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Accelerated transcription of PRPS1 in X-linked overactivity of normal human phosphoribosylpyrophosphate synthetase.

Phosphoribosylpyrophosphate (PRPP) synthetase (PRS) superactivity is an X-linked disorder characterized by gout with overproduction of purine nucleotides and uric acid. Study of the two X-linked PRS isoforms (PRS1 and PRS2) in cells from certain affected individuals has shown selectively increased concentrations of structurally normal PRS1 transcript and isoform, suggesting that this form of the disorder involves pretranslational dysregulation of PRPS1 expression and might be more appropriately termed overactivity of normal PRS. We applied Southern and Northern blot analyses and slot blotting of nuclear runoffs to delineate the process underlying aberrant PRPS1 expression in fibroblasts and lymphoblasts from patients with overactivity of normal PRS. Neither PRPS1 amplification nor altered stability or processing of PRS1 mRNA was identified, but PRPS1 transcription was increased relative to GAPDH (3- to 4-fold normal in fibroblasts; 1.9- to 2.4-fold in lymphoblasts) and PRPS2. Nearly coordinate relative increases in each process mediating transfer of genetic information from PRPS1 transcription to maximal PRS1 isoform expression in patient fibroblasts further supported the idea that accelerated PRPS1 transcription is the major aberration leading to PRS1 overexpression. In addition, modulated relative increases in PRS activities at suboptimal Pi concentration and in rates of PRPP and purine nucleotide synthesis in intact patient fibroblasts indicate that despite an intact allosteric mechanism of regulation of PRS activity, PRPS1 transcription is a major determinant of PRPP and purine synthesis. The genetic basis of disordered PRPS1 transcription remains unresolved; normal- and patient-derived PRPS1s share nucleotide sequence identity at least 850 base pairs 5' to the consensus transcription initiation site.

Allosteric Regulation↗

A polygenic risk score for peripheral artery disease and major adverse limb events.

BACKGROUND AND AIMS: Large-scale genome-wide association studies have identified common genetic variants that predict the risk of peripheral artery disease (PAD). This study assessed whether a polygenic risk score (PRS) is associated with PAD and the incidence of major adverse limb events (MALE) independent of clinical risk factors in patients with established cardiometabolic disease. METHODS: A genetic analysis was performed, pooling individual patient-level data from six TIMI trials. The association of a recently validated PAD PRS with prevalent PAD and the incidence of MALE (acute limb ischaemia, chronic limb-threatening ischaemia, major amputation, or peripheral revascularization) was assessed. RESULTS: A total of 68 816 patients were included in this analysis, with a median follow-up of 2.6 years. Of these, 5986 (8.7%) had known PAD at baseline. After adjusting for clinical risk factors, a higher PAD PRS was independently associated with a 15% greater odds of prevalent PAD (adjusted odds ratio per 1-SD: 1.15 [95% confidence interval 1.12-1.18], P < .0001), a magnitude of risk as strong as established clinical risk factors. A total of 577 patients experienced MALE during follow-up. A higher PAD PRS was associated with a 30% increased risk of MALE (adjusted hazard ratio per 1-SD: 1.30 [1.19-1.42], P < .0001). Adding the PAD PRS to clinical risk factors resulted in a statistically significant but modest improvement in discrimination (area under the curve went from 0.651 to 0.662 P < .0001). CONCLUSIONS: In a broad spectrum of patients with cardiometabolic disease, the PAD PRS is associated with an increased risk of PAD and the incidence of MALE beyond clinical risk factors; however, the improvement in discrimination was statistically significant but clinically modest.

Humans↗

Two Genomes, one Outcome: Stratifying Donor and Recipient Polygenic Risk Score to Improve Kidney Allograft Longevity.

