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Immunization of pregnant women with Group B Streptococcus (GBS) capsular polysaccharide (CPS) conjugate vaccine (CV) could protect young infants against invasive GBS disease. We evaluated the immunogenicity of investigational five GBS monovalent (serotypes Ia, Ib, II, III, and V) CPS-tetanus toxoid (TT)-CV with adjuvant and GBS pentavalent CPS-TT-CV with adjuvant (GBS5-CV-adj) and without adjuvant (GBS5-CV-no-adj), in Balb/c mice. Aluminum phosphate was the adjuvant in the formulations, where included. The homotypic immunoglobulin G (IgG) geometric mean concentration (GMC) and opsonophagocytic activity (OPA) geometric mean titer (GMT) did not differ after the third dose of the GBS5-CV-adj vaccine compared with the monovalent counterparts for all five serotypes. The GBS5-CV-adj induced higher post-vaccination serotype-specific IgG GMCs and OPA GMTs compared to GBS5-CV-no_adj. The GBS5-CV with and without adjuvant should be considered for further development as a potential vaccine for pregnant women to protect their infants against invasive GBS disease., Competing Interests: N.D., S.A.M, G.K. institution received funding from Biovac. F.K., E.M., S.W., P.T., M.W., S.D., P.V.Z, M.J.R., T.A were employees of Biovac at the time the work was carried out and received funding Department of Health and Social Care using UK Aid for this Study. All other authors declare no conflict of interest., (© 2023 The Author(s).)

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: © 2021 Paul P et al.)

High mobility group box (HMGB)1 action contributes to late phases of sepsis, but the effects of increased endogenous plasma HMGB1 levels on brain cells during inflammation are unclear. Here, we aimed to further investigate the role of HMGB1 in the brain during septic-like lipopolysaccharide-induced inflammation in rats (LPS, 10 mg/kg, i.p.). HMGB-1 mRNA expression and release were measured in the periphery/brain by RT-PCR, immunohistochemistry and ELISA. In vitro experiments with disulfide-HMGB1 in primary neuro-glial cell cultures of the area postrema (AP), a circumventricular organ with a leaky blood-brain barrier and direct access to circulating mediators like HMGB1 and LPS, were performed to determine the direct influence of HMGB1 on this pivotal brain structure for immune-to-brain communication. Indeed, HMGB1 plasma levels stayed elevated after LPS injection. Immunohistochemistry of brains and AP cultures confirmed LPS-stimulated cytoplasmatic translocation of HMGB1 indicative of local HMGB1 release. Moreover, disulfide-HMGB1 stimulation induced nuclear factor (NF)-κB activation and a significant release of interleukin-6, but not tumor necrosis factor α, into AP culture supernatants. However, only a few AP cells directly responded to HMGB1 with increased intracellular calcium concentration. Interestingly, priming with LPS induced a seven-fold higher percentage of responsive cells to HMGB1. We conclude that, as a humoral and local mediator, HMGB1 enhances brain inflammatory responses, after LPS priming, linked to sustained sepsis symptoms.

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.)

Brewer's yeast, derived from the yeast species Saccharomyces cerevisiae (S. cerevisiae), is commonly used for inducing pyrexia in pharmacological studies screening antipyretics in rats. Despite its widespread use, the peripheral and central inflammatory response associated with Brewer's yeast-induced fever and sickness behavior in rats has not been investigated. Thus, we injected male Sprague-Dawley rats (150-200 g) subcutaneously with a high (4 g/kg, n = 9), medium (2 g/kg, n = 5) or low (0.4 g/kg, n = 6) dose of Brewer's yeast solution or saline (0.9%, n = 6) and measured core body temperature, cage activity, food intake and body mass for six days after injection. Blood and brain samples were collected at 2, 8, 18 and 72 h after injection; n = 5-7 per time point. Brewer's yeast administration dose-dependently induced fever, lethargy, anorexia and body mass stunting that was accompanied by increased blood plasma levels of interleukin (IL)-6 and tumor necrosis factor (TNF)-α and activation of inflammatory transcription factors (nuclear factor (NF) for interleukin-6, signal transducer and activator of transcription (STAT)-3, and NF-κB)) in the hypothalamus and circumventricular organs. The increased activation of transcription factors following Brewer's yeast administration was accompanied by increased hypothalamic mRNA expression of TNF-α, IL-1β and IL-6 and rate-limiting enzymes for prostaglandin synthesis. Our results show that subcutaneous administration of S. cerevisae induces prolonged fever, anorexia and lethargy that is accompanied by a pronounced increase in the synthesis of pro-inflammatory cytokines, key prostaglandin synthesizing enzymes and transcription factors, in the periphery and brain., (Copyright © 2017 Elsevier Inc. All rights reserved.)

