Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “hypothesis testing”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 1,099 records · Page 61Linked to original sources
PubMed1987

Endocrine mechanisms of puberty in heifers. Role of hypothalamo-pituitary estradiol receptors in the negative feedback of estradiol on luteinizing hormone secretion.

The hypothesis tested was that the decline in negative feedback of estradiol on secretion of luteinizing hormone (LH) that occurs as puberty approaches in heifers results from a decline in the number of receptors for estradiol in the hypothalamus and/or pituitary. In addition, associated changes in receptors for luteinizing hormone-releasing hormone (LHRH) in the pituitary, ovarian follicle development, and uterine growth were characterized. Fifty prepubertal heifers, 234 to 264 days of age, were used. Six heifers of median body weight were designated controls, and sequential blood samples were collected at 20-min intervals for 24 h every 2 wk from 249 days of age through puberty and analyzed for concentrations of LH. Frequency of LH pulses/24 h was regressed on number of days prepuberty to develop a prediction equation for puberty. Thirty of the remaining 44 heifers were killed at 253, 302, and 351 days of age (n = 10/group), and tissues for described analyses were collected. Three to 5 days before tissue collection, sequential blood samples were obtained from these heifers, as described for control heifers to determine frequency of release of LH. With this information, number of days prepuberty at the time of tissue collection was estimated from the prediction equation developed with data from control heifers. The average age at puberty in control heifers was 366 days. The average age at puberty of heifers that were not killed or included in the control group (n = 14) was 360 days. Receptor and morphological data were related to the estimated onset of puberty. Cytosolic concentration of receptors for estradiol (fmoles receptor/mg cytosolic protein) in the anterior hypothalamus, medial basal hypothalamus, and anterior pituitary declined (p less than 0.05) as puberty approached. No change in concentration of receptors for estradiol was observed in the stalk median eminence or preoptic area. The concentration of receptors for LHRH in the anterior pituitary did not change as puberty approached. Uterine weight increased rapidly during the 50 days preceding puberty. The number of small, medium, or large follicles and the wet, pressed, or dry weight of the ovaries did not change as puberty approached. Follicles with a diameter greater than 12 mm were found only in the 3 heifers estimated to be closest to puberty at the time of tissue collection. The hypothesis that the decline in estradiol feedback on secretion of LH during the prepubertal period in heifers may result from a decline in the concentration of binding sites for estradiol at the hypothalamus and/or pituitary is supported by this study.

Animals↗
PubMed1993

Motor response variations: peripheral and central sources of error.

The purpose of this research was to test the hypothesis that the relative involvement of peripheral versus central nervous system activity during response variations determines the locus of error production in a subsequent criterion response. The hypothesis was tested by comparing ipsilateral and contralateral transfer of a criterion response following response variations that emphasized proportionately different involvement of the peripheral and central systems. When subjects were provided with knowledge of results (KR) to maintain a 30% maximum voluntary contraction (MVC), ipsilateral but not contralateral bias errors occurred on a subsequent dynamic response. When subjects maintained a 30% MVC without KR, however, subsequent ipsilateral bias errors were greater than contralateral bias errors. Finally,when subjects imaged a 30% MVC, subsequent bias errors were equivalent across limbs. These results are interpreted as support for the hypothesis.

Journal Article↗
PubMed1988

Calcium ions and 1-palmitoyl carnitine reduce erythrocyte electrophoretic mobility: test of a surface charge hypothesis.

In ventricular muscle, 1-palmitoyl carnitine (1-PC) acted like calcium ions to shift the voltage-dependent inactivation of excitatory ion currents to less negative potentials. We proposed that 1-PC affected ion current kinetics by reducing surface negative charge. This hypothesis was tested in cell electrophoresis experiments where the electrophoretic mobility (EPM) of erythrocytes was measured in the absence and presence of test ligands. Calcium (0.18 to 3.6 mM) or 1-PC (10(-7) to 10(-6) M) reduced erythrocyte EPM in a concentration-dependent manner; the maximum reduction of EPM by either ligand was approximately 40%. In the presence of calcium, 1-PC produced a smaller decrement of EPM as expected from an occlusive interaction. Treatment of erythrocytes to remove sialic acids not only predictably reduced EPM but also diminished the ability of 1-PC and calcium to do so. These results indicate that the surface negative charge of sialic acid carboxyl groups is an important determinant both of erythrocyte EPM and of erythrocyte interaction with either 1-PC or calcium. The findings are consistent with the surface charge hypothesis for 1-PC action. We propose that 1-PC is not a neutral molecule at the cell surface but is able to neutralize surface negative charge by electrostatic interaction between the sialic acid carboxyl groups and the 1-PC quaternary ammonium moiety on the one hand and between the 1-PC carboxyl group and counterions near the membrane surface.

