Estimating seasonal onsets and peaks of bronchiolitis with spatially and temporally uncertain data.

RSV bronchiolitis (an acute lower respiratory tract viral infection in infants) is the most common cause of infant hospitalizations in the United States (US). The only preventive intervention currently available is monthly injections of immunoprophylaxis. However, this treatment is expensive and needs to be administered simultaneously with seasonal bronchiolitis cycles in order to be effective. To increase our understanding of bronchiolitis timing, this research focuses on identifying seasonal bronchiolitis cycles (start times, peaks, and declinations) throughout the continental US using data on infant bronchiolitis cases from the US Military Health System Data Repository. Because this data involved highly personal information, the bronchiolitis dates in the dataset were "jittered" in the sense that the recorded dates were randomized within a time window of the true date. Hence, we develop a statistical change point model that estimates spatially varying seasonal bronchiolitis cycles while accounting for the purposefully introduced jittering in the data. Additionally, by including temperature and humidity data as regressors, we identify a relationship between bronchiolitis seasonality and climate. We found that, in general, bronchiolitis seasons begin earlier and are longer in the southeastern states compared to the western states with peak times lasting approximately 1 month nationwide.

Seasonal patterns of Asthma medication fills among diverse populations of the United States.

OBJECTIVE: Nonadherence to controller and overuse of reliever asthma medications are associated with exacerbations. We aimed to determine patterns of seasonal asthma medication use and to identify time period(s) during which interventions to improve medication adherence could reduce asthma morbidity. METHODS: We conducted a retrospective cohort study of asthmatics 4-50 years of age and enrolled in three diverse health insurance plans. Seasonal patterns of medications were reported by monthly prescription fill rates per 1000 individuals with asthma from 1998 to 2013, and stratified by healthcare plan, sex, and age. RESULTS: There was a distinct and consistent seasonal fill pattern for all asthma medications. The lowest fill rate was observed in the month of July. Fills increased in the autumn and remained high throughout the winter and spring. Compared with the month of May with high medication fills, July represented a relative decrease of fills ranging from 13% (rate ratio, RR: 0.87, 95% confidence interval, 95%CI: 0.72-1.04) for the combination of inhaled corticosteroids (ICS) + long acting beta agonists (LABA) to 45% (RR: 0.55, 95%CI: 0.49-0.61) for oral corticosteroids. Such a seasonal pattern was observed each year across the 16-year study period, among healthcare plans, sexes, and ages. LABA containing control medication (ICS+LABA and LABA) fill rates were more prevalent in older asthmatics, while leukotriene receptor antagonists were more prevalent in the younger population. CONCLUSIONS: A seasonal pattern of asthma medication fill rates likely represents a reactive response to a loss of disease control and increased symptoms. Adherence to and consistent use of asthma medications among individuals who use medications in reaction to seasonal exacerbations might be a key component in reducing the risk of asthma exacerbations.

A dedicated undergraduate gynaecology teaching clinic: The Keele experience.

Much discussion in the literature centres on how best to teach medical students the intricacies of gynaecological assessment and the subsequent formulation of a management plan. At Keele University skills are initially developed in a simulated setting and then transferred to the workplace where students continue to develop their skills. A dedicated undergraduate gynaecology teaching clinic has been developed and comprises of 2-3 students and a tutor. All 38 students rotating through the department between January and June 2013 were invited to complete an anonymous questionnaire to evaluate this clinic and 36 (95%) of them responded. Respondents felt significantly more comfortable taking a gynaecology history, ensuring privacy during examination and formulating a management plan post-clinic (all p < 0.001), with female students feeling significantly more comfortable than their male counterparts (p = 0.04). The use of this clinic shows great promise to help students learn an unfamiliar and challenging skill.

Pedi-R-MAPP | the development, testing, validation, and refinement of a digital nutrition awareness tool.

