Association between asymptomatic infections and linear growth in 18-24-month-old Malawian children.

Inadequate diet and frequent symptomatic infections are considered major causes of growth stunting in low-income countries, but interventions targeting these risk factors have achieved limited success. Asymptomatic infections can restrict growth, but little is known about their role in global stunting prevalence. We investigated factors related to length-for-age Z-score (LAZ) at 24 months by constructing an interconnected network of various infections, biomarkers of inflammation (as assessed by alpha-1-acid glycoprotein [AGP]), and growth (insulin-like growth factor 1 [IGF-1] and collagen X biomarker [CXM]) at 18 months, as well as other children, maternal, and household level factors. Among 604 children, there was a continuous decline in mean LAZ and increased mean length deficit from birth to 24 months. At 18 months of age, the percentage of asymptomatic children who carried each pathogen was: 84.5% enterovirus, 15.5% parechovirus, 7.7% norovirus, 4.6% rhinovirus, 0.6% rotavirus, 69.6% Campylobacter, 53.8% Giardia lamblia, 11.9% malaria parasites, 10.2% Shigella, and 2.7% Cryptosporidium. The mean plasma IGF-1 concentration was 12.5 ng/ml and 68% of the children had systemic inflammation (plasma AGP concentration >1 g/L). Shigella infection was associated with lower LAZ at 24 months through both direct and indirect pathways, whereas enterovirus, norovirus, Campylobacter, Cryptosporidium, and malaria infections were associated with lower LAZ at 24 months indirectly, predominantly through increased systemic inflammation and reduced plasma IGF-1 and CXM concentration at 18 months.

Carbonic anhydrases in metazoan model organisms: molecules, mechanisms, and physiology.

During the past three decades, mice, zebrafish, fruit flies, and Caenorhabditis elegans have been the primary model organisms used for the study of various biological phenomena. These models have also been adopted and developed to investigate the physiological roles of carbonic anhydrases (CAs) and carbonic anhydrase-related proteins (CARPs). These proteins belong to eight CA families and are identified by Greek letters: α, ß, γ, δ, ζ, η, θ, and ι. Studies using model organisms have focused on two CA families, α-CAs and ß-CAs, which are expressed in both prokaryotic and eukaryotic organisms with species-specific distribution patterns and unique functions. This review covers the biological roles of CAs and CARPs in light of investigations performed in model organisms. Functional studies demonstrate that CAs are not only linked to the regulation of pH homeostasis, the classical role of CAs, but also contribute to a plethora of previously undescribed functions.

Infections and systemic inflammation are associated with lower plasma concentration of insulin-like growth factor I among Malawian children.

BACKGROUND: Insulin-like growth factor I (IGF-I) is the most important hormonal promoter of linear growth in infants and young children. OBJECTIVES: The objectives of this study were to compare plasma IGF-I concentration in a low- compared with a high-income country and characterize biological pathways leading to reduced IGF-I concentration in children in a low-income setting. METHODS: We analyzed plasma IGF-I concentration from 716 Malawian and 80 Finnish children at 6-36 mo of age. In the Malawian children, we studied the association between IGF-I concentration and their environmental exposures; nutritional status; systemic and intestinal inflammation; malaria parasitemia and viral, bacterial, and parasitic enteric infections; as well as growth at 18 mo of age. We then conducted a pathway analysis to identify direct and indirect associations between these predictors and IGF-I concentration. RESULTS: The mean IGF-I concentrations were similar in Malawi and Finland among 6-mo-old infants. At age 18 mo, the mean ± SD concentration was almost double among the Finns compared with the Malawians [24.2 ± 11.3 compared with 12.5 ± 7.7 ng/mL, age- and sex-adjusted difference in mean (95% CI): 11.8 (9.9, 13.7) ng/mL; P < 0.01]. Among 18-mo-old Malawians, plasma IGF-I concentration was inversely associated with systemic inflammation, malaria parasitemia, and intestinal Shigella, Campylobacter, and enterovirus infection and positively associated with the children's weight-for-length z score (WLZ), female sex, maternal height, mother's education, and dry season. Seasonally, mean plasma IGF-I concentration was highest in June and July and lowest in December and January, coinciding with changes in children's length gain and preceded by ∼2 mo by the changes in their WLZ. CONCLUSIONS: The mean plasma IGF-I concentrations are similar in Malawi and Finland among 6-mo-old infants. Thereafter, mean concentrations rise markedly in Finland but not in Malawi. Systemic inflammation and clinically nonapparent infections are strongly associated with lower plasma IGF-I concentrations in Malawi through direct and indirect pathways.

Surveillance and diagnosis of zoonotic foodborne parasites.