Calcium↗
PubMed1997

Suppression of drug-induced epileptiform discharges by cyclic AMP in rat hippocampus.

The effect of cyclic adenosine 3',5'-monophosphate (cAMP) on epileptiform activity in rat hippocampal slices was investigated. Bath-applied cAMP reversibly decreased the frequency of extracellularly recorded discharges in the CA3 subfield induced by bethanechol- or theophylline-containing solutions. Because cAMP was presumed to be relatively membrane impermeant, we developed and tested the hypothesis that this cAMP-mediated effect occurred extracellularly through the catabolic conversion of cAMP to 5'-AMP and, in turn, to adenosine, a known inhibitory neuromodulator. Three predictions derived from this catabolic hypothesis were tested. First, blockers of the enzymes involved were predicted to antagonize this effect of cAMP. In contrast, the coapplication of a cAMP-phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine (IBMX), or a 5'-nucleotidase inhibitor, adenosine 5'-[alpha, beta-methylene] diphosphate (AMP-CP), enhanced the cAMP-induced suppressive effect. Second, the nonhydrolyzable cAMP analogs, dibutyryl- and 8-bromo-cAMP, were predicted to be ineffective. Low concentrations (5-40 microM) of these two derivatives, however, also suppressed bethanechol-induced discharges, while, at a higher concentration (100 microM), both analogs increased discharge frequencies. Third, enzymatic catabolism of adenosine was predicted to antagonize cAMP's effect, but coapplying adenosine deaminase (10 U/mL) did not diminish this action. Because these data did not support the catabolic hypothesis, other, as yet undefined, mechanisms must be responsible for the discharge-suppressant effect of cAMP.

1-Methyl-3-isobutylxanthine↗
PubMed1998

The impact of beta-receptor blocker addition to high-dose angiotensin-converting enzyme inhibitor-nitrate therapy in heart failure.

BACKGROUND: The natural history of heart failure is one of continued worsening of cardiac function. Beta-receptor blocker therapy has been effective in improving clinical status and left ventricular function in patients with heart failure. Similarly, high doses of angiotensin-converting enzyme (ACE) inhibitors with nitrates partially reverse the ventricular remodeling of heart failure. HYPOTHESIS: We tested the hypothesis that beta-blocker therapy added to high-dose ACE inhibitor-nitrates would potentiate the reversal of heart failure. METHODS: Thirteen patients, aged 52 +/- 8 years, with moderate to severe heart failure, 12 of whom were referred for transplant consideration, with heart failure duration of 4.8 +/- 2.2 years, were prospectively followed for 12 months. Baseline echocardiographic ejection fraction was 19 +/- 8%, and presenting New York Heart Association class was 2.9 +/- 0.7. Angiotensin-converting enzyme inhibitors and nitrates were uptitrated over 6 months to a final dose of lisinopril 53 +/- 31 mg/day, and isosorbide dinitrate 217 +/- 213 mg/day. At 6 months, beta-blocker therapy with atenolol was initiated and titrated to a final dose of 46 +/- 23 mg/day. Two-dimensional Doppler echocardiography and metabolic stress testing were performed at baseline, at 6 months on lisinopril-nitrates only, and at 12 months on combined ACE inhibitor-nitrate and beta-blocker therapy. RESULTS: New York Heart Association classification improved from 2.9 +/- 0.7 to 1.8 +/- 0.8 on lisinopril-nitrates (p < 0.05), and to 1.5 +/- 0.5 with the addition of beta blockade (p = NS). On follow-up, peak oxygen consumption rose from 17 +/- 7 ml O2/kg/min at baseline to 21 +/- 5 ml O2/kg/min at 6 months on lisinopril-nitrates (p = 0.06) without further change on beta blockade. Ejection fraction rose from 19 +/- 8 to 33 +/- 14% on lisinopril-nitrates at 6 months (p = 0.005) and to 36 +/- 18% on beta blockade at 12 months (p = NS). CONCLUSION: High-dose ACE inhibitor-nitrate therapy significantly improved patient clinical status and left ventricular systolic function in heart failure. The addition of beta-receptor blockade over and above high-dose ACE inhibitor-nitrates was well tolerated but had no further impact on symptomatic status, exercise tolerance, or left ventricular systolic function. The potential for pharmacologic reversal of heart failure remodeling may be finite despite the use of complementary therapies. Larger placebo-controlled and randomized trials of beta-receptor blockade added to high-dose ACE inhibitor-nitrate therapy are needed to confirm these observations.

