Circulating Adipokines and Associations With Incident Cardiovascular Disease in Rheumatoid Arthritis.

OBJECTIVE: To assess whether circulating levels of adiponectin, leptin, and fibroblast growth factor 21 (FGF-21) are associated with incident cardiovascular disease (CVD) in rheumatoid arthritis (RA). METHODS: Adipokines were measured using banked enrollment serum from patients with RA and dichotomized above/below the median value. Incident CVD events (coronary artery disease [CAD], stroke, heart failure [HF] hospitalization, venous thromboembolism, CVD-related deaths) were identified using administrative data and the National Death Index. Covariates were derived from medical record, biorepository, and registry databases. Multivariable Cox models were generated to quantify associations between adipokine concentrations and CVD incidence. Five-year incidence rates were predicted. RESULTS: Among 2,598 participants, 639 (25%) had at least 1 CVD event over 19,585 patient-years of follow-up. High adiponectin levels were independently associated with HF hospitalization (hazard ratio [HR] 1.39 [95% confidence interval (95% CI) 1.07-1.79], P = 0.01) and CVD-related death (HR 1.49 [95% CI 1.16-1.92], P = 0.002) but not with other CVD events. High leptin was independently associated with CVD-related death (HR 1.44 [95% CI 1.05-1.97], P = 0.02). High FGF-21 levels were independently associated with lower rates of CAD (HR 0.75 [95% CI 0.58-0.97], P = 0.03). In subgroup analyses, associations between high adiponectin and leptin levels with CVD-related death were driven by strong associations in nonobese patients. CONCLUSION: Adipokines are associated with HF hospitalization and CVD-related death in patients with RA, with stronger associations in nonobese participants. These findings suggest that adipokines effectively predict clinically important outcomes in RA perhaps through an association with body composition and metabolic health. Further study is needed to determine whether adipokine measures might augment existing tools to identify RA patients at increased risk of CVD.

Elevations in adipocytokines and mortality in rheumatoid arthritis.

OBJECTIVES: This study assessed whether circulating levels of adiponectin and leptin are associated with higher mortality in patients with RA. METHODS: Participants were adults from the Veterans Affairs RA Registry. Adipokines and inflammatory cytokines were measured as part of a multi-analyte panel on banked serum at enrolment. Dates and causes of death were derived from the Corporate Data Warehouse and the National Death Index. Covariates were derived from medical record, biorepository and registry databases. Multivariable Cox proportional hazard models evaluated associations between biomarkers and all-cause and cause-specific mortality. RESULTS: A total of 2583 participants were included. Higher adiponectin levels were associated with older age, male sex, white race, lower BMI, autoantibody seropositivity, radiographic damage, longer disease duration, prednisone use and osteoporosis. Higher adiponectin concentrations were also associated with higher levels of inflammatory cytokines but not higher disease activity at enrolment. Leptin was primarily associated with greater BMI and comorbidity. The highest quartile of adiponectin (vs lowest quartile) was associated with higher all-cause mortality [hazard ratio (HR): 1.46 (95% CI: 1.11, 1.93), P = 0.009] and higher cardiovascular mortality [HR: 1.85 (95% CI: 1.24, 2.75), P = 0.003], after accounting for covariates. Higher leptin levels were also associated with greater all-cause and cancer mortality. CONCLUSIONS: Elevations in adipokines are associated with age, BMI, comorbidity and severe disease features in RA and independently predict early death. Associations between adiponectin and inflammatory cytokines support the hypothesis that chronic subclinical inflammation promotes metabolic changes that drive elevations in adipokines and yield adverse health outcomes.

Palbociclib in combination with endocrine therapy versus capecitabine in hormonal receptor-positive, human epidermal growth factor 2-negative, aromatase inhibitor-resistant metastatic breast cancer: a phase III randomised controlled trial-PEARL.

