Factors Associated with State Variation in Mortality Among Persons Living with Diagnosed HIV Infection.

In the United States, the all-cause mortality rate among persons living with diagnosed HIV infection (PLWH) is almost twice as high as among the general population. We aimed to identify amendable factors that state public health programs can influence to reduce mortality among PLWH. Using generalized estimating equations (GEE), we estimated age-group-specific models (24-34, 35-54, ≥ 55 years) to assess the association between state-level mortality rates among PLWH during 2010-2014 (National HIV Surveillance System) and amendable factors (percentage of Ryan White HIV/AIDS Program (RWHAP) clients with viral suppression, percentage of residents with healthcare coverage, state-enacted anti-discrimination laws index) while controlling for sociodemographic nonamendable factors. Controlling for nonamendable factors, states with 5% higher viral suppression among RWHAP clients had a 3-5% lower mortality rates across all age groups [adjusted Risk Ratio (aRR): 0.95, 95% Confidence Interval (CI): 0.92-0.99 for 24-34 years, aRR: 0.97, 95%CI: 0.94-0.99 for 35-54 years, aRR: 0.96, 95%CI: 0.94-0.99 for ≥ 55 years]; states with 5% higher health care coverage had 4-11% lower mortality rate among older age groups (aRR: 0.96, 95%CI: 0.93-0.99 for 34-54 years; aRR: 0.89, 95%CI: 0.81-0.97 for ≥ 55 years); and having laws that address one additional area of anti-discrimination was associated with a 2-3% lower mortality rate among older age groups (aRR: 0.98, 95%CI: 0.95-1.00 for 34-54 years; aRR: 0.97, 95%CI: 0.94-0.99 for ≥ 55 years). The mortality rate among PLWH was lower in states with higher levels of residents with healthcare coverage, anti-discrimination laws, and viral suppression among RWHAP clients. States can influence these factors through programs and policies.

Vaccination and unexplained sudden death risk in Taiwanese infants.

PURPOSE: In March 1992, eight infants who had died within 36 hours of receiving whole-cell pertussis vaccine (diphtheria, tetanus, and whole-cell pertussis [DTwP]) prompted the Taiwan health authorities to suspend its use. We conducted an investigation of vaccination and sudden unexplained infant death (SUID) and repeated it more recently after Taiwan switched to acellular pertussis vaccine (diphtheria, tetanus, and acellular pertussis [DTaP]) in 2010. METHODS: All SUIDs aged 31-364 days during 1990-1992 and 1996-2013 were selected from the death registration databases. The case-control investigation matched each case to two controls on clinic, sex, and birth date, whereas the follow-up self-controlled case series study compared risk of death during the 30-day post-vaccination risk periods with those in the control periods within the same case. RESULTS: Sudden unexplained infant death was associated with never receiving DTwP (odds ratio 2.28, 95% confidence interval 1.25-4.15) in the case-control investigation. The odds ratios within 0-1, 2-7, 8-14, and 15-30 days of DTwP administration were 1.18, 0.26, 0.50, and 0.77. In the 1996-2013 self-controlled case series studies, this temporal shift between DTwP and SUID was consistently observed for female (incidence rate ratio 1.70, 0.75, 1.01, and 0.84) but not male or DTaP recipients. A pooled analysis showed significant risk within 2 days of receiving DTwP in female infants (incidence rate ratio 1.66, 95% confidence interval 1.05-2.60). CONCLUSIONS: Being unvaccinated and recent receipt of DTwP in female infants was significantly associated with SUID; the latter was consistent with a temporal shift pattern without overall increase in risk. The currently used pertussis vaccine, DTaP, did not increase risk of SUID. Copyright © 2016 John Wiley & Sons, Ltd.

Erythropoietin Ameliorates Neonatal Hypoxia-Ischemia-Induced Neurobehavioral Deficits, Neuroinflammation, and Hippocampal Injury in the Juvenile Rat.