Adrenergic beta-Antagonists↗
PubMed1991

Cyclopiazonic acid is a sarcoplasmic reticulum Ca(2+)-pump inhibitor of rat aortic muscle.

The effects of a mycotoxin, cyclopiazonic acid (CPA), on the contractile function of rat aortic smooth muscle rings were investigated to test the hypothesis that CPA selectively inhibits the sarcoplasmic reticulum Ca(2+)-pump. This hypothesis was tested by two types of experimental approaches. First, we compared the ability of the vascular muscle rings to relax upon washout of the agonists following the contraction induced by high concentration of depolarizing KCl (60 mmol.L-1) and supramaximal concentration of phenylephrine (Phe; 10(-5) mol.L-1). In this case, we found that CPA treatment resulted in slowing the rate of relaxation to both stimuli. In the second approach, the status of Phe-sensitive intracellular Ca2+ pool was assessed by the ability of Phe to elicit sequential responses in Ca(2+)-free medium with loading of Ca2+ by reintroduction of extracellular Ca2+ in the presence and absence of CPA following the first response to Phe 10(-5) mol.L-1 and the washout of the agonist. We found that effective Ca2+ loading resulted in total restoration of the second response to Phe, while CPA treatment caused ineffective loading leading to ultimate prevention of the second response to Phe. Our finding are consistent with the hypothesis that CPA acts by inhibiting the SR Ca(2+)-pump, thus interfering an effective refilling of the agonist-sensitive intracellular Ca2+ stores.

Animals↗
PubMed2004

Do physical leisure time activities prevent fatigue? A 15 month prospective study of nurses' aides.

OBJECTIVE: To test the hypothesis that physical leisure time activities reduce the risk of developing persistent fatigue. METHODS: The hypothesis was tested in a sample that was homogeneous with respect to sex and occupation, with a prospective cohort design. Of 6234 vocationally active, female, Norwegian nurses' aides, not on leave because of illness or pregnancy when they completed a mailed questionnaire in 1999, 5341 (85.7%) completed a second questionnaire 15 months later. The main outcome measure was the prevalence of persistent fatigue-that is, always or usually feeling fatigued in the daytime during the preceding 14 days. RESULTS: In participants without persistent fatigue at baseline, reported engagement in physical leisure time activities for 20 minutes or more at least once a week during the three months before baseline was associated with a reduced risk of persistent fatigue at the follow up (odds ratio = 0.70; 95% confidence interval 0.55 to 0.89), after adjustments for age, affective symptoms, sleeping problems, musculoskeletal pain, long term health problems of any kind, smoking, marital status, tasks of a caring nature during leisure time, and work factors at baseline. CONCLUSION: The study supports the hypothesis that physical leisure time activities reduce the risk of developing persistent fatigue.

Adult↗
PubMed2000

Genetic differences in the frequency of the hinge variants of porcine IgA is breed dependent.

The distribution of the IgA(a) and IgA(b) alleles of porcine IgA in over 160 randomly-selected animals revealed an abundance of heterozygotes but only two b/b homozygotes. Since the IgA(b) allotype is a splice site mutant lacking two-thirds of the hinge, this study tests the hypothesis that pigs with this genotype may be at a selective disadvantage while heterozygous individuals may be at some advantage. This hypothesis was tested by collecting data on 374 animals of known breed and often parentage. We show here that when breed was not considered, young animals of known parentage had genotypic frequencies identical to that expected for Mendelian alleles but that a/b heterozygotes were overrepresented in adults. However, when analyzed with regard to breed, a very strong association between breed and the frequency of the IgA(a) and IgA(b) alleles was discovered. Meishan and NIH minipigs were homozygous for IgA while heterozygotes predominated in Berkshire, Chester White, Durocs, Hampshire and Landrace. Animals homozygous for IgA(b) were best represented in the White Cross line. We show here that this very strong breed dependency of IgA allotypy in swine can produce a sample bias that can explain why only two b/b homozygotes (1.3%) were found in the 160 randomly-selected samples since the original samples came from primarily Landrace and Yorkshire animals. The expected frequency of b/b homozygotes in these breeds would be <3%. Thus, the data presented here reject the hypothesis that swine homozygous for a trait that results in loss of two-thirds of the IgA hinge, are selected against and that heterozygotes are positively selected. Rather, the study shows that IgA(a) and IgA(b) appear to be simple, breed-dependent allotypic markers.