BACKGROUND: Palbociclib plus endocrine therapy (ET) is the standard treatment of hormone receptor-positive and human epidermal growth factor receptor 2-negative, metastatic breast cancer (MBC). However, its efficacy has not been compared with that of chemotherapy in a phase III trial. PATIENTS AND METHODS: PEARL is a multicentre, phase III randomised study in which patients with aromatase inhibitor (AI)-resistant MBC were included in two consecutive cohorts. In cohort 1, patients were randomised 1 : 1 to palbociclib plus exemestane or capecitabine. On discovering new evidence about estrogen receptor-1 (ESR1) mutations inducing resistance to AIs, the trial was amended to include cohort 2, in which patients were randomised 1 : 1 between palbociclib plus fulvestrant and capecitabine. The stratification criteria were disease site, prior sensitivity to ET, prior chemotherapy for MBC, and country of origin. Co-primary endpoints were progression-free survival (PFS) in cohort 2 and in wild-type ESR1 patients (cohort 1 + cohort 2). ESR1 hotspot mutations were analysed in baseline circulating tumour DNA. RESULTS: From March 2014 to July 2018, 296 and 305 patients were included in cohort 1 and cohort 2, respectively. Palbociclib plus ET was not superior to capecitabine in both cohort 2 [median PFS: 7.5 versus 10.0 months; adjusted hazard ratio (aHR): 1.13; 95% confidence interval (CI): 0.85-1.50] and wild-type ESR1 patients (median PFS: 8.0 versus 10.6 months; aHR: 1.11; 95% CI: 0.87-1.41). The most frequent grade 3-4 toxicities with palbociclib plus exemestane, palbociclib plus fulvestrant and capecitabine, respectively, were neutropenia (57.4%, 55.7% and 5.5%), hand/foot syndrome (0%, 0% and 23.5%), and diarrhoea (1.3%, 1.3% and 7.6%). Palbociclib plus ET offered better quality of life (aHR for time to deterioration of global health status: 0.67; 95% CI: 0.53-0.85). CONCLUSIONS: There was no statistical superiority of palbociclib plus ET over capecitabine with respect to PFS in MBC patients resistant to AIs. Palbociclib plus ET showed a better safety profile and improved quality of life.

Disease activity, cytokines, chemokines and the risk of incident diabetes in rheumatoid arthritis.

PURPOSE: Rheumatoid arthritis (RA) is associated with a higher risk of diabetes mellitus (DM). Our aim was to determine associations between inflammatory disease activity (including evaluation of specific cytokines and chemokines) and incident DM. METHODS: Participants were adults with physician-confirmed RA from Veteran's Affairs Rheumatoid Arthritis Registry. Disease activity and clinical assessments occur longitudinally as part of clinical care. Thirty cytokines and chemokines were measured in banked serum obtained at the time of enrolment. Cytokine/chemokine values were log-adjusted and standardised (per SD). Incident DM was defined based on validated algorithms using diagnostic codes and medications. Multivariable Cox proportional hazard models evaluated associations between clinical factors and incident DM. Independent associations between cytokines/chemokines and incident DM were assessed adjusting for age, sex, race, smoking, body mass index (BMI) and medication use at baseline. RESULTS: Among 1866 patients with RA without prevalent DM at enrolment, there were 130 incident cases over 9223 person-years of follow-up. High Disease Activity Score (DAS28)-C reactive protein (CRP), obese BMI, older age and male sex were associated with greater risk for incident DM while current smoking and methotrexate use were protective. Patients using methotrexate were at lower risk. Several cytokines/chemokines evaluated were independently associated (per 1 SD) with DM incidence including interleukin(IL)-1, IL-6 and select macrophage-derived cytokines/chemokines (HR range 1.11-1.26). These associations were independent of the DAS28-CRP. CONCLUSIONS: Higher disease activity and elevated levels of cytokines/chemokines are associated with a higher risk of incident DM in patients with RA. Future study may help to determine if targeted treatments in at-risk individuals could prevent the development of DM.

Derbid Planthoppers (Hemiptera: Fulgoroidea: Derbidae) Associated with Coconut and Oil Palm in Brazil.

We present surveys of derbid planthoppers associated with coconut (Cocos nucifera L.) and oil palm (Elaeis guineensis Jacq.) collected in Northeastern (Sergipe) and North (Pará and Roraima) Brazil. The surveys were intended to contribute to our knowledge of possible vectors of phytoplasmas or other phloem-restricted plant pathogens. Eight derbid taxa were found, two in the subfamily Cedusinae, tribe Cedusini (Cedusa yipara Kramer and C. yowza Kramer) and six in the subfamily Derbinae, tribe Cenchreini: Herpis sp., Persis pugnax Stål, Omolicna anastomosa (Caldwell), O. nigripennis (Caldwell), and two new species in the genus Agoo Bahder & Bartlett are described here. Genus-level features between Omolicna and Agoo are discussed and a key to the species of Agoo is provided.

