Maternal obesity programs mitochondrial and lipid metabolism gene expression in infant umbilical vein endothelial cells.

BACKGROUND/OBJECTIVES: Maternal obesity increases risk for childhood obesity, but molecular mechanisms are not well understood. We hypothesized that primary umbilical vein endothelial cells (HUVEC) from infants of overweight and obese mothers would harbor transcriptional patterns reflecting offspring obesity risk. SUBJECTS/METHODS: In this observational cohort study, we recruited 13 lean (pre-pregnancy body mass index (BMI) <25.0 kg m-2) and 24 overweight-obese ('ov-ob', BMI⩾25.0 kg m-2) women. We isolated primary HUVEC, and analyzed both gene expression (Primeview, Affymetrix) and cord blood levels of hormones and adipokines. RESULTS: A total of 142 transcripts were differentially expressed in HUVEC from infants of overweight-obese mothers (false discovery rate, FDR<0.05). Pathway analysis revealed that genes involved in mitochondrial and lipid metabolism were negatively correlated with maternal BMI (FDR<0.05). To test whether these transcriptomic patterns were associated with distinct nutrient exposures in the setting of maternal obesity, we analyzed the cord blood lipidome and noted significant increases in the levels of total free fatty acids (lean: 95.5±37.1 µg ml-1, ov-ob: 124.1±46.0 µg ml-1, P=0.049), palmitate (lean: 34.5±12.7 µg ml-1, ov-ob: 46.3±18.4 µg ml-1, P=0.03) and stearate (lean: 20.8±8.2 µg ml-1, ov-ob: 29.7±17.2 µg ml-1, P=0.04), in infants of overweight-obese mothers. CONCLUSIONS: Prenatal exposure to maternal obesity alters HUVEC expression of genes involved in mitochondrial and lipid metabolism, potentially reflecting developmentally programmed differences in oxidative and lipid metabolism.

Systematic review of congenital and acquired portal-systemic shunts in otherwise normal livers.

BACKGROUND: Portal-systemic shunts (PSSs) are rarely seen in healthy individuals or patients with non-cirrhotic liver disease. They may play an important role in hepatic metabolism as well as in the spread of gastrointestinal metastatic tumours to specific organs. Small spontaneous PSSs may be more common than generally thought. However, epidemiological data are scarce and inconclusive. This systematic review examined the prevalence of reported PSSs and the associated detection methods. METHODS: Literature up to 2011 was reviewed for adult patients with proven congenital or acquired PSSs. Only PSSs in normal livers were analysed for the methods of diagnosis. Eligible studies were identified by searching relevant databases, including PubMed, Embase, MEDLINE and the Cochrane Library. The selection of eligible articles was carried out using predefined inclusion criteria (adult, non-surgical PSS) and a set of search terms that were established before the articles were identified. RESULTS: Eighty studies were included describing 112 patients with congenital or acquired PSSs. The majority were diagnosed incidentally using Doppler ultrasound imaging and CT. CONCLUSION: Congenital and acquired PSSs are rare. They are usually clinically asymptomatic and discovered incidentally by radiological techniques. They may be clinically relevant owing to drug, tumour cell, metabolic and pathogen shunting.

Birds as bioindicators of plastic pollution in terrestrial and freshwater environments: A 30-year review.