Alleles↗
PubMed2007

Fire effects on stable isotopes in a Sierran forested watershed.

This study tested the hypothesis that stable C and N isotope values in surface soil and litter would be increased by fire due to volatilization of lighter isotopes. The hypothesis was tested by: (1) performing experimental laboratory burns of organic and mineral soil materials from a watershed at combinations of temperature ranging 100 to 600 degrees C and duration ranging from 1 to 60 min; (2) testing field samples of upland soils before, shortly after, and 1 yr following a wildfire in the same watershed; and (3) testing field soil samples from a down-gradient ash/sediment depositional area in a riparian zone following a runoff event after the wildfire. Muffle furnace results indicated the most effective temperature range for using stable isotopes for tracing fire impacts is 200 to 400 degrees C because lower burn temperatures may not produce strong isotopic shifts, and at temperatures>or=600 degrees C, N and C content of residual material is too low. Analyses of field soil samples were inconclusive: there was a slightly significant effect of the wildfire on delta15N values in upland watershed analyses 1 yr postburn, while riparian zone analyses results indicated that delta13C values significantly decreased approximately 0.71 per thousand over a 9 mo post-fire period (p=0.015), and ash/sediment layer delta13C values were approximately 0.65 per thousand higher than those in the A horizon. The lack of field confirmation may have been due to overall wildfire burn temperatures being <200 degrees C and/or microbial recovery and vegetative growth in the field. Thus, the muffle furnace experiment supported the hypothesis, but it is as yet unconfirmed by actual wildfire field data.

Fires↗
PubMed2005

The codon for the methionine at position 129 (M129) in the human prion protein provides an alternative initiation site for translation and renders individuals homozygous for M129 more susceptible to prion disease.

Single amino-acid substitutions in the prion protein have been found to lead to resistance or susceptibility to amyloid fibril formation. In humans, the presence of methionine at position 129 in the prion protein results in increased susceptibility to prion disease, while the presence of valine at that position appears to be protective. It is hypothesized that the codon for M129 is an alternative initiation site for translation, which results in a truncated molecule that is missing the first 128 amino acids, including the signal peptide. This N-terminal truncated form of the prion molecule will not be transported to the extracellular space and thus will accumulate in the cytosol where it is more susceptible to fibril formation and aggregation; this aggregation could hinder normal degradation processes and cause disease. The results of experimental studies on truncated prion molecules support this hypothesis. To test the hypothesis, a gene segment, which when transcribed would result in a prion molecule starting at methionine 129, could be introduced into a convenient experimental animal to see if there is increased incidence of prion disease. Or, fibrils from the brains of affected M129/M129 homozygous individuals could be isolated and the molecules in the fibrils analyzed to determine the identity of the N-terminal amino acid(s). We predict that those isolates will have a preponderance of molecules that start with the methionine at position 129 in the intact protein.

Amino Acid Substitution↗
PubMed1998

Changes in fetal plasma corticotropin-releasing hormone during androstenedione-induced labor in the rhesus monkey: lack of an effect on the fetal hypothalamo-pituitary-adrenal axis.

