SEARCH · Search PubMed

Results for “RRM”

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.

SourceResearch connectionFrom yearThrough year

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

At least 19 recordsLinked to original sources

PubMed1991

Effects of canrenone on RRM-sucrose hypertension in WKY.

Ingestion of a diet high in sucrose content by WKY rats having reduced renal mass (RRM) via a unilateral nephrectomy causes a significant elevation of BP--greater than might be expected from either condition alone. The same findings occur whether the added sucrose calories replace protein or fat. The elevated BP differential remained throughout the 6 months of the study. In some ways, these results resemble a well recognized model of hypertension produced by the removal of 70-80% of renal mass plus excess salt consumption (RRM-salt). When the RRM-sucrose WKY were given canrenone, an agent which is a digoxin antagonist, the BP decreased significantly simulating previous findings in RRM-salt. Therefore, like the RRM-salt model, evidence suggests that the RRM-sucrose model is also caused, at least in part, by a digoxin-like factor (DLF).

Animals↗

PubMed1992

A consistent model of insulin-dependent diabetes mellitus hypertension.

Hypertension is frequently seen in insulin-dependent diabetes mellitus (IDDM), but the mechanism of the hypertension is unknown. An animal model of IDDM hypertension could be helpful in determining the mechanism, but experimental IDDM has been infrequently and irregularly associated with hypertension. In an attempt to develop a consistent model of IDDM hypertension, we superimposed streptozotocin (STZ)-induced IDDM on surgical reduction of renal mass (RRM) in Wistar rats. Seven groups of rats were studied: 1) 60% RRM receiving 65 mg/kg body weight (BW) STZ; 2) 60% RRM receiving 40 mg/kg BW STZ; 3) 25% RRM receiving 65 mg/kg BW STZ; 4) two kidney normal rats receiving 65 mg/kg BW STZ; 5) 60% RRM receiving vehicle (control for group 1); 6) 60% RRM receiving vehicle (control for group 2); and 7) 25% RRM receiving vehicle. STZ produced diabetes and hypertension within 1 to 2 weeks in all three groups of RRM rats but blood pressure was unaffected by 60% or 25% RRM alone. STZ alone had no effect on blood pressure until the 5th week when the blood pressure increased slightly. Progressive weight loss resulted from 65 mg/kg BW STZ combined with 60% RRM; the animals had to be terminated after 5 weeks. In only 60% of animals with 40 mg/kg BW STZ plus 60% RRM was IDDM produced. On the other hand, 65 mg/kg BW STZ in rats with 25% RRM regularly produced IDDM and hypertension without excessive loss of body weight. In these rats, albuminuria developed in 2 weeks. Extracellular fluid volume was elevated and plasma renin activity was depressed. The animals were healthy and hypertensive when killed at the 13th week. We suggest that the 25% RRM rat receiving 65 mg/kg BW STZ is a consistent model of IDDM hypertension, which may be useful in probing the mechanism of this type of hypertension.

Albuminuria↗

PubMed1989

Plasma atrial natriuretic peptide in conscious rats with reduced renal mass.

The effect of salt intake and reduction of renal mass (RRM) on plasma immunoreactive atrial natriuretic peptide (iANP) levels in conscious rats was studied. Rats were divided into RRM and sham-operated groups, and then further subdivided into groups infused with 1 or 6 mEq of sodium per day. Plasma urea nitrogen increased in the groups with RRM. Plasma sodium, sodium balance, and heart rate did not differ between the sham and RRM groups. Rats with RRM maintained on 1 mEq of sodium per day did not have an elevation of water intake, arterial pressure, or plasma iANP. Rats with RRM maintained on 6 mEq of sodium per day had significantly (P less than 0.05) elevated water intake, arterial pressure, and plasma iANP. Arterial pressure and plasma iANP were correlated (r = 0.800) for rats with RRM on either 1 or 6 mEq of sodium per day. Increased plasma iANP in the RRM group on 6 mEq per day was not caused by either RRM or high sodium alone; it was an effect of RRM plus high salt intake. The increase in plasma iANP in the RRM group may be caused by the increase in arterial pressure, possibly due to an increase in extracellular fluid volume. ANP may not be responsible for the sustained increase in fractional sodium excretion observed in RRM.

