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PubMed2002

Description and outcomes of a custom Web-based patient occurrence reporting system developed for Baylor University Medical Center and other system entities.

PROBLEM: To improve the timeliness, efficiency, and effectiveness of occurrence reporting. SETTING: Baylor University Medical Center, a 1000-bed tertiary facility, and other components of the Baylor Health Care System, all located in Dallas and the surrounding area. STRATEGIES FOR IMPROVEMENT: Designing a custom Web-based patient occurrence reporting system through the efforts of the Center for Quality and Care Coordination and Information Services and training staff not only in using the system but also in viewing reporting as a key element for quality and safety rather than as an individual performance or disciplinary measure. EFFECTS OF CHANGE: Both the number of occurrences reported and the timeliness of reports improved: prior to implementation of the Web forms, an average of 128 paper patient occurrence reports were received per month an average of 7.6 days after the occurrence; in the 12 months afterwards, an average of 175 patient occurrence reports were submitted, with 82% reported within 24 hours of the occurrence. Anecdotal comments about the system from end users have been positive. CONCLUSION: Paperless Web-based systems are timely, efficient, and effective. The system developed at Baylor met its goals, including being secure, offering online helps and formal education, creating a risk stratification model, remaining adaptable for system needs, and serving as a tool for data analysis. Efforts to change the culture around patient occurrence reporting are ongoing and an essential element for success.

Journal Article↗

PubMed2000

CHOP gene expression in response to endoplasmic-reticular stress requires NFY interaction with different domains of a conserved DNA-binding element.

The transcription factor CHOP/GADD153 gene is induced by cellular stress and is involved in mediating apoptosis. We report the identification of a conserved region in the promoter of the CHOP gene responsible for its inducibility by endoplasmic reticulum (ER) stress. Deletion mutants of the human CHOP promoter identify a region comprising nucleotides -75 to -104 required for both constitutive and ER-stress-inducible expression. This region of the promoter, the ER-stress element (ERSE) is sufficient to confer both increased basal activity and ER-stress inducibility to an otherwise inactive heterologous promoter. The CHOP ERSE is a novel variant of the ERSE as it contains two different functional domains, and a GA- instead of GC-rich intervening sequence. The CCAAT-box domain occupied by the constitutive transcriptional activator nuclear factor Y (NFY) is required for constitutive activation whereas the variant GCACG 'inducible' domain uniquely mediates ER-stress inducibility. By UV-crosslinking analysis NFY makes contact not only with the constitutive activator CCAAT box but also with the inducible GCACG domain. Deletions and nucleotide substitutions in the CCAAT box as well as its replacement by an SP1 site failed to support ER inducibility. These findings support the notion that NFY is not only required for constitutive activation of CHOP gene transcription, but is also an active and essential element for the assembly of an ER-stress-inducible enhanceosome that activates CHOP gene expression in response to cellular stress.

3T3 Cells↗

PubMed2002

[Effects of exposure to aluminum on some metal elements contents in hippocampus of rat].

OBJECTIVE: To investigate the effects of exposure to aluminum (Al) on Zn, Fe, Cu and Ca contents in hippocampus of rats. METHODS: AlCl(3).6H(2)O was administered orally through diet (8% of body weight) to SD rats at doses of 0 (A), 11.2 (B), 55.9 (C), 111.9 (D) mg Al(3+)/kg BW for successive 90 days. Then Al, Zn, Fe, Cu and Ca contents in hippocampi of rats were determined by atomic absorption spectrophotometry. RESULTS: After oral exposure to Al, the Al content in hippocampus of rat increased significantly with a remarkable dose-effect relationship (r = 0.731, P < 0.001), The Zn, Fe, Ca and Cu contents in these four groups are as follows: Group A (18.29 +/- 2.48, 24.86 +/- 1.97, 48.69 +/- 22.08, 4.53 +/- 0.99) mg/g, Group B (17.22 +/- 2.06, 27.54 +/- 2.87, 42.79 +/- 14.42, 4.06 +/- 0.41) mg/g, Group C (14.46 +/- 1.90, 20.18 +/- 2.79, 29.95 +/- 7.33, 3.98 +/- 0.25) mg/g, Group D (15.85 +/- 2.54, 20.96 +/- 2.83, 36.14 +/- 12.66, 4.53 +/- 0.58) mg/g. Compared with the control group A, the Zn and Fe contents in group B and group C decreased significantly (P < 0.05), and the Ca content in group C also decreased significantly. CONCLUSION: Oral exposure to Al may result in accumulation of Al in hippocampus of brain and thus affect some essential elements (Zn, Fe, Cu and Ca) contents in the hippocampus at different degrees.

