Characterization of Early Cytokine Responses and an Interleukin (IL)-6–dependent Pathway of Endogenous Glucocorticoid Induction during Murine Cytomegalovirus Infection

Early infection with murine cytomegalovirus (MCMV) induces circulating levels of interleukin (IL)-12, interferon (IFN)-γ, and tumor necrosis factor (TNF). Studies presented here further characterize these responses by defining kinetics and extending evaluation to include IL-1, IL-6, and glucocorticoids. IL-12 p40, IFN-γ, TNF, IL-1α, and IL-6 were shown to be increased, but IL-1β was undetectable, in serum of MCMV-infected mice. The IL-12 p40, IFN-γ, TNF, and IL-6 responses were dramatic with peak levels reaching >150–10,000 pg/ml at 32–40 h after infection and rapidly declining thereafter. Glucocorticoid induction, peaking at 36 h and reaching 30-fold increases above control values, accompanied the cytokine responses. Mice with cytokine deficiencies or neutralized cytokine function demonstrated that IL-6 was the pivotal mediator of the glucocorticoid response, with IL-1 contributing to IL-6 production. The IL-6 requirement appeared to be specific for virus-type stimuli as the synthetic analogue of viral nucleic acid, polyinosinic-polycytidylic acid, also induced IL-6–dependent glucocorticoid release, but treatments with the bacterial product lipopolysaccharide and a non-immune physical restraint stressor elicited IL-6–independent responses. Collectively, the results identify IL-6 as a primary mediator of glucocorticoid induction, and elucidate specific pathways of interactions between immune and neuroendocrine systems during viral infection.The cytokines IL-12, IFN-γ, TNF, IL-1, and IL-6 are induced under conditions of sepsis with gram-negative bacteria and in response to administration of the gram-negative bacterial product endotoxin, i.e., LPS (1, 2). High levels of these cytokines contribute to pathologies characterized as endotoxin-induced shock with wasting, thymic atrophy, and life-threatening states (1–3). Circulating TNF, IL-1, and/or IL-6, elicited as a cascade after exposure to LPS (4–6) or after administration of purified cytokines (7), induce the steroid hormones glucocorticoids. Induction is largely a result of hypothalamic-pituitary-adrenal (HPA)¹ axis activation through stimulating hypothalamus production of corticotropin-releasing hormone (CRH), which induces pituitary release of adrenocorticotropin hormone (ACTH) for stimulation of adrenal gland glucocorticoid production. Glucocorticoids can suppress multiple immune functions, including cytokine production and T cell responses (4, 8, 9). Thus, the immune and neuroendocrine systems can communicate to provide feedback inhibition mechanisms limiting immune responses.In addition to stimulation as a result of cytokine responses to bacterial LPS, glucocorticoid release through the HPA axis occurs as part of circadian rhythm (10) and is induced by a variety of other stimuli including physical or cognitive stress (11), a synthetic analogue for viral nucleic acids, i.e., polyinosinic-polycytidylic acid (poly I:C) (12), and turpentine induction of inflammation (3, 13). The precise pathways for HPA axis activation under each of these conditions has yet to be fully elucidated, and little is known about endogenous induction in response to infections. If glucocorticoids are elicited during challenge with pathogens, they may shape or modulate down-stream T cell functions as well as control acute detrimental cytokinemediated pathologies (4, 8, 9).This laboratory has been examining cytokine responses and functions during viral infections (14–16). In particular, responses to infections of mice with the cytopathic (14–18) murine cytomegalovirus (MCMV) are being investigated. Our group has shown that systemic levels of IL-12, IFN-γ, and TNF are induced at early times after infection (15, 16). The present studies were undertaken to more precisely define the early MCMV-elicited cytokine responses, to extend characterization to IL-1 and IL-6, and to determine the effects of cytokine expression on endogenous glucocorticoid responses. Our results demonstrate that MCMV stimulates dramatic and tightly regulated early IL-12, IFN-γ, TNF, IL-1, and IL-6 responses with an accompanying glucocorticoid response. The key mediator of glucocorticoid induction is shown to be IL-6 with IL-1 acting to stimulate IL-6 production. These studies define an IL-6–dependent pathway for endogenous glucocorticoid induction. Moreover, they suggest that distinct pathways are in place for communication between immune and neuroendocrine systems during infections with different types of pathogens.     