Circulating TNF-like protein 1A (TL1A) is elevated early in rheumatoid arthritis and depends on TNF.

BACKGROUND: The tumor necrosis factor (TNF) superfamily cytokine TNF-like protein 1A (TL1A) and its receptor DR3 are essential for diverse animal models of autoimmune disease and may be pathogenic in rheumatoid arthritis (RA). However, the relationship of TL1A to disease duration, activity, and response to anti-TNF and other therapies in RA is not clear. METHODS: We measured soluble TL1A in synovial fluid (SF), serum, or plasma from RA first-degree relatives (FDRs) and in early RA and established disease. We measured the effects of anti-TNF and methotrexate (MTX) therapy on circulating TL1A from multiple independent RA treatment trials. We also determined the ability of a blocking anti-TL1A antibody to inhibit clinical disease and articular bone destruction in the murine collagen-induced arthritis (CIA) model of human RA. RESULTS: Soluble TL1A was specifically elevated in the blood and SF of patients with RA compared to patients with other diseases and was elevated early in disease and in at-risk anti-cyclic citrullinated peptide (CCP) (+) first-degree relatives (FDRs). Therapeutic TNF inhibition reduced serum TL1A in both responders and non-responders, whereas TL1A declined following MTX treatment only in responders. In murine CIA, TL1A blockade was clinically efficacious and reduced bone erosions. CONCLUSIONS: TL1A is specifically elevated in RA from early in the disease course and in at-risk FDRs. The decline in TL1A after TNF blockade suggests that TL1A levels may be a useful biomarker for TNF activity in RA. These results support the further investigation of the relationship between TL1A and TNF and TL1A blockade as a potential therapeutic strategy in RA.

A phase II feasibility study of palbociclib in combination with adjuvant endocrine therapy for hormone receptor-positive invasive breast carcinoma.

BACKGROUND: The CDK4/6 inhibitor palbociclib prolongs progression-free survival in hormone receptor-positive/HER2-negative (HR+/HER2-) metastatic breast cancer when combined with endocrine therapy. This phase II trial was designed to determine the feasibility of adjuvant palbociclib and endocrine therapy for early breast cancer. PATIENTS AND METHODS: Eligible patients with HR+/HER2- stage II-III breast cancer received 2 years of palbociclib at 125 mg daily, 3 weeks on/1 week off, with endocrine therapy. The primary end point was discontinuation from palbociclib due to toxicity, non-adherence, or events related to tolerability. A discontinuation rate of 48% or higher would indicate the treatment duration of 2 years was not feasible, and was evaluated under a binomial test using a one-sided α = 0.025. RESULTS: Overall, 162 patients initiated palbociclib; over half had stage III disease (52%) and most received prior chemotherapy (80%). A total of 102 patients (63%) completed 2 years of palbociclib; 50 patients discontinued early for protocol-related reasons (31%, 95% CI 24% to 39%, P = 0.001), and 10 discontinued due to protocol-unrelated reasons. The cumulative incidence of protocol-related discontinuation was 21% (95% CI 14% to 27%) at 12 months from start of treatment. Rates of palbociclib-related toxicity were congruent with the metastatic experience, and there were no cases of febrile neutropenia. Ninety-one patients (56%) required at least one dose reduction. CONCLUSION: Adjuvant palbociclib is feasible in early breast cancer, with a high proportion of patients able to complete 2 years of therapy. The safety profile in the adjuvant setting mirrors that observed in metastatic disease, with approximately half of the patients requiring dose-modification. As extended duration adjuvant palbociclib appears feasible and tolerable for most patients, randomized phase III trials are evaluating clinical benefit in this population. CLINICALTRIALS.GOV REGISTRATION: NCT02040857.

Palbociclib plus letrozole as first-line therapy in estrogen receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer with extended follow-up.