Foodborne parasites are a source of human parasitic infection. Zoonotic infections of humans arise from a variety of domestic and wild animals, including sheep, goats, cattle, camels, horses, pigs, boars, bears, felines, canids, amphibians, reptiles, poultry, and aquatic animals such as fishes and shrimp. Therefore, the implementation of efficient, accessible, and controllable inspection policies for livestock, fisheries, slaughterhouses, and meat processing and packaging companies is highly recommended. In addition, more attention should be paid to the education of auditors from the quality control (QC) and assurance sectors, livestock breeders, the fishery sector, and meat inspection veterinarians in developing countries with high incidence of zoonotic parasitic infections. Furthermore, both the diagnosis of zoonotic parasitic infections by inexpensive, accessible, and reliable identification methods and the organization of effective control systems with sufficient supervision of product quality are other areas to which more attention should be paid. In this review, we present some examples of successful inspection policies and recent updates on present conventional, serologic, and molecular diagnostic methods for zoonotic foodborne parasites from both human infection and animal-derived foods.

Expression of luteinizing hormone receptors in the mouse penis.

The role of luteinizing hormone (LH) in the regulation of normal reproductive functions in males and females is quite well established. Besides the expression of LH receptors in the target cells in gonads, it has been found in several extragonadal organs. There is no information about the expression of LH receptors in the penis up to now. The aim of the present study is to investigate the expression of the LH receptor in the mouse penis to see if LH effects are possible in the penis. BALB/c mice were used as donors of normal penis and testis tissue. Immunocytochemistry, Western blotting, and quantitative reverse transcriptase polymerase chain reactions (RT-PCRs) were used for the detection of the LH receptor. Positive immunoreaction for LH receptors was present in the nuclei of urethral epithelium and endothelial cells of cavernous spaces in the corpus cavernosum and corpus spongiosum penis. Western blotting experiments demonstrated the presence of LH antigen at M(r) = 97.4 and 78 kd. Quantitative RT-PCRs confirmed the expression of LH receptor in the penis. Our results show that LH receptor is expressed in the body of the mouse penis; thus, it may directly regulate functions of penile tissue.

Changes in protein tyrosine phosphatase type IVA member 1 and zinc finger protein 36 C3H type-like 1 expression demonstrate altered estrogen and progestin effect in medroxyprogesterone acetate-resistant and estrogen-independent breast cancer cell models.

Estrogen stimulates proliferation in hormone-responsive breast cancer cells. Progestins inhibit the estrogen-mediated growth in these cells and are used in the treatment of mammary carcinomas. We applied cDNA microarray and real-time RT-PCR methods to reveal 17beta-estradiol- and medroxyprogesterone acetate (MPA)-regulated genes in MCF-7 breast cancer cells. We identified six genes, two of which were novel MPA and/or 17beta-estradiol-regulated genes: protein tyrosine phosphatase type IVA, member 1 (PTP4A1) and zinc finger protein 36, C3H type-like 1 (ZFP36L1). PTP4A1 expression was upregulated by 17beta-estradiol and this was opposed by MPA treatment of the cells. ZFP36L1 proved to be a direct target of MPA. Since MPA has also been shown to bind to glucocorticoid- and androgen receptors, we studied the regulation of the genes with progesterone, synthetic progestin R5020, dexamethasone and dihydrotestosterone. We also assessed the expression and hormonal regulation of PTP4A1 and ZFP36L1 mRNA in MCF-7-derived MPA-resistant and estrogen-independent sublines. The regulation of PTP4A1 expression upon 17beta-estradiol and combined 17beta-estradiol and MPA treatment was completely reversed in the estrogen-independent and MPA-resistant sublines, respectively. This study suggests an important role for PTP4A1 in cell growth, and shows that MPA may potentiate the effect of 17beta-estradiol in the MPA-resistant breast cancer cells.

Progestins regulate genes that can elicit both proliferative and antiproliferative effects in breast cancer cells.

Sex steroid hormone progesterone is known to have profound effects on the growth and differentiation of the normal mammary gland and malignant breast epithelial cells. In vitro progesterone and synthetic progesterone-like compounds (progestins) inhibit breast cancer cell growth. Medroxyprogesterone acetate (MPA) is a synthetic hormone widely used in the adjuvant treatment of advanced breast cancer, hormone replacement therapy and in oral contraceptives. It is a paradoxical hormone, since it inhibits breast cancer cell proliferation, but has also been implicated in increased breast cancer risk. To better understand the molecular mechanism by which cell proliferation and differentiation are regulated by progesterone and MPA in human breast cancer, we utilized cDNA microarray and quantitative real-time RT-PCR methods to identify their target genes. This study describes novel progestin/progesterone target genes in breast cancer cells and, notably, novel target genes that elucidate the underlying molecular mechanism of the dual role progestins play in the breast. A cDNA microarray containing 3000 genes showed notable regulation in 30 and 27 genes by MPA and progesterone, respectively. Only 6 out of the 30 genes regulated by MPA are down-regulated, but no progesterone down-regulation was observed. Overlapping in gene regulation by progesterone and MPA occurred, but the majority of genes regulated by these hormones were distinct. Given that progestins both stimulate and inhibit cancer cell growth, we report our findings on novel progestin and progesterone targets, which could explain the paradoxical actions of progestins in the breast.

Electric impedance assisted micropipette aspiration.

