Prediction of successful dose reduction or discontinuation of adalimumab,etanercept, or infliximab in rheumatoid arthritis patients using serum drug levels and antidrug antibody measurement

Background: To evaluate if TNF inhibitor serum drug levels (DL) or anti-drug antibodies (ADAb) can predict successful dose reduction (in patients with high DL) or discontinuation (in patients with no/low DL or ADAb) in rheumatoid arthritis (RA) patients.

Research design and methods: RA patients that were using adalimumab (n = 42), etanercept (n = 76) or infliximab (n = 51) and were doing well, were tapered until discontinuation or flare (1–1.5 year follow up). Random timed DL for adalimumab and etanercept and trough DL for infliximab were measured before dose reduction: Receiver-Operator-Curves (ROC) analyses with optimal cut-off DL were determined.

Results: No predictive value of adalimumab and infliximab DL for all outcomes were found, except for an inverse association of lower etanercept DL and higher chance for successful dose reduction (Area Under the Curve (AUC) 0.36, 95% CI 0.23–0.49; cut-off <2.6 mg/l). In sub analyses, higher adalimumab trough DL predicted successful dose reduction (AUC 0.86, 0.58–1.00; cut-off >7.8). ADAb were infrequent and not predictive of successful discontinuation.

Conclusions: No predictive value of baseline adalimumab, etanercept and infliximab DL or ADAb for successful dose reduction or discontinuation in RA was found in this context, with the possible exception of high adalimumab trough levels for successful dose reduction.     

Influence of Age and Tooth Loss on Masticatory Muscles Characteristics: A Population Based MR Imaging Study

Background

Aging is associated with a decline in masticatory muscles mass and performance. The present study aims to examine the differences in the cross-sectional areas of the masseter, medial and lateral pterygoid muscles in relation to age and the present dental status in a population-based magnetic resonance imaging study.

Methods

This cross sectional study involved 747 subjects aged between 30–89 years (344 male, 403 female) who underwent both a whole body MRI and a full oral examination. The cross-sectional areas of the masseter, medial and lateral pterygoid muscles were measured from MRI images using the software Osirix. Dental and prosthetic status data from the oral examination were classified according to Eichner index. The method of generalized least squares, also called growth curve model, was used to examine the associations between the cross-sectional areas, age and tooth status.

Results

The cross-sectional area of the lateral pterygoid muscle decreased substantially with age in women but did not depend on age in men. The medial pterygoid muscle depended on age but an effect modification by gender was uncertain. Masseter muscle was weakly associated with age but strongly associated with the number of teeth in both genders.

Conclusions

Our findings suggest that age has a heterogeneous effect on masticatory muscles. This indicates that age related changes to the masticatory muscles are muscle specific and are not consistent between the different muscles.

     

Surgical delivery of drug releasing poly(lactic-co-glycolic acid)/poly(ethylene glycol) paste with in vivo effects against glioblastoma

Introduction

The median survival of patients with glioblastoma multiforme (astrocytoma grade 4) remains less than 18 months despite radical surgery, radiotherapy and systemic chemotherapy. Surgical implantation of chemotherapy eluting wafers into the resection cavity has been shown to improve length of survival but the current licensed therapy has several drawbacks. This paper investigates in vivo efficacy of a novel drug eluting paste in glioblastoma.

Methods

Poly(lactic-co-glycolic acid)/poly(ethylene glycol) (PLGA/PEG) self-sintering paste was loaded with the chemotherapeutic agent etoposide and delivered surgically into partially resected tumours in a flank murine glioblastoma xenograft model.

Results

Surgical delivery of the paste was successful and practical, with no toxicity or surgical morbidity to the animals. The paste was retained in the tumour cavity, and preliminary results suggest a useful antitumour and antiangiogenic effect, particularly at higher doses. Bioluminescent imaging was not affected significantly by the presence of the paste in the tumour.

