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Supplementary Figures S1-S4; Supplementary Tables S1-S2.

Purpose: Bortezomib (Velcade), a dipeptide boronate 20S proteasome inhibitor and an approved treatment option for multiple myeloma, is associated with a treatment-emergent, painful peripheral neuropathy (PN) in more than 30% of patients. Carfilzomib, a tetrapeptide epoxyketone proteasome inhibitor, currently in clinical investigation in myeloma, is associated with low rates of PN. We sought to determine whether PN represents a target-mediated adverse drug reaction (ADR).Experimental Design: Neurodegenerative effects of proteasome inhibitors were assessed in an in vitro model utilizing a differentiated neuronal cell line. Secondary targets of both inhibitors were identified by a multifaceted approach involving candidate screening, profiling with an activity-based probe, and database mining. Secondary target activity was measured in rats and patients receiving both inhibitors.Results: Despite equivalent levels of proteasome inhibition, only bortezomib reduced neurite length, suggesting a nonproteasomal mechanism. In cell lysates, bortezomib, but not carfilzomib, significantly inhibited the serine proteases cathepsin G (CatG), cathepsin A, chymase, dipeptidyl peptidase II, and HtrA2/Omi at potencies near or equivalent to that for the proteasome. Inhibition of CatG was detected in splenocytes of rats receiving bortezomib and in peripheral blood mononuclear cells derived from bortezomib-treated patients. Levels of HtrA2/Omi, which is known to be involved in neuronal survival, were upregulated in neuronal cells exposed to both proteasome inhibitors but was inhibited only by bortezomib exposure.Conclusion: These data show that bortezomib-induced neurodegeneration in vitro occurs via a proteasome-independent mechanism and that bortezomib inhibits several nonproteasomal targets in vitro and in vivo, which may play a role in its clinical ADR profile. Clin Cancer Res; 17(9); 2734–43. ©2011 AACR.

ObjectiveThe long-term safety and efficacy of filgotinib (from phase II studies), with or without methotrexate (MTX), for the treatment of patients with rheumatoid arthritis was assessed in DARWIN 3, a long-term, open-label extension study (ClinicalTrials.gov: NCT02065700).MethodsEligible patients completing the 24-week DARWIN 1 (filgotinib + MTX) and DARWIN 2 (filgotinib monotherapy) studies entered DARWIN 3, where they received filgotinib 200 mg/day, except for 15 men who received filgotinib 100 mg/day. Safety analyses were performed using the safety analysis set and the exposure-adjusted incidence rate (EAIR) of treatment-emergent adverse events (TEAEs) was calculated. Efficacy was assessed from baseline in the parent studies.ResultsOf 790 patients completing the phase II parent studies, 739 enrolled in the study. Through April 2019, 59.5% of patients had received ≥ 4 years of the study drug. Mean (SD) exposure to filgotinib was 3.55 (1.57) years in the filgotinib + MTX group and 3.38 (1.59) years in the filgotinib monotherapy group. EAIR per 100 patient-years of exposure for TEAEs was 24.6 in the filgotinib + MTX group and 25.8 in the filgotinib monotherapy group, and for serious TEAEs, the EAIR was 3.1 and 4.3, respectively. American College of Rheumatology 20/50/70 responses among patients remaining in the study could be maintained through 4 years, with 89.3%/69.6%/49.1% of the filgotinib + MTX group and 91.8%/69.4%/44.4% of the monotherapy group maintaining ACR20/50/70 responses, respectively, based on observed data.ConclusionFilgotinib was well tolerated with a 4-year safety profile comparable to that of the parent trials, both in patients receiving combination therapy with MTX or as monotherapy.

Background: More efficient screening methods are needed to improve the ability to identify and follow genetic cohorts in Parkinson’s disease (PD). Objective: To explore the use of the electronic medical records (EMRs) to identify participants with PD. Methods: Using an algorithm previously developed in collaboration with Maccabi Healthcare Services (MHS), approximately 5,200 participants with PD were identified, more than 3,200 were screened, and 837 participants were enrolled and genotyped for leucine-rich repeat kinase 2 (LRRK2) and beta-glucocerebrosidase (GBA) variants. Questionnaires were completed to ascertain Ashkenazi Jewish (AJ) ancestry and family history of PD. Results: Among 837 participants with PD, 82% were 65 years and older and 72% had a family history of AJ ancestry. Among those with AJ ancestry, 15.6% reported having relatives with PD. The frequency of observed mutations for LRRK2 and GBA genes combined was approximately 15.4%. The frequency of observed LRRK2 mutation was 6.1% overall and 7.2% from those with AJ ancestry; and for GBA mutation was 9.3% overall and 11.2% from those with AJ ancestry. Conclusion: Although the frequency of observed mutations in this study was lower than anticipated, mutation carriers were enriched among those with a family history of AJ ancestry increasing nearly 2-3-fold, from 3% –7% (LRRK2) and 4% –11% (GBA). The identification (and selection) of PD patients through EMRs prior to genotyping is a viable approach, to establish a genetically defined cohort of patients with PD for clinical research.

Osteoarthritis (OA) is a major cause of disability in the US, with no approved treatments to slow progression, but animal models suggest that pulsed low-intensity ultrasonography (PLIUS) may promote cartilage growth.To evaluate the efficacy of PLIUS in providing symptom reduction and decreased loss of tibiofemoral cartilage thickness in patients with knee OA.A phase 2A, sham-controlled, parallel, double-blind randomized clinical trial was conducted at 2 Veterans Affairs hospitals in Salt Lake City, Utah, and San Diego, California, from May 22, 2015, to January 31, 2019. Data were analyzed from June 27, 2020, to October 20, 2020. Participants recruited through the US Department of Veterans Affairs (N = 132) with clinical and radiographic evidence of early knee OA were randomly assigned to receive PLIUS or a sham device, self-administered for 20 minutes daily over the medial compartment of the knee. All enrollees participated in a 4-week prerandomization sham run-in period, followed by a 48-week treatment period. Randomization was stratified by study site and Kellgren-Lawrence grades 1 (n = 15), 2 (n = 51), and 3 (n = 66).Participants either received 48 weeks of PLIUS or sham ultrasonography.The trial incorporated 2 coprimary outcomes: symptomatic improvement assessed by Outcome Measures in Rheumatology Clinical Trials-Osteoarthritis Research Society International Responder Criteria (ie, met if either50% improvement in pain and function with at least a 20% absolute improvement of at least 2 of the following 3 factors: improvement by at least 20% [pain, function, and patient global assessment] with at least a 10-mm absolute improvement), and cartilage preservation assessed as change in central medial femoral condyle cartilage thickness by magnetic resonance imaging. Intention-to-treat analysis was used.The mean (SD) participant age was 63.6 (10.7) years and 119 were men (90.2%). The mean (SD) duration of OA symptoms was 13.4 (12.3) years. In the PLIUS group, 70.4% (95% CI, 58.2%-82.6%) of the participants experienced symptomatic improvement, compared with 67.3% (95% CI, 54.9%-79.7%) of participants in the sham group (P = .84); there was no statistically significant difference in response rates between the treatment groups, and the between-group rate difference of 3.1% (95% CI, -14.3% to 20.5%) did not meet the predefined 10% threshold for clinically significant symptomatic improvement from application of PLIUS. At 48 weeks of treatment, central medial femoral condyle cartilage thickness decreased by a mean (SD) of 73.8 (168.1) μm in the PLIUS group and by 42.2 (297.0) μm in the sham group. This 48-week mean change between the 2 groups did not reach statistical significance (P = .44), and the between-group 48-week difference of -31.7 μm (95% CI, -129.0 μm to 65.7 μm) did not meet the predefined threshold. There were 99 nonserious adverse events in the PLIUS group and 89 in the sham group during the trial. No serious adverse events were deemed related to the study device.PLIUS, as implemented in this study, demonstrated neither symptomatic benefit nor a decrease in loss of tibiofemoral cartilage thickness in knee OA.ClinicalTrials.gov Identifier: NCT02034409.