Aluminum↗

PubMed1989

Mutations in the hormone regulatory element of mouse mammary tumor virus differentially affect the response to progestins, androgens, and glucocorticoids.

Transcription of the mouse mammary tumor virus DNA is known to be induced by several steroid hormones. Using chimeric MMTV plasmids containing mutations within the hormone regulatory element, we have previously studied the regions required for the glucocorticoid response in mouse fibroblasts. Here we report the characterization of elements essential for the stimulation by progestins and androgens as compared with glucocorticoids. The same set of mutant plasmids was transfected into the human mammary tumor cell line T47D, and the specific transcripts were analyzed by an S1 nuclease protection assay. Androgen-mediated stimulation, although weak, showed an extended sensitivity to mutations, with a slight preference for the proximal region. The results with progestin suggest that sequences within all the described sites protected by the receptor in vitro are required and that the promoter-proximal region (-128 to -78 from the RNA start site) is more important than the distal one (-190 to -160). Moreover, a binding site for nuclear factor I was not required for the progestin response, whereas it was required for glucocorticoids. Thus, the various steroid receptors play a role in the differential regulation of mouse mammary tumor virus transcription by recognizing distinct sequence differences in the hormone regulatory element and interacting with different factors bound to the promoter.

Androgens↗

PubMed2003

Triiodothyronine decreases the activity of the proximal promoter (PII) of the aromatase gene in the mouse Sertoli cell line, TM4.

Estrogens and thyroid hormones play a significant role in regulating functions and development of the testis. The synthesis of estrogens from androgens is catalyzed by the enzyme complex termed aromatase, which in the testis displays an age-related cellular compartmentalization, primarily in Sertoli cells in immature animals, whereas in adults it is expressed in Leydig and germ cells. T3 induces a precocious terminal differentiation of prepubertal Sertoli cells together with a dramatic decrease of their aromatase activity. In the present work, we have examined the mechanism by which T3 exerts this inhibitory action on aromatase expression. As an experimental model, we used the mouse Sertoli cell line TM4, which conserves a large spectrum of functional features present in immature Sertoli cells. For instance, after revealing the presence of aromatase by immunocytochemistry and measuring its enzymatic activity, we confirmed in this cell line the functional events previously characterized in primary cultures of immature rat Sertoli cells: 1) a strong stimulation of aromatase activity by dibutyryl-cAMP [(Bu)2cAMP] (simulating FSH action); and 2) the inhibition of aromatase activity by incubation with T3 under basal condition and after (Bu)2cAMP stimulation. After identifying promoter II as the regulatory region located immediately upstream of the transcriptional initiation site in the TM4 cell line by rapid amplification of cDNA ends analysis, we conducted experiments to examine the molecular mechanism by which thyroid hormones modulate aromatase gene expression in this cell line. TM4 cells were transfected with plasmids containing different segments of the rat promoter II sequence ligated to a luciferase reporter gene. Analysis of the activities of these promoter fusions demonstrated that T3 inhibits basal and (Bu)2cAMP-stimulated activity of the aromatase promoter. This effect was not revealed in T3-treated cells transfected with construct in which the steroidogenic factor-1 (SF-1) response element was mutated. These results indicate that the inhibitory effect of T3 requires the integrity of the SF-1 response element and are further supported in the EMSA. The EMSA experiments demonstrated that thyroid hormone/thyroid receptor alpha1 complex (TH/TRalpha1) is able to compete with SF-1 in binding to oligonucleotides containing an SF-1 motif, an element essential for the activity of the PII aromatase promoter. The findings suggest that the binding of the thyroid hormone/thyroid receptor alpha1 complex to the SF-1 motif is the molecular mechanism by which T3 exerts an inhibitory effect on aromatase gene expression in the TM4 cell line.

Animals↗

PubMed1986

Boundary cells between longitudinal and circular layers: essential for electrical slow waves in cat intestine.