BACKGROUND & AIMS: The Remote Malnutrition Application (R-MAPP) was developed during the COVID-19 pandemic to provide support for health care professionals (HCPs) working in the community to complete remote nutritional assessments and provide practical guidance for nutritional care. R-MAPP was adapted into Pediatric Remote Malnutrition Application (Pedi-R-MAPP) using a modified Delphi consensus, with the goal of providing a structured approach to completing a nutrition focused assessment as part of a technology enabled care service (TECS) consultation. The aim of this study was to develop and validate a digital version of Pedi-R-MAPP using the IDEAS framework (Integrate, Design, Assess and Share). METHODS: A ten-step process was completed using the IDEAS framework. This involved the four concept processes; Stage-1, Integrate (Step 1-3) identify the problem, specify the goal, and use an evidence-based approach. Stage-2, (Step 4-7) design iteratively and rapidly with user feedback. Stage 3, (Step 8-9) Assess rigorously, and Stage 4 (Step 9-10) publish and launch of the tool. RESULTS: Stage 1:Evidence-based development, Pedi-R-MAPP was developed using Delphi consensus methodology. Stage 2:Iteration & design, HCPs (n = 22) from UK, Europe, South Africa, and North America were involved four workshops to further develop a paper prototype of the tool and complete small-scale testing of a beta version of the tool which resulted in eight iterations. Stage 3:Assess rigorously, Small scale retrospective testing of the tool on children with congenital heart disease (n = 80) was completed by a single researcher, with iterative changes made to improve agreement with summary advice. Large scale testing amongst (n = 745) children in different settings was completed by specialist paediatric dietitians (n = 15) advice who recorded agreement with the summary advice compared with their own clinical assessment. Paediatric dietitians were in overall agreement with the summary advice in the tool 86% (n = 640), compared to their own clinical practice. The main reasons for disagreement were i) frequency of planned review 57.1% (n = 60/105), ii) need for ongoing dietetic review due to chronic condition 20.0% (n = 21/105), iii) disagreement with recommendation for discharge 16.2% (n = 17/105) and iv) concerns with faltering growth and/or need for condition specific growth charts 6.7% (7/105). Iterative changes were made to the algorithm, leading to an improvement in agreement of the summary advice on re-evaluation to 98% (p=<0.0001). CONCLUSION: A digital version of the Pedi-R-MAPP nutrition awareness tool was developed using the IDEAS framework. The summary advice provided by the tool achieved a high level of agreement when compared to paediatric dietetic assessment, by providing a structured approach to completing a remote nutrition focused assessment, along with identifying the frequency of follow-up or an in-person assessment.

Validation of International Classification of Diseases criteria to identify severe influenza hospitalizations.

In this cohort study of hospitalized patients with linked medical record data, we developed International Classification of Diseases (ICD) criteria that accurately identified laboratory-confirmed, severe influenza hospitalizations (positive predictive value [PPV] 80%, 95% confidence interval [CI] 71-87%), which we validated through medical record documentation. These criteria identify patients with clinically important influenza illness outcomes to inform evaluation of preventive and therapeutic interventions and public health policy recommendations.

Successful renal transplantation in factor H autoantibody associated HUS with CFHR1 and 3 deficiency and CFH variant G2850T.

Factor H (CFH) autoantibodies are associated with atypical hemolytic uremic syndrome (aHUS). Peritransplantation plasma exchange therapy and intensification of immunosuppression, with adjuvant use of anti-CD20 monoclonal antibodies has recently been advocated for cases of CFH-autoantibody associated aHUS. In this report, we describe successful deceased donor renal transplantation in a case of CFH-autoantibody associated aHUS with combined CFHR1 and 3 deficiency in addition to the CFH sequence variant, (cG2850T, pGln950His). CFH-autoantibodies were detected 2 weeks prior to transplantation. Disease recurrence was not observed using basiliximab, an IL2-receptor antagonist and high-dose corticosteroids with mycophenolate mofetil. Adjuvant therapies such as Rituximab nor intensification of plasma therapy were employed. Consequently, careful consideration needs to be given to the use of additional immunosuppression in certain cases of CFH-autoantibody associated aHUS. Serial measurement of CFH-autoantibodies is required in the immediate pre- and posttransplantation period to further clarify their role as a factor in the recurrence of aHUS posttransplantation. Furthermore, delineation of the functional significance of CFH-autoantibodies is warranted in individual cases.