Plastic pollution is a global concern that has grown ever more acute in recent years. Most research has focused on the impact of plastic pollution in marine environments. However, plastic is increasingly being detected in terrestrial and freshwater environments with key inland sources including landfills, where it is accessible to a wide range of organisms. Birds are effective bioindicators of pollutants for many reasons, including their high mobility and high intra- and interspecific variation in trophic levels. Freshwater and terrestrial bird species are under-represented in plastic pollution research compared to marine species. We reviewed 106 studies (spanning from 1994 onwards) that have detected plastics in bird species dwelling in freshwater and/or terrestrial habitats, identifying knowledge gaps. Seventy-two studies focused solely on macroplastics (fragments >5 mm), compared to 22 microplastic (fragments <5 mm) studies. A further 12 studies identified plastics as both microplastics and macroplastics. No study investigated nanoplastic (particles <100 nm) exposure. Research to date has geographical and species' biases while ignoring nanoplastic sequestration in free-living freshwater, terrestrial and marine bird species. Building on the baseline search presented here, we urge researchers to develop and validate standardised field sampling techniques and laboratory analytical protocols such as Raman spectroscopy to allow for the quantification and identification of micro- and nanoplastics in terrestrial and freshwater environments and the species therein. Future studies should consistently report the internalised and background concentrations, types, sizes and forms of plastics. This will enable a better understanding of the sources of plastic pollution and their routes of exposure to birds of terrestrial and freshwater environments, providing a more comprehensive insight into the potential impacts on birds.

Productive human immunodeficiency virus type 1 (HIV-1) infection of nonproliferating human monocytes.

Human immunodeficiency virus type 1 (HIV-1) infection of T lymphocytes requires cellular proliferation and DNA synthesis. Human monocytes were shown to have low DNA synthesis rates, yet the monocytotropic BaL isolate of HIV-1 was able to infect these cells efficiently. Monocytes that were irradiated to assure no DNA synthesis could also be readily infected with HIV-1BaL. Such infections were associated with the integration of HIV-1BaL DNA into the high molecular weight, chromosomal DNA of monocytes. Thus, normal, nonproliferating monocytes differ from T lymphocytes in that a productive HIV-1 infection can occur independently of cellular DNA synthesis. These results suggest that normal nonproliferating mononuclear phagocytes, which are relatively resistant to the destructive effects of this virus, may serve as persistent and productive reservoirs for HIV-1 in vivo.

Phenotypic variation in the response to the human immunodeficiency virus among derivatives of the CEM T and WIL-2 B cell lines.

Derivatives of the CEM T and WIL-2 B cell lines showed striking diversity in their responses to the HTLV-IIIB strain of the human immunodeficiency virus (HIV). Several stable phenotypic patterns could be defined, based on whether cells were permissive (P+, P-) for virus production, were sensitive or insensitive to cytopathic effects after infection by free virus (C+, C-), and whether they underwent fusion on contact with virus-infected cells (F+, F-). Although expression of CD4 was essential for infection by HTLV-IIIB, very low levels were sufficient for productive infection of WIL-2 derivatives. Conversely, some CEM T cell lines that expressed ample CD4, and which were able to bind virus gp120 and undergo fusion, did not support productive infection by free virus. One nonpermissive, CD4+ derivative of CEM could bind gp120 but failed to undergo fusion, suggesting an alteration in some membrane protein other than CD4 that is essential for virus entry and HIV-induced cell fusion. The AA2 derivative of the WIL-2 cell line is also described, which is remarkably permissive for HIV replication and exquisitely sensitive to virus cytopathic effect. The panel of related cell lines with different host-virus phenotypes could be useful for more precisely defining steps in the infectious cycle of HIV, and for identifying host cell genes and gene products that determine the outcome of HIV infection.

Conversion of an immunogenic human immunodeficiency virus (HIV) envelope synthetic peptide to a tolerogen in chimpanzees by the fusogenic domain of HIV gp41 envelope protein.

