MRgFUS thalamotomy for the treatment of tremor: evaluation of learning curve and operator's experience impact on the procedural and clinical outcome.

BACKGROUND: MRgFUS Vim ablation is increasingly used for the treatment of tremor in ET e PD patients but there is little published research on the importance of operator experience in this procedure. This study aims to evaluate the learning curve and the influence of the operator experience on the procedural and clinical outcomes. METHODS: We retrospectively evaluated 90 patients (38 ET, 52 PD) submitted to MRgFUS unilateral thalamotomy in the period between February 2018 and July 2020. Clinical endpoints, procedural times, and technical parameters were recorded in all procedures. Based on the time of treatment, patients were divided into three groups of 30 units each, comparing all variables between each time period group. RESULTS: In Group A, the average patient preparation time was 120.6 min, the treatment time was 105.2 min, the number of was sonications 14.1, and the mean target shifts 3.1. In Group B, the mean preparation time was 105.5 min, the treatment time was 89.5 min, the number of sonications was 13.2, and the target shifts 3.0. Group C showed inferior values of preparation time (101.9 min), treatment time (71.7 min), numbers of sonications (10.6), and shifts (1.7). Thalamotomy-related complications occurred in 9 patients of Group A, 2 of Group B, and 5 of Group C. Tremor relapse occurred in 7 patients of Group A, 3 of Group B, and 2 of Group C. The days of hospitalization were comparable in the three groups. CONCLUSIONS: The operators experience is associated with the improvement of clinical and procedural outcome in MRgFUS thalatomy for the treatment of ET and PD tremor.

KRD (carfilzomib and lenalidomide plus dexamethasone) for the treatment of relapsed or refractory multiple myeloma in the real-life: a retrospective survey in 123 patients.

From April 2016, carfilzomib, in combination with lenalidomide and dexamethasone (KRD), became available for use in the daily practice in Italy for patients with relapsed or refractory multiple myeloma (RRMM). We performed a retrospective survey at 14 different institutions from Southern Italy in order to evaluate patient characteristics and treatment results from an unselected series of patients treated accordingly so far. One hundred and twenty-three consecutive patients were included, with a median of 2 previous lines of therapy (range 1-9) and a median age of 63 years (range 39-82). At the time of analysis, median number of courses administered is 11 (range 1-34), and all patients are evaluable for response. Overall response rate including complete remission, very good partial remission, and partial remission is 85%. After a median follow-up of 27 months, median overall and progression-free survival are 33 and 23 months, respectively. Sixty-three patients are alive and between them, 45 (37%) are in continuous remission. Sixty patients have died (49%), mainly from progressive disease. There were 6 treatment-related deaths (5% of the whole patient population). Overall, hematological and non-hematological toxicity were manageable, mostly on outpatient basis. Arterial hypertension has been observed in 43 cases (35%) but did not lead to treatment interruption. Our data demonstrate that in real life, KRD is highly effective and well tolerated in the majority of patients with RRMM.

How do the characteristics of breast cancer diagnostic assessment programmes influence service delivery: A mixed methods study.

Diagnostic assessment programmes (DAPs) coordinate multidisciplinary teamwork (MDT), and improve wait times and patient satisfaction. No research has established optimal DAP design. This study explored how DAP characteristics influence service delivery. A mixed methods case study of four breast cancer DAPs was conducted including qualitative interviews with health-care providers and retrospective chart review. Data were integrated using multiple approaches. Twenty-three providers were interviewed; 411 medical records were reviewed. The number of visits and wait times from referral to diagnosis and consultation were lowest at a one-stop model. DAP characteristics (rural-remote region, human resources, referral volume, organisation of services, adherence to service delivery targets and one-stop model) may influence service delivery (number of visits, wait times). MDT, influenced by other DAP characteristics (co-location of staff, patient navigators, team functioning), may also influence service delivery. While the one-stop model may be ideal, all sites experienced similar and unique challenges. Further research is needed to understand how to optimise the organisation and delivery of DAP services. Measures reflecting individual, team and patient-reported outcomes should be used to assess the effectiveness and impact of DAPs in addition to more traditional measures such as wait times.

Cost analysis of breast cancer diagnostic assessment programs.