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 (~200g) injected subcutaneously with Brewer's yeast (20ml/kg of a 20% Brewer's yeast solution=4000mg/kg) or saline (20ml/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 (18h 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 (5-10min), peaked at 15-20min and lasted for 35-50min. 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., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The influence of brain interleukin-1 (IL-1ß) on memory processes includes both detrimental and beneficial effects. To further explore the dynamics of brain IL-1ß in mediating learning and memory during acute sickness, we injected species-homologous rat IL-1ß (100ng/5μl) or vehicle (0.1% bovine serum albumin, 5μl) directly into the cisterna magna (i.c.m.) of male Sprague-Dawley rats. We measured, in parallel, body temperature, food intake, body mass, cage activity, as well as learning and memory using contextual fear conditioning. To investigate the effects of IL-1ß on learning and memory processes we used: (1) a retrograde experiment that involved injecting rats i.c.m. with IL-1ß immediately after training in the novel context, and (2) an anterograde experiment that involved injecting rats i.c.m. with IL-1ß two hours before training in the novel context. In addition, hypothalamic and hippocampal concentrations of IL-1β were measured at several time points following injection. Administration of IL-1ß induced fever, lethargy and anorexia for∼two-to-three days and increased the concentration of IL-1ß in the hippocampus and hypothalamus for at least eight hours. Training in the context immediately before IL-1ß administration (retrograde experiment), did not impair contextual and auditory fear memory. However, when training in the context occurred concurrently with elevated hippocampal IL-1ß levels, two hours after IL-1ß administration (anterograde experiment), contextual, but not auditory, fear memory was impaired. Our results show that there are instances where memory consolidation can occur concurrently with elevated levels of IL-1ß in the hippocampus, fever, anorexia and lethargy during acute short-term sickness., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Despite the documented post-infectious neurological complications of a central nervous system (CNS) Mycoplasma infection in humans, very few studies have investigated the acute inflammatory responses and sickness behaviours induced by CNS Mycoplasma infections. We therefore determined the effect of acute central administration of fibroblast-stimulating lipopeptide-1 (FSL-1), derived from Mycoplasma salivarium, and FAM-20 from a more pathogenic species, namely Mycoplasma pneumoniae, on behavioural and inflammatory responses in rats. Male Sprague-Dawley rats had radiotransmitters implanted, intra-abdominally, to measure body temperature and cage activity continuously. After recovery from surgery, rats were conditioned in a fear conditioning task and then immediately received an intra-cisterna magna (i.c.m.) injection of either: (1) FSL-1 (10 or 100μg/5μl) or its vehicle (phosphate-buffered saline, 5μl), or (2) FAM-20 (10 or 100μg/5μl) or its vehicle (dimethyl sulfoxide, 5μl). Body mass and food intake were measured daily. Memory was assessed seven days after injection using fear conditioning tests. A single, i.c.m. injection of either FSL-1 or FAM-20 induced profound, dose-dependent fever, anorexia, lethargy and body mass stunting in rats. Moreover, rats that received an i.c.m. injection of 100μg/5μl FAM-20 had a significant increase in the concentration of IL-1β in both the hypothalamus and the hippocampus for ~27h after injection. Seven days after FSL-1 or FAM-20 injection, when body mass of rats still was stunted, they maintained their memory for fear of the context and for fear of the tone, despite the increase in hippocampal IL-1β concentration after FAM-20 administration. Thus, acute simulated CNS Mycoplasma infections caused pronounced sickness responses and brain inflammation in rats, but spared fear memory., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Obesity is reaching dramatic proportions in humans and is associated with a higher risk for cardiovascular disease, diabetes, and cognitive alterations, and a higher mortality during infection and inflammation. The focus of the present review is on the influence of obesity on the presentation of fever, sickness behavior, and inflammatory responses during acute systemic inflammation., (©2016 Int. Union Physiol. Sci./Am. Physiol. Soc.)

