Postpartum depression and child growth in Tanzania: a cohort study.

OBJECTIVE: To examine the association between postpartum depression and child growth in a Tanzanian birth cohort. DESIGN: Prospective cohort study. SETTING: Moshi, Tanzania. POPULATION: Pregnant women over the age of 18 who sought antenatal care at two health clinics in Moshi, and the children they were pregnant with, were assessed for inclusion in this study. METHODS: The women were interviewed twice during pregnancy and three times after birth, the final follow up taking place 2-3 years postpartum. Signs of postpartum depression were assessed approximately 40 days postpartum with the Edinburgh Postnatal Depression Scale. MAIN OUTCOME MEASURES: Child growth was assessed with anthropometric measurements at 2-3 years of age and expressed as mean z-scores. RESULTS: In all, 1128 mother-child pairs were followed throughout the duration of the study. In total, 12.2% of the mothers showed signs of postpartum depression. Adjusted mean height-for-age z-score (HAZ) was significantly lower at 2-3 years follow up for children of mothers with postpartum depression than for children of mothers without (difference in HAZ: -0.32, 95% CI-0.49 to -0.15). Adjusted mean weight-for-height z-score (WHZ) was significantly increased for the children exposed to postpartum depression (difference in WHZ: 0.21, 95% CI 0.02-0.40), whereas there was no significant difference in adjusted weight-for-age z-score (WAZ; difference in WAZ: -0.04, 95% CI -0.20 to 0.12). CONCLUSIONS: We found that postpartum depressive symptoms predicted decreased linear height in children at 2-3 years of age and slightly increased weight-for-height. TWEETABLE ABSTRACT: Postpartum depression in Tanzanian mothers is associated with impaired child growth at 2-3 years of age.

HLA-Cw*0409N is associated with HLA-A*2301 and HLA-B*4403-carrying haplotypes.

The associations of HLA-B*4402 and HLA-B*4403 with alleles of HLA-A and HLA-Cw were investigated in panels of HLA-B*4403 and HLA-B*4402 homozygous individuals and in selected individuals carrying HLA-Cw*04 and HLA-B*4403. Some of these individuals were genotyped and also carried (HLA-DRB1*0701, DQB1*02). Among the latter, we studied individuals carrying the conserved extended haplotype (CEH) [HLA-Cw*04, B*4403, FC31, DRB1*0701, DQB1*02]. Four different common (HLA-Cw*, B*44) haplotypes were identified that extended to the HLA-A locus: HLA-A*0201, Cw*0501, B*4402; HLA-A*2902, Cw*1601, B*4403; HLA-A*2301, Cw*0401, B*4403; and HLA-A*2301, Cw*0409N, B*4403. We identified eight unrelated examples of the allele HLA-Cw*0409N. HLA-A*2301 was associated with both HLA-Cw*0401 and HLA-Cw*0409N, suggesting that HLA-Cw*0409N may have arisen from a mutation in a CEH. We estimate that approximately 2 to 5 in 1000 Caucasian individuals carry the allele HLA-Cw*0409N, making it one of the most frequent null HLA alleles known to date. Our findings demonstrate the first example of three different HLA-Cw-determined subtypes of a common or CEH carrying a shared HLA-B allele, in this case HLA-B*4403.

Inheritable variable sizes of DNA stretches in the human MHC: conserved extended haplotypes and their fragments or blocks.

The difference in sizes of conserved stretches of DNA sequence within the major histocompatibility complex (MHC) in human individuals constitutes an underappreciated genetic diversity that has many practical implications. We developed a model to describe the variable sizes of stretches of conserved DNA in the MHC using the known frequencies of four different kinds of small (< 0.2 Mb) blocks of relatively conserved DNA sequence: HLA-Cw/B; TNF; complotype; and HLA-DR/DQ. Each of these small blocks is composed of two or more alleles of closely linked loci inherited as one genetic unit. We updated the concept of the conserved extended haplotype (CEH) using HLA allele identification and TNF microsatellites to show that specific combinations of the four blocks form single genetic units (>/= 1.5 Mb) with a total haplotype frequency in the Caucasian population of 0.30. Some CEHs extend to the HLA-A and -DPB1 loci forming fixed genetic units of up to at least 3.2 Mb of DNA. Finally, intermediate fragments of CEHs also exist, which are, nevertheless, larger than any of the four small blocks. This complexity of genetic fixity at various levels should be taken into account in studies of genetic disease association, immune response control, and human diversity. This knowledge could also be used for matching CEHs and their fragments for patients undergoing allotransplantation.

