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1.
Circ Heart Fail ; 16(5): e009721, 2023 05.
Article in English | MEDLINE | ID: mdl-37192290

ABSTRACT

BACKGROUND: Hemodynamic-guided heart failure management is a superior strategy to prevent decompensation leading to hospitalization compared with traditional clinical methods. It remains unstudied if hemodynamic-guided care is effective across severities of comorbid renal insufficiency or if this strategy impacts renal function over time. METHODS: In the CardioMEMS US PAS (Post-Approval Study), heart failure hospitalizations were compared from 1 year before and after pulmonary artery sensor implantation in 1200 patients with New York Heart Association class III symptoms and a previous hospitalization. Hospitalization rates were evaluated in all patients grouped into baseline estimated glomerular filtration rate (eGFR) quartiles. Chronic kidney disease progression was evaluated in patients with renal function follow-up data (n=911). RESULTS: Patients with stage 2 or greater chronic kidney disease at baseline exceeded 80%. Heart failure hospitalization risk was lower in all eGFR quartiles ranging from a hazard ratio of 0.35 (0.27-0.46; P<0.0001) in patients with eGFR >65 mL/min per 1.73 m2 to 0.53 (0.45-0.62; P<0.0001) in patients with eGFR ≤37 mL/min per 1.73 m2. Renal function was preserved or improved in most patients. Survival was different between quartiles and lower in quartiles with more advanced chronic kidney disease. CONCLUSIONS: Hemodynamic-guided heart failure management using remotely obtained pulmonary artery pressures is associated with lower hospitalization rates and general preservation of renal function in all eGFR quartiles or chronic kidney disease stages.


Subject(s)
Heart Failure , Renal Insufficiency, Chronic , Humans , Heart Failure/diagnosis , Heart Failure/therapy , Heart Failure/complications , Pulmonary Artery , Hospitalization , Glomerular Filtration Rate , Renal Insufficiency, Chronic/complications , Renal Insufficiency, Chronic/diagnosis , Renal Insufficiency, Chronic/therapy
2.
J Card Fail ; 29(1): 56-66, 2023 01.
Article in English | MEDLINE | ID: mdl-36332900

ABSTRACT

BACKGROUND: Therapy guided by pulmonary artery (PA) pressure monitoring reduces PA pressures and heart failure hospitalizations (HFH) during the first year, but the durability of efficacy and safety through 2 years is not known. METHODS AND RESULTS: The CardioMEMS Post-Approval Study investigated whether benefit and safety were generalized and sustained. Enrollment at 104 centers in the United States included 1200 patients with NYHA Class III symptoms on recommended HF therapies with prior HFH. Therapy was adjusted toward PA diastolic pressure 8-20 mmHg. Intervention frequency and PA pressure reduction were most intense during first 90 days, with sustained reduction of PA diastolic pressure from baseline 24.7 mmHg to 21.0 at 1 year and 20.8 at 2 years for all patients. Patients completing two year follow-up (n = 710) showed similar 2-year reduction (23.9 to 20.8 mmHg), with reduction in PA mean pressure (33.7 to 29.4 mmHg) in patients with reduced left ventricular ejection. The HFH rate was 1.25 events/patient/year prior to sensor implant, 0.54 at 1 year, and 0.37 at 2 years, with 59% of patients free of HFH during follow-up. CONCLUSIONS: Reduction in PA pressures and hospitalizations were early and sustained during 2 years of PA pressure-guided management, with no signal of safety concerns regarding the implanted sensor.


Subject(s)
Heart Failure , Hemodynamic Monitoring , Humans , United States , Pulmonary Artery , Monitoring, Ambulatory , Hospitalization , Blood Pressure Monitoring, Ambulatory/methods
3.
Eur J Heart Fail ; 24(12): 2320-2330, 2022 12.
Article in English | MEDLINE | ID: mdl-36054647