Consensus statement on the diagnosis,treatment and follow‐up of patients with primary adrenal insufficiency

Primary adrenal insufficiency (PAI), or Addison's disease, is a rare, potentially deadly, but treatable disease. Most cases of PAI are caused by autoimmune destruction of the adrenal cortex. Consequently, patients with PAI are at higher risk of developing other autoimmune diseases. The diagnosis of PAI is often delayed by many months, and most patients present with symptoms of acute adrenal insufficiency. Because PAI is rare, even medical specialists in this therapeutic area rarely manage more than a few patients. Currently, the procedures for diagnosis, treatment and follow‐up of this rare disease vary greatly within Europe. The common autoimmune form of PAI is characterized by the presence of 21‐hydroxylase autoantibodies; other causes should be sought if no autoantibodies are detected. Acute adrenal crisis is a life‐threatening condition that requires immediate treatment. Standard replacement therapy consists of multiple daily doses of hydrocortisone or cortisone acetate combined with fludrocortisone. Annual follow‐up by an endocrinologist is recommended with the focus on optimization of replacement therapy and detection of new autoimmune diseases. Patient education to enable self‐adjustment of dosages of replacement therapy and crisis prevention is particularly important in this disease. The authors of this document have collaborated within an EU project (Euadrenal) to study the pathogenesis, describe the natural course and improve the treatment for Addison's disease. Based on a synthesis of this research, the available literature, and the views and experiences of the consortium's investigators and key experts, we now attempt to provide a European Expert Consensus Statement for diagnosis, treatment and follow‐up.     

Occupations with an increased prevalence of self-reported asthma in Indian adults

Objectives: Occupational asthma remains relatively under-recognized in India with little or no information regarding preventable causes. We studied occupations with an increased prevalence of self-reported asthma among adult men and women in India. Methods: Analysis is based on 64?725 men aged 15–54 years and 52?994 women aged 15–49 years who participated in India’s third National Family Health Survey, 2005–2006, and reported their current occupation. Prevalence odds ratios (ORs) for specific occupations and asthma were estimated using multivariate logistic regression, separately for men and women, adjusting for age, education, household wealth index, current tobacco smoking, cooking fuel use, rural/urban residence and access to healthcare. Results: The prevalence of asthma among the working population was 1.9%. The highest odds ratios for asthma were found among men in the plant and machine operators and assemblers major occupation category (OR: 1.67; 95% CI: 1.14–2.45; p?=?0.009). Men working in occupation subcategories of machine operators and assemblers (OR: 1.85; 95% CI: 1.24–2.76; p?=?0.002) and mining, construction, manufacturing and transport (OR: 1.33; 95% CI: 1.00–1.77; p?=?0.051) were at the highest risk of asthma. Reduced odds of asthma prevalence in men was observed among extraction and building trades workers (OR: 0.72; 95% CI: 0.53–0.97; p?=?0.029). Among women none of the occupation categories or subcategories was found significant for asthma risk. Men and women employed in high-risk occupations were not at a higher risk of asthma when compared with those in low-risk occupations. Conclusions: This large population-based, nationally representative cross-sectional study has confirmed findings from high income countries showing high prevalence of asthma in men in a number of occupational categories and subcategories; however, with no evidence of increased risks for women in the same occupations.     

Therapy for women hospitalized with acute pyelonephritis: a randomized trial of ampicillin versus trimethoprim-sulfamethoxazole for 14 days

The efficacy of the traditionally recommended ampicillin (Amp) plus gentamicin (GM) regimen was compared with that of a trimethoprim-sulfamethoxazole (TMP/SMZ)-plus-GM regimen and the adequacy of 14 days total therapy for acute uncomplicated pyelonephritis (AUPN). Eighty-five women hospitalized for AUPN were randomly assigned to receive either Amp, 1 g intravenously (iv) every 6 h for 3 days, then 500 mg orally four times daily, or TMP/SMZ, 160/800 mg iv every 12 h for 3 days, then 160/800 mg orally twice daily. Initially, all patients also received GM every 8 h iv (mean, 606 doses). Antimicrobial resistance necessitated modifying therapy of 14 (32%) of the Amp recipients but of none of the TMP/SMZ recipients (P less than .001). Both regimens produced a satisfactory bacteriologic and clinical response in all cases. Reinfection occurred in 11% of Amp and in 8% of TMP/SMZ recipients. No patient experienced relapsing infection. The TMP/SMZ regimen was less costly and less likely to require modification due to antimicrobial resistance.     

