Precision Medicine to Redefine Insulin Secretion and Monogenic Diabetes-Randomized Controlled Trial (PRISM-RCT) in Chinese patients with young-onset diabetes: design, methods and baseline characteristics.

INTRODUCTION: We designed and implemented a patient-centered, data-driven, holistic care model with evaluation of its impacts on clinical outcomes in patients with young-onset type 2 diabetes (T2D) for which there is a lack of evidence-based practice guidelines. RESEARCH DESIGN AND METHODS: In this 3-year Precision Medicine to Redefine Insulin Secretion and Monogenic Diabetes-Randomized Controlled Trial, we evaluate the effects of a multicomponent care model integrating use of information and communication technology (Joint Asia Diabetes Evaluation (JADE) platform), biogenetic markers and patient-reported outcome measures in patients with T2D diagnosed at ≤40 years of age and aged ≤50 years. The JADE-PRISM group received 1 year of specialist-led team-based management using treatment algorithms guided by biogenetic markers (genome-wide single-nucleotide polymorphism arrays, exome-sequencing of 34 monogenic diabetes genes, C-peptide, autoantibodies) to achieve multiple treatment goals (glycated hemoglobin (HbA1c) <6.2%, blood pressure <120/75 mm Hg, low-density lipoprotein-cholesterol <1.2 mmol/L, waist circumference <80 cm (women) or <85 cm (men)) in a diabetes center setting versus usual care (JADE-only). The primary outcome is incidence of all diabetes-related complications. RESULTS: In 2020-2021, 884 patients (56.6% men, median (IQR) diabetes duration: 7 (3-12) years, current/ex-smokers: 32.5%, body mass index: 28.40±5.77 kg/m2, HbA1c: 7.52%±1.66%, insulin-treated: 27.7%) were assigned to JADE-only (n=443) or JADE-PRISM group (n=441). The profiles of the whole group included positive family history (74.7%), general obesity (51.4%), central obesity (79.2%), hypertension (66.7%), dyslipidemia (76.4%), albuminuria (35.4%), estimated glomerular filtration rate <60 mL/min/1.73 m2 (4.0%), retinopathy (13.8%), atherosclerotic cardiovascular disease (5.2%), cancer (3.1%), emotional distress (26%-38%) and suboptimal adherence (54%) with 5-item EuroQol for Quality of Life index of 0.88 (0.87-0.96). Overall, 13.7% attained ≥3 metabolic targets defined in secondary outcomes. In the JADE-PRISM group, 4.5% had pathogenic/likely pathogenic variants of monogenic diabetes genes; 5% had autoantibodies and 8.4% had fasting C-peptide <0.2 nmol/L. Other significant events included low/large birth weight (33.4%), childhood obesity (50.7%), mental illness (10.3%) and previous suicide attempts (3.6%). Among the women, 17.3% had polycystic ovary syndrome, 44.8% required insulin treatment during pregnancy and 17.3% experienced adverse pregnancy outcomes. CONCLUSIONS: Young-onset diabetes is characterized by complex etiologies with comorbidities including mental illness and lifecourse events. TRIAL REGISTRATION NUMBER: NCT04049149.

One-hour post-load plasma glucose level predicts future type 2 diabetes in a community-based study of Hong Kong Chinese workforce.

BACKGROUND: We compared performance of high 1-hour PG level, impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) in predicting type 2 diabetes in a longitudinal community-based cohort of Hong Kong Chinese. METHODS: Between 2001 and 2003, 472 adults aged 18-55 years without diabetes underwent 75-gram oral glucose tolerance test (OGTT). Between 2012 and 2014, progression to diabetes was ascertained by reviewing medical records or repeating OGTT and HbA1c. We defined high 1-hour PG as PG ≥ 8.6 mmol/L at 1-hour. RESULTS: In this cohort, 23.5% had normal glucose tolerance and high 1-hour PG, 10.0% had isolated IGT, 4.2% had isolated IFG. Over 12-year follow-up, 9.3% developed type 2 diabetes. In logistic regression, high 1-hour PG was associated with progression to type 2 diabetes with adjusted odds ratio (95% CI) of 4.20 (1.60, 12.40), independent of IFG, IGT and other clinical variables. Areas under ROC (95% CI) for type 2 diabetes were similar between 1-hour (0.84 [0.78, 0.89], 2-hour (0.79 [0.72, 0.86]) and fasting PG (0.79 [0.71, 0.86]). CONCLUSION: High 1-hour PG identified young Chinese with 5-fold increased risk of type 2 diabetes independent of other intermediate hyperglycaemia status and clinical factors. 1-hour PG is similar to fasting and 2-hour PG in predicting type 2 diabetes.