Electrical slow waves were recorded by intracellular electrodes and by quasi-intracellular pressure and suction electrodes from muscle fibers at different levels in edgewise preparations of cat jejunum. Simultaneous recordings from longitudinal and circular muscle layers showed similar resting potentials from either muscle layer near the boundary zone, and lower resting potentials in cells of circular muscle near the submucosa. Slow waves were maximal in amplitude at the boundary between the two layers and spread electrotonically away from the boundary in both layers. Bipolar recordings were of opposite polarity on the two sides of the boundary. Amplitudes of slow waves from inner circular fibers were significantly lower than from outer circular fibers. Small strips of each muscle layer were prepared with or without the attached interstitial cells of Cajal plexus as identified by methylene blue staining. Either muscle layer showed slow waves from regions where interstitial cells of Cajal (ICC) were observed after the recording. No slow waves were recorded from either layer from regions where ICC were not observed. Strips containing ICC but not strips lacking ICC could be driven electrically. Since blocking of neurons does not abolish slow waves and since regions of muscle lacking ICC do not have slow waves, it is concluded that the interstitial cells (ICC-I) are most likely the boundary elements essential for slow waves in either layer of intestinal muscle.

Animals↗

PubMed1996

Identification of ligand binding determinants in the somatostatin receptor subtypes 1 and 2.

The somatostatin (SRIF) receptors (SSTRs) 1 and 2 bind SRIF and SRIF 28 with high affinity, although a number of synthetic hexapeptide and octapeptide analogs of SRIF bind selectively to SSTR2. Extracellular loop three and its adjoining trans-membrane-spanning regions contain elements essential for the binding of such analogs to murine SSTR2. In particular, a stretch of amino acids from residues 294-297 (FDFV) in murine SSTR2 in trans-membrane domain seven can determine affinity for the SSTR2-selective analogs. Within this region, Phe294 has previously been predicted to be essential for the binding of octapeptides (Kaupmann, K., Bruns, C., Raulf, F., Weber, H., Mattes, H., and Lubbert, H. (1995) EMBO J. 14, 727-735) based on the observation that SSTR1 can bind the octapeptide SMS-201-995 with reasonable affinity after a Ser-to-Phe conversion in the analogous region of this receptor (SSTR1S305F). We find that SSTR1S305F has low affinity for a number of SSTR2-selective hexapeptides, suggesting that these analogs have different binding requirements than SMS-201-995. A correlation is seen between the ability of SSTR1S305F to bind hexapeptide analogs and the presence of a phenylalanine, but not tyrosine, at position two in these small cyclic molecules. Thus, a single hydroxyl group in hexapeptides can play a critical role in determining receptor binding to these receptor mutants. We also find that the second extracellular loop of SSTR1 is important for the selectivity of certain SRIF agonists for binding to SSTR1. Taken together, our data indicate that there are multiple elements in the somatostatin receptors that can determine the binding affinity and selectivity of peptide analogs.

Amino Acid Sequence↗

PubMed1986

Characterization, cloning and sequence analysis of the CDC25 gene which controls the cyclic AMP level of Saccharomyces cerevisiae.

The cell division cycle of the yeast Saccharomyces cerevisiae is triggered at the stage called 'START'. Many results strongly suggest that adenylate cyclase is an essential element of the control of START. We report here results arguing for a positive control of the cAMP level by the CDC25 gene, another gene of START. Firstly, cdc25 cells can be rescued by extracellular cAMP. Secondly, the cellular cAMP content drops when thermosensitive cdc25 mutant cells are shifted to restrictive temperature. We report the molecular cloning of the CDC25 gene by complementation of cdc25 mutant cells. The identity of the cloned gene was confirmed by site-specific gene re-integration experiments and segregation analysis: the isolated fragment is shown to integrate into the cdc25 gene locus. When transferred in cdc25 mutant cells this DNA prevents the drop of the cAMP level at restrictive temperature. This gene is transcribed in a 5200-nucleotides mRNA. We have determined the nucleotide sequence of a 5548-bp DNA fragment which shows an uninterrupted open reading frame (ORF) coding for a 1587-amino acid polypeptide chain. Only the C-terminal part of the ORF appears to be essential for the complementation of the cdc25-5 allele, suggesting a multidomain protein.

Alleles↗

PubMed1996

Neurotoxicity of d-amphetamine in the C57BL/6J and CD-1 mouse. Interactions with stress and the adrenal system.