Calcineurin-inhibitor free immunosuppression with mycophenolate mofetil and corticosteroids in paediatric renal transplantation improves renal allograft function without increasing acute rejection.

The aim of this study was to determine whether CNIs can be safely withdrawn in paediatric patients with declining renal allograft function receiving MMF and corticosteroids for long-term immunosuppression following renal transplantation. We performed a retrospective review of paediatric renal transplant recipients who received MMF with corticosteroids at least three months after transplantation with or without CNI in a single centre. Thirty-eight children (71% male), mean age 7.2 +/- 3.7 yr received MMF and corticosteroids, with 29 (76%) receiving a CNI. Mean follow-up was 59.2 +/- 42 months post-MMF commencement and 109 +/- 98.8 months post-transplantation. Patient and renal allograft survival were 100% and 94%, respectively. There was a significant improvement in eGFR after MMF introduction both in children on a CNI and those where the CNI was withdrawn, with stabilisation of eGFR after two yr. There was no significant difference in the number of acute rejection episodes prior to or following introduction of MMF between the groups. MMF in combination with corticosteroids is a safe and effective immunosuppressive regimen in paediatric renal transplantation. Complete withdrawal of CNIs after conversion to MMF should be considered in all patients, to preserve renal function as evidenced by improved eGFR.

Risks from Breathing Elevated Oxygen.

INTRODUCTION: Effects of breathing gas with elevated oxygen partial pressure (Po2) and/or elevated inspired oxygen fraction (FIo2) at sea level or higher is discussed. High FIo2 is associated with absorption problems in the lungs, middle ear, and paranasal sinuses, particularly if FIo2 > 80% and small airways, Eustachian tubes, or sinus passages are blocked. Absorption becomes faster as cabin altitude increases. Pulmonary oxygen toxicity and direct oxidative injuries, related to elevated Po2, are improbable in flight; no pulmonary oxygen toxicity has been found when Po2 < 55 kPa [418 Torr; 100% O2 higher than 15,000 ft (4570 m)]. Symptoms with Po2 of 75 kPa [520 Torr; 100% O2 at 10,000 ft (3050 m)] were reported after 24 h and the earliest signs at Po2 of 100 kPa (760 Torr, 100% O2 at sea level) occurred after 6 h. However, treatment for decompression sickness entails a risk of pulmonary oxygen toxicity. Elevated Po2 also constricts blood vessels, changes blood pressure control, and reduces the response to low blood sugar. With healthy lungs, gas transport and oxygen delivery are not improved by increasing Po2. Near zero humidity of the breathing gas in which oxygen is delivered may predispose susceptible individuals to bronchoconstriction.Shykoff BE, Lee RL. Risks from breathing elevated oxygen. Aerosp Med Hum Perform. 2019; 90(12):1041-1049.

Reduced thioredoxin increases proinflammatory cytokines and neutrophil influx in rat airways: modulation by airway mucus.

Thioredoxin (Trx) decreases viscosity of cystic fibrosis (CF) sputum. In this study reduced Trx increased the solubility and decreased the size of MUC5B glycoprotein while reducing disulfide bonds in sputum. Because Trx used as a mucolytic would enter airways, this study determined the effects of intratracheal instillation of reduced recombinant human thioredoxin (rhTrx) in naïve rat airways. Reduced rhTrx increased neutrophils and the cytokines TNFalpha, CINC2beta, and MIP3alpha in airways after 4 h. The effect of rhTrx was concentration-dependent. Exposure to saline, human serum albumin, or oxidized rhTrx at equal molarities did not increase airway neutrophils or cytokines. Instilling CF sputum (50 microl) into the lung before reduced rhTrx delivery attenuated these responses. This suggests that rhTrx reduces disulfide bonds present in CF sputum, limiting the reduction of other lung constituents. Together these findings indicate that the chemotactic and cytokine responses are due to the reducing potential of rhTrx and that the potential for inflammation in non-CF and CF patients given aerosolized rhTrx may differ. In parallel studies, increased amounts of the p65 subunit of NF-kappaB were present in nuclear extracts from rat lungs administered reduced rhTrx, suggesting a role for NF-kappaB in these proinflammatory responses.