PURPOSE: In the initial PALOMA-2 (NCT01740427) analysis with median follow-up of 23 months, palbociclib plus letrozole significantly prolonged progression-free survival (PFS) in women with estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC) [hazard ratio (HR) 0.58; P < 0.001]. Herein, we report results overall and by subgroups with extended follow-up. METHODS: In this double-blind, phase 3 study, post-menopausal women with ER+/HER2- ABC who had not received prior systemic therapy for their advanced disease were randomized 2:1 to palbociclib-letrozole or placebo-letrozole. Endpoints include investigator-assessed PFS (primary), safety, and patient-reported outcomes (PROs). RESULTS: After a median follow-up of approximately 38 months, median PFS was 27.6 months for palbociclib-letrozole (n = 444) and 14.5 months for placebo-letrozole (n = 222) (HR 0.563; 1-sided P < 0.0001). All subgroups benefited from palbociclib treatment. The improvement of PFS with palbociclib-letrozole was maintained in the next 2 subsequent lines of therapy and delayed the use of chemotherapy (40.4 vs. 29.9 months for palbociclib-letrozole vs. placebo-letrozole). Safety data were consistent with the known profile. Patients' quality of life was maintained. CONCLUSIONS: With approximately 15 months of additional follow-up, palbociclib plus letrozole continued to demonstrate improved PFS compared with placebo plus letrozole in the overall population and across all patient subgroups, while the safety profile remained favorable and quality of life was maintained. These data confirm that palbociclib-letrozole should be considered the standard of care for first-line therapy in patients with ER+/HER2- ABC, including those with low disease burden or long disease-free interval. Sponsored by Pfizer; ClinicalTrials.gov: NCT01740427.

Impact of palbociclib plus letrozole on patient-reported health-related quality of life: results from the PALOMA-2 trial.

Background: Patient-reported outcomes are integral in benefit-risk assessments of new treatment regimens. The PALOMA-2 study provides the largest body of evidence for patient-reported health-related quality of life (QOL) for patients with metastatic breast cancer (MBC) receiving first-line endocrine-based therapy (palbociclib plus letrozole and letrozole alone). Patients and methods: Treatment-naïve postmenopausal women with estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) MBC were randomized 2 : 1 to palbociclib plus letrozole (n = 444) or placebo plus letrozole (n = 222). Patient-reported outcomes were assessed at baseline, day 1 of cycles 2 and 3, and day 1 of every other cycle from cycle 5 using the Functional Assessment of Cancer Therapy (FACT)-Breast and EuroQOL 5 dimensions (EQ-5D) questionnaires. Results: As of 26 February 2016, the median duration of follow-up was 23 months. Baseline scores were comparable between the two treatment arms. No significant between-arm differences were observed in change from baseline in FACT-Breast Total, FACT-General Total, or EQ-5D scores. Significantly greater improvement in pain scores was observed in the palbociclib plus letrozole arm (-0.256 versus -0.098; P = 0.0183). In both arms, deterioration of FACT-Breast Total score was significantly delayed in patients without progression versus those with progression and patients with partial or complete response versus those without. No significant difference was observed in FACT-Breast and EQ-5D index scores in patients with and without neutropenia. Conclusions: Overall, women with MBC receiving first-line endocrine therapy have a good QOL. The addition of palbociclib to letrozole maintains health-related QOL and improves pain scores in treatment-naïve postmenopausal patients with ER+/HER2- MBC compared with letrozole alone. Significantly greater delay in deterioration of health-related QOL was observed in patients without progression versus those who progressed and in patients with an objective response versus non-responders. ClinicalTrials.gov: NCT01740427 (https://clinicaltrials.gov/ct2/show/NCT01740427).

Clinical considerations of the role of palbociclib in the management of advanced breast cancer patients with and without visceral metastases.