Animals↗

PubMed1983

The pharmacokinetics of metformin: a comparison of the properties of a rapid-release and a sustained-release preparation.

The pharmacokinetic differences between a rapid-release metformin preparation of 500 mg (RRM) and a sustained-release metformin preparation of 500 mg (SRM), whose gastrointestinal side effects may be less, were compared after a single dose and after continuous 5-day use during a steady-state phase. In the single-dose trial the mean peak serum level of 1.00 micrograms/ml from RRM and 0.61 micrograms/ml from SRM were reached at 3 h, and at 3 and 4 h, respectively, after ingestion of the drugs. Serum metformin levels from RRM were consistently higher up to 8 h, and the AUC0-8h value for RRM was from 4.25 and 2.49 for SRM (p less than 0.001). Over a 24-h period 40% of the given dose was recovered in urine from RRM. The value for SRM was 25%. The elimination half-life was 2.0 h for RRM and 2.6 h for SRM. During the steady-state trial the mean basal serum metformin concentration was higher after SRM (0.33 micrograms/ml) than after RRM (0.20 micrograms/ml), although the mean peak serum metformin level remained lower after SRM. On the 5th day the AUC0-8h values obtained after RRM and SRM were comparable (6.88 vs 6.59; N.S.).

Adult↗

PubMed1988

Endogenous noradrenaline re-uptake blocking factor in rats with reduced renal mass hypertension.

This study was carried out to elucidate the involvement of the peripheral sympathetic nervous system in the pathogenesis of reduced renal mass (RRM)-salt hypertension in rats. Male Wistar rats underwent subtotal nephrectomy (70-80% reduction in renal mass). On the 10th postoperative day, systolic blood pressure was higher in RRM-salt rats than in RRM-water rats. Perfusion of isolated mesenteric vasculature from normotensive rats, with the deproteinized plasma from RRM-salt hypertensive rats induced significantly higher pressor responses and noradrenaline overflow with electrical stimulation than the perfusate from RRM-water normotensive rats; the responses to exogenous noradrenaline showed no significant changes. In the presence of desipramine, noradrenaline overflow did not increase following perfusion with plasma from RRM-salt hypertensive rats. These data indicate that plasma from rats with RRM-salt hypertension might contain some noradrenaline re-uptake blocking factor.

Animals↗

PubMed1985

Decreased myocardial Na+K+ATPase activity in rats with reduced renal mass-saline hypertension.

Inhibition of cardiovascular Na,K-pump activity has been shown to promote an increase in the contractile activity of myocardial and vascular smooth muscle and a consequent rise in blood pressure (BP). It has also been shown that vascular Na,K-pump activity and myocardial Na+K+ATPase activity [the energy source for active sodium (Na) and potassium (K) transport] are decreased in rats with various forms of low renin hypertension including rats with reduced renal mass-saline (RRM-saline) hypertension. In the present study, left ventricular Na+K+ATPase activity from rats with RRM-saline hypertension was found to be decreased in membranes prepared by two independent methods: deoxycholate, sodium iodide (Nal)-treated microsomal fractions (method 1) and membranes prepared by the hypotonic, lithium bromide (LiBr) method (method 2). Relative to RRM normotensive control rats which drank distilled water, myocardial Na+K+ATPase activity from RRM-saline drinking rats was decreased by 18.2% in membranes prepared by method 1 and 33.6% in membranes prepared by method 2. The apparent affinities of Na+K+ATPase for K and for ouabain were unaltered relative to controls in membranes prepared from these hypertensive rats by method 1, and the sialic acid content and 5'-nucleotidase activity (two putative sarcolemmal markers) were unaltered in membranes from the hypertensive rats, prepared by methods 1 and 2 respectively. The Mg2+ATPase activity of membranes prepared by method 1 was increased in the RRM-saline hypertensive rats but because it was not increased in membranes prepared by method 2 the former observation does not appear to be of any pathophysiological importance. In other experiments, hypertension was reversed in RRM-saline hypertensive rats by restricting their salt intake (substitution of distilled water for drinking).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1991

Structural alterations of microvascular smooth muscle cells in reduced renal mass hypertension.