ABSTRACT

AIM: The CardioMEMS European Monitoring Study for Heart Failure (MEMS-HF) investigated safety and efficacy of pulmonary artery pressure (PAP)-guided remote patient management (RPM) in New York Heart Association (NYHA) class III outpatients with at least one heart failure hospitalization (HFH) during the previous 12 months. This pre-specified subgroup analysis investigated whether RPM effects depended on presence and subtype of pulmonary hypertension (PH). METHODS AND RESULTS: In 106/234 MEMS-HF participants, Swan-Ganz catheter tracings obtained during sensor implant were available for off-line manual analysis jointly performed by two experts. Patients were classified into subgroups according to current PH definitions. Isolated post-capillary PH (IpcPH) and combined post- and pre-capillary PH (CpcPH) were present in 38 and 36 patients, respectively, whereas 31 patients had no PH. Clinical characteristics were comparable between subgroups, but among patients with PH pulmonary vascular resistance was higher (p = 0.029) and pulmonary artery compliance lower (p = 0.003) in patients with CpcPH. During 12 months of PAP-guided RPM, all PAPs declined in IpcPH and CpcPH subgroups (all p < 0.05), whereas only mean and diastolic PAP decreased in patients without PH (both p < 0.05). Improvements in post- versus pre-implant HFH rates were similar in CpcPH (0.639 events/patient-year; hazard ratio [HR] 0.37) and IpcPH (0.72 events/patient-year; HR 0.45) patients. Participants without PH benefited most (0.26 events/patient-year; HR 0.17, p = 0.04 vs. IpcPH/CpcPH patients). Quality of life and NYHA class improved significantly in all subgroups. CONCLUSIONS: Outpatients with NYHA class III symptoms with at least one HFH during 1 year pre-implant benefitted significantly from PAP-guided RPM during post-implant follow-up irrespective of presence or subtype of PH at baseline.


Subject(s)
Heart Failure , Hypertension, Pulmonary , Micro-Electrical-Mechanical Systems , Humans , Hypertension, Pulmonary/therapy , Heart Failure/diagnosis , Quality of Life , Hemodynamics
4.
ESC Heart Fail ; 9(1): 155-163, 2022 02.
Article in English | MEDLINE | ID: mdl-34738340

ABSTRACT

AIMS: Control of pulmonary pressures monitored remotely reduced heart failure hospitalizations mainly by lowering filling pressures through the use of loop diuretics. Sacubitril/valsartan improves heart failure outcomes and increases the kidney sensitivity for diuretics. We explored whether sacubitril/valsartan is associated with less utilization of loop diuretics in patients guided with haemodynamic monitoring in the CardioMEMS European Monitoring Study for Heart Failure (MEMS-HF). METHODS AND RESULTS: The MEMS-HF population (n = 239) was separated by the use of sacubitril/valsartan (n = 68) or no use of it (n = 164). Utilization of diuretics and their doses was prespecified in the protocol and was monitored in both groups. Multivariable regression, ANCOVA, and a generalized linear model were used to fit baseline covariates with furosemide equivalents and changes for 12 months. MEMS-HF participants (n = 239) were grouped in sacubitril/valsartan users [n = 68, 64 ± 11 years, left ventricular ejection fraction (LVEF) 25 ± 9%, cardiac index (CI) 1.89 ± 0.4 L/min/m2 ] vs. non-users (n = 164, 70 ± 10 years, LVEF 36 ± 16%, CI 2.11 ± 0.58 L/min/m2 , P = 0.0002, P < 0.0001, and P = 0.0015, respectively). In contrast, mean pulmonary artery pressure (PAP) values were comparable between groups (29 ± 11 vs. 31 ± 11 mmHg, P = 0.127). Utilization of loop diuretics was lower in patients taking sacubitril/valsartan compared with those without (P = 0.01). Significant predictor of loop diuretic use was a history of renal failure (P = 0.005) but not age (P = 0.091). After subjects were stratified by sacubitril/valsartan or other diuretic use, PAP was nominally, but not significantly lower in sacubitril/valsartan-treated patients (baseline: P = 0.52; 6 months: P = 0.07; 12 months: P = 0.53), while there was no difference in outcome or PAP changes. This difference was observed despite lower CI (P = 0.0015). Comparable changes were not observed for other non-loop diuretics (P = 0.21). CONCLUSIONS: In patients whose treatment was guided by remote PAP monitoring, concomitant use of sacubitril/valsartan was associated with reduced utilization of loop diuretics, which could potentially be relevant for outcomes.