Expression of pro-opiomelanocortin gene and quantification of adrenocorticotropic hormone-like immunoreactivity in human normal peripheral mononuclear cells and lymphoid and myeloid malignancies.

Using Northern blotting with a human genomic DNA probe for the pro-opiomelanocortin (POMC) gene, we have shown specific mRNA in normal human peripheral mononuclear cells (PBMC); the presence of specific mRNA was also observed in a T lymphocyte cell line derived from a patient with lymphoma. We then demonstrated that PBMC translate the message into protein. Thus, using a radioimmunoassay with an antibody for ACTH, a median of 29 pg of ACTH-like immunoreactivity (ACTH-LIR) was found in 10(7) PBMC. ACTH-LIR was also detected in seven different cell lines derived from patients with lymphoid and myeloid malignancies, two of them JM and U937 showing the highest values 135 and 108 pg/10(7) cells, respectively. The chromatographic characterization of this ACTH-LIR showed, at least, three molecular forms of immunoreactive ACTH with molecular weights of the order of 31,000 POMC, 22,000 ACTH, and 4,500 ACTH, in addition to high-molecular-weight material (greater than 43,000). We conclude that PBMC produce ACTH-LIR which may act as a paracrine immunomodulator in a similar way to lymphokines and/or may signal the adrenal gland to secrete glucocorticoids.

Mothers of Africa--an anaesthesia charity.

An anaesthetic charity 'Mothers of Africa' has been established as a link between the academic departments of anaesthesia in Togo and Benin and the University Hospital of Wales. Visits by UK consultant anaesthetists have identified a number of clinical areas where collaborative working in both classroom and theatre has the potential to improve outcomes in maternal mortality and morbidity.

Perinatal renal venous thrombosis: presenting renal length predicts outcome.

BACKGROUND: Renal venous thrombosis (RVT) is the most common form of venous thrombosis in neonates, causing both acute and long term kidney dysfunction. Historical predisposing factors include dehydration, maternal diabetes, and umbilical catheters, but recent reports highlight associations with prothrombotic abnormalities. STUDY: Twenty three patients with neonatal RVT were analysed over 15 years. Predisposing factors, presentation, and procoagulant status were compared with renal outcome using multilevel modelling. RESULTS: Median presentation was on day 1: 19/23 (83%) had pre/perinatal problems, including fetal distress (14), intrauterine growth retardation (five), and pre-identified renal abnormalities (two); 8/18 (44%) had procoagulant abnormalities, particularly factor V Leiden mutations (4/18). Long term abnormalities were detected in 28/34 (82%) affected kidneys; mean glomerular filtration rate was 93.6 versus 70.2 ml/min/1.73 m2 in unilateral versus bilateral cases (difference 23.4; 95% confidence interval 6.4 to 40.4; p = 0.01). No correlation was observed between procoagulant tendencies and outcome, but presenting renal length had a significant negative correlation: mean fall in estimated single kidney glomerular filtration rate was 3 ml/min/1.73 m2 (95% confidence interval 3.7 to -2.2; p = 0.001) per 1 mm increase, and kidneys larger than 6 cm at presentation never had a normal outcome. CONCLUSIONS: This subgroup of neonatal RVT would be better termed perinatal RVT to reflect antenatal and birth related antecedents. Prothrombotic defects should be considered in all patients with perinatal RVT. Kidney length at presentation correlated negatively with renal outcome. The latter, novel observation raises the question of whether larger organs should be treated more aggressively in future.

The economic burden of spinal muscular atrophy.