Loss of microvessels (anatomic rarefaction) occurs in chronic reduced renal mass (RRM) hypertension and is mediated via structural degeneration of vascular smooth muscle (VSM) and endothelial cells. The purpose of the present study was to determine if structural changes occur in VSM cells of the microvessels that remain in the tissue of rats with chronic RRM hypertension. Samples of cremaster muscles were taken from normotensive control rats and rats with acute (3-7 days) and chronic (14-28 days) RRM hypertension (75% reduction in kidney mass with 4% NaCl loading). The samples were fixed in situ and processed for light and electron microscopy. Ultrastructural morphology of VSM cells in terminal arterioles of control animals was normal. Although VSM morphology in many microvessels of RRM hypertensive rats was also normal, some vessels exhibited structural changes that were not present in arterioles of the normotensive animals. The most striking change was the appearance of more extensive dense bodies anchoring the contractile filaments around the outer membrane of the cells. Extreme vasoconstriction was observed in some arterioles of RRM rats as long as 2 weeks after salt loading. Focal areas of VSM cell proliferation were evident. Many of the changes occurring in RRM were detected as early as 1 week after the onset of hypertension. These observations suggest that renal mass reduction-salt loading hypertension is associated with early structural and functional changes in the VSM cells.

Animals↗

PubMed1989

The relationship of the resonant recognition model to effects of low-intensity light on cell growth.

The resonant recognition model (RRM) is a model of protein-protein and protein-DNA interaction based on a significant correlation between spectra of numerical presentation of the amino acid or nucleotide sequences and their biological activity. Having compared absorption characteristics of photosensitive proteins with their RRM spectral characteristics we obtained a linear correlation between the RRM frequency space and real frequency space, which determines a scaling factor between these two frequency spaces. On applying the RRM model to several groups of peptide growth factors, characteristic RRM frequencies were revealed and the corresponding real characteristic frequencies for these groups of growth factors were calculated using the scaling factor previously obtained. The real frequency characteristics of growth factors obtained in this way correspond with maxima in the action spectra of low-intensity light irradiation effects on cell proliferation.

Animals↗

PubMed1985

Effect of GTP on the affinity of denopamine, a new cardiotonic agent, for beta-adrenergic receptors of turkey erythrocytes and rat reticulocyte membranes.

Affinities of denopamine, a new cardiotonic agent, and several beta-adrenergic drugs for turkey erythrocyte membranes (TEM) and rat reticulocyte membranes (RRM) which contain homogeneous beta 1- and beta 2-receptors, respectively, were studied by receptor binding. The order of potencies of denopamine and several beta-adrenergic agonists in displacing 3H-dihydroalprenolol binding (Ki, nM) in TEM was isoproterenol (Iso, 27) greater than norepinephrine (Nor, 360) greater than epinephrine (Epi, 860) greater than dobutamine (DB, 1380) greater than denopamine (1540) greater than dopamine (DA, 49500). The order in RRM was Iso (7.3) greater than Epi (58) greater than DB (750) greater than Nor (1090) greater than denopamine (2300) greater than DA (26800). In the presence of GTP, competition curves for full agonists like Iso, Epi and Nor shifted to the low affinity side (Ki values increased by 300-500% in TEM and 200-460% in RRM), and the slopes were steepened in both membrane preparations. The Ki value for denopamine increased only in TEM (70%) and that in RRM was not influenced by GTP. This suggests that denopamine has an agonist property at the beta 1-receptor but not at the beta 2-receptor and that the intrinsic activity at the beta 1-receptor of the drug is lower than full agonists. Affinities of DB and DA for TEM were influenced by GTP as well as those for RRM, although the extent of the rightward shift was less than full agonists.

Animals↗

PubMed1986

Increased arterial potassium transport in reduced renal mass hypertension of the rat.

Aortic potassium turnover was studied during the development of hypertension induced by salt load in male rats after 70-75% of total renal mass was removed. Systolic blood pressure in the saline-drinking experimental reduced renal mass (RRM) rats steadily increased until the fourth week after surgery and thereafter stayed at the same level. Control RRM rats given tap water for drinking, and unilaterally nephrectomized saline-drinking control rats maintained normal blood pressure. Compared to controls, experimental RRM rats exhibited increased plasma aldosterone concentration while plasma renin activity was low in all groups with no significant difference. Aortic hypertrophy, greater 42K turnover, and elevated 42K exchange were observed with experimental RRM hypertension. Sensitivity to the effect of norepinephrine (NE) on aortic 42K turnover was increased four- to ninefold in the experimental RRM group as compared to controls. These results indicate that reduced renal mass hypertension is associated with increased potassium permeability and NE supersensitivity in vascular smooth muscle.

