Risk for stroke and myocardial infarction with abiraterone versus enzalutamide in metastatic prostate cancer patients.

BACKGROUND: Abiraterone and enzalutamide use is associated with significant cardiovascular (CV) morbidity in clinical trials, but the magnitude and clinical relevance of this association in real-world prostate cancer (PC) population remain unknown. MATERIALS AND METHODS: We retrospectively reviewed the MarketScan claims databases (1 January 2013 to 30 September 2018) to identify adults with diagnosis of metastatic PC who received treatment with androgen deprivation therapy (ADT) and novel antiandrogen agents (abiraterone or enzalutamide). The primary CV outcome measure was composite outcome of acute myocardial infarction (MI) or stroke. Secondary outcomes were individual risks of MI or stroke. We used an intention-to-treat approach to analyze the CV outcomes associated with drug exposure among patients with metastatic PC. Cox regression model was used to estimate the independent association of two drugs with CV risk after adjustment for age, baseline atrial fibrillation, and Charlson Comorbidity Index. RESULTS: A total of 6294 patients with metastatic PC who were treated with ADT and either abiraterone or enzalutamide were included in the final analysis. Of these, 4017 (63.8%) patients used abiraterone and 2217 (32.2%) patients used enzalutamide. During the study period, 255 (6.3%) primary endpoint events occurred, resulting in an incidence rate of 4.3 per 100 patient-years. In multivariable analysis, abiraterone use was associated with a 31% increased risk of MI or stroke compared to enzalutamide (hazard ratio 1.31; 95% confidence interval 1.05-1.63; P = 0.01). The incidence rate was similar in patients who switched initial therapy from abiraterone to enzalutamide or vice versa (5.0 versus 5.6 per 100 patient-years, respectively). CONCLUSIONS: To our knowledge, this is the first real-world assessment of MI and stroke among metastatic PC patients receiving novel anti-androgens. Our findings of increased MI and stroke risk with abiraterone compared with enzalutamide are consistent with data from clinical trials and suggest that enzalutamide may be preferable for prostate cancer patients at high CV risk.

Associations between diet quality and mental health in socially disadvantaged New Zealand adolescents.

BACKGROUND/OBJECTIVES: To examine the relationship between diet quality and mental health in an ethnically diverse adolescent population in New Zealand. SUBJECTS/METHODS: Cross-sectional, population-based study design. Data were available at baseline for 4249 students. Responses from self-reported dietary questionnaires were used to assess diet quality; healthy eating and unhealthy eating were assessed as two separate scales. Mental health was assessed by the emotional subscale of the PedsQL instrument. RESULTS: Eating a healthy diet was significantly associated with better emotional health (P<0.001) and eating an unhealthy diet was significantly associated with greater emotional distress (P<0.001), after controlling for age, ethnicity and gender. The healthy and unhealthy eating scales were independently related to mental health scores. CONCLUSIONS: These findings contribute to a growing body of literature that diet quality is associated with mental health in adolescents. Further research is warranted to determine whether improvements to the diets of adolescents can have meaningful improvements to mental well-being.

The effect of labour on the coagulation system in the term neonate.

The coagulation system of the foetus is markedly different from that of adults. To assess the influence of maternal age, mode of delivery and intrapartum events, and foetal gender and weight on the foetal coagulation system. Cord blood was collected from 154 healthy pregnant women, with gestational age 37 - 42 weeks at birth. Mann-Whitney test was used for analysis of binary data and continuous variables were analysed using Pearson's correlation coefficient. Mean cord blood levels of FVIII:C, VWF:Ag, VWF:CB, FIX, FXI, FXII and plasminogen were significantly higher in babies delivered after labour, compared to those delivered after an elective caesarean. Mean cord blood levels of FII (P = 0.003), FV (P = 0.009), FVII (P = 0.0004) and FX (P = 0.0009) were significantly lower in the babies with meconium stained liquor in labour, compared with those with clear liquor. Augmentation with oxytocin, instrumental delivery, did not affect any of the factor levels and duration of labour did not have an effect on the level of coagulation proteins in cord blood. This study provides valuable information about effect of labour on the coagulation system of the foetus. It is concluded that, in cord blood, the results of coagulation parameters in the newborn baby should be considered in light of mode of delivery and events of labour.

Electrophilic PPARγ ligands inhibit corneal fibroblast to myofibroblast differentiation in vitro: a potentially novel therapy for corneal scarring.