OBJECTIVES: Diagnostic assessment programs (daps) appear to improve the diagnosis of cancer, but evidence of their cost-effectiveness is lacking. Given that no earlier study used secondary financial data to estimate the cost of diagnostic tests in the province of Ontario, we explored how to use secondary financial data to retrieve the cost of key diagnostic test services in daps, and we tested the reliability of that cost-retrieving method with hospital-reported costs in preparation for future cost-effectiveness studies. METHODS: We powered our sample at an alpha of 0.05, a power of 80%, and a margin of error of ±5%, and randomly selected a sample of eligible patients referred to a dap for suspected breast cancer during 1 January-31 December 2012. Confirmatory diagnostic tests received by each patient were identified in medical records. Canadian Classification of Health Intervention procedure codes were used to search the secondary financial data Web portal at the Ontario Case Costing Initiative for an estimate of the direct, indirect, and total costs of each test. The hospital-reported cost of each test received was obtained from the host-hospital's finance department. Descriptive statistics were used to calculate the cost of individual or group confirmatory diagnostic tests, and the Wilcoxon signed-rank test or the paired t-test was used to compare the Ontario Case Costing Initiative and hospital-reported costs. RESULTS: For the 191 identified patients with suspected breast cancer, the estimated total cost of $72,195.50 was not significantly different from the hospital-reported total cost of $72,035.52 (p = 0.24). Costs differed significantly when multiple tests to confirm the diagnosis were completed during one patient visit and when confirmatory tests reported in hospital data and in medical records were discrepant. The additional estimated cost for non-salaried physicians delivering diagnostic services was $28,387.50. CONCLUSIONS: It was feasible to use secondary financial data to retrieve the cost of key diagnostic tests in a breast cancer dap and to compare the reliability of the costs obtained by that estimation method with hospital-reported costs. We identified the strengths and challenges of each approach. Lessons learned from this study have to be taken into consideration in future cost-effectiveness studies.

Classification of cardiorespiratory fitness using the six-minute walk test in adults: Comparison with cardiopulmonary exercise testing.

BACKGROUND: The six-minute walk test (6MWT) distance could facilitate the assessment of cardiorespiratory fitness (CRF) in clinical practice as recommended. We aimed to develop a CRF classification using the 6MWT distance in asymptomatic adults considering the treadmill maximum oxygen uptake (V˙O2max) as the gold standard method. METHODS: We evaluated V˙O2max and 6MWT distance in 1295 asymptomatic participants aged 18-80 years (60% women). Age- and sex-related CRF was classified based on the percentiles as very low (<5th percentile), low (5th-25th percentile), regular (26th-50th percentile), good (51st-75th percentile), excellent (76th-95th percentile), and superior (>95th percentile) for both V˙O2max and 6MWT distance. We investigated the 6MWT distance cut-off (%pred.) with the highest sensitivity and specificity for identifying each V˙O2max classification. RESULTS: V˙O2max declined by 8.7% per decade in both men and women. The 6MWT distance declined by 9.3% per decade in women and 9.5% in men. We formulated age- and sex-related classification tables for CRF using the 6MWT distance. Moreover, the 6MWT distance (%pred.) showed excellent ability to identify very low CRF (6MWT distance ≤ 96%; AUC=0.819) and good ability to differentiate CRF as low (6MWT distance=97%-103%; AUC=0.735), excellent (6MWT distance=107%-109%; AUC=0.715), or superior (6MWT distance>109%; AUC=0.790). It was not possible to differentiate between participants with regular and good CRF. CONCLUSION: The CRF classification by the 6MWT distance is valid in comparison with V˙O2max, especially for identifying adults with low CRF. It could be useful in clinical practice for screening and monitoring the cardiorespiratory risk in adults.

Multidisciplinary cancer conferences: identifying opportunities to promote implementation.

BACKGROUND: Cancer care is complex and multimodal therapy is now considered the standard of care. Multidisciplinary cancer conferences (MCCs) offer a venue to prospectively discuss cancer patients and plan treatment. MCCs are believed to improve patient outcomes and consequently have been internationally adopted. The purpose of this study was to describe the prevalence of MCCs in Ontario and identify individual and organizational barriers to their adoption. METHODS: A cross-sectional, mailed questionnaire of general surgeons in Ontario, Canada who care for patients with cancer was used to assess prevalence, and organizational and individual barriers to MCC implementation. Responses were summarized overall, by hospital, and by academic status. RESULTS: The response rate was 44.2% (170/385). Respondents worked at 57 unique hospitals, of which 29 (52%) were reported to have MCCs, including all academic hospitals (7/7) and 22 of 50 (44%) community hospitals. Forty-nine MCCs were reported at 29 hospitals. MCCs occurred weekly at academic centers and biweekly or monthly at community hospitals. Few MCCs (28%) had a designated coordinator. Surgeons perceived that MCCs helped them to incorporate multidisciplinary opinions into their patient care plans, improved collegiality, and provided opportunity for continuing professional development. CONCLUSIONS: Despite the perceived benefits expressed by respondents, administrative support for MCCs may be minimal. In particular, surgeons at community hospitals may have limited access to multidisciplinary patient care planning. This information will be utilized to shape a provincial strategy for implementing MCCs. However, further research is required to understand barriers and enablers to establish and maintain MCCs, especially in community practice.

