Developing a vape shop-based smoking cessation intervention: a Delphi study.

INTRODUCTION: Providing access to a vape shop-based smoking cessation intervention may simultaneously increase e-cigarette use and increase the effectiveness of e-cigarettes for smoking cessation. The aim of this study was to identify the most important elements of vape shop-based smoking intervention to stakeholders who would be involved in delivering or accessing such an intervention. METHODS: We conducted a three-round Delphi study of vape shop staff (n=40), stop smoking professionals and tobacco control leads (n=30), and smokers, vapers and dual users (n=30) in the United Kingdom in May-August 2021. In each round participants were asked whether they agreed or disagreed statements related to vape shop-based interventions. RESULTS: Forty-six of 95 statements reached consensus in round one, 29 out of 49 in round two and eight out of 20 in round three. There was support for a vape shop-based intervention across stakeholder groups (96%). There was consensus that the service should comprise both product (98%) and behavioural support (97%), and that quitting vaping should not be a goal of the service (79%). Although there was consensus that there should be some free product provision, there was less consensus as to what this should involve. Views were mostly consistent across stakeholder groups. CONCLUSIONS: There was broad consensus on how to deliver a vape shop-based smoking cessation intervention, providing a strong basis for future intervention development and implementation. Challenges around misuse of the service and misperceptions about vaping would need to be addressed for such an intervention to be feasible and effective. IMPLICATIONS: Many smokers who make a quit attempt using e-cigarettes purchase their vaping products in vape shops. Delivering vape-shop based smoking cessation interventions could help to maximise the effectiveness of e-cigarettes for quitting smoking. This study used a Delphi approach to identify the most important elements of a vape shop-based intervention among stakeholders. The findings could be used to help develop future interventions.

Identification of an N-terminal tag (580N) that improves the biosynthesis of fluorescent proteins in Francisella tularensis and other Gram-negative bacteria.

Utilization of fluorescent proteins is widespread for the study of microbial pathogenesis and host-pathogen interactions. Here, we discovered that linkage of the 36 N-terminal amino acids of FTL_0580 (a hypothetical protein of Francisella tularensis) to fluorescent proteins increases the fluorescence emission of bacteria that express these recombinant fusions. This N-terminal peptide will be referred to as 580N. Western blotting revealed that the linkage of 580N to Emerald Green Fluorescent Protein (EmGFP) in F. tularensis markedly improved detection of this protein. We therefore hypothesized that transcripts containing 580N may be translated more efficiently than those lacking the coding sequence for this leader peptide. In support, expression of emGFPFt that had been codon-optimized for F. tularensis, yielded significantly enhanced fluorescence than its non-optimized counterpart. Furthermore, fusing emGFP with coding sequence for a small N-terminal peptide (Serine-Lysine-Isoleucine-Lysine), which had previously been shown to inhibit ribosomal stalling, produced robust fluorescence when expressed in F. tularensis. These findings support the interpretation that 580N enhances the translation efficiency of fluorescent proteins in F. tularensis. Interestingly, expression of non-optimized 580N-emGFP produced greater fluorescence intensity than any other construct. Structural predictions suggested that RNA secondary structure also may be influencing translation efficiency. When expressed in Escherichia coli and Klebsiella pneumoniae bacteria, 580N-emGFP produced increased green fluorescence compared to untagged emGFP (neither allele was codon optimized for these bacteria). In conclusion, fusing the coding sequence for the 580N leader peptide to recombinant genes might serve as an economical alternative to codon optimization for enhancing protein expression in bacteria.

How should a vape shop-based smoking cessation intervention be delivered? A qualitative study.

