Requirements of NK cells and proinflammatory cytokines in T cell-dependent neonatal autoimmune ovarian disease triggered by immune complex

A model of neonatal autoimmune disease has been described recently in which an epitope-specific autoantibody to murine zona pellucida 3 induces severe ovarian disease in neonatal, but not adult, mice (neonatal AOD). The autoantibody forms immune complex with endogenous ovarian zona pellucida 3, and a pathogenic CD4(+) T cell response is triggered. The basis for the predominant neonatal susceptibility has not been clarified. In this study innate immunity, including neonatal NK cells, in neonatal AOD was investigated. Neonatal spleen contained readily detectable NK1.1(+)TCRVbeta(-), but not NK1.1(+)TCRVbeta(+), cells. Ab depletion of NK1.1(+)TCRVbeta(-) cells inhibited neonatal AOD development. Moreover, in adoptive transfer of neonatal AOD, recipient disease was ameliorated when either donor or recipient NK cells were depleted. Thus, NK cells operate in both induction and effector phases of the disease. IFN-gamma was produced by neonatal NK cells in vivo, and it may be important in neonatal AOD. Indeed, ovaries with neonatal AOD expressed high levels of IFN-gamma and TNF-alpha which correlated with disease severity, and the disease was inhibited by IFN-gamma or TNF-alpha Ab. Importantly, disease was enhanced by recombinant IFN-gamma, and treatment of T cell donors with IFN-gamma Ab also significantly reduced adoptive transfer of neonatal AOD. Finally, neonatal AOD was ameliorated in mice deficient in FcgammaRIII and was enhanced in FcgammaRIIB-deficient mice. We conclude that neonatal NK cells promote pathogenic T cell response at multiple stages during neonatal autoimmune disease pathogenesis. Also operative in neonatal AOD are other mediators of the innate system, including proinflammatory cytokines and FcgammaRIII signaling.     

Determinants and Causes of Neonatal Mortality in Jimma Zone,Southwest Ethiopia: A Multilevel Analysis of Prospective Follow Up Study

Background

Ethiopia is among the countries with the highest neonatal mortality with the rate of 37 deaths per 1000 live births. In spite of many efforts by the government and other partners, non-significant decline has been achieved in the last 15 years. Thus, identifying the determinants and causes are very crucial for policy and program improvement. However, studies are scarce in the country in general and in Jimma zone in particular.

Objective

To identify the determinants and causes of neonatal mortality in Jimma Zone, Southwest Ethiopia.

Methods

A prospective follow-up study was conducted among 3463 neonates from September 2012 to December 2013. The data were collected by interviewer-administered structured questionnaire and analyzed by SPSS V.20.0 and STATA 13. Verbal autopsies were conducted to identify causes of neonatal death. Mixed-effects multilevel logistic regression model was used to identify determinants of neonatal mortality.

Results

The status of neonatal mortality rate was 35.5 (95%CI: 28.3, 42.6) per 1000 live births. Though significant variation existed between clusters in relation to neonatal mortality, cluster-level variables were found to have non-significant effect on neonatal mortality. Individual-level variables such as birth order, frequency of antenatal care use, delivery place, gestation age at birth, premature rupture of membrane, complication during labor, twin births, size of neonate at birth and neonatal care practice were identified as determinants of neonatal mortality. Birth asphyxia (47.5%), neonatal infections (34.3%) and prematurity (11.1%) were the three leading causes of neonatal mortality accounting for 93%.

Conclusions

This study revealed high status of neonatal mortality in the study area. Higher-level variables had less importance in determining neonatal mortality. Individual level variables related to care during pregnancy, intra-partum complications and care, neonatal conditions and the immediate neonatal care practices were identified as determinant factors. Improving antenatal care, intra-partum care and immediate neonatal care are recommended.     

