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PubMed1996

A reevaluation of the cap-binding protein, eIF4E, as a rate-limiting factor for initiation of translation in reticulocyte lysate.

The cap-binding eukaryotic initiation factor, eIF4E, is a key target for the regulation of translation in mammalian cells and is widely thought to be present at very low molar concentrations. Here we present observations with the reticulocyte lysate that challenge this view. When reticulocyte ribosomes are harvested by centrifugation, most (approximately 75%) of the eIF4E remains in the postribosomal supernatant (PRS). In a reconstituted translation system we find that the ribosome-associated eIF4E alone can sustain much of the overall activity, suggesting that much of the factor in the PRS is functionally redundant. Consistent with this, our estimates of eIF4E in the reticulocyte lysate reveal much higher concentrations than previously reported. The association of a small proportion of eIF4E with the ribosome fraction appears to be functional and dependent on interaction with the factor eIF4G. This fraction of eIF4E is, as expected, more highly phosphorylated than that in the PRS; however, at least half the total phosphorylated eIF4E in reticulocyte lysate translation systems resides in the PRS fraction, suggesting that, while phosphorylation may enhance activity, it is not in itself sufficient to promote utilization of the factor. We also show that the eIF4E-binding factor, eIF4E-BP1 or PHAS-I, which regulates eIF4E activity in insulin-responsive cells, is present in the reticulocyte PRS at an approximately 1:1 molar ratio relative to eIF4E and demonstrate by co-immunoprecipitation studies that the binding of PHAS-I and eIF4G to eIF4E is mutually exclusive. These data are consistent with a potential regulatory role for PHAS-I in the reticulocyte lysate.

Amino Acid Sequence↗

PubMed1996

Treatment of metastatic melanoma with combined chemotherapy containing cisplatin, vinblastine and dacarbazine (CVD) and biotherapy using interleukin-2 and interferon-alpha.

BACKGROUND: Metastatic melanoma is commonly treated with chemotherapy and/or biological agents used separately. In this study we have investigated the efficacy of combined chemotherapy using cisplatin, vinblastine, DTIC (CVD) and biological therapy using interleukin-2 (IL-2) and interferon-alpha (IFN-alpha) in patients with metastatic melanoma. PATIENTS AND METHODS: All patients had advanced, inoperable melanoma without prior treatment with chemotherapy or biotherapy, a performance status of ECOG 0-2 and no evidence of symptomatic brain metastases. The CVD regimen consisted of cisplatin 20 mg/m2/d x 4, vinblastine 1.6 mg/m2/d x 5 and DTIC 800 mg/m2 x 1, repeated at 21-day intervals. The biotherapy regimen included IL-2, 9 x 10(6) IU/ m2/d x 4 days and IFN-alpha 5 x 10(6) U/m2/d SC x 5 days. The CVD and biotherapy regimens were integrated initially, in an alternating manner at 6-week intervals and subsequently, in a sequential fashion where patients were randomized to receive either CVD immediately followed by biotherapy (CVD/Bio) or the reverse sequence (Bio/CVD). Patients were admitted to the hospital for IL-2 administration and for monitoring and treatment of IL-2 induced side effects. The phase II results of the integrated therapy (biochemotherapy) studies were retrospectively compared to our previously reported results with the CVD regimen used alone. RESULTS: The alternating biochemotherapy program was used in 40 patients and the sequential biochemotherapy was used in 62 patients. The alternating regimen produced 2 CRs and 11 PRs for an overall response rate of 33% among 39 evaluable patients. The sequential biochemotherapy produced 14 CRs and 23 PRs for an overall response rate of 60% (95% CI, 47% to 72%). The sequence of CVD/Bio resulted in a higher response rate (11 CRs + 11 PRs (69%)) compared to the Bio/CVD sequence (3 CRs + 12 PRs (50%)). Although the duration of PRs was short (median, 8 months), the median duration of CRs was 3+years and 10 of 16 CRs are currently disease free for periods of 3+ to 6+ years. The median survival of patients receiving sequential biochemotherapy was 13 months compared to 9 months for the CVD treated group (P = 0.04). Treatment with biochemotherapy was associated with severe toxicity including intense myelosuppression, infections, IL-2 induced constitutional toxicity and hypotension. However, the IL-2 induced toxicities were generally manageable on a regular ward, except for 15% of the patients who required transfer to an intensive care unit for treatment of complications associated with the treatment. CONCLUSIONS: The sequential combination of CVD with IL-2 + IFN-alpha appears to have produced an increase in the number of durable responses in patients with metastatic melanoma. The toxicity of this program, although severe, was manageable. The biochemotherapy regimen produced an apparent increase in the median survival compared to that observed with the CVD regimen. However, a prospective comparison of these two regimens will be required to confirm these observations.

