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Although it has been established that some acute phase responses present differently depending on whether a virus or bacteria activates the innate immune system, it has not yet been established whether fever and sickness behaviors, such as anorexia and lethargy, present differently. We therefore investigated the effects of administering lipopolysaccharide (LPS) and polyinosinic : polycytidylic acid (poly I:C) on body temperature, food intake, body mass, and activity (cage activity and wheel running). Male Sprague-Dawley rats were randomly assigned to receive an intraperitoneal injection of one of LPS (75 µg/kg or 250 µg/kg), poly I:C (3000 µg/kg or 4000 µg/kg), or saline. Administration of LPS or poly I:C induced fever, anorexia, and lethargy. Although voluntary wheel running and cage activity were both significantly reduced after administration of LPS or poly I:C, they were not affected equally. Indeed voluntary wheel running was decreased on average by approximately 30% more than cage activity regardless of the dose or type of mimetic administered. Our results indicate that poly I:C is less effective at inducing anorexia, lethargy, and fever in rats than is LPS, and that avoidance of exercise in animals and humans during infection is likely to be a more prominent feature of illness than is avoidance of routine daily activity. Key words: lipopolysaccharide, polyinosinic : polycytidylic acid, sickness behavior. Il a ete etabli que certaines reponses de phase aigue se presentent differemment selon qu'une virus ou une bacterie active le systeme immunitaire inne; toutefois, on ignore ce qu'il en est des comportements de fievre ou de maladie, comme l'anorexie et la lethargie. Nous avons examine les effets de l'administration de lipopolysaccharide (LPS) et d'acide polyinosinique : polycytidylique (poly I:C) sur la temperature corporelle, l'ingestion de nourriture, la masse corporelle et l'activite (activite de cage et course sur roue). On a soumis aleatoirement des rats Sprague-Dawley males a une injection intraperitoneale de LPS (75 µg/kg ou 250 µ/kg), de poly I:C (3000 µg/kg ou 4000 µg/kg) ou de solution saline. L'administration de LPS ou de poly I:C a induit fievre, anorexie ou lethargie. La course volontaire et l'activite de cage ont diminue de maniere significative apres l'administration de LPS ou de poly I:C, mais a des degres differents. De fait, la course volontaire a diminue en moyenne d'environ 30% de plus que l'activite de cage, independamment de la dose ou du type de substance mimetique administree. Nos resultats indiquent que le poly I:C est moins efficace que le LPS pour induire l'anorexie, la lethargie et la fievre chez les rats et que l'evitement de l'exercice chez les animaux et les humains durant une infection est probablement une caracteristique plus importante de maladie que ne l'est l'evitement d'une activite quotidienne. Mots-cles : lipopolysaccharide, acide polyinosinique : polycytidylique, comportement de maladie. [Traduit par la Redaction], Introduction Fever and sickness behaviors, such as anorexia and decreased activity, are common clinical features of bacterial infections in sick humans and animals (Hart 1988; Plata-Salaman 1996; Cartmell et al. [...]

Abstract Background Whereas the role played by interleukin (IL)-10 in modulating fever and sickness behavior has been linked to it targeting the production of pro-inflammatory cytokines in the circulation, liver and spleen, it is not known whether it could directly target the local production of pro-inflammatory cytokines within the sensory circumventricular organs (CVOs) situated within the brain, but outside the blood–brain barrier. Using inactivation of IL-10, we, therefore, investigated whether IL-10 could modulate the synthesis of pro-inflammatory cytokines within the sensory CVOs, in particular the organum vasculosum laminae terminalis (OVLT) and area postrema (AP). Findings Primary OVLT and AP microcultures were established from topographically excised rat pup brain tissue. The microcultures were pretreated with either IL-10 antibodies (AB) (10 μl/350 μl medium) or phosphate-buffered saline (PBS) (10 μl/350 μl medium) before being incubated with lipopolysaccharide (LPS) (100 μg/ml) or PBS in complete medium for 6 h. Supernatants were removed from the microcultures after 6 h of incubation with LPS and used for the determination of IL-6 and tumor necrosis factor (TNF)-α. Pre-treating the OVLT and AP microcultures with IL-10 antibodies significantly enhanced the LPS-induced increase in TNF-α and IL-6 in the supernatant obtained from the microcultures. Conclusions Our results show for the first time that the LPS-induced release of pro-inflammatory cytokines in cells cultured from the AP and OVLT can be modulated in the presence of IL-10 antibodies. Thus, we have identified that the sensory CVOs may have a key role to play in both the initiation and modulation of neuroinflammation.

