Diminished adrenal sensitivity to endogenous and exogenous adrenocorticotropic hormone in critical illness: a prospective cohort study

IntroductionAdrenal dysfunction may represent critical illness-related corticosteroid insufficiency (CIRCI), as evidenced by a diminished cortisol response to exogenous adrenocorticotropic hormone (ACTH), but this concept and its clinical significance remain highly controversial. We studied the adrenal response to exogenous ACTH as a function of the endogenous cortisol-to-ACTH ratio, a measure of adrenal sensitivity, and of clinical variables, during critical illness and recovery from the acute phase.MethodsWe prospectively included 59 consecutive septic and nonseptic patients in the intensive care unit with treatment-insensitive hypotension in whom CIRCI was suspected; patients having received etomidate and prolonged corticosteroids were excluded. An ACTH test (250 μg) was performed, followed by a second test after ≥7 days in acute-phase survivors. Serum total and free cortisol, ACTH, and clinical variables were assessed. Patients were divided according to responses (delta, Δ) of cortisol to ACTH at the first and second tests.ResultsPatients with low (<250 nM) Δ cortisol (n = 14 to 17) had higher baseline cortisol and ACTH but lower cortisol/ACTH ratios than patients with a normal Δ cortisol (≥250 nM) in the course of time. A low Δ cortisol in time was associated with more-severe disease, culture-positive sepsis, and prolonged activated prothrombin time. Results for free cortisol were similar.ConclusionsEven though the pituitary-adrenal axis is activated after stress during critical illness, diminished adrenal sensitivity to endogenous ACTH predicts a low increase of cortisol to exogenous ACTH, suggesting adrenal dysfunction, irrespective of the stage of disease. The data further suggest a role of disease severity and culture-positive sepsis.     

Distribution of T cells and signs of T-cell activation in the rheumatoid joint: implications for semiquantitative comparative histology

A prerequisite for comparative histology of synovial tissue by means of biopsies is insight into the distribution of a marker under study. This investigation focuses on the variation in the presence of T cells and signs of T-cell activation within the rheumatoid joint. For this purpose, multiple slides from several pieces of synovial tissue from different parts of a joint were stained and scored for the expression of CD3, CD25, HLA-DR, Ki67 and interferon-gamma. The variation in scores for the presence of T cells and markers of activation was more pronounced in slides prepared from different pieces of tissue than in slides from one piece of tissue. Based on multiple analysis of variance, methods are suggested to establish a reliable overall score for the expression of a certain marker within a joint. Following validation, such methods may prove to be useful by allowing semiquantitative histology of synovial tissue for studies on arthritis.      

Bone matrix degradation by the plasminogen activation system. Possible mechanism of bone destruction in arthritis

The observed increase in urokinase-type plasminogen activator (u-PA) and its receptor (u-PAR) in synovial tissue of patients with rheumatoid arthritis (RA) suggests pathophysiological involvement of the plasminogen activation (PA) system in inflammatory joint disease. In the present study, we investigated the capacity of the PA system to degrade non-mineralized and mineralized bone-like matrix in vitro as a model for bone destruction. Transfected mouse LB6 cell lines, that expressed either human u-PA or u-PAR, were cultured separately and simultaneously on radiolabelled bone matrix in the presence of plasminogen. Osteoblast-like murine calvarial MC3T3-E1 cells were used to produce a well-characterized, highly organized bone-like matrix, that could be mineralized in the presence of beta-glycerol phosphate. Bone matrix degradation was followed by the release of radioactivity in the culture medium. u-PA-producing cells, in contrast to u-PAR- producing cells, degraded both non-mineralized and mineralized bone matrix. This effect could be inhibited by anti-u-PA antibodies, as well as by tranexamic acid and by aprotinin, indicating that the degrading activity is u-PA mediated and plasmin dependent. Co-cultivation of a small portion of u-PA-producing cells with u-PAR-expressing cells resulted in a marked increase in degradation activity. Reduction of this potentiating effect by suramin or the amino-terminal fragment of u- PA, both competitive inhibitors of u-PA receptor binding, shows that this synergistic effect is due to binding of u-PA to u-PAR. u-PAR must be cell associated, as binding of u-PA to a soluble u-PAR prevented this enhancement. The capability of the PA system to degrade bone matrix in vitro, and the previously demonstrated increased expression of u-PA and u-PAR in synovial tissue of patients with RA, further support a role for the PA system in the development of bone erosions.      

Development of a real-time rt-PCR assay for the detection of crimean-congo hemorrhagic Fever virus

Abstract Crimean-Congo hemorrhagic fever (CCHF) is a virulent tick-borne disease with a case fatality rate ranging from 10-50% for tick-borne transmission, and up to 80% for nosocomial transmission. Human cases have been reported in over 30 countries across Europe, Asia, and Africa. It appears to be spreading to new areas with several countries reporting their first human cases of CCHF disease within the past 10 years. We report a novel real-time RT-PCR assay designed to amplify a conserved region of the CCHF virus S segment. It is capable of detecting strains from all 7 groups of CCHF, including the AP92 strain that until recently represented a lineage of strains that were not associated with human disease. The limit of detection of the assay is 5 copies of target RNA, and the assay shows no cross-reactivity with other viruses from within the same genus, or with viruses causing similar human disease.     