Adult↗

PubMed2025

Genetic Differences in Reactivity to the Environment Impact Psychotic-Like and Affective Reactivity in Daily Life.

BACKGROUND AND HYPOTHESIS: Consistent with diathesis-stress models, psychosis research has focused on genetic moderation of adverse environmental exposures. In contrast, the Differential Susceptibility (DS) model suggests that the same genetic variants that increase risk-inducing effects of adverse experiences also enhance beneficial effects from positive experiences. This study examined whether individuals with high genetic susceptibility to the environment showed differential psychotic-like and affective reactivity in response to positive and negative events in daily life. STUDY DESIGN: Experience sampling methodology assessed context (positive and stressful) and momentary levels of paranoia, psychotic-like experiences (PLE), and positive (PA) and negative affect (NA) in 217 non-clinical adults oversampled for schizotypy. Linear mixed models examined whether Polygenic Risk Scores of Environmental Sensitivity (PRS-ES) moderated the impact of current context on subsequent experiences. STUDY RESULTS: PRS-ES moderated positive, but not stressful, context on subsequent levels of momentary paranoia, NA, and PA, but not PLE. Genetic and environmental (G × E) interactions indicated diathesis-stress at lower thresholds of PRS-ES, but a DS model at the highest threshold of the PRS-ES. Participants with elevated PRS-ES showed increased paranoia and NA and decreased PA in subsequent assessments when reporting low levels of positive situations, but also decreased paranoia and NA and increased PA when rating contexts as positive. CONCLUSIONS: Findings support the influence of genetic sensitivity to the environment on psychotic-like and affective reactivity in daily life, particularly in response to positive contexts. This highlights the transdiagnostic protective role of positive experiences and informs ecological momentary interventions.

Humans↗

PubMed1996

Estrogen and progesterone receptor expression in endometrial polyps.

Endometrial polyps are a frequent cause of abnormal uterine bleeding, but their pathogenesis is poorly understood. This study was undertaken to investigate if endometrial polyps result from localized overexpression of estrogen receptors (ERs) or reduced expression of progesterone receptors (PRs). Fourteen cases of endometrial polyps, in which normal cycling endometrium was also present on the same slide, were immunostained for ERs and PRs. Percentages of positive cells in glands and stroma for each receptor were subjectively assessed to the nearest 5%. The intensity of staining was recorded on a scale from 1+ to 4+. The level and intensity of staining in polyps were compared with the staining in normal endometrium. Fewer stromal cells in polyps expressed ERs and PRs compared with cycling endometrium (% ER = 55.9 +/- 25.8 vs. 74.3 +/- 25.8, p = 0.03; % PR = 56.1 +/- 28.2 vs. 87.5 +/- 10.1, p = 0.002). Stroma in polyps also had significantly reduced intensity of staining for PRs, but not for ERs (intensity PR = 2.7 +/- 1.4 vs. 3.5 +/- 0.7, p = 0.015; intensity ER = 2.1 +/- 0.7 vs. 2.4 +/- 0.8, p = 0.45). There were no significant differences in expression of ERs and PRs in the endometrial glands in endometrial polyps compared with normal endometrium (% ER = 75.4 +/- 32.5 vs. 70.7 +/- 39.2. p = 0.25; % PR = 79.6 +/- 32.8 vs. 80.4 +/- 34.4, p = 0.8; intensity ER = 2.7 +/- 0.9 vs. 2.4 +/- 1, p = 0.15; intensity PR = 2.9 +/- 1.4 vs. 3.4 +/- 0.7, p = 0.15). We conclude that endometrial polyps may result from a decrease in ER and PR expression in stromal cells. Because of these receptor-negative stromal cells, endometrial polyps may be relatively insensitive to cyclic hormonal changes.

Adult↗

PubMed1999

Pierre Robin sequences: secondary respiratory difficulties and intrinsic feeding abnormalities.