The hematopoietic growth factor erythropoietin (EPO) has been shown to be neuroprotective against hypoxia-ischemia (HI) in Postnatal Day 7 (P7)-P10 or adult animal models. The current study was aimed to determine whether EPO also provides long-lasting neuroprotection against HI in P5 rats, which is relevant to immature human infants. Sprague-Dawley rats at P5 were subjected to right common carotid artery ligation followed by an exposure to 6% oxygen with balanced nitrogen for 1.5 h. Human recombinant EPO (rEPO, at a dose of 5 units/g) was administered intraperitoneally one hour before or immediately after insult, followed by additional injections at 24 and 48 h post-insult. The control rats were injected with normal saline following HI. Neurobehavioral tests were performed on P8 and P20, and brain injury was examined on P21. HI insult significantly impaired neurobehavioral performance including sensorimotor, locomotor activity and cognitive ability on the P8 and P20 rats. HI insult also resulted in brain inflammation (as indicated by microglia activation) and neuronal death (as indicated by Jade B positive staining) in the white matter, striatum, cortex, and hippocampal areas of the P21 rat. Both pre- and post-treatment with rEPO significantly improved neurobehavioral performance and protected against the HI-induced neuronal death, microglia activation (OX42+) as well as loss of mature oligodendrocytes (APC-CC1+) and hippocampal neurons (Nissl+). The long-lasting protective effects of rEPO in the neonatal rat HI model suggest that to exert neurotrophic activity in the brain might be an effective approach for therapeutic treatment of neonatal brain injury induced by hypoxia-ischemia.

HIV transmission in the United States: considerations of viral load, risk behavior, and health disparities.

Ongoing HIV transmission is related to prevalence, risk behavior and viral load among persons with HIV. We assessed the contribution of these factors to HIV transmission with transmission rate models and data reported to National HIV Surveillance and published rates of risk behavior. We also estimated numbers of persons with risk behaviors and unsuppressed viral load among sexual risk groups. The transmission rate is higher considering risk behavior (18.5 infections per 100 people with HIV) than that attributed to unsuppressed viral load (4.6). Since persons without risk behavior or suppressed viral load presumably transmit HIV at very low rates, transmission can be attributed to a combination of these factors (28.9). Service needs are greatest for MSM; their number with unsuppressed viral load engaging in unprotected discordant sex was 8 times the number of male heterosexuals and more than twice the number of female heterosexuals with high-risk transmission potential. While all persons with HIV need optimal care, treatment as prevention is most relevant when risk behavior is present among persons with unsuppressed HIV viral load.

Dexamethasone and betamethasone protect against lipopolysaccharide-induced brain damage in neonatal rats.

INTRODUCTION: The aim of this study was to test whether dexamethasone (Dex) and betamethasone (Beta), two of the most commonly used corticosteroids, protect against lipopolysaccharide (LPS)-induced white matter damage and neurobehavioral dysfunction. METHODS: LPS or sterile saline was injected into the brain white matter of rat pups at postnatal day 5 (P5), and Dex or Beta was given intraperitoneally to the rat pups 1 h before the LPS microinjection. Brain inflammatory response, brain damage, and myelination were examined at P6, P8, and P14. Neurobehavioral tests were performed from P3 through P22. RESULTS: Our results demonstrate that Dex and Beta markedly diminish the LPS-induced brain inflammatory response, restore myelin basic protein (MBP) expression, and alleviate lateral ventricle dilation. Both corticosteroids demonstrate significant protection against most LPS-induced behavioral deficits, including those in rearing, vibrissa-elicited forelimb-placing, beam walking, learning, and elevated plus-maze test. Of note, only Beta improved the locomotion and stereotype dysfunction. In contrast to their beneficial effects, neither drug prevented LPS-induced delay in body weight gain from P6 through P21. DISCUSSION: Our study suggests that if their adverse effects are minimized, corticosteroids may be the potential candidate drugs to prevent brain damage in premature infants.

Intracerebral lipopolysaccharide induces neuroinflammatory change and augmented brain injury in growth-restricted neonatal rats.