Fever has been recognized as an important symptom of disease since ancient times. For many years, fever was treated as a putative life-threatening phenomenon. More recently, it has been recognized as an important part of the body's defense mechanisms; indeed at times it has even been used as a therapeutic agent. The knowledge of the functional role of the central nervous system in the genesis of fever has greatly improved over the last decade. It is clear that the febrile process, which develops in the sick individual, is just one of many brain-controlled sickness symptoms. Not only will the sick individual appear "feverish" but they may also display a range of behavioral changes, such as anorexia, fatigue, loss of interest in usual daily activities, social withdrawal, listlessness or malaise, hyperalgesia, sleep disturbances and cognitive dysfunction, collectively termed "sickness behavior". In this review we consider the issue of whether fever and sickness behaviors are friend or foe during: a critical illness, the common cold or influenza, in pregnancy and in the newborn. Deciding whether these sickness responses are beneficial or harmful will very much shape our approach to the use of antipyretics during illness., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Subcutaneous or intraperitoneal administration of Toll-like receptor (TLR)-9 agonist, ODN 1668 caused moderate fever and anorexia. In comparison to stimulation of other intracellular TLRs, activation of TLR9 did not result in pronounced peripheral induction of interferons, but rather induced interleukin-6. Expression of cytokines (TNFα, IL-1β) and inducible forms of enzymes for prostaglandin E2 synthesis occurred in the brain, in conjunction with a moderate activation of the transcription factors STAT3 and NF-IL6 in brain endothelial cells. The lack of a septic-like state in ODN 1668-treated rats reinforces the therapeutic value of this drug., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Although peripherally released interleukin (IL)-10 has a critical regulatory role in limiting fever in mild-to-moderate forms of inflammation, its role in regulating the more complex thermoregulatory manifestations of hypothermia and fever noted during severe inflammation is less clear. Using cytokine antagonism, we therefore investigated the involvement of peripherally released IL-10 in mediating hypothermia, fever and inflammation induced by intraperitoneal (IP) administration of a large dose of lipopolysaccharide (LPS). Male Wistar rats (200-250 g) were anaesthetized and implanted intra-abdominally with temperature-sensitive radiotelemeters. Rats were randomly assigned to receive IL-10 antiserum (IL-10AS) or normal sheep serum IP, 4 h before receiving an IP injection of LPS (10 mg/kg) or phosphate-buffered saline (PBS). Inflammatory responses were measured in plasma and tissue samples (spleen, liver and brain) at 90 min and 6 h after the IP injection of LPS or PBS. Administration of LPS induced an initial period of hypothermia (~90 min) after which fever developed. Pre-treating rats with IL-10AS abolished the LPS-induced increase in plasma IL-10 levels, attenuated the hypothermia and increased the amplitude of the fever. Moreover, IL-10AS pre-treatment augmented the LPS-induced increase in plasma levels of tumor necrosis factor-alpha (90 min and 6 h), IL-1β (90 min), prostaglandin E2 (90 min) and IL-6 (6 h), in the periphery, but not the hypothalamus, over the duration of hypothermia and fever. Via its action on the synthesis of inflammatory mediators in the spleen and liver, endogenous IL-10 plays a crucial regulatory role in mediating hypothermia and fever during severe aspectic (LPS-induced) systemic inflammation.