Subject(s)
Hemodynamic Monitoring , Sodium Potassium Chloride Symporter Inhibitors , Aminobutyrates , Angiotensin Receptor Antagonists/therapeutic use , Biphenyl Compounds , Humans , Pulmonary Artery , Stroke Volume , Tetrazoles/therapeutic use , Valsartan/therapeutic use , Ventricular Function, Left
5.
JACC Heart Fail ; 9(11): 784-794, 2021 11.
Article in English | MEDLINE | ID: mdl-34509410

ABSTRACT

OBJECTIVES: This study sought to determine the impact of therapy guided by pulmonary artery (PA) pressure monitoring in patients with heart failure (HF) and obesity. BACKGROUND: Obesity is prevalent in HF and associated with volume retention, but it complicates clinical assessment of congestion. METHODS: The CardioMEMS Post Approval Study was a prospective, multicenter, open-label trial in 1,200 patients with New York Heart Association functional class III HF and prior HF hospitalization (HFH) within 12 months. Patients with a body mass index (BMI) >35 kg/m2 were required to have a chest circumference <65 inches. Therapy was guided by PA pressure monitoring at sites, and HFHs were adjudicated 1 year before implantation and throughout follow-up. This analysis stratified patients according to ejection fraction (EF) <40% or ≥40% and by BMI <35 kg/m2 or ≥35 kg/m2. RESULTS: Baseline PA diastolic pressure was higher in patients with BMI ≥35 kg/m2 regardless of EF, but all PA pressures were reduced at 12 months in each cohort (P < 0.0001). HFH rate was reduced by >50% in both cohorts for EF <40% (BMI <35 kg/m2 [HR: 0.48; 95% CI: 0.41-0.55] and ≥35 kg/m2 [HR: 0.40; 95% CI: 0.31-0.53]) and EF ≥40% (BMI <35 kg/m2 [HR: 0.42; 95% CI: 0.35-0.52] and ≥35 kg/m2 [HR: 0.34; 95% CI: 0.25-0.45]; P < 0.0001). There was a nonsignificant trend toward greater reduction with more obesity. The all-cause hospitalization rate was also significantly reduced during monitoring (P < 0.01). CONCLUSIONS: Management guided by PA pressure monitoring effectively reduced pressures, HFH, and all-cause hospitalization in patients with obesity regardless of EF. (CardioMEMS HF System Post Approval Study; NCT02279888).


Subject(s)
Heart Failure , Pulmonary Artery , Blood Pressure Monitoring, Ambulatory , Heart Failure/therapy , Hospitalization , Humans , Obesity/complications , Prospective Studies
7.
Circ Heart Fail ; 14(6): e007892, 2021 06.
Article in English | MEDLINE | ID: mdl-34129363

ABSTRACT

BACKGROUND: Response to pharmacological and device-based therapy for heart failure (HF) may vary by sex. We examined sex differences in response to ambulatory hemodynamic monitoring in clinical practice using the CardioMEMS PAS (Post-Approval Study). METHODS: The CardioMEMS PAS was a prospective, single-arm, multicenter, open-label study of 1200 adults with New York Heart Association class III HF and at least 1 HF hospitalization (HFH) within 12 months who underwent pulmonary artery pressure sensor implantation between 2014 and 2017. Changes in pulmonary artery pressure over time were stratified by ejection fraction <40% and sex. Clinical outcomes including HFH rate at 12 months, 1-year mortality, and quality of life were examined in women and men. RESULTS: Four hundred fifty-two women (38% of total) enrolled in the PAS were less likely to be White (78% versus 86%) and more likely to have nonischemic cardiomyopathy (44% versus 34%) and had significantly higher SBP (132 versus 124 mm Hg), mean ejection fraction (44% versus 36%), and pulmonary vascular resistance (3.2 versus 2.6 WU) than men (P<0.001 for all). There were similar reductions in pulmonary artery pressure from baseline to 12 months in both men and women for the whole cohort and for subgroups with HF with reduced ejection fraction and HF with preserved ejection fraction. Both sexes experienced significant decreases in HFH over 12 months (men: HR, 0.46 [95% CI, 0.40-0.52]; women: HR, 0.39 [95% CI, 0.33-0.46]). In adjusted models, there were no significant differences in change in HFH between men and women (interaction P=0.13) or all-cause mortality at 1 year (adjusted HR, 1.25 [95% CI, 0.88-1.77]). CONCLUSIONS: Women and men enrolled in the CardioMEMS PAS had similar reductions from baseline in pulmonary artery pressure over 1 year and experienced similar reductions in HFH. Hemodynamic monitoring provides similar benefit with regard to HF events in both women and men. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02279888.