Androstenedione infusion to pregnant monkeys leads to premature labor and live delivery. Androstenedione-induced labor also increased placental CRH messenger RNA and peptide to concentrations observed at term in pregnant monkeys. Placental CRH may modulate fetal pituitary-adrenal function during pregnancy in primates. This study tested the hypothesis that androstenedione-induced premature delivery in pregnant monkeys results from androstenedione-induced increases in placental CRH, which stimulate premature activation of the fetal pituitary-adrenal axis. The hypothesis was tested by comparing fetal umbilical vein (FUV) plasma CRH, ACTH, dehydroepiandrosterone sulfate, and cortisol concentrations at cesarean section in fetuses from mothers undergoing spontaneous, term labor (group I), with those in fetuses from mothers undergoing androstenedione-induced, premature labor (group II) and with those from mothers not in labor (group III). In addition, gestation-related changes in maternal plasma CRH concentrations were investigated, and CRH immunoactivity was characterized by Sephadex G50 chromatography in pooled maternal plasma extracts. FUV CRH concentrations were similarly elevated in group I and group II fetuses, compared with group III fetuses. Despite similar FUV blood gases in all fetuses, FUV ACTH and dehydroepiandrosterone sulfate concentrations were higher in group I fetuses than in group II or group III fetuses. The majority of CRH immunoactivity coeluted with synthetic human CRH. Maternal plasma CRH concentrations showed a modest increase with gestation in the rhesus monkey. These data: 1) demonstrate that androstenedione treatment of pregnant monkeys at 0.8 of gestation elevates fetal plasma CRH to similar concentrations measured at term; 2) do not support the hypothesis that androstenedione-induced delivery in the monkey results from premature activation of the fetal pituitary-adrenal axis by placental CRH; but 3) do support a role for activation of the fetal hypothalamo-pituitary-adrenal axis in association with spontaneous term labor in the monkey; and 4) demonstrate important interprimate species differences in maternal CRH physiology.

Androstenedione↗
PubMed1991

A theoretical test of the DNA repair hypothesis for the maintenance of sex in eukaryotes.

The DNA repair hypothesis for the maintenance of sex states that recombination is necessary for the repair of double-strand DNA damage. In a closed (mitotic) genetic system crossing-over generates homozygosity. This reduces fitness if deleterious recessive alleles become expressed. Thus, outcrossing is required to restore heterozygosity destroyed by recombination. The repair hypothesis is tested by comparing outcrossing sexuality with a hypothetical parthenogenic strategy (the Prudent Reparator) which destroys as little heterozygosity during repair as possible. In the Prudent Reparator, repair of double-strand DNA damage results in a small amount of homozygosity due to gene conversion only, since this process does not render outside markers homozygous. Diploidy, deleterious recessives, multiplicative fitness and linkage equilibrium in mutation-selection balance are assumed. The average fitness of this population increases, and complementation (i.e. masking of recessives in heterozygous form) decreases with the rate of damage per locus. The equilibrium fitness of the Prudent Reparator can be well above that of the sexual population. A lower complementation ability of parthenogens may not be an impenetrable barrier to their successful establishment if the invader's genome is relatively uncontaminated by mutant alleles: there are always such genotypes in the sexual population. Thus, the Prudent Reparator could solve the problem of repairing damage as well as that of invading an existing outcrossing population. As we do not see this strategy widely adopted instead of sexuality, the repair hypothesis is likely to miss some essential feature of the evolution of sex.

Animals↗
PubMed2005

The role of calcitonin gene-related Peptide in the in vivo pituitary-adrenocortical response to acute hypoxemia in the late-gestation sheep fetus.

This study tested the hypothesis that calcitonin gene-related peptide (CGRP) has a role in mediating the in vivo fetal adrenal glucocorticoid response to acute stress. The hypothesis was tested by investigating the effects of fetal treatment with a selective CGRP antagonist on plasma ACTH and cortisol responses to acute hypoxemia in the late-gestation sheep fetus. Under anesthesia, six fetuses at 0.8 of gestation were surgically instrumented with vascular catheters. Five days later, fetuses were subjected to 0.5-h hypoxemia during treatment with either iv saline or a CGRP antagonist, in randomized order, on different days. Treatment started 30 min before hypoxemia and ran continuously until the end of the challenge. Arterial blood samples were collected for plasma ACTH and cortisol measurements (RIA) and blood gas monitoring. CGRP antagonism did not alter basal arterial blood gas or endocrine status. During hypoxemia, similar falls in arterial partial pressure of oxygen occurred in all fetuses. During saline infusion, acute hypoxemia induced significant increases in fetal ACTH and cortisol concentrations. During CGRP antagonism, the pituitary-adrenal responses were markedly attenuated. Correlation of paired plasma ACTH and cortisol values from all individual fetuses during normoxia and hypoxemia showed positive linear relationships; however, neither the slope nor the intercept of the peptide-steroid relationship was affected by CGRP antagonism. These data support the hypothesis that CGRP is involved in the in vivo regulation of fetal adrenocortical steroidogenesis during acute hypoxemia. In addition, the data reveal that CGRP may have a role in the control of other components of the hypothalamo-pituitary-adrenal axis during stimulated conditions in fetal life.