INTRODUCTION: Encouraging smokers to quit smoking tobacco using e-cigarettes could substantially reduce smoking-related diseases. Vape shops therefore have the potential to play an important role in supporting smoking cessation. The aim of this study was to explore how to deliver a vape shop-based smoking cessation intervention in the United Kingdom. METHOD: Semi-structured telephone interviews were undertaken with four stakeholder groups: 20 stop smoking service (SSS) providers, seven tobacco control leads (TCL), seven smokers/vapers and five vape shop staff). Interviews were analysed thematically. RESULTS: Stakeholder groups were positive about the idea of delivering a vape shop-based intervention. Themes that were identified were the characteristics of the intervention (duration and timing; delivery; style and content; and product provisions); barriers to the intervention (challenges for new vapers; false information; tobacco company involvement; and conflicts of interest); facilitators to the intervention (positive views on vaping; cost-effectiveness; popularity; and accessibility); and considerations for the intervention (data protection and privacy; aesthetics; and regulation and management). The results suggest that the intervention should be delivered by vape shop workers with mandatory training with the support of SSS. Most stakeholders agreed quitting vaping was not a priority, but that information on how to reduce nicotine use should be given. Concerns around privacy, GDPR, misinformation about vaping and tobacco company involvement would need to be addressed. CONCLUSIONS: Stakeholders agree that vape shops should offer stop smoking interventions and hold similar opinions on how this should be delivered. IMPLICATIONS: This study suggests that smokers, vapers and other key stakeholders are positive about the idea of a stop smoking vape-shop based intervention and that they hold similar opinions on how this should be delivered. Most participants felt that this should be primarily delivered by trained vape shop staff and run with support from SSS. Participants agreed that a stop smoking vape shop-based intervention should be flexible in terms of the type, duration and frequency of support provided, and that the intervention should comprise both technical guidance on using a vape and behavioural support to prevent a return to smoking.

Using Health Education to Address Student Physical Activity and Nutrition: Evidence and Implications to Advance Practice.

BACKGROUND: School-based health education can provide students with learning experiences that improve knowledge, attitudes, and perceptions (KAP) and behaviors regarding physical activity and nutrition. METHODS: We conducted a 2-phase systematic review. Phase 1 was a review of reviews (ie, systematic reviews or meta-analyses) that were published 2010-2018. Phase 2 was a search for individual articles published 2010-2020 addressing topics relevant to our review; we searched for articles that had not been part of a sufficiently relevant or recent review or that had been part of a review that concluded that too few articles were available to assert sufficient evidence. RESULTS: Forty-three studies were assessed: 20 randomized controlled trials and 23 quasi-experimental designs. Collectively, interventions had a favorable impact on students' PA and nutrition KAP, but behavioral and secondary outcome results (eg, body mass index) were mixed. CONCLUSIONS: Using the evidence-based health education strategies identified in this review can help contribute to improvements in students' KAP and behaviors.

Transradial approach for pediatric interventions: A review and analysis of the literature.

BACKGROUND: Transradial access for interventions has been well studied in the adult population, but there is a paucity of literature of its use in the pediatric population. METHODS: We conducted a systematic literature review and gathered and synthesized all of the available data into a cohesive resource for review and analysis of the topic. RESULTS: Pooled analysis of the available data shows that transradial access in pediatric patients has a success rate of 91%, a vasospasm rate of 11.4%, and loss of pulse rate of 3.0% for a total complication rate of 14%. No permanent complications, or complications requiring surgery, were observed in any study. After stratifying for indication of intervention, neurological indications were associated with a lower complication rate compared to cardiac indications (0.1 vs 0.43, respectively, p = 0.004). In addition, studies published after 2013 were associated with a lower complication rate compared to those published during or before 2013 (0.11 vs 0.33, respectively, p = 0.01). CONCLUSION: Compared to prior studies on pediatric transfemoral access, transradial access has a higher complication rate. But there may be a lower rate of complications that require surgical intervention. Further studies are needed to clarify any advantages that transradial access may have over transfemoral access for pediatric patients.

Long-Term Implant Survivorship and Modes of Failure in Simultaneous Concurrent Bilateral Total Knee Arthroplasty.