Psychosocial assessment of adolescents and young adults in paediatric hospital settings: patient and staff perspectives on implementation of the e-HEEADSSS.

BACKGROUND: The main causes of morbidity and mortality for adolescents and young adults are preventable and stem from psychosocial and behavioural concerns. Psychosocial assessments can help clinicians to identify and respond holistically to risks and strengths that may impact upon a young person's physical and mental health. Despite broad support at a policy level, the implementation of routine psychosocial screening for young people remains varied in Australian health settings. The current study focused on the pilot implementation of a digital patient-completed psychosocial assessment (the e-HEEADSSS) at the Sydney Children's Hospital Network. The aim of this research was to evaluate patient and staff barriers and facilitators to local implementation. METHODS: The research used a qualitative descriptive research design. Semi-structured interviews were conducted online with 8 young patients and 8 staff members who had completed or actioned an e-HEEADSSS assessment within the prior 5 weeks. Qualitative coding of interview transcripts was carried out in NVivo 12. The Consolidated Framework for Implementation Research guided the interview framework and qualitative analyses. RESULTS: Results demonstrated strong support for the e-HEEADSSS from patients and staff. Key reported facilitators included strong design and functionality, reduced time requirements, greater convenience, improved disclosure, adaptability across settings, greater perceived privacy, improved fidelity, and reduced stigma for young people. The key barriers were related to concerns over available resources, the sustainability and continuity of staff training, perceived availability of clinical pathways for follow-up and referrals, and risks related to off-site completions. Clinicians need to adequately explain the e-HEEADSSS assessment to patients, educate them about it, and make sure that they receive timely feedback on the results. Greater reassurance and education regarding the rigour of confidentiality and data handling procedures is required for patients and staff. CONCLUSIONS: Our findings indicate that continued work is required to support the integration and sustainability of digital psychosocial assessments for young people at the Sydney Children's Hospital Network. The e-HEEADSSS shows promise as an implementable intervention to achieve this goal. Further research is required to determine the scalability of this intervention across the broader health system.

Safety, Tolerability, and Effects of a Single Subcutaneous Administration of SP16 - a SERPIN-like, Small Peptide Agonist of the Low-Density Lipoprotein-like Receptor 1- on the Acute Inflammatory Response in Patients With ST-Segment Elevation Myocardial Infarction.