Contains fulltext : 229477.pdf (Publisher’s version ) (Open Access) Innovative tools are urgently needed to accelerate the evaluation and subsequent approval of novel treatments that may slow, halt, or reverse the relentless progression of Parkinson disease (PD). Therapies that intervene early in the disease continuum are a priority for the many candidates in the drug development pipeline. There is a paucity of sensitive and objective, yet clinically interpretable, measures that can capture meaningful aspects of the disease. This poses a major challenge for the development of new therapies and is compounded by the considerable heterogeneity in clinical manifestations across patients and the fluctuating nature of many signs and symptoms of PD. Digital health technologies (DHT), such as smartphone applications, wearable sensors, and digital diaries, have the potential to address many of these gaps by enabling the objective, remote, and frequent measurement of PD signs and symptoms in natural living environments. The current climate of the COVID-19 pandemic creates a heightened sense of urgency for effective implementation of such strategies. In order for these technologies to be adopted in drug development studies, a regulatory-aligned consensus on best practices in implementing appropriate technologies, including the collection, processing, and interpretation of digital sensor data, is required. A growing number of collaborative initiatives are being launched to identify effective ways to advance the use of DHT in PD clinical trials. The Critical Path for Parkinson’s Consortium of the Critical Path Institute is highlighted as a case example where stakeholders collectively engaged regulatory agencies on the effective use of DHT in PD clinical trials. Global regulatory agencies, including the US Food and Drug Administration and the European Medicines Agency, are encouraging the efficiencies of data-driven engagements through multistakeholder consortia. To this end, we review how the advancement of DHT can be most effectively achieved by aligning knowledge, expertise, and data sharing in ways that maximize efficiencies.

Objective To evaluate the single-dose pharmacokinetics (PK), pharmacodynamics (PD), and safety of sitagliptin in pediatric patients with type 2 diabetes mellitus (T2DM). Study design This was a randomized, placebo-controlled, double-blind evaluation of sitagliptin in 35 patients 10 to 17 years old with T2DM at 7 clinical research sites. The safety, tolerability, PK, and PD (dipeptidyl peptidase-4 [DPP-4] inhibition and aspects of glucose metabolism) of single doses of 50, 100, and 200 mg were assessed. Appropriate transformations on the PK parameters were used and back-transformed summary statistics are reported. Results Adverse experiences were reported by eight study participants; all were of mild intensity except one (intravenous site pain of moderate intensity). PK characteristics in the young patients were comparable to reference adult data, with geometric mean ratios (youths/adults) for AUC0-∞ , Cmax , and C24hr of 0.82, 1.04, and 0.74, respectively. Single doses of 50, 100, and 200 mg sitagliptin inhibited 67.2%, 73.8%, and 81.2% of plasma DPP-4 activity over 24 hours, respectively. Least squares (LS) mean glucose concentrations 2 hours after an oral glucose tolerance test or a meal tolerance test decreased in study participants treated with sitagliptin, compared to placebo, while active LS mean glucagon-like peptide 1 concentrations increased significantly at all sitagliptin doses in both tests. Conclusions Single doses of sitagliptin as high as 200 mg were generally well tolerated in 10- to 17-year-old male and female study participants with T2DM, and a daily sitagliptin dose of 100 mg is appropriate for evaluation in Phase III safety and efficacy studies in pediatric patients with T2DM. (ClinicalTrials.gov: NCT00730275).

Background:In the FINCH 1 study, filgotinib (FIL)—an oral, potent, selective Janus kinase 1 inhibitor—in combination with methotrexate (MTX) provided significant improvements in the signs and symptoms of rheumatoid arthritis (RA) in patients (pts) with inadequate response to MTX.1While EULAR guidelines recommend a treat-to-target approach focusing on reducing inflammation to prevent joint damage, physical disability, and mortality, pts consider control of pain and fatigue, along with maintenance of physical function and health-related quality of life (HRQoL), to be important aspects for their care.2,3Objectives:To evaluate the rate and magnitude of change in patient-reported outcomes (PROs) from FINCH 1.Methods:In the FINCH 1 study (NCT02889796), pts with active RA received oral FIL 200 mg + MTX, FIL 100 mg + MTX, PBO + MTX, or subcutaneous adalimumab (ADA) 40 mg + MTX for up to 52 weeks (W); pts receiving PBO at W24 were rerandomised 1:1 to FIL 100 or 200 mg. PROs included the HAQ-DI and VAS pain scale, SF-36, and FACIT-Fatigue questionnaire. The change from baseline (CFB) at each time point was assessed up to W52 for each treatment group. The mixed-effects model for repeated measures was used to compare each FIL group with PBO for the CFB at each time point through W24. The logistic regression model was used to compare each FIL group with PBO for the proportion of pts achieving the minimum clinically important difference (MCID) of ≥0.22 reduction in CFB in HAQ-DI at each time point through W24.Results:Of 1755 pts randomised and treated (475 FIL 200 mg + MTX; 480 FIL 100 mg + MTX; 325 ADA + MTX; and 475 PBO + MTX), 1417 (80.7%) received study drug through W52. As early as W2 through W24, pts receiving either dose of FIL experienced nominally significantly greater (p A, B). At W2, compared with PBO (40.2%), a nominally significantly greater proportion of pts achieved the HAQ-DI MCID in both the FIL 200 (52.5%; p A, B). By W4, pts receiving either dose of FIL reported a nominally significantly greater mean CFB in FACIT-Fatigue scores vs PBO (p C). In general, CFB for HAQ-DI, VAS pain scale, and FACIT-Fatigue observed for the FIL groups was higher or comparable to ADA at various time points (Fig 1, 2).Conclusion:Both doses of FIL provided rapid and sustained improvements in functional status, pain, HRQoL, and fatigue compared with PBO for pts with RA and inadequate response to MTX throughout the 52-week period.References:[1]Combe BG, et al.Ann Rheum Dis.2019;78 (Suppl 2):A77.[2]Fautrel B, et al.Rheumatol Int.2018;38:935–47.[3]Smolen JS, et al.Ann Rheum Dis.2017;76:960–77.Disclosure of Interests:Alan Kivitz Shareholder of: AbbVie, Amgen, Gilead, GSK, Pfizer Inc, Sanofi, Consultant of: AbbVie, Boehringer Ingelheim,,Flexion, Genzyme, Gilead, Janssen, Novartis, Pfizer Inc, Regeneron, Sanofi, SUN Pharma Advanced Research, UCB, Paid instructor for: Celgene, Genzyme, Horizon, Merck, Novartis, Pfizer, Regeneron, Sanofi, Speakers bureau: AbbVie, Celgene, Flexion, Genzyme, Horizon, Merck, Novartis, Pfizer Inc, Regeneron, Sanofi, Yoshiya Tanaka Grant/research support from: Asahi-kasei, Astellas, Mitsubishi-Tanabe, Chugai, Takeda, Sanofi, Bristol-Myers, UCB, Daiichi-Sankyo, Eisai, Pfizer, and Ono, Consultant of: Abbvie, Astellas, Bristol-Myers Squibb, Eli Lilly, Pfizer, Speakers bureau: Daiichi-Sankyo, Astellas, Chugai, Eli Lilly, Pfizer, AbbVie, YL Biologics, Bristol-Myers, Takeda, Mitsubishi-Tanabe, Novartis, Eisai, Janssen, Sanofi, UCB, and Teijin, Susan Lee Shareholder of: Gilead Sciences Inc., Employee of: Gilead Sciences Inc., Lei Ye Shareholder of: Gilead Sciences Inc., Employee of: Gilead Sciences Inc., Hao Hu Shareholder of: Gilead Sciences Inc., Employee of: Gilead Sciences Inc., Robin Besuyen Shareholder of: Galapagos, Employee of: Galapagos, Bernard Combe Grant/research support from: Novartis, Pfizer, Roche-Chugai, Consultant of: AbbVie; Gilead Sciences, Inc.; Janssen; Eli Lilly and Company; Pfizer; Roche-Chugai; Sanofi, Speakers bureau: Bristol-Myers Squibb; Gilead Sciences, Inc.; Eli Lilly and Company; Merck Sharp & Dohme; Pfizer; Roche-Chugai; UCB

