Lymphatic clearance of the human skin in patients with acute deep vein thrombosis using a novel fluorescent technique

The purpose of this study was to investigate lymphatic clearance of the human skin in patients with acute deep thrombosis of the femoral vein. In 13 patients with deep vein thrombosis and no other cause for swelling of the limbs, lymphatic clearance of the skin at the foot was measured. Ten microliters of fluorescein isothiocyanatedextran 150,000 were injected intradermally and the fluorescent light intensity of the deposit measured 10 min and 24 hours after injection by window densitometry. In addition, intralymphatic pressure was measured by the servo-nulling system. The results were compared with a sex- and age-matched control group. Fluorescent light intensity decreased by 23.8 +/- 12.3 arbitrary units or by a factor of 1.8 +/- 0.5 in patients with DVT after 24 hours, which was significantly less than in healthy controls (33.7 +/- 8.9 arbitrary units or by factor 5.0 +/- 4.1, p < 0.013). Intralymphatic pressure was not different between the two groups. These results indicate that lymphatic clearance is significantly reduced in the acute phase of deep venous thrombosis.

Orosomucoid (alpha1-acid glycoprotein) plasma concentration and genetic variants: effects on human immunodeficiency virus protease inhibitor clearance and cellular accumulation

BACKGROUND AND OBJECTIVE: Protease inhibitors are highly bound to orosomucoid (ORM) (alpha1-acid glycoprotein), an acute-phase plasma protein encoded by 2 polymorphic genes, which may modulate their disposition. Our objective was to determine the influence of ORM concentration and phenotype on indinavir, lopinavir, and nelfinavir apparent clearance (CL(app)) and cellular accumulation. Efavirenz, mainly bound to albumin, was included as a control drug. METHODS: Plasma and cells samples were collected from 434 human immunodeficiency virus-infected patients. Total plasma and cellular drug concentrations and ORM concentrations and phenotypes were determined. RESULTS: Indinavir CL(app) was strongly influenced by ORM concentration (n = 36) (r2 = 0.47 [P = .00004]), particularly in the presence of ritonavir (r2 = 0.54 [P = .004]). Lopinavir CL(app) was weakly influenced by ORM concentration (n = 81) (r2 = 0.18 [P = .0001]). For both drugs, the ORM1 S variant concentration mainly explained this influence (r2 = 0.55 [P = .00004] and r2 = 0.23 [P = .0002], respectively). Indinavir CL(app) was significantly higher in F1F1 individuals than in F1S and SS patients (41.3, 23.4, and 10.3 L/h [P = .0004] without ritonavir and 21.1, 13.2, and 10.1 L/h [P = .05] with ritonavir, respectively). Lopinavir cellular exposure was not influenced by ORM abundance and phenotype. Finally, ORM concentration or phenotype did not influence nelfinavir (n = 153) or efavirenz (n = 198) pharmacokinetics. CONCLUSION: ORM concentration and phenotype modulate indinavir pharmacokinetics and, to a lesser extent, lopinavir pharmacokinetics but without influencing their cellular exposure. This confounding influence of ORM should be taken into account for appropriate interpretation of therapeutic drug monitoring results. Further studies are needed to investigate whether the measure of unbound drug plasma concentration gives more meaningful information than total drug concentration for indinavir and lopinavir.

Randomized trial comparing axillary clearance versus no axillary clearance in older patients with breast cancer: first results of International Breast Cancer Study Group Trial 10-93

Axillary clearance in early breast cancer aims to improve locoregional control and provide staging information but is associated with undesirable morbidity. We therefore investigated whether avoiding axillary surgery in older women would result in improved quality of life (QL) with similar disease-free survival (DFS) and overall survival (OS).