Hepatitis B surface antigen- and tetanus toxoid-specific clonal expansion of CD4+ cells in vitro determined by TCRBV CDR3 length and nucleotide sequence.

We demonstrate activation of primary human TCRBV-specific CD4+ cells in vitro towards hepatitis B surface antigen (HBsAg) and tetanus toxoid (TT) without the use of cell lines, clones or added cytokines. By multiplex PCR analysis and spectratyping, antigen-activated cells exhibited clonal T cell receptor expansion within specific and limited TCRBV families. The expanded CD4+ T cells were CD45RO. Three of four unrelated HBsAg responders showed CD4+ expansion within the TCRBV16 family. The response comprised predominantly single CDR3 sequences in all three donors and was completely monoclonal in one of them. However, the CDR3 lengths and sequences differed among the responders. Clonality induced by HBsAg in TCRBV16 was specific, reproducible and distinct from that induced by TT in terms of sequence, nucleotide addition and diversity (BD) or junctional (BJ) element usage. Thus, for the first time, we show monoclonal or oligoclonal expansion of primary human CD4- peripheral blood mononuclear cells (PBMC) in vitro in response to nominal protein antigen without manipulations utilizing exogenous IL-2. The ability to induce monoclonal/ oligoclonal responses to HBsAg now permits motif identification studies for determining the T cell role in nonresponsiveness to the HBsAg vaccine.

Complex cytokine responses to hepatitis B surface antigen and tetanus toxoid in responders, nonresponders and subjects naive to hepatitis B surface antigen.

Some human subjects vaccinated with hepatitis B surface antigen (HBsAg) do not produce antibodies to the vaccine (nonresponders). The mechanism for nonresponse is unknown. To understand the response and nonresponse to nominal antigens better, we determined the level and kinetics of cytokine secretion in response to HBsAg and tetanus toxoid (TT) by peripheral blood mononuclear cells (PBMC) in vitro from HBsAg vaccine responders and nonresponders and from individuals naive to HBsAg. Proliferating PBMC secreted peak levels of interleukin-2 (IL-2) at 2 days and peak levels of tumor necrosis factor-beta (TNF-beta), interferon-gamma (IFN-gamma), IL-4 and IL-10 at 3-6 days post-stimulation. In contrast, nonproliferating PBMC (whether from nonresponders, naive subjects or weak responders) did not produce detectable levels of TNF-beta or IFN-gamma, nor was IL-4 or IL-10 produced significantly, and that produced had a different kinetic profile from that of proliferating PBMC. HBsAg-specific cytokine production by PBMC from strong responders broadly paralleled their cytokine responses to TT. Cellular cytokine mRNA levels measured by reverse transcriptase-polymerase chain reaction corroborated the secreted cytokine results. The anti-HBsAg- and anti-TT-specific T cell cytokine responses were mixed Th(1/2)-like and donor-specific. An HBsAg-specific cytokine response, but not a TT-specific cytokine response, was completely missing in nonresponders. These data suggest that the T cell defect of HBsAg nonresponse is not due to a skewed cytokine profile.

Immunotargeting of liposomes to activated vascular endothelial cells: a strategy for site-selective delivery in the cardiovascular system.

Endothelial-selective delivery of therapeutic agents, such as drugs or genes, would provide a useful tool for modifying vascular function in various disease states. A potential molecular target for such delivery is E-selectin, an endothelial-specific cell surface molecule expressed at sites of activation in vivo and inducible in cultured human umbilical vein endothelial cells (HUVEC) by treatment with cytokines such as recombinant human interleukin 1beta (IL-1beta). Liposomes of various types (classical, sterically stabilized, cationic, pH-sensitive), each conjugated with mAb H18/7, a murine monoclonal antibody that recognizes the extracellular domain of E-selectin, bound selectively and specifically to IL-1beta-activated HUVEC at levels up to 275-fold higher than to unactivated HUVEC. E-selectin-targeted immunoliposomes appeared in acidic, perinuclear vesicles 2-4 hr after binding to the cell surface, consistent with internalization via the endosome/lysosome pathway. Activated HUVEC incubated with E-selectin-targeted immunoliposomes, loaded with the cytotoxic agent doxorubicin, exhibited significantly decreased cell survival, whereas unactivated HUVEC were unaffected by such treatment. These results demonstrate the feasibility of exploiting cell surface activation markers for the endothelial-selective delivery of biologically active agents via immunoliposomes. Application of this targeting approach in vivo may lead to novel therapeutic strategies in the treatment of cardiovascular disease.

Magnetic resonance imaging of nalbuphine-induced myocutaneous sclerosis.