Subject(s)
Heart Failure/physiopathology , Heart Failure/therapy , Hemodynamic Monitoring , Hospitalization/statistics & numerical data , Blood Pressure Monitoring, Ambulatory/methods , Hemodynamics/physiology , Humans , Prospective Studies , Pulmonary Artery/physiopathology , Pulmonary Wedge Pressure/physiology , Quality of Life
8.
Circ Heart Fail ; 13(8): e006863, 2020 08.
Article in English | MEDLINE | ID: mdl-32757642

ABSTRACT

BACKGROUND: Ambulatory hemodynamic monitoring with an implantable pulmonary artery (PA) sensor is approved for patients with New York Heart Association Class III heart failure (HF) and a prior HF hospitalization (HFH) within 12 months. The objective of this study was to assess the efficacy and safety of PA pressure-guided therapy in routine clinical practice with special focus on subgroups defined by sex, race, and ejection fraction. METHODS: This multi-center, prospective, open-label, observational, single-arm trial of 1200 patients across 104 centers within the United States with New York Heart Association class III HF and a prior HFH within 12 months evaluated patients undergoing PA pressure sensor implantation between September 1, 2014, and October 11, 2017. The primary efficacy outcome was the difference between rates of adjudicated HFH 1 year after compared with the 1 year before sensor implantation. Safety end points were freedom from device- or system-related complications at 2 years and freedom from pressure sensor failure at 2 years. RESULTS: Mean age for the population was 69 years, 37.7% were women, 17.2% were non-White, and 46.8% had preserved ejection fraction. During the year after sensor implantation, the mean rate of daily pressure transmission was 76±24% and PA pressures declined significantly. The rate of HFH was significantly lower at 1 year compared with the year before implantation (0.54 versus 1.25 events/patient-years, hazard ratio 0.43 [95% CI, 0.39-0.47], P<0.0001). The rate of all-cause hospitalization was also lower following sensor implantation (1.67 versus 2.28 events/patient-years, hazard ratio 0.73 [95% CI, 0.68-0.78], P<0.0001). Results were consistent across subgroups defined by ejection fraction, sex, race, cause of cardiomyopathy, presence/absence of implantable cardiac defibrillator or cardiac resynchronization therapy and ejection fraction. Freedom from device- or system-related complications was 99.6%, and freedom from pressure sensor failure was 99.9% at 1 year. CONCLUSIONS: In routine clinical practice as in clinical trials, PA pressure-guided therapy for HF was associated with lower PA pressures, lower rates of HFH and all-cause hospitalization, and low rates of adverse events across a broad range of patients with symptomatic HF and prior HFH. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02279888.


Subject(s)
Blood Pressure Monitoring, Ambulatory , Heart Failure/therapy , Hospitalization/statistics & numerical data , Pulmonary Wedge Pressure/physiology , Aged , Female , Heart Failure/epidemiology , Heart Failure/physiopathology , Hemodynamics , Humans , Male , Prospective Studies , Pulmonary Artery , United States/epidemiology
9.
Eur J Heart Fail ; 22(10): 1891-1901, 2020 10.
Article in English | MEDLINE | ID: mdl-32592227