Kidney transplantation outcomes arise from complex interactions among donor organ quality, recipient susceptibility, and immunologic compatibility, yet conventional clinical risk models explain only a modest fraction of outcome variability. Polygenic risk scores (PRS) offer a promising framework to enhance transplant risk assessment by integrating genome-wide genetic information from both donor and recipient into biologically informed models. This narrative review examines the mechanistic basis for PRS application in kidney transplantation and variant clustering approaches that link polygenic signals to specific biological pathways underlying alloimmunity, fibrosis, and metabolic dysfunction. We compare current PRS construction methodologies, highlighting their respective strengths and limitations in transplant cohorts. Transplant PRS are distinguished from single-genome disease models by their capacity to capture dual-genome interactions, simultaneously quantifying inherited donor organ liability and recipient genetic susceptibility within an integrated framework. This dual-genome architecture requires novel risk stratification paradigms in which combined donor-recipient polygenic profiles inform pretransplant decision-making in ways that neither genome alone can achieve. However, current PRS contribute only incremental variance beyond established clinical predictors, and critical limitations persist, including European ancestry bias, small cohort sizes, incomplete replication, and undefined clinical actionability thresholds. We critically evaluate these implementation barriers and outline future directions for integrating dual-genome PRS with clinical, molecular, and environmental data. The longer-term goal is to advance precision kidney transplantation through applications such as donor selection, immunosuppression tailoring, and individualized posttransplant surveillance. Realizing this potential will require validation in adequately powered, ancestry diverse, prospective transplant cohorts.

Journal Article↗

Evaluating the impact of modeling choices on the performance of integrated genetic and clinical models.

The value of genetic information for improving the performance of clinical risk prediction models has yielded variable conclusions. Many methodological decisions have the potential to contribute to differential results across studies. Here, we performed multiple modeling experiments integrating clinical and demographic data from electronic health records (EHR) and genetic data to understand which decision points may affect performance. Clinical data in the form of structured diagnostic codes, medications, procedural codes, and demographics were extracted from two large independent health systems and polygenic risk scores (PRS) were generated across all patients with genetic data in the corresponding biobanks. Crohn's disease was used as the model phenotype based on its substantial genetic component, established EHR-based definition, and sufficient prevalence for model training and testing. We investigated the impact of PRS integration method, as well as choices regarding training sample, model complexity, and performance metrics. Overall, our results show that including PRS resulted in higher performance by some metrics but the gain in performance was only robust when combined with demographic data alone. Improvements were inconsistent or negligible after including additional clinical information. The impact of genetic information on performance also varied by PRS integration method, with a small improvement in some cases from combining PRS with the output of a clinical model (late-fusion) compared to its inclusion an additional feature (early-fusion). The effects of other modeling decisions varied between institutions though performance increased with more compute-intensive models such as random forest. This work highlights the importance of considering methodological decision points in interpreting the impact on prediction performance when including PRS information in clinical models.

Preprint↗

A homeobox gene, PRESSED FLOWER, regulates lateral axis-dependent development of Arabidopsis flowers.

It is postulated that the symmetric organization of plant lateral organs is based on two crossed axes, the abaxial-adaxial and the lateral axes. The PRESSED FLOWER (PRS) gene, the expression and function of which are dependent on the lateral axis, is reported in this study. In the prs mutant, growth of the lateral sepals is repressed, and although the size and shape of the abaxial and adaxial sepals are normal, the cell files at the lateral margins are missing. Double-mutant analyses showed that the PRS gene functions independently of the determinations of both floral organ identity and floral meristem size. The PRS gene, encoding a putative transcriptional factor with a homeodomain, was shown to be required for cell proliferation. PRS gene expression is spatially and temporally unique and is expressed in a restricted number of L1 cells at the lateral regions of flower primordia, floral organ primordia, and young leaf primordia. Our study strongly suggests that the PRS gene is involved in the molecular mechanism of lateral axis-dependent development of lateral organs in Arabidopsis.

Alleles↗

Do presenters to paediatric meetings get their work published?

BACKGROUND: Research presented to a scientific meeting is inaccessible to clinicians, unless it is also published in a cited journal. AIMS: To assess the publication rate of studies presented to two UK national paediatric meetings: the Paediatric Research Society (PRS) and the British Paediatric Association (BPA). METHODS: A Medline search in December 1999 for the first authors of all plenary abstracts presented in 1996. If not found, authors contacted by postal questionnaire. RESULTS: Information was obtained on 88/89 presentations. Twenty five of 48 PRS and 31 of 40 BPA studies were published in Medline listed journals. The major reason for non-publication was that they had not been submitted (PRS 15/48, BPA 6/40). Some authors were still hoping to do so (PRS 7, BPA 2). Other reasons were: publication in other forms (theses, book chapters, non-Medline journals) (PRS 5, BPA 2), or still being reviewed (PRS 3, BPA 1). Ten of 11 randomised, controlled trials were published, but only 20 of 37 observational studies were submitted and published. CONCLUSION: Presenters to paediatric meetings need help in submitting and publishing their work.