Acid-Base Equilibrium↗
PubMed2003

Enhanced nitric oxide activity offsets peripheral vasoconstriction during acute hypoxaemia via chemoreflex and adrenomedullary actions in the sheep fetus.

We tested the hypothesis that enhanced nitric oxide (NO) opposes fetal peripheral vasoconstrictor responses to acute hypoxaemia via actions involving the carotid chemoreflex and the adrenal medulla. The hypothesis was tested in the late gestation ovine fetus using a novel NO clamp technique, which involves fetal combined treatment with the NO synthase inhibitor, L-NAME, and the NO donor, sodium nitroprusside. In contrast to treatment with L-NAME alone, combined fetal treatment with L-NAME and nitroprusside prevents generalized vasoconstriction and pronounced hypertension, not only maintaining basal cardiovascular function, but also permitting blockade of the de novo synthesis of NO during hypoxaemia while compensating for the tonic production of the gas. Under general anaesthesia, seven sheep fetuses were surgically prepared with catheters and a femoral Transonic flow probe. Five days after surgery, fetuses were subjected to a 3 h protocol: 1 h normoxia, 1 h hypoxaemia and 1 h recovery. Fetal hypoxaemia was induced during either fetal infusion with saline or treatment with the NO clamp. During saline infusion, fetuses responded to hypoxaemia with transient bradycardia, femoral vasoconstriction and increases in plasma noradrenaline and adrenaline. During fetal treatment with the NO clamp, bradycardia persisted and there were greater peripheral vasoconstrictor and catecholaminergic responses to hypoxaemia. Further analysis showed that NO clamp treatment enhanced the chemoreflex component of the fetal cardiovascular defence to acute hypoxaemia. These data support the hypothesis that enhanced NO synthesis during acute hypoxaemia offsets fetal peripheral vasoconstrictor responses to hypoxaemia via chemoreflex and adrenomedullary actions.

Acute Disease↗
PubMed2001

Reappearance of myocytes in ovine infarcts produced by six hours of complete ischemia followed by reperfusion.

BACKGROUND: In this study we tested the hypothesis that delayed reperfusion of ischemic myocardium-too late to save myocytes-attenuates infarct expansion and improves collagen synthesis. METHODS: The hypothesis was tested in a sheep model of anteroapical infarction that has no collateral blood flow to the area at risk. After coronary ligation or arterial occlusion for 1 or 6 hours, sheep had serial hemodynamic and quantitative echocardiographic studies before and after infarction and 2, 5, 8, and 12 weeks later. Hearts were examined by light and electron microscopy at 2 and 12 weeks; hydroxyproline and ratios of type I/III collagen were measured at 12 weeks. RESULTS: After coronary occlusion, left ventricular (LV) function progressively decreased and size increased to form an anteroapical aneurysm. After 1 hour of ischemia, neither resting LV size nor function changed; the infarct contained a midmyocardial scar between epicardial and endocardial muscle. After 6 hours of ischemia, LV function was significantly better than that in nonperfused sheep. Two weeks after 6 hours of ischemia, no viable myocytes were visible by light microscopy, but electron micrographs showed rare intact nucleated myocytes with scarce cytoplasmic myofibrils. At the 12th week epicardial and endocardial myocytes reappeared in the infarct. Infarct collagen type I/III ratios were 1.2 in reperfused groups and 0.7 in nonperfused sheep. CONCLUSIONS: Delayed reperfusion causes loss and subsequent reappearance of ovine epicardial myocytes, improves collagen type I/III ratios, and attenuates LV dilatation and loss of function. One hypothesis to explain the reappearance of myocytes is that reperfusion partially reverses an incomplete apoptotic process.

Animals↗
PubMed2004

ERBB2, TBX2, RPS6KB1, and MYC alterations in breast tissues of BRCA1 and BRCA2 mutation carriers.