Objective.To determine the effect of rheumatoid arthritis (RA) disease severity on pregnancy outcomes in pregnant women with and without autoimmune diseases.Methods.A prospective cohort study was conducted using the Organization of Teratology Information Specialists Autoimmune Diseases in Pregnancy Project. Pregnant women with RA enrolled between 2005 and 2013 were selected if they (1) delivered a live-born singleton infant; and (2) completed 3 telephone-based measures of RA disease severity prior to 20 weeks’ gestation, including the Health Assessment Questionnaire Disability Index (HAQ-DI), pain score, and patient’s global scale. Associations between RA disease severity and preterm delivery, small for gestational age (SGA), or cesarean delivery were tested in unadjusted and multivariate analyses using modified Poisson regression models.Results.The sample consisted of 440 women with RA. Several unadjusted comparisons yielded significant associations. After adjustment for covariates, increasing disease severity was associated with risk for preterm delivery and SGA. For each unit increase in HAQ-DI (0–1), the adjusted relative risk (aRR) for preterm delivery increased by 58% (aRR 1.58, 95% CI 1.17–2.15). Among those with HAQ-DI > 0.5, the aRR for SGA was 1.81 (95% CI 1.01–3.33).Conclusion.RA disease severity in early pregnancy, as measured in this study, was predictive of preterm delivery and SGA. These findings suggest that the risk of preterm delivery and SGA in women with RA might be lowered if RA is well controlled early in pregnancy.

BackgroundThere is increasing interest in discontinuing biological therapies for patients with rheumatoid arthritis (RA) achieving good clinical responses, provided patients maintain clinical benefit.MethodsWe assessed patients with RA from the Corrona registry who discontinued treatment with their first tumour necrosis factor inhibitor (TNFi) while in low-disease activity (LDA) or lower levels of disease activity. Patients were followed until they lost clinical benefit, defined as increased disease activity or change in RA medications. Duration of maintenance of clinical benefit was estimated using the Kaplan–Meier method. Cox proportional hazard models were assessed to identify factors related to maintenance of benefit.ResultsWe identified 717 eligible patients with RA from 35 656 in the Corrona registry. At discontinuation, patients had a median RA duration of 8 years, mean clinical disease activity score of 4.3±0.11; 41.8% were using TNFi as monotherapy. 73.4% of patients maintained benefit for >12 months after discontinuing therapy and 42.2% did so through 24 months. Factors predictive of maintaining clinical benefit in multivariate analysis included lower disease activity, less pain and better functional status at the time of TNFi discontinuation. Among 301 patients initiating their first TNFi within the registry, faster responders (ie, those who achieved LDA in 4 months or less) did better than slower responders (HR 1.54 (95% CI 1.17 to 2.04)). RA disease duration did not affect maintenance of clinical benefit.ConclusionsDiscontinuation of a first course of TNFi may be associated with persistent clinical benefit. Half of patients maintained response through 20 months. Several patient characteristics may help predict persistent benefit.

Multiple myeloma (MM) is a hematologic cancer derived from malignant plasma cells within the bone marrow. Unlike most solid tumors, which originate from epithelial cells, the myeloma tumor is a plasma cell derived from the lymphoid cell lineage originating from a post-germinal B-cell. As such, the MM plasma cell represents an integral component of the immune system in terms of both antibody production and antigen presentation, albeit not efficiently. This fundamental difference has significant implications when one considers the implications of immunotherapy. In the case of lymphoid malignancies such as myeloma, immune-based strategies must take into consideration this important difference, potentially necessitating immunotherapy targeted toward MM to be altered from that targeted at solid tumors. Typically, the immune system "surveys" cells within our body and is able to recognize and attack cancerous cells that may arise. However, some cancer cells are able to evade immune surveillance and continue to flourish, causing disease. The major mechanism leading to an effective tumor-specific response is one that enables effective antigen processing and presentation with subsequent T-cell activation, expansion, and effective trafficking to the tumor site. Plasma cells employ several mechanisms to escape immune surveillance which include altered interactions with T-cells, DCs, bone marrow stromal cells (BMSC's), and natural killer cells (NK Cells) that can be mediated by immunosuppressive cells such as and myeloid-derived suppressor cells (MDSC's) and cytokines such as IL-10, TGFβ, and IL-6 as well as down-regulation of the antigen processing machinery. Many therapies have been developed to reestablish a functional immune system in MM patients. These include adoptive T-cell therapies to deliver more tumor-specific T-cells, vaccines to increase the tumor-specific precursor frequency of the endogenous T-cell population, immunomodulatory agents (IMiDs) such as thalidomide and lenalidomide to enhance global endogenous immunity, immunostimulatory cytokines, and antibodies to specifically target tumor-specific cell-surface proteins or cytokines. This review will dissect these various approaches currently being explored in MM as well as highlight some future directions for myeloma-specific immune-based strategies.

In response to a request for proposal from the American College of Rheumatology (ACR), our group was charged with developing non-pharmacologic and pharmacologic guidelines for treatments in gout that are safe and effective, i.e., with acceptable risk-benefit ratio. These guidelines for the management and anti-inflammatory prophylaxis of acute attacks of gouty arthritis complements our manuscript on guidelines to treat hyperuricemia in patients with evidence of gout (or gouty arthritis) (1). Gout is the most common cause of inflammatory arthritis in adults in the USA. Clinical manifestations in joints and bursa are superimposed on top of local deposition of monosodium urate crystals. Acute gout characteristically presents as self-limited, attack of synovitis (also called “gout flares”). Acute gout attacks account for a major component of the reported decreased health-related quality of life in patients with gout (2, 3). Acute gout attacks can be debilitating and are associated with decreased work productivity (4, 5). Urate lowering therapy (ULT) is a cornerstone in the management of gout, and, when effective in lowering serum urate (SUA), is associated with decreased risk of acute gouty attacks (6). However, during the initial phase of ULT, there is an early increase in acute gout attacks, which has been hypothesized due to remodeling of articular urate crystal deposits as a result of rapid and substantial lowering of ambient urate concentrations (7). Acute gout attacks attributable to the initiation of ULT may contribute to non-adherence in long-term gout treatment, as reported in recent studies (8). In order to systematically evaluate a broad spectrum of acute gouty arthritis, we generated multifaceted case scenarios to elucidate decision making based primarily on clinical and laboratory test-based data that can be obtained in a gout patient by both non-specialist and specialist health care providers in an office practice setting. This effort was not intended to create a novel classification system of gout, or new gout diagnostic criteria, as such endeavors are beyond the scope of this work. Prior gout recommendations and guidelines, at the independent (i.e, non pharmaceutical industry-sponsored) national or multinational rheumatology society level, have been published by EULAR (9, 10), the Dutch College of General Practitioners (11), and the British Society for Rheumatology (BSR)(12). The ACR requested new guidelines, in view of the increasing prevalence of gout (13), the clinical complexity of management of gouty arthritis imposed by co-morbidities common in gout patients (14), and increasing numbers of treatment options via clinical development of agents(15–17). The ACR charged us to develop these guidelines to be useful for both rheumatologists and other health care providers on an international level. As such, this process and resultant recommendations, involved a diverse and international panel of experts. In this manuscript, we concentrate on 2 of the 4 gout domains that the ACR requested for evaluation of pharmacologic and non-pharmacologic management approaches: (i) analgesic and anti-inflammatory management of acute attacks of gouty arthritis, and (ii) pharmacologic anti-inflammatory prophylaxis of acute attacks of gouty arthritis. Part I of the guidelines focused on systematic non-pharmacologic measures (patient education, diet and lifestyle choices, identification and management of co-morbidities) that impact on hyperuricemia, and made recommendations on pharmacologic ULT in a broad range of case scenarios of patients with disease activity manifested by acute and chronic forms of gouty arthritis, including chronic tophaceous gouty arthropathy(1). Each individual and specific statement is designated as a “recommendation”, in order to reflect the non-prescriptive nature of decision making for the hypothetical clinical scenarios. So that the voting panel could focus on gout treatment decisions, a number of key assumptions were made, as described in Part I of the guidelines (1). Importantly, each proposed recommendation assumed that correct diagnoses of gout and acute gouty arthritis attacks had been made for the voting scenario in question. For treatment purposes, it was also assumed that treating clinicians were competent, and considered underlying medical comorbidities (including diabetes, gastrointestinal disease, hypertension, and hepatic, cardiac, and renal disease), and potential drug toxicities and drug-drug interactions, when making both treatment choicesand dosing decisions on chosen pharmacologic interventions. The RAND/UCLA methodology used here emphasizes level of evidence, safety, and quality of therapy, and excludes analyses of societal cost of health care. As such, the ACR gout guidelines are designed to reflect best practice, supported either by level of evidence or consensus-based decision-making. These guidelines cannot substitute for individualized, direct assessment of the patient, coupled with clinical decision making by a competent health care practitioner. The motivation, financial circumstances, and preferences of the gout patient also need to be considered in clinical practice, and it is incumbent on the treating clinician to weigh the issues not addressed by this methodology, such as treatment costs, when making management decisions. Last, the guidelines for gout management presented herein were not designed to determine eligibility for health care cost coverage by third party payers.