Child↗

Microarray-based comparison of three amplification methods for nanogram amounts of total RNA.

Gene expression profiling using microarrays requires microgram amounts of RNA, which limits its direct application for the study of nanogram RNA samples obtained using microdissection, laser capture microscopy, or needle biopsy. A novel system based on Ribo-SPIA technology (RS, Ovation-Biotin amplification and labeling system) was recently introduced. The utility of the RS system, an optimized prototype system for picogram RNA samples (pRS), and two T7-based systems involving one or two rounds of amplification (One RA, Standard Protocol, or Two RA, Small Sample Prototcol, version II) were evaluated in the present study. Mouse kidney (MK) and mouse universal reference (MUR) RNA samples, 0.3 ng to 10 mug, were analyzed using high-density Affymetrix Mouse Genome 430 2.0 GeneChip arrays. Call concordance between replicates, correlations of signal intensity, signal intensity ratios, and minimal fold increase necessary for significance were determined. All systems amplified partially overlapping sets of genes with similar signal intensity correlations. pRS amplified the highest number of genes from 10-ng RNA samples. We detected 24 of 26 genes verified by RT-PCR in samples prepared using pRS. Two RA yielded somewhat higher call concordances than did RS and pRS (91.8% vs. 89.3% and 88.1%, respectively). Although all target preparation methods were suitable, pRS amplified the highest number of targets and was found to be suitable for amplification of as little as 0.3 ng of total RNA. In addition, RS and pRS were faster and simpler to use than the T7-based methods and resulted in the generation of cDNA, which is more stable than cRNA.

Animals↗

Evaluation of Multiple Breast Cancer Polygenic Risk Score Panels in Women of Latin American Heritage.

BACKGROUND: A substantial portion of the genetic predisposition for breast cancer is explained by multiple common genetic variants of relatively small effect. A subset of these variants, which have been identified mostly in individuals of European (EUR) and Asian ancestries, have been combined to construct a polygenic risk score (PRS) to predict breast cancer risk, but the prediction accuracy of existing PRSs in Hispanic/Latinx individuals (H/L) remain relatively low. We assessed the performance of several existing PRS panels with and without addition of H/L-specific variants among self-reported H/L women. METHODS: PRS performance was evaluated using multivariable logistic regression and the area under the ROC curve. RESULTS: Both EUR and Asian PRSs performed worse in H/L samples compared with original reports. The best EUR PRS performed better than the best Asian PRS in pooled H/L samples. EUR PRSs had decreased performance with increasing Indigenous American (IA) ancestry, while Asian PRSs had increased performance with increasing IA ancestry. The addition of two H/L SNPs increased performance for all PRSs, most notably in the samples with high IA ancestry, and did not impact the performance of PRSs in individuals with lower IA ancestry. CONCLUSIONS: A single PRS that incorporates risk variants relevant to the multiple ancestral components of individuals from Latin America, instead of a set of ancestry-specific panels, could be used in clinical practice. IMPACT: The results highlight the importance of population-specific discovery and suggest a straightforward approach to integrate ancestry-specific variants into PRSs for clinical application.

Adult↗

Stereotactic interstitial radiosurgery with a miniature X-ray device in the minimally invasive treatment of selected tumors in the thalamus and the basal Ganglia.