Animals↗

PubMed1985

Hypotensive action of canrenone in a model of hypertension where ouabain-like factors are present.

It has been proposed that peripheral resistance can be increased by ouabain-like factors that are able to increase cell sodium and thereby cell calcium. Canrenone has been reported to be a partial agonist of ouabain. The effect of canrenone was investigated in rats with reduced renal mass (RRM) showing evidence of excess circulating ouabain-like factors. Wistar rats were uninephrectomized, 30% of the other kidney was removed, and they were given a 0.8% NaCl solution to drink. Half of them received 60 mg/kg per day of canrenone orally for 26 days. In RRM, the following indices of a ouabain-like activity were found: erythrocyte Na+K(+)-pump activity was decreased by 39% (P < 0.001), sodium content increased by 12% (P < 0.01), net erythrocyte sodium extrusion in plasma decreased by 20% (P < 0.01), and plasma digoxin equivalents increased by 62% (P < 0.02). Canrenone increased the IC50 for ouabain from 1.05 to 2.16 x 10(-4) mol/l (P < 0.05) in erythrocytes. In RRM with systolic blood pressure of 165 mmHg, acute administration of canrenone decreased blood pressure by 36 mmHg. Chronic administration blunted the blood pressure rise by 12, 26 and 21 mmHg at days 5, 14 and 26, respectively (P < 0.05). Haematocrit was markedly reduced in RRM (33%) and much less when treated with canrenone (37.5%). In conclusion, in contrast with spontaneously hypertensive rats, RRM hypertension is a model where a ouabain-like factor is present and in which canrenone reduces blood pressure. The hypotensive effect of canrenone may be related to a competition with ouabain-like factors.

Animals↗

PubMed1984

Criteria for selection of decedent versus living controls in a mortality case-control study.

The mortality odds ratio computed with a decedent control series (ORD) and the mortality odds ratio obtained with a living control series (ORL) estimate the mortality rate ratio (RRM) under very different assumptions. The bias of the ORD as an estimate of RRM is a function of the mortality rates from other causes (those causes for which controls were selected) in the underlying exposed (E) and nonexposed (E) populations, while the bias of ORL as an estimate of RRM is a function of the prevalence of the study disease in the underlying E and E populations. The ORL closely estimates the RRM if the prevalence of the disease under study is small. If the study disease mortality rate is small relative to the other-causes mortality rate, the ORD closely estimates the cause-specific proportional mortality ratio.

Epidemiologic Methods↗

PubMed1988

Antihypertensive effect of canrenone in a model where endogenous ouabain-like factors are present.

The effect of canrenone, an antialdosterone and partial ouabain-agonist drug, was studied in rats that developed volume expansion and hypertension after renal mass reduction and excess Na+ intake (RRM-salt). The RRM-salt was characterized by: (1) increased endogenous "digitalis-like" compounds in plasma [cross reactivity with digoxin-antibodies (57.5 +/- 5.0 vs. 42.1 +/- 3.8 pg/ml, p less than 0.02); inhibition of kidney Na+, K+-ATPase activity (135 +/- 5 vs. 154 +/- 5 mumol/mg/h, p less than 0.01); and inhibition of Na+ extrusion from normal erythrocytes (5.96 +/- 0.40 vs. 7.68 +/- 0.34 mmol/L cells/h, p less than 0.01)]; (2) reduced Na+, K+-pump activity (7.34 +/- 0.29 vs. 10.88 +/- 0.41 mmol/L cells/h, p less than 0.001) and increased Na+ content (4.66 +/- .08 vs. 4.16 +/- 0.11 mmol/L cells, p less than 0.01) in erythrocytes; and (3) low plasma renin activity (2.1 +/- 0.9 vs. 12.6 +/- 1.6 ng/ml/h). Ninety minutes after the administration to RRM-salt of a single oral dose of 60 mg/kg of canrenone, the systolic blood pressure decreased by 36 +/- 4 mm Hg (mean +/- SEM). Chronic canrenone administration (60 mg/kg/day) resulted in a marked antihypertensive effect associated to a correction of volume expansion, a decrease in endogenous "digitalis-like" compounds, and a partial recovery of Na+, K+-pump activity and Na+ content in erythrocytes. Our results suggest that the antihypertensive effect in RRM-salt rats results, at least in part, from antagonism with endogenous "digitalis-like" compounds.

