Rheumatic heart disease in pregnancy: cardiac and obstetric outcomes.

BACKGROUND: Rheumatic heart disease (RHD) remains an important health issue for indigenous women of child-bearing age in northern Australia. However, the influence of RHD on maternal outcomes with current clinical practice is unclear. AIMS: To determine maternal cardiac complications and obstetric outcomes in patients with RHD. METHODS: Retrospective case note analysis of women with RHD who received obstetric care between July 1999 and May 2010 at Cairns Base Hospital in north Queensland. Outcome measures were obstetric interventions and outcomes, cardiac interventions and complications, stratified according to a cardiac risk score (CRS). RESULTS: Ninety-five confinements occurred in 54 patients, of whom 52 were Indigenous Australians. There were no maternal or neonatal deaths. With a CRS of 0, cardiac complications occurred in 0 of 70 confinements; with a CRS of 1, complications occurred in 5 of 17 confinements (29%); with a CRS of >1, complications occurred in 2 of 4 confinements (50%). Another four patients were first diagnosed with RHD after developing acute pulmonary oedema during the peripartum period. CONCLUSIONS: RHD has a major impact on maternal cardiac outcomes. However, with current management practices, maternal and fetal mortality are low, and the incidence of complications is predictable based on known risk factors.

Altered localization of Cav1.2 (L-type) calcium channels in nerve fibers, Schwann cells, odontoblasts, and fibroblasts of tooth pulp after tooth injury.

We have determined the localization of Cav1.2 (L-Type) Ca2+ channels in the cells and nerve fibers in molars of normal or injured rats. We observed high levels of immunostaining of L-type Ca2+ channels in odontoblast cell bodies and their processes, in fibroblast cell bodies and in Schwann cells. Many Cav1.2-containing unmyelinated and myelinated axons were also present in root nerves and proximal branches in coronal pulp, but were usually missing from nerve fibers in dentin. Labeling in the larger fibers was present along the axonal membrane, localized in axonal vesicles, and in nodal regions. After focal tooth injury, there is a marked loss of Cav1.2 channels in injured teeth. Immunostaining of Cav1.2 channels was lost selectively in nerve fibers and local cells of the tooth pulp within 10 min of the lesion, without loss of other Cav channel or pulpal labels. By 60 min, Cav1.2 channels in odontoblasts were detected again but at levels below controls, whereas fibroblasts were labeled well above control levels, similar to upregulation of Cav1.2 channels in astrocytes after injury. By 3 days after the injury, Cav1.2 channels were again detected in nerve fibers and immunostaining of fibroblasts and odontoblasts had returned to control levels. These findings provide new insight into the localization of Cav1.2 channels in dental pulp and sensory fibers, and demonstrate unexpected plasticity of channel distribution in response to nerve injury.

Back to the future: the human protein index (HPI) and the agenda for post-proteomic biology.

The effort to produce an index of all human proteins (the human protein index, or HPI) began twenty years ago, before the initiation of the human genome program. Because DNA sequencing technology is inherently simpler and more scalable than protein analytical technology, and because the finiteness of genomes invited a spirit of rapid conquest, the notion of genome sequencing has displaced that of protein databases in the minds of most molecular biologists for the last decade. However, now that the human genome sequence is nearing completion, a major realignment is under way that brings proteins back to the center of biological thinking. Using an influx of new and improved protein technologies--from mass spectrometry to re-engineered two-dimensional (2-D) gel systems, the original objectives of the HPI have been expanded and the time frame for its execution radically shortened. Several additional large scale technology efforts flowing from the HPI are also described.

Perceptions about risk for HIV/AIDS among adolescents in juvenile detention.

Although progress has been made toward reducing risk-taking behavior among teens, adolescents confined in juvenile detention facilities and youths living in inner cities remain vulnerable. Reaching these populations with appropriate risk-reduction strategies continues to challenge health providers and educators. Crucial first steps in the design of relevant programs involve discovering how at-risk teens perceive risk and which risks and dangers within their communities occupy their attention. Participants in this study did not identify HIV/AIDS as a primary concern; instead, they described the dangers and risks they encountered in their home neighborhoods. Based on these findings, this discussion addresses the implications for the development of health education programs to empower teens for responsible behavior after release from detention.

Cholesterol biosynthesis regulation and protein changes in rat liver following treatment with fluvastatin.

The enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase is a key regulator in cholesterol biosynthesis and HMG CoA reductase inhibitors (statins) have become a widely prescribed family of lipid lowering agents. Cholesterol synthesis occurs predominantly in liver which is the target organ of statins. We studied the effects of fluvastatin (Lescol), a member of the statin family, on hepatic protein regulation. Male F344 rats treated with 0.8 mg/kg per day fluvastatin or 24 mg/kg per day fluvastatin for 7 days showed treatment-related changes in 58 liver proteins (P<0.005). Major effects were evident in the cholesterol biosynthesis pathway including the induction of enzymes upstream and downstream of the target enzyme HMG CoA reductase. Treatment also triggered alterations in key enzymes of carbohydrate metabolism and was associated with changes in a heterogeneous set of cellular stress proteins involved in cytoskeletal structure, calcium homeostasis and protease activity. The latter set of protein alterations indicates that hepatotoxicity is associated with high-dose treatment. Based on the results it is suggested that HMG-CoA synthase and isopentenyl-diphosphate delta-isomerase may be explored as alternative drug targets and that the induction levels of these enzymes may serve as a measure of potency of individual statin drugs. It is proposed that efficacy and cellular stress markers discovered in this study may be used in a high throughput screen (HTS) assay format to compare efficiently and accurately the therapeutic windows of different members of the statin family.

Pharmaceutical proteomics.

Genomics and proteomics are today well established in drug discovery and, in combination with combinatorial chemistry and high-throughput screening, are helping to bring forward an unprecedented number of potential lead compounds. To avoid the generation of bottlenecks downstream in drug development, increasing pressure is arising to integrate these technologies into the development environment. Proteomics has demonstrated proof-of-concept in toxicology as shown by a number of successful applications in mechanistic toxicology and lead selection. The "technology wave" is now starting to impact the clinical phase of drug development. Expected benefits are optimized clinical trials based on the availability of biologically relevant markers of drug efficacy and safety.

Proteomics: applications in basic and applied biology.

The rapid evolution of proteomics has continued during the past year, with a series of innovations in the core technologies of two-dimensional electrophoresis and mass spectrometry, and a diversity of productive research programmes. Well-annotated proteomics databases are now emerging in a number of fields to provide a platform for systematic research, with particularly promising progress in clinical applications such as cardiology and oncology. Large-scale quantitative research, comparable in power and sensitivity to that achieved for gene expression, is thus becoming a reality at the protein level.

Two-dimensional electrophoresis of liver proteins: characterization of a drug-induced hepatomegaly in rats.

Two-dimensional electrophoresis (2-DE) of liver proteins was applied to further characterize an unusual drug-induced increase in hepatocellular rough endoplasmic reticulum (RER) in Sprague-Dawley rats given a substituted pyrimidine derivative. Absolute liver weights of drug-treated rats (9.9 +/- 0.4 g) increased above vehicle-treated controls (7.2 +/- 0.2 g) by 37%. Light microscopy revealed diffuse granular basophilia of the hepatocellular cytoplasm, uncharacteristic of hepatocytes and suggested cells rich in ribosomes, which was confirmed by electron microscopy. Immunostaining for cell proliferation, viz., 5-bromo-2'-deoxyuridine (BrdU) and proliferating cell nuclear antigen (PCNA), indicated marked hepatocellular proliferative activity. 2-DE of solubilized liver using an ISO-DALT gel system indicated significant (p<0.001) quantitative changes in at least 17 liver proteins (12 increased, 5 decreased) compared to controls. The protein with the largest increase was homologous to acute-phase reactant, contrapsin-like protein inhibitor-6. Other markedly upregulated proteins were methionine adenosyltransferase, a catalyst in methionine/ATP metabolism and mitochondrial HMG-CoA synthase, involved in cholesterol synthesis. The complementary strategies of 2-DE coupled either with database spot mapping or protein isolation and amino acid sequencing successfully identified a subset of proteins from xenobiotic-damaged rodent livers, the expression of which differed from controls. However, the current bioinformatics platform for rodent hepatic proteins and limited knowledge of specific protein functionality restricted application of this proteomics profile to further define a mechanistic basis for this unusual hepatotoxicity.

Proteomics to display lovastatin-induced protein and pathway regulation in rat liver.