The aim of this study was to evaluate the role of interstitial radiosurgery (IR) using the photon radiosurgery system (PRS) in the treatment of selected tumors within the thalamus and the basal ganglia. The PRS is a miniature X-ray generator that was developed for interstitial irradiation. This series included 14 patients (5 with glioblastomas, 4 with low-grade astrocytomas and 5 with metastases) harboring spheroidal lesions with dimensions ranging from 13 to 42 mm (mean 30 mm). After stereotactic biopsy, a radiation dose ranging from 6 to 15.4 Gy (mean 11.3 Gy) was delivered at the target volume margins. Follow-up varied from 3 to 26 months (mean 10.2 months). In the group of glioblastomas, 3 patients died (3-12 months after the procedure) because of tumor progression, while the remaining had tumor control. Two patients with metastases died from systemic disease (4-9 months after the treatment), and 3 were alive and well at the end of the study. Local control was achieved in all metastases. Patients with low-grade astrocytomas were well and imaging studies showed tumor control PRS IR is a minimally invasive procedure for the treatment of selected glial or secondary brain tumors. Compared to conventional radiosurgery (brachytherapy and external radiosurgery), PRS IR presents dose delivery characteristics useful for the treatment of tumors in the thalamus and basal ganglia, without inconveniences such as handling radioisotopes, the need of expensive facilities and radiation protection measures. Although the clinical value needs further investigations, PRS IR seems to be effective in metastases while it provides less benefit in malignant gliomas. PRS IR could have a major role in the treatment of low-grade astrocytomas.

Adolescent↗

Convergent and criterion-related validity of the Behavior Assessment System for Children-Parent Rating Scale.

Examined aspects of the validity of the Behavior Assessment System for Children (BASC; Reynolds & Kamphaus, 1992) Parent Rating Scale (BASC-PRS) in 156 children with cross-setting disruptive behavior. The BASC-PRS is a recently published multidimensional measure composed of conceptually derived scales created for use in conjunction with psychiatric and educational classification systems. Convergent validity was assessed through correlations of BASC-PRS scale scores with scale scores on the Child Behavior Checklist/4-18 (CBCL/4-18; Achenbach, 1991b). Criterion-related validity was evaluated as the ability of BASC-PRS and CBCL/4-18 scales to predict membership in diagnostic groupings (no diagnosis, attention deficit hyperactivity disorder [ADHD] only, and ADHD with a comorbid externalizing disorder) derived via structured interviews based on the third, revised edition of the Diagnostic and Statistical Manual of Mental Disorders (American Psychiatric Association, 1987). Results showed the validity of the BASC-PRS to be comparable to that of the CBCL/4-18. Given its conceptually derived scales, the BASC-PRS may prove to be a useful-tool for assessing childhood disruptive behavior.

Attention Deficit Disorder with Hyperactivity↗

Corepressor binding to progesterone and glucocorticoid receptors involves the activation function-1 domain and is inhibited by molybdate.

Corepressors are known to interact via their receptor interaction domains (RIDs) with the ligand binding domain in the carboxyl terminal half of steroid/nuclear receptors. We now report that a portion of the activation function-1 domain of glucocorticoid receptors (GRs) and progesterone receptors (PRs), which is the major transactivation sequence, is necessary but not sufficient for corepressor [nuclear receptor corepressor (NCoR) and silencing mediator of retinoid and thyroid hormone receptor (SMRT)] RID binding to GRs and PRs in both mammalian two-hybrid and coimmunoprecipitation assays. Importantly, these two receptor sequences are functionally interchangeable in the context of GR for transactivation, corepressor binding, and corepressor modulatory activity assays. This suggests that corepressors may act in part by physically blocking portions of receptor activation function-1 domains. However, differences exist in corepressor binding to GRs and PRs. The C-terminal domain of PRs has a higher affinity for corepressor than that of GRs. The ability of some segments of the coactivator TIF2 to competitively inhibit corepressor binding to receptors is different for GRs and PRs. With each receptor, the cell-free binding of corepressors to ligand-free receptor is prevented by sodium molybdate, which is a well-known inhibitor of receptor activation to the DNA-binding state. This suggests that receptor activation precedes binding to corepressors. Collectively, these results indicate that corepressor binding to GRs and PRs involve both N- and C-terminal sequences of activated receptors but differ in ways that may contribute to the unique biological responses of each receptor in intact cells.

Animals↗

Processes of care: comparison between nurse practitioners and physician residents in acute care.