The functional significance for activation of inflammatory transcription factors, such as signal transducer and activator of transcription (STAT3), nuclear factor (NF)κB or NF-interleukin (IL)6 and their contribution to the induction of brain controlled sickness responses, such as fever, during infection and inflammation is unknown. Using AG490, previously shown to inhibit the STAT3- and NF-IL6-signaling pathway, we therefore investigated the central involvement of these two signaling pathways in mediating sickness behavior, fever and accompanying brain inflammation induced by peripheral lipopolysaccharide (LPS)-stimulation. Rats pre-treated i.c.v. with AG490 1 h before the i.p. LPS-challenge (100 μg/kg) showed a modestly exaggerated fever, attenuated adipsia and almost unimpaired locomotor activity compared to LPS-controls receiving vehicle (i.c.v.). The LPS-induced anorexia was not altered and AG490 did not have any effect on rats receiving PBS (i.p.). We did observe effects of AG490 on STAT3-signaling at 4 h, while AG490-mediated changes in brain activity of inflammatory transcription factors at 8 h were not significant. Increased NF-IL6 and suppressor of cytokines 3 mRNA-expression in AG490/LPS-treated rats were indicative of a compensative activation at 24 h. Moreover, a significant decrease in hypothalamic anti-inflammatory IL-10-expression and an increase in inflammatory microsomal prostaglandin E synthase (mPGES) mRNA-expression 8 h after LPS-injection was revealed in AG490 pre-treated animals compared to solvent-treated LPS-controls. In summary, we have shown a dissociation between the effects of central AG490 treatment on fever and components of sickness behavior, which appears to be related to reduced IL-10 and increased mPGES-expression in the brain. Thus, AG490 might have therapeutic potential to reduce sickness behavior., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

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 [Pyr(1)]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, 100 μg/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 (100 μg/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 © 2013 Elsevier B.V. All rights reserved.)

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.

In spite of their prevalence and importance, recurrent acute infections seldom have been investigated in the laboratory. We set out to measure fever and sickness behaviour in simulated recurrent Mycoplasma infection; Mycoplasma is a common clinical cause of recurrent acute infection. Male Sprague-Dawley rats had radiotransponders implanted to measure abdominal temperature and cage activity. After recovery, rats received three intraperitoneal (I.P.) injections, 10 days apart, of either fibroblast-stimulating lipopeptide-1 (FLS-1), a pyrogenic moiety of Mycoplasma salivarium, at a dose of 500 μg.kg(-1) in 1 ml.kg(-1) phosphate-buffered saline (PBS), or vehicle (PBS, 1 ml.kg(-1)). Body mass and food intake were measured daily. For measurement of learning and memory, training in a Morris Water Maze commenced 10 days after the last of the three successive injections and continued daily for 4 days. Spatial memory was assessed on the following day. Hippocampal tissue of rats was collected on the day of the last exposure to the maze. Recurrent FSL-1 administration induced recurrent fevers (~1°C) for about 9h, recurrent lethargy (~40-60%) for 1 day, recurrent anorexia (~16-30%) for 1 day, and recurrent reductions in the rate of mass gain (~112%) for 1 day, but did not induce persistent stunting. Recurrent FSL-1 administration did not result in tolerance to fever, lethargy or anorexia. There was no residual histological damage to the hippocampus and no residual detrimental effect in learning or memory in rats. Though we cannot extrapolate our results directly to humans, clinical recurrent acute Mycoplasma infection may not impose a high risk of stunting or impaired spatial learning and memory., (Copyright © 2011 Elsevier Inc. All rights reserved.)