Effects of glucose on insulin release and 86Rb permeability in cultured neonatal and adult rat islets

Glucose-induced insulin release and modifications in 86Rb outflow were studied in cultured neonatal and adult rat islets. The dose-response curve for neonatal islets was steeper than for adult islets and the maximal response was clearly shifted towards lower glucose concentrations. In neonatal islets, glucose-induced insulin release was inhibited by the Ca2+-channel blocker, nifedipine. In the absence of glucose, the 86Rb outflow from neonatal islets was lower than from adult islets. Also, the glucose-induced reduction in 86Rb outflow was less pronounced in neonatal islets. Altered K+ permeability in the B-cell membrane could explain the change in glucose sensitivity of neonatal islets.     

Neonatal animal models of opiate withdrawal

The symptoms of opiate withdrawal in infants are defined as neonatal abstinence syndrome (NAS). NAS is a significant cause of morbidity in term and preterm infants. Factors, such as polysubstance abuse, inadequate prenatal care, nutritional deprivation, and the biology of the developing central nervous system contribute to the challenge of evaluating and treating opiate-induced alterations in the newborn. Although research on the effects of opiates in neonatal animal models is limited, the data from adult animal models have greatly contributed to understanding and treating opiate tolerance, addiction, and withdrawal in adult humans. Yet the limited neonatal data that are available indicate that the mechanisms involved in these processes in the newborn differ from those in adult animals, and that neonatal models of opiate withdrawal are needed to understand and develop effective treatment regimens for NAS. In this review, the behavioral and neurochemical evidence from the literature is presented and suggests that mechanisms responsible for opiate tolerance, dependence, and withdrawal differ between adult and neonatal models. Also reviewed are studies that have used neonatal rodent models, the authors' preliminary data based on the use of neonatal rat and mouse models of opiate withdrawal, and other neonatal models that have been proposed for the study of neonatal opiate withdrawal.     

Differential sialylation modulates voltage-gated Na+ channel gating throughout the developing myocardium

Voltage-gated sodium channel function from neonatal and adult rat cardiomyocytes was measured and compared. Channels from neonatal ventricles required an approximately 10 mV greater depolarization for voltage-dependent gating events than did channels from neonatal atria and adult atria and ventricles. We questioned whether such gating shifts were due to developmental and/or chamber-dependent changes in channel-associated functional sialic acids. Thus, all gating characteristics for channels from neonatal atria and adult atria and ventricles shifted significantly to more depolarized potentials after removal of surface sialic acids. Desialylation of channels from neonatal ventricles did not affect channel gating. After removal of the complete surface N-glycosylation structures, gating of channels from neonatal atria and adult atria and ventricles shifted to depolarized potentials nearly identical to those measured for channels from neonatal ventricles. Gating of channels from neonatal ventricles were unaffected by such deglycosylation. Immunoblot gel shift analyses indicated that voltage-gated sodium channel alpha subunits from neonatal atria and adult atria and ventricles are more heavily sialylated than alpha subunits from neonatal ventricles. The data are consistent with approximately 15 more sialic acid residues attached to each alpha subunit from neonatal atria and adult atria and ventricles. The data indicate that differential sialylation of myocyte voltage-gated sodium channel alpha subunits is responsible for much of the developmental and chamber-specific remodeling of channel gating observed here. Further, cardiac excitability is likely impacted by these sialic acid-dependent gating effects, such as modulation of the rate of recovery from inactivation. A novel mechanism is described by which cardiac voltage-gated sodium channel gating and subsequently cardiac rhythms are modulated by changes in channel-associated sialic acids.     