A critical component of corneal scarring is the TGFß-induced differentiation of corneal keratocytes into myofibroblasts. Inhibitors of this differentiation are potentially therapeutic for corneal scarring. In this study, we tested the relative effectiveness and mechanisms of action of two electrophilic peroxisome proliferator-activated receptor gamma (PPARγ) ligands: cyano-3,12-dioxolean-1,9-dien-28-oic acid-methyl ester (CDDO-Me) and 15-deoxy-Δ(-12,14)-prostaglandin J(2) (15d-PGJ(2)) for inhibiting TGFß-induced myofibroblast differentiation in vitro. TGFß was used to induce myofibroblast differentiation in cultured, primary human corneal fibroblasts. CDDO-Me and 15d-PGJ(2) were added to cultures to test their ability to inhibit this process. Myofibroblast differentiation was assessed by measuring the expression of myofibroblast-specific proteins (αSMA, collagen I, and fibronectin) and mRNA (αSMA and collagen III). The role of PPARγ in the inhibition of myofibroblast differentiation by these agents was tested in genetically and pharmacologically manipulated cells. Finally, we assayed the importance of electrophilicity in the actions of these agents on TGFß-induced αSMA expression via Western blotting and immunofluorescence. Both electrophilic PPARγ ligands (CDDO-Me and 15d-PGJ(2)) potently inhibited TGFß-induced myofibroblast differentiation, but PPARγ was only partially required for inhibition of myofibroblast differentiation by either agent. Electrophilic PPARγ ligands were able to inhibit myofibroblast differentiation more potently than non-electrophilic PPARγ ligands, suggesting an important role of electrophilicity in this process. CDDO-Me and 15d-PGJ(2) are strong inhibitors of TGFß-induced corneal fibroblast to myofibroblast differentiation in vitro, suggesting this class of agents as potential novel therapies for corneal scarring warranting further study in pre-clinical animal models.

Pregnancy in women with congenital factor VII deficiency.

The aim was to review the pregnancy and obstetric outcome in women with factor VII (FVII) deficiency. The study group contained women with FVII deficiency, registered with Haemophilia centre and Haemostasis Unit at the Royal Free Hospital, London. The women were interviewed and case notes were reviewed. The main outcome measures were changes in FVII levels in pregnancy, maternal and perinatal outcome. The FVII levels ranged from 7-36 IU dL(-1) in the 13 women included in the study. There were a total of 14 pregnancies in seven women. Ten pregnancies in four women were prior to the diagnosis of FVII deficiency. Following the diagnosis of FVII deficiency, there were four pregnancies in three women. There was an increase in the FVII level during pregnancy in these women from a mean baseline level of 33 IU dL(-1) to a mean of 73 IU dL(-1). These women received recombinant FVIIa replacement during labour and delivery. There were two early pregnancy losses, both associated with excessive haemorrhage. There was only one postpartum haemorrhage in the study. There is a significant increase in FVII levels in pregnancy in women with heterozygous FVII deficiency. The risk of bleeding in early pregnancy might be higher than that at term, due to inadequate rise in the FVII level in early pregnancy.

Mycophenolate mofetil: a promising immunosuppressive agent.

With avaibility of newer immunosuppressive agents, incidence of acute graft rejection has decreased. Mycophenolate mofetil is one such new drug, now available in the Indian market It has been found to be useful in prevention and treatment of acute and chronic rejection after transplantation. Besides transplant it has been used successfully in primary and secondary glomerulopathies (e.g. SLE) and other autoimmune diseases. The drug is well tolerated with side effects limited mainly to gastrointestinal system in the form of epigastric pain, vomiting and diarrhoea.

Cytomegalovirus nasal polyp after renal transplant.

Infection is a major problem after transplantation. Cytomegalovirus (CMV) is the most common viral infection affecting transplant patients. We describe a case of CMV infection with rare clinical manifestation in the form of nasal polyp. Patient presented 6 weeks following renal transplantation with history of fever and stuffy nose. On evaluation he was found to have nasal polyp which was excised. Histopathology revealed characteristic CMV inclusion bodies. Patient responded to ganciclovir therapy and is presently doing well eighteen months after transplantation.

Gln3p nuclear localization and interaction with Ure2p in Saccharomyces cerevisiae.

Gln3p is one of two well characterized GATA family transcriptional activation factors whose function is regulated by the nitrogen supply of the cell. When nitrogen is limiting, Gln3p and Gat1p are concentrated in the nucleus where they bind GATA sequences upstream of nitrogen catabolite repression (NCR)-sensitive genes and activate their transcription. Conversely, in excess nitrogen, these GATA sequences are unoccupied by Gln3p and Gat1p because these transcription activators are excluded from the nucleus. Ure2p binds to Gln3p and Gat1p and is required for NCR-sensitive transcription to be repressed and for nuclear exclusion of these transcription factors. Here we show the following. (i) Gln3p residues 344-365 are required for nuclear localization. (ii) Replacing Ser-344, Ser-347, and Ser-355 with alanines has minimal effects on GFP-Gln3p localization. However, replacing Gln3p Ser-344, Ser-347, and Ser-355 with aspartates results in significant loss of its ability to be concentrated in the nucleus. (iii) N and C termini of the Gln3p region required for it to complex with Ure2p and be excluded from the nucleus are between residues 1-103 and 301-365, respectively. (iv) N and C termini of the Ure2p region required for it to interact with Gln3p are situated between residues 101-151 and 330-346, respectively. (v) Loss of Ure2p residues participating in either dimer or prion formation diminishes its ability to carry out NCR-sensitive regulation of Gln3p activity.