Solving the brain synchrony eigenvalue problem: conservation of temporal dynamics (fMRI) over subjects doing the same task.

Brain measures often show highly structured temporal dynamics that synchronize when observers are doing the same task. The standard method for analysis of brain imaging signals (e.g. fMRI) uses the GLM for each voxel indexed against a specified experimental design but does not explicitly involve temporal dynamics. Consequently, the design variables that determine the functional brain areas are those correlated with the design variation rather than the common or conserved brain areas across subjects with the same temporal dynamics given the same stimulus conditions. This raises an important theoretical question: Are temporal dynamics conserved across individuals experiencing the same stimulus task? This general question can be framed in a dynamical systems context and further be posed as an eigenvalue problem about the conservation of synchrony across all brains simultaneously. We show that solving the problem results in a non-arbitrary measure of temporal dynamics across brains that scales over any number of subjects, stabilizes with increasing sample size, and varies systematically across tasks and stimulus conditions.

Kinetic Monte Carlo Study of the Role of the Energetic Disorder on the Open-Circuit Voltage in Polymer/Fullerene Solar Cells.

One major factor limiting the efficiency in organic solar cells (OSCs) is the low open-circuit voltage (Voc). Existing theoretical studies link the Voc with the charge transfer (CT) state and nonradiative recombination. However, also morphology and energetic disorder can have a strong impact on the Voc within realistic bulk-heterojunction OSCs. In this work, we present a kinetic Monte Carlo study on the role of the energetic disorder on the maximum Voc. We compute the quasi-Fermi level splitting for different energetic disorder and analyze the impact of the energetic disorder at the donor-acceptor interface as well as correlations in the site energies on the Voc. Our results show that the interface strongly controls the maximum Voc. For a higher interface disorder, charge densities and nongeminate recombination increase and the Voc is reduced. Furthermore, the correlated morphologies show an increase in the maximum Voc and a reduced impact of the energetic disorder.

Use of cardiopulmonary exercise testing to assess early ventilatory changes related to occupational particulate matter.

Spirometry has been used as the main strategy for assessing ventilatory changes related to occupational exposure to particulate matter (OEPM). However, in some cases, as one of its limitations, it may not be sensitive enough to show abnormalities before extensive damage, as seen in restrictive lung diseases. Therefore, we hypothesized that cardiopulmonary exercise testing (CPET) may be better than spirometry to detect early ventilatory impairment caused by OEPM. We selected 135 male workers with at least one year of exposure. After collection of self-reported socioeconomic status, educational level, and cardiovascular risk data, participants underwent spirometry, CPET, body composition assessment (bioelectrical impedance), and triaxial accelerometry (for level of physical activity in daily life). CPET was performed using a ramp protocol on a treadmill. Metabolic, cardiovascular, ventilatory, and submaximal relationships were measured. We compared 52 exposed to 83 non-exposed workers. Multiple linear regressions were developed using spirometry and CPET variables as outcomes and OEPM as the main predictor, and adjusted by the main covariates. Our results showed that OEPM was associated with significant reductions in peak minute ventilation, peak tidal volume, and breathing reserve index. Exposed participants presented shallower slope of ΔVT/ΔlnV̇E (breathing pattern), i.e., increased tachypneic breathing pattern. The OEPM explained 7.4% of the ΔVT/ΔlnV̇E variability. We found no significant influence of spirometric indices after multiple linear regressions. We conclude that CPET might be a more sensitive feature of assessing early pulmonary impairment related to OEPM. Our cross-sectional results suggested that CPET is a promising tool for the screening of asymptomatic male workers.