The Toll-like receptor 7 (TLR7) agonist imiquimod is used for topical treatment of skin cancers. We studied the consequences of injections of imiquimod into a subcutaneous (s.c.) air pouch or of intraperitoneal (i.p.) injections on the manifestation of fever, sickness behavior, and the peripheral and brain-intrinsic induction of a variety of inflammatory molecules. Rats were given imiqimod s.c. or i.p. (1 or 5 mg/kg). Body temperature, motor activity, and food and water intake were recorded by telemetric devices. Peripheral and brain-intrinsic induction of inflammatory mediators was analyzed by real-time polymerase chain reaction (RT-PCR), bioassays, enzyme-linked immunosorbent assays (ELISAs), and immunohistochemistry. Imiquimod is the first TLR-agonist to produce more potent effects with s.c. than i.p. administration. Peripheral induction of interferons (IFNs) and putative circulating pyrogens corresponded to the magnitude of the illness responses. In the brain, an expression of cytokines (TNFα, IL-1β, and IL-6) and inducible forms of enzymes for prostaglandin E2 synthesis (COX-2 and mPGES) occurred, which was accompanied by a moderate activation of the transcription factors NFκB and STAT3, and a strong activation of the transcription factor NF-IL6, in cells of specific areas with an open blood-brain barrier. These inflammatory responses noted within the brain were more marked after s.c. administration, than i.p. administration of imiquimod. At a dose of 5 mg/kg, imiquimod causes rather moderate brain-inflammatory responses, which are related to peripheral IFN-expression and possibly mediated by brain-intrinsic activation of NF-IL6 and induction of a proinflammatory cocktail. The lack of a septic-like state in imiquimod-treated rats reinforces the therapeutic use of this drug., (Copyright © 2011 IBRO. Published by Elsevier Ltd. All rights reserved.)

To investigate potential consequences for learning and memory, we have simulated the effects of Mycoplasma infection, in rats, by administering fibroblast-stimulating lipopepide-1 (FSL-1), a pyrogenic moiety of Mycoplasma salivarium. We measured the effects on body temperature, cage activity, food intake, and on spatial learning and memory in a Morris Water Maze. Male Sprague-Dawley rats had radio transponders implanted to measure abdominal temperature and cage activity. After recovery, rats were assigned randomly to receive intraperitoneal (I.P.) injections of FSL-1 (500 or 1000 μg kg(-1) in 1 ml kg(-1) phosphate-buffered saline; PBS) or vehicle (PBS, 1 ml kg(-1)). Body mass and food intake were measured daily. Training in the Maze commenced 18 h after injections and continued daily for four days. Spatial memory was assessed on the fifth day. In other rats, we measured concentrations of brain pro-inflammatory cytokines, interleukin (IL)-1β and IL-6, at 3 and 18 h after injections. FSL-1 administration induced a dose-dependent fever (∼1°C) for two days, lethargy (∼78%) for four days, anorexia (∼65%) for three days and body mass stunting (∼6%) for at least four days. Eighteen hours after FSL-1 administration, when concentrations of IL-1β, but not that of IL-6, were elevated in both the hypothalamus and the hippocampus, and when rats were febrile, lethargic and anorexic, learning in the Maze was unaffected. There also was no memory impairment. Our results support emerging evidence that impaired learning and memory is not inevitable during simulated infection., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Although peripherally released interleukin (IL)-6 is critical for fever, its role in sickness behaviors, in particular anorexia and lethargy, induced by lipopolysaccharide (LPS) administration appears to be less important. Using quantifiable measures of fever, anorexia and lethargy, that is, body temperature, food intake and voluntary wheel-running, we investigated whether the less-than-essential role for IL-6 in mediating sickness behaviors compared to fever implies important roles for other inflammatory mediators, particularly IL-1β and prostanoids, in these responses. Male Sprague-Dawley rats were randomly assigned to receive one of the following three injections before receiving a subcutaneous (SC) injection of LPS (250 μg/kg) or saline: (1) intraperitoneal injection of pre-immune serum or antiserum to IL-6 (IL-6AS), to reduce the biological activity of peripherally released IL-6; (2) intracerebroventricular injection of vehicle or a caspase-1 inhibitor, to inhibit the production of mature IL-1β; or (3) intraperitoneal injection of vehicle or one of the two doses (1 or 10 mg/kg) of diclofenac, a nonselective cyclooxygenase inhibitor shown to block the formation of prostanoids. LPS administration induced fever, anorexia and lethargy with an accompanying increase in IL-6 and IL-1β concentrations in the circulation and IL-1β in the brain. Rats pre-treated with: (1) IL-6AS had reduced plasma levels of bioactive IL-6, no fever and attenuated sickness behaviors; (2) the caspase-1 inhibitor had reduced concentrations of IL-1β in the pre-frontal cortex, hypothalamus and hippocampus, and attenuated fever and sickness behaviors; (3) diclofenac had a dose-dependent attenuation in fever and sickness behaviors. Doses of diclofenac which completely abolished fever however had lesser effects on anorexia and lethargy. Our results confirm a difference in the sensitivity of sickness responses to IL-6 antagonism and identify that it may be related to different levels of sensitivity or responsiveness in brain regions and/or mechanisms, to prostanoids, IL-1β, or IL-6 itself., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Objective: To report a case of a 35-year-old female initially treated for anorexia nervosa who was found to have Stiff-Person Syndrome (SPS)., Method: Case report., Results: The patient reported panic attacks at meal times that were found to consist of tetanic contractions of the axial musculature. Swallowing initiated reflexive painful muscle spasms that consequently resulted in cibophobia and significant weight loss. Her serum tested positive for anti-glutamic acid decarboxylase antibodies, and she subsequently improved with appropriate treatment for SPS., Discussion: SPS has not been previously reported in the context of eating disorders, although it has been linked to other psychiatric disorders. Often the psychiatrist may be the first physician to diagnose SPS. We present this case to alert practitioners to the potential co-morbidity and symptom overlap between SPS and eating disorders, to aid in early recognition and appropriate treatment of this rare illness., (Copyright © 2010 Wiley Periodicals, Inc.)