OBJECTIVE: There is considerable variation in opinion regarding the optimal management of patients with Pierre Robin sequence (PRS). No single method of airway intervention or feeding strategy is universally appropriate and effective. This study was performed to examine methods used for airway and feeding management and to identify specific problems encountered. STUDY DESIGN: A retrospective study of 252 patient charts between 1989 and 1997 at Children's Hospital of Wisconsin. METHODS: Patient information was collected regarding perinatal history, genetics evaluation, and airway and feeding evaluations and intervention. A group of 47 patients was determined as having PRS. RESULTS: Secondary respiratory difficulties, defined as respiratory abnormalities in addition to the expected PRS obstruction, were identified in 23% of patients. Also, intrinsic feeding abnormalities not associated with airway obstruction were identified in 11% of patients. Analysis by Fisher's Exact Test revealed patients with a syndromic diagnosis to have a significantly higher rate for tracheotomies and gastrostomy tube placement (P = .041, and P = .0004, respectively). Syndromic patients were also found to have significantly lower Apgar scores and longer hospital stays. Positioning techniques, tongue-lip adhesion, and tracheotomy were also employed effectively with specific indications and specific difficulties that need to be considered. CONCLUSION: Patients with PRS require thorough airway and feeding evaluation. Those with additional syndromic diagnoses demonstrate higher rates of more invasive interventions. Patients with PRS must undergo individualized approaches with consideration of multiple factors for successful management.

Apgar Score↗

PubMed1997

Randomized controlled trial to evaluate flush and reperfusion techniques in liver transplantation.

To determine the impact of different flush and reperfusion techniques on postreperfusion syndrome (PRS) and postoperative graft function, 100 transplants were randomly assigned into four groups as follows: group 1 (n=31), portal vein flush, no vena caval venting; group 2 (n=21), hepatic arterial flush, no vena caval venting; group 3 (n=29), portal vein flush with vena caval venting; and group 4 (n=19), hepatic artery flush with vena caval venting. Donor and recipient characteristics were similar. Extensive intraoperative and postoperative monitoring was performed and measurements were documented immediately before reperfusion and at 1, 5, 15, and 30 min after reperfusion. PRS was defined by three criteria: mean arterial pressure (MAP) <60 mmHg at 1 min after reperfusion, MAP <60 mmHg at 5 min after reperfusion, and a decrease of 30% or more for the MAP percent area under the curve during the initial 5 min after reperfusion (%AUC). Using these definitions, the overall incidence of PRS was 21%, 8%, and 43%, respectively. Group 1 was the most hemodynamically stable; the incidence of PRS in group 1 was 2/31 (7%) at 1 min and 8/31 (25%) using %AUC criteria compared with 7/21 (33%) at 1 min and 12/21 (57%) using %AUC criteria for group 2 (P<0.05). The patients in groups 3 and 4 (vena caval venting) demonstrated smaller percentage increases in serum potassium levels (as determined by %AUC; 4.3+/-6.8 and 0.3+/-5.4, vs. 15.1+/-8.1 for group 1 and 22.9+/-8.2 for group 2). The difference between group 4 and group 2 was statistically significant (P<0.05). The increases in serum potassium did not translate into increased cardiac or hemodynamic instability. Combining all data obtained over the first 30 min after reperfusion, there was no statistically significant difference in hemodynamic or biochemical changes noted among the four groups. Postoperative liver function was similar among the four groups. We conclude that portal vein flush without vena caval venting provided a lower incidence of PRS than any other technique. Vena caval venting decreased the release of potassium into the circulation. Postoperative graft function was not significantly affected by flush and reperfusion techniques.

Adult↗

PubMed2004

Preliminary crystallographic analysis of sugar cane phosphoribosylpyrophosphate synthase.

Phosphoribosylpyrophosphate synthases (PRS; EC 2.7.6.1) are enzymes that are of central importance in several metabolic pathways in all cells. The sugar cane PRS enzyme contains 328 amino acids with a molecular weight of 36.6 kDa and represents the first plant PRS to be crystallized, as well as the first phosphate-independent PRS to be studied in molecular detail. Sugar cane PRS was overexpressed in Escherichia coli, purified and crystallized using the hanging-drop vapour-diffusion method. Using X-ray diffraction experiments it was determined that the crystals belong to the orthorhombic system, with space group P2(1)2(1)2 and unit-cell parameters a = 213.2, b = 152.6, c = 149.3 A. The crystals diffract to a maximum resolution of 3.3 A and a complete data set to 3.5 A resolution was collected and analysed.