Background: This report assesses the efficacy and safety of palbociclib plus endocrine therapy (ET) in women with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer (ABC) with or without visceral metastases. Patients and methods: Pre- and postmenopausal women with disease progression following prior ET (PALOMA-3; N = 521) and postmenopausal women untreated for ABC (PALOMA-2; N = 666) were randomized 2 : 1 to ET (fulvestrant or letrozole, respectively) plus palbociclib or placebo. Progression-free survival (PFS), safety, and patient-reported quality of life (QoL) were evaluated by prior treatment and visceral involvement. Results: Visceral metastases incidence was higher in patients with prior resistance to ET (58.3%, PALOMA-3) than in patients naive to ET in the ABC setting (48.6%, PALOMA-2). In patients with prior resistance to ET and visceral metastases, median PFS (mPFS) was 9.2 months with palbociclib plus fulvestrant versus 3.4 months with placebo plus fulvestrant [hazard ratio (HR), 0.47; 95% confidence interval (CI), 0.35-0.61], and objective response rate (ORR) was 28.0% versus 6.7%, respectively. In patients with nonvisceral metastases, mPFS was 16.6 versus 7.3 months, HR 0.53; 95% CI 0.36-0.77. In patients with visceral disease and naive to ET in the advanced disease setting, mPFS was 19.3 months with palbociclib plus letrozole versus 12.9 months with placebo plus letrozole (HR 0.63; 95% CI 0.47-0.85); ORR was 55.1% versus 40.0%; in patients with nonvisceral disease, mPFS was not reached with palbociclib plus letrozole versus 16.8 months with placebo plus letrozole (HR 0.50; 95% CI 0.36-0.70). In patients with prior resistance to ET with visceral metastases, palbociclib plus fulvestrant significantly delayed deterioration of QoL versus placebo plus fulvestrant, whereas patient-reported QoL was maintained with palbociclib plus letrozole in patients naive to endocrine-based therapy for ABC. Conclusions: Palbociclib plus ET prolonged mPFS in patients with visceral metastases, increased ORRs, and in patients previously treated for ABC, delayed QoL deterioration, presenting a standard treatment option among patients with visceral metastases amenable to endocrine-based therapy. Clinical trial registration: NCT01942135, NCT01740427.

Quality of life with palbociclib plus fulvestrant in previously treated hormone receptor-positive, HER2-negative metastatic breast cancer: patient-reported outcomes from the PALOMA-3 trial.

BACKGROUND: In the PALOMA-3 study, palbociclib plus fulvestrant demonstrated improved progression-free survival compared with fulvestrant plus placebo in hormone receptor-positive, HER2- endocrine-resistant metastatic breast cancer (MBC). This analysis compared patient-reported outcomes (PROs) between the two treatment groups. PATIENTS AND METHODS: Patients were randomized 2 : 1 to receive palbociclib 125 mg/day orally for 3 weeks followed by 1 week off (n = 347) plus fulvestrant (500 mg i.m. per standard of care) or placebo plus fulvestrant (n = 174). PROs were assessed on day 1 of cycles 1-4 and of every other subsequent cycle starting with cycle 6 using the EORTC QLQ-C30 and its breast cancer module, QLQ-BR23. High scores (range 0-100) could indicate better functioning/quality of life (QoL) or worse symptom severity. Repeated-measures mixed-effect analyses were carried out to compare on-treatment overall scores and changes from baseline between treatment groups while controlling for baseline. Between-group comparisons of time to deterioration in global QoL and pain were made using an unstratified log-rank test and Cox proportional hazards model. RESULTS: Questionnaire completion rates were high at baseline and during treatment (from baseline to cycle 14, ≥95.8% in each group completed ≥1 question on the EORTC QLQ-C30). On treatment, estimated overall global QoL scores significantly favored the palbociclib plus fulvestrant group [66.1, 95% confidence interval (CI) 64.5-67.7 versus 63.0, 95% CI 60.6-65.3; P = 0.0313]. Significantly greater improvement from baseline in pain was also observed in this group (-3.3, 95% CI -5.1 to -1.5 versus 2.0, 95% CI -0.6 to 4.6; P = 0.0011). No significant differences were observed for other QLQ-BR23 functioning domains, breast or arm symptoms. Treatment with palbociclib plus fulvestrant significantly delayed deterioration in global QoL (P < 0.025) and pain (P < 0.001) compared with fulvestrant alone. CONCLUSION: Palbociclib plus fulvestrant allowed patients to maintain good QoL in the endocrine resistance setting while experiencing substantially delayed disease progression. CLINICAL TRIAL REGISTRATION: NCT01942135.

Impact of palbociclib plus letrozole on pain severity and pain interference with daily activities in patients with estrogen receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer as first-line treatment.