Breast cancer risk is greatly increased in women who carry mutations in the BRCA1 or BRCA2 genes. Because breast cancer initiation is different between BRCA1/2 mutation carriers and women who do not carry mutations, it is possible that the mechanism of breast cancer progression is also different. Histopathologic and genetic studies have supported this hypothesis. To test this hypothesis further, we utilized a large cohort of women who underwent therapeutic mastectomy (TM) and contralateral prophylactic mastectomy (PM). From this cohort, we developed case groups of women with a family history of breast cancer with BRCA1/2 deleterious mutations, with unclassified variant alterations, and with no detected mutation and matched these cases with sporadic controls from the same TM and PM cohort. Fluorescence in situ hybridization was performed on paraffin sections by use of dual-color probes for ERBB2/CEP17, MYC/CEP8, TBX2/CEP17, and RPS6KB1/CEP17. All malignant and benign lesions, including putative precursor lesions, were studied. The invasive cancers from deleterious mutation carriers had a higher prevalence of duplication of MYC (P = 0.006) and TBX2 (P = 0.0008) compared to controls and a lower prevalence of ERBB2 amplification (P = 0.011). Coduplication of MYC and TBX2 was common in the in situ and invasive lesions from the deleterious mutation carriers. The odds ratio of having a BRCA1/2 mutation is 31.4 (95% CI = 1.7-569) when MYC and TBX2 are coduplicated but ERBB2 is normal. Unclassified variant carriers/no mutation detected and sporadic controls had a similar prevalence of alterations, suggesting that hereditary patients with no deleterious mutations follow a progression pathway similar to that of sporadic cases. With the exception of one atypical ductal hyperplasia lesion, no putative precursor lesion showed any detectable alteration of the probes tested. There was no significant intratumoral heterogeneity of genetic alterations. Our data confirm that a specific pattern of genomic instability characterizes BRCA1/2-related cancers and that this pattern has implications for the biology of these cancers. Moreover, our current and previous results emphasize the interaction between phenotype and genotype in BRCA1/2-related breast cancers and that a combination of morphologic features and alterations of ERBB2, MYC, and TBX2 may better define mechanisms of tumor progression, as well as determine which patients are more likely to carry BRCA1/2 mutations.

Adult↗
PubMed1996

Central effects of caffeine on renal renin secretion and norepinephrine spillover.

Endogenous adenosine in the brain may inhibit central sympathetic tone and thereby restrain renin release, a mechanism that may be particularly important when sympathetic activity is enhanced. The purpose of our study was to test the hypothesis that the adenosine receptor antagonist caffeine increases renin release in part by disabling the central nervous system (CNS) adenosine brake on renin release. This hypothesis was tested by conducting three protocols in anesthetized rats. In the first protocol, intracerebroventricular (i.c.v.) infusions of caffeine (10 micrograms/kg/min) did not alter either bradycardic responses to intravenous (i.v.) infusion of N6-cyclopentyladenosine (CPA, A1-receptor agonist) or depressor responses to i.v. infusions of CGS21680 (A1-receptor agonist). However, i.c.v. caffeine did block bradycardic responses to i.c.v. boluses of CPA and depressor responses to i.c.v. boluses of CGS21680, thus demonstrating that i.c.v. caffeine at the dose used blocks CNS but not peripheral adenosine receptors. In the second protocol, hydralazine (1 and 10 mg/kg, administered intraperitoneally) significantly enhanced both the renal secretion of renin and the renal spillover of norepinephrine (NE), thus confirming that hydralazine can increase renin release by unloading arterial baroreceptors and increasing sympathetic tone to the kidneys. In the third protocol, the effects of i.c.v. caffeine (10 micrograms/kg/min) on hydralazine-induced (1 and 10 mg/kg, administered intraperitoneally) changes in renal secretion of renin and renal NE spillover were investigated. In this protocol, i.c.v. caffeine did not alter baseline values for either the renal secretion of renin or NE. In contrast, i.c.v. caffeine significantly (p = 0.03) enhanced the increase in renal renin secretion induced by 1 and 10 mg/kg hydralazine (for 1 mg/kg hydralazine delta of 6.4 +/- 46.7 and 142.4 +/- 142.9 renin activity/min/kg body weight in control and caffeine-treated animals, respectively; for 10 mg/kg hydralazine, delta 227.8 +/- 73.9 and 600.8 +/- 168.9 renin activity/min/kg body weight in control and caffeine-treated animals, respectively). The enhanced renin-secretion response to hydralazine in caffeine-treated rats was accompanied by augmented hydralazine-induced increase in renal NE spillover (p = 0.035). These data strongly support the hypothesis of a CNS adenosine brake on renin release that is disabled by caffeine.

Adenosine↗