Stress-induced hyperthermia following rectal thermometry is reported in normothermic rats, but appears to be muted or even absent in febrile rats. We therefore investigated whether the use of rectal thermometry affects the accuracy of temperature responses recorded in normothermic and febrile rats. Using intra-abdominally implanted temperature-sensitive radiotelemeters we measured the temperature response to rectal temperature measurement in male Sprague Dawley rats (~ 200 g) injected subcutaneously with Brewer's yeast (20 ml/kg of a 20% Brewer's yeast solution = 4000 mg/kg) or saline (20 ml/kg of 0.9% saline). Rats had been pre-exposed to, or were naive to rectal temperature measurement before the injection. The first rectal temperature measurement was taken in the plateau phase of the fever (18 h after injection) and at hourly intervals thereafter. In normothermic rats, rectal temperature measurement was associated with an increase in abdominal temperature (0.66 ± 0.27 °C) that had a rapid onset (5–10 min), peaked at 15–20 min and lasted for 35–50 min. The hyperthermic response to rectal temperature measurement was absent in febrile rats. Exposure to rectal temperature measurement on two previous occasions did not reduce the hyperthermia. There was a significant positive linear association between temperatures recorded using the two methods, but the agreement interval identified that rectal temperature measured with a thermocouple probe could either be 0.7 °C greater or 0.5 °C lower than abdominal temperature measured with radiotelemeter. Thus, due to stress-induced hyperthermia, rectal thermometry does not ensure accurate recording of body temperature in short-spaced, intermittent intervals in normothermic and febrile rats. [ABSTRACT FROM AUTHOR]

Abstract: Intracerebroventricular (i.c.v.) injections of apelins have been shown to modulate the central control of cardiovascular function, as well as the homeostasis of fluid and salt balance, and to some extent also body core temperature. Here, we investigated the effects of i.c.v. administration of [Pyr1]apelin13 (PyrAp13; 20nmol) dissolved in artificial cerebrospinal fluid (aCSF), as compared to aCSF alone, on fever and sickness behavior elicited in rats by intraperitoneal injection of bacterial lipopolysaccharide (LPS, 100μg/kg). Injections of LPS induced a short phase of hypothermia followed by a biphasic fever, depression of motor activity, anorexia and adipsia. I.c.v. injections of PyrAp13 without systemic LPS application slightly augmented motor activity at statistically unaltered core temperature. In combination with LPS, central administration of PyrAp13 significantly reduced fever during the time period of 3–9h after injection, but did not significantly attenuate anorexia and adipsia, and had no effect on LPS-induced lethargy. Rats injected with PyrAp13 along with LPS showed a reduced level of LPS-induced circulating tumor necrosis factor-α (TNF-α). Primary neuroglial cultures established from the hypothalamic paraventricular nucleus (PVN) and the median preoptic nucleus (MnPO), brain sites being of major importance for central thermoregulation and also expressing the apelin receptor, were incubated with medium alone, medium containing LPS (100μg/ml) or LPS plus PyrAp13 (10−6 mol/L). Ninety minutes after start of the incubation, LPS alone but not LPS in combination with PyrAp13 (10−6 mol/L) caused a significant elevation of TNF-α in the supernatants. The novel observation that PyrAp13 represents a centrally acting endogenous antipyretic peptide is discussed in relation to its capacity to modulate peripheral and central formation of TNF-α. [Copyright &y& Elsevier]