The fusogenic (F) domain of human immunodeficiency virus (HIV) gp41 envelope (env) protein has sequence similarities to many virus and mediates the fusion of HIV-infected cells. During a survey of the immunogenicity of HIV env peptides in chimpanzees, we have observed that HIV peptide immunogenicity was dramatically altered by the NH2-terminal synthesis of the gp41 F domain to an otherwise immunogenic peptide. We compared two hybrid peptide types comprised of T helper (Th) and B cell epitopes of HIV gp120 env protein for their immunogenicity in chimpanzees. The Th-B epitope hybrid peptides contained the HIV gp120 Th cell determinant, T1 (amino acids [aa] 428-440)-synthesized NH2 terminal to gp120 V3 loop peptides, which contain B cell epitopes that induce anti-HIV-neutralizing antibodies (SP10IIIB [aa 303-321] and SP10IIIB [A] [aa 303-327]). The F-Th-B peptide contained the HIV gp41 F domain of HIVIIIB gp41 (aa 519-530)-synthesized NH2 terminal to the Th-B peptide. Whereas Th-B peptides were potent immunogens for chimpanzee antibody and T cell-proliferative responses, the F-Th-B peptide induced lower anti-HIV gp120 T and B cell responses. Moreover, immunization of chimpanzees with F-Th-B peptide but not Th-B peptides induced a significant decrease in peripheral blood T lymphocytes (mean decrease during immunization, 52%; p < 0.02). Chimpanzees previously immunized with F-Th-B peptide did not respond well to immunization with Th-B peptide with T or B cell responses to HIV peptides, demonstrating that the F-Th-B peptide induced immune hyporesponsiveness to Th and B HIV gp120 env determinants. These observations raise the hypothesis that the HIV gp41 env F domain may be a biologically active immunoregulatory peptide in vivo, and by an as yet uncharacterized mechanism, promotes primate immune system hyporesponsiveness to otherwise immunogenic peptides.

HTLV-III/LAV-neutralizing antibodies to an E. coli-produced fragment of the virus envelope.

Immunization with either an Escherichia coli recombinant segment of the human T-cell lymphotropic virus (HTLV-III/LAV) envelope protein (gp 120) or with deglycosylated gp 120 envelope protein produced antibodies that neutralize HTLV-III/LAV infection in vitro. Virus neutralization titers of these antisera were equivalent to those obtained with purified native gp120 as immunogen. This localizes at least one class of neutralizing epitopes to the carboxyl-terminal half of the molecule. In addition, native gp120 prevented HTLV-III/LAV--mediated cell fusion, whereas the recombinant gp120 fragment did not. This shows that although glycosylation is not required for induction of neutralizing antibodies, it may be important for interaction with CD4, the virus receptor. A segment of the HTLV-III/LAV envelope produced in E. coli may be an important ingredient of a vaccine for acquired immune deficiency syndrome.

Broadly neutralizing antibodies elicited by the hypervariable neutralizing determinant of HIV-1.

The principal neutralizing determinant (PND) of human immunodeficiency virus (HIV)-1 resides within the V3 loop of the envelope protein. Antibodies elicited by peptides of this region were able to neutralize diverse isolates. Serum from one of three animals immunized with the human T cell lymphoma virus (HTLV)-IIIMN PND peptide, RP142, neutralized MN and the sequence-divergent HTLV-IIIB isolate. Serum from one of three animals immunized with a 13-amino acid IIIB PND peptide (RP337) also neutralized both of these isolates. Characterization of these sera revealed that the cross-neutralizing antibodies bound the amino acid sequence GlyProGlyArgAlaPhe (GPGRAF) that is present in both isolates. This sequence is frequently found in the PNDs analyzed in randomly selected HIV-1 isolates. Sera from two rabbits immunized with a peptide containing only the GPGRAF residues neutralized divergent isolates, including IIIB and MN.

Educational Attainment of Mothers Aged 25 and Over: United States, 2017.

Maternal education has been shown to be associated with the number of children a woman has during her childbearing years, as well as maternal and infant health (1-5). Using 2017 national birth certificate data, this report describes educational attainment of mothers aged 25 and over, overall and by race and Hispanic origin and state, and the mean numbers of live births by mothers' educational attainment.

Total Fertility Rates by State and Race and Hispanic Origin: United States, 2017.

