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.

Lipoprotein-associated phospholipase A2 and carotid intima-media thickness in individuals classified as low-risk according to Framingham.

BACKGROUND: The Framingham risk score (FRS) has long been used as a global tool to estimate coronary heart disease (CHD) risk, but data has shown that subclinical CHD may exist in those classified as low risk by FRS, and as a result, there is potential for misclassification. Lipoprotein-associated phospholipase A2 (Lp-PLA2) and carotid intima-media thickness (CIMT) are two emerging risk markers that are predictive of future CHD events. PURPOSE: To examine Lp-PLA2 and CIMT values in low risk individuals, and to explore the relationship between Lp-PLA2 and CIMT. METHODS: A total of 229 men and women (age =53±7 years) underwent body composition analysis, objective physical activity measurement, fasting blood draw to determine standard lipid values and Lp-PLA2 mass, and CIMT measurement through ultrasound. RESULTS: For all subjects, mean CIMT was 0.61±0.1 mm, mean Lp-PLA2 mass was 197±45 ng/dL. A total of 19.5% and 34.6% of women and 4.6% and 73.8% of men were considered at elevated risk for CHD by CIMT (>75(th) percentile for age) and Lp-PLA2 mass (>200 ng/dL) standards, respectively. Both CIMT and Lp-PLA2 mass were significant independent predictors of each other, whereas traditional risk markers (lipids, glucose) were not. CONCLUSIONS: Results suggest that in those classified as low risk by FRS, evidence of increased CHD risk may exist through the use of newer risk markers like CIMT and Lp-PLA2. These emerging markers may aid in the earlier detection and intervention of subclinical CHD.

Differences in human immunodeficiency virus care and treatment among subpopulations in the United States.

IMPORTANCE: Early diagnosis of human immunodeficiency virus (HIV) infection, prompt linkage to and sustained care, and antiretroviral therapy are associated with reduced individual morbidity, mortality, and transmission of the virus. However, levels of these indicators may differ among population groups with HIV. Disparities in care and treatment may contribute to the higher incidence rates among groups with higher prevalence of HIV. OBJECTIVE: To examine differences between groups of persons living with HIV by sex, age, race/ethnicity, and transmission category at essential steps in the continuum of care. DESIGN AND SETTING: We obtained data from the National HIV Surveillance System of the Centers for Disease Control and Prevention to determine the number of persons living with HIV who are aware and unaware of their infection using back-calculation models. We calculated the percentage of persons linked to care within 3 months of diagnosis on the basis of CD4 level and viral load test results. We estimated the percentages of persons retained in care, prescribed antiretroviral therapy, and with viral suppression using data from the Medical Monitoring Project, a surveillance system of persons receiving HIV care in select areas representative of all such persons in the United States. PARTICIPANTS: All HIV-infected persons in the United States. MAIN OUTCOMES AND MEASURES: Percentage of persons living with HIV who are aware of their infection, linked to care, retained in care, receiving antiretroviral therapy, and achieving viral suppression. RESULTS: Of the estimated 1,148,200 persons living with HIV in 2009 in the United States, 81.9% had been diagnosed, 65.8% were linked to care, 36.7% were retained in care, 32.7% were prescribed antiretroviral therapy, and 25.3% had a suppressed viral load (≤200 copies/mL). Overall, 857 276 persons with HIV had not achieved viral suppression, including 74.8% of male, 79.0% of black, 73.9% of Hispanic/Latino, and 70.3% of white persons. The percentage of blacks in each step of the continuum was lower than that for whites, but these differences were not statistically significant. Among persons with HIV who were 13 to 24 years of age, only 40.5% had received a diagnosis and 30.6% were linked to care. Persons aged 25 to 34, 35 to 44, and 45 to 54 years were all significantly less likely to achieve viral suppression than were persons aged 55 to 64 years. CONCLUSIONS AND RELEVANCE: Significant age disparities exist at each step of the continuum of care. Additional efforts are needed to ensure that all persons with HIV receive a diagnosis and optimal care to reduce morbidity, mortality, disparities in care and treatment, and ultimately HIV transmission. Ensuring that people stay in care and receive treatment will increase the proportion of HIV-infected individuals who achieve and maintain a suppressed viral load.

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.

Prevalence of undiagnosed HIV infection among persons aged ≥13 years--National HIV Surveillance System, United States, 2005-2008.

