Innate Immune Pathways in the Draining Lymph Node

The draining lymph node (dLN) is the anatomical site in which adaptive immune responses are initiated following vaccination. It is increasingly recognised that the dLN also serves an important innate barrier function and that inflammatory stimuli (including vaccine adjuvants) drive cardinal aspects of the innate immune response within the dLN. The characterisation of these intranodal innate immune processes and their impact upon the concurrently developing adaptive immune response is therefore central to the design of novel vaccines and adjuvants. Neutrophil and monocyte infiltration is a cardinal feature of the innate immune response. This phenomenon is studied within the dLN in the context of two key innate immune pathways; cyclooxygenase-dependent prostanoids and type I interferons. These processes were studied using a murine skin immunisation model following challenge with killed E. coli (KEC), which induced the rapid and sequential infiltration of neutrophils and monocytes into the dLN. These infiltrating myeloid cells were major expressers of cardinal prostanoid synthases (cyclooxygenase-2, microsomal PGE synthase-1 and thromboxane synthase), as well as important interferon-stimulated genes such as CXCL9 and CXCL10. Notably, cyclooxygenase inhibition during their infiltration did not modulate the developing humoral immune response. In contrast, type 1 interferons drove the differential upregulation of CD69 by different lymphocyte subsets and the acute production of interferon-γ by dLN NK cells; processes that play important roles in the retention and activation of T cells. In vitro evidence suggests that these processes are driven by interferon-stimulated monocytes, a hypothesis supported by the markedly increased expression of type I interferon stimulated genes by dLN monocytes in vivo. In conclusion, this thesis highlights the role of infiltrating myeloid cells as unappreciated orchestrators of type I interferon-driven innate immune pathways in the dLN. This finding informs hypotheses that assert that inflammatory monocytes drive Th1 T cell responses in the dLN

Hipotermia para la neuroprotección en adultos después de la reanimación cardiopulmonar

ResumenAntecedentesEs difícil lograr un buen resultado neurológico después de un paro cardíaco. Las intervenciones durante la fase de reanimación y el tratamiento en las primeras horas después del evento son críticas. Las pruebas experimentales indican que la hipotermia terapéutica es beneficiosa, y se han publicado varios estudios clínicos sobre este tema.ObjetivosSe realizó una revisión sistemática y un metanálisis para evaluar la efectividad de la hipotermia terapéutica en pacientes que sufrieron un paro cardíaco. Las principales medidas de resultado fueron los resultados neurológicos, la supervivencia y los eventos adversos. Se propuso realizar el análisis de los datos de los pacientes individuales si estaban disponibles, y de subgrupos según la situación del paro cardíaco.Estrategia de búsquedaSe hicieron búsquedas en las siguientes bases de datos: Registro Cochrane Central de Ensayos Controlados (Cochrane Central Register of Controlled Trials, CENTRAL) (The Cochrane Library, 2007, número 1); MEDLINE (1971 hasta enero 2007); EMBASE (1987 hasta enero 2007); CINAHL (1988 hasta enero 2007); PASCAL (2000 hasta enero 2007); y BIOSIS (1989 hasta enero 2007).Criterios de selecciónSe incluyeron todos los ensayos controlados aleatorios que evaluaron la efectividad de la hipotermia terapéutica en los pacientes después de un paro cardíaco, sin restricciones de idiomas. Los estudios estaban restringidos a las poblaciones adultas que recibieron el enfriamiento con cualquier método, aplicado en las seis horas siguientes al paro cardíaco.Obtención y análisis de los datosSe introdujeron en la base de datos las medidas de validez, la intervención, los parámetros de las medidas de resultado y variables iniciales adicionales. Se realizó metanálisis sólo en un subconjunto de estudios comparables con heterogeneidad insignificante. En estos estudios se contó con los datos de los pacientes individuales.Resultados principalesaSe incluyeron en la revisión sistemática cuatro ensayos y un resumen con datos sobre 481 pacientes. La calidad de los estudios incluidos fue buena en tres de los cinco estudios incluidos. En los tres estudios comparables sobre los métodos de enfriamiento convencional todos los autores proporcionaron datos de los pacientes individuales. Con métodos de enfriamiento convencional, los pacientes en el grupo con hipotermia tuvieron mayor probabilidad de alcanzar una mejor puntuación de las categorías de rendimiento cerebral de 1 o 2 (CRC, escala de 5 puntos; 1 = buen rendimiento cerebral, a 5 = muerte cerebral) durante la estancia hospitalaria (datos de los pacientes individuales; RR, 1,55, IC del 95%: 1,22 a 1,96) y tuvieron mayor probabilidad de sobrevivir al alta hospitalaria (datos de los pacientes individuales; RR, 1,35, IC del 95%: 1,10 a 1,65) comparados con la atención estándar después de la reanimación. En la totalidad de los estudios no hubo diferencias significativas de los eventos adversos informados entre la hipotermia y el control.Conclusiones de los autoresLos métodos de enfriamiento convencional para inducir la hipotermia terapéutica leve parecen mejorar la supervivencia y el estado neurológico después de un paro cardíaco. Esta revisión apoya la mejor práctica médica actual recomendada por las International Resuscitation Guidelines (Guías internacionales de reanimación).Resumen en términos sencillosEnfriamiento del cuerpo después de un paro cardíacoHasta la fecha, aproximadamente un décimo a un tercio de los pacientes reanimados con éxito dejan el hospital para reiniciar una vida independiente. Estudios clínicos han mostrado que este resultado puede mejorarse con el enfriamiento del cuerpo aproximadamente a 33°C durante varias horas después de un paro cardíaco. Se incluyeron cinco ensayos aleatorios con datos de un total de 481 supervivientes de un paro cardíaco. Los pacientes en los que se usaron los métodos de enfriamiento convencional tuvieron mayor probabilidad de salir del hospital sin daño cerebral importante y de sobrevivir al alta hospitalaria. No se informaron eventos adversos específicos del enfriamiento. En resumen, actualmente hay pruebas que apoyan el uso del enfriamiento convencional para inducir la hipotermia leve en las primeras horas después de la restauración de la circulación espontánea en los supervivientes de un paro cardíaco