Sociodemographic determinants of telehealth utilisation in general practice during the COVID-19 pandemic in Australia

This analysis assessed the sociodemographic characteristics of telehealth utilisation during the coronavirus disease 2019 (COVID-19) pandemic from March 2020 to August 2021 in Australia. Drawing on 860 general practice providers among 3 161 868 patients, 24 527 274 consultations were recorded. Telehealth accounted for 37.6% of the consultations, with 2.4% through videoconferencing and 35.2% through phone consultations. Our multivariate regression analyses indicated low utilisation of videoconferencing compared with phone consultations among older adults, those living in rural communities and migrants from non-English speaking countries.     

Use of angioplasty in the management of complicated perioperative infarction following bypass surgery

The optimal level of heparin anticoagulation for elective PTCA is unknown. To determine if PTCA complications are related to the level of anticoagulation, serial ACT values were prospectively measured in 189 patients undergoing 201 elective PTCA procedures. The mean heparin dose before balloon inflation (pre-inflation) was 10,100 units, and the mean dose per procedure was 13,200 units. The mean pre-inflation ACT was 295 sec, but was <300 sec in more than 50% of patients. Acute complications were not related to any ACT parameter and the development of new intracoronary thrombus was not observed. In elective PTCA procedures, the routine monitoring of ACT values is unnecessary when standard heparin doses are used. © 1993 Wiley-Liss, Inc.     

Gene transfer into inflamed glomeruli using macrophages transfected with adenovirus

In vivo gene transfer to sites of inflammatory disease provides a novel method both for studying the effects of cytokines and growth factors, and for therapeutic intervention. Macrophages play a pivotal role in the development and control of inflammation and are therefore logical cells to use for genetic modification and in vivo gene delivery. In this study we show that macrophages (both cell lines and primary cultures) can be transfected by recombinant adenoviruses expressing beta-galactosidase, that the macrophages become activated by the transfection process as determined by generation of nitric oxide and can be easily manipulated to localise to inflamed glomeruli after direct injection into the renal artery of rats with an experimentally induced glomerular inflammation caused by nephrotoxic nephritis. The injection of transfected macrophages reduces the severity of injury in this model of glomerulonephritis as shown by a reduction in the degree of albuminuria. This approach provides a favourable system for gene delivery in inflammatory disease and shows that both the functional properties of the transfected macrophage as well the transgene it is engineered to produce are relevant for in vivo gene transfer. Gene Therapy (2000) 7, 263-270.     

The Kozak sequence polymorphism of platelet glycoprotein Ibalpha and risk of nonfatal myocardial infarction and nonfatal stroke in young women

Several platelet membrane glycoprotein polymorphisms have been identified as potential risk factors for cardiovascular disease. Recently a nucleotide -5T/C dimorphism in the translation initiation site (Kozak sequence) of the platelet glycoprotein Ibalpha (GPIbalpha) gene was associated with increased platelet surface levels of the GPIb-IX-V receptor complex. The role of this GPIbalpha Kozak sequence polymorphism in the occurrence of arterial thrombotic disease is unknown. We performed genotype analysis of the Kozak sequence polymorphism of GPIbalpha in a population-based study of 18- to 44-year-old women with nonfatal myocardial infarction (MI) (n = 78), nonfatal stroke (n = 106), and 384 demographically similar female control subjects. Analysis of -5T/C genotypes revealed that at least one copy of the C allele was present in 14.1% of MI cases, 23.6% of stroke cases, and 23.7% of controls. The age-adjusted odds ratio for MI in women carrying at least one copy of the C allele was 0.53 (95% confidence interval [CI] 0.27-1.05). The age-adjusted odds ratio for stroke in women carrying at least one copy of the C allele was 0.99 (95% CI 0.59-1.65). Analyses stratified by stroke type (ischemic, hemorrhagic) yielded similar results. In conclusion, young women carrying the C allele of the Kozak sequence polymorphism of GPIbalpha are not at increased risk of MI or stroke. Paradoxically, the C allele may even be associated with a reduced risk of MI in this population. This finding requires further study.