In the United States, approximately 1.1 million adults and adolescents are living with human immunodeficiency virus (HIV) infection and, each year, another 50,000 become infected. At the end of 2008, approximately 20% of the persons living with HIV had an undiagnosed infection. Of those living with HIV at the end of 2008, nearly two thirds were racial/ethnic minorities and half were men who have sex with men (MSM). In 2007, HIV ranked fifth as a leading cause of death among persons aged 35-44 years in the United States but third among blacks or African Americans in this age group. In 40 states with longstanding confidential name-based HIV surveillance systems, 33% of the estimated 41,768 adults and adolescents diagnosed with HIV infection in 2008 developed acquired immunodeficiency syndrome (AIDS) within 1 year and, of these, 44% received their initial diagnosis in an acute care setting, suggesting that they received HIV testing late in the course of the infection. HIV-infected persons who are unaware of their infection or who receive a late diagnosis cannot benefit fully from timely initiation of therapy and are more likely to experience HIV-related morbidity and premature mortality. In addition, persons unaware of their infection are more likely to transmit HIV to others because of a higher prevalence of high-risk sexual behaviors and higher levels of viral RNA that continue to replicate without appropriate antiretroviral treatment.

Neuron-oligodendrocyte myelination co-culture derived from embryonic rat spinal cord and cerebral cortex.

An in vitro myelination model derived from rat central nervous system (CNS) remains to be established. Here, we describe a simple and reproducible myelination culture method using dissociated neuron-oligodendrocyte (OL) co-cultures from either the embryonic day 16 (E16) rat spinal cord or cerebral cortex. The dissociated cells are plated directly on poly-L-lysine-coated cover slips and maintained in a modified myelination medium that supports both OL and neuron differentiation. The spinal cord derived OL progenitor cells develop quickly into myelin basic protein (MBP)+ mature OLs and start to myelinate axons around 17 days in vitro (DIV17). Myelination reaches its peak around six weeks (DIV40) and the typical nodes of Ranvier are revealed by paranodal proteins Caspr and juxaparanodal protein Kv1.2 immunoreactivity. Electron microscopy (EM) shows typical myelination cytoarchitecture and synaptic organization. In contrast, the cortical-derived co-culture requires triiodothyronine (T3) in the culture medium for myelination. Finally, either hypomyelination and/or demyelination can be induced by exposing proinflammatory cytokines or demyelinating agents to the co-culture, suggesting the feasibility of this modified in vitro myelination model for myelin-deficit investigation.

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.

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.

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.

Neonatal exposure to lipopolysaccharide enhances methamphetamine-induced reinstated behavioral sensitization in adult rats.

Our previous studies have shown that neonatal exposure to lipopolysaccharide (LPS) resulted in long-lasting dopaminergic injury and enhanced methamphetamine (METH)-induced increase of locomotion in the adult male rat. To further investigate the effect of neonatal LPS exposure-induced dopaminergic injury, we used our neonatal rat model of LPS exposure (1mg/kg, intracerebral injection in postnatal day 5, P5, rats) to examine the METH sensitization as an indicator of drug addiction in the adult rats. On P70, animals began a treatment schedule of 5 daily subcutaneous (s.c.) administration of METH (0.5mg/kg) or saline (P70-P74) to induce behavioral sensitization. Ninety-six hours after the 5th treatment with METH or saline (P78), animals received a single dose of 0.5mg/kg METH (s.c.) or saline. Neonatal LPS exposure enhanced the level of development of behavioral sensitization including distance traveled, rearing events and stereotypy to METH administration in both male and female rats. Neonatal LPS exposure also enhanced the reinstated behavioral sensitization in both male and female rats after the administration had ceased for 96h. However, neonatal LPS exposure induced alteration in the reinstated behaviors sensitization of distance traveled and rearing events to METH administration appears to be greater in male than in female rats. These results indicate that neonatal brain LPS exposure produces a persistent lesion in the dopaminergic system, as indicated by enhanced METH-induced locomotor and stereotyped behavioral sensitization in later life. These findings show that early-life brain inflammation may enhance susceptibility to the development of drug addiction in later life.

Whole body hypothermia broadens the therapeutic window of intranasally administered IGF-1 in a neonatal rat model of cerebral hypoxia-ischemia.