Objectives-This report presents 2017 total fertility rates by state of residence and race and Hispanic origin of mother for the United States. Methods-Data are from birth certificates of the 50 states and the District of Columbia. Total fertility rates, the expected number of lifetime births per 1,000 women given current birth rates by age, are shown by state for all births, and for non-Hispanic single-race white, non-Hispanic single-race black, and Hispanic women for 2017. Results-Total fertility rates varied by state for each race and Hispanic-origin group. In 2017, South Dakota (2,227.5) had the highest total fertility rate of the 50 states and the District of Columbia; the District of Columbia had the lowest (1,421.0). For non-Hispanic white women, the highest total fertility rate was in Utah (2,099.5) and the lowest in the District of Columbia (1,012.0). Among non-Hispanic black women, the highest total fertility rate was in Maine (4,003.5) and the lowest in Wyoming (1,146.0) along with California (1,503.5), Connecticut (1,575.5), Montana (1,641.0), New Mexico (1,651.0), New York (1,574.5), Rhode Island (1,594.0), and West Virginia (1,579.5). For Hispanic women, the highest total fertility rate was in Alabama (3,085.0) and the lowest in Vermont (1,200.5) and Maine (1,281.5).

Declines in Births to Females Aged 10-14 in the United States, 2000-2016.

The birth rate for teen mothers aged 15-19 declined 57% from 2000 through 2016. During this time, the rate for young adolescent mothers aged 10-14 also declined. Childbearing by very young mothers is a matter of public concern because of the elevated health risks for these mothers and their infants and the socioeconomic consequences. This report describes recent trends and variations in births to young mothers aged 10-14 by race and Hispanic origin and state.

Infant Mortality by Age at Death in the United States, 2016.

Infant mortality is an important public health measure in the United States and other countries (1-3). The United States' infant mortality rate started to decline in 2007 (the most recent high), but has remained relatively unchanged in recent years (4,5). Previous research shows differences in infant mortality rates by age at death (i.e., neonatal, or deaths to infants aged 0-27 days, and postneonatal, or deaths to infants aged 28-364 days), age and race and Hispanic origin of the mother, and leading causes of death (4-6). This report examines infant mortality rates for the United States by age at death in 2016, by maternal age and race and Hispanic origin, and for the five leading causes of neonatal and postneonatal mortality.

State Variations in Infant Mortality by Race and Hispanic Origin of Mother, 2013-2015.

Infant mortality has long been a basic measure of public health for countries around the world (1­3). While the overall infant mortality rate in the United States is lower than a decade ago, declining 14% from 6.86 infant deaths per 1,000 live births in 2005, a recent high, to 5.90 in 2015, the rate in 2015 was not statistically different from that in 2014 (5.82) (4­6). The variability in infant mortality rates by state and by race and Hispanic origin continues to receive attention (7,8). This report uses linked birth and infant death data from 2013 through 2015 to describe infant mortality rates in the United States by state, and for race and Hispanic-origin groups by state.

In vivo measurement of tissue metabolism in tendons of the rotator cuff: implications for surgical management.

We have undertaken an in vivo assessment of the tissue metabolism and cellular activity in torn tendons of the rotator cuff. Cellular oxygen consumption was measured in 13 patients undergoing mini-open repair of small, medium, large and massive full-thickness tears. Measurements were also taken from three control patients who were undergoing open stabilisation of the shoulder with grossly normal tendons. The level of oxygen and nitrous oxide was measured amperometrically using silver needle microelectrodes at the apex of the tear and 1.5 cm from its edge. With nitrous oxide indicating the degree of perfusion, oxygen consumption was calculated at each location to reflect cellular activity. All of the torn tendons had lower levels of cellular activity than the control group. This activity was lower still in the tissue nearest to the edge of the tear with the larger tears showing the lowest activity. This indicated reduced levels of tissue metabolism and infers a reduction in tendon viability. Our findings suggest that surgical repair of torn tendons of the rotator-cuff should include the more proximal, viable tissue, and may help to explain the high rate of re-rupture seen in larger tears.

Infant Mortality Rates in Rural and Urban Areas in the United States, 2014.