Evaluation of dose-response relationship between smoking load and cardiopulmonary fitness in adult smokers: A cross-sectional study.

OBJECTIVE: To evaluate the dose-response relationship between smoking load and cardiopulmonary fitness, as measured with cardiopulmonary exercise testing (CPET), in adult smokers free of respiratory diseases. METHODS: After a complete clinical evaluation and spirometry, 95 adult smokers (35 men and 60 women) underwent CPET on a treadmill. RESULTS: The physiological responses during CPET showed lower cardiorespiratory fitness levels, regardless of smoking load, with a peak [Formula: see text] lower than 100% of the expected value and a lower maximum heart rate. We observed a significant moderate negative correlation between smoking load and peak [Formula: see text] . The smoking load also presented a significant negative correlation with maximum heart rate(r=-0.36; p<0.05), lactate threshold(r=-0.45; p<0.05), and peak ventilation(r=-0.43; p<0.05). However, a dose-response relationship between smoking load quartiles and cardiopulmonary fitness was not found comparing quartiles of smoking loads after adjustment for age, sex and cardiovascular risk. CONCLUSION: There appears to be no dose-response relationship between SL and cardiopulmonary fitness in adult smokers with preserved pulmonary function, after adjusting the analysis for age and cardiovascular risk. Our results suggest that smoking cessation might be useful as the primary strategy to prevent cardiopulmonary fitness decline in smokers, regardless of smoking load. Thus, even a very low dose of tobacco use must be avoided in preventive strategies focusing on becoming people more physically active and fit.

Inhibition of angiogenesis by antiestrogens.

In this study, we have determined the ability of the partial estrogen antagonists, clomiphene, tamoxifen, and nafoxidine, and the pure estrogen antagonists, ICI 164,384 and ICI 182,780, to inhibit angiogenesis in the chick egg chorioallantoic membrane. All of the partial estrogen antagonists and the pure estrogen antagonist, ICI 182,780, showed significant angiostatic activity in a dose-related manner. The addition of up to 5-fold of 17 beta-estradiol to the disks containing clomiphene, tamoxifen, or ICI 182,780 did not alter the angiostatic activity of these antiestrogens. These novel findings show that the antiestrogens are effective inhibitors of angiogenesis. The finding that angiostatic activity is not altered in the presence of excess estrogens suggests that this activity is exerted via mechanisms other than their inhibition of estrogen action. This angiostatic activity may contribute to the therapeutic effect of antiestrogens in estrogen receptor-negative tumors.

Inhibition of angiogenesis by suramin.

In this study, we have determined the ability of suramin to inhibit angiogenesis in the chick chorioallantoic membrane. Suramin alone showed significant angiostatic activity in a dose-related manner. Suramin also potentiated the activity of the angiostatic steroids, cortisol-21-phosphate, 17 alpha-hydroxyprogesterone, tetrahydrocortisol, and tetrahydrocortexolone. The presence of heparin decreased the angiostatic activity of suramin. These results suggest that suramin may decrease tumor growth by inhibiting angiogenesis. These novel findings indicate that suramin, perhaps in combination with angiostatic steroids, may be the basis for important new therapeutic approaches for diseases of neovascularization.

Comparative proteomic analysis of bronchoalveolar lavage of familial and sporadic cases of idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease characterized by progressive deterioration of the alveolar integrity. Among IPF identified phenotypes, that of familial (f-)IPF is usually associated with several gene mutations which are seldom observed in sporadic (s-)IPF. This study aimed at investigating the molecular patterns and variability in f-IPF and s-IPF patients through a differential proteomic analysis. Protein patterns of bronchoalveolar lavage fluid (BALF) samples from 10 familial and 17 sporadic IPF patients were compared using 2D electrophoresis and mass spectrometry. Principal component analysis (PCA) was applied to proteomic data and an enrichment analysis was also performed to characterize specific pathogenic mechanisms and to identify potential biomarkers. BALF samples from f-IPF showed 87 protein spots differentially expressed than those from s-IPF samples; once identified, these spots revealed 22 unique proteins. The functional analysis showed that the endothelial reticulum stress probably plays a central pathogenetic role in f-IPF with an up-regulation of proteins involved in wounding and immune responses, coagulation system, and ion homeostasis. Up-regulated proteins in the s-IPF group were those involved in the oxidative stress response. PCA analysis of differentially expressed proteins clearly distinguished f-IPF from s-IPF patients, and in agreement with radiological and histological patterns, pointed out a higher heterogeneity in f-IPF than s-IPF samples. The 'Slit/Robo signaling', 'clathrin-coated vesicle' and 'cytoskeleton remodelling', were extrapolated by 'pathways analysis' and the results of 'diseases (by biomarkers)' highlighted a 'connective tissue and autoimmune disease', two aspects of increasing interest in IPF.