Substantial evidence suggests that stress can alter the general toxicological properties of the substituted amphetamines (AMPs) as well as their psychostimulant properties. Research concerning the interactions between stress and the neurotoxicity associated with the AMPs is, however, limited. Our previous work demonstrated that a variety of AMPs, including d-METH, d-MDA, d-MDMA but not d-FEN are able to damage dopaminergic elements of the striatum as shown by decreases in dopamine and tyrosine hydroxylase. The neurotoxic capabilities of these AMPs appear linked to their hyperpyrexic actions as diverse manipulations able to block AMP-induced hyperthermia are also neuroprotective. Surprising, since stress usually potentiates the actions of the AMPs, it is our finding that restraint, a commonly used stressor, is protective against the injurious actions of all neurotoxic AMPs evaluated to date. In the mouse restraint acts to elevate blood levels of corticosterone (CORT) by activating the hypothalamic-pituitary-adrenal (HPA) axis as well as inducing a profound hypothermia. The role CORT may play in the neuroprotective actions of restraint, if any, is unknown. Here, data is presented showing the impact of several HPA axis manipulations, including restraint, supplementation with CORT in the drinking water and removal of CORT by adrenalectomy (ADX) on the striatal dopaminergic neurotoxicity of d-AMP. As strain is known to be a powerful determinant of the actions of stress an essential element of these experiments was the evaluation of both an inbred, C57BL/6J and outbred, CD-1, mouse strain. Exposure to d-AMP caused hyperthermia and substantial striatal dopaminergic neurotoxicity in both strains suggesting that an elevation in body temperature is as important a component of the neurotoxicity of d-AMP, as it is of the other neurotoxic AMPs. Restraint was equally effective in both strains and completely blocked the hyperthermia and striatal neurotoxicity induced by d-AMP. CORT supplementation, evaluated in only the C57BL/6J mouse at dosages not capable of involuting either the thymus or the spleen, did not alter d-AMP-induced neurotoxicity. Although the immune system organs of the two strains responded differentially to the removal of CORT, ADX provided equivalent partial protection against the loss of dopaminergic elements in striatum for both strains. Adrenal status clearly affects d-AMP neurotoxicity but the interaction is complex. Future work should examine the roles of the cortical and medullary components of the adrenal gland in the neuroprotective actions of ADX. A precise assessment of the role of circulating CORT In the neurotoxicity of the AMPs will require additional work in which a wider range of CORT dosages, including those capable of involuting thymus and spleen, are evaluated.

Adrenal Cortex Hormones↗

PubMed1990

Erythrocyte rosettes provide an analogue for Schiff base formation in specific T cell activation.

Human T cells spontaneously bind sheep E and this reflects physiologic interactions between specific adhesion molecules, principally T cell CD2, and the sheep equivalent of LFA-3. This interaction is important in T cell adhesion and in transmission of accessory activational signals. In this respect, E rosettes provide a partial analogue for T cell:accessory cell interaction and rosetting induces functional alterations in T cells. In studies of Ag-dependent T cell activation, we have obtained evidence that the formation of covalent Schiff bases between ligands on APC and T cell is an essential element. In our study, the specific chemical criteria defining Schiff base formation were applied to T cell E rosettes formed at room temperature, as follows: 1) Prior formation of Schiff bases on T cell epsilon-amino groups by glutaraldehyde inhibited E rosette formation. 2) Rosette formation was inhibited in the presence of exogenous lysine. 3) Reduction of constitutive T cell aldehydes by NaBH4 inhibited subsequent E rosette formation. In response to these chemical modifications of cellular ligands, T cell E rosette formation and T cell inductive interaction with APC were affected in the same way. 4) Oxidation of NaBH4-treated T cells by NaIO4 or galactose oxidase to regenerate cell-surface aldehydes on N-acetylneuraminic acid or galactose residues respectively, consistently restored E rosette formation. 5) Conversion of reversible Schiff bases to irreversible secondary amines by NaCNBH3 stabilized E rosettes against mechanical disruption. Together, these data demonstrate that E rosettes provide an analogue for the Schiff base-forming reactions that are essential in specific T cell activation.

Animals↗

PubMed2006

Involvement of the cynABDS operon and the CO2-concentrating mechanism in the light-dependent transport and metabolism of cyanate by cyanobacteria.