Out-of-hospital therapeutic hypothermia in cardiac arrest victims

Despite many years of research, outcome after cardiac arrest is dismal. Since 2005, the European Resuscitation Council recommends in its guidelines the use of mild therapeutic hypothermia (32-34°) for 12 to 24 hours in patients successfully resuscitated from cardiac arrest. The benefit of resuscitative mild hypothermia (induced after resuscitation) is well established, while the benefit of preservative mild to moderate hypothermia (induced during cardiac arrest) needs further investigation before recommending it for clinical routine. Animal data and limited human data suggest that early and fast cooling might be essential for the beneficial effect of resuscitative mild hypothermia. Out-of-hospital cooling has been shown to be feasible and safe by means of intravenous infusion with cold fluids or non-invasively with cooling pads. A combination of these cooling methods might further improve cooling efficacy. If out-of-hospital cooling will further improve functional outcome as compared with in-hospital cooling needs to be determined in a prospective, randomised, sufficiently powered clinical trial

Predictors for prehospital first-pass intubation success in Germany

(1) Background: Endotracheal intubation in the prehospital setting is an important skill for emergency physicians, paramedics, and other members of the EMS providing airway management. Its success determines complications and patient mortality. The aim of this study was to find predictors for first-pass intubation success in the prehospital emergency setting. (2) The study was based on a retrospective analysis of a population-based registry of prehospital advanced airway management in Germany. Cases of endotracheal intubation by the emergency medical services in the cities of Tübingen and Jena between 2016 and 2019 were included. The outcome of interest was first-pass intubation success. Univariate and multivariable regression analysis were used to analyse the influence of predefined predictors, including the characteristics of patients, the intubating staff, and the clinical situation. (3) Results: A total of 308 patients were analysed. After adjustment for multiple confounders, the direct vocal cord view, a less favourable Cormack–Lehane classification, the general practitioner as medical specialty, and location and type of EMS were independent predictors for first-pass intubation success. (4) Conclusions: In physician-led emergency medical services, the laryngoscopic view, medical specialty, type of EMS, and career level are associated with FPS. The latter points towards the importance of experience and regular training in endotracheal intubation

Therapeutic hypothermia

Pioneer works on therapeutic hypothermia (TH) half a century ago already showed promising results but clinical application was limited by a lack of understanding of the underlying pathophysiology, lack of reliable method for temperature control and lack of intensive care facilities to deal with possible complications. More recently, 2 studies in 2002 supported the application of moderate TH (32.0-34.0℃) in post-cardiac arrest patients. Although the studies included only patients suffering from out-of-hospital VF, many ICUs world-wide are applying the therapy to all post-cardiac arrest patients irrespective of site or presenting rhythm. While primary coagulopathy and cardiogenic shock are usually stated as relative contraindications, evidences are accumulating to support the application of TH in patients with cardiogenic shock. TH can be divided into 4 phases: Induction, maintenance, de-cooling and normothermia. Induction is usually achieved by infusion of cold isotonic fluid. The precautions included avoidance of over-cooling, hypokalaemia, hyperglycaemia, and shivering. TH can be maintained by many different methods, varying in their level of invasiveness, cost and effectiveness. Issues including changes in pharmacokinetics and haemodynamics, and susceptibility to infection need to the addressed. The optimal duration of maintenance is unknown but the usual practice is 12-24 hours. De-cooling and rewarming is especially challenging because complications can be serious if temperature rise by more than 1℃ every 3-5 hours. Life-theatening hyperkalaemia can occur especially if patient suffers from renal insufficiency. Fever is a frequent complication either due to infection or post-cardiac arrest syndrome but patient must be kept normothermic for 72 hours