To investigate whether whole body hypothermia after neonatal cerebral hypoxia-ischemia (HI) could broaden the therapeutic window of intranasal treatment of IGF-1 (iN-IGF-1), postnatal day 7 rat pups were subjected to right common carotid artery ligation, followed by 8% oxygen inhalation for 2h. After HI, one group of pups were returned to their dams and kept at room temperature (24.5±0.2°C). A second group of pups were subjected to whole body hypothermia in a cool environment (21.5±0.3°C) for 2 or 4h before being returned to their dams. Two doses of 50 µg recombinant human IGF-1 were administered intranasally at a 1h interval starting at 0, 2 or 4h after hypothermia. Hypothermia decreased the rectal temperature of pups by 4.5°C as compared to those kept at room temperature. While hypothermia or iN-IGF-1 administered 2h after HI alone did not provide neuroprotection, the combined treatment of hypothermia with iN-IGF-1 significantly protected the neonatal rat brain from HI injury. Hypothermia treatment extended the therapeutic window of IGF-1 to 6h after HI. The extended IGF-1 therapeutic window by hypothermia was associated with decreases in infiltration of polymorphonuclear leukocytes and activation of microglia/macrophages and with attenuation of NF-κB activation in the ipsilateral hemisphere following HI.

Interleukin-1 receptor antagonist ameliorates neonatal lipopolysaccharide-induced long-lasting hyperalgesia in the adult rats.

An increasing amount of data show that central inflammation contributes to many debilitating diseases and produces spontaneous pain and hyperalgesia (an increased sensitivity to painful stimuli), and these processes may be associated with the production of proinflammatory cytokines by activated microglia. In the present study, we demonstrate that neonatal intracerebral injection of lipopolysaccharide (LPS) (1mg/kg) in postnatal day 5 (P5) rats produced hyperalgesia that lasted into adulthood as indicated by decreased latency in the tail-flick test. Neonatal LPS administration resulted in a long-lasting increase in the number of activated microglial in the P70 rat brain. The effects of interleukin-1beta (IL-1ß) and IL-1 receptor antagonists on hyperalgesia were determined to examine the possible role of inflammatory cytokines in LPS-induced hyperalgesia. Our data show that neonatal intracerebral injection of IL-1ß (1 µg/kg) produced a hyperalgesic tendency similar to that induced by LPS. Neonatal administration of an IL-1 receptor antagonist (0.1mg/kg) significantly attenuated long-lasting hyperalgesia induced by LPS and reduced the number of activated microglia in the adult rat brain. These data reveal that neonatal intracerebral LPS exposure results in long-lasting hyperalgesia and an elevated number of activated microglia in later life. This effect is similar to that induced by IL-1ß and can be prevented by an IL-1 receptor antagonist. The present study suggests that an IL-1 receptor antagonist effectively attenuates or blocks long-lasting hyperalgesia and microglia activation produced by LPS exposure in the neonatal period of rats.

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.

Estimated future HIV prevalence, incidence, and potential infections averted in the United States: a multiple scenario analysis.

OBJECTIVES: To estimate the potential future burden of HIV in the United States under different intervention scenarios. METHODS: We modeled future HIV incidence, prevalence, and infections averted using 2006 estimates of HIV incidence (55,400 new infections per year), prevalence (1,107,000 persons living with HIV), and transmission rate (5.0 per 100 persons living with HIV). We modeled 10-year trends for 3 base-case scenarios (steady incidence, steady transmission rate, declining transmission rate based on the 2000-2006 trend) and 2 intensified HIV intervention scenarios (50% reduction in transmission rate within 10 and 5 years). RESULTS: Base-case scenarios predicted HIV prevalence increases of 24%-38% in 10 years. Reducing the transmission rate by 50% within 10 years reduces incidence by 40%; prevalence increases 20% to an estimated 1,329,000 persons living with HIV. Halving the transmission rate within 5 years reduces incidence by 46%; prevalence increases 13%, to 1,247,000. Although in year 10 incidence is similar regardless of the intervention time frame, more infections are averted when halving the transmission rate within 5 years. CONCLUSIONS: HIV prevalence will likely increase creating additional demands for health care services. These analyses are instructive for setting HIV prevention goals for the nation and assessing potential cost savings of intensified HIV prevention efforts.

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.

Hypoxic preconditioning provides neuroprotection and increases vascular endothelial growth factor A, preserves the phosphorylation of Akt-Ser-473 and diminishes the increase in caspase-3 activity in neonatal rat hypoxic-ischemic model.