BACKGROUND: Modulation of the inflammatory response is a promising therapeutic strategy in acute myocardial infarction. The novel approach is based on the anti-inflammatory and cytoprotective properties mediated by the engagement of the low-density lipoprotein‒related protein 1 (LRP1) receptor. SERPIN peptide 16 (SP16) is a synthetic, selective LRP1 agonist. We herein present the results of a study with a single subcutaneous administration of SP16 in 10 patients with STEMI, to appraise its safety and tolerability and explore the effects on the acute inflammatory response, infarct size, and cardiac function. METHODS: Ten patients with ST-segment elevation myocardial infarction (STEMI) were enrolled within 12 hours of symptoms onset and 6 hours of percutaneous coronary intervention in a single-center, single-arm, open-label study of a single subcutaneous administration of SP16 (0.2 mg/kg). Serial clinical biomarkers and echocardiography data were collected up to 12 months. The data are presented separately for the treatment group and compared with historical controls from a placebo-treated arm in a recently completed clinical trial (N = 28) with similar enrollment criteria. RESULTS: All ten patients with STEMI received subcutaneous administration of SP16, 381 [272-478] minutes after percutaneous coronary intervention, without any treatment-related adverse events. The area under the curve for C-reactive protein was 133 [46-528] mg·d/L in the SP16-treated group versus 286 [141-581] mg·d/L in the historical placebo-treated group ( P = 0.161). The area under the curve for creatine kinase-myocardial band was 1432 [675-3089] ng·d/mL in the SP16-treated group versus 2367 [830-4750] ng·d/mL in the historical placebo-treated patients ( P = 0.428). Left ventricular ejection fraction was 46% [39-54] at baseline and 51% [46-58] at 1 year follow-up in SP16-treated patients (interval change 5% [-0.3% to +9%] P = 0.05) and 44% [38%-56%] at baseline and 53% [43%-59%] at 1 year follow-up in historical placebo-treated patients (interval change 3% [-5% to 10%], P = 0.305). CONCLUSION: A single subcutaneous administration of SP16, a synthetic targeted LRP1 agonist, was safe and well-tolerated in patients with STEMI. A trend toward reduction in the inflammatory response and infarct size with SP16 was noted; however, the sample size for this study was not based on formal statistical criteria. More extensive studies are planned to determine the clinical efficacy of SP16 in STEMI.NCT: NCT04225533.

Temporal Trends in New Registrations for the Ontario Cleft Lip and Palate/Craniofacial Dental Program Between 2007 and 2018.

BACKGROUND: The Ontario Cleft Lip and Palate/Craniofacial Dental Program was established to fund dental care for those with oral clefts, craniofacial anomalies, congenital oral defects, and acquired facial/oral defects. AIM: To determine the annual rates of newly registered oral clefts, craniofacial anomalies, congenital oral defects, and acquired oral defects cases on the Program from 2007 to 2018 and identify trends in registration rates during this time period. DESIGN: Data were obtained from the Program from 2007 to 2018. Annual, age-specific incidence rates (for age groups 0-4, 5-9, 10-14, 15-19, and 20-24 years) were calculated for new registrations in each diagnostic category, plotted and examined using Poisson regression analysis to identify trends. RESULTS: Rates of new registration for oral clefts and acquired oral defects were stable from 2007 to 2018. The rates of newly registered cases of craniofacial anomalies and congenital oral defects showed an increased trend from 2007 to 2018, although year-by-year comparison of the change in rates did not reach statistical significance. For craniofacial anomalies, congenital oral defects, and acquired oral defects, the highest rates of new registrations occurred in the age group 10 to 14 years, while those aged 0 to 4 recorded the highest registration rates in the oral cleft group. CONCLUSION: Rates in new cleft and acquired oral defects registrations were stable from 2007 to 2018. Rates in newly registered cases of craniofacial anomalies and congenital oral defects increased over the 11-year period.

Future needs of young people receiving botulinum toxin A in paediatric rehabilitation services of New South Wales: focus on transition.

Young people (YP) with neurological disabilities such as cerebral palsy are increasingly living into adulthood and require healthcare transition for services including for botulinum toxin A (BoNT-A). We analysed medical records in the three children's hospitals in New South Wales (NSW) and identified 253 YP who are expected to transition from paediatric to adult BoNT-A services in NSW and Australian Capital Territory during 2018-2023. A substantial proportion of these YP have additional needs that will require paediatric and adult health services to work together to improve their life-long health outcomes.

Digital psychosocial assessment: An efficient and effective screening tool.

