios de Salud de varios países de la Región de las Américas, la Organización Mundial de la Salud (OMS), la Organización Panamericana de la Salud (OPS), el Instituto Nacional de Salud y Excelencia Clínica (NICE) de Reino Unido, los Centros para el Control y la Prevención de Enfermedades (CDC) de Estados Unidos y los Institutos Nacionales de Salud (NIH) de Estados Unidos.

Tofacitinib treatment aggravates Staphylococcus aureus septic arthritis, but attenuates sepsis and enterotoxin induced shock in mice.

Tofacitinib, a janus kinase inhibitor, is a novel immunosuppressive drug for treatment of rheumatoid arthritis (RA). Septic arthritis (SA) and sepsis caused by Staphylococcus aureus (S. aureus), for which RA patients are at risk, are infections with high mortality. The aim of this study was to investigate the effect of tofacitinib on S. aureus infections using mouse models. In vitro tofacitinib treated mouse splenocytes were stimulated with S. aureus derived stimuli. Mice pre-treated with tofacitinib were inoculated intravenously with either arthritogenic- or septic doses of S. aureus. Arthritis severity and mortality were compared between groups. Additionally, pre-treated mice were challenged with staphylococcal toxin TSST-1 to induce shock. Tofacitinib inhibited splenocyte proliferation and IFN-γ production in response to TSST-1 and dead S. aureus. In SA, tofacitinib treatment aggravated arthritis with more severe bone erosions. However, in sepsis, treated mice displayed significantly prolonged survival compared to controls. Similarly, in staphylococcal enterotoxin-induced shock tofacitinib pre-treatment, but not late treatment dramatically reduced mortality, which was accompanied by decreased levels of TNF-α and IFN-γ. Our findings show that tofacitinib treatment increase susceptibility of SA in mice, but has a positive effect on survival in S. aureus-induced sepsis and a strong protective effect in toxin-induced shock.

Effects of a single dose of vitamin D in septic children: a randomized, double-blinded, controlled trial.

OBJECTIVE: To assess the effects of a single dose of vitamin D on 25-hydroxyvitamin D (25OHD) levels and clinical outcomes in children with vitamin D deficiency (VDD) and sepsis. METHODS: In this randomized, controlled trial, eligible children with VDD and sepsis were assigned to receive one dose of 150,000 IU of cholecalciferol or placebo. Serum concentrations of 25OHD, angiotensin-II (Ang-II), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) were assessed at baseline and 8 days after treatment. The cardiovascular Sequential Organ Failure Assessment (cv-SOFA) score, septic shock incidence, duration of ventilation, and mortality were also examined. RESULTS: One hundred nine participants fulfilled the study requirements. The two groups had comparable baseline characteristics. Ang-II, IL-6, and TNF-α concentrations were all reduced after vitamin D supplementation. Furthermore, the cv-SOFA score (1.76 ± 0.8 vs. 2.3 ± 1.1) and incidence of septic shock (7% vs. 20%) were lower in the treatment group than in the control group. The duration of ventilation and mortality rates did not differ between two groups. CONCLUSIONS: A single dose of vitamin D improved 25OHD levels and the incidence of septic shock in children with VDD and sepsis.

The Protective Effects of Melatonin Against LPS-Induced Septic Myocardial Injury: A Potential Role of AMPK-Mediated Autophagy.

Aim: Melatonin is an indolamine secreted by the pineal gland, as well as most of the organs and tissues. In addition to regulating circadian biology, studies have confirmed the multiple pharmacological effects of melatonin. Melatonin provides a strong defense against septic myocardial injury. However, the underlying mechanism has not been fully described. In this study, we investigated the protective effects of melatonin against lipopolysaccharide (LPS)-induced myocardial injury as well as the mechanisms involved. Methods: Mice were intraperitoneally injected with LPS to induce a septic myocardial injury model or an LPS shock model, depending on the dose of LPS. Melatonin was given (20 mg/kg/day, via intraperitoneal injection) for a week prior to LPS insult. 6 h after LPS injection, echocardiographic analysis, TUNEL staining, transmission electron microscopy (TEM), western blot, quantitative real-time PCR and ELISA were used to investigate the protective effects of melatonin against LPS induced myocardial injury. AMPK inhibitor, autophagy activator and inhibitor, siRNAs were used for further validation. Results: Survival test showed that melatonin significantly increased the survival rate after LPS-induced shock. In the sepsis model, melatonin markedly ameliorated myocardial dysfunction, decreased the release of inflammatory cytokines, activated AMP-activated protein kinase (AMPK), improved mitochondrial function, and activated autophagy. To confirm whether the protection of melatonin was mediated by AMPK and autophagy, Compound C, an AMPK inhibitor; 3-MA, an autophagy inhibitor; and Rapamycin (Rapa), an autophagy activator, were used in this study. AMPK inhibition down-regulated autophagy, abolished protection of melatonin, as indicated by significantly decreased cardiac function, increased inflammation and damaged mitochondrial function. Furthermore, autophagy inhibition by 3-MA significantly impaired the protective effects of melatonin, whereas autophagy activation by Rapa reversed LPS + Compound C induced myocardial injury. In addition, in vitro studies further confirmed the protection of melatonin against LPS-induced myocardial injury and the mechanisms involving AMPK-mediated autophagy signaling. Conclusions: In summary, our results demonstrated that melatonin protects against LPS-induced septic myocardial injury by activating AMPK mediated autophagy pathway.

Síndrome de CREST asociado a shock séptico por osteomielitis hematógena aguda / CREST syndrome associated with septic shock due to acute osteomyelitis hematologic

El síndrome de CREST (calcinosis, fenómeno de Raynaud, dismotilidad esofágica, esclerodactilia, telangiectasias) forma parte del espectro clínico de la esclerosis sistémica, enfermedad del colágeno, denominada en la clasificación clínica como esclerodermia cutánea limitada. Se presenta un paciente masculino de 53 años, raza blanca y procedencia rural, que desde hace 10 años presenta poliartritis, cambios en zonas distales de la piel que subyace adherida al hueso, falanges de manos y pies, fenómeno de Raynaud, aparición de nódulos subcutáneos de pequeño tamaño en varias localizaciones, que luego se tornan calcificaciones. Llega con una úlcera en el quinto metatarsiano del pie izquierdo, de 14 meses de evolución con varios ingresos para tratamiento de la lesión con resolución aparente y luego recidiva. Desarrolla un cuadro de osteomielitis hematógena aguda con shock séptico. El tratamiento multidisciplinario y oportuno permitió la sobrevida del paciente(AU)

CREST's Syndrome (calcinosis, Raynaud's phenomenon, dysmotilitic esofhagical, sclerodactilitys, telanghiectasis), the form departs from the clinical spectrum of the Systemic Sclerosis, disease of collagen, named in the clinical classification like cutaneous limited scleroderma. Patient, masculine of 53 years, white race, peasant procedence. 10 years ago with changes at zones level distally of the skin that underlies once the bone was adhered, phalanges of hands and feet, Raynaud's phenomenon so big a child's appearing of subcutaneous nodules at several locations, that next calcifications appear. Ulcer in metatarsal foot left-hand fifth, of 14 months of evolution with multiple entrances for treatment of the lesion with apparent resolution and next relapse. Develop acute osteomyelitis hematologic with septic shock. The multi-disciplinary and opportune treatment enabled the patient's over-life(AU)