The role of acoustofluidics in targeted drug delivery.

With the fast development of acoustic systems in clinical and therapeutic applications, acoustically driven microbubbles have gained a prominent role as powerful tools to carry, transfer, direct, and target drug molecules in cells, tissues, and tumors in the expanding fields of targeted drug delivery and gene therapy. The aim of the present study is to establish a biocompatible acoustic microfluidic system and to demonstrate the generation of an acoustic field and its effects on microbubbles and biological cells in the microfluidic system. The acoustic field creates non-linear oscillations of the microbubble-clusters, which results in generation of shear stress on cells in such microsystems. This effectively helps in delivering extracellular probes in living cells by sonoporation. The sonoporation is investigated under the combined effects of acoustic stress and hydrodynamic stress during targeted drug and gene delivery.

Evaluation of the effect of ambrisentan on digital microvascular flow in patients with systemic sclerosis using laser Doppler perfusion imaging: a 12-week randomized double-blind placebo controlled trial.

INTRODUCTION: In patients with systemic sclerosis (SSc), digital ischemia results from an occlusive microvasculopathy that may not respond adequately to conventional vasodilators. Endothelin receptor antagonists can potentially modify the fibroproliferative vascular remodeling in SSc, and hence their use may be justified in the management of digital ischemia. The objective of this clinical trial was to evaluate the effect of ambrisentan, a selective endothelin type A receptor antagonist, on microvascular blood flow in patients with limited systemic sclerosis (SSc) using laser Doppler perfusion imaging (LDPI). METHODS: In this randomized, double-blind, placebo controlled study we enrolled 20 patients with limited SSc. Fifteen patients received ambrisentan 5 mg daily for one month and then 10 mg daily for two months, and five received a placebo. There were three visits: weeks 0 (baseline), one and 12. Three patient-oriented questionnaires were completed at each visit: Scleroderma-Health Assessment Questionnaire (S-HAQ), Raynaud Condition Score (RCS), and Pain-Visual Analog Scale (P-VAS). At each visit, LDPI was used to obtain three blood flow readings involving regions of interest in second to fifth fingers of the non-dominant hand at room temperature (25°C) and after cooling (10°C) for two minutes. RESULTS: There were 16 females (80%); mean age was 50 years. None of the differences in blood flow (as measured by LDPI) were significant both at baseline and after cooling. However, patients in the ambrisentan group showed significant improvement in the patient-oriented outcomes: RCS (P=0.001) and S-HAQ score (P=0.005). CONCLUSIONS: This pilot study did not show evidence of significant increase in digital blood flow over time; however, there was an improvement in RCS and S-HAQ score. We conclude that continuous use of ambrisentan for three months does not seem to significantly improve digital blood flow in SSc patients. TRIAL REGISTRATION: Clinicaltrials.gov NCT01072669. Registered 19 February 2010.

Scleroderma renal crisis.

OBJECTIVES: To discuss the pathophysiology, risk factors, clinical manifestations, diagnosis, treatment, prevention, and outcomes of scleroderma renal crisis (SRC), a serious yet potentially treatable complication of scleroderma (systemic sclerosis). METHODS: A PubMed search for articles published up until April 2014 was conducted using the following keywords: scleroderma, systemic sclerosis, scleroderma renal crisis, renal, treatment, and prognosis. Literature was carefully reviewed, and different risk factors, treatment options, prognostic factors, and survival data were assessed. RESULTS: SRC occurs in about 10% of all patients with scleroderma. It is characterized by malignant hypertension and progressive renal failure. Around 10% of SRC cases may present with normal blood pressure, termed normotensive renal crisis. The etiopathogenesis is presumed to be a series of insults to the kidneys resulting in endothelial injury, intimal proliferation, and narrowing of renal arterioles leading to decreased blood flow, hyperplasia of the juxtaglomerular apparatus, hyperreninemia, and accelerated hypertension. Risk factors include rapid skin thickening, use of certain medications such corticosteroids or cyclosporine, new-onset microangiopathic hemolytic anemia and/or thrombocytopenia, cardiac complications (pericardial effusion, congestive heart failure, and/or arrhythmias), large joint contractures, and presence of anti-RNA polymerase III antibody. Since the 1970s, with the advent of angiotensin-converting enzyme (ACE) inhibitors, mortality associated with SRC decreased from 76% to <10%. Some patients may progress to end-stage renal disease and need dialysis. Renal transplantation has improved survival, though SRC may recur in transplanted kidneys. CONCLUSIONS: More than 60 years after its initial description, SRC still remains an important cause of morbidity and mortality in scleroderma. Since the advent of ACE inhibitors, the prognosis of SRC has improved substantially. Prompt diagnosis and treatment may help prevent adverse outcomes and improve survival.