DINESH KHANNA, JOHN D. FITZGERALD, PUJA P. KHANNA, SANGMEE BAE, MANJIT K. SINGH, TUHINA NEOGI, MICHAEL H. PILLINGER, JOAN MERILL, SUSAN LEE, SHRADDHA PRAKASH, MARIAN KALDAS, MANEESH GOGIA, FERNANDO PEREZ-RUIZ, WILL TAYLOR, FREDERIC LIOTE, HYON CHOI, JASVINDER A. SINGH, NICOLA DALBETH, SANFORD KAPLAN, VANDANA NIYYAR, DANIELLE JONES, STEVEN A. YAROWS, BLAKE ROESSLER, GAIL KERR, CHARLES KING, GERALD LEVY, DANIEL E. FURST, N. LAWRENCE EDWARDS, BRIAN MANDELL, H. RALPH SCHUMACHER, MARK ROBBINS, NEIL WENGER, AND ROBERT TERKELTAUB

Objective To study health care utilization patterns in patients with gout. Methods In a gout population from primary care and rheumatology clinics in 3 U.S. metropolitan cities, we collected data on gout-related utilization (primary care, rheumatology, urgent care, emergency room, and other) in the past year. We evaluated the association of comorbidities, age, gender, gout characteristics (time since last gout attack and tophi), and gout severity ratings (mean of serum uric acid, patient-rated, and physician-rated gout severity) and with emergency/urgent care and primary care utilization using regression and correlation analyses. Results Of the 296 patients who reported visiting at least 1 type of health practitioner for gout in the past year, the percentage of patients utilizing the service at least once and annual utilization rates among utilizers were as follows: primary care physician, 60%, 3.0 ± 3.4; nurse practitioner/physician assistant, 26%, 2.7 ± 2.5; rheumatologist, 51%, 3.7 ± 5.7; urgent care, 23%, 2.1 ± 2.2; emergency room, 20%, 2.0 ± 1.7; and hospitalization, 7%, 2.1 ± 1.4. Higher overall gout severity was associated with greater use of each resource type and with overall gout-related utilization. Nonemergency/nonurgent care utilization (primary care physician, nurse practitioner, physician's assistant, and rheumatologist for gout) was the strongest predictor of gout-related emergency/urgent care utilization. Patients with more comorbidities had greater gout-related primary care utilization. Conclusions Overall gout severity was associated with all types of gout-related utilization. This may help to screen high utilizers for targeted behavioral and therapeutic interventions. Having a higher number of comorbid conditions was a risk factor for higher gout-related primary care utilization.

A series of six-membered heterocycle carboxamides were synthesized and evaluated as cholecystokinin 1 receptor (CCK1R) agonists. A pyrimidine core proved to be the best heterocycle, and SAR studies resulted in the discovery of analog 5, a potent and structurally diverse CCK1R agonist.

Surrogate decision makers and clinicians often have discordant perceptions about a patient's prognosis. There is a paucity of empirical data to guide communication about prognosis.To assess: (1) whether numeric or qualitative statements more reliably convey prognostic estimates; and (2) whether surrogates believe physicians' prognostic estimates.A total of 169 surrogate decision makers for intensive care unit patients were randomized to view 1 of 2 versions of a video portraying a simulated family conference involving a hypothetical patient. The videos varied only by whether prognosis was conveyed in numeric terms ("10% chance of surviving") or qualitative terms ("very unlikely" to survive).We assessed: (1) surrogates' personal estimates of the patient's prognosis; and (2) surrogates' understanding of the physician's prognostic estimate. Neither surrogates' personal estimates nor their understanding of the physician's prognostication differed when prognosis was conveyed numerically versus qualitatively (surrogates' estimate, 22 ± 23% chance of survival versus 26 ± 24%, P = 0.26; understanding of physician's estimate, 17 ± 22% chance of survival versus 16 ± 17%, P = 0.62). One in five surrogates estimated the patient's prognosis was greater than 20% more optimistic than the physician's prognostication. Less trust in physicians was associated with larger discrepancies between surrogates' personal estimates and their understanding of the physician's estimate.Neither numeric nor qualitative statements reliably convey news of a poor prognosis to surrogates in intensive care units. Many surrogates do not view physicians' prognostications as absolutely accurate. Factors other than ineffective communication may contribute to physician-surrogate discordance about prognosis.

Rationale, aims and objectives Our objective was to describe the factors associated with doctor-rated and patient-rated gout severity to explain how doctor assessment involving patient-reported outcomes can improve the clinical management of gout. Methods Patients completed a newly validated gout-specific health-related quality of life instrument, the Gout Impact Scale (GIS) and other questions regarding their gout. Both patients and their doctors gave an overall gout severity assessment. We conducted correlation analyses between each predictor of interest and the two different severity ratings (doctor-rated severity and patient-rated severity). Stepwise multiple regressions were performed to determine the best predictors for doctor-rated and patient-rated severity, respectively. Results Doctor-rated severity more closely correlated with objective clinical and laboratory findings, particularly the presence of tophi, which was not a leading factor in patient-rated severity assessments. Patient-rated severity more closely correlated with the domains of the GIS, which expressed the impact of gout on health-related quality of life. Conclusion Doctors might have a better understanding of their patients' level of disease impact if they incorporate an instrument such as the GIS in their evaluation of gout severity and their decisions regarding aggressiveness of treatment. The increased use of patient-reported outcomes measures has the potential to improve quality of care and patient satisfaction, as well as reduce costs of health care utilization.

Objective.Studies have suggested that early institution of tumor necrosis factor (TNF) inhibitors improves functional status and slows radiographic progression among patients with rheumatoid arthritis (RA). To determine whether these findings have altered practice patterns, we used the Consortium of Rheumatology Researchers of North America (CORRONA) registry to assess the pattern of TNF inhibitor utilization in the US over time.Methods.Demographics and disease activity data were collected for patients with RA. The trend of TNF inhibitor use during 2002–06 was evaluated prospectively using linear and logistic regression models.Results.Of the 11,397 patients with RA, 66% and 34% had established RA and early RA (disease duration < 3 yrs), respectively. The majority of patients were female and Caucasian. Despite comparable levels of disease activity, more of the patients with established RA were taking TNF inhibitors than those with early RA (40% vs 25%; p < 0.0001). The majority of patients (70%) taking TNF inhibitors were also receiving disease modifying antirheumatic drugs. The use of TNF inhibitors increased at a rate of 2.8% per year in established RA and 1.2% per year in early RA. The mean Clinical Disease Activity Index at the start of TNF inhibitors decreased at a rate of −0.233 per quarter (p = 0.006), while the mean Disease Activity Score decreased at a rate of −0.04 per quarter (p = 0.022).Conclusion.Utilization of TNF inhibitors in this multicenter, observational US cohort is increasing in both early and established RA, although it is more prominent among patients with established RA. The level of disease activity at which TNF inhibitors were initiated decreased over time in patients with both established and early RA.

