National and Sub-National Estimates of Household Coverage of Iodized Salt and Urinary Iodine Status among Women of Reproductive Age in India: Insights from the India Iodine Survey, 2018-19.

BACKGROUND: Iodine deficiency is a significant public health problem for many populations worldwide, including India, particularly during the "first 1000 days" of life. Though Universal Salt iodization (USI) is mandatory in India, prior to 2018-19, there was no state-wide survey with estimates of iodine concentrations in salt using iodometric titration. Taking cognizance of this fact, Nutrition International commissioned the first-of-its-kind national-level survey in India, titled the India Iodine Survey 2018-19. OBJECTIVES: The study was conducted across the country to provide national and subnational estimates of iodine concentrations in household salt using iodometric titration and iodine nutrition status among women of reproductive age (15-49 y). METHODS: The survey adopted a multi-stage randomcluster probability proportional to size sampling design, covering 21,406 households in all the states and union territories (UTs) of India. RESULTS: At the national level, the household coverage of edible salt with adequate iodine (content ≥15 parts/million) was 76.3%. At the sub-national level, the coverage varied, with 10 states and 3 UTs achieving USI and 11 states and 2 UTs falling below the national average, with the highest among all the states and UTs, being Jammu and Kashmir and the lowest being Tamil Nadu. At the national level, the median urinary iodine concentration for pregnant women was 173.4 µg/L, for lactating women was 172.8 µg/L, and for non-pregnant, non-lactating women, it was 178.0 µg/L, which is within the adequate iodine nutrition range according to the WHO guidelines. CONCLUSIONS: The survey results can be widely used by various stakeholders, including government, academia, and industry, to understand the iodine nutrition status of the population, enable the scale-up of sustained efforts toward consolidating gains and achieving USI, leading to the reduction and elimination of Iodine Deficiency Disorders.

Antenatal care is associated with adherence to iron supplementation among pregnant women in selected low-middle-income-countries of Asia, Africa, and Latin America & the Caribbean regions: Insights from Demographic and Health Surveys.

Anaemia is a global public health problem affecting 800 million women and children globally. Anaemia is associated with perinatal mortality, child morbidity and mortality, mental development, immune competence, susceptibility to lead poisoning and performance at work. The objective of this article is to identify whether antenatal care-seeking was associated with the uptake of iron supplementation among pregnant women, adjusting for a range of covariates. This article used data from the cross-sectional recent Demographic and Health Surveys (DHS) of 12 countries in Asia, Africa and Latin America & the Caribbean regions. The individual-level data from 273,144 women of reproductive age (15-49 years) were analysed from multi-country DHS. Multiple Logistic regression analyses were conducted using Predictive Analytics Software for Windows (PASW), Release 18.0. Receiving at least four antenatal care visits was significantly associated with the consumption of 90 or more iron-containing supplements in 12 low and middle income countries across three regions after adjusting for different household and respondent characteristics, while mass media exposure was found to be a significant predictor in India and Indonesia. Antenatal care seems to be the most important predictor of adherence to iron intake in the selected countries across Africa, Asia, Latin America and Caribbean regions.

A pneumonia practice guideline and a hospitalist-based reorganization lead to equivalent efficiency gains.

OBJECTIVE: To compare the impact of a practice guideline for a common inpatient disorder with that of a hospitalist-based reorganization of an academic medical service. STUDY DESIGN: Retrospective cohort study. PATIENTS AND METHODS: In July 1995 we introduced a clinical practice guideline for the treatment of community-acquired pneumonia at University of California San Francisco Moffitt-Long Hospital. Simultaneously, we implemented a structural change for half of the inpatient medical service, requiring earlier and more intensive faculty intervention, primarily by hospitalists. For 1 year, we studied the effect of these interventions on hospital costs, length of stay, and resource use. RESULTS: As reported previously, the hospitalist-based intervention resulted in significant decreases in average adjusted cost ($7777 vs $7007, P = .05) and length of stay (4.9 days vs 4.3 days, P = .01) compared with both concurrent and historical controls. For patients with community-acquired pneumonia, a similar savings occurred when fiscal year 1996 was compared with fiscal year 1995 ($8164 vs $6282, P= .015; 5.0 vs 4.2 days, P= .04). However, the effect was identical for the hospitalist and nonhospitalist groups. The reduced length of stay was associated with a borderline significant reduction in readmission rates (from 4.8% to 0.7%, P = .055) and no change in mortality rates. CONCLUSIONS: In this study, a hospitalist-based reorganization improved efficiency, with its greatest impact on the care of patients with disorders not covered by a practice guideline. The introduction of a guideline for a common diagnosis improved efficiency on both hospitalist- and nonhospitalist-based services. For common diagnoses amenable to practice guidelines, successful implementation of and compliance with guidelines may be an alternative to major organizational change.