INTRODUCTION: Intrauterine growth restriction (IUGR) alters fetal development and is associated with neurodevelopmental abnormalities. We hypothesized that growth restriction from reduced intrauterine perfusion would predispose neonatal rats to subsequent inflammatory brain injury. METHODS: In this study, IUGR was achieved by induced placental insufficiency in pregnant rats at 14 days of gestation. IUGR offspring and sham-operated control pups were subsequently injected with intracerebral lipopolysaccharide (LPS) as a model of periventricular leukomalacia (PVL). RESULTS: LPS similarly elevates proinflammatory cytokines in the brains of both IUGR and control rat pups. However, the chemokines cytokine-induced neutrophil chemoattractant-1 (CINC-1) and macrophage chemoattractant protein-1 (MCP-1), as well as microglia activation, were significantly higher in LPS-treated IUGR rat pups as compared with LPS-treated controls. In addition to the unique brain inflammatory response, IUGR rat pups demonstrated increased brain damage with an increased number of apoptotic cells, larger lateral ventricular size, and more severe impairment of myelination. DISCUSSION: This study provides evidence that placental insufficiency may sensitize the innate immune system in the immature brain and reveals a possible link between brain inflammation and injury.

Neonatal exposure to lipopolysaccharide enhances vulnerability of nigrostriatal dopaminergic neurons to rotenone neurotoxicity in later life.

Brain inflammation in early life has been proposed to play important roles in the development of neurodegenerative disorders in adult life. To test this hypothesis, we used a neonatal rat model of lipopolysaccharide (LPS) exposure (1000 EU/g body weight, intracerebral injection on P5) to produce brain inflammation. By P70, when LPS-induced behavioral deficits were spontaneously recovered, animals were challenged with rotenone, a commonly used pesticide, through subcutaneous mini-pump infusion at a dose of 1.25 mg/kg per day for 14 days. This rotenone treatment regimen ordinarily does not produce toxic effects on behaviors in normal adult rats. Our results show that neonatal LPS exposure enhanced the vulnerability of nigrostriatal dopaminergic neurons to rotenone neurotoxicity in later life. Rotenone treatment resulted in motor neurobehavioral impairments in rats with the neonatal LPS exposure, but not in those without the neonatal LPS exposure. Rotenone induced losses of tyrosine hydroxylase immunoreactive neurons in the substantia nigra and decreased mitochondrial complex I activity in the striatum of rats with neonatal LPS exposure, but not in those without this exposure. Neonatal LPS exposure with later exposure to rotenone decreased retrogradely labeled nigrostriatal dopaminergic projecting neurons. The current study suggests that perinatal brain inflammation may enhance adult susceptibility to the development of neurodegenerative disorders triggered later on by environmental toxins at an ordinarily non-toxic or sub-toxic dose. Our model may be useful for studying mechanisms involved in the pathogenesis of nonfamilial Parkinson's disease and the development of potential therapeutic treatments.

Dopaminergic neuronal injury in the adult rat brain following neonatal exposure to lipopolysaccharide and the silent neurotoxicity.

Our previous studies have shown that neonatal exposure to lipopolysaccharide (LPS) resulted in motor dysfunction and dopaminergic neuronal injury in the juvenile rat brain. To further examine whether neonatal LPS exposure has persisting effects in adult rats, motor behaviors were examined from postnatal day 7 (P7) to P70 and brain injury was determined in P70 rats following an intracerebral injection of LPS (1 mg/kg) in P5 Sprague-Dawley male rats. Although neonatal LPS exposure resulted in hyperactivity in locomotion and stereotyped tasks, and other disturbances of motor behaviors, the impaired motor functions were spontaneously recovered by P70. On the other hand, neonatal LPS-induced injury to the dopaminergic system such as the loss of dendrites and reduced tyrosine hydroxylase immunoreactivity in the substantia nigra persisted in P70 rats. Neonatal LPS exposure also resulted in sustained inflammatory responses in the P70 rat brain, as indicated by an increased number of activated microglia and elevation of interleukin-1ß and interleukin-6 content in the rat brain. In addition, when challenged with methamphetamine (METH, 0.5 mg/kg) subcutaneously, rats with neonatal LPS exposure had significantly increased responses in METH-induced locomotion and stereotypy behaviors as compared to those without LPS exposure. These results indicate that although neonatal LPS-induced neurobehavioral impairment is spontaneously recoverable, the LPS exposure-induced persistent injury to the dopaminergic system and the chronic inflammation may represent the existence of silent neurotoxicity. Our data further suggest that the compromised dendritic mitochondrial function might contribute, at least partially, to the silent neurotoxicity.