Therapeutic Hypothermia Reduces Intracranial Pressure and Partial Brain Oxygen Tension in Patients with Severe Traumatic Brain Injury:Preliminary Data from the Eurotherm3235 Trial

Traumatic brain injury (TBI) is a significant cause of disability and death and a huge economic burden throughout the world. Much of the morbidity associated with TBI is attributed to secondary brain injuries resulting in hypoxia and ischemia after the initial trauma. Intracranial hypertension and decreased partial brain oxygen tension (P(bt)O(2)) are targeted as potentially avoidable causes of morbidity. Therapeutic hypothermia (TH) may be an effective intervention to reduce intracranial pressure (ICP), but could also affect cerebral blood flow (CBF). This is a retrospective analysis of prospectively collected data from 17 patients admitted to the Western General Hospital, Edinburgh. Patients with an ICP >20 mmHg refractory to initial therapy were randomized to standard care or standard care and TH (intervention group) titrated between 32°C and 35°C to reduce ICP. ICP and P(bt)O(2) were measured using the Licox system and core temperature was recorded through rectal thermometer. Data were analyzed at the hour before cooling, the first hour at target temperature, 2 consecutive hours at target temperature, and after 6 hours of hypothermia. There was a mean decrease in ICP of 4.3±1.6 mmHg (p<0.04) from 15.7 to 11.4 mmHg, from precooling to the first epoch of hypothermia in the intervention group (n=9) that was not seen in the control group (n=8). A decrease in ICP was maintained throughout all time periods. There was a mean decrease in P(bt)O(2) of 7.8±3.1 mmHg (p<0.05) from 30.2 to 22.4 mmHg, from precooling to stable hypothermia, which was not seen in the control group. This research supports others in demonstrating a decrease in ICP with temperature, which could facilitate a reduction in the use of hyperosmolar agents or other stage II interventions. The decrease in P(bt)O(2) is not below the suggested treatment threshold of 20 mmHg, but might indicate a decrease in CBF

Acute Renal Failure in Association with Community-Acquired Clostridium difficile Infection and McKittrick-Wheelock Syndrome

We report the case of a 65-year-old Caucasian woman who experienced two separate episodes of acute renal failure within an 18-month period, both requiring emergency admission and complicated treatment. Each episode was precipitated by hypovolaemia from intestinal fluid losses, but from two rare and independent pathologies. Her first admission was attributed to community-acquired Clostridium difficile-associated diarrhoea (CDAD) and was treated in the intensive therapy unit. She returned 18 months later with volume depletion and electrolyte disturbances, but on this occasion a giant hypersecretory villous adenoma of the rectum (McKittrick-Wheelock syndrome) was diagnosed following initial abnormal findings on digital rectal examination by a junior physician. Unlike hospital-acquired C. difficile, community-acquired infection is not common, although increasing numbers are being reported. Whilst community-acquired CDAD can be severe, it rarely causes acute renal failure. This case report highlights the pathological mechanisms whereby C. difficile toxin and hypersecretory villous adenoma of the rectum can predispose to acute renal failure, as well as the values of thorough clinical examination in the emergency room, and early communication with intensivist colleagues in dire situations

Systematic review and meta-analysis of intravascular temperature management vs. surface cooling in comatose patients resuscitated from cardiac arrest

Objective: To systematically review the effectiveness and safety of intravascular temperature management (IVTM) vs. surface cooling methods (SCM) for induced hypothermia (IH). Methods: Systematic review and meta-analysis. English-language PubMed, Embase and the Cochrane Database of Systematic Reviews were searched on May 27, 2019. The quality of included observational studies was graded using the Newcastle-Ottawa Quality Assessment tool. The quality of included randomized trials was evaluated using the Cochrane Collaboration's risk of bias tool. Random effects modeling was used to calculate risk differences for each outcome. Statistical heterogeneity and publication bias were assessed using standard methods. Eligibility: Observational or randomized studies comparing survival and/or neurologic outcomes in adults aged 18 years or greater resuscitated from out-of-hospital cardiac arrest receiving IH via IVTM vs. SCM were eligible for inclusion. Results: In total, 12 studies met inclusion criteria. These enrolled 1573 patients who received IVTM; and 4008 who received SCM. Survival was 55.0% in the IVTM group and 51.2% in the SCM group [pooled risk difference 2% (95% CI - 1%, 5%)] Good neurological outcome was achieved in 40.9% in the IVTM and 29.5% in the surface group [pooled risk difference 5% (95% CI 2%, 8%)]. There was a 6% (95% CI 11%, 2%) lower risk of arrhythmia with use of IVTM and 15% (95% CI 22%, 7%) decreased risk of overcooling with use of IVTM vs. SCM. There was no significant difference in other evaluated adverse events between groups. Conclusions: IVTM was associated with improved neurological outcomes vs. SCM among survivors resuscitated following cardiac arrest. These results may have implications for care of patients in the emergency department and intensive care settings after resuscitation from cardiac arrest.Peer reviewe