新生儿肠道双歧杆菌数量与其相关影响因素的探讨

目的　探讨影响新生儿肠道双歧杆菌数量的相关因素。方法　以重庆医科大学附属二院和重庆市妇幼保健院的12 0例新生儿为研究对象,每例生后5～7d,均采集新鲜大便做双歧杆菌定量培养,并做10个相关因素的准确登记。结果　母亲分娩方式、临产期及产后是否使用抗生素、母亲妊娠期饮食习惯以及新生儿黄疸期长短与新生儿肠道双歧杆菌数量有相关性( P均<0 .0 1)。结论　提倡阴道分娩、临产期及产后不用抗生素、妊娠期多食发酵制品和素食,并尽量设法缩短新生儿黄疸时间,均有益于新生儿肠道双歧杆菌数量相对充足     

Neonatal coagulopathies: A review of established and emerging treatments

Despite the relative frequency of both bleeding and clotting disorders among patients treated in the neonatal intensive care unit, few clear guidelines exist for treatment of neonatal coagulopathies. The study and treatment of neonatal coagulopathies are complicated by the distinct hemostatic balance and clotting components present during this developmental stage as well as the relative scarcity of studies specific to this age group. This mini-review examines the current understanding of neonatal hemostatic balance and treatment of neonatal coagulopathies, with particular emphasis on emerging treatment methods and areas in need of further investigative efforts.     

人轮状病毒感染昆明小鼠乳鼠模型的建立

目的建立人轮状病毒G3型709株感染4d龄昆明小鼠乳鼠模型。方法通过灌胃病毒的方式造模,观察乳鼠被病毒攻击后不同时间其临床表现、小肠组织病理改变、小肠组织上皮细胞超微结构改变。酶联免疫吸附法检测轮状病毒抗原在乳鼠粪便中的表达,免疫荧光法检测轮状病毒在乳鼠小肠组织中的表达。结果4d龄昆明小鼠乳鼠被轮状病毒攻击24h后出现腹泻表现和小肠组织病理改变,72h最严重,之后腹泻率下降,病理改变减轻,第7天腹泻停止,病理改变消失。乳鼠小肠上皮细胞出现糖、脂肪代谢紊乱,其粪便和小肠组织中都可以检测出轮状病毒抗原表达。结论4d龄昆明小鼠乳鼠被人轮状病毒A组G3型709株经口攻击后病毒能够在其体内复制,出现腹泻表现。该病毒感染腹泻过程具有自愈特点。     

Mechanisms of neonatal mucosal antibody protection

Following an abrupt transition at birth from the sterile uterus to an environment with abundant commensal and pathogenic microbes, neonatal mammals are protected by maternal Abs at mucosal surfaces. We show in mice that different Ab isotypes work in distinct ways to protect the neonatal mucosal surface. Secretory IgA acts to limit penetration of commensal intestinal bacteria through the neonatal intestinal epithelium: an apparently primitive process that does not require diversification of the primary natural Ab repertoire. In contrast, neonatal protection against the exclusively luminal parasite Heligmosomoides polygyrus required IgG from primed females. This immune IgG could either be delivered directly in milk or retrotransported via neonatal Fc receptor from the neonatal serum into the intestinal lumen to exert its protective effect.     

Maternal autoantibody triggers de novo T cell-mediated neonatal autoimmune disease

Although human maternal autoantibodies may transfer transient manifestation of autoimmune disease to their progeny, some neonatal autoimmune diseases can progress, leading to the loss of tissue structure and function. In this study we document that murine maternal autoantibody transmitted to progeny can trigger de novo neonatal pathogenic autoreactive T cell response and T cell-mediated organ-specific autoimmune disease. Autoantibody to a zona pellucida 3 (ZP3) epitope was found to induce autoimmune ovarian disease (AOD) and premature ovarian failure in neonatal, but not adult, mice. Neonatal AOD did not occur in T cell-deficient pups, and the ovarian pathology was transferable by CD4(+) T cells from diseased donors. Interestingly, neonatal AOD occurred only in pups exposed to ZP3 autoantibody from neonatal days 1-5, but not from day 7 or day 9. The disease susceptibility neonatal time window was not related to a propensity of neonatal ovaries to autoimmune inflammation, and it was not affected by infusion of functional adult CD4(+)CD25(+) T cells. However, resistance to neonatal AOD in 9-day-old mice was abrogated by CD4(+)CD25(+) T cell depletion. Finally, neonatal AOD was blocked by Ab to IgG-FcR, and interestingly, the disease was not elicited by autoantibody to a second, independent native ZP3 B cell epitope. Therefore, a new mechanism of neonatal autoimmunity is presented in which epitope-specific autoantibody stimulates de novo autoimmune pathogenic CD4(+) T cell response.     