Solid-state structures of trans-[RuCl2{Cl2PN(Me)N(Me)PCl2}2] (1), cis-[PdCl2{Cl2PN(Me)N(Me)PCl2}] (2), and cis-[PtCl2{Cl2PN(Me)N(Me)PCl2}] (3) were studied by using 13C CPMAS NMR spectroscopy and X...

Patient-derived measures of disease activity have been proven to be reliable, valid, sensitive to change, and less susceptible to placebo effects in the assessment of many rheumatic diseases. Traditionally, paper forms have been used to capture this information but with advances in technology and a growing number of computer users, computerized versions have been developed. The computerized patient-derived questionnaires have been shown to be valid and reliable in many studies. Despite a concern for the usability and acceptability among inexperienced computer users and certain subgroups, such as older persons, a majority of patients queried preferred the electronic versions and found them easy to use. In addition, these computerized versions offer several advantages over the paper format, including improved data capture with less ambiguity, less long-term cost, immediate scoring and availability of the results, and – most importantly – the ability for more frequent disease activity, efficacy, and safety assessments.

The prevalence of gout has increased markedly in the United States in the past two decades, and new treatments for hyperuricemia are being developed. Recent molecular identification of urate transporter-1 (URAT1) as the central mediator of renal urate reabsorption has provided novel understanding of the pathogenesis of hyperuricemia, and the target site for current and possibly future primary uricosuric agents. Recent studies have also highlighted uricosuric effects of several drugs (losartan, atorvastatin, fenofibrate) that are prescribed for primary indications other than hyperuricemia. The niche of these agents in current management of hyperuricemia is discussed. We also review the ongoing development of recombinant uricase preparations and of novel xanthine oxidase inhibitors exemplified by febuxostat. These agents should provide novel options for patients with chronic, refractory gout and hyperuricemia, particularly in association with allopurinol hypersensitivity and renal insufficiency.

Rheumatoid arthritis is a chronic, inflammatory condition of unknown etiology, affecting about 1% of the general population. Adalimumab was added to our armamentarium against rheumatoid arthritis in December 2002. It can be used either alone or in combination with methotrexate in those patients who continue to have persistent disease activity despite their therapy. Adalimumab has been shown to rapidly improve the clinical status and retard radiographic progression in a substantial number of treated patients. Its clinical efficacy has been shown to be sustained through several years of continued therapy. The rate of adverse events is comparable to that of other tumor necrosis factor inhibitors. As with those agents, while infections are the main adverse event clinicians should be aware of, patients should also be counseled about, and monitored for, rare events such as tuberculosis, opportunistic infections, lymphoma, and demyelinating or autoimmune diseases.

Multicellular organisms defend themselves from microbial infections by mounting an innate immune response that serves to neutralize pathogenic invaders (Kimbrell and Beutler 2001; Janeway and Medzhitov 2002). Receptors that recognize pathogen-associated molecular patterns (PAMPs) trigger signaling cascades that culminate in expression of immune effector genes encoding antimicrobial peptides, cytokines, chemokines, and various inflammatory mediators. In both vertebrates and invertebrates, the NF-κB family of transcription factors serves a pivotal role in signal-induced gene activation during the innate immune response (Silverman and Maniatis 2001). Owing to the broad evolutionary conservation of innate immunity, studies in genetically tractable invertebrates, especially Drosophila melanogaster, have contributed greatly to our understanding of the mechanisms underlying innate immunity. Drosophila, like other invertebrates, lacks an adaptive immune system, being entirely dependent on innate immunity for its resistance to microbial infection. Genetic screens for Drosophila mutants susceptible to pathogenic challenge have identified two distinct signaling cascades—the Toll and Imd pathways—that govern expression of antimicrobial peptides (Hoffmann and Reichhart 2002; Tzou et al. 2002; Hultmark 2003). The Toll pathway, originally characterized for its role in establishing embryonic dorsoventral polarity, mediates resistance to fungal and Gram-positive infections by activating two NF-κB proteins: Dorsal and Dif (Wasserman 2000). The Imd pathway induces expression of a distinct set of genes coding for antimicrobial peptides, such as Diptericin and Attacin, that provide immunity to Gram-negative bacteria. Components of the Imd pathway include a peptidoglycan recognition protein (PGRP-LC; Choe et al. 2002; Gottar et al. 2002; Ramet et al. 2002), as well as several counterparts to signal transducers involved in NF-κB activation in mammalian cells. These include IMD itself, a homolog of the TNF signaling pathway kinase RIP (Georgel et al. 2001), as well as TAK1, a MAP kinase kinase kinase (MAPKKK), and two IκB kinase (IKK) complex components, IKKβ (ird5), and IKKγ (Kenny; Rutschmann et al. 2000; Silverman et al. 2000, 2003; Lu et al. 2001; Vidal et al. 2001). In conjunction with the IKK complex, the Drosophila caspase Dredd functions in proteolytic activation of a third NF-κB family protein, Relish, that directly activates antibacterial peptide genes (Leulier et al. 2000; Stoven et al. 2000, 2003). There is also evidence that the Drosophila FADD homolog acts downstream of IMD, independently of TAK1 and IKK, to control Dredd activation (Leulier et al. 2002; Naitza et al. 2002). Although Relish, Dif, and Dorsal are critical for transcriptional induction of antimicrobial peptides, they are unlikely to be the sole mediators of PAMP-triggered signal transduction. In mammalian macrophages and dendritic cells, Toll-like receptors (TLRs) specific to particular PAMP ligands induce activation of ERK, JNK, and p38 MAP kinases (MAPKs) in addition to NF-κB (Akira et al. 2001). Furthermore, the nematode Caenorhabditis elegans and the plant Arabidopsis thaliana encode no orthologs of NF-κB, but rely instead on MAPK signaling cascades to mediate innate immune responses (Asai et al. 2002; Kim et al. 2002; Mallo et al. 2002). JNK signaling is required for a variety of biological processes in flies and mammals, including developmental morphogenesis, apoptosis, and immunity (Stronach and Perrimon 1999; Chang and Karin 2001). In mammals, JNK activation is required for inflammation-induced apoptosis (Deng et al. 2003; Maeda et al. 2003). Curiously, JNK activation is negatively regulated by the IKK-NF-κB pathway (De Smaele et al. 2001; Tang et al. 2001). Although this cross-talk appears to be an important mediator of the antiapoptotic function of NF-κB (Karin and Lin 2002), the mechanism by which NF-κB negatively regulates JNK activation in mammals is not well understood (Kyriakis 2001). In Drosophila, lipopolysaccharide (LPS) has been reported to activate JNK (Sluss et al. 1996), which is required for induction of a subset of immune response genes (Boutros et al. 2002), as well as the NF-κB family member Relish, which directs transcription of a distinct group of immune response loci (Boutros et al. 2002). However, it has been difficult to assess the biological role of the JNK module in the innate immune response because loss-of-function mutations in this pathway are usually embryonic lethal (Glise et al. 1995; Riesgo-Escovar et al. 1996; Sluss et al. 1996). We have found that activation of the Relish module in Drosophila results in attenuation of JNK activity after challenge with a commercial LPS preparation. Moreover, we demonstrate that Relish activation is mechanistically linked to switching off the JNK signaling module after LPS stimulation. In the absence of Relish activation, LPS treatment causes a sustained activation of JNK, which, in turn, leads to prolonged expression of JNK target genes. Biochemical experiments reveal that the negative regulation of JNK signaling involves proteasomal degradation of TAK1. Hence, it appears that the Relish-dependent genes not only serve their own immune effector roles, but also participate in shaping the temporal pattern of the JNK-mediated immune response. These findings reveal an unanticipated cross-talk between Drosophila innate immune pathways and hold promise for mechanistic insight into the mammalian counterpart of this regulatory interaction.