AIM: A large proportion of young people with chronic health conditions are surviving into adulthood. They face the same challenges as their healthy peers and are at increased risk of mental health problems. Psychosocial assessment is a crucial aspect of clinical care. Interviews using the internationally used and accepted HEEADSSS (home environment, education/employment, eating, peer-related activities, drugs, sexuality, suicide/depression, and safety) framework require trained clinicians, rapid interpersonal engagement, time and manual documentation. HEEADSSS-derived digital self-report surveys can be initiated by non-trained staff. This study compares the utility and information recorded using both methods. METHODS: A retrospective analysis comparing documentation from HEEADSSS guided face-to-face interview and a digital survey tool was conducted using 146 records collected by the Trapeze transition service across the two locations of the Sydney Children's Hospital Network (NSW, Australia) between 2013 and 2016. A panel of four experts used an iterative process to identify 29 data verification points, falling into seven categories. Wilcoxon signed-rank tests were used to compare category scores. RESULTS: The digital survey took an average of 15 min and showed a significantly higher rate of disclosure across all psychosocial categories, particularly in the sensitive areas of emotions, drug use, sex and safety, compared to electronic medical record documentation of interview. CONCLUSIONS: Digital survey provided a time-efficient psychosocial screening tool that was self-administered, able to be introduced by non-trained staff, had a consistent record of responses, and elicited a substantially higher disclosure rate for important areas of strength and risk that may otherwise be avoided or not recorded.

Mobile and Web-Based Apps That Support Self-Management and Transition in Young People With Chronic Illness: Systematic Review.

BACKGROUND: More adolescents with chronic physical illness are living into adulthood, and they require the development of proficient self-management skills to maintain optimal physical health as they transition into adult care services. It is often during this vulnerable transition period that deterioration in illness control is seen as a result of inadequate self-management skills and understanding of their chronic illness. Mobile technology has been proposed as an innovative opportunity to assist in improving the management of chronic conditions as young people transition to adult care services. Over the past 5 years, there has been a significant increase in research into the use of health-related apps. OBJECTIVE: This study aimed to evaluate the utility and effectiveness of mobile and Web-based health apps that support self-management and transition in young people with chronic physical health illnesses. METHODS: We conducted a comprehensive review of the literature in 5 bibliographic databases, using key search terms, considering only articles published from 2013, as we were extending the data from 2 previous systematic reviews. Abstracts were screened for possible inclusion by 2 reviewers. Data extraction and quality assessment tools were used for the evaluation of included studies. RESULTS: A total of 1737 records were identified from the combined electronic searches, and 854 records were removed as duplicates. A total of 68 full articles were further assessed for eligibility, and 6 articles met our review criteria: 3 pilot studies, 2 randomized controlled trials, and 1 prospective cohort study. Publication years ranged from 2015 to 2018. The apps reported were targeted at type 1 diabetes mellitus, epilepsy, asthma, beta thalassemia major, and sickle cell disease, with a combined sample size of 336. A total of 4 studies included in this review reported being effective in increasing knowledge of the targeted condition and increasing therapy adherence, including increased medication adherence. A total of 2 manuscripts only mentioned the word transition. Participant's satisfaction was reported for all studies. Heterogeneity of the studies prevented meta-analysis. CONCLUSIONS: There remain limited data on the effectiveness and use of mobile and Web-based apps, which might facilitate the transition of adolescents with chronic illnesses from pediatric to adult health care services. This systematic review provides an updated overview of available apps for adolescents with chronic illnesses. This systematic review has been unable to provide evidence for effectiveness of this approach, but it does provide insights into future study design, with reference to the development, evaluation, and efficacy of apps tailored for adolescents with chronic illnesses, including the involvement of adolescents in such designs. TRIAL REGISTRATION: PROSPERO CRD42018104611; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=104611.

Implementing a new adolescent epilepsy service: Improving patient experience and readiness for transition.