The purpose of this study was to compare the processes of care (performance of role functions, provision of comprehensive care, coordination of services) of acute care nurse practitioners (ACNPs) and physician residents (PRs) assigned to various medical and surgical programs in acute care settings. A cross-sectional comparative design was used. ACNPs (n = 31) and PRs (n = 10) completed the study questionnaire within two weeks of consenting. Patients who received ACNP care (n = 320) and those who received PR care (n = 46) completed the questionnaire within one week of discharge. The results indicate that ACNPs engaged in management and informal coordination activities more than PRs did, while PRs engaged in more formal coordination activities compared to ACNPs. ACNPs encouraged more patient participation in care and provided more patient education than PRs. These findings, which reflect differences in the processes used by ACNPs and PRs to provide care to patients, could influence the quality and cost outcomes expected of these two groups of healthcare providers.

Acute Disease↗

[Studies on the renin-angiotensin system in adrenal regeneration hypertension (author's transl)].

1) To clarify the role of adrenal enucleation on plasma renin activity (PRA), plasma renin substrate (PRS), PRA response to furosemide administration and vacular reaction to renin in adrenal regeneration hypertension (ARH), serial changes of PRA and PRS during adrenal regeneration, PRA response to furosemide administration, and pressor response to exogenous renin in ARH were investigated by comparison with those of intact rats, unilaterally adrenalectomized rats, and unilaterally nephroadrenalectomized rats with contralateral adrenalectomy or with contralateral adrenal exploration (control) on both tap water and high sodium intake. 2) The control rats drinking saline, when compared with intact rats drinking tap water, showed significant decreases in PRA and, concomitantly, significant increases in PRS throughout the experimental period. In the unilaterally nephroadrenalectomized rats drinking saline, two days after adrenal enucleation or adrenalectomy, a significant increase in PRA, with a concomitant decrease in PRS, was observed. Those changes were less pronounced in the adrenal enucleated group than in the adrenalectomized group. Ten days later PRA markedly decreased to the control level in both groups. PRS rose to the control level on the 10th day after adrenal enucleation without increasing further, while that in the adrenalectomized group remained as low as before. 3) No significant differences in any of the experimental groups were found in diuresis, natriuresis, or in changes in body weight and hematocrit during the one and a half hours after furosemide administration performed at the 9th experimental week. The basal PRA was significantly decreased in the other groups with unilateral nephroadrenalectomy and/or a high sodium intake as compared with the unilaterally adrenalectomized rats drinking tap water. The decrease in basal PRA was much more pronounced in the unilaterally nephroadrenalectomized rats drinking saline, with or without adrenal enucleation. After furosemide administration, PRA significantly increased in the unilaterally adrenalectomized rats drinking saline as well as in the unilaterally nephroadrenalectomized rats drinking tap water, with or without adrenal enucleation, while PRA values in three groups were only a half of the unilaterally adrenalectomized rats drinking tap water. An insignificant increase was found in the unilaterally nephroadrenalectomized rats drinking saline, independent of adrenall enucleation. 4) Pressor responses to hog renin in rats with ARH at the 10th postoperative day, and the 4th and 9th postoperative week did not show any significant differences as compared with those of intact rats drinking tap water and unilaterally nephroadrenalectomized rats drinking saline. 5) The effects of adrenal enucleation on PRA, PRS, PRA response to furosemide administration and pressor response to renin in ARH were discussed based on the observed results.

Adrenal Glands↗

Evaluation of population-specific polygenic risk scores for blood lipids: insights from Taiwanese cohorts and multiancestry meta-analysis.