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 microg/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 microg, compared to the slopes for food intake (-30%/log microg, F(1,2)=244, P=0.004) and body mass (-2.2%/log microg, 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.

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 microg/kg or 250 microg/kg), poly I:C (3000 microg/kg or 4000 microg/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.

Pro-inflammatory cytokines interleukin (IL)-6 and IL-1 beta can act in the brain (centrally) to cause fever. Sickness behaviors which accompany fever also appear to involve the central action of IL-1 beta. We injected species-homologous rat IL-6 and IL-1 beta directly into the brains of conscious rats to examine the effect of these cytokines on fever, and two behaviors affected by sickness, voluntary wheel-running and food intake. Male Sprague-Dawley rats selected for their predisposition to spontaneously run on running wheels were used in the experiment. Each rat was anaesthetized and had a temperature-sensitive radiotransmitter implanted intra-abdominally, and a 23-gauge stainless steel guide cannula inserted stereotaxically over the lateral cerebral ventricle. Rats were randomly assigned to receive intracerebroventricular injections of three doses of either IL-1 beta or IL-6 (100 ng, 1 ng or 0.1 ng IL-1 beta and 200 ng, 20 ng or 2 ng IL-6), or one of three different combinations of IL-1 beta and IL-6. Rats receiving either IL-1 beta or IL-6 showed a dose-dependent increase in body temperature and decrease in wheel-running (ANOVA, p<0.0001). Only rats receiving the highest dose of IL-1 beta significantly decreased food intake and body mass compared to rats receiving vehicle (ANOVA, p<0.001). Doses of IL-1 beta and IL-6 which, when injected on their own were non-pyrogenic and did not affect food intake and body mass, induced fever and anorexia when they were co-injected centrally. These results show that species-homologous rat IL-6 and IL-1 beta can act directly within the brain to decrease voluntary activity and suggest they also can act synergistically to induce anorexia and fever.