The infant mortality rate is often used as a measure of a country's health because similar factors influence population health and infant mortality (1). Although infant mortality has declined in the United States, disparities still exist across geographic areas and demographic groups (2­4). Urbanization level, based on the number and concentration of people in a county, can impact health outcomes (3­9). Previous research indicates that infant mortality rates vary by urbanization level and also by maternal and infant characteristics (3­9). This report describes differences in infant mortality among rural, small and medium urban, and large urban counties in the United States by infant's age at death, mother's age, and race and Hispanic origin in 2014.

Characterization of envelope glycoprotein gp41 genotype and phenotypic susceptibility to enfuvirtide at baseline and on treatment in the phase III clinical trials TORO-1 and TORO-2.

Enfuvirtide (T-20) is the first entry inhibitor approved for treatment of HIV infection and acts by inhibiting conformational changes in the viral envelope protein gp41 that are necessary for fusion of the virus and host cell membranes. Here we present genotypic and phenotypic data on viral envelopes obtained at baseline (n = 627) and after 48 weeks of enfuvirtide treatment (n = 302) from patients in the TORO (T-20 versus Optimized Regimen Only)-1 and -2 phase III pivotal studies. The amino acid sequence at residues 36-45 of gp41 was highly conserved at baseline except for polymorphism of approximately 16% at position 42. Substitutions within gp41 residues 36-45 on treatment were observed in virus from 92.7% of patients who met protocol defined virological failure criteria and occurred in nearly all cases (98.8%) when decreases in susceptibility to enfuvirtide from baseline of greater than 4-fold were observed. Consistent with previous observations, a wide range of baseline susceptibilities (spanning 3 logs) was observed; however, lower in vitro baseline susceptibility was not significantly associated with a decreased virological response in vivo. Virological response was also independent of baseline coreceptor tropism and viral subtype.

Pathology of the torn rotator cuff tendon. Reduction in potential for repair as tear size increases.

We have studied cellular and vascular changes in different stages of full thickness tears of the rotator cuff. We examined biopsies from the supraspinatus tendon in 40 patients with chronic rotator cuff tears who were undergoing surgery and compared them with biopsies from four uninjured subscapularis tendons. Morphological and immunocytochemical methods using monoclonal antibodies directed against leucocytes, macrophages, mast cells, proliferative and vascular markers were used. Histological changes indicative of repair and inflammation were most evident in small sized rotator cuff tears with increased fibroblast cellularity and intimal hyperplasia, together with increased expression of leucocyte and vascular markers. These reparative and inflammatory changes diminished as the size of the rotator cuff tear increased. Marked oedema and degeneration was seen in large and massive tears, which more often showed chondroid metaplasia and amyloid deposition. There was no association between the age of the patient and the duration of symptoms. In contrast, large and massive tears showed no increase in the number of inflammatory cells and blood vessels. Small sized rotator cuff tears retained the greatest potential to heal, showing increased fibroblast cellularity, blood vessel proliferation and the presence of a significant inflammatory component. Tissue from large and massive tears is of such a degenerative nature that it may be a significant cause of re-rupture after surgical repair and could make healing improbable in this group.

Immunologic control of a retrovirus-associated murine adenocarcinoma. VIII. Corynebacterium parvum-activated natural killer cells as potent antibody-dependent cell-mediated cytotoxicity effectors.