The pubertal development of the hypothalamic-pituitary-adrenal (HPA) axis has received relatively little experimental attention. As puberty is marked by an increase in the susceptibility to various psychiatric disorders that may be related to HPA dysfunction, it is imperative to elucidate the pubertal development of this neuroendocrine axis. To date, the limited research in this area has been conducted primarily on males. Presently, we investigated stress responsiveness, as measured by both stress hormones (e.g., corticotropin (ACTH) and corticosterone) and gonadal steroids, in intact and ovariectomized prepubertal and adult female rats before and after a 30-min session of restraint stress. We report here that intact prepubertal females exhibit an extended corticosterone stress response (30–45 min longer) compared to intact adults. Moreover, ovariectomized prepubertal females continue to exhibit a prolonged stress-induced corticosterone and progesterone response compared to ovariectomized adults, indicating these protracted responses prior to puberty are independent of ovarian hormones. ACTH levels were not significantly different between intact and ovariectomized prepubertal and adult animals at all the post-stress time points measured, suggesting that the prolonged corticosterone response in prepubertal females is due to an enhanced sensitivity to ACTH at the level of the adrenal cortex. Taken together, these data indicate that stress reactivity changes dramatically during puberty in females. Furthermore, these data demonstrate additional development of the HPA axis during pubertal maturation, resulting in a more quickly terminated stress response in adulthood.

The activity of the serotonin (5-hydroxytryptamine, 5-HT) system is sensitive to estradiol and progesterone. During the ovarian cycle, dendritic spines on CA1 pyramidal neurons of the dorsal hippocampus are increased by estradiol and later decreased by progesterone. We sought to determine whether 5-HT is involved in maintaining CA1 spine density and/or in steroid regulation of synaptic plasticity in dorsal hippocampus. Ovariectomized rats were treated (sc) over 10 days with the tryptophan hydroxylase inhibitor parachlorophenylalanine (pCPA) to deplete 5-HT, followed by estradiol benzoate on days 10 and 11. A subset of animals received progesterone on day 12. The day after the last treatment, rats were perfused and brains were processed for Golgi impregnation. Separate groups were processed for radioimmunocytochemistry (RICC) for the spine-associated protein, spinophilin, or high-performance liquid chromatography (HPLC) for monoamine analysis. Golgi and RICC data indicate that CA1 apical spine density was significantly decreased by pCPA (17-20%). Estradiol increased spine density in both saline- and pCPA-treated rats compared to respective controls (30%); however, pCPA animals maintained significantly fewer spines. No differences in spine densities were observed between saline- and pCPA-treated rats given estradiol and progesterone. Depletion of 5-HT by pCPA was confirmed in the CA1 (-90%) and dorsal raphe (-80%) by HPLC analysis. While 5-HT depletion was associated with a 57% decrease in CA1 norepinephrine (NE), there was no difference in dorsal raphe NE. Thus, whereas 5-HT is involved in maintaining spine density in the adult female rat CA1, it is not crucial for steroid-mediated plasticity. 5-HT-regulated spines/synapses may represent distinct populations from those modulated by estradiol and progesterone in dorsal hippocampus.

The rate of metabolism of the multifunctional neurosteroid, dehydroepiandrosterone (DHEA), by embryonic rat hippocampal cells maintained in culture was compared to that of 4-androstenedione (AD), the immediate precursor of estrone (E1). The experiments were carried out to assess the relative contribution of DHEA, its 7-hydroxylated metabolites and estrogen on their reported effects on memory and neuroprotection. The 3H-labeled steroids of high specific radioactivity were incubated for 1, 8, 24 and 48 h and the putative metabolites extracted from the culture medium with acetone-ethyl acetate before separation by TLC for radioassay. [3H]DHEA (2.0 ng/5x10(5) cells) yielded primarily the 7alpha- and 7beta-hydroxylated steroids in an almost equal ratio under conditions that resembled those used by others to study the protection of neurons by hippocampal astrocytes against excitatory amino acid-induced toxicity. The rate of conversion of DHEA to AD, and particularly to E1, was much lower. With [3H]AD as substrate, significant aromatization to estrogen occurred only after 24 h when most of [3H]DHEA had already been converted to its 7-hydroxylated products and the hydroxylase and aromatase systems would no longer be competing for the same coenzyme (NADPH). The hippocampal cells were still viable after 48 h of incubation with the steroids and were able to oxidize estradiol (E2) to E1 and reduce E1 to E2 and AD to testosterone (T). It is suggested that 7alpha- and 7beta-OHDHEA, the main metabolites formed in the rat hippocampus, might be responsible for some of the functions previously ascribed to estrogens in the brain and the reasons for this proposal are discussed.

IGF-I and the IGF-I receptor are necessary for normal embryonic growth. VIP is an important regulator of early postimplantation growth and acts indirectly through the release of other factors, including activity-dependent neurotrophic factor. The relationship of IGF-I growth regulation to VIP/activity-dependent neurotrophic factor-stimulated growth was examined with whole cultured embryonic d 9.5 mouse embryos. Somite numbers and DNA and protein contents were measured in embryos treated with IGF-I, anti-IGF-I, VIP, activity-dependent neurotrophic factor, and anti-activity-dependent neurotrophic factor-14 (antiserum to an activity-dependent neurotrophic factor agonist). IGF-I mRNA content was measured after incubation with and without VIP for 30 and 60 min using competitive RT-PCR. IGF-I induced a significant, dose-dependent increase in growth as measured by somite number, DNA levels, and protein content. Furthermore, anti-IGF-I inhibited embryonic growth and also prevented exogenous IGF-mediated growth. Both VIP- and activity-dependent neurotrophic factor-stimulated growth were blocked by anti-IGF-I, whereas anti-activity-dependent neurotrophic factor-14 had no detectable effect on IGF-I-induced growth. Treatment with VIP resulted in a 2-fold increase in embryonic IGF-I mRNA. These data suggest that IGF-I is a downstream mediator of VIP and activity-dependent neurotrophic factor in a regulatory pathway coordinating embryonic growth and that VIP may function as a regulator of IGF-I gene expression in the embryo.

Structural studies have shown that estrogens increase dendritic spine number in the dorsal CA1 field of rat hippocampus using Golgi impregnation as well as the number of dorsal CA1 synapses visualized via electron microscopy. The present study was carried out to further these findings by examining changes in the levels of pre- and postsynaptic proteins using radioimmunocytochemistry (RICC). In this study, 2 days of estradiol-benzoate treatment produced significant and comparable increases in synaptophysin, syntaxin, and spinophilin immunoreactivity (IR) in the CA1 region of the dorsal hippocampus of ovariectomized female rats. For spinophilin, IR was also increased in the hilar region of the dentate gyrus as well as CA3. In all cases, the nonsteroidal estrogen antagonist CI628, which has been previously shown to block spine formation, inhibited the effects of estrogen. However, these protein differences were not detected in whole hippocampus using Western blots. These findings add to a growing body of evi...

Activity-dependent neurotrophic factor is a potent, neuroprotective protein released from astroglia by VIP and accounts in part for the neuroprotective properties of this neuropeptide. The growth-regulatory actions of VIP during embryogenesis may also occur indirectly through the release of activity-dependent neurotrophic factor. Whole cultured day-9 mouse embryos treated with activity-dependent neurotrophic factor (10(-13) M) for 4 hr grew 3.1 somites, compared with 1.6 somites in control embryos. Treated embryos appeared morphologically normal and exhibited significant increases in cross-sectional area, protein, and DNA content and bromodeoxyuridine incorporation. Anti-activity-dependent neurotrophic factor significantly inhibited growth. Co-treatment of embryos with anti-activity-dependent neurotrophic factor inhibited VIP-stimulated growth; however, anti-VIP did not inhibit activity-dependent neurotrophic factor-induced growth. These data indicate that an activity-dependent neurotrophic factor-like substance is an endogenous embryonic growth factor and that VIP-regulated growth occurs, at least in part, through activity-dependent neurotrophic factor.