Correlation between heart rate variability and pulmonary function adjusted by confounding factors in healthy adults.

The autonomic nervous system maintains homeostasis, which is the state of balance in the body. That balance can be determined simply and noninvasively by evaluating heart rate variability (HRV). However, independently of autonomic control of the heart, HRV can be influenced by other factors, such as respiratory parameters. Little is known about the relationship between HRV and spirometric indices. In this study, our objective was to determine whether HRV correlates with spirometric indices in adults without cardiopulmonary disease, considering the main confounders (e.g., smoking and physical inactivity). In a sample of 119 asymptomatic adults (age 20-80 years), we evaluated forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1). We evaluated resting HRV indices within a 5-min window in the middle of a 10-min recording period, thereafter analyzing time and frequency domains. To evaluate daily physical activity, we instructed participants to use a triaxial accelerometer for 7 days. Physical inactivity was defined as <150 min/week of moderate to intense physical activity. We found that FVC and FEV1, respectively, correlated significantly with the following aspects of the RR interval: standard deviation of the RR intervals (r =0.31 and 0.35), low-frequency component (r =0.38 and 0.40), and Poincaré plot SD2 (r =0.34 and 0.36). Multivariate regression analysis, adjusted for age, sex, smoking, physical inactivity, and cardiovascular risk, identified the SD2 and dyslipidemia as independent predictors of FVC and FEV1 (R2=0.125 and 0.180, respectively, for both). We conclude that pulmonary function is influenced by autonomic control of cardiovascular function, independently of the main confounders.

Zebrafish Collagen Type I: Molecular and Biochemical Characterization of the Major Structural Protein in Bone and Skin.

Over the last years the zebrafish imposed itself as a powerful model to study skeletal diseases, but a limit to its use is the poor characterization of collagen type I, the most abundant protein in bone and skin. In tetrapods collagen type I is a trimer mainly composed of two α1 chains and one α2 chain, encoded by COL1A1 and COL1A2 genes, respectively. In contrast, in zebrafish three type I collagen genes exist, col1a1a, col1a1b and col1a2 coding for α1(I), α3(I) and α2(I) chains. During embryonic and larval development the three collagen type I genes showed a similar spatio-temporal expression pattern, indicating their co-regulation and interdependence at these stages. In both embryonic and adult tissues, the presence of the three α(I) chains was demonstrated, although in embryos α1(I) was present in two distinct glycosylated states, suggesting a developmental-specific collagen composition. Even though in adult bone, skin and scales equal amounts of α1(I), α3(I) and α2(I) chains are present, the presented data suggest a tissue-specific stoichiometry and/or post-translational modification status for collagen type I. In conclusion, this data will be useful to properly interpret results and insights gained from zebrafish models of skeletal diseases.

Posterior capsule opacity in Retinitis Pigmentosa according to different biomaterials of intraocular lenses: Our clinical experience.

BACKGROUND AND AIM: Complicated Cataract is frequently associated with Retinitis Pigmentosa (RP). This retinopathy is a great cause of visual impairment, and cataract surgery may resolve partially the situation and restore sight. Unfortunately, in this case there is a very high incidence of Posterior Capsule Opacity (PCO) ranging in several studies a percentage of 100% at six months. Our goal was to evaluate whether the high incidence of PCO is associated to specific type of Intraocular Lens (IOL) biomaterials. MATERIALS AND METHODS: This observational retrospective study deals with 75 eyes of 43 patients affected with RP who underwent to cataract surgery with posterior chamber IOL implants (40% ECCE and 60% Phaco). Selected biomaterials were: 30 Poly (methyl methacrylate) (PMMA), 11 silicone, 34 acrylic. Observations were performed with retro-illumination camera and when recorded capsular fibrosis a PCO YAG laser capsulotomy was made. The patients were controlled at 3-6-12 months after the initial surgical treatment. RESULTS: At three months of follow up, 80% of patients with PMMA, 81.8% silicone implants underwent to YAG capsulotomy while only 44% of acrylic type. At six months of follow-up 83.3% of patients with PMMA and 81.8% silicone implants underwent to YAG capsulotomy while only 49.88% of acrylic type. At 12 months of follow up 89.9% of patients with PMMA and 90.95 silicone implants underwent to YAG capsulotomy while only 52.82% of acrylic type. CONCLUSIONS: We could not be able to differentiate incidence between different brand type of lens in PMMA. For Acrylic lens instead we noted an incidence of PCO of 41.38% with hydrophobic material and 60.0% of hydrophilic material. In conclusion to avoid massive PCO in RP, our experience is statistically significant, in fact the protective action of smooth material hydrophobic lens avoids the epithelial growth and fibrosis towards the center of visual axis.