Conclusions

Chemotherapy loaded PLGA/PEG paste seems to be a promising technology capable of delivering active drugs into partially resected tumours. The preliminary results of this study suggest efficacy with no toxicity and will lead to larger scale efficacy studies in orthotopic glioblastoma models.     

Congestive Heart Failure: A Case of Protein Misfolding

This article describes an interesting case of a patient presenting with congestive heart failure found to have restrictive cardiomyopathy with initial laboratory evaluation showing hypogammaglobuminemia without a monoclonal band on serum and urine electrophoresis. This case highlights the clinically significant cardiac manifestation caused by protein misfolding, a defect in protein homeostasis. In addition, the utility of a relatively newer laboratory test, serum free light chains as well as the importance of clinical and pathophysiologic correlation is also discussed. We present a relatively uncommon cause of heart disease, cardiac amyloidosis in a patient with a systemic plasma cell dyscrasia, and multiple myeloma.     

Risk factors for tuberculosis in older children and adolescents: a matched case–control study in Recife,Brazil

Background

Tuberculosis is a major disease worldwide and most research focus on risk factors for adults, although there is a marked adolescent peak in incidence. The objective of this study was to identify risk factors for tuberculosis in children aged 7 to 19.

Methods

A case control study matched by age with 169 cases and 477 controls. The study population consisted of adolescents and older children from Recife, Brazil. Cases were individuals diagnosed with tuberculosis in the control programme and controls were selected in the neighborhood of cases. Conditional logistic regression was used to identify risk factors.

Results

Cigarette smoking increased by 50% the risk of tuberculosis but that this was not statistically significant (OR?=?1.6). Other risk factors were sleeping in the same house as a case of tuberculosis (OR?=?31.6), living in a house with no piped water (OR?=?7.7) (probably as a proxy for bad living conditions), illiteracy (OR?=?3.7) and male sex (OR?=?1.8). The increase in risk with living in houses with no piped water was much more marked in males. The proportion of cases of tuberculosis attributed to contact with someone with TB was 38% and to illiteracy, lack of piped water and smoking, 20%.

Conclusion

Household contact with tuberculosis, social factors and male sex play the biggest role in determining risk of TB disease among children and adolescents in the study. We recommend further research on the relationship of cigarette smoking on tuberculosis in adolescents, and on whether the sex differentials are more marked in bad living conditions. Separate studies should be conducted in older children and in adolescents.

     

Differential coupling of CC chemokine receptors to multiple heterotrimeric G proteins in human interleukin-2-activated natural killer cells

Using two different approaches, we have investigated the types of G proteins coupled to CC chemokine receptors. First, permeabilization of interleukin-2-activated natural killer (IANK) cells with streptolysin-O and introduction of anti-G protein antibodies inside these cells resulted in the following. (1) Anti-G(s), anti-G(o), and anti-G(z) inhibited the migration of IANK cells in response to macrophage- inflammatory protein-1 alpha (MIP-1 alpha), monocyte chemoattractant protein-1 (MCP-1), or regulated on activation normal T cell expressed and secreted (RANTES). (2) Anti-Gi inhibited their migration in response to MCP-1 or RANTES but not in response to MIP-1 alpha. Second, incubation of IANK cell membranes with anti-G protein antibodies before incubating with (gamma-35S) GTP or (gamma-32P) GTP, resulted in the following. (1) Anti-G(s), anti-G(o), or anti-G(z) inhibited GTP binding and GTPase activity in the presence of MIP-1 alpha, or RANTES. (2) Anti- G(i) inhibited GTP binding and GTPase activity in the presence of MCP-1 or RANTES but not in the presence of MIP-1 alpha. The inhibitory effect of anti-G protein antibodies was reversed upon incubating these antibodies with their respective synthetic peptides before addition to IANK cell membranes. These results suggest that MCP-1 and RANTES receptors are promiscuously coupled to multiple G proteins in IANK cell membranes and that this coupling is different from MIP-1 alpha receptors, which seem to be coupled to G(s), G(o), and G(z) but not to G(i).     