WT1 expression induces features of renal epithelial differentiation in mesenchymal fibroblasts.

The WT1 tumor suppressor gene, implicated in hereditofamilial and sporadic Wilms' tumor, is required for normal renal development and is up-regulated during the mesenchymal-epithelial transition. NIH3T3 fibroblasts overexpressing WT1 were less proliferative, larger in size and more firmly attached to tissue culture plastic, suggesting an alteration of their state of differentiation. These cells were studied in vivo by subcutaneous injection into nude mice. The resulting tumors exhibited epithelioid histopathology and formed desmosome-like structures. Molecular analyses of these WT1 expressing fibroblasts grown in culture and in nude mice revealed significant alterations in the expression of many kidney epithelial markers. These studies indicate that WT1 expression can initiate features of a program of epithelial differentiation consistent with a prominent role for WT1 in the mesenchymal epithelial transition that occurs during renal development. Through this work we identified a number of novel target genes for the WT1 transcription factor, including uvomorulin, integrin alpha8 and perlecan, and suggest that WTI may activate the IGF-II gene, also implicated in the development of Wilms' tumor.

Reduced and altered DNA-binding and transcriptional properties of the PLZF-retinoic acid receptor-alpha chimera generated in t(11;17)-associated acute promyelocytic leukemia.

Acute promyelocytic leukemia (APL) associated with chromosomal rearrangement t(11;17) is a distinct syndrome which, unlike typical t(15;17) APL, fails to respond to all-trans retinoic acid (ATRA) therapy. In t(11;17) the PLZF gene, encoding a Krüppel-like zinc finger protein, is fused to the retinoic acid receptor-alpha (RAR alpha) gene, yielding two classes of chimeric proteins. PLZF protein was found in the nucleus in a punctate speckled pattern that differed from the nuclear body expression pattern of the PML protein affected in t(15;17) APL. The reciprocal PLZF-RAR alpha and RAR alpha-PLZF fusion proteins were localized to the nucleus both in the presence and absence of ATRA. PLZF-RAR alpha, in combination with the retinoid X receptor (RXR) bound to a retinoic acid-responsive element (RARE) less efficiently than RAR alpha and formed multimeric DNA-protein complexes. PLZF-RAR alpha stimulated ATRA-dependent transcription of RARE-containing reporter genes with diminished activity compared to wild-type RAR alpha. In addition, PLZF-RAR alpha antagonized the function of coexpressed wild-type RAR alpha, an effect relieved by over-expression of RXR. Leukemogenesis in t(11;17) APL may be related to interference with ATRA-mediated differentiation due to sequestration of RXR by the PLZF-RAR alpha chimera. However, disruption of the function of the myeloid-specific PLZF protein may also play an important role.

The transcriptional effect of WT1 is modulated by choice of expression vector.

The WT1 Wilms' tumor suppressor gene encodes a zinc finger transcription factor which plays a critical role in renal and genitourinary development. The WT1 protein was reported to both activate and repress transcription. We found that the transcriptional effect of WT1 on the Egr1 promoter could be modulated by the use of expression vectors containing different promoters. WT1 activated the Egr1 promoter when expression of WT1 was driven by the Rous sarcoma virus promoter. In contrast, a cytomegalovirus (CMV) promoter-containing WT1 expression vector repressed the Egr1 promoter. However, WT1 activated transcription of a simple test promoter, EGR3tkCAT, regardless of the expression vector used. Co-transfection of the parental CMV-based vector strongly depressed the basal activity of the Egr1-CAT reporter, suggesting that the CMV promoter competes with the Egr1 promoter for transcription factors or co-factors which may be required for activation by WT1. In support of this hypothesis, WT1 was converted from an activator to a repressor by co-transfection of an excess of the parental CMV-based vector. These results provide an important caveat to the interpretation of co-transfection studies and confirm the bi-functional nature of the WT1 transcription factor.