Animals↗

PubMed1986

Prostaglandin and thromboxane formation in glomeruli from rats with reduced renal mass.

In vitro formation of prostaglandins (PG) E2, F2 alpha, 6-keto-F1 alpha, and thromboxane B2 (TxB2) by glomeruli from rats with reduced renal mass (RRM) were evaluated by radioimmunoassay. Four weeks following ablation of renal mass, PGE2, PGF2 alpha, and TxB2 production by glomeruli from RRM rats was significantly greater, when compared with glomerular PG and TxB2 production of sham-operated control (C) rats. The effect of cyclooxygenase inhibition with indomethacin and the selective inhibition of thromboxane formation with UK 38485 on glomerular filtration rate (GFR) was investigated in experiments in vivo. In RRM rats indomethacin reduced GFR from 212 +/- 17 to 138 +/- 14 microliter/100 g/body weight (p less than 0.05) without effect on C rats. Thromboxane synthesis inhibition with UK 38485, however, increased GFR significantly in RRM rats (221 +/- 26 to 303 +/- 21; p less than 0.05). The data suggest that vasodilatory PGs and TxB2 modulate GFR in rats with ablation of renal mass.

Animals↗

PubMed1991

Sympathetic neural control of vascular muscle in reduced renal mass hypertension.

Vascular smooth muscle (VSM) transmembrane potentials (Em) were measured in situ in small branch arteries (150-300-microns o.d.), small branch veins (300-400-microns o.d.), arterioles (90-150-microns o.d.), and venules (80-250-microns o.d.) in the mesenteric and gracilis muscle and the arterioles and venules of cremaster muscle vascular beds in anesthetized rats with reduced renal mass hypertension (HT-RRM) and normotensive sham-operated RRM control rats. All rats were given a 4% NaCl diet for 2 weeks with water ad libitum. Relative to sham, HT-RRM mesenteric and gracilis arterial and venous vessels, but not the microvessels of the cremaster muscle bed, were less polarized during superfusion with normal physiological salt solution. Also relative to sham, hyperpolarization responses to local sympathetic neural (SNS) denervation with 6-hydroxydopamine were greater in mesenteric and gracilis small arteries, arterioles, veins, and venules but not in cremaster microvessels. The immediate (less than 5-minute) electrogenic depolarization response to local blockade of VSM Na(+)-K+ pump activity with 10(-3) M ouabain was similar between each respective HT-RRM and sham vessel pair in each vascular bed.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1978

Partial protection against acute renal failure in rats with reduced renal mass.

Glycerol-induced acute renal failure (ARF) was studied in rats with two degrees of reduced renal mass (RRM). RRM animals, when compared with sham-operated animals, showed a partial protection against this model of ARF. This protection depends on a less marked decrease in glomerular filtration rate and renal plasma flow after ARF induction in RRM rats, with an increased filtration fraction. It is suggested that glycerol injection in RRM rats could induce a mainly efferent arteriolar vasoconstriction, in contrast to control rats, whose glomerular arteriolar vasoconstriction is mainly afferent.

Acute Kidney Injury↗

PubMed2018

Risk-reducing bilateral salpingo-oophorectomy in women with BRCA1 or BRCA2 mutations.