AIM: To implement and appraise a new model of care in terms of: patient experience, knowledge of epilepsy, readiness for transition and emotional and behavioural support in a new purpose-built facility for adolescents and young adults. METHODS: The new model of care included: upskilling of neurology staff in adolescent engagement and provision of group education sessions on epilepsy and mental health (MH), along with MH support, in a new purpose-built adolescent facility. Parameters examined pre- and post-attendance at the new clinic included: adolescent experience of service delivery, transition readiness, emotional and behavioural well-being, epilepsy knowledge and medication adherence. RESULTS: A total of 45 adolescents (mean age 15.7 years) attended the new epilepsy clinic between February 2017 and December 2017. Adolescents felt significantly better informed following education in relation to epilepsy and driving, alcohol/street drugs and birth control/pregnancy. There was no significant improvement in self-reported medication adherence, transition readiness or mental well-being at follow-up. While MH education was ranked highly in terms of importance by adolescents and parents at baseline, attendance at MH education and engagement with MH support was low. CONCLUSIONS: This paper documents what is important to young people with epilepsy regarding service delivery. The new adolescent service was well received. Based on feedback from adolescents and parents relating to the service, and the suboptimal uptake of MH supports, the model of care has been revised to reduce attendance burden on families and improve patient experience.

Off-Label Prescribing for Children with Migraines in U.S. Ambulatory Care Settings.

BACKGROUND: Migraines, Which Affect About 10% Of School-Age Children In The United States, Can Significantly Impair Quality Of Life. Despite Potential Disability, Many Children Do Not Receive Treatment Or Prophylaxis, Since Medications Specifically Approved For Children Are Significantly Less Than For Adults. There Is Also Controversy Surrounding The Apparent Widespread Practice Of Prescribing Off-Label Medications For Children With Migraines. However, Little Research Has Been Done To Identify Physician-Prescribing Patterns Of Migraine Medication For Children. OBJECTIVE: To Investigate The Prevalence And Pattern Of Off-Label Prescribing For Children With Migraines. METHODS: A Secondary Data Analysis Was Conducted Using The Pooled National Ambulatory Medical Care Survey (Namcs) 2011 And 2012. Patients Aged 17 Years Or Younger With A Migraine Diagnosis Were Included. A Series Of Weighted Descriptive Analyses Were Used To Estimate The Prevalence Of Migraine Drugs Prescribed During Pediatric Office Visits. A Weighted Logistic Regression Was Constructed To Compare The Prescribing Patterns Between Off-Label And Fda-Approved Medications. Analyses Used Sas 9.4 Methodology And Incorporated Sample Weights To Adjust For The Complex Sampling Design Employed By Namcs. RESULTS: Of The 12.9 Million Outpatient Visits With A Migraine Diagnosis That Took Place Between 2010 And 2012, 1.2 Million Were Pediatric Visits. Females Accounted For Nearly Twice The Number Of Migraine Visits Than Males (66% Vs. 34%). Children Aged 12-17 Years Accounted For The Highest Frequency Of Visits (84%), Compared With Those Aged Under 12 Years (16%). 66.7% Of These Pediatric Patients Received At Least 1 Migraine Drug. Of These, Off-Label Medications Were Prescribed 1.5 Times More Than Fda-Approved Medications For Children (60.34% Vs. 39.65%). The Results Of Logistic Regression Showed A Significant Likelihood Of Prescribing Off-Label Medications Based On Physician Specialty, Patient Race, And Reason For Visit. Neurologists (Or = 0.028, P < 0.05) And Pediatricians (Or = 0.095, P < 0.05) Were Less Likely To Prescribe Off-Label Drugs Than General And Family Practitioners. Visits For Preventive Care (Or = 5.8, P < 0.05) And Flare-Ups From Chronic Migraines (Or = 5.0, P < 0.05) Were More Likely To Result In Off-Label Drug Prescriptions Than Visits For New Migraine Incidence. CONCLUSIONS: This Study Provides Significant Real-World Evidence Of The Widespread Practice Of Prescribing Off-Label Drugs To Children With Migraines. Although Medical Literature Shows That Off-Label Prescribing May Not Be Harmful, There Is A Dearth Of Research And Practice Guidelines To Help Practitioners Uphold Safety Standards And Ensure The Prescription Of Age-Appropriate Medications To Children. DISCLOSURES: No outside funding supported this study. The authors report no potential conflicts of interest relevant to this research. Lai and Ting contributed to study concept and design and collected the data, along with the other authors. Data interpretation was performed by Lai, Koh, Obi, Ho, and Ting. The manuscript was written and revised by Lai, Koh, and Ho, with assistance from Ting and Obi.