The tumor suppressor gene WT1 inhibits ras-mediated transformation.

Wilms' tumor belongs to a small group of pediatric neoplasms that have served as paradigms of human cancers in which recessive mutations play a primary role in tumorigenesis. WT1 is a candidate tumor suppressor gene that is mutationally inactivated in a proportion of both familial and sporadic Wilms' tumors. Recent studies demonstrated that WT1 can partially suppress growth of a Wilms' tumor cell line in vitro and in vivo. We investigated the ability of WT1 to inhibit the expression of the transformed phenotype in non-Wilms' tumor cells. The expression of WT1 cDNA in ras-transformed NIH3T3 cells yielded large, flat cells that exhibited complete contact-inhibition. These morphologic changes were associated with decreased proliferation, suppression of clonogenicity in soft agar and inhibition of tumor growth in nude mice. Moreover, expression of WT1 in non-transformed NIH3T3 cells resulted in similar morphologic changes and profound resistance to transformation by an activated ras oncogene. These studies suggest that tumor inhibition by WT1 in these cells may be achieved by interference with the ras-mediated signalling pathway.

WT1-mediated transcriptional activation is inhibited by dominant negative mutant proteins.

The WT1 tumor suppressor gene encodes four isoforms of a zinc finger transcription factor with both activation and repression functions which are dependent upon promoter architecture. Using a simple HSV-tk promoter containing 5'-Egr-1/WT1-binding sites, we found that WT1 isoforms (A) and (B) strongly activated transcription. WT1(A) and (B) bound equally well to the Egr-1/WT1-binding site, but WT1(B), which contains a 17 amino acid insertion compared to WT1(A), was a consistently stronger activator of transcription than WT1(A). Transcriptional activation by wild-type WT1 was inhibited by coexpression of WT(PM) or WT(AR), genetically defined dominant negative alleles of WT1. In vitro, as well as in the yeast two-hybrid system, WT1 protein associated with itself and with dominant negative mutant proteins. The major domain required for self-association and inhibition of transcriptional activation mapped to the first 182 amino acids of WT1. Dominant negative WT1 alleles may play a role in tumorigenesis by associating with wild-type WT1 proteins and decreasing their transcriptional activity.

Mapping and mutagenesis of the amino-terminal transcriptional repression domain of the Drosophila Krüppel protein.

We previously demonstrated that the Drosophila Krüppel protein is a transcriptional repressor with separable DNA-binding and transcriptional repression activities. In this study, the minimal amino (N)-terminal repression region of the Krüppel protein was defined by transferring regions of the Krüppel protein to a heterologous DNA-binding protein, the lacI protein. Fusion of a predicted alpha-helical region from amino acids 62 to 92 in the N terminus of the Krüppel protein was sufficient to transfer repression activity. This putative alpha-helix has several hydrophobic surfaces, as well as a glutamine-rich surface. Mutants containing multiple amino acid substitutions of the glutamine residues demonstrated that this putative alpha-helical region is essential for repression activity of a Krüppel protein containing the entire N-terminal and DNA-binding regions. Furthermore, one point mutant with only a single glutamine on this surface altered to lysine abolished the ability of the Krüppel protein to repress, indicating the importance of the amino acid at residue 86 for repression. The N terminus also contained an adjacent activation region localized between amino acids 86 and 117. Finally, in accordance with predictions from primary amino acid sequence similarity, a repression region from the Drosophila even-skipped protein, which was six times more potent than that of the Krüppel protein in the mammalian cells, was characterized. This segment included a hydrophobic stretch of 11 consecutive alanine residues and a proline-rich region.