A thiazide test for the diagnosis of renal tubular hypokalemic disorders

Although the diagnosis of Gitelman syndrome (GS) and Bartter syndrome (BS) is now feasible by genetic analysis, implementation of genetic testing for these disorders is still hampered by several difficulties, including large gene dimensions, lack of hot-spot mutations, heavy workup time, and costs. This study evaluated in a cohort of patients with genetically proven GS or BS diagnostic sensibility and specificity of a diuretic test with oral hydrochlorothiazide (HCT test). Forty-one patients with GS (22 adults, aged 25 to 57; 19 children-adolescents, aged 7 to 17) and seven patients with BS (five type I, two type III) were studied; three patients with "pseudo-BS" from surreptitious diuretic intake (two patients) or vomiting (one patient) were also included. HCT test consisted of the administration of 50 mg of HCT orally (1 mg/kg in children-adolescents) and measurement of the maximal diuretic-induced increase over basal in the subsequent 3 h of chloride fractional clearance. All but three patients with GS but no patients with BS and pseudo-BS showed blunted (<2.3%) response to HCT; patients with BS and the two patients with pseudo-BS from diuretic intake had increased response to HCT. No overlap existed between patients with GS and both patients with BS and pseudo-BS. The response to HCT test is blunted in patients with GS but not in patients with BS or nongenetic hypokalemia. In patients with the highly selected phenotype of normotensive hypokalemic alkalosis, abnormal HCT test allows prediction with a very high sensitivity and specificity of the Gitelman genotype and may avoid genotyping.

Re-evaluation of pulmonary titanium dioxide nanoparticle distribution using the "relative deposition index": Evidence for clearance through microvasculature

ABSTRACT: BACKGROUND: Translocation of nanoparticles (NP) from the pulmonary airways into other pulmonary compartments or the systemic circulation is controversially discussed in the literature. In a previous study it was shown that titanium dioxide (TiO2) NP were "distributed in four lung compartments (air-filled spaces, epithelium/endothelium, connective tissue, capillary lumen) in correlation with compartment size". It was concluded that particles can move freely between these tissue compartments. To analyze whether the distribution of TiO2 NP in the lungs is really random or shows a preferential targeting we applied a newly developed method for comparing NP distributions. METHODS: Rat lungs exposed to an aerosol containing TiO2 NP were prepared for light and electron microscopy at 1 h and at 24 h after exposure. Numbers of TiO2 NP associated with each compartment were counted using energy filtering transmission electron microscopy. Compartment size was estimated by unbiased stereology from systematically sampled light micrographs. Numbers of particles were related to compartment size using a relative deposition index and chi-squared analysis. RESULTS: Nanoparticle distribution within the four compartments was not random at 1 h or at 24 h after exposure. At 1 h the connective tissue was the preferential target of the particles. At 24 h the NP were preferentially located in the capillary lumen. CONCLUSION: We conclude that TiO2 NP do not move freely between pulmonary tissue compartments, although they can pass from one compartment to another with relative ease. The residence time of NP in each tissue compartment of the respiratory system depends on the compartment and the time after exposure. It is suggested that a small fraction of TiO2 NP are rapidly transported from the airway lumen to the connective tissue and subsequently released into the systemic circulation.

The role of macrophages in the clearance of inhaled ultrafine titanium dioxide particles

The role of macrophages in the clearance of particles with diameters less than 100 nm (ultrafine or nanoparticles) is not well established, although these particles deposit highly efficiently in peripheral lungs, where particle phagocytosis by macrophages is the primary clearance mechanism. To investigate the uptake of nanoparticles by lung phagocytes, we analyzed the distribution of titanium dioxide particles of 20 nm count median diameter in macrophages obtained by bronchoalveolar lavage at 1 hour and 24 hours after a 1-hour aerosol inhalation. Differential cell counts revealing greater than 96% macrophages and less than 1% neutrophils and lymphocytes excluded inflammatory cell responses. Employing energy-filtering transmission electron microscopy (EFTEM) for elemental microanalysis, we examined 1,594 macrophage profiles in the 1-hour group (n = 6) and 1,609 in the 24-hour group (n = 6). We found 4 particles in 3 macrophage profiles at 1 hour and 47 particles in 27 macrophage profiles at 24 hours. Model-based data analysis revealed an uptake of 0.06 to 0.12% ultrafine titanium-dioxide particles by lung-surface macrophages within 24 hours. Mean (SD) particle diameters were 31 (8) nm at 1 hour and 34 (10) nm at 24 hours. Particles were localized adjacent (within 13-83 nm) to the membrane in vesicles with mean (SD) diameters of 592 (375) nm at 1 hour and 414 (309) nm at 24 hours, containing other material like surfactant. Additional screening of macrophage profiles by conventional TEM revealed no evidence for agglomerated nanoparticles. These results give evidence for a sporadic and rather unspecific uptake of TiO(2)-nanoparticles by lung-surface macrophages within 24 hours after their deposition, and hence for an insufficient role of the key clearance mechanism in peripheral lungs.