Transition, It's More Than Just An Event: Supporting Young People With Type 1 Diabetes.

This paper discusses the importance of holistic person-centered care coordination services for young people with type 1 diabetes as they transition to adult health services. In response to the growing need for comprehensive, flexible, person-centered care for young people with chronic conditions, the new service Trapeze: a supported leap into adult health was established. Based in Sydney, Australia, Trapeze is a specialist adolescent chronic care service offering comprehensive care coordination services to young people with chronic conditions aged 14-25 years. Trapeze aims to support young people with type 1 diabetes by focusing on the individual needs of the young person and developing a mutually recognized relationship based on trust and respect, in order to facilitate a process whereby a young person feels safe enough to discuss some of the challenges they face in self-management, keeping their whole of life issues central to this process. The importance of holistic person-centered work is best exemplified through the stories of the young people enrolled in Trapeze. It is hoped that through the 'eyes' of the young people and by sharing their stories the approach to self-management and care coordination can be better understood.

A systematic review of the psychometric properties of transition readiness assessment tools in adolescents with chronic disease.

BACKGROUND: Health care transition of adolescents with chronic conditions may be unsuccessful when patients have not acquired the necessary skills and developmental milestones. It is therefore critical for health care providers to assess the readiness for transition of their adolescent patients. This is currently hindered by the lack of a recognised, well-established transition-readiness assessment tool. METHODS: We conducted a systematic review of all transition-readiness tools for adolescents with chronic medical conditions published in peer-reviewed journals. Tools were rated by the methodological quality of the validation studies, and the psychometric measurement qualities of each tool. RESULTS: Ten different assessment tools were identified. Seven targeted specific diseases and 3 tools were generic. Most tools were poorly validated with only one tool, the Transition Readiness Assessment Questionnaire (TRAQ) demonstrating adequate content validity, construct validity, and internal consistency. CONCLUSION: The TRAQ was the best-validated transition-readiness tool, with additional benefits of disease-neutrality. Further research should focus on testing the predictive validity of this tool, and exploring correlation with transition-outcomes, in an international population.

Uptake of influenza vaccine by pregnant women: a cross-sectional survey.

OBJECTIVES: To determine influenza vaccination coverage among pregnant women in New South Wales, and factors associated with vaccine uptake during pregnancy. DESIGN, SETTING AND PARTICIPANTS: Quantitative self-administered survey of pregnant women, using a non-random, stratified sample from antenatal clinics at three demographically diverse hospitals in NSW during the influenza season of 2011. MAIN OUTCOME MEASURES: Self-reported influenza vaccine uptake while pregnant; and attitudes, barriers and facilitators to vaccine acceptance during pregnancy. RESULTS: Of 939 women approached, 815 participated (87%). Influenza vaccine uptake in pregnant women was 27%. Women who had received a recommendation to have the vaccine were 20.0 times (95% CI, 10.9-36.9) more likely to have been vaccinated. Forty-two per cent recalled receiving a recommendation to be vaccinated. Other factors associated with vaccination were study site, perceived infection severity, overall feelings toward vaccination during pregnancy, vaccine accessibility, and willingness to take up the vaccine if recommended. Concern about the baby's safety was negatively associated with vaccination (odds ratio, 0.5; 95% CI, 0.2-0.9), but 68% (95% CI, 63%-71%) of women who expressed concern agreed they would have the vaccine if their health care professional recommended it. CONCLUSION: Recommendation from a health care provider is strongly associated with influenza vaccine uptake among pregnant women and can overcome their concerns about safety, but less than half the women surveyed reported receiving such a recommendation. Educational material targeting pregnant women and professional education and support for antenatal health care providers are needed to increase awareness and recommendation.

Discovery of oxazole-based PDE4 inhibitors with picomolar potency.

Optimization of oxazole-based PDE4 inhibitors has led to the discovery of a series of quinolyl oxazoles, with 4-benzylcarboxamide and 5-α-aminoethyl groups which exhibit picomolar potency against PDE4. Selectivity profiles and in vivo biological activity are also reported.