Lovastatin is a lipid lowering agent that acts by inhibiting 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, a key regulatory enzyme in cholesterol biosynthesis. In this study the pattern of gene network regulation induced in hepatic proteins as a response to lovastatin treatment was analyzed by proteomics. In livers of male F344 rats treated with 1.6 mg/kg/day lovastatin or 150 mg/kg/day lovastatin for seven days, 36 proteins were found to be significantly altered (p<0.001) in relation to treatment. The changed proteins were classified according to their cellular function and participation in biochemical pathways. The following observations were made: (i) inhibition of HMG-CoA reductase provoked a regulatory response in the cholesterol synthesis pathway including the induction of cytosolic HMG-CoA synthase and of isopentenyl-diphosphate delta-isomerase, (ii) manipulation of the lipid metabolism triggered alterations in key enzymes of the carbohydrate metabolism, and (iii) lovastatin treatment was associated with signs of toxicity as reflected by changes in a heterogeneous set of cellular stress proteins involved in functions such as cytoskeletal structure, calcium homeostasis, protease inhibition, cell signaling or apoptosis. These results present new insights into liver gene network regulations induced by lovastatin and illustrate a yet unexplored application of proteomics to discover new targets by analysis of existing drugs and the pathways that they regulate.

Proteomic analysis of the atrophying rat soleus muscle following denervation.

A proteomic analysis was performed comparing normal rat soleus muscle to denervated soleus muscle at 0.5, 1, 2, 4, 6, 8 and 10 days post denervation. Muscle mass measurements demonstrated that the times of major mass changes occurred between 2 and 4 days post denervation. Proteomic analysis of the denervated soleus muscle during the atrophy process demonstrated statistically significant (at the p < 0.01 level) changes in 73 soleus proteins, including coordinated changes in select groups of proteins. Sequence analysis of ten differentially regulated proteins identified metabolic proteins, chaperone and contractile apparatus proteins. Together these data indicate that coordinated temporally regulated changes in the proteome occur during denervation-induced soleus muscle atrophy, including changes in muscle metabolism and contractile apparatus proteins.

A public health nursing early intervention program for adolescent mothers: outcomes from pregnancy through 6 weeks postpartum.

BACKGROUND: Adolescent pregnancy and parenting remain a major public concern because of their impact on maternal-child health and on the social and economic well-being of the nation. Federal welfare reform legislation has created an urgent need for community-based nursing intervention programs to improve health and social outcomes for disadvantaged adolescent mothers and to promote their self-sufficiency. OBJECTIVE: To evaluate the effects of an early intervention program (EIP) that uses a public health nursing model on health and social outcomes of adolescent mothers and their children and on the quality of mother-child interaction. METHODS: Pregnant adolescents referred to a county health department were randomly assigned to an experimental (EIP) or control (traditional public health nursing [TPHN]) group. The sample included 121 adolescents from predominantly minority and impoverished backgrounds who were followed from pregnancy through 6 weeks postpartum. Intense and comprehensive home visitation by public health nurses and preparation-for-motherhood classes were provided to adolescents in the EIP. Health outcomes were determined on the basis of medical record data. Other measures included maternal self-report on selected behaviors, nurse interviews, and the Nursing Child Assessment Teaching Scale (NCATS). RESULTS: Early findings indicate reduced premature birth and low-birth-weight (LBW) rates for young mothers receiving both forms of public health nursing care. No significant differences between groups were found for infant birth weight or type of delivery. Infants in the EIP had significantly fewer total days of birth-related hospitalization and rehospitalization than those in the TPHN group during the first 6 weeks of life (chi2(1) = 6.41; p = 0.01). Adolescents in the EIP demonstrated significantly more positive educational outcomes (e.g., lower school dropout rates) than those in the TPHN group (chi2(1) = 6.76; p < 0.009). CONCLUSIONS: The early findings of this study demonstrate that pregnant adolescents benefit from both traditional and more intense public health nursing care in terms of prenatal and perinatal outcomes. The EIP was associated with decreased infant morbidity during the first 6 weeks of life and decreased maternal school dropout. Long-term outcomes for the EIP are being evaluated.

Expression profiling in toxicology--potentials and limitations.

Recent progress in genomics and proteomics technologies has created a unique opportunity to significantly impact the pharmaceutical drug development processes. The perception that cells and whole organisms express specific inducible responses to stimuli such as drug treatment implies that unique expression patterns, molecular fingerprints, indicative of a drug's efficacy and potential toxicity are accessible. The integration into state-of-the-art toxicology of assays allowing one to profile treatment-related changes in gene expression patterns promises new insights into mechanisms of drug action and toxicity. The benefits will be improved lead selection, and optimized monitoring of drug efficacy and safety in pre-clinical and clinical studies based on biologically relevant tissue and surrogate markers.