Escherichia coli↗

PubMed1978

Plasma renin substrate sensitivity to oestrogens and oestrogen metabolism in cirrhosis.

Oestrogen stimulation of plasma renin substrate (PRS) was studied in men with alcoholic cirrhosis. PRS values, before and 1, 2, 4 and 6 days after a single oral administration of 100 microgram of an oestrogen derivative, 11beta-methoxy-17-ethynyl-1,3,5(10)-estratriene-3,17beta-diol (Moxestrol), were measured by radioimmunoassay of generated angiotensin I in five men with normal liver function and five men with alcoholic cirrhosis. Basal PRS was 0.93 +/- 0.22 nmol/ml (mean +/- 1 SD) in the normal men and significantly lower (P less than 0.01) in the men with cirrhosis (0.33 +/- 0.14 nmol/ml). Two days after administration of Moxestrol, PRS rose significantly but transiently (P less than 0.05) to 1.41 +/- 0.42 nmol/ml in the normal men and to 0.47 +/- 0.15 in the cirrhotic men, the relative increase (approximately 50%) being similar in both groups. A study of the plasma kinetics and urinary excretion of Moxestrol was also performed to evaluate its metabolic clearance rate and absorption. Since the intestinal absorption of [14C] Moxestrol was not depressed in cirrhotic men, the low PRS values recorded are probably the consequence of hepatocyte dysfunction.

Adult↗

PubMed1999

REM sleep components predict the response to initial treatment of infantile spasms.

PURPOSE: The phasic inhibition index (PII) is the rate of the simultaneous occurrence of rapid eye movement bursts (RBs) and phasic chin muscle activity (PCMA) during rapid eye movement sleep (REMS). PII is low insofar as physiologically occurring REM-related phasic inhibition acts on chin muscles. Previously we found that PII was significantly higher in patients with infantile spasms (ISs) who had a recurrence of convulsions than in patients with ISs who exhibited no recurrence. We aimed to predict the response of patients with ISs to conventional anticonvulsants (AEDs) by means of REMS components including PII, expecting to facilitate avoidance of potentially hazardous hormonal therapy. METHODS: REMS, recorded before the beginning of any medication, was retrospectively examined in 15 patients with ISs. The patients were classified into two groups according to the response to initial treatment with conventional AEDs. Conventional AEDs were enough to control the spasms in six good responders (GRs), whereas further hormonal therapy was required in nine poor responders (PRs) to control the spasms. RESULTS: The amount of REMS was significantly lower in patients with ISs than in controls. GRs had less REMS than did PRs, although no significant difference was observed. Although the frequencies of RB and PCMA showed no significant differences among GRs, PRs, and controls, the average PII value in PRs (12.6+/-3.4; mean+/-SD) was significantly (p < 0.001) higher than that in GRs (6.1+/-1.7). CONCLUSIONS: PII is a useful parameter for differentiating GRs from PRs.

Anticonvulsants↗

PubMed2001

Molecular basis for the relative substrate specificity of human immunodeficiency virus type 1 and feline immunodeficiency virus proteases.

We have used a random hexamer phage library to delineate similarities and differences between the substrate specificities of human immunodeficiency virus type 1 (HIV-1) and feline immunodeficiency virus (FIV) proteases (PRs). Peptide sequences were identified that were specifically cleaved by each protease, as well as sequences cleaved equally well by both enzymes. Based on amino acid distinctions within the P3-P3' region of substrates that appeared to correlate with these cleavage specificities, we prepared a series of synthetic peptides within the framework of a peptide sequence cleaved with essentially the same efficiency by both HIV-1 and FIV PRs, Ac-KSGVF/VVNGLVK-NH(2) (arrow denotes cleavage site). We used the resultant peptide set to assess the influence of specific amino acid substitutions on the cleavage characteristics of the two proteases. The findings show that when Asn is substituted for Val at the P2 position, HIV-1 PR cleaves the substrate at a much greater rate than does FIV PR. Likewise, Glu or Gln substituted for Val at the P2' position also yields peptides specifically susceptible to HIV-1 PR. In contrast, when Ser is substituted for Val at P1', FIV PR cleaves the substrate at a much higher rate than does HIV-1 PR. In addition, Asn or Gln at the P1 position, in combination with an appropriate P3 amino acid, Arg, also strongly favors cleavage by FIV PR over HIV PR. Structural analysis identified several protease residues likely to dictate the observed specificity differences. Interestingly, HIV PR Asp30 (Ile-35 in FIV PR), which influences specificity at the S2 and S2' subsites, and HIV-1 PR Pro-81 and Val-82 (Ile-98 and Gln-99 in FIV PR), which influence specificity at the S1 and S1' subsites, are residues which are often involved in development of drug resistance in HIV-1 protease. The peptide substrate KSGVF/VVNGK, cleaved by both PRs, was used as a template for the design of a reduced amide inhibitor, Ac-GSGVF Psi(CH(2)NH)VVNGL-NH(2.) This compound inhibited both FIV and HIV-1 PRs with approximately equal efficiency. These findings establish a molecular basis for distinctions in substrate specificity between human and feline lentivirus PRs and offer a framework for development of efficient broad-based inhibitors.