BACKGROUND: The presence of deleterious mutations in breast cancer 1 gene (BRCA1) or breast cancer 2 gene (BRCA2) significantly increases the risk of developing some cancers, such as breast and high-grade serous cancer (HGSC) of ovarian, tubal and peritoneal origin. Risk-reducing salpingo-oophorectomy (RRSO) is usually recommended to BRCA1 or BRCA2 carriers after completion of childbearing. Despite prior systematic reviews and meta-analyses on the role of RRSO in reducing the mortality and incidence of breast, HGSC and other cancers, RRSO is still an area of debate and it is unclear whether RRSO differs in effectiveness by type of mutation carried. OBJECTIVES: To assess the benefits and harms of RRSO in women with BRCA1 or BRCA2 mutations. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 7) in The Cochrane Library, MEDLINE Ovid, Embase Ovid and trial registries, with no language restrictions up to July 2017. We handsearched abstracts of scientific meetings and other relevant publications. SELECTION CRITERIA: We included non-randomised trials (NRS), prospective and retrospective cohort studies, and case series that used statistical adjustment for baseline case mix using multivariable analyses comparing RRSO versus no RRSO in women without a previous or coexisting breast, ovarian or fallopian tube malignancy, in women with or without hysterectomy, and in women with a risk-reducing mastectomy (RRM) before, with or after RRSO. DATA COLLECTION AND ANALYSIS: We extracted data and performed meta-analyses of hazard ratios (HR) for time-to-event variables and risk ratios (RR) for dichotomous outcomes, with 95% confidence intervals (CI). To assess bias in the studies, we used the ROBINS-I 'Risk of bias' assessment tool. We quantified inconsistency between studies by estimating the I2 statistic. We used random-effects models to calculate pooled effect estimates. MAIN RESULTS: We included 10 cohort studies, comprising 8087 participants (2936 (36%) surgical participants and 5151 (64%) control participants who were BRCA1 or BRCA2 mutation carriers. All the studies compared RRSO with or without RRM versus no RRSO (surveillance). The certainty of evidence by GRADE assessment was very low due to serious risk of bias. Nine studies, including 7927 women, were included in the meta-analyses. The median follow-up period ranged from 0.5 to 27.4 years. MAIN OUTCOMES: overall survival was longer with RRSO compared with no RRSO (HR 0.32, 95% CI 0.19 to 0.54; P < 0.001; 3 studies, 2548 women; very low-certainty evidence). HGSC cancer mortality (HR 0.06, 95% CI 0.02 to 0.17; I² = 69%; P < 0.0001; 3 studies, 2534 women; very low-certainty evidence) and breast cancer mortality (HR 0.58, 95% CI 0.39 to 0.88; I² = 65%; P = 0.009; 7 studies, 7198 women; very low-certainty evidence) were lower with RRSO compared with no RRSO. None of the studies reported bone fracture incidence. There was a difference in favour of RRSO compared with no RRSO in terms of ovarian cancer risk perception quality of life (MD 15.40, 95% CI 8.76 to 22.04; P < 0.00001; 1 study; very low-certainty evidence). None of the studies reported adverse events.Subgroup analyses for main outcomes: meta-analysis showed an increase in overall survival among women who had RRSO versus women without RRSO who were BRCA1 mutation carriers (HR 0.30, 95% CI 0.17 to 0.52; P < 0001; I² = 23%; 3 studies; very low-certainty evidence) and BRCA2 mutation carriers (HR 0.44, 95% CI 0.23 to 0.85; P = 0.01; I² = 0%; 2 studies; very low-certainty evidence). The meta-analysis showed a decrease in HGSC cancer mortality among women with RRSO versus no RRSO who were BRCA1 mutation carriers (HR 0.10, 95% CI 0.02 to 0.41; I² = 54%; P = 0.001; 2 studies; very low-certainty evidence), but uncertain for BRCA2 mutation carriers due to low frequency of HGSC cancer deaths in BRCA2 mutation carriers. There was a decrease in breast cancer mortality among women with RRSO versus no RRSO who were BRCA1 mutation carriers (HR 0.45, 95% CI 0.30 to 0.67; I² = 0%; P < 0.0001; 4 studies; very low-certainty evidence), but not for BRCA2 mutation carriers (HR 0.88, 95% CI 0.42 to 1.87; I² = 63%; P = 0.75; 3 studies; very low-certainty evidence). One study showed a difference in favour of RRSO versus no RRSO in improving quality of life for ovarian cancer risk perception in women who were BRCA1 mutation carriers (MD 10.70, 95% CI 2.45 to 18.95; P = 0.01; 98 women; very low-certainty evidence) and BRCA2 mutation carriers (MD 13.00, 95% CI 3.59 to 22.41; P = 0.007; very low-certainty evidence). Data from one study showed a difference in favour of RRSO and RRM versus no RRSO in increasing overall survival (HR 0.14, 95% CI 0.02 to 0.98; P = 0.0001; I² = 0%; low-certainty evidence), but no difference for breast cancer mortality (HR 0.78, 95% CI 0.51 to 1.19; P = 0.25; very low-certainty evidence). The risk estimates for breast cancer mortality according to age at RRSO (50 years of age or less versus more than 50 years) was not protective and did not differ for BRCA1 (HR 0.85, 95% CI 0.64 to 1.11; I² = 16%; P = 0.23; very low-certainty evidence) and BRCA2 carriers (HR 0.88, 95% CI 0.42 to 1.87; I² = 63%; P = 0.75; very low-certainty evidence). AUTHORS' CONCLUSIONS: There is very low-certainty evidence that RRSO may increase overall survival and lower HGSC and breast cancer mortality for BRCA1 and BRCA2 carriers. Very low-certainty evidence suggests that RRSO reduces the risk of death from HGSC and breast cancer in women with BRCA1 mutations. Evidence for the effect of RRSO on HGSC and breast cancer in BRCA2 carriers was very uncertain due to low numbers. These results should be interpreted with caution due to questionable study designs, risk of bias profiles, and very low-certainty evidence. We cannot draw any conclusions regarding bone fracture incidence, quality of life, or severe adverse events for RRSO, or for effects of RRSO based on type and age at risk-reducing surgery. Further research on these outcomes is warranted to explore differential effects for BRCA1 or BRCA2 mutations.

