Incremental prognostic value of coronary computed tomographic angiography over coronary artery calcium score for risk prediction of major adverse cardiac events in asymptomatic diabetic individuals

Background

Coronary artery disease (CAD) diagnosis by coronary computed tomographic angiography (CCTA) is useful for identification of symptomatic diabetic individuals at heightened risk for death. Whether CCTA-detected CAD enables improved risk assessment of asymptomatic diabetic individuals beyond clinical risk factors and coronary artery calcium scoring (CACS) remains unexplored.

Methods

From a prospective 12-center international registry of 27,125 individuals undergoing CCTA, we identified 400 asymptomatic diabetic individuals without known CAD. Coronary stenosis by CCTA was graded as 0%, 1–49%, 50–69%, and ≥70%. CAD was judged on a per-patient, per-vessel and per-segment basis as maximal stenosis severity, number of vessels with ≥50% stenosis, and coronary segments weighted for stenosis severity (segment stenosis score), respectively. We assessed major adverse cardiovascular events (MACE) – inclusive of mortality, nonfatal myocardial infarction (MI), and late target vessel revascularization ≥90 days (REV) – and evaluated the incremental utility of CCTA for risk prediction, discrimination and reclassification.

Results

Mean age was 60.4 ± 9.9 years; 65.0% were male. At a mean follow-up 2.4 ± 1.1 years, 33 MACE occurred (13 deaths, 8 MI, 12 REV) [8.25%; annualized rate 3.4%]. By univariate analysis, per-patient maximal stenosis [hazards ratio (HR) 2.24 per stenosis grade, 95% confidence interval (CI) 1.61–3.10, p < 0.001], increasing numbers of obstructive vessels (HR 2.30 per vessel, 95% CI 1.75–3.03, p < 0.001) and segment stenosis score (HR 1.14 per segment, 95% CI 1.09–1.19, p < 0.001) were associated with increased MACE. After adjustment for CAD risk factors and CACS, maximal stenosis (HR 1.80 per grade, 95% CI 1.18–2.75, p = 0.006), number of obstructive vessels (HR 1.85 per vessel, 95% CI 1.29–2.65, p < 0.001) and segment stenosis score (HR 1.11 per segment, 95% CI 1.05–1.18, p < 0.001) were associated with increased risk of MACE. Beyond age, gender and CACS (C-index 0.64), CCTA improved discrimination by maximal stenosis, number of obstructive vessels and segment stenosis score (C-index 0.77, 0.77 and 0.78, respectively). Similarly, CCTA findings improved risk reclassification by per-patient maximal stenosis [integrated discrimination improvement (IDI) index 0.03, p = 0.03] and number of obstructive vessels (IDI index 0.06, p = 0.002), and by trend for segment stenosis score (IDI 0.03, p = 0.06).

Conclusion

For asymptomatic diabetic individuals, CCTA measures of CAD severity confer incremental risk prediction, discrimination and reclassification on a per-patient, per-vessel and per-segment basis.     

PDZD7 is a modifier of retinal disease and a contributor to digenic Usher syndrome

Usher syndrome is a genetically heterogeneous recessive disease characterized by hearing loss and retinitis pigmentosa (RP). It frequently presents with unexplained, often intrafamilial, variability of the visual phenotype. Although 9 genes have been linked with Usher syndrome, many patients do not have mutations in any of these genes, suggesting that there are still unidentified genes involved in the syndrome. Here, we have determined that mutations in PDZ domain–containing 7 (PDZD7), which encodes a homolog of proteins mutated in Usher syndrome subtype 1C (USH1C) and USH2D, contribute to Usher syndrome. Mutations in PDZD7 were identified only in patients with mutations in other known Usher genes. In a set of sisters, each with a homozygous mutation in USH2A, a frame-shift mutation in PDZD7 was present in the sister with more severe RP and earlier disease onset. Further, heterozygous PDZD7 mutations were present in patients with truncating mutations in USH2A, G protein–coupled receptor 98 (GPR98; also known as USH2C), and an unidentified locus. We validated the human genotypes using zebrafish, and our findings were consistent with digenic inheritance of PDZD7 and GPR98, and with PDZD7 as a retinal disease modifier in patients with USH2A. Pdzd7 knockdown produced an Usher-like phenotype in zebrafish, exacerbated retinal cell death in combination with ush2a or gpr98, and reduced Gpr98 localization in the region of the photoreceptor connecting cilium. Our data challenge the view of Usher syndrome as a traditional Mendelian disorder and support the reclassification of Usher syndrome as an oligogenic disease.     