The cyanobacteria Synechococcus elongatus strain PCC7942 and Synechococcus sp. strain UTEX625 decomposed exogenously supplied cyanate (NCO-) to CO2 and NH3 through the action of a cytosolic cyanase which required HCO3- as a second substrate. The ability to metabolize NCO- relied on three essential elements: proteins encoded by the cynABDS operon, the biophysical activity of the CO2-concentrating mechanism (CCM), and light. Inactivation of cynS, encoding cyanase, and cynA yielded mutants unable to decompose cyanate. Furthermore, loss of CynA, the periplasmic binding protein of a multicomponent ABC-type transporter, resulted in loss of active cyanate transport. Competition experiments revealed that native transport systems for CO2, HCO3-, NO3-, NO2-, Cl-, PO4(2-), and SO4(2-) did not contribute to the cellular flux of NCO- and that CynABD did not contribute to the flux of these nutrients, implicating CynABD as a novel primary active NCO- transporter. In the S. elongatus strain PCC7942 DeltachpX DeltachpY mutant that is defective in the full expression of the CCM, mass spectrometry revealed that the cellular rate of cyanate decomposition depended upon the size of the internal inorganic carbon (Ci) (HCO3- + CO2) pool. Unlike wild-type cells, the rate of NCO- decomposition by the DeltachpX DeltachpY mutant was severely depressed at low external Ci concentrations, indicating that the CCM was essential in providing HCO3- for cyanase under typical growth conditions. Light was required to activate and/or energize the active transport of both NCO- and Ci. Putative cynABDS operons were identified in the genomes of diverse Proteobacteria, suggesting that CynABDS-mediated cyanate metabolism is not restricted to cyanobacteria.

Bacterial Proteins↗

PubMed2005

[Trace elements and sperm parameters in semen of male partners of infertile couples].

OBJECTIVE: The relationships between element concentrations and sperm parameters in semen samples were investigated. METHODS: Semen samples (n = 113) were donated voluntarily by male partners of infertile couples. The concentrations of fourteen elements (Na, K, P, Ca, Zn, Mg, Fe, Cu, Se, Mn, Sn, Co, Ni, and Cd) in semen were determined by atomic absorption spectrometry, fluorometry, or colorimetry. Element concentrations in seminal plasma and in sperm were also measured. RESULTS: Element concentrations in semen were in the order Na > P, K > Ca > Zn > Mg > > Fe> Cu, Se > Mn > Sn, Ni, Co, Cd. When the samples were divided into two groups in terms of sperm concentration and number, the Se concentration in semen with normal parameter values (sperm concentration > or = 20 x 10(6) and sperm number > or = 40 x 10(6)), 99.4 +/- 37.4 ng/ml, was higher than that in semen with abnormal parameter values (sperm concentration < or = 20 x 10(6) and/or sperm number < or = 40 x 10(6)), 72.1 +/- 33.9 ng/ml (p < 0.001). A clearer positive correlation between the Se concentration and the sperm concentration was observed in the sperm portion (r = 0.853, p < 0.001) than in semen (r = 0.512, p < 0.001) and seminal plasma (r = 0.292, p = 0.003). Statistically significant correlations were also observed between the concentration of Se, P, Zn, Cu, Fe, or Mn in semen, the sperm portion or seminal plasma and the sperm concentration, semen volume or abnormal morphology, although correlation coefficients were small. CONCLUSION: Among biologically essential elements in semen of infertile males, Se was a good indicator of sperm concentration; however, other trace elements did not indicate clear relationships between their concentrations and sperm parameters.

Humans↗

PubMed2000

Spread of Mycobacterium tuberculosis in a community implementing recommended elements of tuberculosis control.