BACKGROUND: There is limited evidence describing long-term implant survivorship and modes of failure in simultaneous concurrent bilateral total knee arthroplasty (TKA). METHODS: We performed a retrospective review of 266 consecutive patients (532 knees) who underwent simultaneous concurrent bilateral TKA. We reviewed medical records for preoperative characteristics, perioperative complications, and revision surgeries. The primary outcome was TKA survivorship. Secondary outcomes included indication and type of revision surgery. We used the Kaplan-Meier method to estimate survivorship and characterize risk of revision up to 20 years post-TKA. RESULTS: Our cohort had median follow-up of 9.8 years (interquartile range, 3.9-15.9). Forty-four patients (17%) underwent revision. Revision was more common among younger and male patients. The cumulative incidence of first-time revision per knee (n = 532) was 1.27 per 100 component-years. Implant survival was 99% (confidence interval, 97%-99%) at 5 years, 92% (89%-95%) at 10 years, 83% (77%-87%) at 15 years, and 62% (50%-73%) at 20 years. Five and 10-year survivorship compared favorably to estimates of TKA survivorship in the literature. The cumulative incidence of revision surgery per patient was 1.91 per 100 component-years. Implant survival at 5-, 10-, 15-, and 20-year time points was 96% (CI, 92%-98%), 84% (77%-89%), 71% (62%-79%), and 59% (46%-70%), respectively. Aseptic loosening (40%), polyethylene wear (34%), and infection (11%) were the most common indications for revision. CONCLUSION: Simultaneous concurrent bilateral TKA is associated with a higher risk of reoperation for the patient when both knees are evaluated but similar implant survivorship to the literature when each knee was evaluated in isolation.

Identification of novel risk loci, causal insights, and heritable risk for Parkinson's disease: a meta-analysis of genome-wide association studies.

BACKGROUND: Genome-wide association studies (GWAS) in Parkinson's disease have increased the scope of biological knowledge about the disease over the past decade. We aimed to use the largest aggregate of GWAS data to identify novel risk loci and gain further insight into the causes of Parkinson's disease. METHODS: We did a meta-analysis of 17 datasets from Parkinson's disease GWAS available from European ancestry samples to nominate novel loci for disease risk. These datasets incorporated all available data. We then used these data to estimate heritable risk and develop predictive models of this heritability. We also used large gene expression and methylation resources to examine possible functional consequences as well as tissue, cell type, and biological pathway enrichments for the identified risk factors. Additionally, we examined shared genetic risk between Parkinson's disease and other phenotypes of interest via genetic correlations followed by Mendelian randomisation. FINDINGS: Between Oct 1, 2017, and Aug 9, 2018, we analysed 7·8 million single nucleotide polymorphisms in 37 688 cases, 18 618 UK Biobank proxy-cases (ie, individuals who do not have Parkinson's disease but have a first degree relative that does), and 1·4 million controls. We identified 90 independent genome-wide significant risk signals across 78 genomic regions, including 38 novel independent risk signals in 37 loci. These 90 variants explained 16-36% of the heritable risk of Parkinson's disease depending on prevalence. Integrating methylation and expression data within a Mendelian randomisation framework identified putatively associated genes at 70 risk signals underlying GWAS loci for follow-up functional studies. Tissue-specific expression enrichment analyses suggested Parkinson's disease loci were heavily brain-enriched, with specific neuronal cell types being implicated from single cell data. We found significant genetic correlations with brain volumes (false discovery rate-adjusted p=0·0035 for intracranial volume, p=0·024 for putamen volume), smoking status (p=0·024), and educational attainment (p=0·038). Mendelian randomisation between cognitive performance and Parkinson's disease risk showed a robust association (p=8·00 × 10-7). INTERPRETATION: These data provide the most comprehensive survey of genetic risk within Parkinson's disease to date, to the best of our knowledge, by revealing many additional Parkinson's disease risk loci, providing a biological context for these risk factors, and showing that a considerable genetic component of this disease remains unidentified. These associations derived from European ancestry datasets will need to be followed-up with more diverse data. FUNDING: The National Institute on Aging at the National Institutes of Health (USA), The Michael J Fox Foundation, and The Parkinson's Foundation (see appendix for full list of funding sources).

The prognostic value and pathophysiologic significance of three-dimensional fluid-attenuated inversion recovery (3D-FLAIR) magnetic resonance imaging in idiopathic sudden sensorineural hearing loss: A systematic review and meta-analysis.