The antibody-dependent lytic activity of Corynebacterium parvum-induced peritoneal exudate cells was examined in vitro by utilizing AD755a tumor targets and a homologous anti-AD755a hyperimmune serum. Maximum antibody-dependent cell-mediated cytolysis (ADCC) of tumor targets was achieved within 4 hours of incubation. ADCC activity was found primarily in the plastic nonadherent cell population and was greatly enriched following removal of phagocytic cells by carbonyl iron. Phenotypically, the cells active in short-term ADCC were Qa-5+, ASGM-1+, Thy 1.2+, and NK 1.1+ and were unaffected by treatment with Lyt 1.2, Lyt 2.2, MAC-1, or I-Ab antibodies plus complement. Cells active in antibody-independent lysis of AD755a targets were phenotypically identical to antibody-dependent effectors. Although indicative of a natural killer (NK) cell phenotype, C. parvum-induced effectors differed from "spontaneous" splenic NK cells in their relative sensitivity to anti-Thy 1.2 as well as to anti-NK 1.1 treatment. Unlike the IgG2a-dependent lysis of AD755a-derived cells by inflammatory macrophages, all IgG isotypes of antiAD755a serum were equally effective in ADCC mediated by C. parvum NK cells. Finally, treatment of C. parvum-inoculated animals with anti-ASGM-1 serum eliminated in vitro NK activity and abrogated the in vivo therapeutic effects of hyperimmune serum. These findings, together with other correlations detailed herein, strongly suggested that C. parvum-activated NK cells appeared to represent a unique subset of NK cells that can serve as potent effectors in the antibody-dependent killing of AD755a tumor cells.

Immunologic control of a retrovirus-associated murine adenocarcinoma. VI. Augmentation of antibody-dependent killing following quantitative and qualitative changes in host peritoneal cells.

Attempts were made to augment the antibody-dependent killing of the ascitic AD755a tumor in vivo to protect C57BL/6J mice against the outgrowth of larger tumor burdens. The lethal dose for this tumor is less than 100 cells, and antibodies contained in a hyperimmune antitumor serum (HIS) were found to suppress the outgrowth of a maximum of about 5 X 10(5) cells. Thioglycollate injected ip increased the number of peritoneal macrophages, potential effectors for antibody-dependent cell-mediated cytotoxicity (ADCC), by tenfold to fortyfold and raised the maximum treatable tumor challenge (MTTC) to about 4 X 10(6) cells. By comparison, ip injection of Corynebacterium parvum increased the total peritoneal cell population by only twofold but raised the MTTC to about 20 X 10(6) cells. Neither agent alone had an effect on long-term survival, even at very low tumor inocula (1 X 10(3) cells). The protective HIS is known to contain tumor-binding antibodies in each of the IgG1, IgG2A, and IgG2B isotype fractions. Although the IgG2A fraction is far superior in vivo in the suppression of tumor outgrowth, the IgG2A fraction was also found to be most effective in combination with thioglycollate treatment in agreement with the observed preference of thioglycollate-elicited macrophages for this isotype in in vitro killing assays. In contrast following C. parvum treatment, all three isoptype fractions were equally suppressive to tumor outgrowth. A second major change following C. parvum treatment was that tumor cells precoated in vitro with antibodies were effectively eliminated in vivo. The same antibody-coated cells administered to thioglycollate-treated or unmanipulated animals were uniformly lethal even at much lower tumor doses. Taken together these results suggested a major qualitative change in the antibody-dependent tumor-killing process following C. parvum treatment. This change was most likely due to the C. parvum activation of highly lytic effector cells for ADCC, the identity of which was examined in an accompanying manuscript.

Immunologic control of a retrovirus-associated murine adenocarcinoma. VII. Tumor cell destruction by macrophages and IgG2A.

The mechanism by which IgG2A from a syngeneic antitumor hyperimmune serum mediates destruction of target cells in the presence of thioglycollate-elicited peritoneal macrophages was investigated by using an in vitro assay system. Labeled tumor cells were found to exhibit a biphasic pattern of binding to the effector cells; this binding pattern was dependent on the presence of specific antibody. The initial binding phase produced no apparent changes in the target cell population. Target cells coated with specific antibody exhibited a similar early binding phase, but excess free antibody was required for the subsequent binding phase and its associated release of radiolabel and cell destruction. Several features of this process observed distinguished it from more conventional forms of antibody-dependent cell-mediated cytoxicity. These included 1) the preference for antibodies of the IgG2A isotype, 2) the association of cell destruction with the release of nuclear but not cytoplasmic label, and 3) the requirement of excess free antibody for target cell killing.