Pro-inflammatory cytokines, interleukin (IL)-1beta, IL-6 and tumor necrosis factor-alpha (TNF-alpha) synthesized by activated macrophages and monocytes in response to administration of lipopolysaccharide (LPS), are considered important mediators of fever and sickness behavior. We administered rat-specific antisera for TNF-alpha, IL-1beta, IL-6 and leptin, to determine the involvement of peripherally released cytokines in LPS-induced fever and sickness behavior, measured as suppression of voluntary wheel-running and food intake. Male Sprague-Dawley rats (approximately 200 g) selected for their predisposition to spontaneously run on running wheels were anaesthetized with a combination of ketamine hydrochloride (80 mg/kg i.m.) and xylazine (4 mg/kg i.m.) and implanted intra-abdominally with temperature-sensitive radiotelemeters. Rats were injected intraperitoneally with anti-rat sera to one of the following, TNF-alpha, IL-1beta, IL-6 or leptin or with pre-immune sheep serum, followed by a subcutaneous injection of either LPS (250 microg/kg) or sterile saline. Lipopolysaccharide administration induced a approximately 1.3 (0.2) degrees C fever lasting approximately 10 h and reduced voluntary running by 93 (8.6)% and food intake by 51 (21.3)% compared to the saline response (ANOVA, P<0.05). Injection of anti-IL-6 serum or anti-leptin serum abolished the LPS-induced fever, anti-TNF-alpha serum affected only the early phase of fever and anti-IL-1beta serum had no effect on fever (ANOVA, P<0.05). LPS-induced suppression of voluntary running and food intake were attenuated in rats receiving anti-IL-6 serum, while the decrease in food intake was totally abolished in rats receiving anti-leptin serum (ANOVA, P<0.05). Injection of anti-TNF-alpha or anti-IL-1beta serum had no effect on LPS-induced sickness behavior. Peripherally released IL-6 and leptin therefore appear to be important in regulating LPS-induced fever and sickness behavior.

Aim: Studies investigating determinants of ball release speed have examined the technique and anthropometry of fast bowlers with little work being done on muscular strength. The aim of our study was to determine whether knee biomechanics during bowling and strength of the shoulder and knee could predict ball release speed., Methods: Twelve cricketers, aged 16.6+/-0.7) years, from schools in Johannesburg, South Africa, volunteered for the study. Subjects were fast-medium bowlers (mean ball release speed of 29.2+/-1.8 m.s(-1)) and had been bowling for at least 5 years. Three accurate deliveries were filmed on an outdoor cricket pitch, in the sagittal plane with a high-speed digital camera recording at 250 frames per second. The mean ball release speed, knee angle at ball release and knee angle at front foot strike were determined using simple two-dimensional kinematics. On a separate day, peak concentric isokinetic muscle torque was measured for both knees and the dominant shoulder., Results: Ball release speed was positively correlated to a straight knee at front foot strike (r=0.72, P=0.009) and at ball release (r=0.71, P=0.011). No significant correlation was found between ball release speed and any of the peak torque values (knee extension peak torque, r=-0.11, knee flexion peak torque, r=-0.08, shoulder internal rotation peak torque, r=0.21 and shoulder external rotation, r=0.29, P>0.05). A multiple regression model using knee angle at front foot strike and at ball release, and the angle at which peak torque is generated during shoulder internal and external rotation, predicted ball release speed (adjusted r2=0.85, P<0.002)., Conclusions: We have confirmed that the angle of the front knee at the beginning and end of a delivery is an important correlate of ball release speed in schoolboy fast-medium bowlers. In addition we have also demonstrated that a multiple regression model based on knee kinematics and shoulder peak torque angles can be used to predict ball release speed.

Aim: Few studies have examined the physiology of cricket, including the difference in ability between batsmen to make controlled contact with a ball bowled at high speed., Methods: We therefore measured visual evoked potentials and choice reaction times with dominant eyes, non-dominant eyes, and both eyes together, in 15 elite batsmen and 10 elite bowlers (aged 20.9 SD 1.9 years) and 9 control subjects (aged 20.2 SD 1.5 years). The latency and amplitude of waves N70, P100 and N145 were determined for each visual evoked potential (VEP). In addition interpeak latencies and peak to peak amplitudes were measured. The subjects also completed a choice reaction test to a visual stimulus., Results: We found that cricketers were not more likely to have crossed dominance (dominant eye contralateral to dominant hand) than controls. Cricketers had a faster latency for VEP wave N70 than controls (p=0.03). However reaction time was not different between cricketers and the control group. Across all subjects, in comparison to monocular testing, binocular testing led to a faster choice reaction time (p=0.02) and larger amplitudes of VEP wave N70 (p=0.01)., Conclusion: Visual processing during the first 100(-1)50 ms of the balls flight together with binocular vision facilitates retinal activation in talented cricketers.