Confirmed identities of proteins from a two-dimensional map of Syrian hamster embryo cells.

The Syrian hamster embryo (SHE) cell transformation assay is widely used to screen chemicals for carcinogenic potential. However, the biochemical mechanisms of transformation in SHE cells are incompletely understood relative to other rodent systems. Thus identification of proteins which change during transformation can provide clues to biochemical mechanisms. Previously, we published a map of SHE cell proteins based on comparisons to other maps. In this report we provide direct sequence analysis of numerous proteins which were previously identified solely by electrophoretic mobility. Protein sequencing verified original spot identifications and extended the range of identified proteins. The updated map will assist in evaluating biochemical mechanisms of morphological transformation in hamster cells.

Depressed adolescent mothers' perceptions of their own maternal role.

Although there is a growing body of research in the area of adolescent pregnancy and parenting, little is known about the more personal experiences of these teens. Ethnographic research methods were used in the present study with the goal of narrowing existing gaps in knowledge about the affective component of adolescent mothers' role attainment. The sample consisted of 15 voluntary informants who reported depressive symptoms during pregnancy or postpartum. The findings suggest that for some adolescent mothers the experience of motherhood may help them improve their previously self-destructive lives. Many adolescent mothers have engaged in impulsive high-risk activities prior to their pregnancies. Through the establishment of a maternal identity and simultaneous development of a strong sense of maternal protectiveness these young women are making realistic, future-oriented decisions that are motivating them to leave gang life, finish high school, go to college, and get vocational training. However, a subset of adolescent mothers who experience chronic depressive mood along with social isolation in the postpartum period may be at increased risk for development of problematic maternal behaviors.

An early intervention program for adolescent mothers: a nursing demonstration project.

OBJECTIVE: To improve health outcomes in a vulnerable population of adolescent mothers and their infants. DESIGN: Effects of an intensive early intervention program (EIP) are compared with those of traditional public health nursing (TPHN) care. SETTING: A large California county with urban and rural communities, an ethnically diverse population, and a high teen birth rate. PARTICIPANTS: One hundred twenty-one young mothers and their children from impoverished and predominantly minority backgrounds. INTERVENTIONS: During pregnancy and through 1 year postpartum, participants (n=63) in the EIP were provided with 4 prenatal classes and approximately 17 home visits by specially trained public health nurses. Interventions addressed health issues, sexuality and family planning, life skills, the maternal role, and social support systems. Participants in TPHN (n=58) received three home visits (for intake, prenatal care, and postpartum/well-baby care information). MAIN OUTCOME MEASURES: Antepartum, intrapartum, and newborn medical records; maternal responses to written questionnaires; and nurse interviews. RESULTS: Early program outcomes indicate reduced premature birth rates for both groups compared with national data on adolescent mothers, and fewer days of infant hospitalization during the first 6 weeks postpartum for the EIP participants. CONCLUSION: Public health nurse care (both traditional and intensive) significantly improved perinatal outcomes; the intensive intervention significantly reduced the number of infant hospitalization days.

Evaluating the outcomes of parent-child family life education.

Conducted in diverse sociocultural communities in Los Angeles County, the project implemented and evaluated a family life education program designed to prevent the negative outcomes of risky sexual behavior. A sample of 251 male and female early adolescents 9 through 14 years of age participated with their parents in this abstinence-based adolescent pregnancy prevention program. The project sought to improve parent-child communications and delay the onset of sex-related behaviors through direct involvement of parents in the education process. Naturally occurring community groups were randomly assigned by site to treatment or delayed treatment conditions in a longitudinal quasi-experimental evaluation design. The evaluation demonstrated significant improvements in communication between parents and children immediately following the intervention; however, these improvements were no longer present 12 months postintervention. The process and outcome evaluation methods employed in the study triangulated qualitative and quantitative data collection and analysis procedures. This combination provided other sources of data than the traditional outcome measures used in most evaluation studies, thus addressing some of the gaps in present program evaluations. Descriptions of the process evaluation, integrated with the outcome data, are intended to heighten nurses' awareness of the importance of this component of research and the rich qualitative data it may yield. The qualitative process components in the project captured the experience of the investigators when they encountered many of the complex challenges that confront researchers who implement and evaluate family life education programs among early adolescents. This experience provided the basis for suggested strategies that nurse clinicians and researchers can use in their work with early adolescents and their parents in clinical-, school-, and community-based settings.