Maternal, neonatal and community factors influencing neonatal mortality in Brazil

Child mortality (the mortality of children less than five years old) declined considerably in the developing world in the 1990s, but infant mortality declined less. The reductions in neonatal mortality were not impressive and, as a consequence, there is an increasing percentage of infant deaths in the neonatal period. Any further reduction in child mortality, therefore, requires an understanding of the determinants of neonatal mortality. 209,628 birth and 2581 neonatal death records for the 1998 birth cohort from the city of S?o Paulo, Brazil, were probabilistically matched. Data were from SINASC and SIM, Information Systems on Live Births and Deaths of Brazil. Logistic regression was used to find the association between neonatal mortality and the following risk factors: birth weight, gestational age, Apgar scores at 1 and 5 minutes, delivery mode, plurality, sex, maternal education, maternal age, number of prior losses, prenatal care, race, parity and community development. Infants of older mothers were less likely to die in the neonatal period. Caesarean delivery was not found to be associated with neonatal mortality. Low birth weight, pre-term birth and low Apgar scores were associated with neonatal death. Having a mother who lives in the highest developed community decreased the odds of neonatal death, suggesting that factors not measured in this study are behind such association. This result may also indicate that other factors over and above biological and more proximate factors could affect neonatal death.     

广西新生儿专科护士的现况调查

目的了解并分析广西新生儿专科护士的现况,为广西新生儿专科护士的培训提供客观依据。方法通过查阅文献,结合广西新生儿专科护士培训方案及培训计划,采用自制调查表及自评式问卷对3期共163名广西新生儿专科护士进行培训技能需求调查,并对培训前、培训后的专科技能掌握现况进行自评。结果基本技能需求构成比为80.98%,重症护理需求构成比为93.25,外科护理需求构成比为51.53%,科研指导需求构成比为41.72%。培训前后新生儿专科基本技能和科研能力掌握评分比较,差异有统计学意义(P<0.05);新生儿重症护理技术和新生儿外科护理技术培训前后的评分比较,差异无统计学意义(P>0.05)。结论广西新生儿专科护士在重症护理技术和外科护理技术能力较低,系统、全面、规范的人才培养及培训有助于提高专科护士的专业技术水平。     

Comparison of respiratory effects of intravenous adenosine in neonatal and adult rabbits

We administered adenosine by repeated intravenous bolus doses to 34 neonatal rabbits in a dose of 120 micrograms X kg-1 (which we had previously found to stimulate respiration in adult rabbits). In 13 neonatal animals adenosine produced transient respiratory depression. In 15 neonatal animals the change in respiration in response to adenosine did not reach statistical significance. In two animals a transient increase in respiration occurred in response to adenosine. In the neonatal group as a whole intravenous adenosine significantly depressed ventilation. In eleven of the animals studied as neonates, respiratory responses to adenosine were again studied in adulthood. In 10 animals respiratory stimulation occurred in response to adenosine. In the adult group adenosine significantly increased ventilation, in contrast to its effects in the neonatal group. The respiratory effects of intravenous adenosine have not been previously described in neonatal animals. Respiratory stimulation produced by intravenous adenosine in adult rabbits contrasts with the respiratory depression commonly seen in neonatal rabbits in this study. It is suggested that altered responses to adenosine may be involved in the difference between the ventilatory response to hypoxia in adult and neonatal animals.     