IGF-1 can either protect against or increase LPS-induced damage in the developing rat brain.

Periventricular leukomalacia (PVL) is a major form of brain damage in premature infants. This study was to test whether IGF-1 can prevent PVL-like brain damage induced by lipopolysaccharide (LPS) in the neonatal rat. Intraventricular delivery of LPS resulted in an acute brain inflammatory response, i.e., rapid recruitment of polymorphonuclear leukocytes (PMNs), activation of microglia and astrocytes, and induction of IL-1beta (IL1beta) expression. Brain inflammation was associated with the loss of O4+ preoligodendrocytes (preOLs), a decrease of myelin basic protein (MBP) in the white matter and an increase of pyknotic cells in the cortex. IGF-1 at a low dose significantly prevented LPS-induced deleterious effects without alteration of IL-1beta expression and microglia/astrocytes activation. On the other hand, the low dose of IGF-1 enhanced LPS-induced PMNs recruitment and blood-brain barrier (BBB) permeability, and caused intracerebral hemorrhage. At higher doses, co-application of IGF-1 with LPS resulted in a high mortality rate. Brains from the surviving rats showed massive PMN infiltration and intracerebral hemorrhage. However, these adverse effects were not found in rats treated with IGF-1 alone. This study provides the alarming evidence that in an acute inflammatory condition, IGF-1 may have severe, harmful effects on the developing brain.

Alpha-phenyl-n-tert-butyl-nitrone ameliorates hippocampal injury and improves learning and memory in juvenile rats following neonatal exposure to lipopolysaccharide.

Neonatal exposure to infectious agents may result in long-term neurological disability, and is particularly associated with the subsequent development of motor and cognitive disturbances. Our previous studies have shown that treatment with alpha-phenyl-n-tert-butyl-nitrone (PBN) following exposure to lipopolysaccharide (LPS) reduces LPS-induced brain injury in the neonatal rat. To examine whether PBN has long-lasting protective effects and ameliorates LPS-induced motor and cognitive dysfunction, PBN (100 mg/kg) was administered intraperitoneally 5 min after an LPS (1 mg/kg) intracerebral injection in postnatal day 5 (P5) Sprague-Dawley rat pups. Neurobehavioral tests were carried out from P3 to P21, and brain injury was examined at 24 h and 16 days after LPS injection. Neonatal LPS exposure resulted in hyperactivity from P13 to P17 in the open field task as compared with the control rat. Neurobehavioral deficits that were still observable at P21 included dysfunction in the beam-walking and pole tests, learning and memory deficits in the passive avoidance task, and less anxiety-like response in the elevated plus-maze task. These behavioral findings were matched by LPS-induced axonal injury in the CA1 region of the middle dorsal hippocampus (HP), reduction in the size of the HP and the number of neurons in the CA1 region of the middle dorsal HP, and loss of tyrosine hydroxylase immunoreactivity in neurons in the substantia nigra and ventral tegmental areas. Treatment with PBN provided long-lasting protection against the LPS-induced axonal injury and neuronal loss, and improved the associated neurological dysfunctions in juvenile rats.

alpha-Phenyl-n-tert-butyl-nitrone attenuates lipopolysaccharide-induced brain injury and improves neurological reflexes and early sensorimotor behavioral performance in juvenile rats.