Perceptions about substance use among male adolescents in juvenile detention.

Although adolescents in juvenile detention represent a vulnerable population who are exposed to situations that foster risk-taking behaviors, few studies have been conducted with detained adolescents to determine their perceptions regarding substance use. Ethnographic interviews and observations were conducted with 20 male adolescents who resided in a large metropolitan area juvenile detention facility, to discover their substance use beliefs and the decisions they make to continue or discontinue substance use or abuse. The participants described how they initiated substance use and said that they had rarely made active decisions about substance use until they were detained. They explained the decisions they made, while they were in detention, to stop or cut down their substance use after release. They talked about the problems they anticipated when they returned home and how they hoped to balance their resolutions with their reputations and obligations. Time-out in juvenile detention may offer nurses the opportunity to capitalize on the potential readiness of detained adolescents to make resolution decisions regarding risky behaviors. Findings from a similar study conducted with 20 detained adolescent women were reported elsewhere.

Changes in the liver protein pattern of female Wistar rats treated with the hypoglycemic agent SDZ PGU 693.

SDZ PGU 693 acts as a hypoglycemic agent by stimulating glucose utilisation in insulin-sensitive peripheral tissues, such as skeletal muscle and fat. In a 28 day toxicity study the compound was found to induce hepatocellular hypertrophy in Wistar rats treated with 300 mg/kg/day. To gain insights into the pathomechanism of these alterations, aliquots of liver samples from control and treated female Wistar rats were separated by two-dimensional protein gel electrophoresis and the digitized images of the protein patterns were searched for protein abundance changes. Significant treatment-related quantitative changes (P < 0.001) were found in 29 liver proteins. Major increases were observed in several microsomal proteins, including NADPH cytochrome P-450 reductase, cytochrome b5 and serine protease inhibitor. The changes in the cytochrome related enzymes, both known co-factors of the P-450 enzyme system, strongly suggest that SDZ PGU 693 induces microsomal proliferation and induction of the P-450 enzyme system. Decreases were observed in a series of mitochondrial proteins, such as F1ATPase-delta subunit and ornithine aminotransferase precursor as well as in several cytosolic proteins such as the liver fatty acid binding protein, arylsulfotransferase and the senescence marker protein-30. The changes in F1ATPase-delta subunit and liver fatty acid binding protein together suggest a down-regulation of the mitochondrial liver fatty acid metabolism, likely reflecting the pharmacological action of the compound. These results show that SDZ PGU 693 produces a complex pattern of gene expression changes which give insights into the molecular mechanisms of both its pharmacological action and a toxic response.

Electron microscopic analysis of gamma-aminobutyric acid and glycine colocalization in rat trigeminal subnucleus caudalis.

Postembedding immunogold methods were used to examine the distribution of gamma-aminobutyric acid (GABA) and glycine and especially their colocalization in glomerular neuronal profiles adjacent to trigeminal primary afferent profiles in lamina II of rat subnucleus caudalis. We found that 60% of the profiles adjacent to the trigeminal primary afferent terminals exhibited colocalization of GABA and glycine. GABA alone was found to localize in 17% of the adjacent profiles. Glycine alone was found to localize in 18% of the adjacent profiles. Of interest, 10% of the trigeminal primary afferent fibers showed glycine localization. All the profiles with colocalization of GABA and glycine were identified as presynaptic axonal terminals, suggesting a possible cumulative effect by these two inhibitory neurotransmitters in presynaptic inhibition. These findings show that GABA and glycine colocalize in a subpopulation of presynaptic axonal terminals within lamina II of the subnucleus caudalis. The possible origins of these axons are discussed, as well as their potential involvement in presynaptic inhibition of orofacial nociception.

Proteome and proteomics: new technologies, new concepts, and new words.

The goal of proteomics is a comprehensive, quantitative description of protein expression and its changes under the influence of biological perturbations such as disease or drug treatment. Quantitative analysis of protein expression data obtained by high-throughput methods has led us to define the concept of "regulatory homology" and use it to begin to elucidate the basic structure of gene expression control in vivo. Such investigations lay the groundwork for construction of comprehensive databases of mechanisms (cataloguing possible biological outcomes), the next logical step after the soon to be completed cataloguing of genes and gene products. Mechanism databases provide a roadmap towards effective therapeutic intervention that is more direct than that offered by conventional genomics approaches.