AIM: To evaluate the economic burden of spinal muscular atrophy (SMA). MATERIALS AND METHODS: This study used Department of Defense Military Healthcare System (MHS) data from 2003-2012. Healthcare costs were determined for patients with at least one inpatient or three outpatient claims with a diagnosis of SMA before 18 years of age and who had ≥ 6 months of data after first SMA diagnosis or expired within 6 months of initial diagnosis. A comparator cohort was selected using a 3:1 match based on age and gender. RESULTS: A total of 239 individuals with SMA diagnosis met the inclusion criteria along with 717 matched comparator patients. More patients with SMA had hospitalizations (69.5%) compared to the comparator cohort (17.2%, p < 0.001). Median total expenditures across all years of data for patients with SMA were $83 652 (25-75th percentile = $29 620-228 754) vs the comparator group of $4329 (25-75(th) percentile = $1229-10 062 (p < 0.001)) over an average (SD) of 6.9 ± 3.6 years. The annualized mean costs of total healthcare expenditures were significantly higher for the SMA cases than the comparison cohort, $47 862 ± 88 607 compared to $1861 ± 6374, respectively (p < 0.001). The sub-group of patients with early diagnosis (n = 45) had 4.3 ± 2.9 years of observation with a median cost of $167 921 ($53 349-678 412). Mean age (SD) at first observed SMA diagnosis was 7.5 ± 6.4 years. Mean (SD) duration of follow-up after initial SMA diagnosis was 4.8 ± 3.3 years, with a median post-diagnosis cost of $60 213 ($18 229-192 559). The major costs for all patients were outpatient visits [median = $53 152 ($23 902-136 150)], followed by inpatient costs [median = $11 258 ($0-51 987)] and total prescription costs [median = $3167 ($943-13 283)]. LIMITATIONS: The analysis is limited to the data available and may under-estimate the total cost of SMA. CONCLUSIONS: Individuals with SMA have a high degree of morbidity, particularly those diagnosed during infancy. SMA patients have significant medical expenditures and high utilization of healthcare services.

Does oral folic acid lower total homocysteine levels and improve endothelial function in children with chronic renal failure?

BACKGROUND: Accelerated vascular disease is common in chronic renal failure (CRF) and accounts for significant mortality and morbidity. Elevated homocysteine levels may contribute by an effect on endothelial function. METHODS AND RESULTS: We performed a double-blind placebo-controlled randomized crossover trial of folic acid at 5 mg/m2 in 25 normotensive children 12+/-3 (7 to 17) years of age with CRF (glomerular filtration rate 26.8+/-13.2 mL/min per 1.73 m2) of noninflammatory etiology. Each subject underwent two 8-week periods of folic acid and placebo separated by an 8-week washout period. The effect of folic acid on homocysteine levels, LDL oxidation, and both endothelial-dependent and -independent vascular function were measured. After oral folic acid, serum folate levels rose from 11.7+/-4.25 to 635+/-519 microg/L (P=0.001), red cell folate levels rose from 364+/-195 to 2891+/-2623 microg/L (P<0.001), and total homocysteine levels fell from 10.28+/-4.16 to 8.62+/-2.32 micromol/L (P=0.03). In addition, there was a significant improvement in flow-mediated dilatation (FMD) (endothelial-dependent dilatation) from 7.21+/-2.8% to 8.47+/-3.01% (P=0.036) with no change in response to glyceryl trinitrate (endothelial-independent dilatation). There was no significant change in FMD or glyceryl trinitrate during the placebo phase. There was, however, no significant difference in final FMD after placebo or folic acid. Lag times for LDL oxidation were prolonged during the treatment phase (58.4+/-18.7 to 68.1+/-25.9 minutes, P=0.01). CONCLUSION: Folic acid supplementation in children with CRF may improve endothelial function with an increased resistance of LDL to oxidation.

Validation of computer-assisted, pixel-based analysis of multiple-colour immunofluorescence histology.