Our previous study showed that treatment with alpha-phenyl-n-tert-butyl-nitrone (PBN) after exposure to lipopolysaccharide (LPS) reduced LPS-induced white matter injury in the neonatal rat brain. The object of the current study was to further examine whether PBN has long-lasting protective effects and ameliorates LPS-induced neurological dysfunction. Intracerebral (i.c.) injection of LPS (1 mg/kg) was performed in postnatal day (P) 5 Sprague Dawley rat pups and PBN (100 mg/kg) or saline was administered intraperitoneally 5 min after LPS injection. The control rats were injected (i.c.) with sterile saline. Neurobehavioral tests were carried out from P3 to P21, and brain injury was examined after these tests. LPS exposure resulted in severe brain damage, including enlargement of ventricles bilaterally, loss of mature oligodendrocytes, impaired myelination as indicated by the decrease in myelin basic protein immunostaining, and alterations in dendritic processes in the cortical gray matter of the parietal cortex. Electron microscopic examination showed that LPS exposure caused impaired myelination as indicated by the disintegrated myelin sheaths in the juvenile rat brain. LPS administration also significantly affected neurobehavioral functions such as performance in righting reflex, wire hanging maneuver, cliff avoidance, negative geotaxis, vibrissa-elicited forelimb-placing test, beam walking, and gait test. Treatment with PBN, a free radical scavenger and antioxidant, provided protection against LPS-induced brain injury and associated neurological dysfunction in juvenile rats, suggesting that antioxidation might be an effective approach for therapeutic treatment of neonatal brain injury induced by infection/inflammation.

Neuroprotective effects of vascular endothelial growth factor following hypoxic ischemic brain injury in neonatal rats.

Vascular Endothelial Growth Factor (VEGF) protects the brain against ischemic injury in adult animals. We evaluated whether VEGF has neuroprotective effects against hypoxic-ischemic (HI) brain injury in newborn rats. Seven-day-old rat pups had the right carotid artery permanently ligated followed by 140 min of hypoxia (8% oxygen). VEGF (5, 10, 20, or 40 ng) or vehicle was administered intracerebroventricularly 5 min after reoxygenation following HI. Brain damage was evaluated by weight loss of the right hemisphere at 22 d after HI and by gross and microscopic morphology. Body weight, rectal temperature, and mortality were not significantly different in the VEGF and vehicle treated groups. VEGF treatment increased brain VEGF levels at 15 min after injection. VEGF (10 and 20 ng) significantly reduced brain weight loss (p < 0.05) and gross brain injury (p < 0.05); however, treatment with 5 or 40 ng did not. VEGF (10 ng) also decreased brain damage assessed by histologic scoring. VEGF increased phosphorylation of protein kinase B (Akt) and extracellular-signal regulated kinase 1/2 (ERK1/2) in the cortex (p < 0.05). These results suggest that VEGF has neuroprotective effects in the neonatal rat HI model that may be related to activation of the Akt/ERK signaling pathway.

Estimation of HIV incidence in the United States.

CONTEXT: Incidence of human immunodeficiency virus (HIV) in the United States has not been directly measured. New assays that differentiate recent vs long-standing HIV infections allow improved estimation of HIV incidence. OBJECTIVE: To estimate HIV incidence in the United States. DESIGN, SETTING, AND PATIENTS: Remnant diagnostic serum specimens from patients 13 years or older and newly diagnosed with HIV during 2006 in 22 states were tested with the BED HIV-1 capture enzyme immunoassay to classify infections as recent or long-standing. Information on HIV cases was reported to the Centers for Disease Control and Prevention through June 2007. Incidence of HIV in the 22 states during 2006 was estimated using a statistical approach with adjustment for testing frequency and extrapolated to the United States. Results were corroborated with back-calculation of HIV incidence for 1977-2006 based on HIV diagnoses from 40 states and AIDS incidence from 50 states and the District of Columbia. MAIN OUTCOME MEASURE: Estimated HIV incidence. RESULTS: An estimated 39,400 persons were diagnosed with HIV in 2006 in the 22 states. Of 6864 diagnostic specimens tested using the BED assay, 2133 (31%) were classified as recent infections. Based on extrapolations from these data, the estimated number of new infections for the United States in 2006 was 56,300 (95% confidence interval [CI], 48,200-64,500); the estimated incidence rate was 22.8 per 100,000 population (95% CI, 19.5-26.1). Forty-five percent of infections were among black individuals and 53% among men who have sex with men. The back-calculation (n = 1.230 million HIV/AIDS cases reported by the end of 2006) yielded an estimate of 55,400 (95% CI, 50,000-60,800) new infections per year for 2003-2006 and indicated that HIV incidence increased in the mid-1990s, then slightly declined after 1999 and has been stable thereafter. CONCLUSIONS: This study provides the first direct estimates of HIV incidence in the United States using laboratory technologies previously implemented only in clinic-based settings. New HIV infections in the United States remain concentrated among men who have sex with men and among black individuals.