Vascular endothelial growth factor A (VEGF) likely plays a role in the hypoxic preconditioning (PC) induced tolerance to subsequent hypoxic-ischemic (HI) injury to the brain. However, limited data is available concerning VEGF in the developing brain after HI following PC. Neuroprotection by VEGF involves activation of Akt which inhibits apoptotic processes that contribute significantly to the brain injury in neonatal HI. We evaluated whether PC provides neuroprotection and affects VEGF, Akt and caspase-3 following HI in the developing rat brain. Newborn rats (6 days) were subjected to normoxia (21% O(2)) or PC (8% O(2)) for 3h followed by 24h of reoxygenation. The rats then had the right carotid artery permanently ligated followed by 140 min of hypoxia (8% O(2)) (HI or PC+HI). Brains from rats at the corresponding age without any exposure to PC or HI were examined for comparison (Sham). PC significantly reduced brain damage as measured by weight loss of the right hemisphere at 22 days after HI and by gross and microscopic morphology. PC amplified and prolonged the induction of mRNA of VEGF splice variants measured by real-time RT-PCR and enhanced the increase in VEGF protein measured by ELISA in brain following HI. PC preserved the phosphorylation of Akt-Ser-473 and diminished the increase in caspase-3 activity in brain following HI. We conclude that PC provides neuroprotection and augments and preserves the increase in VEGF following HI in the newborn rat brain which may play an important role in neuroprotection.

Undiagnosed HIV prevalence among adults and adolescents in the United States at the end of 2006.

OBJECTIVES: To describe adults/adolescents (age 13 years and older) living with undiagnosed HIV infection in the United States at the end of 2006. METHODS: HIV prevalence and percentage undiagnosed were estimated from cumulative HIV incidence using an extended back-calculation model (using both HIV and AIDS data, the time of first diagnosis with HIV, and disease severity at diagnosis) and estimated cumulative deaths. RESULTS: An estimated 1,106,400 adults/adolescents (95% confidence interval = 1,056,400-1,156,400) were living with HIV in the United States at the end of 2006; overall, 21.0% (232,700; 95% confidence interval = 221,200-244,200) were undiagnosed. Whites had the lowest percentage undiagnosed (18.8%) compared with Hispanics/Latinos (21.6%), blacks/African Americans (22.2%), American Indians/Alaska Natives (25.8%), and Asians/Pacific Islanders (29.5%; all P < 0.001). Persons with a behavioral risk of injection drug use (IDU) had the lowest percentage undiagnosed (female IDU: 13.7% and male IDU: 14.5%); men exposed through heterosexual contact had the highest (26.7%) followed by men who have sex with men (23.5%). CONCLUSIONS: Differences in undiagnosed HIV were evident across demographic and behavior groups. Effective testing programs and early access to treatment and prevention services are necessary to reduce undiagnosed HIV infections and HIV prevalence.

Adult-onset obesity reveals prenatal programming of glucose-insulin sensitivity in male sheep nutrient restricted during late gestation.

BACKGROUND: Obesity invokes a range of metabolic disturbances, but the transition from a poor to excessive nutritional environment may exacerbate adult metabolic dysfunction. The current study investigated global maternal nutrient restriction during early or late gestation on glucose tolerance and insulin sensitivity in the adult offspring when lean and obese. METHODS/PRINCIPAL FINDINGS: Pregnant sheep received adequate (1.0M; CE, n = 6) or energy restricted (0.7M) diet during early (1-65 days; LEE, n = 6) or late (65-128 days; LEL, n = 7) gestation (term approximately 147 days). Subsequent offspring remained on pasture until 1.5 years when all received glucose and insulin tolerance tests (GTT & ITT) and body composition determination by dual energy x-ray absorptiometry (DXA). All animals were then exposed to an obesogenic environment for 6-7 months and all protocols repeated. Prenatal dietary treatment had no effect on birth weight or on metabolic endpoints when animals were 'lean' (1.5 years). Obesity revealed generalised metabolic 'inflexibility' and insulin resistance; characterised by blunted excursions of plasma NEFA and increased insulin(AUC) (from 133 to 341 [s.e.d. 26] ng.ml(-1).120 mins) during a GTT, respectively. For LEL vs. CE, the peak in plasma insulin when obese was greater (7.8 vs. 4.7 [s.e.d. 1.1] ng.ml(-1)) and was exacerbated by offspring sex (i.e. 9.8 vs. 4.4 [s.e.d. 1.16] ng.ml(-1); LEL male vs. CE male, respectively). Acquisition of obesity also significantly influenced the plasma lipid and protein profile to suggest, overall, greater net lipogenesis and reduced protein metabolism. CONCLUSIONS: This study indicates generalised metabolic dysfunction with adult-onset obesity which also exacerbates and 'reveals' programming of glucose-insulin sensitivity in male offspring prenatally exposed to maternal undernutrition during late gestation. Taken together, the data suggest that metabolic function appears little compromised in young prenatally 'programmed' animals so long as weight is adequately controlled. Nutritional excess in adulthood exacerbates any programmed phenotype, indicating greater vigilance over weight control is required for those individuals exposed to nutritional thrift during gestation.