BACKGROUND: The underlying pathophysiology of idiopathic sudden sensorineural hearing loss (ISSNHL) is still unknown. However, an increasing number of observational studies report intralabyrinthine signal alterations in patients with ISSNHL using three-dimensional fluid-attenuated inversion recovery (3D-FLAIR) magnetic resonance imaging (MRI). These findings warrant a meta-analysis. OBJECTIVE OF REVIEW: To conduct a meta-analysis assessing the value of 3D-FLAIR MRI in identifying possible underlying labyrinthine pathophysiologic mechanisms and prognostication in patients with ISSNHL. SEARCH STRATEGY: Two reviewers independently searched the Pubmed, Embase and Cochrane Library from inception until October 10, 2018 and evaluated eligibility based on titles and abstracts of all retrieved studies. All studies reporting on 3D-FLAIR imaging in ISSNHL were included. Subsequently, the full text of eligible studies were evaluated. EVALUATION METHOD: Adhering to the MOOSE guideline, two independent reviewers extracted data, assessed risk of bias and evaluated the relevance and quality of evidence. Data on the number of patients and events were extracted and hearing levels were converted to standardised mean differences (SMD) for conducting meta-analyses. Random effects models for meta-analyses were applied. RESULTS: Eight observational studies met our inclusion criteria (n = 638 patients). In 29%, high signal intensity was found on 3D-FLAIR imaging, suggesting labyrinthine pathology (labyrinthitis [79%], intralabyrinthine haemorrhage [21%]). High signal intensity on 3D-FLAIR was associated with poorer hearing (SMD: 14 dB, 95% CI 5.67-22.94) and vertigo (RR: 1.92, 95% CI 1.16-3.17) at baseline. Multivariate analyses demonstrated that patients with high 3D-FLAIR signal intensity had 21 dB lower final hearing pure-tone averages (SMD: 21 dB, 95% CI 9.08-33.24). CONCLUSIONS: Three-dimensional fluid-attenuated inversion recovery MR imaging can identify an underlying labyrinthine condition in up to 29% of patients with sudden hearing loss in whom previously no cause could be identified. Their final pure-tone averages are more than 20 dB worse than 3D-FLAIR-negative patients, suggesting more severe labyrinthine damage. Findings such as these may contribute to our understanding of pathophysiologic mechanisms of ISSNHL.

Subjective and objective vestibular changes that occur following paediatric cochlear implantation: systematic review and meta-analysis.

OBJECTIVE: Cochlear implantation can result in post-operative vestibular dysfunction of unknown clinical significance. The objective of this study was to characterize the presence, magnitude, and clinical significance of vestibular dysfunction that occurs after pediatric cochlear implantation. DATA SOURCES: The databases Embase, Medline (OvidSP), and PubMed were used. Only articles published in English were included. Grey literature and unpublished sources were also reviewed. STUDY SELECTION: Articles published from 1980 until the present which documented pre-operative and post-operative vestibular testing on children under the age of 18 were used. DATA EXTRACTION: Parameters that were assessed included number of patients, pre- and post-operative vestibular-evoked myogenic potentials (VEMPs), head impulse testing (HIT), calorics, and posturography, timing of pre- and post-operative testing, symptomatology, and other demographic data such as etiology of the hearing loss. DATA SYNTHESIS: Ten articles were included. Relative risk values evaluating the effect of cochlear implantation on vestibular function were calculated for VEMPs and caloric testing due to the availability of published data. I2 values were calculated and 95% confidence intervals were reported. Separate analyses were conducted for each individual study and a pooled analysis was conducted to yield an overall relative risk. Assessment on risk of bias in individual studies and overall was performed. CONCLUSION: Pediatric cochlear implantation is associated with a statistically significant decrease in VEMP responses post-operatively (RR 1.8, p < 0.001, I2 91.86, 95%CI 1.57-2.02). Similar results are not seen in caloric testing. Insufficient data is available for analysis of HIT and posturography. Further studies are necessary to determine the effect of cochlear implantation on objective vestibular measures post-operatively and whether any changes seen are clinically relevant in this population.

Pulsatile nystagmus secondary to semicircular canal dehiscence.

We report the case of a 69-year-old man with a history of mastoidectomy for cholesteatoma, who developed spontaneous spinning vertigo on debridement of his cavity. Subsequent CT confirmed a lateral semicircular canal fistula, which was surgically closed with mastoid cavity obliteration. Following surgery, he developed a spontaneous, pulse-synchronous horizontal pendular nystagmus. We discuss the pathophysiology of this rare clinical sign.

The olfactory mucosa: a potential source of stem cells for hearing regeneration.

