Assessment of Vascular Effects of Tamoxifen and Its Metabolites on the Rat Perfused Hindquarter Vascular Bed

Abstract: Tamoxifen has been suggested to produce beneficial cardiovascular effects, although the mechanisms for these effects are not fully known. Moreover, although tamoxifen metabolites may exhibit 30–100 times higher potency than the parent drug, no previous study has compared the effects produced by tamoxifen and its metabolites on vascular function. Here, we assessed the vascular responses to acetylcholine and sodium nitroprusside on perfused hindquarter vascular bed of rats treated with tamoxifen or its main metabolites (N‐desmethyl‐tamoxifen, 4‐hydroxy‐tamoxifen, and endoxifen) for 2 weeks. Plasma and whole‐blood thiobarbituric acid reactive substances (TBARS) concentrations were determined using a fluorometric method. Plasma nitrite and NOx (nitrite + nitrate) concentrations were determined using an ozone‐based chemiluminescence assay and Griess reaction, respectively. Treatment with tamoxifen reduced the responses to acetylcholine (pD₂ = 2.2 ± 0.06 and 1.9 ± 0.05 after vehicle and tamoxifen, respectively; P < 0.05), while its metabolites improved these responses (pD₂ = 2.5 ± 0.04 after N‐desmethyl‐tamoxifen, 2.5 ± 0.03 after 4‐hydroxy‐tamoxifen, and 2.6 ± 0.08 after endoxifen; P < 0.01). Tamoxifen and its metabolites showed no effect on endothelial‐independent responses to sodium nitroprusside (P > 0.05). While tamoxifen treatment resulted in significantly higher plasma and whole blood lipid peroxide levels (37% and 62%, respectively; both P < 0.05), its metabolites significantly decreased lipid peroxide levels (by approximately 50%; P < 0.05). While treatment with tamoxifen decreased the concentrations of markers of nitric oxide formation by approximately 50% (P < 0.05), tamoxifen metabolites had no effect on these parameters (P > 0.05). These results suggest that while tamoxifen produces detrimental effects, its metabolites produce counteracting beneficial effects on the vascular system and on nitric oxide/reactive oxygen species formation.     

Intimate partner violence and women’s cancer quality of life

Purpose

Because intimate partner violence (IPV) may disproportionately impact women’s quality of life (QOL) when undergoing cancer treatment, women experiencing IPV were hypothesized to have (a) more symptoms of depression or stress and (b) lower QOL as measured with the Functional Assessment of Cancer Therapy (FACT-B) and Functional Assessment of Chronic Illness Therapy—Spiritual Well-being (FACIT-SP) Scales relative to those never experiencing IPV.

Methods

Women, aged 18–79, who were included in one of two state cancer registries from 2009 to 2015 with a recent incident, primary, invasive biopsy-confirmed cancer diagnosis were recruited and asked to complete a phone interview, within 12 months of diagnosis. This interview measured IPV by timing (current and past) and type (physical, sexual, psychological), socio-demographics, and health status. Cancer registries provided consenting women’s cancer stage, site, date of diagnosis, and age.

Results

In this large cohort of 3,278 women who completed a phone interview, 1,221 (37.3%) disclosed lifetime IPV (10.6% sexual, 24.5% physical, and 33.6% psychological IPV). Experiencing IPV (particularly current IPV) was associated with poorer cancer-related QOL defined as having more symptoms of depression and stress after cancer diagnosis and lower FACIT-SP and FACT scores than women not experiencing IPV and controlling for confounders including demographic factors, cancer stage, site, and number of comorbid conditions. Current IPV was more strongly associated with poorer QOL. When compared with those experiencing past IPV (and no IPV), women with cancer who experienced current IPV had significantly higher depression and stress symptoms scores and lower FACIT-SP and FACT-G scores indicating poorer QOL for all domains. While IPV was not associated with being diagnosed at a later cancer stage, current IPV was significantly associated with having more than one comorbid physical conditions at interview (adjusted rate ratio = 1.35; 95% confidence interval 1.19–1.54) and particularly for women diagnosed with cancer when <55 years of age.

Conclusions

Current and past IPV were associated with poorer mental and physical health functioning among women recently diagnosed with cancer. Including clinical IPV screening may improve women’s cancer-related QOL.

     

The analytical value for kinin concentration in blood depends on the antiserum used in the bradykinin radioimmunoassay

Recently published blood kinin concentrations are subject a wide scatter, due to sampling time and technique. In our study we tested the influence of the used antibradykinin antiserum on the measured kinin concentration in blood. Blood was collected from the anticubital vein by a teflon cannula and inactivated immediately by hydrochloric acid in the syringe. Subsequent extraction was performed using diethylether, n-butanol, distilled water and Biorex-70. The blood extract containing the kinins was divided into four samples and measured by four radioimmunoassays using different antibradykinin antibodies. All four assays were performed under standard conditions and at the same time. The resulting kinin values were similar in two assays: 7.4 +/- 2.6 ng/l and 5.6 +/- 1.3 ng/l. In the two other assays, however, the measured kinin concentrations differed markedly from these values: 127.5 +/- 46.7 ng/l and 693.0 +/- 85.7 ng/l. These results indicate clearly that the antibody used in the assay can be a major factor determining the range of the recorded kinin concentration.     

Ultrasound evaluation of prognosis in fetuses with posterior urethral valves

Purpose

The aim of this study was to evaluate the ability of prenatal ultrasound markers to predict postnatal renal prognosis in fetuses with posterior urethral valves.

Methods

Medical files on fetuses with prenatal diagnosis of posterior urethral valves from 2000 to 2006 were reviewed retrospectively. Data from prenatal follow-up included gestational age at diagnosis, ultrasound renal parenchyma evaluation, and presence and time of oligohydramnios onset. Prenatal parameters studied were correlated to postnatal renal function.