Abstract: Although fever and sickness behavior are common responses to infection, it has been proposed that the sickness behaviors associated with infection, in particular lethargy and fatigue, may be more valuable clinical markers of illness and recovery in patients, than is body temperature alone. Measuring abdominal temperature, food intake and wheel running we therefore determined the dose thresholds and sensitivities of these responses to lipopolysaccharide (LPS). Male Sprague–Dawley rats were randomly assigned to receive one of three LPS doses (10, 50, 250 μg/kg), or saline, subcutaneously. Administration of LPS induced a dose-dependent increase in abdominal temperature and decrease in wheel running, food intake and body mass. Regression analysis revealed that decreased running was the most-sensitive of the sickness responses to LPS administration, with a regression slope of −41%/log μg, compared to the slopes for food intake (−30%/log μg, F (1,2) =244, P =0.004) and body mass (−2.2%/log μg, F (1,5) =7491, P <0.0001). To determine the likelihood that exercise training influenced the sickness responses we measured in our dose–response study we performed a second experiment in which we investigated whether fever and anorexia induced by LPS administration would present differently depending on whether rats had been exercising or sedentary. Six weeks of wheel running had no effect on the magnitude of fever and anorexia induced by LPS administration. Avoidance of physical activity therefore appears to be a more-sensitive indicator of a host''s reaction to LPS than is anorexia and fever. [Copyright &y& Elsevier]

Background: Invasive group B Streptococcus (iGBS) sepsis and meningitis are important causes of child mortality, but studies on neurodevelopmental impairment (NDI) after iGBS are limited. Using Griffiths Mental Development Scales-Extended Revised (GMDS-ER), we described NDI in iGBS survivors and non-iGBS children from South Africa, as part of a 5-country study., Methods: We identified children aged 5-8 years with a history of iGBS and children with no history of iGBS between October 2019 and January 2021. Children were matched on sex, and birth data (month, year) (matched cohort study). Moderate or Severe NDI was the primary outcome as a composite of GMDS-ER motor, GMDS-ER cognition, hearing, and vision. Secondary outcomes included mild NDI, any emotional-behavioral problems, and GMDS-ER developmental quotients (DQ) calculated by dividing the age equivalent GMDS-ER score by the chronological age., Results: In total, 160 children (iGBS survivors, 43; non-iGBS, 117) were assessed. Among iGBS survivors 13 (30.2%) had meningitis, and 30 (69.8%) had sepsis. Six (13.9%) iGBS survivors, and 5 (4.3%) non-iGBS children had moderate or severe NDI. Children who survived iGBS were 5.56 (95% confidence interval [CI]: 1.07-28.93; P = .041) times more likely to have moderate or severe NDI at 5-8 years than non-iGBS children. Compared to the non-iGBS children, iGBS meningitis survivors had a significantly lower global median DQ (P < .05), as well as a lower median DQ for the language GMDS-ER subscale and performance GMDS-ER subscale (P < .05)., Conclusions: Children surviving iGBS, particularly meningitis, are more likely to have NDI at 5-8 years compared to non-iGBS children. Further research is required to improve detection and care for at-risk newborns., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America.)

Sepsis and meningitis due to invasive group B Streptococcus (iGBS) disease during early infancy is a leading cause of child mortality. Recent systematic estimates of the worldwide burden of GBS suggested that there are 319,000 cases of infant iGBS disease each year, and an estimated 147,000 stillbirths and young-infant deaths, with the highest burden occurring in Sub-Saharan Africa.  The following priority data gaps were highlighted: (1) long-term outcome data after infant iGBS, including mild disability, to calculate quality-adjusted life years (QALYs) or disability-adjusted life years (DALYs) and (2) economic burden for iGBS survivors and their families. Geographic data gaps were also noted with few studies from low- and middle- income countries (LMIC), where the GBS burden is estimated to be the highest. In this paper we present the protocol for a multi-country matched cohort study designed to estimate the risk of long-term neurodevelopmental impairment (NDI), socioemotional behaviors, and economic outcomes for children who survive invasive GBS disease in Argentina, India, Kenya, Mozambique, and South Africa. Children will be identified from health demographic surveillance systems, hospital records, and among participants of previous epidemiological studies. The children will be aged between 18 months to 17 years. A tablet-based custom-designed application will be used to capture data from direct assessment of the child and interviews with the main caregiver. In addition, a parallel sub-study will prospectively measure the acute costs of hospitalization due to neonatal sepsis or meningitis, irrespective of underlying etiology. In summary, these data are necessary to characterize the consequences of iGBS disease and enable the advancement of effective strategies for survivors to reach their developmental and economic potential. In particular, our study will inform the development of a full public health value proposition on maternal GBS immunization that is being coordinated by the World Health Organization., Competing Interests: Competing interests: P. Lambach works for the World Health Organization (WHO). The authors alone are responsible for the views expressed in this publication and they do not necessarily represent the decisions, policy or views of the WHO., (Copyright: © 2020 Paul P et al.)