The olfactory mucosa contains cells that enable it to generate new neurons and other supporting cells throughout life, allowing it to replace cells of the mucosa that have been damaged by exposure to various insults. In this article, we discuss the different types of stem cell found within the olfactory mucosa and their properties. In particular, the mesenchymal-like cells found within the lamina propria will be reviewed in detail. In addition, we discuss potential applications of olfactory-derived stem cells toward hearing regeneration secondary to either inner hair cell loss or primary or secondary auditory nerve degeneration.

Incorporation of a Physical Education and Nutrition Program Into Neurosurgery: A Proof of Concept Pilot Program.

BACKGROUND: Balancing the demands of a busy medical career with personal wellness can be daunting, and there is little education on these principles available to physicians in training. OBJECTIVE: To implement a voluntary wellness initiative in our neurosurgery department to promote healthy lifestyle choices. This report details the baseline data collected as part of this quality improvement initiative. METHODS: The wellness initiative was implemented in July 2015 and available to all faculty and resident physicians in the Department of Neurological Surgery in collaboration with the Medical University of South Carolina Wellness Center. All participants were provided a Fitbit Surge HR wrist monitor (Fitbit, Boston, Massachusetts) and underwent baseline physical and psychological testing. RESULTS: Six faculty physicians and 9 residents participated. Overall physical fitness levels varied widely between subjects. Health screening demonstrated abnormalities in 80% of participants (elevated systolic blood pressure in 60%, elevated diastolic in 47%, elevated serum low-density lipoprotein in 53%). Body composition analysis demonstrated body weight higher than ideal in 69% (47% overweight; 13% obese). Recommended average body fat mass reduction was 25.4 pounds. Seventy-nine percent reported below-average quality of life compared with the average healthy adult. All subjects reported wanting more time for personal health. CONCLUSION: Baseline health and psychological screenings in our department demonstrated alarmingly prevalent, previously undiagnosed abnormalities on cardiovascular and body weight screenings. Obstacles to leading a healthier lifestyle have been identified and solutions have been incorporated into the program. This quality improvement initiative may serve as a template for other programs seeking to improve physician physical and mental well-being. ABBREVIATIONS: BMI, body mass indexESS, Epworth Sleepiness ScaleHR, heart rate.

Estrogen receptor α polymorphism in a species with alternative behavioral phenotypes.

The evolution of behavior relies on changes at the level of the genome; yet the ability to attribute a behavioral change to a specific, naturally occurring genetic change is rare in vertebrates. In the white-throated sparrow (Zonotrichia albicollis), a chromosomal polymorphism (ZAL2/2(m)) is known to segregate with a behavioral phenotype. Individuals with the ZAL2(m) haplotype engage in more territorial aggression and less parental behavior than individuals without it. These behaviors are thought to be mediated by sensitivity to sex steroids, and the chromosomal rearrangement underlying the polymorphism has captured a prime candidate gene: estrogen receptor 1 (ESR1), which encodes estrogen receptor α (ERα). We therefore hypothesized that the behavioral effects of the ZAL2(m) rearrangement are mediated by polymorphism in ESR1. We report here that (i) the ESR1 promoter region contains fixed polymorphisms distinguishing the ZAL2(m) and ZAL2 alleles; (ii); those polymorphisms regulate transcription efficiency in vitro and therefore potentially do the same in vivo (iii); the local expression of ERα in the brain depends strongly on genotype in a free-living population; and (iv) ERα expression in the medial amygdala and medial preoptic area may fully mediate the effects of genotype on territorial aggression and parenting, respectively. Thus, our study provides a rare glimpse of how a chromosomal polymorphism has affected the brain and social behavior in a vertebrate. Our results suggest that in this species, differentiation of ESR1 has played a causal role in the evolution of phenotypes with alternative life-history strategies.

Preoperative cardiopulmonary exercise testing in England - a national survey.