Use of the inactivated intranasal influenza vaccine and the risk of Bell's palsy in Switzerland.

BACKGROUND: After the introduction of an inactivated intranasal influenza vaccine that was used only in Switzerland, 46 cases of Bell's palsy were reported. METHODS: We conducted a matched case-control study and a case-series analysis. All primary care physicians, ear, nose, and throat specialists, and neurologists in German-speaking regions of Switzerland were requested to identify cases of Bell's palsy diagnosed in adults between October 1, 2000, and April 30, 2001. Each physician was invited to select three control patients for each patient with Bell's palsy, with matching according to age, date of the clinic visit, and physician. Vaccination information was provided by the physicians. RESULTS: A total of 773 patients with Bell's palsy were identified. Of the 412 (53.3 percent) who could be evaluated, 250 (60.7 percent) were enrolled and matched with 722 control patients; the other 162 patients had no controls. In the case-control study, we found that 68 patients with Bell's palsy (27.2 percent) and 8 controls (1.1 percent) had received the intranasal vaccine (P<0.001). In contrast to parenteral vaccines, the intranasal vaccine significantly increased the risk of Bell's palsy (adjusted odds ratio, 84.0; 95 percent confidence interval, 20.1 to 351.9). Even according to conservative assumptions, the relative risk of Bell's palsy was estimated to be 19 times the risk in the controls, corresponding to 13 excess cases per 10,000 vaccinees within 1 to 91 days after vaccination. In the case-series analysis, the period of highest risk was 31 to 60 days after vaccination. CONCLUSIONS: This study suggests a strong association between the inactivated intranasal influenza vaccine used in Switzerland and Bell's palsy. This vaccine is no longer in clinical use.

Rhesus rotavirus vaccine effectiveness and factors associated with receipt of vaccine.

BACKGROUND: The rhesus rotavirus tetravalent vaccine (RotaShield) had an efficacy of 75%-100% in preventing severe rotavirus disease in prelicensure clinical trials. Before RotaShield's withdrawal because of reports of intussusception, there was an opportunity to evaluate the postlicensure effectiveness of the vaccine. The objective of this study was to determine the effectiveness of the RotaShield vaccine against rotavirus gastroenteritis requiring hospitalization and to evaluate factors associated with vaccine receipt. METHODS: Rotavirus cases were identified through active hospital-based rotavirus surveillance at 3 children's hospitals in Cincinnati, New Orleans and Providence. Cases were selected if they had been eligible for vaccine during the 10-month period when vaccine was available. Controls were matched to cases by date and county or state of birth. Immunization records were obtained from cases and controls to document receipt of RotaShield. Vaccine effectiveness (VE) was calculated for 1, 2, and 3 doses of vaccine with 95% confidence intervals (CI). RESULTS: For the 10-month period, 136 cases and 440 controls were enrolled. For 3 versus 0 doses of RotaShield, the VE was 100% (CI: 75%, 100%); for 2 versus 0 doses, the VE was 100% (CI: 62%, 100%), and for 1 versus 0 doses the VE was 89% (CI: 49%, 97%). RotaShield receipt was associated with white race, having more than 1 adult in the household, having insurance and having an older, more educated mother. CONCLUSIONS: This postlicensure study of RotaShield effectiveness found the vaccine to be highly effective in preventing rotavirus disease requiring hospitalization.