The clinical utility of anti-chromatin antibodies as measured by BioPlex 2200 in the diagnosis of systemic lupus erythematosus versus other rheumatic diseases.

BACKGROUND: The detection of autoantibodies is indispensable to systemic lupus erythematosus (SLE). Bioplex 2200 ANA screen is a multiplex immunoassay system that allows simultaneous determination of autoantibodies to extractable nuclear antigens (ENA) including anti-chromatin antibodies (ACAs). However, the clinical significance of the ACAs by this new method in SLE patients has not been studied in comparison with other rheumatic disorders. We performed a retrospective study of patients with rheumatic diseases to assess the diagnostic value of the ACAs by Bioplex 2200 method in SLE. METHODS: Adult patients with rheumatic complaints seen by rheumatologists at the Cleveland Clinic between January 2008 and February 2010 were screened for positive anti-ENA antibodies by the Bioplex 2200. Patients with positive anti-ENA antibodies were classified into two populations based upon the presence and absence of the ACAs. We retrospectively studied the clinical and laboratory data of these patients. RESULTS: A total of 764 subjects with positive anti-ENA antibodies were screened, including 115 with positive ACAs. There were 93 SLE patients consisting of 58 with positive ACAs and 35 with negative ACAs. The sensitivity, specificity, positive predictive value and negative predictive value of the ACAs in SLE were 62.4%, 91.5%, 50.4% and 94.6% respectively. Apart from SLE, positive ACAs were associated with mixed connective tissue disease (MCTD)/undifferentiated CTD (UCTD) and other autoimmune diseases. No correlation was found between the ACAs and lupus glomerulonephritis or anti-dsDNA antibodies. CONCLUSIONS: Measurement of the ACAs by the Bioplex 2200 is specific for diagnosing SLE but not useful for differentiating between SLE and MCTD/UCTD.

Effect of dispersion on the diffusion zone in two-phase laminar flows in microchannels.

Aim of the present work is to investigate the reaction-diffusion process of a two species system under laminar flow in a T-shaped microchannel. A zone formed at the interface between the aqueous solutions of these two species is affected by advection and diffusion. Through theoretical analyses and experimental results, the effect of dispersion has been shown to influence this diffusion zone. We have defined a parameter called effective diffusivity, to account for the dispersion effects and observed it to be a function of the channel Peclet number. In the limiting case of low Peclet number, this parameter is constant and turns out to be equal to the molecular diffusivity. We have also related effective diffusivity and the dispersion coefficient through scaling estimates.

Enhancement of static incubation time in microfluidic cell culture platforms exploiting extended air-liquid interface.

Microfluidics based cell culture applications have facilitated the study of cellular dynamics at the single entity level. Yet, long term versions of such applications in a static framework suffer from the fast exhaustion of available oxygen, dissolved in the limited media volume available per cell, within the microconfined environment. In order to circumvent such drawbacks, we have improvised a microfluidic cell culture platform for prolonged sustenance of adherent mammalian cells by formation of an air-liquid interface through functionalizing inner surfaces of a polydimethylsiloxane (PDMS) based microdevice. We have demonstrated an augmented static incubation time for different cell lines using this approach.

A new category of autoinflammatory disease associated with NOD2 gene mutations.

INTRODUCTION: Autoinflammatory diseases are characterized by seemingly unprovoked episodes of inflammation, without high titers of autoantibodies or antigen-specific T cells, and derive from genetic variants of the innate immune system. This study characterized a cohort of patients with similar phenotypes and nucleotide oligomerization domain 2 (NOD2) gene mutations. METHODS: Diagnostically challenging patients with the following clinical and genetic characteristics were prospectively studied between January 2009 and April 2011: periodic fever, dermatitis, polyarthritis, serositis, negative serum autoantibodies and additional positive NOD2 IVS8+158 gene mutation. Genetic testing for gene mutations of NOD2, tumor necrosis factor receptor-associated periodic fever syndrome (TRAPS) and familial Mediterranean fever (FMF) was performed. RESULTS: All seven patients with the disease were Caucasians, with four being male. The mean age at disease onset was 40.7 years and disease duration was 3.2 years. These patients characteristically presented with periodic fever, dermatitis and inflammatory polyarthritis. There were gastrointestinal symptoms in three patients, granulomas of the skin and gut in two, and recurrent chest pain in two, with one having pleuritis and pericarditis. Three patients had sicca-like symptoms. Five patients had increased acute phase reactants. All seven patients had negative tests for autoantibodies but carried the NOD2 gene mutation IVS8+158 with four having concurrent R702W mutation. CONCLUSIONS: Our cohort may represent a new disease category of autoinflammatory disease with characteristic clinical phenotypes and genotypes. It may somewhat resemble pediatric Blau's syndrome.