Amino Acid Substitution↗

PubMed1991

Factors influencing plasma renin and renin substrate in premature infants.

Concentrations of plasma renin (PRC) and plasma renin substrate (PRS) were measured during the first week of life in 52 infants born at less than 37 weeks' gestation (mean (SEM) gestation 30 (0.4) weeks, mean (SEM) birth weight 1.35 (0.08) kg). Both PRC (median 35, interquartiles 16.3, 94.5 ng/ml/hour) and PRS (median 2.3, interquartiles 1.3, 5.0 micrograms/ml) were raised compared with adults. The proportional rise in PRC was much greater than that in PRS, suggesting that PRS may be rate limiting in the generation of angiotensin I. Log10 PRC was inversely proportional to gestational age and a high urinary sodium loss was associated with a significantly raised log10 PRC. In hypoxaemic infants, there was a strong correlation between log10 PRS and haemoglobin concentration; this is a new observation in human infants but consistent with data available from other species.

Angiotensinogen↗

PubMed1980

Observations on plasma renin substrate in the nephrotic syndrome.

Literature data on renin in the nephrotic syndrome are conflicting: renin values are reported to be elevated as the rule, but sometimes normal or low; data on renin substrate are scanty and pointing to low values. In the present study, plasma renin activity (PRA) and plasma renin substrates (PRS) were measured in 27 episodes of the nephrotic phase in 24 patients with nephrotic syndrome with various lesions. 10 patients were reinvestigated after remission; 1 patient could be followed during development of the edema phase as well as during prednisone-induced remission. During the nephrotic phase, PRS was suppressed in 8%, normal in 44 and elevated in 48%, while PRA was suppressed in 41%, normal in 48 and elevated in 11% of the patients. After remission, PRA increased in 70% and PRS decreased in 20 and increased in 50% of the cases. The purpose of this study was to investigate PRA and PRS in nephrotic patients; it is concluded that low PRS and high PRA are not as characteristic for the nephrotic syndrome as they are generally thought to be.

Adult↗

PubMed2026

Multi-trait polygenic scores for COPD and COPD exacerbations implicate druggable proteins.

BACKGROUNDWe constructed multi-trait polygenic risk scores (PRSs) predicting chronic obstructive pulmonary disease (COPD) and exacerbations, validated their performance in diverse cohorts, and identified PRS-related proteins for potential therapeutic targeting.METHODSPRSmix+, a multi-trait PRS framework, is used to train a composite PRS (PRSmulti) in COPDGene non-Hispanic White participants (n = 6,647). Associations of PRSmulti with COPD status (GOLD 2-4 vs. GOLD 0 or ICD) and exacerbation frequency were tested in COPDGene African American (n = 2,466), ECLIPSE (n = 1,858), Mass General Brigham Biobank (n = 15,152), and All of Us (n = 118,566). Protein prediction models were applied to GWAS summary statistics from traits contributing to PRSmulti and were validated with proteomic data in COPDGene (n = 5,173) and UK Biobank (n = 5,012).RESULTSPRSmix+ selected 7 traits for PRSmulti. In multivariable models, PRSmulti was associated with COPD status (meta-analysis random effects [RE] OR 1.58 [95% CI: 1.28-1.94]) and exacerbation frequency (meta-analysis RE β 0.21 [95% CI: 0.11-0.31]), with higher effect sizes observed in smoking-enriched cohorts. PRSmulti outperformed traditional single-trait PRS in all tested cohorts. Using protein prediction models, we identified 73 proteins associated with the PRSs that were also validated with measured protein levels in COPDGene and UK Biobank. Of these proteins, 25 were linked to approved or investigational drugs. Notable targets include RAGE/sRAGE, IL1RL1, and SCARF2, all implicated in COPD pathogenesis and exacerbations.CONCLUSIONSMulti-trait PRS improves prediction of COPD and exacerbation risk. Integration with proteomic data identifies druggable protein targets, offering a promising avenue for precision medicine in COPD management.TRIAL REGISTRATIONCOPDGene: ClinicalTrials.gov NCT00608764; ECLIPSE: ClinicalTrials.gov NCT00292552.