Background Palbociclib is a recently approved drug for use in combination with letrozole as initial endocrine-based therapy for the treatment of postmenopausal women with advanced estrogen receptor-positive/human epidermal growth factor receptor 2-negative (ER+/HER2-) breast cancer. This report assesses the impact of palbociclib in combination with letrozole versus letrozole alone on patient-reported outcomes of pain. Methods Palbociclib was evaluated in an open-label, randomized, phase II study (PALOMA-1/TRIO-18) among postmenopausal women with advanced ER+/HER2- breast cancer who had not received prior systemic treatment for their advanced disease. Patients received continuous oral letrozole 2.5 mg daily alone or the same letrozole dose and schedule plus oral palbociclib 125 mg, given once daily for 3 weeks followed by 1 week off over repeated 28-day cycles. The primary study endpoint was investigator-assessed progression-free survival in the intent-to-treat population, and these results have recently been published (Finn et al., Lancet Oncol 2015;16:25-35). One of the key secondary endpoints was the evaluation of pain, as measured using the Brief Pain Inventory (BPI) patient-reported outcome tool. The BPI was administered at baseline and on day 1 of every cycle thereafter until disease progression and/or treatment discontinuation. Clinical trial registration This study is registered with ClinicalTrials.gov (NCT00721409). Results There were no statistically significant differences in Pain Severity or Pain Interference scores of the BPI between the two treatment groups for the overall population or among those with any bone disease at baseline. A limitation of the study is that results were not adjusted for the concomitant use of opioids or other medications used to control pain. Conclusions The addition of palbociclib to letrozole was associated with increased efficacy without negatively impacting pain severity or pain interference with daily activities.

Estimating the impact of better management of glycaemic control in adults with Type 1 and Type 2 diabetes on the number of clinical complications and the associated financial benefit.

AIM: To estimate potential cost avoidance through modest and achievable improvements in glycaemic control in adults with Type 1 or Type 2 diabetes mellitus in the UK healthcare system. METHODS: The IMS Core Diabetes Model was used to examine the impact of improved glycaemic control (indicated by reduction in HbA1c level), in a representative cohort of adults with Type 1 or Type 2 diabetes. The cumulative incidence of microvascular and macrovascular complications was modelled across 5-year periods to a 25-year time horizon. Complication costs were applied to the data to estimate potential accrued cost avoidance. RESULTS: Significant cost avoidance of ~£340 m is apparent in the first 5 years, increasing to ~£5.5bn after 25 years of sustained improvement in control. The overwhelming majority of cost avoidance arises from reductions in microvascular complications. In people with Type 1 diabetes the greatest cost avoidance comes from a reduction in renal disease (74% of cost avoidance), while in people with Type 2 diabetes it is generated by a reduction in foot ulcers, amputations and neuropathy: 57% cost avoidance). Greater cost reduction is accrued more rapidly in people with higher starting HbA1c levels. CONCLUSION: Modest improvements in glycaemic control generate significant reductions in the incidence and, therefore, cost of microvascular complications in people with Type 1 or Type 2 diabetes. This study provides clear support for the premise that prioritized and sustained investment in early and better intervention can provide concrete financial benefits in both the short and longer term.

Enabling dual cellular destinations of polymeric nanoparticles for treatment following partial injury to the central nervous system.

Following neurotrauma, oxidative stress is spread via the astrocytic syncytium and is associated with increased aquaporin 4 (AQP4), inflammatory cell infiltration, loss of neurons and glia and functional deficits. Herein we evaluate multimodal polymeric nanoparticles functionalized with an antibody to an extracellular epitope of AQP4, for targeted delivery of an anti-oxidant as a therapeutic strategy following partial optic nerve transection. Using fluorescence microscopy, spectrophotometry, correlative nanoscale secondary ion mass spectrometry (NanoSIMS) and transmission electron microscopy, in vitro and in vivo, we demonstrate that functionalized nanoparticles are coated with serum proteins such as albumin and enter both macrophages and astrocytes when administered to the site of a partial optic nerve transection in rat. Antibody functionalized nanoparticles synthesized to deliver the antioxidant resveratrol are effective in reducing oxidative damage to DNA, AQP4 immunoreactivity and preserving visual function. Non-functionalized nanoparticles evade macrophages more effectively and are found more diffusely, including in astrocytes, however they do not preserve the optic nerve from oxidative damage or functional loss following injury. Our study highlights the need to comprehensively investigate nanoparticle location, interactions and effects, both in vitro and in vivo, in order to fully understand functional outcomes.

The role of candidate-gene CNTNAP2 in childhood apraxia of speech and specific language impairment.