Functional immaturity in neonatal polymorphonuclear leukocytes of rhesus monkeys

Abstract: Despite major advances in the management and care of critically ill and low-birthweight human and nonhuman primate infants over the past two decades, infection remains a major source of neonatal morbidity and mortality. Although the causes of enhanced susceptibility and dissemination of neonatal infections are incompletely defined in the literature, substantial evidence from this and other laboratories has implied that functional abnormalities of neonatal polymorphonuclear leukocytes (PMNs) may be a major contributor. Increased understanding of the functional characteristics of neonatal PMNs should, therefore, provide significant insight into the pathogenesis and possible therapy of infections in neonates. Our laboratory has been actively involved in evaluating the functional competence of PMNs in neonatal human and nonhuman primates. This report describes a study in which we have confirmed and characterized the functional compromises in neonatal PMNs of rhesus monkeys, including deficiencies in chemotaxis, membrane deformability, phagocytosis, and killing.     

GM-CSF augments the immunosuppressive capacity of neonatal spleen cells in vitro

Addition of exogenous granulocyte-macrophage colony stimulating factor (GM-CSF) to cultures of adult murine spleen cells with sheep red blood cells (SRBC) results in an augmented plaque forming cell (PFC) response. The influence of GM-CSF on the ability of neonatal spleen cells to suppress the anti-SRBC plaque forming response of adult spleen cells was tested by adding GM-CSF to cultures of neonatal and adult spleen cells. The suppressive capacity of the neonatal spleen cells was augmented by exogenous GM-CSF. The augmented suppression of the neonatal spleen cells was dependent on a G-10 adherent population since the addition of GM-CSF to cultures containing G-10 passed neonatal spleen cells resulted in an augmented PFC response and not suppression. Neonatal splenic glass adherent cells were also capable of suppressing the response. Neonatal spleen cells or purified neonatal glass adherent spleen cells cultured in the presence of GM-CSF had markedly increased levels of PGE2 in the culture supernatant. Neonatal spleen cells cultured with GM-CSF had increased numbers of morphologically identifiable macrophages after 48 hr of culture. Both irradiation and G-10 passage of the neonatal spleen diminished the numbers of macrophages formed in response to GM-CSF, and both of these manipulations resulted in reversal of suppression in response to GM-CSF. Thus, the augmented suppressive capacity of neonatal spleen cells in response to GM-CSF is probably mediated by its ability to drive monocyte to macrophage differentiation as well as increase the suppressive capacity of the existing neonatal splenic macrophages by increasing their production of PGE2.     

Heterosis for neonatal survival in the guppy

Neonatal survival rate ranged from 91.8 to 100.0% in 12 populations of the guppy Poecilia reticulata , and was higher in naturalized Japanese stream populations than in domestic strains. Mean heterozygosity at five allozyme and four microsatellite loci varied between 0.112 and 0.430 and was significantly correlated with neonatal survival rate among populations, suggest ing that inbreeding decreases neonatal survival. Diallel and reciprocal crosses among four domestic strains demonstrated heterosis for neonatal survival. These results indicate that neonatal survival is genetically affected by heterosis and its antithesis, inbreeding depression. The relationship between neonatal survival and the mean heterozygosity suggests that overall heterozygosity is important for neonatal survival of the guppy.     

Neonatal vaccination against respiratory syncytial virus infection

Respiratory syncytial virus (RSV) is the leading cause of pneumonia and bronchiolitis in infants and is the most frequent cause of lower respiratory tract infections in children.Efficacious vaccination...     

Freshly isolated, murine neonatal T cells produce IL-4 in response to anti-CD3 stimulation.