ABSTRACT

AIMS: Heart failure (HF) leads to repeat hospitalisations and reduces the duration and quality of life. Pulmonary artery pressure (PAP)-guided HF management using the CardioMEMS™ HF system was shown to be safe and reduce HF hospitalisation (HFH) rates in New York Heart Association (NYHA) class III patients. However, these findings have not been replicated in health systems outside the United States. Therefore, the CardioMEMS European Monitoring Study for Heart Failure (MEMS-HF) evaluated the safety, feasibility, and performance of this device in Germany, The Netherlands, and Ireland. METHODS AND RESULTS: A total of 234 NYHA class III patients (68 ± 11 years, 22% female, ≥1 HFH in the preceding year) from 31 centres were implanted with a CardioMEMS sensor and underwent PAP-guided HF management. One-year rates of freedom from device- or system-related complications and from sensor failure (co-primary outcomes) were 98.3% [95% confidence interval (CI) 95.8-100.0] and 99.6% (95% CI 97.6-100.0), respectively. Survival rate was 86.2%. For the 12 months post- vs. pre-implant, HFHs decreased by 62% (0.60 vs. 1.55 events/patient-year; hazard ratio 0.38, 95% CI 0.31-0.48; P < 0.0001). After 12 months, mean PAP decreased by 5.1 ± 7.4 mmHg, Kansas City Cardiomyopathy Questionnaire (KCCQ) overall/clinical summary scores increased from 47.0 ± 24.0/51.2 ± 24.8 to 60.5 ± 24.3/62.4 ± 24.1 (P < 0.0001), and the 9-item Patient Health Questionnaire sum score improved from 8.7 ± 5.9 to 6.3 ± 5.1 (P < 0.0001). CONCLUSION: Haemodynamic-guided HF management proved feasible and safe in the health systems of Germany, The Netherlands, and Ireland. Physician-directed treatment modifications based on remotely obtained PAP values were associated with fewer HFH, sustainable PAP decreases, marked KCCQ improvements, and remission of depressive symptoms.


Subject(s)
Heart Failure , Micro-Electrical-Mechanical Systems , Aged , Female , Germany , Heart Failure/epidemiology , Heart Failure/therapy , Humans , Ireland , Male , Middle Aged , Netherlands , Pulmonary Artery , Quality of Life , United States
10.
ESC Heart Fail ; 7(3): 865-872, 2020 06.
Article in English | MEDLINE | ID: mdl-32031758

ABSTRACT

AIMS: Chronic heart failure reduces quality and quantity of life and is expensive for healthcare systems. Medical treatment relies on guideline-directed therapy, but clinical follow-up and remote management is highly variable and poorly effective. New remote management strategies are needed to maintain clinical stability and avoid hospitalizations for acute decompensation. METHODS AND RESULTS: The CardioMEMS Post-Market Study is a prospective, international, single-arm, multicentre, open-label study (NCT02954341) designed to examine the feasibility of haemodynamic guided heart failure management using a small pressure sensor permanently implanted in the pulmonary artery (PA). Daily uploaded PA pressures will be reviewed weekly to remotely guide medical management of patients with persistent NYHA Class III symptoms at baseline and a hospitalization in the prior 12 months. The study will enrol up to 800 patients from 85 sites across the United Kingdom, Europe, and Australia. The primary safety endpoint will assess device or system-related complications or sensor failures after 2 years of follow-up. Efficacy will be estimated after 1 year of follow-up comparing HF hospitalization rates before and after sensor implantation. Observational endpoints will include mortality, patient, and investigator monitoring compliance, PA pressure changes, quality of life, and several pre-defined subgroup analyses. CONCLUSIONS: The CardioMEMS Post-Market Study will investigate the generalizability of remote haemodynamic guided HF management in a number of national settings. The results may support the more widespread implementation of this novel clinical management approach.


Subject(s)
Blood Pressure Monitoring, Ambulatory , Quality of Life , Research Design , Australia , Europe , Humans , Prospective Studies , United Kingdom/epidemiology
11.
Integr Biol (Camb) ; 10(4): 242-252, 2018 04 23.
Article in English | MEDLINE | ID: mdl-29623978

ABSTRACT

Numerous studies have demonstrated the importance of altered hyaluronan metabolism to malignant progression of multiple tumor types, including breast carcinomas. Increased hyaluronan (HA) metabolism in the stroma of primary tumors promotes activation of oncogenic signaling pathways that impact tumor initiation, growth, and invasion. Carcinoma cell synthesis and assembly of HA-rich pericellular matrices induces a stromal-independent phenotype, which is associated with cancer progression. Although the pro-tumorigenic role of stromal HA is well established, a novel but unexplored hypothesis is that carcinoma cell-associated HA pericellular matrices promote metastasis of circulating tumor cells. Here, we report the development of an in vitro assay that employs microfluidic techniques to directly measure the importance of an HA-rich pericellular matrix in the entry of carcinoma cells into ectopic sites. This model provides the capability to visualize specific steps in metastasis, which is difficult using animal models. The results show that the presence of a HA-rich pericellular matrix correlates to the invasive and metastatic potential of breast carcinoma cells. Furthermore, enzymatic removal or pharmacologic inhibition of HA synthesis significantly inhibits carcinoma cell extravasation and invasion in this model system. These results implicate pericellular HA-rich carcinoma cell associated pericellular matrices in colonization of ectopic sites by circulating tumor cells and support specific targeting of this matrix to limit metastasis in patients.