Micropipette aspiration is a technique to selectively isolate cells from cell cultures using suction pressure. Cells can selectively be isolated one by one from neighboring cells into the micropipette. This paper presents a novel micropipette aspiration system assisted by an impedance measurement system. Furthermore, a method to reduce the adhesion force at a single cell level for a gentler detachment of the cell from a cultivation surface and surrounding cell connections is proposed.

Interaction of nuclear receptors with hsp90 in living cells.

The ubiquitous heat shock protein 90 (hsp90) has been shown to participate directly in the function of a wide variety of cellular signal transduction components, including steroid receptors (SRs). However, there is still no direct evidence for an in vivo association of SRs with hsp90. This study utilizes the mammalian two-hybrid system to study the ability of hsp90 to interact with various (non)liganded nuclear receptors (NRs) in vivo in mammalian cells. As bait, we used ligand-binding domain (LBD) of various NRs fused with the GAL4-DBD. hsp90/Receptor interactions were monitored in COS cells. When NR-LBDs were co-transfected along with hsp90/VP16, none (RxR(2)-LBD) or only minimal (SR-LBDs) transcription inductions were observed (1.9-4.7-fold) in the absence of ligand. Addition of ligand further abolished the observed minimal induction. As a positive control for interaction we used TIF-2, which interacts with SRs in a ligand inducible manner. When co-transfected with NR-LBDs in the absence of ligand TIF-2/VP16 induced minimal activation of transcription (1.6-4.5-fold) that was comparable to the activation induced by the NR-LBDs. In contrast, in the presence of the ligand, the activation ranged between 62- and 134-fold depending on the receptor. The results suggest that the interaction of SRs with the hsp90 is minimal when compared to a bona fide type of interaction with the co-factors.

HDLG5/KIAA0583, encoding a MAGUK-family protein, is a primary progesterone target gene in breast cancer cells.

The steroid hormone progesterone is known to have profound effects on growth and differentiation of normal and malignant breast epithelial cells. The biologic actions of progesterone are exerted through the nuclear progesterone receptor-mediated control of target gene transcription. We utilized differential display polymerase chain reaction (DD-RT-PCR) to identify genes whose expression is altered in response to progestins in cultured breast cancer cells. Here we report identification of a gene encoding a member of the MAGUK protein family, hDlg5 (also known as KIAA0583 and P-dlg), as being the primary progestin target gene in MCF-7 breast cancer cells. Quantitative real-time RT-PCR analysis showed a rapid and strong upregulation of hDlg5 mRNA in cells treated with synthetic progestin medroxyprogesterone acetate (MPA) in the presence of estrogen in MCF-7, T47D and ZR-75-1 cells. The induction was abrogated by antiprogestin RU486. hDlg5 mRNA was also upregulated by progesterone, R5020 and dexamethasone. Protein synthesis inhibitor cycloheximide failed to block progestin-mediated induction of the hDlg5 gene. hDlg5 is a member of the growing family of MAGUKs (membrane-associated guanylate kinase homologs) and is to our knowledge the first member of the family reported to be hormonally regulated. hDlg5 is one of the human homologs of the Drosophila gene dlg [lethal(1)discs-large], which was initially identified as a tumor suppressor gene. The Dlg has a well-established role in cell growth control and maintenance of cell adhesion and cell polarity. Domain profile analysis revealed that hDlg5 has 2 additional PDZ domains than previously reported.

Progestin upregulates G-protein-coupled receptor 30 in breast cancer cells.

A differential display method was used to study genes the expression of which is altered during growth inhibition induced by medroxyprogesterone acetate (MPA). A transcript of G-protein-coupled receptor 30 (GPR30) was upregulated by MPA in estrogen-treated MCF-7 breast cancer cells. Northern-blot analysis showed a progestin-specific primary target gene, which was enhanced by progesterone and different progestins, but not by dihydrotestosterone or dexamethasone, and which was abrogated by antiprogestin RU486. The dose-dependent and time-dependent increase in GPR30 mRNA expression correlated with MPA-induced growth inhibition in MCF-7 cells. Additionally, GPR30 upregulation by progestin correlated with growth inhibition when a comparison was made between different breast cancer cell lines. The ERK1/ERK2 pathway is capable of inducing progesterone receptor-dependent and ligand-dependent transcription. Thus we sought to establish whether different MAPK pathway inhibitors affect progestin-induced GPR30 mRNA regulation. The regulation of GPR30 was independent of ERK pathway activation, but the p38 pathway inhibitor induced GPR30 expression, which suggested a potential gene regulation pathway. These data demonstrate a new progestin target gene, the expression of which correlates with growth inhibition.

Antiproliferative action of vitamin D.

During the past few years, it has become apparent that vitamin D may play an important role in malignant transformation. Epidemiological studies suggest that low vitamin D serum concentration increases especially the risk of hormone-related cancers. Experimentally, vitamin D suppresses the proliferation of normal and malignant cells and induces differentiation and apoptosis. In the present review we discuss the mechanisms whereby vitamin D regulates cell proliferation and whether it could be used in prevention and treatment of hyperproliferative disorders like cancers.