Developments in immunohistology allow the routine simultaneous use on tissue sections of three monoclonal antibodies, tagged with different fluorochromes. Such staining can identify seven different cell populations and the limiting factor is rapid, reliable and reproducible analysis. Future reliance on computer-assisted analysis of digitised images depends on validation against manual counting, often viewed as the 'gold standard'. In this study images were digitised from sections of normal porcine skin, inflamed skin and tonsil, simultaneously stained with three monoclonal antibodies. Combinations of staining were quantified by four manual counts and by pixel-based area measurement. On individual images, the correlation between automated and manual measurements was poor. Despite this, the concordance between manual and automated measurements in the means and variances of tissues was good, and both techniques identified the same changes in inflamed versus normal tissues. In addition, pixel-based counting permitted statistical analysis of co-localisation of cell types in tissue sections. We conclude that automated counting is acceptable for the assessment of tissues, is faster and provides less opportunity for observer variation than manual counting. We also demonstrate that the technique is applicable where more than three fluorochromes are used such that manual counting becomes essentially impossible.

In vitro and in vivo analysis of the processing and fate of the peptide products of the short proopiomelanocortin mRNA.

Many peripheral tissues express the proopiomelanocortin (POMC) gene as an 800-base mRNA that lacks the 5' end of the 1200-base pituitary transcript. The missing region encodes the peptide signal sequence, and thus, it is unlikely that any translation product would be secreted. We have found that a RNA transcript equivalent to this short message, generated by transcription in vitro from a T7 polymerase promoter, is translatable in a rabbit reticulocyte lysate, generating peptides of 27.5, 22.5, and 15.5 kD. None of these peptides appears to be processed or protected from proteinase-K digestion by a microsomal membrane fraction. In vivo studies were undertaken by transfecting into GH3 cells one of two expression vectors containing sequences that would produce either a full-length mRNA or a short (800-base) mRNA. The neomycin resistance gene was cotransfected with these plasmids, and 30 permanent cell lines were produced after selection in G418. Cell lines containing the full-length RNA secreted large quantities of ACTH and beta-endorphin immunoreactivity, whereas those expressing the short transcript secreted neither of these peptides. However extractable peptide was present in this latter type of cell line, thereby suggesting that the 800-base mRNA was translated, and that no peptide reached the secretory vesicle. These findings raise important questions about the role of peripheral POMC gene expression.

Acetylcholine and norepinephrine stimulate the release of corticotropin-releasing factor-41 from the rat hypothalamus in vitro.

The effects of the two putative neurotransmitters acetylcholine and norepinephrine on immunoreactive CRF-41 release from incubated rat hypothalami were studied. Acetylcholine at concentrations of 10(-11) to 10(-7) M stimulated CRF-41 release. This effect was blocked in a dose-dependent manner by the muscarinic antagonist atropine (10(-9) to (-7) M). The nicotinic antagonist hexamethonium was ineffective at a dose of 10(-7) M, but produced slight inhibition of this response at 10(-5) M. Norepinephrine at concentrations of 10(-10) to 10(-6) M also produced a dose-dependent stimulation of CRF-41 release. The beta-adrenoceptor antagonists propranolol (10(-5) M) and timolol (10(-6) M) blocked norepinephrine-induced CRF-41 release. The alpha 1-adrenoceptor antagonists thymoxamine (10(-5) M), prazosin (10(-5) M), and corynanthine (10(-4) M), and the alpha 2-antagonist idazoxan (10(-5) M), were ineffective. Potassium depolarization (56 mM) caused stimulation of CRF-41 release which was dependent on the presence of calcium in the incubation medium. Authenticity of immunoreactive CRF-41 released was demonstrated by chromatographic criteria using gel filtration and reversed phase HPLC. These results provide evidence for a stimulatory role of acetylcholine and norepinephrine on CRF-41 release, and consequently on hypothalamo-pituitary-adrenal axis in the rat, through actions at a hypothalamic level. The stimulatory effect of acetylcholine is mediated principally through muscarinic receptors and that of norepinephrine through beta-adrenoceptors.