In cats, each sensorimotor cortex has bilateral corticospinal (CS) terminations during early postnatal life, with contralateral terminations denser than ipsilateral ones. Subsequent development depends on neural activity: silencing CS neurons on one side results in development of sparse terminations from that side and dense bilateral terminations from the active side. In this study we determined whether activity-dependent competition between CS terminations is important in shaping their development. We compared the effect of bilateral sensorimotor cortex activity blockade (activity deprivation alone, without competition) on CS development, with that produced by unilateral blockade (activity deprivation with competition). We found that the extent of the spinal gray matter labeled is substantially greater when the motor cortex on each side is silenced rather than when only one side is silenced. These findings support the hypothesis that competition between developing CS terminations is important in shaping the topography of CS connections.

In vitro autoradiography with [ 125 I]vasoactive intestinal peptide revealed that the vasoactive intestinal peptide analogue, stearyl-norleucine 17 vasoactive intestinal peptide, reported to be inactive at adenylyl cyclase-linked receptors in astrocytes, displaced a subset of vasoactive intestinal peptide binding sites on rat brain sections. These sites were widespread in adult rat brains and enriched in the olfactory bulb and thalamus, and corresponded to previously demonstrated GTP-insensitive vasoactive intestinal peptide binding sites. Stearyl-norleucine 17 vasoactive intestinal peptide also identified receptors in rat lung and liver. In the adult brain, the stearyl-norleucine analog displaced only GTP-insensitive vasoactive intestinal peptide binding sites. In contrast, stearyl-norleucine 17 vasoactive intestinal peptide-displaceable sites in the embryonic day 9 mouse appeared to include both GTP-sensitive and GTP-insensitive binding sites. This observation suggested the presence of an embryonic vasoactive intestinal peptide receptor with distinct pharmacological properties. Treatment of whole cultured mouse embryos with stearyl-norleucine 17 vasoactive intestinal peptide resulted in stimulation of embryonic growth, with the stearyl-norleucine analog equipotent to vasoactive intestinal peptide, but less efficacious at higher concentrations (10 −7 M). Embryonic growth was inhibited by pituitary adenylyl cyclase-activating peptide and 8-bromoadenosine 3′,5′-cyclic monophosphate. In addition, 8-bromoadenosine 3′,5′-cyclic monophosphate inhibited stearyl-norleucine 17 vasoactive intestinal peptide-stimulated growth. The results of the current study support the hypothesis that vasoactive intestinal peptide regulation of early postimplantation embryonic growth occurs, at least in part, independently of adenylyl cyclase stimulation.

Vasoactive intestinal peptide (VIP) is an important growth regulator of the embryonic day (E)9-E11 mouse. In comparably aged rat embryos, VIP messenger RNA (mRNA) is not detectable; however, peak concentrations of VIP in maternal rat serum indicate a nonembryonic source. In the current study, mouse maternal and embryonic tissues were examined from E6-E12. Although RT-PCR revealed VIP mRNA in E6-E7 conceptuses, by E8 (when extraembryonic tissues could be separated from the embryo), VIP mRNA was detected only in the decidua/trophoblast. Decidual/trophoblastic VIP mRNA decreased until E10, after which it was not detectable. VIP mRNA was not apparent in the embryo until E11-E12. At E9, VIP immunoreactivity was localized to abundant, diffuse cells in the decidua basalis, which were also immunoreactive for T cell markers. VIP binding sites were dense in the decidua/trophoblast at E6, but gradually decreased until E10, after which they were not apparent. VIP binding sites were detected in embryonic neuroepithelium by E9. The transient presence of VIP binding sites and mRNA in the decidua/trophoblast correlate with the critical period of VIP growth regulation, when VIP mRNA is absent in the embryo. These findings suggest that maternal lymphocytes are the source of VIP's regulating early postimplantation embryonic growth.

The Gout Impact Scale (GIS) is a gout-specific quality of life instrument that assesses impact of gout during an attack and impact of overall gout. The GIS has five scales and each is scored from 0 to 100 (worse health). Our objective was to assess minimally important differences (MIDs) for the GIS administered in a randomized controlled trial (RCT) assessing rilonacept vs placebo for prevention of gout flares during initiation of allopurinol therapy.Trial subjects (n = 83) included those with two or more gout flares (self-reported) in the past year. Of these, 73 had data for Weeks 8 vs 4 and formed the MID analysis group and were analysed irrespective of the treatment assignment. Subjects completed the GIS and seven patient-reported anchors. Subjects with a one-step change (e.g. from very poor to poor) were considered as the MID group for each anchor. The mean change in GIS scores and effect size (ES) was calculated for each anchor's MID group. The average of these created the overall summary MID statistics for each GIS. An ES of 0.2-0.5 was considered to represent MID estimates. Results. Trial subjects (n = 73) were males (96.0%), White (90.4%), with mean age of 50.5 years and serum uric acid of 9.0 mg/dl. The mean change score for the MID improvement group for scales ranged from -5.24 to -7.61 (0-100 scale). The ES for the MID improvement group for the four scales ranged from 0.22 to 0.38.The MID estimates for GIS scales are between 5 and 8 points (0-100 scale). This information can aid in interpreting the GIS results in future gout RCTs. Trial Registration. Clinicaltrials.gov, www.clinicaltrials.gov, NCT00610363.

We are constantly reminded of the exploding elderly population and the increasing demand to meet their needs. But do we fully understand and appreciate the impact that this fastest-growing segment of the population will have upon our profession? Whether we realize it or not, today's dental student is training for tomorrow's elderly baby boomer. The baby boomer generation is 76 million strong, representing 19 years worth of births spanning from 1946-1964. That makes the oldest baby boomer 55 years old and the youngest 37 years old. What does this all mean? That from 2011-2030, the age group of 65 years of age and older will make up approximately 22% of the population, vastly changing our patient population, not to mention a significant increase in patient load. The future holds promise for not only a busy career, but also potentially a financially rewarding one as well. To some extent, we are all going to be geriatric clinicians. There is little doubt that there will be a great demand for services in restorative dentistry, prosthodontic dentistry, endodontics, periodontics, oral surgery, and perhaps orthodontics. As the baby boomers benefited from fluoride and sanitation, more people have been able to maintain their dentition and health into their older years. Dental students graduating today will be only beginning the prime of their careers as the baby boomers make their introduction in full force in the year 2011.

Our objective was to describe the factors associated with doctor-rated and patient-rated gout severity to explain how doctor assessment involving patient-reported outcomes can improve the clinical management of gout.Patients completed a newly validated gout-specific health-related quality of life instrument, the Gout Impact Scale (GIS) and other questions regarding their gout. Both patients and their doctors gave an overall gout severity assessment. We conducted correlation analyses between each predictor of interest and the two different severity ratings (doctor-rated severity and patient-rated severity). Stepwise multiple regressions were performed to determine the best predictors for doctor-rated and patient-rated severity, respectively.Doctor-rated severity more closely correlated with objective clinical and laboratory findings, particularly the presence of tophi, which was not a leading factor in patient-rated severity assessments. Patient-rated severity more closely correlated with the domains of the GIS, which expressed the impact of gout on health-related quality of life.Doctors might have a better understanding of their patients' level of disease impact if they incorporate an instrument such as the GIS in their evaluation of gout severity and their decisions regarding aggressiveness of treatment. The increased use of patient-reported outcomes measures has the potential to improve quality of care and patient satisfaction, as well as reduce costs of health care utilization.