Humans↗

PubMed2006

Post-radiation sarcoma of the neck treated with re-irradiation followed by wide excision.

BACKGROUND: Post-radiation sarcoma (PRS) is an uncommon disease manifesting as sarcoma in a previously irradiated field, usually with a latent period of 5 years or more. Literature is limited to small series. Optimal management of this disease is unclear. Positive margins are common following attempted curative surgery and outcomes are poor. Radiotherapy is hardly used and its effect on PRS is not known. We described a case of PRS treated with preoperative radiotherapy followed by margin-negative wide excision. CASE PRESENTATION: The 59-year-old patient presented with a mass in the left supraclavicular fossa and numbness in the arm, six years following radical irradiation of the head and neck for nasopharyngeal carcinoma. Open biopsy showed pleomorphic spindle cell sarcoma. She was treated with pre-operative hyperfractionated radiotherapy followed by margin-negative wide excision and nerve grafting. Cumulative radiation dose to the supraclavicular fossa was 98 Gy. Histological examination of the post-irradiation tumor specimens showed evidence of significant tumor response to re-irradiation. The patient remained free of disease five years after surgery with excellent functional outcome. CONCLUSION: Role of radiotherapy in PRS is uncertain. We described a case that was successfully managed with preoperative radiotherapy and margin-negative wide excision in terms of tumor control and functional outcomes. The impact of radiotherapy was demonstrated in the post-irradiation resected specimen. Further investigation using re-irradiation and surgery in PRS is warranted.

Journal Article↗

PubMed2002

Colocalization of progesterone receptors in parvicellular dynorphin neurons of the ovine preoptic area and hypothalamus.

Recent evidence suggests that the dynorphin-kappa receptor opioid system acts to mediate the inhibitory effect of progesterone (P) on GnRH pulse frequency during the luteal phase of the ovine estrous cycle. It is known that progesterone receptors (PRs) are required for the actions of P on GnRH secretion. Therefore, if P acts directly on dynorphin (DYN) neurons, then these neurons should contain PRs. To test this hypothesis, we used a dual-label immunoperoxidase procedure to visualize PRs and DYN in the preoptic area (POA) and hypothalamus of ovary-intact ewes killed during the luteal phase of the estrous cycle. The PR was colocalized in more than 90% of parvicellular DYN neurons in the POA, anterior hypothalamus (AHA), and arcuate nucleus (ARC). By contrast, none of magnocellular DYN cells of the paraventricular and supraoptic nuclei coexpressed immunoreactive PRs. The high percentage of colocalization of PRs in parvicellular DYN cells of the POA, AHA, and ARC suggests that these cells are prime targets of P. In addition, DYN cells in the ARC, but not the POA or AHA, were found to receive synaptic inputs from DYN-positive axon terminals. This observation raises the possibility that an ultrashort feedback loop controls the release of DYN from ARC neurons.

Animals↗

PubMed1977

The role of estrogen in the regulation of luteal progesterone secretion in the rat after day 12 of pregnancy.