BACKGROUND: Cardiopulmonary exercise testing (CPET) has become well established in the preoperative assessment of patients presenting for major surgery in the United Kingdom. There is evidence supporting its use in risk-stratifying patients prior to major high-risk surgical procedures.We set out to establish how CPET services in England have developed since the only survey on this subject was undertaken in 2008 (J Intensive Care Soc 2009, 10:275-278). METHODS: Availability of preoperative CPET and contact details were collected via a telephone survey and email invites to complete the online survey were sent to all contacts. The survey was live during March and April 2011. RESULTS: We received 123 (74%) responses from the 166 emails that were sent out. In total, 32% (53/166) of all adult anesthetic departments in England have access to preoperative CPET services and a further 4% (6) were in the process of setting up services. The number of departments offering preoperative CPET, including those in the process of setting up services, has risen from 42 in 2008 to 59 in 2011, a rise of over 40%. Only 61% of the clinics are run by anesthetists and 39% of clinics have trained cardiorespiratory technicians assisting in the performance of the test. Most of the clinics (55%) rely solely on a bicycle ergometer. Vascular surgical patients are the largest group of patients tested, and the majority of tests are run to a symptom-limited maximum. We estimate that 15,000 tests are performed annually for preoperative assessment in England. Only 37% of respondents were confident that the tests performed were being billed for. CONCLUSIONS: CPET is increasing in popularity as a preoperative risk assessment tool. There remains a lack of consistency in the way tests are reported and utilized. The results highlight the extent and diversity of the use of preoperative CPET and the potential for further research into its use in unstudied patient groups.

Locoregional anesthesia for endovascular aneurysm repair.

OBJECTIVE: This was a systematic review and meta-analysis of the mode of anesthesia and outcome after endovascular aneurysm repair (EVAR). METHODS: Review methods were according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. Published and unpublished literature was searched. The primary outcome was 30-day mortality. Secondary outcomes were categorized for patient selection, perioperative outcomes, and postoperative outcomes. Weighted mean differences (WMD) were calculated for continuous variables, such as length of stay, and pooled odds ratios (OR) were calculated for discrete variables such as major morbidity. RESULTS: Ten studies of 13,459 patients given local anesthesia (LA) or general anesthesia (GA) were eligible for analysis. There was no difference in 30-day mortality. The LA patients were older than the GA patients (WMD, 0.17; P = .006), with an increased burden of cardiac (LA vs GA: OR, 1.28; P = .011) and respiratory (LA vs GA: OR, 1.28; P = .006) comorbidity. LA EVAR was reported with shorter operative time (WMD, -0.54; P = .001) and hospital stay (WMD, -0.27; P = .001) vs GA. LA patients developed fewer postoperative complications than GA patients (OR, 0.54; P < .001). CONCLUSIONS: The absence of randomized data is a major hurdle to understanding the effect of anesthetic technique on morbidity after EVAR. The data presented are encouraging in selected patients. The use of locoregional anesthesia for EVAR should be further investigated with better reporting of aneurysm morphology to clarify its potential benefits and identify the subgroups that will derive greatest benefit.

Postmenopausal obesity promotes tumor angiogenesis and breast cancer progression in mice.

Obese postmenopausal women have a 50% higher risk of breast cancer than non-obese women. There is not an animal model that mimics postmenopausal obesity related to breast cancer progression. Using age-relevant C57BL/6 mice, this study determined whether postmenopausal obesity increases VEGF expression, tumor angiogenesis, and breast tumor growth. Ovariectomy (OVX) was performed in 12 sixty week-old female mice, then followed by a low-fat (5%, LF, n=6) or a high-fat (60%, HF, n=6) diet for 12 weeks. In the eighth week of the dietary program, 10(6) E0771 (mouse breast cancer) cells were injected in the left fourth mammary gland. Tumor size was monitored for 4 weeks. Body weights were monitored weekly. At the end of the experiment, blood samples, visceral fat and tumors were collected for measuring VEGF expression using ELISA and intratumoral microvessel density (IMD) using CD31 immunochemistry. Body weight was significantly increased in OVX/HF mice, compared to OVX/LF group (55.3±1.7 vs. 41.5±1.5 g; p < 0.01). There was a two-fold increase in the ratio of visceral fat/BW in OVX/HF mice, compared to those in OVX/LF group (0.062±0.005 vs. 0.032±0.003; p < 0.01). Postmenopausal obesity significantly increased breast tumor weight over the control (4.62±0.63 vs. 1.98±0.27 g; p < 0.01) and IMD (173±3.7 vs. 139±4.3 IM#/mm^2; p < 0.01). Tumor VEGF levels were higher in OVX/HF mice, compared to OVX/LF group (73.3±3.8 vs. 49.5±4.3 pg/mg protein; p < 0.01). Plasma VEGF levels (69±7.1 vs. 48±3.5 pg/ml) and visceral fat VEGF levels (424.4±39.5 vs. 208.5±22.4 pg/mg protein) were significantly increased in OVX/HF mice, compared to OVX/LF group, respectively (n=6; p < 0.01). Interestingly, adipose tissue primary culture showed that subcutaneous fat released more VEGF, compared to visceral fat (6.77±1.14 vs. 0.94±0.16 pg/mg tissue; n=6; p < 0.01). These findings support the hypothesis that postmenopausal obesity promotes tumor angiogenesis and breast cancer progression, possibly through increased adipose tissue mass and adipokines such as VEGF that could systemically and locally affect breast cancer progression.