Objective.To investigate the correlation between the Disease Activity Score using a 28-joint count (DAS28) based on physician-derived joint counts and the DAS28 based on patient-derived joint counts (Pt-DAS28) in rheumatoid arthritis (RA).Methods.Data from a multicenter, open-label study investigating the immunogenicity of etanercept (ETN) were analyzed. ETN-naive patients with active RA received ETN 50 mg once weekly alone or with methotrexate (MTX). Joint counts were performed at baseline, Week 12, and Week 24 by the physician and patient independently. Patients received instruction in performing joint assessments.Results.Of 447 patients enrolled (ETN, n = 218; ETN + MTX, n = 229), most were women (79%) and the mean age was 54.5 years. Correlation coefficients between DAS28 and Pt-DAS28 were ≥ 0.57 at baseline, Week 12, and Week 24. At Week 24, 48%, 39%, and 12% of patients could be classified as having low, moderate, or high disease activity, respectively, using DAS28. Using Pt-DAS28, 43%, 39%, and 18% were similarly classified. Agreement in the category of disease activity classification occurred in 72% of patients (kappa = 0.55). At Week 24, 78% of patients using DAS28 and 72% of patients using Pt-DAS28 were classified as moderate or good European League Against Rheumatism responders.Conclusion.These results support the possible use of patient-derived tender and swollen joint counts to aid in the assessment of disease activity and clinical response in patients with RA.

The immune system consists of a complex array of immunocompetent cells and inflammatory mediators that exist in complex networks. These components interact through cascades and feedback circuits, maintaining physiologic inflammation and immunosurveillance. In various autoimmune conditions, a foreign or auto-antigen may upset this fine balance, leading to dysregulated immunity, persistent inflammation, and ultimately pathologic sequelae. In recent years, there has been tremendous progress delineating the specific components of the immune system that contribute to normal immunity and specific disease states. With this greater understanding of pathogenesis coupled with advances in biotechnology, many immunomodulatory agents, commonly called biologic agents, have been introduced. The 2 most common classes of biologic agents are monoclonal antibodies and fusion proteins. These agents can inhibit targets with exquisite specificity to optimize outcomes and minimize toxicity. B cells contribute significantly to the initiation and perpetuation of the immune responses. B cells not only can produce potentially pathologic autoantibodies and proinflammatory cytokines but also can present antigens to T cells and provide costimulatory signals essential for T-cell activation, clonal expansion, and effector function. This review focuses on biologic agents targeting B cells in the treatment of rheumatoid arthritis and systemic lupus erythematosus.

The immune system consists of a diverse array of immunocompetent cells and inflammatory mediators that exist in complex networks. These components interact through cascades and feedback circuits, maintaining physiologic inflammation (eg, tissue repair) and immunosurveillance. In various autoimmune and allergic diseases, a foreign antigen or autoantigen might upset this fine balance, leading to dysregulated immunity, persistent inflammation, and ultimately pathologic sequelae. In recent years, there has been tremendous progress delineating the specific components of the immune system that contribute to various aspects of normal immunity and specific disease states. With this greater understanding of pathogenesis coupled with advances in biotechnology, many immunomodulatory agents commonly called "biologic agents" have been introduced into the clinic for the treatment of various conditions, including immune globulins and cytokines. The 2 most common classes of approved biologic agents are mAbs and fusion proteins with exquisite specificity. These agents have the potential both to optimize outcomes through more thorough modulation of specific parts of the dysregulated immune response and to minimize toxicity compared with less specific methods of immunosuppression.

Objective. To assess the impact of gout on health-related quality of life (HRQoL) among patients in three large US cities. Methods. Gout patients completed the Short Form-36 (SF-36) and a series of questions regarding their gout, comorbidities and demographics. Their physicians confirmed the gout diagnosis and evaluated the severity of patient’s gout. The differences in mean norm-based SF-36 scores between the US norms and gout patients and between subgroups of gout patients were calculated. The relative weight and significance of gout-related characteristics associated with patients’ HRQoL were also calculated. Results. The majority of the patients were males with a mean age of 62.2 years and median disease duration of 13.8 years. Most were overweight/obese with several comorbidities. Half of the patients experienced three or more gout attacks per year with a typical gout attack involving five joints and lasting for at least 4 days. The Physical Component Summary (PCS) and Mental Component Summary (MCS) was significantly lower for gout patients (P < 0.002 and P < 0.001, respectively). Among gout patients, the mean PCS and MCS were lower for those with more frequent gout attacks and greater number of affected joints (P < 0.005 and P < 0.001, respectively). After adjusting for age, gender and comorbidities, the number of joints involved during a typical and the worst gout attack had the greatest impact on patient’s PCS and MCS. Conclusion. Gout patients had clinically significant lower HRQoL than their age-matched US norm. Comorbidities and several additional gout-related factors significantly impacted the overall HRQoL.

ObjectiveTo evaluate the reliability and validity of an instrument assessing the influence of gout (acute and chronic) on health-related quality of life (HRQOL).MethodsFocus groups were used to examine the content of an existing Gout Assessment Questionnaire (GAQ1.0). GAQ2.0 was developed, consisting of a section describing the impact of gout on HRQOL [Gout Impact (GI)] and 4 sections describing subjects’ gout overall and demographic data. The GAQ2.0 and the Medical Outcomes Study Short Form-36 Version 2 (SF-36v2) were completed by gout patients in 3 US cities. GI scales were examined using clinical judgment, review of item statistics, Rasch analysis, and confirmatory factor analysis.ResultsSubjects (n = 308) were predominantly male (90.2%), Caucasian (75.9%), with a mean age 62.2 ± 11.8 years. Half the subjects (49.7%) reported ≥ 3 attacks in the past year. Two-week test-retest reliability for each scale was good (0.77 to 0.89) for all 5 GI scales. All scales achieved high sufficient (0.86 to 0.89) or excellent (0.93 to 0.97) ratings based on 10-item adjusted alpha coefficients. Correlations and tests among known groups indicated subjects with more severe gout had higher GI scores (i.e., greater gout impact). GI scores correlated more highly with patient-reported measures of gout severity than the SF-36v2 and several traditional measures of gout severity.ConclusionThe GAQ2.0 is an instrument for measuring the impact of gout on HRQOL. The GI section exhibited acceptable reliability and validity characteristics. Future studies should assess GI responsiveness, minimally important differences, and psychometric properties in other patient populations.

Summary In the last two decades, a voluminous amount of research from multiple disciplines has been generated for Alzheimer’s disease (AD). Despite the increased knowledge and understanding of AD and the potential therapeutics that are emerging, there is still no clear understanding of the pathogenesis. Without a precise, known mechanism, current potential targets for treatment may fall short of addressing an underlying cause. Any hypothesis must not only account for pathologic findings, but also the neurologic findings. Proposed hypotheses in the past have not completely accomplished this task, and have left many research findings unexplained. As AD is considered a heterogeneous disease, it may be helpful to compare and contrast it to other heterogeneous medical conditions. It is possible that today, there is sufficient knowledge and research on AD, but insufficient integration of that information. Thus, a unifying hypothesis that attempts to integrate much of the interdisciplinary research is presented to explain AD under a new paradigm. Stasis of cerebrospinal fluid (CSF) has been previously suggested to be a factor in the etiology of AD, but it has generated little attention among researchers. Therefore, CSF is discussed in greater detail and how disruption of its flow may have adverse consequences. The following hypothesis proposes that dependent, localized cerebrospinal fluid stasis in select areas of the brain may be one way to initiate and perpetuate AD pathogenesis. In that vein, it is also proposed that craniomaxillofacial function, involving the dentition and paranasal sinuses, plays a vital role for proper CSF flow dynamics. In this way, a possible mechanical risk factor involving a compromised craniomaxillofacial complex will be described for AD. The identification of a mechanical risk factor would open a discussion for immediate, inexpensive possibilities to prevent AD.

The discovery and structure–activity relationship of 1,2-diarylimidazole piperazine carboxamides bearing polar side chains as potent and selective cholecystokinin 1 receptor (CCK1R) agonists are described. Optimization of this series resulted in the discovery of isopropyl carboxamide 40, a CCK1R agonist with sub-nanomolar functional and binding activity as well as excellent potency in a mouse overnight food intake reduction assay.