Adult↗

PubMed1992

The effects of 2,3,5-(triglutathion-S-yl)hydroquinone on renal mitochondrial respiratory function in vivo and in vitro: possible role in cytotoxicity.

Administration of 2,3,5-(triglutathion-S-yl)hydroquinone [2,3,5-(triGSyl)HQ] to rats causes severe renal proximal tubular necrosis. Although the cellular target(s) for 2,3,5-(triGSyl)HQ is not known, substantial evidence implicates mitochondria as the primary cellular target for aliphatic S-conjugates. To determine whether mitochondria are targets for 2,3,5-(triGSyl)HQ, the in vivo and in vitro effects of this conjugate on rat renal mitochondria (RRM) were investigated. In vitro exposure of RRM to 2,3,5-(triGSyl)HQ inhibited site I-supported respiration to a much greater extent than site II-supported respiration. Inhibition of mitochondrial function, as manifested by decreases in the respiratory control ratios, were a consequence of significant elevations in state 4 respiration. Inhibition of constitutive gamma-GT activity with AT-125 had no effect on the ability of 2,3,5-(triGSyl)HQ to decrease mitochondrial function. The effects of 2,3,5-(triGSyl)HQ on mitochondrial function in vivo were subsequently assessed. Shortly (0.5-2.0 hr) following administration of 2,3,5-(triGSyl)HQ (20 mumol/kg, iv) to rats, a significant elevation of state 4 respiration was observed. Thereafter (4-16 hr) state 4 respiration returned to control values and state 3 respiration became significantly depressed. A total collapse in RRM function occurred by 24 hr. The effects of 2,3,5-(triGSyl)HQ on state 4 respiration preceded significant elevations in blood urea nitrogen, which occurred at 8 hr. However, pretreatment of animals with probenecid, an inhibitor of organic anion transport, caused a significant decrease in the 2,3,5-(triGSyl)HQ-mediated elevations in state 4 respiration at 1 hr, without preventing the subsequent development of renal necrosis. In contrast, AT-125, which protected animals from 2,3,5-(triGSyl)HQ-mediated nephrotoxicity, had no effect on the early (1 hr) elevations in state 4 respiration but did prevent the later (8 hr) decreases in state 3 respiration. The data suggest that the early elevation in state 4 respiration observed in vivo is unlikely to contribute to 2,3,5-(triGSyl)HQ-mediated nephrotoxicity. The relationship between the decrease in state 3 respiration seen at later time points and the subsequent development of toxicity require further study before a cause and effect relationship can be determined.

Animals↗