CONTEXT: Despite improvements in tuberculosis (TB) control during the past decade, Mycobacterium tuberculosis transmission and resulting disease continue to occur in the United States. OBJECTIVE: To determine the primary reasons for disease development from a particular strain of M tuberculosis. DESIGN: Population-based, molecular epidemiological study. SETTING: Urban community in the San Francisco Bay area of California with recommended elements of TB control in place. PATIENTS: Seventy-three TB cases were reported in 1996-1997 that resulted from 1 strain of M tuberculosis as identified by TB genotyping and epidemiological linkage. MAIN OUTCOME MEASURES: Transmission patterns involving source and secondary case-patients; primary reasons for disease development. RESULTS: Seventy-three (33%) of 221 TB case-patients in this community resulted from this strain of M tuberculosis. Thirty-nine (53%) of the 73 case-patients developed TB because they were not identified as contacts of source case-patients; 20 case-patients (27%) developed TB because of delayed diagnosis of their sources; and 13 case-patients (18%) developed TB because of problems associated with the evaluation or treatment of contacts; and 1 case-patient (1%) developed TB because of delay in being elicited as a contact. Of the 51 TB cases identified with sources, 49 (96%) were infected within the 2 years prior to diagnosis. CONCLUSIONS: Our results indicate that in a community that has implemented the essential elements of TB control, TB from ongoing transmission of M tuberculosis will continue to develop unless patients are diagnosed earlier and contacts are more completely identified. JAMA. 2000.

Adolescent↗

PubMed2000

Essentialist beliefs about social categories.

This study examines beliefs about the ontological status of social categories, asking whether their members are understood to share fixed, inhering essences or natures. Forty social categories were rated on nine elements of essentialism. These elements formed two independent dimensions, representing the degrees to which categories are understood as natural kinds and as coherent entities with inhering cores ('entitativity' or reification), respectively. Reification was negatively associated with categories' evaluative status, especially among those categories understood to be natural kinds. Essentialism is not a unitary syndrome of social beliefs, and is not monolithically associated with devaluation and prejudice, but it illuminates several aspects of social categorization.

Adult↗

PubMed2004

[Hospital risk management from the viewpoint of insurers].

The present article deals with the significance of risk management in hospitals from the viewpoint of liability insurers. From the perspective of insurance companies, the liability risk of a hospital and its personnel has considerably increased during the past 25 years. The present risk situation is characterized by a growing number of reported liability cases, as well as by an enormous increase of average compensation claims. This development has led some insurance companies to financial deficits in the segment of hospital liability. While some insurers have withdrawn their activities from this market segment, others have reacted by raising their premiums. Since in Germany the premiums usually depend on the number of beds held by a hospital, the problem of rising premiums is exacerbated by the general increase of the number of clinical cases in the face of a parallel reduction of the number of beds. In the process of finding new criteria or methods for adequate premium calculation, a key role will be played by the individual future risk development of a hospital and by the evaluation of this risk by its insurance company. An extensive system of clinical quality management supported by elements of risk management will have persistent positive effects on the development of individual insurance premiums and on the insurability of clinical liability. Risk management is defined as the totality of measures taken by a company to identify risks that could lead to reduced success. Clinical risk management must be regarded in the context of a general trend that is not limited to the field of health service. In this process, the handling of errors and their causes plays a central role. Further variants of hospital risk management are the technical and economic risk management, both of which are increasingly important and are in part implemented in the German legislation. Clinical risk management has originated from the U.S., where as early as in the nineteen-seventies instruments and methods have been developed to avoid errors. Important application fields are anesthetics, surgery, orthopedics, and obstetrics. Risk management is primarily a task of the internal personnel of a hospital. The support by external consultants promises additional benefits for the hospital. Measures of classical risk management usually are essential elements of any quality management system; as such, they are therefore certifiable. Certification alone, however, does not prove the sustained efficiency of a risk-prevention system.

Humans↗

PubMedDate not supplied

Initiating a novel therapy in preventing postpartum hemorrhage in rural India: a joint collaboration between the United States and India.