BACKGROUND: Blood lipids are heritable risk factors for cardiovascular disease (CVD), a leading cause of mortality worldwide. However, the genetic architecture of lipid traits and the performance of polygenic risk scores (PRSs) remain underexplored in East Asian (EAS) populations, including Taiwanese Han individuals. METHODS: We conducted genome-wide association studies and PRS analyses for five lipid traits: total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, and the ratio of low-density lipoprotein cholesterol to total cholesterol. Lipid profile data were obtained from the China Medical University Hospital cohort. PRSs were evaluated on the basis of their correlations with measured lipid levels. To evaluate trans-ancestry PRS transferability, localized models were systematically compared against models derived from discovery-stage GWAS meta-analyses incorporating five ancestry groups from the Global Lipids Genetics Consortium. The performance of the PRS models in predicting lipid-related diseases was evaluated through receiver operating characteristic curve analyses. RESULTS: The population-specific PRS models explained 11%-40% of the variance in lipid levels within the target cohort. Models leveraging global multiancestry GWAS meta-analysis weights revealed limited predictive performance (r 2 = 0.04-0.19), whereas analyses incorporating EAS-specific data yielded higher correlations (r 2 = 0.13-0.30), although these correlations did not exceed those derived from the hospital-based cohort alone. When combined with age and sex, the PRS models demonstrated strong predictive performance for coronary artery disease, atherosclerosis, and ischemic stroke, with area under the curve values of 0.910, 0.926, and 0.854, respectively. CONCLUSION: Population-specific PRS models derived from a Taiwanese population outperformed meta-analysis-derived frameworks in predicting lipid levels and demonstrated substantial potential for predicting CVD risk, indicating the importance of ancestry-matched genetic studies in precision medicine.

LDL-C/TC ratio↗

Association of Genetic Liability to Psychiatric Disorders with Peripheral Metabolic Dysregulation.

IMPORTANCE: Individuals with psychiatric disorders face elevated cardiometabolic risk which is linked to increased mortality. The extent to which this reflects shared pathogenesis or the downstream effects of illness and treatment remains poorly understood. OBJECTIVE: To characterize the direct pleiotropic effects of psychiatric genetic liability on circulating metabolites and aggregate cardiometabolic risk, independent of psychiatric diagnosis and psychotropic medication use. DESIGN SETTING AND PARTICIPANTS: Cross-sectional analysis of Mass General Brigham Biobank participants with metabolomic profiling, genomic data, and linked electronic health records. EXPOSURES: Genetic liability to nine psychiatric disorders quantified using polygenic risk scores (PRS): attention deficit/hyperactivity disorder (ADHD), anorexia nervosa (ANO), anxiety disorder (ANX), autism spectrum disorder (ASD), bipolar disorder (BD), major depressive disorder (MDD), PTSD, schizophrenia (SCZ), and substance use disorder (SUD). MAIN OUTCOMES AND MEASURES: 249 circulating metabolites and four metabolomic risk scores (MRS) for type 2 diabetes, myocardial infarction, ischemic stroke, and vascular dementia. PRS-metabolite associations were estimated using nested models adjusting for lifetime psychiatric diagnosis and psychotropic medication use. RESULTS: Across 25,290 participants, we identified 604 significant PRS-metabolite associations (Bonferroni p< 1.36 x 10-4), of which 89% persisted after adjustment for lifetime diagnosis and medication use, suggesting that the direct genetic effects on metabolism are largely independent of illness or treatment. PRS for MDD, PTSD, and ADHD showed the most extensive dysregulation, with a transdiagnostic pattern of elevated lipids and systemic inflammation, specifically triglycerides (&#x3b2; = 0.04 to 0.05, all p< 4.4 x10-13) and glycoprotein acetyls (&#x3b2; = 0.05, all p< 2.2 x10-16). Notably, PRS for SCZ and BD showed minimal metabolite dysregulation despite having the strongest association with their target diagnoses. PRS for MDD, PTSD, ADHD, and SUD were associated with increased MRS across cardiometabolic conditions (&#x3b2; = 0.03 to 0.08, all p< 2.1 x10-4). Sensitivity analyses controlling for BMI or excluding participants without any psychiatric history (N: 21,305 and 11,150, respectively) showed a similar pattern. CONCLUSIONS AND RELEVANCE: Psychiatric genetic liability is associated with systemic metabolic dysregulation independent of illness onset or treatment, supporting a partially pleiotropic basis for psychiatric-cardiometabolic comorbidity.

Journal Article↗

The HIV/AIDS Prevention Research Synthesis Project: scope, methods, and study classification results.