SU11248, a selective tyrosine kinases inhibitor suppresses breast tumor angiogenesis and growth via targeting both tumor vasculature and breast cancer cells.

SU11248 is a selective inhibitor of certain protein kinases including VEGFR types 1-3 that are expressed in human breast cancer. The present study determines whether the anti-tumor activity of SU11248 results from the inhibition of angiogenesis, as well as direct anti-proliferation and anti-migration effects on breast tumors. Eight-wk old female mice (C57BL/6) were given SU11248 at 20-40 mg/kg/d in drinking (distilled) water for 4 wks. Control mice received drinking water only. In the 2nd wk, 10(6) E0771 (mouse breast cancer) cells were injected in the left fourth mammary gland. Tumor size was monitored using dial calipers. At the end, tumors were isolated for measuring tumor size and intratumoral microvessel density (IMD) using CD31 immunohistochemistry. SU11248 significantly reduced tumor weight over the control (1.22 ± 0.28 vs. 3.28 ± 0.31 g; n = 8; p < 0.01) and IMD (111 ± 10 vs. 155 ± 6 IM#/mm2; p < 0.01). RT-PCR indicated that VEGFR1 and R2 were expressed in cultured E0771 cells. VEGF (10 ng/ml) caused a 42% increase in proliferation of E0771 cells, compared to the control (p < 0.01; n = 8), and there was a significant decrease in proliferation of E0771 cells treated with VEGF plus SU11248 (10 µmol/L) vs. the control (65%, p < 0.01). VEGF caused a 2-fold increase in the proliferation of HUVEC vs. the control (p < 0.01; n = 8), but its action was completely eradicated by SU11248. Neither VEGF nor SU11248 had any effect on the proliferation of cultured HAS MC. Migration assay showed that SU11248 (10 µmol/L) significantly inhibited the migration of cultured E0771 cells. SU11248 significantly inhibited the proliferation of MCF-7 and MDAMB-231 cells in a dose-related manner. These findings support the hypothesis that the antitumor activity of SU11248 on breast cancer is possibly mediated by targeting the paracrine and autocrine effects of VEGF on breast cancer to suppress tumor angiogenesis, proliferation and migration.

Long-term high salt diet causes hypertension and alters renal cytokine gene expression profiles in Sprague-Dawley rats.

OBJECTIVE: The present study examines whether a long-term high salt diet causes hypertension and renal injury in normal subjects [Sprague-Dawley (SD) rats] and alters renal cytokine-related gene expression profiles. METHODS: Four 10 week old male SD rats received a high salt diet (HS, 8%) and the other 4 SD rats received a normal salt diet (NS, 0.5%) for 8 weeks. Mean arterial pressure (MAP) and renal damages such as albuminuria and histological renal injury were determined. The relative mRNA levels of 514 cytokine-related genes (normalized by beta-actin) in rat kidneys following NS or HS were determined quantitatively through analysis of 4 sets of gene expression profiles using the mouse cDNA membrane microarrays. RESULTS: We demonstrated that 8 weeks of HS diet increased MAP [(140.0+/-5.3) vs (112.0+/-2.2) mmHg; 1 mmHg=0.133 kPa, P<0.01], albuminuria [(41.4+/-3.2) vs (20.1+/-4.5) mg/d; P<0.01], and caused histological renal injury in SD rats, compared to NS group. Of the 514 genes in the array, there were 27 (5.25%) genes with significantly different expression in the kidney of SD rats with HS compared to those of SD rats with NS. Functional clustering analysis indicated the following functional pathways related to high salt diet-induced hypertension: (1) pro-inflammatory response ( upward arrowIL-17, CCL28; downward arrow NFkappabib); (2) endothelial dysfunction ( downward arrowVEGF-A, VEGF-B, endoglin); (3) pro-matrix formation ( upward arrowosteopontin, IGFBP-5; downward arrow IFN-gamma); and (4) attenuated cell survival and differentiation ( downward arrowCNTF, IGF-II R, ephrin-B1). Northern blot confirmed that 8 weeks of HS diet significantly decreased renal expression of VEGF mRNA, compared to NS group (P<0.01). ELISA showed that HS diet significantly decreased renal protein levels of VEGF and CCL28. CONCLUSION: These findings support the hypothesis that hypertension can be induced in normal rats by a long-term high salt diet, which is associated with increased renal injury and marked changes in renal cytokine gene expression profiles that are closely related to the pro-inflammatory response, pro-matrix formation, endothelial dysfunction, and attenuated cell survival and differentiation.