Effect of transcutaneous electrical muscle stimulation and passive cycling movements on blood pressure and removal of urea and phosphate during hemodialysis

BACKGROUND: Intradialytic exercise has been described to improve blood pressure stability and dialysis efficacy. However, comorbid conditions in the dialysis population often preclude the widespread use of active intradialytic exercise. Therefore, we investigated the effect of intradialytic transcutaneous muscle stimulation (TEMS) and passive cycling movements (PCMs) on blood pressure and dialysis efficacy in patients. STUDY DESIGN: Prospective, controlled, randomized, crossover investigation. SETTING ; PARTICIPANTS: Ten patients were randomly allocated to TEMS, PCMs, or no intervention (NI) for 9 consecutive dialysis sessions. INTERVENTION: Participants were studied with NI, PCMs using a motor-driven ergometer, and bilateral TEMS of the leg musculature. Individual dialysis prescriptions were unchanged during the investigation. OUTCOMES ; MEASUREMENTS: The effect of TEMS and PCMs on blood pressure and dialysis efficacy in patients was assessed. RESULTS: Mean blood pressure increased from 121/64 +/- 21/15 mm Hg with NI to 132/69 +/- 21/15 mm Hg (P < 0.001) during sessions with PCMs and 125/66 +/- 22/16 mm Hg (P < 0.05) during sessions with TEMS. Urea and phosphate removal during dialysis were significantly (P < 0.001) greater with TEMS (19.4 +/- 3.7 g/dialysis and 1,197 +/- 265 mg/dialysis) or PCMs (20.1 +/- 3.4 g/dialysis and 1,172 +/- 315 mg/dialysis) than with NI (15.1 +/- 3.9 g/dialysis and 895 +/- 202 mg/dialysis). Body weight, ultrafiltration, Kt/V, and increases in hemoglobin and albumin levels during dialysis did not differ among the NI, PCMs, and TEMS groups. LIMITATIONS: The study design does not allow extension of the findings to prolonged treatment. CONCLUSION: Future studies during longer observation periods will have to prove the persistence of these acute findings. Both TEMS and PCMs deserve future investigations in dialysis patients because they increase intradialytic blood pressure and facilitate urea and phosphate removal when applied short term.

Increased cytotoxic T-lymphocyte epitope variant cross-recognition and functional avidity are associated with hepatitis C virus clearance

Hepatitis C virus (HCV) clearance has been associated with reduced viral evolution in targeted cytotoxic T-lymphocyte (CTL) epitopes, suggesting that HCV clearers may mount CTL responses with a superior ability to recognize epitope variants and prevent viral immune escape. Here, 40 HCV-infected subjects were tested with 406 10-mer peptides covering the vast majority of the sequence diversity spanning a 197-residue region of the NS3 protein. HCV clearers mounted significantly broader CTL responses of higher functional avidity and with wider variant cross-recognition capacity than nonclearers. These observations have important implications for vaccine approaches that may need to induce high-avidity responses in vivo.

Effect of 6-month supervised exercise on low-density lipoprotein apolipoprotein B kinetics in patients with type 2 diabetes mellitus

Although low-density lipoprotein (LDL) cholesterol is often normal in patients with type 2 diabetes mellitus, there is evidence for a reduced fractional catabolic rate and consequently an increased mean residence time (MRT), which can increase atherogenic risk. The dyslipidemia and insulin resistance of type 2 diabetes mellitus can be improved by aerobic exercise, but effects on LDL kinetics are unknown. The effect of 6-month supervised exercise on LDL apolipoprotein B kinetics was studied in a group of 17 patients with type 2 diabetes mellitus (mean age, 56.8 years; range, 38-68 years). Patients were randomized into a supervised group, who had a weekly training session, and an unsupervised group. LDL kinetics were measured with an infusion of 1-(13)C leucine at baseline in all groups and after 6 months of exercise in the patients. Eight body mass index-matched nondiabetic controls (mean age, 50.3 years; range, 40-67 years) were also studied at baseline only. At baseline, LDL MRT was significantly longer in the diabetic patients, whereas LDL production rate and fractional clearance rates were significantly lower than in controls. Percentage of glycated hemoglobin A(1c), body mass index, insulin sensitivity measured by the homeostasis model assessment, and very low-density lipoprotein triglyceride decreased (P < .02) in the supervised group, with no change in the unsupervised group. After 6 months, LDL cholesterol did not change in either the supervised or unsupervised group; but there was a significant change in LDL MRT between groups (P < .05) that correlated positively with very low-density lipoprotein triglyceride (r = 0.51, P < .04) and negatively with maximal oxygen uptake, a measure of fitness (r = -0.51, P = .035), in all patients. The LDL production and clearance rates did not change in either group. This study suggests that a supervised exercise program can reduce deleterious changes in LDL MRT.