Subject(s)
Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Microfluidics , Animals , Carcinoma/metabolism , Carcinoma/pathology , Cell Adhesion , Cell Line, Tumor , Cell Movement , Extracellular Matrix/metabolism , Female , Green Fluorescent Proteins/metabolism , Human Umbilical Vein Endothelial Cells , Humans , Hyaluronic Acid/chemistry , Hymecromone/chemistry , Mice , Mice, Nude , Neoplasm Invasiveness , Neoplasm Metastasis , Phenotype
12.
J Cell Sci ; 126(Pt 14): 2997-3009, 2013 Jul 15.
Article in English | MEDLINE | ID: mdl-23613469

ABSTRACT

Mating yeast cells interpret complex pheromone gradients and polarize their growth in the direction of the closest partner. Chemotropic growth depends on both the pheromone receptor and its associated G-protein. Upon activation by the receptor, Gα dissociates from Gßγ and Gß is subsequently phosphorylated. Free Gßγ signals to the nucleus via a MAPK cascade and recruits Far1-Cdc24 to the incipient growth site. It is not clear how the cell establishes and stabilizes the axis of polarity, but this process is thought to require local signal amplification via the Gßγ-Far1-Cdc24 chemotropic complex, as well as communication between this complex and the activated receptor. Here we show that a mutant form of Gß that cannot be phosphorylated confers defects in directional sensing and chemotropic growth. Our data suggest that phosphorylation of Gß plays a role in localized signal amplification and in the dynamic communication between the receptor and the chemotropic complex, which underlie growth site selection and maintenance.


Subject(s)
Chemotaxis , GTP-Binding Protein alpha Subunits/metabolism , GTP-Binding Protein beta Subunits/metabolism , Saccharomyces cerevisiae/physiology , Aldehyde Oxidoreductases/metabolism , Cell Cycle Proteins/metabolism , Cell Polarity/genetics , Cyclin-Dependent Kinase Inhibitor Proteins/metabolism , GTP-Binding Protein beta Subunits/genetics , Guanine Nucleotide Exchange Factors/metabolism , MAP Kinase Signaling System/genetics , Mutation/genetics , Phosphorylation/genetics , Protein Binding , Receptors, Pheromone/metabolism , Saccharomyces cerevisiae/metabolism , Saccharomyces cerevisiae Proteins/metabolism
13.
Lab Chip ; 12(17): 3127-34, 2012 Sep 07.
Article in English | MEDLINE | ID: mdl-22760670

ABSTRACT

Chemotropism, or directed cell growth in response to a chemical gradient, is integral to many biological processes. The mating response of the budding yeast, Saccharomyces cerevisiae, is a well studied model chemotropic system. Yeast cells of opposite mating type signal their positions by secreting soluble mating pheromones. The mutual exchange of pheromones induces the cells to grow towards one another, resulting in mating projections or "shmoos." Yeast cells exhibit a remarkable ability to orient their growth toward the nearest potential mating partner, and to reorient (i.e., bend their mating projections) in response to a change in the direction of the pheromone gradient. Although a number of microfluidic devices have been used to generate linear pheromone gradients and to measure initial orientation, none of them have the capability to change the direction of the gradient, other than to invert it. We have developed a microfluidic device that can produce stable pheromone gradients and rapidly rotate them in 90° increments, mimicking the dynamic gradients yeast are exposed to in situ, and allowing for the study of reorientation as well as initial orientation. The mean angle of orientation exhibited by gradient-stimulated yeast cells in this device was 56.9°. In control experiments, cells subjected to pheromone coming from all four directions showed no evidence of orientation. Switching the direction of the pheromone source by 90° induced 83.6% of the polarized cells to change their direction of growth. Of these, 85.2% bent their mating projections toward the second source, demonstrating the utility of this device in the study of reorientation with specifically controlled gradients.