Morphine directly modulates the release of stimulated corticotrophin-releasing factor-41 from rat hypothalamus in vitro.

The actions of opioids and opiates on the hypothalamo-pituitary-adrenal axis are currently controversial. In the rat, morphine is reported to both stimulate and inhibit ACTH and corticosterone secretion, but the precise sites and mechanisms of these effects have remained unclear. To analyze further the hypothalamic actions of morphine, we have investigated its effect on hypothalamic fragments in vitro and measured the major CRF, CRF-41, by a specific RIA. The acute effects of morphine on both basal and stimulated ACTH release from dispersed pituitary cells were also investigated. Morphine (10(-8)-10(-6) M) did not significantly alter the basal secretion of CRF-41. However, similar concentrations of morphine inhibited CRF-41 release stimulated by norepinephrine in a dose-dependent manner. Similarly, morphine (10(-6) M) inhibited acetylcholine (10(-9) M)- and serotonin (10(-7) M)-stimulated CRF-41 release. The stimulatory effect on CRF-41 release induced by veratridine (10(-6) M) was inhibited by approximately 50% in the presence of morphine. KCl (28 nM)-mediated CRF-41 release was also significantly inhibited by morphine. Naloxone (10(-7)-10(-5) M) had no significant effect on either basal or norepinephrine-induced CRF-41 release, but reversed the inhibitory effect of morphine on norepinephrine-induced CRF-41 secretion in a dose-dependent manner. Morphine (10(-6)-10(-5) M) had no effect on either basal or CRF-41-stimulated ACTH release from dispersed pituitary cells. These data suggest that the predominant effect of morphine on hypothalamic CRF-41 release in vitro is suppression of the release induced by a variety of putative neurotransmitters and depolarizing agents. This inhibitory effect is reversed by naloxone, suggesting that it is mediated by opiate receptors, presumably situated directly on CRF-41 neurons.

Interleukins-1 and -6 stimulate the release of corticotropin-releasing hormone-41 from rat hypothalamus in vitro via the eicosanoid cyclooxygenase pathway.

It has previously been shown that interleukin-1 (IL-1) directly stimulates the release of CRH-41 from rat hypothalamus in vitro, suggesting that cytokines may mediate the effects of changes in immune state on the hypothalamo-pituitary adrenal axis (HPA). However, it is likely that several cytokines can cause changes in neuroendocrine function, and we have now investigated a series of others for central activity on the HPA: IL-2, IL-6, IL-8, tumor necrosis factor (cachectin), interferon-alpha 2, and interferon-gamma. The static rat hypothalamic incubation system used involves fresh hypothalamic explants with consecutive 20-min incubation, and estimation of CRH-41 concentrations in the medium by a specific RIA; the acute effects of cytokines on ACTH release from rat dispersed pituitary cells were also measured. IL-6 increased hypothalamic CRH-41 secretion in the range 10-100 U/ml, but had no effect on isolated median eminences incubated in vitro under the same conditions. IL-6 (1-1000 U/ml) also had no effect on the secretion of ACTH from freshly dispersed rat anterior pituitary cells when administered in 10-min pulses. The effects of both IL-1 and IL-6 were antagonized by blockade of the eicosanoid cyclooxygenase pathway, but not by lipooxygenase blockade. Neither IL-2 (1-10000 U/ml), IL-8 (0.1-10 nM), tumor necrosis factor (10-1000 U/ml), interferon-alpha 2 (10-1000 U/ml) nor interferon-gamma (10-1000 U/ml) had any effect on hypothalamic CRH-41 release or pituitary ACTH release. It is therefore concluded that IL-6, like IL-1, can exert a potent enhancing effect on the HPA by acutely stimulating the secretion of CRH-41 from the hypothalamus at a site above the level of the median eminence, at concentrations known to occur in human plasma and cerebrospinal fluid. These effects are probably mediated by cyclooxygenase products. Acute stimulatory effects of the other cytokines investigated on the HPA are unlikely to be exerted through changes in either CRH-41 or ACTH directly.