In previous studies of chimeric animals, we found that fetal intrathymic T cell precursors give rise to phenotypically abnormal peripheral T cell populations. Because most peripheral T lymphocytes in newborn mice are the progeny of fetal T cell precursors, this result led to the hypothesis that neonatal and adult T cells differ in their functional capacities. To investigate this issue, the responses of neonatal and adult T cells to anti-CD3 antibody and TCR-independent stimulation were compared. When stimulated with soluble anti-CD3 antibody in the presence of adult accessory cells, neonatal T cell proliferation was markedly decreased compared with that of adult T cells. This reduction in proliferation was associated with both quantitative and qualitative differences in lymphokine production. At 48 h of stimulation with anti-CD3 antibody, neonatal T cells produced at least 10-fold less IL-2 than adult T cells. This apparently accounted for their reduced proliferation because the addition of exogenous IL-2 restored their proliferation to the levels achieved by adult T cells. In striking contrast to adult T cells, neonatal T cells secreted large amounts of IL-4 upon primary stimulation in vitro. The differences between neonatal and adult T cells in proliferation and lymphokine production were shown to be specific for CD3-mediated stimulation. In the presence of phorbol ester and calcium ionophore, neonatal and adult T cells showed equivalent proliferation and IL-2 production. Under these conditions, IL-4 production by neonatal or adult T cells was essentially undetectable. Thus, in response to TCR-independent stimulation, freshly isolated neonatal and adult T cells show similar functional responses. However, when stimulation occurs via the CD3 components of the TCR, the responses of neonatal T cells resemble those of primed T cells from adult animals.     

A single form of metallothionein is Present in both heavy metal induced and neonatal chicken liver

MultiPlicity of metallothionein and their genes in higher animals are documented extensively in recent literature. In contrast, chicken liver Produced aPParently a single form of metallothionein uPon heavy metal exPosure. This Protein was Purified by gel filtration and ion exchange chromatograPhy and another technique based on heat treatment and acetone fractionation, followed by ion exchange chromatograPhy. In adult uninduced chicken liver the Presence of metallothionein was below the detection limit. But, like mammalian system, chicken liver was found to contain high amount of metallothionein at neonatal stage. This naturally occurring neonatal chicken hePatic metallothionein was Purified and comPared with the heavy metal induced adult hePatic metallothionein. The biochemical and immunobiological comParative analysis of adult and neonatal hePatic metallothionein showed identical characteristics. The neonatal metaltothionein exPressed naturally was a zinc metallothionein and unlike few other mammalian neonatal metallothionein did not contain any coPPer. Metallothionein was undectable in unfertilized eggs, in early embryos, and in Postnatal chicken, from 4 weeks after birth. The highest level of this naturally occurring neonatal metallothionein was found in 1–4 day old neonatal liver, which was about 1.5% of the total cytosolic Protein. This is the first rePorted evidence for the Presence of ontogenically modulated exPression of metallothionein in avian system. Possible biological role of neonatal metallothionein and their cellular interactions has been discussed.     

HOW MAMMALS PRODUCE LARGE-BRAINED OFFSPRING

Two explanations for species differences in neonatal brain size in eutherian mammals relate the size of the brain at birth to maternal metabolic rate. Martin (1981, 1983) argued that maternal basal metabolic rate puts an upper bound on the mother's ability to supply energy to the fetus, thereby limiting neonatal brain size. Hofman (1983) proposed that gestation length in mammals is constrained by maternal metabolic rate, implying an indirect constraint on neonatal brain size. Since individuals of precocial species have much larger neonatal brain sizes and are gestated longer for a given maternal body size than individuals of altricial species, Martin's and Hofman's ideas also require that mothers of precocial offspring have higher metabolic rates for their body sizes than mothers of altricial offspring. Data on 116 mammal species from 13 orders show that neither neonatal brain size nor gestation length is correlated with maternal metabolic rate when maternal body-size effects are removed. For a given maternal size, there is no difference in metabolic rates between precocial and altricial species, despite a two-fold difference between them in average neonatal brain size. However, neonatal brain size is strongly correlated with gestation length and litter size, independently of maternal size and metabolic rate. Analyses conducted within orders replicated the findings for gestation length and suggested that neonatal brain size may be at best only weakly related to metabolic rate. Differences in neonatal brain size appear to have evolved primarily with species differences in gestation length and litter size but not with differences in metabolic rate; large-brained offspring are typically produced from litters of one that have been gestated for a long time relative to maternal size. We conclude that species differences in relative neonatal brain size reflect different life-history tactics rather than constraints imposed by metabolic rate.