Multicentre, prospective, open study to evaluate the safety and efficacy of hylan G-F 20 in knee osteoarthritis subjects presenting with pain following arthroscopic meniscectomy

The aim of the study was to evaluate the safety and efficacy of viscosupplementation with hylan G-F 20 in patients with mild to moderate osteoarthritis (OA) presenting with persistent knee pain 4–12 weeks after arthroscopic meniscectomy. A prospective, multi-centre, open study was carried out in patients with pain due to OA of the knee, not resolved by simple analgesics, 4–12 weeks after undergoing arthroscopic meniscectomy. To be eligible, patients had to score ≥50 mm and ≤90 mm on both walking pain and patient global assessment visual analogue scales (VAS; 0–100 mm) at baseline and be radiologically diagnosed pre-operatively with OA grade I or II on the Kellgren-Lawrence scale, with <50% joint space narrowing. Patients received three intra-articular, 2 ml injections of hylan G-F 20 in the target knee with an interval of 1 week between injections, and were followed for 52 weeks. The primary efficacy endpoint was the change from baseline in the walking pain VAS score at 26 weeks. Secondary outcome measures were the walking pain VAS scores at all other time points, the WOMAC Index at all time points, and patient and physician global assessment at all time points. The safety of the treatment was assessed using adverse event (AE) reports. A total of 62 patients (mean age 55.4 years, 52% male) were enrolled. The mean walking pain VAS score decreased by 36.8 mm from baseline at 26 weeks (P < 0.0001), and also showed statistically significant decreases (P < 0.0001) at all other time points. The change in WOMAC total and subscale scores from baseline were statistically significant (P < 0.0001) at all time points, as were the decreases in the physician and patient global assessment VAS scores. There were 18 target knee AEs (mostly pain and/or swelling and/or effusion) in 12 patients (19%) considered to be at least possibly related to treatment. The majority of these (78%) were mild or moderate in intensity. One patient (1.6%) experienced a serious adverse event (synovitis) in the target knee that was considered possibly related to study treatment. Hylan G-F 20 provides effective pain relief and improves stiffness and physical function in patients with mild to moderate OA presenting with persistent osteoarthritic pain 4–12 weeks after arthroscopic meniscectomy. Symptomatic efficacy was maximised at 12 weeks and maintained at 26 and 52 weeks. The type (pain and/or swelling and/or effusion) and the intensity (mostly mild/moderate) of AEs reported in this study are similar to those reported in other trials in different patient populations, but the incidence was higher (19%). The risk/benefit of hylan G-F 20 in this particular population of patients is favourable

The effect of socioeconomic status on three-year mortality after first-ever ischemic stroke in Nanjing, China

BACKGROUND: Low socioeconomic status (SES) is associated with increased mortality after stroke in developed countries. This study was performed to determine whether a similar association also exists in China. METHODS: A total of 806 patients with first-ever ischemic stroke were enrolled in our study. From August 1999 to August 2005, the three-year all-cause mortality following the stroke was determined. Level of education, occupation, taxable income and housing space were used as indicators for SES. Stepwise univariate and multivariate COX proportional hazards models were used to study the association between the SES measures and the three-year mortality. RESULTS: Our analyses confirmed that occupation, taxable income and housing space were significantly associated with three-year mortality after first-ever stroke. Manual workers had a significant hazard ratio of 5.44 (95% CI 2.75 to 10.77) for death within three years when compared with non-manual workers. Those in the zero income group had a significant hazard ratio of 5.35 (95% CI 2.95 to 9.70) and those in the intermediate income group 2.10 (95% CI 1.24 to 3.58) when compared with those in the highest income group. Those in two of the three groups with the smallest housing space also had significant hazard ratios of 2.06 (95% CI 1.16 to 3.65) and 1.68 (95% CI 1.12 to 2.52) when compared with those in group with the largest housing space. These hazard ratios remained largely unchanged after multivariate adjustment for age, gender, baseline cardiovascular disease risk factors, and stroke severity. The analyses did not confirm an association with educational level. CONCLUSION: Lower SES has a negative impact on the outcome of first-ever stroke in Nanjing, China. This confirms the need to improve preventive and secondary care for stroke among low SES groups