Myocutaneous sclerosis is a known complication of intramuscular and subcutaneous injection of narcotics. We have described the MRI findings of this entity with superimposed infection in a patient addicted to intramuscular and subcutaneously administered nalbuphine. The clinical and imaging features of this disorder are sufficiently characteristic to allow confident diagnosis. This is the first report of this disorder due to nalbuphine.

Human immunodeficiency virus type 1 (HIV-1) fusion with model membranes: kinetic analysis and the role of lipid composition, pH and divalent cations.

The kinetics and extent of HIV-1 fusion with model membranes was studied. HIV-1 was labeled with octadecyl rhodamine B chloride, and fusion was monitored continuously as the dilution of the probe into target membranes. The results were analyzed by a mass action model which yielded good simulations and predictions for the kinetics and final extents of fluorescence increase. The model determined the percent of virions capable of fusing and rate constants of fusion, aggregation and dissociation. Ultrastructural analysis of the virus and reaction products by electron microscopy also provided evidence of HIV-1 fusion with membranes lacking CD4. HIV-1 fusion activity depends on the target membrane lipid composition according to the sequence: cardiolipin (CL) > > phosphatidylinositol > CL/dioleoylphosphatidylcholine (DOPC) (3:7), phosphatidic acid > phosphatidylserine (PS), PS/cholesterol (2:1) > PS/PC (1:1), PS/phosphatidylethanolamine (1:1) > DOPC, erythrocyte ghosts. Reduction of pH from 7.5 generally enhances the rate and extent of HIV-1 fusion. Physiologically relevant concentrations of calcium stimulate HIV-1 fusion with several liposome compositions and with erythrocyte ghost membranes. The fusion products of HIV-1 with liposomes consist of a single virus and several liposomes. The mass action analysis revealed that, compared to intact virions, the fusion products show a striking reduction in the fusion rate constant. Like influenza and Sendai viruses, HIV-1 fusion with membranes containing its own envelope glycoprotein(s) is strongly inhibited. Unlike these viruses, HIV-1 fusion is promoted by physiological levels of calcium. HIV-1 fusion with liposomes is qualitatively similar to simian immunodeficiency virus fusion.

Abdominal (liver, spleen) and bone manifestations of cat scratch disease.

Cat scratch disease is usually a self-limiting illness. Patients may develop systemic complications including hepatic granulomas, splenic abscesses, mesenteric adenitis, osteolytic lesions, as well as dermatologic and CNS complications. In this paper the literature is reviewed and two cases are discussed which present the imaging findings in patients with hepatic, splenic, mesenteric, and bony manifestations of cat scratch disease.

Enhancement of human immunodeficiency virus type 1 infection by cationic liposomes: the role of CD4, serum and liposome-cell interactions.

We have reported previously the enhancement of the infectivity of human immunodeficiency virus type 1 (HIV-1) by liposomes composed of the cationic lipid N-[2,3-(dioleyloxy) propyl]-N,N,N-trimethylammonium chloride (DOTMA). To determine the mechanism by which this process occurs, we have investigated the role of CD4, serum concentration and liposome-cell interactions in the DOTMA-mediated stimulation of HIV-1 infection of A3.01 cells. Serum alone significantly inhibited the binding and infectivity of HIV-1, but DOTMA-mediated enhancement of infectivity was more pronounced in the presence of serum than in its absence. HIV-1 binding to cells was increased in the presence of DOTMA liposomes, DEAE-dextran and polybrene, all of which also enhanced infectivity to a similar extent at comparable concentrations. Fluorescence dequenching measurements indicated that DOTMA liposomes fused with HIV-1, but not with cell membranes, in the presence of serum. The enhancing effect of DOTMA liposomes on HIV-1 infectivity was CD4-dependent, and appeared to involve virus-liposome fusion and liposome binding to the cell surface. DOTMA liposomes did not mediate infection of the CD4-K562 and Raji cell lines.

Liposomes modulate human immunodeficiency virus infectivity.