Intergenerational change and familial aggregation of body mass index

The relationship between parental BMI and that of their adult offspring, when increased adiposity can become a clinical issue, is unknown. We investigated the intergenerational change in body mass index (BMI) distribution, and examined the sex-specific relationship between parental and adult offspring BMI. Intergenerational change in the distribution of adjusted BMI in 1,443 complete families (both parents and at least one offspring) with 2,286 offspring (1,263 daughters and 1,023 sons) from the west of Scotland, UK, was investigated using quantile regression. Familial correlations were estimated from linear mixed effects regression models. The distribution of BMI showed little intergenerational change in the normal range (<25 kg/m²), decreasing overweightness (25–<30 kg/m²) and increasing obesity (≥30 kg/m²). Median BMI was static across generations in males and decreased in females by 0.4 (95% CI: 0.0, 0.7) kg/m²; the 95th percentile increased by 2.2 (1.1, 3.2) kg/m² in males and 2.7 (1.4, 3.9) kg/m² in females. Mothers’ BMI was more strongly associated with daughters’ BMI than was fathers’ (correlation coefficient (95% CI): mothers 0.31 (0.27, 0.36), fathers 0.19 (0.14, 0.25); P = 0.001). Mothers’ and fathers’ BMI were equally correlated with sons’ BMI (correlation coefficient: mothers 0.28 (0.22, 0.33), fathers 0.27 (0.22, 0.33). The increase in BMI between generations was concentrated at the upper end of the distribution. This, alongside the strong parent-offspring correlation, suggests that the increase in BMI is disproportionally greater among offspring of heavier parents. Familial influences on BMI among middle-aged women appear significantly stronger from mothers than fathers.     

THYROTOXICOSIS PRESENTING AS A LIFE THREATENING HYPOKALAEMIC PARALYSIS: INVESTIGATION OF THE Na/K PUMP IN ISOLATED LEUCOCYTES

A 37-year-old Chinese man presented with the rapid onset of profound muscle weakness, and a serum potassium of 1.7 mmol/l. The intravenous infusion of undiluted potassium chloride (2 mmol/ml) through a central venous catheter resulted in rapid recovery. Further investigation revealed thyrotoxicosis. He was treated with carbimazole and subsequently remained well. We assessed Na/K pump activity in isolated leucocytes taken from the patient and found an exaggerated response to adrenaline which ceased after he became euthyroid.     

Brain-derived neurotrophic factor does not improve recovery after cardiac arrest in rats

Increased brain-derived neurotrophic factor (BDNF) levels and extracellular-signal regulated kinase (ERK) signaling are associated with reduced brain injury after cerebral ischemia. In particular, mild hypothermia after cardiac arrest increases BDNF and ERK signaling. This study tested whether intracerebroventricular infusions (0.025 microg/h x 3 days) of BDNF also improved recovery of rats resuscitated from cardiac arrest and maintained at 37 degrees C. BDNF infusions initiated at the time of cardiac arrest did not alter survival, neurological recovery, or histological injury. Separate experiments confirmed that BDNF infusions increased tissue levels of BDNF. However, these infusions did not increase ERK activation in hippocampus. These data suggest that increased BDNF levels are not sufficient to explain the beneficial effects of mild hypothermia after cardiac arrest, and that exogenous BDNF administration does not increase extracellular ERK signaling.     

注射用右兰索拉唑治疗急性胃和/或十二指肠溃疡引起的上消化道出血的有效性及安全性

目的：以注射用兰索拉唑为对照,评价注射用右兰索拉唑15 mg q12 h治疗急性胃和/或十二指肠溃疡引起的上消化道出血的有效性及安全性。方法：选取全国31家研究中心的急性胃和/或十二指肠溃疡引起的上消化道出血患者共202例,按照1∶1随机分配至试验组（注射用右兰索拉唑组）和对照组（注射用兰索拉唑组）。主要疗效终点为72 h有效止血率。对主要疗效终点采用非劣效评价,非劣效性界值δ是10%。结果：有效性方面,全分析数据集分析结果显示：用药72 h后,注射用右兰索拉唑组有效止血率为96.08%(98/102);注射用兰索拉唑组有效止血率为98.00%(98/100),两组率差为-1.92%(95%CI-6.58,2.74)。两组72 h有效止血率差异无统计学意义（P=0.682 9）。两组率差的双侧界值均低于δ(10%),注射用右兰索拉唑非劣于注射用兰索拉唑。安全性方面,试验组的不良事件及不良反应发生率与对照组差异无统计学意义,无非预期不良反应和严重不良反应。主要的不良反应为白细胞计数降低、中性粒细胞计数降低等。结论：注射用右兰索拉唑15 mg q12 h在治疗急性胃和/或十二指肠溃疡引起的...     

Timing of antibiotics in febrile children meeting sepsis criteria at a paediatric emergency department

Objective

Delay in antibiotic administration in paediatric sepsis is associated with increased mortality and prolonged organ dysfunction. This pre-intervention study evaluated performance in paediatric sepsis management.

Methods

Retrospective cohort study of febrile children admitted through the ED at The Children's Hospital at Westmead, Sydney, between 1 May and 31 July 2017. Participants were children aged 29 days to 60 months excluding children with simple febrile seizures, neonates and children who had received intravenous antibiotics elsewhere. We assessed the timing of antibiotic administration in children meeting local sepsis guidelines. We conducted a survey of clinicians in ED in 2018 to describe contributing factors.

Results

There were 160 febrile children admitted and 144 presentations were included in the analysis. Male 53% (n = 76); median age 20.1 months (interquartile range [IQR] 3.9–37 months). Thirty-seven (26%) febrile children met local sepsis criteria. The median time from triage to first dose of intravenous antibiotic was 109 min (IQR 62–183 min). Delay (>60 min) occurred in 26 (76%) children. Reported reasons contributing to delay included high patient load, long waiting times, difficult intravenous access, delayed prescribing, inadequate staffing and difficulty distinguishing between a viral infection and serious bacterial infection.

Conclusion

There was frequent delay in administering antibiotics in children meeting local sepsis criteria, more commonly in young infants. Reasons contributing to delay were specific to young children along with departmental factors that will require addressing through targeted quality improvement interventions.