Dietary intake of phytoestrogens, estrogen receptor-beta polymorphisms and the risk of prostate cancer

BACKGROUND: The causes of prostate cancer are poorly understood, but genetic factors may be more important than for many other malignancies, and dietary phytoestrogens may be protective. Because phytoestrogens bind tightly to the estrogen receptor-beta, we conducted an epidemiologic investigation of synergistic effects between phytoestrogen intake and estrogen receptor-beta gene polymorphisms. METHODS: We performed a population-based case-control study in Sweden. All participants reported their phytoestrogen intake and donated a blood sample. We identified four haplotype-tagging single nucleotide polymorphisms (htSNPs) and genotyped these htSNPs in 1314 prostate cancer patients and 782 controls. Odds ratios were estimated by multivariate logistic regression. Interactions between phytoestrogen intake and estrogen receptor-beta SNPs on prostate cancer risk were evaluated considering both multiplicative and additive effect scales. RESULTS: We found a significant multiplicative interaction (P = 0.04) between dietary intake of phytoestrogens and a promoter SNP in the estrogen receptor-beta gene (rs 2987983-13950), but not with any of the three other htSNPs (P = 0.11, 0.69, 0.85). Among carriers of the variant promoter alleles, we found strong inverse associations with increasing intake of total phytoestrogens (odds ratio for highest vs. lowest quartile = 0.43; P for trend <0.001), isoflavonoids (odds ratio = 0.63; P for trend = 0.05), and coumestrol (odds ratio = 0.57; P for trend = 0.003). We found no association between phytoestrogens and prostate cancer among carriers homozygous for the wild-type allele (TT). CONCLUSIONS: Our study provides strong evidence that high intake of phytoestrogens substantially reduce prostate cancer risk among men with specific polymorphic variation in the promoter region of the estrogen receptor-beta gene.     

Robot-assisted Radical Cystectomy: Description of an Evolved Approach to Radical Cystectomy

Background

Although open radical cystectomy (ORC) remains the gold standard of care for muscle-invasive bladder cancer, robot-assisted radical cystectomy (RARC) continues to gain wider acceptance. In this article, we focus on the steps of RARC, describing our approach, which has been developed over the past 10 yr. Totally intracorporeal RARC aims to offer the benefits of a complete minimally invasive approach while replicating the oncologic outcomes of open surgery.

Objective

We report our outcomes of a totally intracorporeal RARC procedure, describing step by step our technique and highlighting the variations on this standard template of nerve-sparing and female organ–preserving approaches in men and women.

Design, setting, and participants

Between December 2003 and October 2012, a total of 113 patients (94 male and 19 female) underwent totally intracorporeal RARC.

Surgical procedure

We performed RARC, extended pelvic lymph node dissection, and a totally intracorporeal urinary diversion (UD) in all patients. In the accompanying video, we focus on the standard template for RARC, also describing nerve-sparing and female organ–preserving approaches.

Outcome measurements and statistical analysis

Complications and oncologic outcomes are reported, including overall survival (OS) and cancer-specific survival (CSS) using Kaplan-Meier analysis.

Results and limitations

RARC with intracorporeal UD was performed in 113 patients. Mean age was 64 yr (range: 37–84). Forty-three patients underwent intracorporeal ileal conduit, and 70 had intracorporeal neobladder. On surgical pathology, 48% of patients had ≤pT1 disease, 27% had pT2 disease, 13% had pT3 disease, and 12% had pT4 disease. The mean number of lymph nodes removed was 21 (range: 0–57). Twenty percent of patients had lymph node–positive disease. Positive surgical margins occurred in six cases (5.3%). Median follow-up was 25 mo (range: 3–107). We recorded a total of 70 early complications (0–30 d) in 54 patients (47.8%), with 37 patients (32.7%) having Clavien grade ≥3. Thirty-six late complications (>30 d) were recorded in 30 patients (26.5%), with 20 patients (17.7%) having Clavien grade ≥3. One patient (0.9%) died within 90 days of operation from pulmonary embolism. Using Kaplan-Meier analysis, CSS was 81% at 3 yr and 67% at 5 yr.

Conclusions

Our structured approach to RARC has enabled us to develop this complex service while maintaining patient outcomes and complication rates comparable with ORC series. Our results demonstrate acceptable oncologic outcomes and encouraging long-term CSS rates.     