We have investigated the effects of the fusion of liposomes with human immunodeficiency virus type 1 (HIV-1LVA) on the ability of the virus to infect CD4+ and CD4- cells. Fluorescence dequenching measurements indicated that HIV-1 fuses with liposomes composed of either cardiolipin (CL) or N-[2,3-(dioleyloxy) propyl]-N,N,N-trimethyl ammonium chloride (DOTMA) but not appreciably with dioleoylphosphatidylcholine (DOPC) liposomes. Pre-incubation of HIV-1 with DOTMA liposomes enhanced virus production (measured by p24 gag antigen production in the culture medium and in situ) in CD4+ A3.01 and H9 cells in a concentration-dependent manner, but did not mediate the infection of the CD4- cell line, K562. Preincubation of HIV-1 with between 10 and 30 microM-DOTMA liposomes, and subsequent incubation with A3.01 cells, resulted in the production of about 30-fold greater levels of virus than controls. The presence of DOTMA liposomes during the incubation of A3.01 cells with HIV-1 enhanced the infectivity of the virus up to 90-fold compared to controls. Conversely, preincubation of HIV-1 with CL liposomes inhibited infection of A3.01 cells, dependent on the concentration of liposomes; DOPC liposomes did not alter the infectivity of the virus under any of the incubation conditions. Our results thus indicate that fusion of HIV-1 with liposomes alters the ability of the virus to infect its target cells.

Fusion of simian immunodeficiency virus with liposomes and erythrocyte ghost membranes: effects of lipid composition, pH and calcium.

Simian immunodeficiency virus from macaques (SIVmac) is closely related in its structure and biological activity to human immunodeficiency virus, and is the best animal model for the acquired immunodeficiency syndrome. We investigated the kinetics of membrane fusion between SIVmac and phospholipid vesicles and the effects of various parameters on this process. Purified SIVmac was labelled with octadecyl rhodamine B chloride, and fusion was continuously monitored as the dilution of the probe in target membranes. These studies show that SIVmac fusion is strongly dependent upon the liposome composition. Fusion with pure cardiolipin (CL) liposomes is significantly faster than with CL/dioleoylphosphatidylcholine (DOPC) (3:7), phosphatidylserine (PS) or disialoganglioside (GD1a)/DOPC (1.5:8.5) vesicles. SIVmac does not fuse appreciably with pure DOPC liposomes. Reduction of pH from 7.5 to 4.5 greatly enhances the rate of SIVmac fusion with CL, CL/DOPC and PS membranes, but does not affect fusion with DOPC or GD1a/DOPC membranes. Calcium stimulates viral fusion with CL liposomes, but not with CL/DOPC or DOPC liposomes. SIVmac fuses with human erythrocyte ghost membranes only slowly at reduced pH. Our results indicate that SIVmac can fuse with membranes lacking the known viral receptor, CD4. Although the mechanism of SIVmac fusion with model and biological membranes remains to be determined, the fusion activity of SIVmac shares similarities with other lipid-enveloped viruses such as Sendai and influenza viruses.

Macrosomia: influence of maternal overweight among a low-income population.

Macrosomia (birth weight greater than 4000 gm) is associated with a wide variety of adverse intrapartum and perinatal outcomes. To evaluate the effect of pregravid obesity on infant birth weight, we examined data from a low-income population of women (n = 127,879). The population was divided into five groups on the basis of pregravid body mass index (weight/height) designated by the National Health and Nutrition Examination Survey II reference population (less than 25th percentile, 25th to less than 75th percentile, 75th to less than 85th percentile, 85th to less than 95th percentile, and greater than or equal to 95th percentile). The prevalence of infant macrosomia ranged from 5% for the lowest group to 17% for the highest group. With the use of the second group (25th to less than 75th percentile) as a reference, odds ratios (adjusted for maternal age, smoking status, race, height, parity, gestational age, and infant sex) for macrosomia for the five sequential weight groups were 0.6, 1.0, 1.3, 1.6 and 2.2. We conclude that pregravid overweight had a significant independent effect on birth weight outcome.

Renal haemodynamics and extracellular homeostasis during the menstrual cycle.

Renal haemodynamics and extracellular homeostasis during the menstrual cycle were studied in 14 healthy women (age 21-41 years) who were not taking oral contraceptives in the follicular (Period I) and luteal phase (Period II). The glomerular filtration rate [( 51Cr] EDTA clearance) and the effective renal plasma flow ([125I] hippuran clearance) increased from Period I to II by a median of 6.3% (95% confidence interval (CI): 0.6-9.2%) and 7.3% (95% CI: -0.4-22%) respectively. Serum sodium decreased from period I to II (p less than 0.01) by a median of 1 mmol/l (95% CI: -2.0 to -0.5 mmol/l) and the urinary excretion rate of potassium increased (p less than 0.02) from a median value of 35 mumol/min in Period I to 45 mumol/min in Period II. The extracellular fluid volume did not change between the two periods but the concentration of water in serum increased (p less than 0.05) from a median value of 91.7-92.0 g/100 g in Period II. Serum total protein and serum albumin both showed a borderline statistically significant decrease from Period I to II. The investigation demonstrated a number of physiological and biochemical changes from the follicular to the luteal phase, most of which in a lower scale mimic well known changes that occur during pregnancy.