BACKGROUND: Maternal mortality rates in India are estimated at 560/100,000 live births and postpartum hemorrhage (PPH) accounts for 35-56% of these deaths. Given that 50% of births in rural India occur at home, oral Misoprostol administered by minimally trained midwives may be an effective uterotonic agent for preventing PPH when the use of other uterotonics is not feasible. While the import for testing the effectiveness of this intervention may be readily obvious, the elements essential for the conduct of a scientific study in rural areas served by indigenous health workers may not be as evident. METHODS: We present the design as well as the preparation and development of an ongoing NICHD sponsored U.S.-Indian collaborative randomized, placebo-controlled, clinical trial (RCT) conducted in four Primary Health Center areas of Belgaum District, Karnataka, India. The primary goal of the trial is to assess the effectiveness of Misoprostol 600 microg orally in reducing the incidence of acute PPH (> or = 500 mL) in women delivering at home or in neighboring sub-centers. 1600 pregnant women will be randomized to receive Misoprostol or placebo immediately post-delivery of the infant. However, beyond testing the scientific merit of the RCT, this study also tests the feasibility of having indigenous midwives regularly using Misoprostol in rural areas as well as the willingness of these communities to accept this intervention. In addition, this paper also explores the international and community collaborations necessary for the conduct of this study. FINDINGS: It is necessary to have several critical elements in place, including international collaboration between the Indian and US research sites, funding through a private/public collaboration and trained scientists, as well as commitment from the community for the successful conduct of such a study. In the development and implementation of a RCT, careful attention must be paid to the training of field personnel involved in the delivery process and developing a data collection and monitoring system to ensure that information gathered is valid. CONCLUSIONS: A joint U.S.-Indian collaboration to test the efficacy and the feasibility of an innovative method to reduce PPH can serve as collaborative model to develop additional interventions to improve maternal mortality and morbidity. If Misoprostol is shown to be sufficiently safe and efficacious in the prevention of PPH, the appropriate government agencies will be encouraged to make the drug available to midwives (ANMs) and rurally located physicians for whom parenteral medications are either not permitted or impractical and/or unavailable. Such a project can serve as a model applicable to rural settings throughout the developing world for improving delivery practices and reducing maternal mortality and morbidity. These are important public health concerns in India and other developing nations.

Feasibility Studies↗

PubMed1999

Multiple cis-acting regulatory regions are required for restricted spatio-temporal Hoxa5 gene expression.

Genetic analyses have revealed the essential role of the murine Hoxa5 gene for the correct specification of the cervical and upper thoracic region of the skeleton, and for the normal organogenesis and function of the respiratory tract, both structures expressing Hoxa5 during embryogenesis. To understand how the expression domains of the Hoxa5 gene are established during development, we have analyzed the cis-acting control regions mediating Hoxa5 gene expression using a transgenic approach. Four transcripts are derived from the Hoxa5 locus. The shortest and most abundant one displays a specific spatio-temporal profile of expression at earlier stages and in more anterior structures along the embryonic axis than the larger forms. We established that an 11.1 kilobase pair (kb) genomic fragment, extending from position -3.8 kb to +7.3 kb relative to Hoxa5 transcription initiation site, was sufficient to reproduce the temporal expression and substantially reconstitute the spatial pattern of the major Hoxa5 transcript. By deletion analyses, we identified a 2.1 kb fragment located downstream of the Hoxa5 gene that possesses mesodermal enhancer activity. Overall, the findings demonstrate that cis-acting regulatory elements essential for the correct expression of the major Hoxa5 transcript are located both upstream and downstream of the Hoxa5 coding sequences.

Animals↗

PubMed1996

Analysis of the binding of Xenopus transcription factor IIIA to oocyte 5 S rRNA and to the 5 S rRNA gene.

Binding of transcription factor IIIA (TFIIIA) to site-specific mutants of Xenopus oocyte 5 S rRNA has been used to identify important recognition elements in the molecule. The putative base triple G75:U76:A100 appears to determine the conformation of the loop E region whose integrity is especially important for binding of the factor. Proximal substitutions in helices IV and V indicate that the proper folding of loop E is also dependent on these structures. Mutations in helix V affect binding of TFIIIA to 5 S rRNA and to the gene similarly and provide evidence that zinc finger 5 makes sequence-specific contact through the major groove of both nucleic acids. Although fingers 1-3 are positioned along helix IV and loop D, mutations in this region, including those that disrupt the tetraloop or close the opening in the major groove of the helix created by the U80:U96 mismatch, have no impact on binding. Substitutions made at stem-loop junctions in the arm of the RNA comprised of helix II-loop B-helix III display minor decreases in affinity for TFIIIA. Despite the alignment of the factor along nearly the entire length of 5 S rRNA, the essential elements for high affinity binding are limited to the central region of the molecule. Analysis of the corresponding mutations in the gene confirm that box C and the intermediate element provide the high affinity sites for binding of the factor to the DNA. Despite the small thermodynamic contribution made by contacts to box A, mutations made in this element can cause substantial changes in the orientation of the carboxyl-terminal fingers along the 5'-end of the internal control region.

Animals↗