Intensity and physiological responses to the 6-minute walk test in middle-aged and older adults: a comparison with cardiopulmonary exercise testing.

The 6-minute walk test (6MWT) is a simple field test that is widely used in clinical settings to assess functional exercise capacity. However, studies with healthy subjects are scarce. We hypothesized that the 6MWT might be useful to assess exercise capacity in healthy subjects. The purpose of this study was to evaluate 6MWT intensity in middle-aged and older adults, as well as to develop a simple equation to predict oxygen uptake ( V ˙ O 2 ) from the 6-min walk distance (6MWD). Eighty-six participants, 40 men and 46 women, 40-74 years of age and with a mean body mass index of 28±6 kg/m2, performed the 6MWT according to American Thoracic Society guidelines. Physiological responses were evaluated during the 6MWT using a K4b2 Cosmed telemetry gas analyzer. On a different occasion, the subjects performed ramp protocol cardiopulmonary exercise testing (CPET) on a treadmill. Peak V ˙ O 2 in the 6MWT corresponded to 78±13% of the peak V ˙ O 2 during CPET, and the maximum heart rate corresponded to 80±23% of that obtained in CPET. Peak V ˙ O 2 in CPET was adequately predicted by the 6MWD by a linear regression equation: V ˙ O 2 mL·min-1·kg-1 = -2.863 + (0.0563×6MWDm) (R2=0.76). The 6MWT represents a moderate-to-high intensity activity in middle-aged and older adults and proved to be useful for predicting cardiorespiratory fitness in the present study. Our results suggest that the 6MWT may also be useful in asymptomatic individuals, and its use in walk-based conditioning programs should be encouraged.

A functional proteomics approach to the comprehension of sarcoidosis.

Pulmonary sarcoidosis (Sar) is an idiopathic disease histologically typified by non-caseating epitheliod cell sarcoid granulomas. A cohort of 37 Sar patients with chronic persistent pulmonary disease was described in this study. BAL protein profiles from 9 of these Sar patients were compared with those from 8 smoker (SC) and 10 no-smoker controls (NSC) by proteomic approach. Principal Component Analysis was performed to clusterize the samples in the corresponding conditions highlighting a differential pattern profiles primarily in Sar than SC. Spot identification reveals thirty-four unique proteins involved in lipid, mineral, and vitamin Dmetabolism, and immuneregulation of macrophage function. Enrichment analysis has been elaborated by MetaCore, revealing 14-3-3ε, α1-antitrypsin, GSTP1, and ApoA1 as "central hubs". Process Network as well as Pathway Maps underline proteins involved in immune response and inflammation induced by complement system, innate inflammatory response and IL-6signalling. Disease Biomarker Network highlights Tuberculosis and COPD as pathologies that share biomarkers with sarcoidosis. In conclusion, Sar protein expression profile seems more similar to that of NSC than SC, conversely to other ILDs. Moreover, Disease Biomarker Network revealed several common features between Sar and TB, exhorting to orientate the future proteomics investigations also in comparative BALF analysis of Sar and TB.

Uptake of suramin by human microvascular endothelial cells.

We have demonstrated for the first time that suramin is taken up by human dermal microvascular endothelial (HMEC-1) cells by an active process involving the caveolae system. The uptake of suramin was time-dependent and reduced by more than 90% when incubated in the presence of albumin or at 4 degrees C. Suramin uptake was also inhibited when incubated in the presence of filipin and digitonin, both potent cholesterol-binding agents, but not in the presence of probenecid. The [3H]suramin taken up by the HMEC-1 cells was located primarily within the nucleus, followed by the cytoplasmic fraction. The presence of suramin in these cellular compartments suggests that this drug may act through intracellular mechanisms.