Endogenous overnight creatinine clearance compared with 51Cr-EDTA clearance during the menstrual cycle.

Fourteen healthy women aged 21-41 years, who did not take oral contraceptives and who all had ovulatory cycles, were examined once in the follicular phase and once in the luteal phase of a single menstrual cycle. The glomerular filtration rate (51Cr-EDTA clearance) increased from the follicular to the luteal phase by a median of 7.0% (95% confidence interval: 0.7-10.3%). Endogenous overnight (22.00-08.00 hours) creatinine clearance increased by a median of 7.3% (95% confidence interval: 1.0-14.6%). The urinary creatinine excretion rate also increased with a median of 7.3% (95% confidence interval: 1.5-11.9%) whereas the serum concentrations of creatinine and beta 2-microglobulin, urine flow and urinary excretion rate of urea did not change. The results confirm previous observations of an increase in creatinine clearance in the luteal phase of the menstrual cycle and indicate that the increase in overnight creatinine clearance reflects a true change in glomerular filtration rate.

Endogenous overnight creatinine clearance, serum beta 2-microglobulin and serum water during the menstrual cycle.

Endogenous overnight (22.00-08.00 hours) creatinine clearance and serum concentrations of beta 2-microglobulin and water were measured three times a week during 11 ovulatory menstrual cycles. In some of the women creatinine clearance changed more than 100% within a week from values below reference range to high normal levels. In all the women the creatinine clearance was higher during the luteal than during the follicular phase and correlated with the production of ovarian hormones. The urinary excretion rate of creatinine was highest during the luteal phase. Urinary volume, serum creatinine and serum water were not significantly influenced by the menstrual phases. An unexplained finding was a parallel change in the individual creatinine clearance and serum beta 2-microglobulin during the luteal, but not during the follicular phase. Our results suggest that ovarian hormones influence creatinine clearance during the menstrual cycle. One must therefore accept even considerable short-time variations in creatinine clearance in fertile women. It remains to be settled if these changes reflect true alterations in glomerular filtration rate or mainly changes in the urinary (tubular) excretion rate of creatinine.

Biosynthesis of bacterial glycogen. Primary structure of Escherichia coli ADP-glucose:alpha-1,4-glucan, 4-glucosyltransferase as deduced from the nucleotide sequence of the glgA gene.

The nucleotide sequence of the glgA gene, coding for glycogen synthase (EC 2.4.1.21) was elucidated. It consists of 1431 base pairs specifying a protein of 477 amino acids. The deduced amino acid sequence was consistent with the amino acid analysis obtained with the pure protein as well as with the molecular weight as determined from sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The deduced amino acid sequence was also consistent with the amino-terminal acid sequence and amino acid sequence analysis of various peptides obtained from CNBr degradation of purified glycogen synthase.

Covalent modification of the inhibitor-binding site(s) of Escherichia coli ADP-glucose synthetase. Isolation and structural characterization of 8-azido-AMP-incorporated peptides.

The photoaffinity inhibitor analog [2-3H]8-azido-AMP is specifically and covalently incorporated into Escherichia coli ADP-glucose synthetase. The reaction site(s) of [2-3H]8-azido-AMP with the enzyme was identified by reverse phase high performance liquid chromatography isolation and chemical characterization of CNBr and mouse submaxillary arginyl protease-generated peptides containing the labeled analog. Three regions of modification, represented by six labeled peptides, accounted for over 85% of the covalently bound label. The major binding region of the azido analog, composed of residues 108-128, contained approximately 55% of the recovered covalently bound radioactivity. A single residue, Tyr-113, contained between 50 and 75% of the label found in the major binding region. This site is the same as the major binding region of the substrate site-specific probe, 8-azido-ADP-[14C]glucose (Lee, Y. M., and Preiss, J. (1986) J. Biol. Chem. 261, 1058-1064). Conformational analysis of this region predicts that it is a part of a Rossmann fold, the supersecondary structure found in many adenine nucleotide-binding proteins. Two minor reaction regions of the enzyme with [2-3H]8-azido-AMP were also identified by chemical characterization. One region, containing 20% of the covalently bound label, was composed of residues 11-68. This region contains Lys-38, the previously determined pyridoxal phosphate-modified allosteric activator site (Parsons, T. F., and Preiss, J. (1978) J. Biol. Chem. 253, 7638-7645). The third minor region of modification, residues 222-254, contained approximately 15% of the covalently bound label. The three modified peptide regions may be juxtaposed in the enzyme's tertiary structure.