Pre-B acute lymphoblastic leukemia cells may induce T-cell anergy to alloantigen

Even if neoplastic cells express tumor associated antigens they still may fail to function as antigen presenting cells (APC) if they lack expression of one or more molecules critical for the induction of productive immunity. These cellular defects can be repaired by physiologic activation, transfection, or fusion of tumor cells with professional APC. Although such defects can be repaired, antitumor specific T cells may still fail to respond in vivo if they may have been tolerized. Here, human pre-B cell acute lymphoblastic leukemia (pre-B ALL) was used as a model to determine if primary human tumor cells can function as alloantigen presenting cells (alloAPC) or alternatively whether they induce anergy. In the present report, we show that pre-B cell ALL express alloantigen and adhesion molecules but uniformly lack B7-1 (CD80) and only a subset express B7-2 (CD86). Pre-B ALL cells are inefficient or ineffective alloAPC and those cases that lack expression of B7-1 and B7-2 also induce alloantigen specific T- cell unresponsiveness. Under these circumstances, T-cell unresponsiveness could be prevented by physiologic activation of tumor cells via CD40, cross-linking CD28, or signaling through the common gamma chain of the interleukin-2 receptor on T cells. Taken together, these results suggest that pre-B ALL may be incapable of inducing clinically significant T-cell-mediated antileukemia responses. This defect may be not only due to their inability to function as APC, but also due to their potential to induce tolerance. Attempts to induce clinically significant antitumor immune responses may then require not only mechanisms to repair the antigen presenting capacity of the tumor cells, but also reversal of tolerance.     

IgG Against Dengue Virus in Healthy Blood Donors,Zanzibar, Tanzania

We conducted a seroprevalence survey among 500 healthy adult donors at Zanzibar National Blood Transfusion Services. Dengue virus IgG seroprevalence was 50.6% and independently associated with age and urban residence. These data will aid in building a surveillance, preparedness, and response plan for dengue virus infections in the Zanzibar Archipelago.Key words: dengue, seroprevalence, Zanzibar, viruses, vector-borne infections     

The Affordable Care Act and Emergency Care

The Affordable Care Act (ACA) will have far-reaching effects on the way health care is designed and delivered. Several elements of the ACA will directly affect both demand for ED care and expectations for its role in providing coordinated care. Hospitals will need to employ strategies to reduce ED crowding as the ACA expands insurance coverage. Discussions between EDs and primary care physicians about their respective roles providing acute unscheduled care would promote the goals of the ACA.The Affordable Care Act (ACA) focuses on improving access and quality by expanding insurance coverage, using payment reform strategies, and increasing quality reporting.1 In the ACA, hospital-based emergency departments (EDs) are referenced as places to be avoided and reduced; no new payment models focus on ED care, and there are no plans to broadly address ED-specific quality through new measurement programs.Promoting value in ED care needs to be a greater focus for policymakers as the ACA is implemented. Emergency departments play a central role in health care delivery as the staging area for the ill and injured, and as an always-available resource for unscheduled care. Emergency department physicians constitute less than 5% of the US physician workforce, yet manage 28% of acute care encounters.2 Historically, the need for EDs arose from increases in vehicular trauma that accompanied the expansion of the Interstate Highway System in the 1960s.3 However, EDs also quickly became providers of low acuity unscheduled care as well.4 The Emergency Medical Treatment and Active Labor Act legislation passed in 1986 institutionalized EDs as provider of last resort for all, regardless of their ability to pay. Emergency departments have replaced the community physician’s office as the primary source for hospital admissions and provide a safety net for the uninsured, underinsured, and medically disenfranchised.5,6Several elements of the ACA—the insurance expansion, patient-centered medical homes, accountable care organizations, and bundled payments—will directly affect both demand for ED care and expectations for its role in providing coordinated care. We explore these effects and suggest some practical ways that EDs can be better integrated into these efforts.