A case-control study to determine risk factors for hospitalization for rotavirus gastroenteritis in U.S. children.

OBJECTIVE: The objective of this case-control study nested within a surveillance study conducted at 3 hospitals (Cincinnati Children's Hospital Medical Center, Cincinnati, OH; Children's Hospital of New Orleans, New Orleans, LA; and Hasbro Children's Hospital, Providence, RI) was to identify risk factors for rotavirus gastroenteritis requiring hospitalization. PATIENTS: Cases were children < or =59 months of age who were admitted with acute gastroenteritis (AGE) and found to have rotavirus infection. Controls were selected from a birth certificate registry (Cincinnati and Providence) or a registry of patients from a large practice consortium in 11 locations (New Orleans). RESULTS: Three hundred forty-nine rotavirus-infected cases and 1242 control subjects were enrolled. Breast feeding was protective against hospitalization for rotavirus AGE for infants <6 months of age. (odds ratio [OR], 5.1; 95% confidence interval [CI], 1.2-13.2). Low-birth-weight (<2500 g) infants had increased risk for hospitalization even beyond the first few months of life (OR, 2.8; 95% CI, 1.6-5.0). Children in child care were more likely to be hospitalized for rotavirus AGE than those cared for at home, particularly those > or =24 months of age (OR, 3.0; 95% CI, 1.8-5.3). Other characteristics associated with rotavirus AGE hospitalization were children <24 months of age covered by Medicaid or without insurance (OR, 2.1; 95% CI, 1.4-3.2) and having another child in the house <24 months of age (OR, 1.6; 95% CI, 1.1-2.3). The data suggest that maternal age <25 years (OR, 1.4; 95% CI, 1.0-2.0) and a mother with less than a high school education (OR, 1.5; 95% CI, 1.0-2.3) may also increase risk of rotavirus hospitalization. CONCLUSION: There are socioeconomic and environmental factors and aspects of the child's medical and dietary history that identify children at risk for hospitalization with rotavirus AGE.

Neuroprotection of alpha-phenyl-n-tert-butyl-nitrone on the neonatal white matter is associated with anti-inflammation.

Our previous study has demonstrated that alpha-phenyl-tert-butyl-nitrone (PBN) provided neuroprotection to the neonatal white matter following cerebral hypoxia-ischemia (HI). Free radical scavenging was involved in the neuroprotection of PBN. To investigate if other mechanisms contribute to the neuroprotection of PBN, postnatal day 4 SD rats were subjected to bilateral common carotid artery ligation, followed by 8% oxygen exposure for 20min. A single dose of PBN (100mg/kg, i.p.) was given prior to the hypoxic exposure. Expression of inflammatory cytokines: interleukin-1beta (IL-1beta), inducible nitric oxide synthase (iNOS) and tumor necrosis factor-alpha (TNF-alpha) was determined by RT-PCR, ELISA and immunohistochemistry. Activation of transcriptional factor nuclear factor-kappa B (NF-kappaB) was measured by ELISA. PBN significantly inhibited HI-induced up-regulation of IL-1beta, TNF-alpha and iNOS mRNA expression at 4h following HI. PBN treatment also reduced the brain concentration of IL-1beta significantly and decreased the number of IL-1beta- or iNOS-expressing cells in the white matter area at 12h following HI. Moreover, PBN suppressed the HI-induced NF-kappaB activation at 1h after HI. The overall results indicate that besides free radical scavenging, anti-inflammation might partly contribute to the neuroprotection afforded by PBN on neonatal white matter following cerebral HI.

Hypoxia-ischemia induced neurological dysfunction and brain injury in the neonatal rat.