Results

Thirty-one male fetuses were included. Six pregnancies were terminated. Of the remaining 25 pregnancies that were continued, 4 children had abnormal creatine and 21 normal creatinine levels at follow-up. Presence and time of oligohydramnios onset did not differ between groups (P = .43). Ultrasound detected bilateral renal abnormalities in 3 fetuses (75%) with altered renal function, and 10 fetuses (55%) with normal creatinine, at follow-up.

Conclusions

None of the ultrasound parameters evaluated were able to reliably predict postnatal renal function.     

Relative trochanteric overgrowth after ischemic necrosis in congenital dislocation of the hip

To determine the relative trochanteric overgrowth after ischemic necrosis of the femoral head during treatment of congenital dislocation of the hip (CDH), we reviewed radiographs of patients with ischemic necrosis and no femoral side surgery. The articulotrochanteric distance (ATD) was recorded after physeal closure. Ischemic necrosis was classified with the systems proposed by Salter et al. and Kalamchi and MacEwen. The resultant overgrowth was correlated with these systems. The articulotrochanteric distance in 29 patients with a Trendelenburg gait was also measured. The Kalamchi classification is more useful for predicting relative trochanteric overgrowth. Children with an ATD of less than or equal to 0 mm are likely to have a Trendelenburg gait.     

Central serotonergic and adrenergic/imidazoline inhibitory mechanisms on sodium and water intake

Recent studies have shown the existence of two important inhibitory mechanisms for the control of NACL and water intake: one mechanism involves serotonin in the lateral parabrachial nucleus (LPBN) and the other depends on alpha(2)-adrenergic/imidazoline receptors probably in the forebrain areas. In the present study we investigated if alpha(2)-adrenergic/imidazoline and serotonergic inhibitory mechanisms interact to control NaCl and water intake. Male Holtzman rats with cannulas implanted simultaneously into the lateral ventricle (LV) and bilaterally into the LPBN were used. The ingestion of 0.3 M NaCl and water was induced by treatment with the diuretic furosemide (10 mg/kg of body weight)+the angiotensin converting enzyme inhibitor captopril (5 mg/kg) injected subcutaneously 1 h before the access of rats to water and 0.3 M NaCl. Intracerebroventricular (i.c.v.) injection of the alpha(2)-adrenergic/imidazoline agonist clonidine (20 nmol/1 microl) almost abolished water (1.6+/-1.2, vs. vehicle: 7.5+/-2.2 ml/2 h) and 0.3 M NaCl intake (0.5+/-0.3, vs. vehicle: 2.2+/-0.8 ml/2 h). Similar effects were produced by bilateral injections of the 5HT(2a/2c) serotonergic agonist 2,5-dimetoxy-4-iodoamphetamine (DOI, 5 microg/0.2 microl each site) into the LPBN on water (3.6+/-0.9 ml/2 h) and 0.3 M NaCl intake (0.4+/-0.2 ml/2 h). Injection of the alpha(2)-adrenergic/imidazoline antagonist idazoxan (320 nmol) i.c.v. completely blocked the effects of clonidine on water (8.4+/-1.5 ml/2 h) and NaCl intake (4.0+/-1.2 ml/2 h), but did not change the effects of LPBN injections of DOI on water (4.2+/-1.0 ml/2 h) and NaCl intake (0.7+/-0.2 ml/2 h). Bilateral injections of methysergide (4 microg/0.2 microl each site) into the LPBN increased 0.3 M NaCl intake (6.4+/-1.9 ml/2 h), not water intake. The inhibitory effect of i.c.v. clonidine on water and 0.3 M NaCl was still present after injections of methysergide into the LPBN (1.5+/-0.8 and 1.7+/-1.4 ml/2 h, respectively). The results show that the inhibitory effects of the activation of alpha(2)-adrenergic/imidazoline receptors in the forebrain are still present after blockade of the LPBN serotonergic mechanisms and vice versa for the activation of serotonergic mechanisms of the LPBN. Therefore, each system may act independently to inhibit NaCl and water intake.     

Assessment of the value of detecting specific IgA antibodies for the diagnosis of a recently acquired primary Toxoplasma infection

OBJECTIVE: To assess the value of detecting IgA antibodies for the diagnosis of a recently acquired primary Toxoplasma infection. METHODS: IgA antibodies were screened in sera from 87 women with different serological profiles of Toxoplasma gondii IgM and IgG antibodies and Toxoplasma-specific IgG avidity. The IgM and IgG antibodies and the IgG avidity were measured with an automated Vitek Immuno Diagnostic Assay System (VIDAS). Anti-T.gondii IgA was measured with Platelia Toxo IgA TMB kits. RESULTS: All 12 sera obtained from women with clinical and/or serological evidence of a recently acquired Toxoplasma infection were positive for IgA. In 42 serum samples obtained more than 6 months after T. gondii infection from women with no clinical evidence of infection, but who had a positive IgM test and a high IgG avidity index, the IgA-enzyme linked immunosorbent assay (ELISA) test results were positive, negative, and doubtful in 16 (38.1%), 23 (54.8%), and 3 (7.1%) sera, respectively. In eight women, IgA was detected in sera collected more than 9 months after the onset of infection. The IgA test result was also positive in 11 of 12 sera (91.7%) obtained from women with no clinical evidence of toxoplasmosis, but who had a positive IgM test and a borderline IgG avidity index. The IgA-ELISA was negative in 21 sera obtained more than 2 years after the onset of T. gondii infection from women with no clinical evidence of toxoplasmosis, but who had a negative IgM test and a positive IgG test. CONCLUSION: These results show that IgA is not a dependable marker for a recently acquired primary Toxoplasma infection.