Early serum procalcitonin, interleukin-6, and 24-hour lactate clearance: useful indicators of septic infections in severely traumatized patients

BACKGROUND: Elevated lactate and interleukin-6 (IL-6) levels were shown to correlate with mortality and multiple organ dysfunction in severely traumatized patients. The purpose of this study was to test whether an association exists between 24-hour lactate clearance, IL-6 and procalcitonin (PCT) levels, and the development of infectious complications in trauma patients. METHODS: A total of 1757 consecutive trauma patients with an Injury Severity Score (ISS) > 16 admitted over a 10-year period were retrospectively analyzed over a 21-day period. Exclusion criteria included death within 72 h of admission (24.5%), late admission > 12 h after injury (16%), and age < 16 years (0.5%). Data are stated as the median (range). RESULTS: Altogether, 1032 trauma patients (76.2% male) with an average age of 38 years, a median ISS of 29 (16-75), and an Acute Physiology, Age, and Chronic Health Evaluation (APACHE) II score of 14 (0-40) were evaluated. The in-hospital mortality (>3 days) was 10%. Patients with insufficient 24-hour lactate clearance had a high rate of overall mortality and infections. Elevated early serum procalcitonin on days 1 to 5 after trauma was strongly associated with the subsequent development of sepsis (p < 0.01) but not with nonseptic infections. The kinetics of IL-6 were similar to those of PCT but did differentiate between infected and noninfected patients after day 5. CONCLUSIONS: This study demonstrates that elevated early procalcitonin and IL-6 levels and inadequate 24-hour lactate clearance help identify trauma patients who develop septic and nonseptic infectious complications. Definition of specific cutoff values and early monitoring of these parameters may help direct early surgical and antibiotic therapy and reduce infectious mortality.

Host genetic determinants of spontaneous hepatitis C clearance

Acute infection with the hepatitis C virus (HCV) induces a wide range of innate and adaptive immune responses. A total of 20-50% of acutely HCV-infected individuals permanently control the virus, referred to as 'spontaneous hepatitis C clearance', while the infection progresses to chronic hepatitis C in the majority of cases. Numerous studies have examined host genetic determinants of hepatitis C infection outcome and revealed the influence of genetic polymorphisms of human leukocyte antigens, killer immunoglobulin-like receptors, chemokines, interleukins and interferon-stimulated genes on spontaneous hepatitis C clearance. However, most genetic associations were not confirmed in independent cohorts, revealed opposing results in diverse populations or were limited by varying definitions of hepatitis C outcomes or small sample size. Coordinated efforts are needed in the search for key genetic determinants of spontaneous hepatitis C clearance that include well-conducted candidate genetic and genome-wide association studies, direct sequencing and follow-up functional studies.

Modeling and Vibration Suppression for Telescopic Systems of Structural Members with Clearance

Telescopic systems of structural members with clearance are found in many applications, e.g., mobile cranes, rack feeders, fork lifters, stacker cranes (see Figure 1). Operating these machines, undesirable vibrations may reduce the performance and increase safety problems. Therefore, this contribution has the aim to reduce these harmful vibrations. For a better understanding, the dynamic behaviour of these constructions is analysed. The main interest is the overlapping area of each two sections of the above described systems (see markings in Figure 1) which is investigated by measurements and by computations. A test rig is constructed to determine the dynamic behaviour by measuring fundamental vibrations and higher frequent oscillations, damping coefficients, special appearances and more. For an appropriate physical model, the governing boundary value problem is derived by applying Hamilton’s principle and a classical discretisation procedure is used to generate a coupled system of nonlinear ordinary differential equations as the corresponding truncated mathematical model. On the basis of this model, a controller concept for preventing harmful vibrations is developed.