Bilateral carotid artery occlusion (BCAO) followed by exposure to a hypoxic condition (8% oxygen for 10 or 15 min) was performed in postnatal day 4 SD rats. Brain injury and myelination changes were examined on postnatal day 21 (P21) and tests for neurobehavioral toxicity were performed from P3 to P21. BCAO followed by 10 or 15 min hypoxic insult resulted in mild and severe, respectively, brain injury, reduction in mature oligodendrocytes and tyrosine hydroxylase positive neurons and impaired myelination as indicated by decreased myelin basic protein immunostaining in the P21 rat brain. Hypoxia-ischemia also affected physical development (body weight gain and eye opening) and neurobehavioral performance, such as righting reflex, wire hanging maneuver, cliff avoidance, locomotor activity, gait analysis, responses in the elevated plus-maze and passive avoidance. BCAO followed by 15 min of hypoxia caused more severely impaired neurobehavioral performance as compared with BCAO followed by 10 min of hypoxia in the rat. The overall results demonstrate that hypoxia-ischemia-induced brain injury not only persists, but also is linked with neurobehavioral deficits in juvenile rats. The present data also indicate that the degree of brain injury and the deficits of neurobehavioral performance in the rat are dependent on the hypoxic-ischemic condition, i.e., the exposure time to hypoxia.

IGF-1 protects oligodendrocyte progenitor cells and improves neurological functions following cerebral hypoxia-ischemia in the neonatal rat.

To investigate if insulin-like growth factor-1 (IGF-1) provides neuroprotection to oligodendrocyte progenitor cells (OPCs) following cerebral hypoxia-ischemia, a previously developed neonatal rat model of white matter damage was used in this study. Postnatal day 4 (P4) SD rat pups were subjected to bilateral common carotid artery ligation, followed by exposure to 8% oxygen for 10 min. IGF-1 (0.5 microg) or vehicle was injected into the left ventricle after artery ligation and before the hypoxic exposure. Cerebral hypoxia-ischemia caused death of O4+ late OPCs in the P5 rat brain and impaired myelination in the P9 and P21 rat brain. Caspase-3 activation was involved in the death of OPCs. Moreover, cerebral hypoxia-ischemia impaired neurobehavioral performance in juvenile rats. IGF-1 treatment attenuated damages to OPCs and improved neurological functions after cerebral hypoxia-ischemia. It reduced death of O4+ OPCs by 39% on P5 and enhanced myelination on P9 and P21. Bromodeoxyuridine uptake assay showed that cerebral hypoxia-ischemia inhibited proliferation of stem/progenitor cells in the subventricular zone and NG2+ early OPCs in the white matter area. IGF-1 treatment increased cell proliferation in the subventricular zone by 31% 1 day following hypoxic-ischemic insult. Proliferation of early and late OPCs in the IGF-1-treated group was 1.5- and 2.4-fold of that in the vehicle-treated group, respectively. In conclusion, IGF-1 provided potent neuroprotection to OPCs and improved neurological functions following cerebral hypoxia-ischemia in the neonatal rat. The neuroprotection of IGF-1 was associated with its antiapoptotic and mitogenic effects.

Apoptosis and necrosis in developing cerebellum and brainstem induced after focal cerebral hypoxic-ischemic injury.

Focal cerebral hypoxia-ischemia due to isolated vascular insufficiency is well known to cause ipsilateral, but not contralateral, cerebral apoptosis. Hypoxic-ischemic damage to the cerebellum and brainstem in such a model has not been established. This experimental rodent study demonstrates, through deoxyribonucleic acid fragmentation and terminal deoxynucleotidyl transferase-mediated deoxyuridine 5'-triphosphate-digoxigenin nick end labeling analysis, that neuronal cells in these infratentorial regions also suffer mild apoptosis and necrosis after focal cerebral hypoxic-ischemic injury in the newborn rat. These data provide additional insight into the mechanisms of neurological injury in the cerebellum and brainstem areas resulting from a focal cerebral hypoxic-ischemic insult and demonstrate that future therapeutic interventions for hypoxic-ischemic encephalopathy system should deal with the entire central nervous system.