Pregnant rats, hypophysectomized-hysterectomized on day 12 (day 1=insemination), secreted progesterone (P) at about 50% of the day 12 level for 3-5 days. Daily treatment with estradiol 100 microng (E100) but not with E25 or E50, from day 12 to day 20, of such rats, restored P secretion until day 16 to that of intact pregnant rats; on day 17 a drastic permanent fall occurred. E100 had no effect after ovariectomy, and did not change the metabolic clearance rate of P. This E100 effect was absent in decidual tissue (DT)-bearing, or hysterectomized pseudopregnant (PSP) rats, and in pregnant ones before day 11. When pregnant rats were hypophysectomized-hysterectomized on day 10, and were treated with rat placental luteotrophin (rPL) (in the form of day 12 pregnant rat serum: "PRS-12") on days 10 and 11, however, E100 increased P secretion above that found with either PRS-12 or E100 alone. DT-bearing PSP rats, similarly operated on on day 12 and treated with PRS-12 on day 12, responded in the same way to E100. In these rats also the E100 effect lasted for four days. In the day 12 hypophysectomized-hysterectomized pregnant rat, the E100 effect could not be prolonged by single treatments with PRS-12 on either days 13, 14 or 16, but when PRS-12 was given daily from day 12 to 19, P was secreted until day 20 only slightly below the day 12 level; this treatment plus E100 raised P secretion, prolonged it to day 18, and led to a marked fall by day 20 similar to that of the intact pregnant rat at term. The marked increase in P secretion between days 12 and 15 of normal pregnancy may thus be a response to intraluteal estrogen; the pattern of P secretion from day 12 to term may reflect the effects of both estrogen and rPL. rPL probably induces this effect by generating luteal estrogen and LH receptors. The placenta may also secrete an LH-like hormone (rCG?) which, through the LH receptors, could stimulate intraluteal estrogen production.

Animals↗

PubMed2004

Rate of production of plasma and very-low-density lipoprotein (VLDL) apolipoprotein C-III is strongly related to the concentration and level of production of VLDL triglyceride in male subjects with different body weights and levels of insulin sensitivity.

Overweight individuals with reduced insulin sensitivity often have mild to moderate hypertriglyceridemia. To investigate the role of apolipoprotein (apo)C-III metabolism in the etiology of hypertriglyceridemia in these individuals, we investigated 10 male subjects with different body weights (body mass index, 24-34 kg/m(2)) and insulin sensitivity (homeostasis model assessment, 4.7-35.0). Total plasma and very-low-density lipoprotein (VLDL) apoC-III kinetics, as well as VLDL triglyceride (TG) and VLDL apoB kinetics, were measured with iv injected stable isotopes. The apoC-III, TG, and apoB levels in VLDL ranged from 2.9-18.2 mg/dl, 0.49-2.89 mmol/liter, and 6.7-29.3 mg/dl, respectively. Mean production rates (PRs) were: VLDL apoC-III, 20.2 +/- 4.1 micromol/d (range, 8.0-44.8); VLDL TG, 26.9 +/- 4.6 mmol/d (range, 10.2-51.1); and VLDL apoB, 4.4 +/- 0.8 micromol/d (range, 1.5-9.1). VLDL apoC-III PRs were significantly correlated with body mass index, homeostasis model assessment, and plasma TG (r = 0.66, P < 0.05; r = 0.80, P < 0.01; r = 0.95, P < 0.001, respectively). Similar correlations were found for plasma apoC-III PRs (r = 0.70, P < 0.05; r = 0.67, P < 0.05; r = 0.80, P < 0.01, respectively). Fractional catabolic rates (FCRs) were not significantly related to metabolic variables. VLDL TG levels were strongly related to VLDL apoC-III levels (r = 0.99, P < 0.001) and VLDL apoC-III PRs (r = 0.94, P < 0.001). VLDL apoC-III levels were more strongly correlated with VLDL TG PRs (r = 0.81, P < 0.01) than with VLDL TG FCRs or VLDL apoB FCRs (r = -0.53, P = 0.12; r = -0.37, P = 0.29). These results suggest that increased hepatic production of VLDL apoC-III is characteristic of subjects with higher body weights and lower levels of insulin sensitivity and is strongly related to the plasma concentration and level of production of VLDL TG.

Adult↗

PubMed1977

The effect of conjugated estrogens on the renin-angiotensin system.

In a survey of 3 California communities by the Stanford Heart Disease Prevention Program, we obtained data on blood pressure, medications, age, height and weight, blood for measurement of plasma renin activity (PRA), plasma renin concentration (PRC), plasma renin reactivity (RR), and plasma renin substate concentration (PRS), and urine for measurement of urinary sodium and creatinine. No effect of conjugated estrogens (Premarin) on blood pressure could be discerned when the blood pressure, corrected for age and relative weight, of 575 women on no medication was compared to that of 82 women taking only Premarin. Premarin increased PRA, PRS, and RR, but had no effect on PRC. We also found in both Premarin-treated woman and controls 1) that RR was positively correlated with PRS, and 2) that PRA is dependent on PRC and PRS. These data indicate that the reninrenin substrate reaction of plasma, even at normal substrate concentration, is strongly deprendent on PRS.

Adult↗