Childhood apraxia of speech (CAS) is a debilitating pediatric speech disorder characterized by varying symptom profiles, comorbid deficits, and limited response to intervention. Specific Language Impairment (SLI) is an inherited pediatric language disorder characterized by delayed and/or disordered oral language skills including impaired semantics, syntax, and discourse. To date, the genes associated with CAS and SLI are not fully characterized. In the current study, we evaluated behavioral and genetic profiles of seven children with CAS and eight children with SLI, while ensuring all children were free of comorbid impairments. Deletions within CNTNAP2 were found in two children with CAS but not in any of the children with SLI. These children exhibited average to high performance on language and word reading assessments in spite of poor articulation scores. These findings suggest that genetic variation within CNTNAP2 may be related to speech production deficits.

Periodontitis and Porphyromonas gingivalis in patients with rheumatoid arthritis.

OBJECTIVE: To examine the degree to which shared risk factors explain the relationship of periodontitis (PD) to rheumatoid arthritis (RA) and to determine the associations of PD and Porphyromonas gingivalis with pathologic and clinical features of RA. METHODS: Patients with RA (n = 287) and patients with osteoarthritis as disease controls (n = 330) underwent a standardized periodontal examination. The HLA-DRB1 status of all participants was imputed using single-nucleotide polymorphisms from the extended major histocompatibility complex. Circulating anti-P gingivalis antibodies were measured using an enzyme-linked immunosorbent assay, and subgingival plaque was assessed for the presence of P gingivalis using polymerase chain reaction (PCR). Associations of PD with RA were examined using multivariable regression. RESULTS: Presence of PD was more common in patients with RA and patients with anti-citrullinated protein antibody (ACPA)-positive RA (n = 240; determined using the anti-cyclic citrullinated peptide 2 [anti-CCP-2] test) than in controls (35% and 37%, respectively, versus 26%; P = 0.022 and P = 0.006, respectively). There were no differences between RA patients and controls in the levels of anti-P gingivalis or the frequency of P gingivalis positivity by PCR. The anti-P gingivalis findings showed a weak, but statistically significant, association with the findings for both anti-CCP-2 (r = 0.14, P = 0.022) and rheumatoid factor (RF) (r = 0.19, P = 0.001). Presence of PD was associated with increased swollen joint counts (P = 0.004), greater disease activity according to the 28-joint Disease Activity Score using C-reactive protein level (P = 0.045), and higher total Sharp scores of radiographic damage (P = 0.015), as well as with the presence and levels of anti-CCP-2 (P = 0.011) and RF (P < 0.001). The expression levels of select ACPAs (including antibodies to citrullinated filaggrin) were higher in patients with subgingival P gingivalis and in those with higher levels of anti-P gingivalis antibodies, irrespective of smoking status. Associations of PD with established seropositive RA were independent of all covariates examined, including evidence of P gingivalis infection. CONCLUSION: Both PD and P gingivalis appear to shape the autoreactivity of RA. In addition, these results demonstrate an independent relationship between PD and established seropositive RA.

Clinical benefit of continuing ALK inhibition with crizotinib beyond initial disease progression in patients with advanced ALK-positive NSCLC.

BACKGROUND: Crizotinib is approved to treat advanced ALK-positive non-small-cell lung cancer (NSCLC), but most patients ultimately develop progressive disease (PD). We investigated whether continuing ALK inhibition with crizotinib beyond PD (CBPD) is clinically beneficial and attempted to identify clinicopathologic characteristics associated with patients who experience clinical benefit. PATIENTS AND METHODS: Patients with advanced ALK-positive NSCLC enrolled in two ongoing multicenter, single-arm trials who developed RECIST-defined PD were allowed to continue crizotinib if they were deriving ongoing clinical benefit. In the present retrospective analysis, continuation of CBPD was defined as >3 weeks of crizotinib treatment after PD documentation. Patients who had PD as best response to initial crizotinib treatment were excluded. Baseline and post-progression characteristics, sites of PD, and overall survival (OS) were compared in patients who continued CBPD versus those who did not. The impact of continuing CBPD on OS after adjusting for potential confounding factors was assessed. RESULTS: Among 194 crizotinib-treated patients with RECIST-defined PD, 120 (62%) continued CBPD. A significantly higher proportion of patients who continued CBPD than patients who did not had an ECOG performance status (PS) of 0/1 at PD (96% versus 82%; P=0.02). CBPD patients had significantly longer OS from the time of PD [median 16.4 versus 3.9 months; hazards ratio (HR) 0.27, 95% confidence interval (CI): 0.17-0.42; P<0.0001] and from the time of initial crizotinib treatment (median 29.6 versus 10.8 months; HR 0.30, 95% CI: 0.19-0.46; P<0.0001). The multiple-covariate Cox regression analysis revealed that CBPD remained significantly associated with improved OS after adjusting for relevant factors. CONCLUSIONS: Patients who continued CBPD were more likely to have good ECOG PS (0/1) at the time of PD. Continuing ALK inhibition with crizotinib after PD may provide survival benefit to patients with advanced ALK-positive NSCLC.