Zinc induces chemokine and inflammatory cytokine release from human promonocytes.

Our previous studies found that zinc oxide (ZnO) particles induced expression of intercellular adhesion molecule-1 (ICAM-1) protein in vascular endothelial cells via NF-κB and that zinc ions dissolved from ZnO particles might play the major role in the process. This study aimed to determine if zinc ions could cause inflammatory responses in a human promonocytic leukemia cell line HL-CZ. Conditioned media from the zinc-treated HL-CZ cells induced ICAM-1 protein expression in human umbilical vein endothelial cells (HUVEC). Zinc treatment induced chemokine and inflammatory cytokine release from HL-CZ cells. Inhibition of NFκB activity by over-expression of IκBα in HL-CZ cells did not block the conditioned medium-induced ICAM-1 protein expression in HUVEC cells. Zinc treatment induced activation of multiple immune response-related transcription factors in HL-CZ cells. These results clearly show that zinc ions induce chemokine and inflammatory cytokine release from human promonocytes, accompanied with activation of multiple immune response-related transcription factors. Our in vitro evidence in the zinc-induced inflammatory responses of vascular cells provides a critical linkage between zinc exposure and pathogenesis of those inflammatory vascular diseases.

Zinc oxide particles induce inflammatory responses in vascular endothelial cells via NF-κB signaling.

This study investigated inflammatory effects of zinc oxide (ZnO) particles on vascular endothelial cells. The effects of 50 and 100-nm ZnO particles on human umbilical vein endothelial cells (HUVECs) were characterized by assaying cytotoxicity, cell proliferation, and glutathione levels. A marked drop in survival rate was observed when ZnO concentration was increased to 45 µg/ml. ZnO concentrations of ≤3 µg/ml resulted in increased cell proliferation, while those of ≤45 µg/ml caused dose-dependent increases in oxidized glutathione levels. Treatments with ZnO concentrations ≤45 µg/ml were performed to determine the expression of intercellular adhesion molecule-1 (ICAM-1) protein, an indicator of vascular endothelium inflammation, revealing that ZnO particles induced a dose-dependent increase in ICAM-1 expression and marked increases in NF-κB reporter activity. Overexpression of IκBα completely inhibited ZnO-induced ICAM-1 expression, suggesting NF-κB plays a pivotal role in regulation of ZnO-induced inflammation in HUVECs. Additionally, TNF-α, a typical inflammatory cytokine, induced ICAM-1 expression in an NF-κB-dependent manner, and ZnO synergistically enhanced TNF-α-induced ICAM-1 expression. Both 50 and 100-nm ZnO particles agglomerated to similar size distributions. This study reveals an important role for ZnO in modulating inflammatory responses of vascular endothelial cells via NF-κB signaling, which could have important implications for treatments of vascular disease.

Discovery of a highly potent series of oxazole-based phosphodiesterase 4 inhibitors.

Substituted quinolyl oxazoles were discovered as a novel and highly potent series of phosphodiesterase 4 (PDE4) inhibitors. Structure-activity relationship studies revealed that the oxazole core, with 4-carboxamide and 5-aminomethyl groups, is a novel PDE4 inhibitory pharmacophore. Selectivity profiles and in vivo biological activity are also reported.

Cyclic urea derivatives as potent NK1 selective antagonists. Part II: Effects of fluoro and benzylic methyl substitutions.

A series of novel five-membered urea derivatives as potent NK1 receptor antagonists is described. The effects of substitution of a 4-fluoro group at the phenyl ring and the introduction of an alpha-methyl group at the benzylic position to improve potency and duration of in vivo activity are discussed. Several compounds with high affinity and sustained in vivo activity were identified.

Cyclic urea derivatives as potent NK1 selective antagonists.

A series of novel five- and six-membered ring urea derivatives have been described as potent and selective NK1 receptor antagonists. Several compounds in this series exhibited good oral activity and brain penetration. Syntheses of these compounds are also described herein.