Colonization of pregnant women and their newborn infants with group-B streptococci.

As group B streptococci (GBS) prevalence varies from place to place and this organism is responsible for serious infections in newborns such as septicaemia and meningitis, the present study was carried out to find the prevalence of GBS in pregnant women and their neonates. From June 1998 to April 1999 a total of 317 pregnant women and their neonates were examined for GBS. GBS colonization rate was 2.52% and 1.26% in pregnant women and their neonates respectively. Four sites - viz. throat, external ears, external nares and stump of umbilicus from neonates were found to be equally colonized by GBS immediately after birth and at the time of discharge from hospital, except the umbilicus which was not swabbed at the time of discharge. None of the neonates developed GBS related sepsis. Selective broth medium (SBM) was found to be a superior transport method over Stuart transport medium and filter paper method. All the isolates were sensitive to Ampicillin, Erythromycin, Penicillin followed by Chloramphenicol 66.6% (12/18). All the strains were resistant to Gentamicin, followed by Tetracycline 94.4% (17/18) and Kanamycin 88.8% (16/18).

Pharmacological modulation of fluid secretion in the pigmented rabbit conjunctiva.

We determined net fluid secretion rate across the pigmented rabbit conjunctiva in the presence and absence of pharmacological agents known to affect active Cl- secretion and Na+ absorption. Fluid flow across a freshly excised pigmented rabbit conjunctiva mounted between two Lucite half chambers was measured by a pair of capacitance probes in an enclosed cabinet maintained at 37 degrees C and a relative humidity of 70%. Fluid transport was also measured in the presence of compounds known to affect active Cl- secretion (cAMP, UTP, and ouabain), Na+ absorption (D-glucose), or under the Cl--free condition on both sides of the tissue. Net fluid secretion rate across the pigmented rabbit conjunctiva in the serosal-to-mucosal direction at baseline was 4.3+/-0.2 microl/hr/cm2 (mean +/- s.e.m.). Net fluid secretion rate was increased approximately two-fold by mucosally applied 1 mM 8-Br cAMP (8.4+/-0.4 microl/hr/cm2) and 10 microM UTP (9.8+/-0.6 microl/hr/cm2), but was abolished by either serosally applied 0.5 mM ouabain (0.3+/-0.1 microl/hr/cm2) or under the Cl--free conditions (0.06+/-0.04 microl/hr/cm2). Mucosal addition of 20 mM D-glucose decreased net fluid secretion rate to 1.0+/-0.5 microl/hr/cm2. In conclusion, the pigmented rabbit conjunctiva appears to secrete fluid secondary to active Cl- secretion. This net fluid secretion is subject to modulation by changes in active Cl- secretion rate and in mucosal fluid composition such as glucose concentration.

Admission test: a predictive test for fetal distress in high risk labour.

OBJECTIVE: To study predictive utility of admission test (AT) for perinatal outcome in high risk labours. METHOD: A hundred patients at risk of fetal jeopardy due to uteroplacental insufficiency were screened by admission test. The traces were classified as per the criteria suggested by Ingemarsson and Arulkumaran (1986). The perinatal outcome was correlated with the initial FHR pattern and Chi square test was applied to the results. RESULTS: Fifty-eight patients had reactive, 35 had equivocal and 7 had ominous tracing. The incidence of operative delivery for fetal distress showed a progressive rise from reactive (5.17%) to ominous (28.5%) pattern group. The perinatal morbidity also showed a rise from 6.89% in the reactive to 31.42% in the equivocal (p < 0.01) and 85.71% in the ominous group (p < 0.02). The reactive pattern was assuring of the fetal well being for next 5 hours. Presence of late decelerations and decelerations of 60 beats or more below the baseline were additional ominous characteristics, associated with a significant increase in perinatal morbidity. CONCLUSION: Reactive AT appears to be predictive of fetal well being in high risk labours also. Repeat tracing 4 to 5 hours apart may improve the predictive accuracy. Equivocal and ominous patterns require vigilant monitoring.

Retinoids inhibit mammalian glutathione transferases.

Affinity-purified cytosolic glutathione transferases from adult female rat liver, adult human liver and human term placenta were used. Of the 8 retinoids tested, all-trans retinoic acid was found to be the most potent inhibitor of placental glutathione transferase. The inhibition was non-competitive and exhibited Ki values of 20 and 41 microM for all-trans retinoic acid in the presence of varying concentrations of 1-chloro-2,4-dinitrobenzene and glutathione, respectively. Micromolar all-trans retinoic acid also caused significant (30-90%) inhibition of rat and human liver glutathione transferases. Taken together, the data suggest that inhibition of glutathione transferase(s) may represent yet another mechanism of retinoid action.