Validation of the translation and cross-cultural adaptation into Finnish of the Abdominal Symptom Questionnaire, the Hospital Anxiety and Depression Scale and the Complaint Score Questionnaire

BACKGROUND: Epidemiological surveys require questionnaires to be validated in the native language of the participants. The aim of this study was to validate the Finnish translations of the Abdominal Symptom Questionnaire (ASQ), the Hospital Anxiety and Depression Scale (HAD) and the Complaint Score Questionnaire (CSQ). METHODS: A random sample of adults (n = 3000) in a northern Swedish bilingual district was surveyed using a mailed ASQ offered in both SwedIsh and Finnish, and 2122 responded (239 in Finnish). A random subsample of the responders (n = 1001, 123 preferring Finish) was then surveyed once more using the ASQ, the HAD and the CSQ. The first 50 responders of the latter survey were then given the three questionnaires again within two weeks. The Finnish versions had been put through a comprehensive translation procedure RESULTS: A factor analysis comparison between the responders using either language in the mailed survey gave a comparable factor construction, and this was also comparable with an earlier analysis of the Swedish version. The Finnish responses to the second survey were further evaluated by testing internal consistency reliability, convergent validity towards previously validated relevant instruments (ShortForm-36 and the Gastrointestinal Symptom Rating Scale) and the test/re-test accuracy of the three questionnaires. These were found to be reliable, as was the correlation between the ASQ and the CSQ, for relevant domains. CONCLUSION: The Finnish translations of the ASQ, HAD and CSQ questionnaires all seem to be robust and usable for population-based surveys among Finnish adults.     

Changes in nitric oxide release in vivo in response to vasoactive substances.

1. Changes in the release of nitric oxide (NO) in vivo were studied in rats following the administration of endothelium-dependent and -independent vasodilators as well as the NO synthesis inhibitor, NG-nitro-L-arginine methyl ester (L-NAME). NO production was assessed by measuring variations of nitrate in plasma by capillary ion analysis. 2. Intravenous administration of the endothelium-dependent vasodilators, bradykinin (2 and 10 micrograms kg-1 min-1) or substance P (0.3-3 micrograms kg-1 min-1) caused a transient dose-dependent hypotension followed by an increase in plasma nitrate concentration (maximal increments: 33 +/- 5% and 38 +/- 6%, for bradykinin and substance P, respectively). Prior administration of L-NAME (10 mg kg-1 min-1) inhibited the hypotension and increase in plasma nitrate caused by these substances. Intravenous administration of sodium nitrate (200 micrograms kg-1) also produced a transitory elevation in plasma nitrate which was similar in magnitude as that caused by the vasodilators. A rapid and transitory increment in plasma nitrate was observed after i.v. administration of authentic NO (400 micrograms kg-1). 3. Rats receiving the endothelium-dependent vasodilators, prostacyclin (0.6 micrograms kg-1 min-1) or adenosine (3 mg kg-1 min-1) intravenously showed a drop in blood pressure paralleled by a decrease in plasma nitrate (maximal decreases: 34 +/- 5% and 24 +/- 4%, for prostacyclin and adenosine, respectively). A similar effect on the plasmatic concentration of nitrate was observed when L-NAME (10 mg kg-1 min-1, i.v.) was administered to the animals. 4. This study demonstrates that (i) changes in plasma nitrate can be detected in vivo after stimulation or inhibition of NO synthase, (ii) an increased production of NO, measured as plasma nitrate, is related to the hypotension caused by bradykinin and substance P and (iii) a diminished concentration of plasmatic nitrate is associated to the hypotension induced by adenosine or prostacyclin (endothelium-independent vasodilators), suggesting that the L-arginine: NO pathway is capable of rapid down-regulation in response to a fall in blood pressure.     

Brain activation by short-term nicotine exposure in anesthetized wild-type and beta2-nicotinic receptors knockout mice: a BOLD fMRI study

Rationale

The behavioral effects of nicotine and the role of the beta2-containing nicotinic receptors in these behaviors are well documented. However, the behaviors altered by nicotine rely on the functioning on multiple brain circuits where the high-affinity beta2-containing nicotinic receptors (β2*nAChRs) are located.

Objectives

We intend to see which brain circuits are activated when nicotine is given in animals naïve for nicotine and whether the β2*nAChRs are needed for its activation of the blood oxygen level dependent (BOLD) signal in all brain areas.

Materials and methods

We used functional magnetic resonance imaging (fMRI) to measure the brain activation evoked by nicotine (1 mg/kg delivered at a slow rate for 45 min) in anesthetized C57BL/6J mice and beta2 knockout (KO) mice.

Results

Acute nicotine injection results in a significant increased activation in anterior frontal, motor, and somatosensory cortices and in the ventral tegmental area and the substantia nigra. Anesthetized mice receiving no nicotine injection exhibited a major decreased activation in all cortical and subcortical structures, likely due to prolonged anesthesia. At a global level, beta2 KO mice were not rescued from the globally declining BOLD signal. However, nicotine still activated regions of a meso-cortico-limbic circuit likely via alpha7 nicotinic receptors.

Conclusions

Acute nicotine exposure compensates for the drop in brain activation due to anesthesia through the meso-cortico-limbic network via the action of nicotine on β2*nAChRs. The developed fMRI method is suitable for comparing responses in wild-type and mutant mice.