Bacterial meningitis causes two distinct forms of cellular damage in the hippocampal dentate gyrus in infant rats.

Bacterial meningitis causes neurological sequelae in up to 50% of survivors. Two pathogens known for their propensity to cause severe neurological damage are Streptococcus pneumoniae and group B streptococci. Some forms of neuronal sequelae, such as learning and memory deficits, have been associated with neuronal injury in the hippocampus. To learn more about hippocampal injury in meningitis, we performed a comparative study in bacterial meningitis due to S. pneumoniae and group B streptococcus, in which 11-day-old infant rats were infected intracisternally with either of the two pathogens. Histopathological examination of the neuronal injury in the dentate gyrus of the hippocampus showed that S. pneumoniae caused predominantly classical apoptotic cell death. Cells undergoing apoptosis were located only in the subgranular zone and stained positive for activated caspase-3 and TUNEL. Furthermore, dividing progenitor cells seemed particularly sensitive to this form of cell death. Group B streptococcus was mainly responsible for a caspase-3-independent (and TUNEL-negative) form of cell death. Compared with the morphological features found in apoptosis (e.g., apoptotic bodies), this form of neuronal death was characterized by clusters of uniformly shrunken cells. It affected the dentate gyrus throughout the blade, showing no preferences for immature or mature neurons. Thus, depending on the infecting agent, bacterial meningitis causes two distinct forms of cell injury in the dentate gyrus.

Reactive oxygen intermediates contribute to necrotic and apoptotic neuronal injury in an infant rat model of bacterial meningitis due to group B streptococci.

Reactive oxygen intermediates (ROI) contribute to neuronal injury in cerebral ischemia and trauma. In this study we explored the role of ROI in bacterial meningitis. Meningitis caused by group B streptococci in infant rats led to two distinct forms of neuronal injury, areas of necrosis in the cortex and neuronal loss in the dentate gyrus of the hippocampus, the latter showing evidence for apoptosis. Staining of brain sections with diaminobenzidine after perfusion with manganese buffer and measurement of lipid peroxidation products in brain homogenates both provided evidence that meningitis led to the generation of ROI. Treatment with the radical scavenger alpha-phenyl-tert-butyl nitrone (PBN) (100 mg/kg q8h i.p.) beginning at the time of infection completely abolished ROI detection and the increase in lipidperoxidation. Cerebral cortical perfusion was reduced in animals with meningitis to 37.5+/-21.0% of uninfected controls (P < 0.05), and PBN restored cortical perfusion to 72.0+/-8.1% of controls (P < 0.05 vs meningitis). PBN also completely prevented neuronal injury in the cortex and hippocampus, when started at the time of infection (P < 0.02), and significantly reduced both forms of injury, when started 18 h after infection together with antibiotics (P < 0.004 for cortex and P < 0.001 for hippocampus). These data indicate that the generation of ROI is a major contributor to cerebral ischemia and necrotic and apoptotic neuronal injury in this model of neonatal meningitis.

A tick-borne encephalitis model in infant rats infected with langat virus

Tick-borne encephalitis virus (TBEV) is the causative agent of human TBE, a severe infection that can cause long-lasting neurologic sequelae. Langat virus (LGTV), which is closely related to TBEV, has a low virulence for human hosts and has been used as a live vaccine against TBEV. Tick-borne encephalitis by natural infection of LGTV in humans has not been described, but one of 18,500 LGTV vaccinees developed encephalitis. The pathogenetic mechanisms of TBEV are poorly understood and, currently, no effective therapy is available. We developed an infant rat model of TBE using LGTV as infective agent. Infant Wistar rats were inoculated intracisternally with 10 focus-forming units of LGTV and assessed for clinical disease and neuropathologic findings at Days 2, 4, 7, and 9 after infection. Infection with LGTV led to gait disturbance, hypokinesia, and reduced weight gain or weight loss. Cerebrospinal fluid concentrations of RANTES, interferon-γ, interferon-β, interleukin-6, and monocyte chemotactic protein-1 were increased in infected animals. The brains of animals with LGTV encephalitis exhibited characteristic perivascular inflammatory cuffs and glial nodules; immunohistochemistry documented the presence of LGTV in the thalamus, hippocampus, midbrain, frontal pole, and cerebellum. Thus, LGTV meningoencephalitis in infant rats mimics important clinical and histopathologic features of human TBE. This new model provides a tool to investigate disease mechanisms and to evaluate new therapeutic strategies against encephalitogenic flaviviruses.

Menstrual cycle phase affects discrimination of infant cuteness

Recent studies have shown that women are more sensitive than men to subtle cuteness differences in infant faces. It has been suggested that raised levels in estradiol and progesterone may be responsible for this advantage. We compared young women's sensitivity to computer-manipulated baby faces varying in cuteness. Thirty-six women were tested once during ovulation and once during the luteal phase of their menstrual cycle. In a two alternative forced-choice experiment, participants chose the baby which they thought was cuter (Task 1), younger (Task 2), or the baby that they would prefer to babysit (Task 3). Saliva samples to assess levels of estradiol, progesterone and testosterone were collected at each test session. During ovulation, women were more likely to choose the cuter baby than during the luteal phase, in all three tasks. These results suggest that cuteness discrimination may be driven by cyclic hormonal shifts. However none of the measured hormones were related to increased cuteness sensitivity. We speculate that other hormones than the ones measured here might be responsible for the increased sensitivity to subtle cuteness differences during ovulation.

Inhibition of Hippocampal Regeneration by Adjuvant Dexamethasone in Experimental Infant Rat Pneumococcal Meningitis

Pneumococcal meningitis (PM) causes neurological sequelae in up to half of surviving patients. Neuronal damage associated with poor outcome is largely mediated by the inflammatory host response. Dexamethasone (DXM) is used as an adjuvant therapy in adult PM, but its efficacy in the treatment of pneumococcal meningitis in children is controversially discussed. While DXM has previously been shown to enhance hippocampal apoptosis in experimental PM, its impact on hippocampal cell proliferation is not known. This study investigated the impact of DXM on hippocampal proliferation in infant rat PM. Eleven-day-old nursing Wistar rats (n = 90) were intracisternally infected with Streptococcus pneumoniae to induce experimental meningitis. Treatment with DXM or vehicle was started 18 h after infection, concomitantly with antibiotics (ceftriaxone 100 mg/kg of body weight twice a day [b.i.d.]). Clinical parameters were monitored, and the amount of cells with proliferating activity was assessed using in vivo incorporation of bromodeoxyuridine (BrdU) and an in vitro neurosphere culture system at 3 and 4 d postinfection. DXM significantly worsened weight loss and survival. Density of BrdU-positive cells, as an index of cells with proliferating activity, was significantly lower in DXM-treated animals compared to vehicle controls (P < 0.0001). In parallel, DXM reduced neurosphere formation as an index for stem/progenitor cell density compared to vehicle treatment (P = 0.01). Our findings provide clear evidence that DXM exerts an antiproliferative effect on the hippocampus in infant rat PM. We conclude that an impairment of regenerative hippocampal capacity should be taken into account when considering adjuvant DXM in the therapeutic regimen for PM in children.