Subject(s)
Chemotaxis/drug effects , Microfluidic Analytical Techniques/instrumentation , Pheromones/pharmacology , Saccharomyces cerevisiae/drug effects , Rhodamines/pharmacology , Saccharomyces cerevisiae/physiology
14.
Biomed Microdevices ; 13(4): 633-9, 2011 Aug.
Article in English | MEDLINE | ID: mdl-21472409

ABSTRACT

There is a need for a simple method to control fluid flow within microfluidic channels. To meet this need, a simple push pin with a polydimethylsiloxane (PDMS) tip has been integrated into microfluidic networks to be placed within the microchannel to obstruct flow. This new valve design can attain on/off control of fluid flow without an external power source using readily-available, low-cost materials. The valve consists of a 14 gauge (1.6 mm) one inch piece of metal tubing with a PDMS pad at the tip to achieve a fluidic seal when pressed against a microfluidic channel's substrate. The metal tubing or pin is then either manually pushed down to block or pulled up to allow fluid flow. The valve was validated using a pressure transducer and fluorescent dye to determine the breakthrough pressure the valve can withstand over multiple cycles. In the first cycle, the median value for pressure withstood by the valve was 8.8 psi with a range of 17.5-2.7 psi. The pressure the valves were able to withstand during each successive trial was lower suggesting they may be most valuable as a method to control the initial introduction of fluids into a microfluidic device. These valves can achieve flow regulation within microfluidic devices, have a small dead volume, and are simple to fabricate and use, making this technique widely suitable for a range of applications.


Subject(s)
Flow Injection Analysis/instrumentation , Microfluidic Analytical Techniques/instrumentation , Dimethylpolysiloxanes/chemistry , Equipment Design , Equipment Failure Analysis , Microfluidic Analytical Techniques/methods , Pressure
15.
J Virol ; 76(18): 9434-45, 2002 Sep.
Article in English | MEDLINE | ID: mdl-12186925

ABSTRACT

The gamma(1)34.5 protein of herpes simplex virus type 1 (HSV-1) is required for viral neurovirulence in vivo. In infected cells, this viral protein prevents the shutoff of protein synthesis mediated by double-stranded-RNA-dependent protein kinase PKR. This is accomplished by recruiting protein phosphatase 1 to dephosphorylate the alpha subunit of translation initiation factor eIF-2 (eIF-2 alpha). Moreover, the gamma(1)34.5 protein is implicated in viral egress and interacts with proliferating cell nuclear antigen. In this report, we show that the gamma(1)34.5 protein encoded by HSV-1(F) is distributed in the nucleus, nucleolus, and cytoplasm in transfected or superinfected cells. Deletion analysis revealed that the Arg-rich cluster from amino acids 1 to 16 in the gamma(1)34.5 protein functions as a nucleolar localization signal. The region from amino acids 208 to 236, containing a bipartite basic amino acid cluster, is able to mediate nuclear localization. R(215)A and R(216)A substitutions in the bipartite motif disrupt this activity. Intriguingly, leptomycin B, an inhibitor of nuclear export, blocks the cytoplasmic accumulation of the gamma(1)34.5 protein. L(134)A and L(136)A substitutions in the leucine-rich motif completely excluded the gamma(1)34.5 protein from the cytoplasm. These results suggest that the gamma(1)34.5 protein continuously shuttles between the nucleus, nucleolus, and cytoplasm, which may be a requirement for the different activities of the gamma(1)34.5 protein in virus-infected cells.


Subject(s)
Cell Nucleolus/metabolism , Cell Nucleus/metabolism , Cytoplasm/metabolism , Herpesvirus 1, Human/metabolism , Protein Sorting Signals , Viral Proteins/metabolism , Amino Acid Sequence , Animals , Cell Line , Fatty Acids, Unsaturated/pharmacology , Gene Deletion , HeLa Cells , Humans , Microscopy, Confocal , Molecular Sequence Data , Nuclear Localization Signals/chemistry , Nuclear Localization Signals/metabolism , Protein Sorting Signals/genetics , Protein Transport , Transfection , Viral Proteins/genetics
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