The effects of two weeks of recombinant growth hormone administration on the response of IGF-I and N-terminal pro-peptide of collagen type III (P-III-NP) during a single bout of high resistance exercise in resistance trained young men.

OBJECTIVE: Recombinant human growth hormone (rhGH) is used by some athletes and body builders with the aim of enhancing performance, building muscle and improving physique. Detection of the misuse of rhGH has proved difficult for a number of reasons. One of these is the effect of preceding exercise. In this randomised, double blind placebo-controlled study, we determined the effects of rhGH administration in male amateur athletes on two candidate markers of rhGH abuse, IGF-I and N-terminal pro-peptide of collagen type III (P-III-NP), following a bout of weightlifting exercise. DESIGN: Sixteen men entered a four-week general weight training programme to homogenise their activity profile. They then undertook repeated bouts of standardised leg press weightlifting exercise (AHRET-acute heavy resistance exercise test). Blood samples were taken before and up to one hour after the AHRET. After the first laboratory visit (Test 1), the subjects were randomly assigned to receive daily injections of either rhGH (0.1 IU kg(-1) day(-1)) or placebo for two weeks. The AHRET was repeated after the two-week dosing period (Test 2) and a further test was undertaken following a one-week washout (Test 3). RESULTS: There was no effect of exercise on either IGF-I or P-III-NP in any test. Both markers were markedly elevated at Test 2 (p<0.001), with P-III-NP remaining elevated at Test 3 in the GH administration group (p<0.05). Application of the GH-2000 discriminant function positively identified GH administration in 17 of 40 blood samples taken at Test 2 from the rhGH group and none from the placebo group. CONCLUSION: The data show that rhGH results in elevated levels of IGF-I and P-III-NP in well-trained individuals and that leg press weightlifting exercise does not affect these markers. The GH-2000 discriminant function identified four of eight subjects taking rhGH with no false positive results.

Estimating the current and future costs of Type 1 and Type 2 diabetes in the UK, including direct health costs and indirect societal and productivity costs.

AIMS: To estimate the current and future economic burdens of Type 1 and Type 2 diabetes in the UK. METHODS: A top-down approach was used to estimate costs for 2010/2011 from aggregated data sets and literature. Prevalence and population data were used to project costs for 2035/2036. Direct health costs were estimated from data on diagnosis, lifestyle interventions, ongoing treatment and management, and complications. Indirect costs were estimated from data on mortality, sickness, presenteeism (potential loss of productivity among people who remain in work) and informal care. RESULTS: Diabetes cost approximately £ 23.7bn in the UK in 2010/2011: £ 9.8bn in direct costs (£1bn for Type 1 diabetes and £ 8.8bn for Type 2 diabetes) and £ 13.9bn in indirect costs (£ 0.9bn and £ 13bn). In real terms, the 2035/2036 cost is estimated at £ 39.8bn: £ 16.9bn in direct costs (£ 1.8bn for Type 1 diabetes and £ 15.1bn for Type 2 diabetes) and £ 22.9bn in indirect costs (£ 2.4bn and £ 20.5bn). Sensitivity analysis applied to the direct costs produced a range of costs: between £ 7.9bn and £ 11.7bn in 2010/2011 and between £ 13.8bn and £20bn in 2035/2036. Diabetes currently accounts for approximately 10% of the total health resource expenditure and is projected to account for around 17% in 2035/2036. CONCLUSIONS: Type 1 and Type 2 diabetes are prominent diseases in the UK and are a significant economic burden. Data differentiating between the costs of Type 1 and Type 2 diabetes are sparse. Complications related to the diseases account for a substantial proportion of the direct health costs. As prevalence increases, the cost of treating complications will grow if current care regimes are maintained.