Comparison of atherosclerotic plaque burden and composition between diabetic and non diabetic patients by non invasive CT angiography.

Type 2 diabetes mellitus (DM) is associated with a higher risk of cardiovascular disease and atherosclerotic burden. However little data exists in regards to plaque distribution and plaque composition in these patients. To assess for differences in the coronary plaques burden and composition among symptomatic patients with and without type 2 DM using multidetector computed tomography angiography (MDCTA). The 416 symptomatic patients (64% males, mean age: 61 +/- 13 years) with 61 (15%) reporting type 2 DM, who underwent contrast-enhanced MDCTA were studied. Enrolled patients had an intermediate to high pre-test probability of obstructive coronary artery disease. Multivariate analysis was used to correct for differences in age and gender. Patients with type 2 DM were more likely to have significant stenosis >or=70% in at least one coronary segments (33% in type 2 DM vs. 18% in non diabetic, P = 0.013), whereas 11% of both type 2 DM and non diabetics had stenosis of 50-70% (P = NS). Also type 2 DM patients had a higher number of coronary segments with mixed plaques compared to nondiabetic patients (1.67 +/- 2.01 vs. 1.23 +/- 1.61, P = 0.05), whereas no such differences were observed for non-calcified or calcified plaques. Nearly half (43%) of type 2 DM had coronary artery calcium scores (CACS) >or=400 vs. 29% in non diabetic patients (P = 0.03). Patients with type 2 DM tend to have atherosclerotic plaques which are more likely to be mixed in nature. Future studies need to elucidate the prognostic value of differences in plaque characteristics observed according to type 2 diabetic status.

Vascular endothelial growth factor receptor inhibitor enhances dietary salt-induced hypertension in Sprague-Dawley rats.

Clinical evidence links the inhibition of VEGF to hypertension. However, the mechanisms by which VEGF affects the pathogenesis of hypertension remain in question. We determined 1) whether administration of VEGF receptor inhibitor SU5416 enhances dietary salt-induced hypertension in Sprague-Dawley (SD) rats, and 2) whether VEGF or SU5416 directly affects proliferation of cultured human renal proximal tubular epithelial cells (HRPTEC) and endothelial nitric oxide synthase (eNOS) expression in cultured human glomerular microvessel endothelial cells (HGMEC). Ten 10-wk-old male SD rats received a high sodium diet (HS; 8%) and the other 10 SD rats received a normal sodium diet (NS; 0.5%) for 4 wks. After 2 wks of the dietary program, five rats were administered with SU5416 at 10 mg x kg(-1) x day(-1) ip or DMSO (vehicle) for 14 days in HS and NS groups. Mean arterial pressure was significantly higher in rats treated with SU5416, as opposed to those treated with DMSO and fed with HS for 4 wk (157.6 +/- 3.9 vs. 125.9 +/- 4.3 mmHg, P < 0.01). Increased proteinuria and albuminuria were associated with marked renal histological abnormalities in HS group with SU5416 administration, compared with those in the vehicle HS group. 3H-thymidine incorporation assay showed that SU5416 blocked the actions of both exogenous and endogenous VEGF on the proliferation of HRPTEC. VEGF (10 ng/ml) significantly increased eNOS protein levels by 29% in cultured HGMEC, but its action was completely abolished by SU5416. These results suggest that VEGF receptor inhibition enhances dietary salt-induced hypertension and kidney injury, possibly by direct damage on renal cells and decreasing NO production by eNOS.