In 1996, the Centers for Disease Control and Prevention (CDC), in collaboration with many partners, initiated the HIV/AIDS Prevention Research Synthesis (PRS) project to accumulate HIV prevention research studies and analyze their effectiveness in reducing sexual and drug-related risk behaviors for HIV transmission. The PRS team developed standardized guidelines and procedures for the systematic reviews, conducted systematic searches for pertinent studies, characterized the selected studies, analyzed effectiveness data, and established a cumulative database. As of June 1998, the database contained more than 5000 reports: 4068 were reports that met the PRS scope criteria for inclusion and 586 of those reports contained outcome data from an intervention study. Of the 586 reports that included outcome data, 276 have been reviewed: 223 (81%) included measures of PRS-specified behavioral or biologic HIV-related outcomes, and 124 of the 223 (56%) used PRS-defined rigorous study designs. The PRS database is a valuable resource for accessing and integrating the literature on HIV prevention research. CDC is committed to 1) updating the database; 2) producing systematic reviews, including meta-analyses, related to key research questions; and 3) disseminating findings to encourage and facilitate the use of science-based research in preventing HIV infection.

Acquired Immunodeficiency Syndrome↗

[Effect of tegaserod on the serotonin content in rat ileocaecal mucosa under partial restraint stress].

OBJECTIVE: To investigate the content and distribution of serotonin in the ileocecal mucosa of rats under partial restraint stress (PRS) and to study the effect of tegaserod on the content of serotonin in the positive cells. METHODS: Male Wistar rats (n = 24) were divided into three test groups. After sham-stress (control group) or PRS had been applied to the rats for two hours, 1-methyl-2-pyrrolidinone (solvent) or tegaserod (a partial 5-HT(4) receptor agonist) was administered intra-peritoneally to the corresponding groups. The cellular distribution and quantitative analysis of 5-HT in the ileocecal mucosa were achieved with immunohistochemical method and computerized image system. The 5-HT content of individual enterochromaffin cells (EC) in tegaserod group and PRS group were observed with immunoelectron microscopic technique. RESULTS: Serotonin immunoreactivity was mainly found in the epithelium and lamina propria of the mucosa. As compared with the control group, the optical density of serotonin-immunoreactive cells in ileocecal mucosa decreased in the PRS rats (0.326 +/- 0.035 vs 0.362 +/- 0.042, P < 0.001), the optical density of serotonin-immunoreactive cells in ileocecal mucosa in the tegaserod group (0.364 +/- 0.033) was much higher than in the PRS rats (P < 0.001). Immunoelectron microscopic study showed that in the tegaserod group, EC in the epithelium contained more serotonin-positive secretary granules than in the PRS rats. CONCLUSIONS: The increased 5-HT release of positive cells in gut mucosa may be partly responsible for visceral hypersensitivity. The effect of tegaserod on visceral hypersensitivity, at least in part, is likely to act through the pathway involving regulation of gastrointestinal 5-HT release.

Animals↗

Comparative morphology of the eyes of Sagitta (Chaetognatha) in relation to depth of habitat.

A survey of the eye structure in 10 species of Sagitta (phylum Chaetognatha) which differ in habitat was carried out: 5 epipelagic, 4 mesopelagic and 1 bathypelagic species. Paying attention to the dimension of the pigment cell, and assuming that the perforated lamellae are the photoreceptive regions (PRs), we classified the eyes of the 10 species into 5 types. In type I and II eyes there is one large pigment cell. The maximum length of the pigment cell relative to that of the eye (PC/E) is more than 30% in dorsal view and more than 50% in transverse sections. The pigment cell is surrounded by a wide area of the PR that we designated "central PR". The type II eye possesses, in addition, near the periphery of the eye, masses of PRs which measure about 15% of the central one in size. We call these positionally separated PRs "peripheral PR". In type III eyes the pigment cell and the central PR are small (PC/E is about 10% in dorsal view and less than 40% in transverse sections) and the peripheral PRs are scattered. In type IV eye the pigment cell is also small and the central PRs extend to the periphery. In type V eye the pigment cell is absent and the PR occupies a wide area of the dorsal half of the eye. The type I and II eyes were found mostly in epipelagic species, the type III and IV, in mesopelagic species, and the type V, in bathypelagic species. The adaptational significance of the small pigment cells, the peripheral PRs, and the pigmentless eye is discussed. In addition, we report a new type of photoreceptive cell in mesopelagic Sagitta zetesios, in which two receptoral processes emerge from single cells, in contrast to one in all the other species of Sagitta.

Animals↗