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Musical training-induced functional reorganization of the adult brain: functional magnetic resonance imaging and transcranial magnetic stimulation study on amateur string players.

We used the combined technique of functional magnetic resonance imaging (fMRI) and transcranial magnetic stimulation (TMS) to observe changes that occur in adult brains after the practice of stringed musical instruments. We carried out fMRI on eight volunteers (aged 20-22 years): five novices and three individuals who had discontinued practice for more than 5 years. The motor paradigm contained a repetitive lift-abduction/fall-adduction movement of the left/right little finger, carried out with maximum efforts without pacing. The sensory paradigm was to stimulate the same little finger using a string. In parallel to the fMRI acquisition, TMS motor maps for the little finger were obtained using a frameless stereotactic neuronavigation system. After the baseline study, each participant began to learn a stringed instrument. Newly developed fMRI activations for the left little finger were observed 6 months after practice at multiple brain regions including inferior parietal lobule, premotor area (PMA), left precuneus, right anterior superior temporal gyrus, and posterior middle temporal gyrus. In contrast, new activations were rarely observed for the right little finger. The TMS study revealed new motor representation sites for the left little finger in the PMA or supplementary motor area (SMA). Unexpectedly, TMS motor maps for the right little finger were reduced significantly. Among new fMRI activations for sensory stimuli of the left little finger, the cluster of highest activation was located in the SMA. Collectively, these data provide insight into orchestrated reorganization of the sensorimotor and temporal association cortices contributing to the skillful fingering and musical processing after the practice of playing stringed instruments.

Adult↗

Pancreolauryl test. Evaluation of a tubeless pancreatic function test in comparison with other indirect and direct tests for exocrine pancreatic function.

The sensitivity and specificity of the pancreolauryl test was evaluated in comparison with the NBT-PABA test, the estimation of fecal chymotrypsin and fat, and the secretin-pancreozymin test in 168 patients with and without pancreatic disease. The overall sensitivity rate was as follows: pancreolauryl test 90%, NBT-PABA test 86%, fecal chymotrypsin 66%. In patients with pancreatic steatorrhea the sensitivity of the pancreolauryl test was 100%, the NBT-PABA test 97%, and the fecal chymotrypsin estimation 92%. The specificity of these tests was: pancreolauryl test 97.6%, fecal chymotrypsin 87%, and NBT-PABA test 81.8%. The pancreolauryl test may be recommended as a noninvasive easy-to-perform tubeless pancreatic function test with a sufficiently high sensitivity and specificity.

4-Aminobenzoic Acid↗

[The effect of long-term increased protein administration on mineral metabolism and kidney function in the rat. II. Kidney function and bone mineralization].

In the Federal Republic of Germany the average daily protein intake exceeds the Recommended Dietary Allowances for adults (0.8 g protein/kg body weight) by about 100%. On the other hand calcium intake is below the recommendations for certain age groups. Protein-induced hypercalciuria involves the risk of depletion of skeletal calcium stores, especially for older people who have a decreased absorption capacity for calcium. As a result of our study we postulate, that an altered renal function probably is one inducing factor of hypercalciuria. While urea excretion and serum urea concentration increased with an elevated dietary protein content from 13 to 26 or 40 J%, glomerular filtration rate remained unchanged. Fractional tubular reabsorption of calcium was significantly reduced by about 3% with increased endogenous acid production and renal excretion of hydrogen ions (first part of the study), which were accompanying a higher protein intake of 40 J% compared to 13 J% protein in the control group. Increasing the phosphorus content of the diet improved the reabsorption of calcium and magnesium. The kidneys of rats fed diets high in protein and phosphorus were hypertrophied. Histology of the kidneys showed signs of glomerulonephrosis. While the calcium content of the femora was slightly reduced with a higher protein intake of 40 compared to 13 J%, the magnesium content was increased (after 61 weeks: calcium from 261.4 to 257.1 mg/g dry fat-free wt [p less than or equal to 0.05]; magnesium from 3.2 to 3.5 mg/g dry fat-free wt [p less than or equal to 0.001]). Calcium and magnesium metabolism depends not only on the level of protein intake, but also on its interrelation with the dietary phosphorus content. With continuous high protein intake higher intakes for calcium, phosphorus and magnesium should be recommended, especially for older people.

Animals↗

Prediction of improvement in global left ventricular function in patients with chronic coronary artery disease and impaired left ventricular function: rest thallium-201 SPET versus low-dose dobutamine echocardiography.

Accurate assessment of myocardial viability permits selection of patients who would benefit from myocardial revascularization. Currently, rest-redistribution thallium-201 scintigraphy and low-dose dobutamine echocardiography are among the most used techniques for the identification of viable myocardium. Thirty-one consecutive patients (all men, mean age 60 +/- 8 years) with chronic coronary artery disease and reduced left ventricular ejection fraction (31% +/- 7%) were studied. Rest 201Tl single-photon emission tomography (SPET), low-dose dobutamine echocardiography and radionuclide angiography were performed before revascularization. Radionuclide angiography and echocardiography were repeated after revascularization. An a/dyskinetic segment was considered viable on 201Tl SPET when tracer uptake was >65%, while improvement on low-dose dobutamine echocardiography was considered a marker of viability. Increase in global ejection fraction was considered significant at > or = 5%. In identifying viable segments, rest 201Tl SPET showed higher sensitivity than low-dose dobutamine echocardiography (72% vs 53%, P<0.05), while specificity was not significantly different (86% vs 88%). In 17 patients, global ejection fraction increased > or = 5% (group 1) while in 14 it did not (group 2). A higher number of a/dyskinetic segments were viable on 201Tl SPET in group 1 than in group 2 (2.6 +/- 1.9 vs 0.6 +/- 1.2, P < 0.005), while no significant differences were observed on low-dose dobutamine echocardiography (1.7 +/- 1.6 vs 1.1 +/- 1.6). A significant correlation was found between the number of a/dyskinetic segments viable on 201Tl SPET and post-revascularization changes in ejection fraction (r = 0.52, P < 0.05), but such a correlation was not observed for low-dose dobutamine echocardiography. Using as the cut-off the presence of at least one viable a/dyskinetic segment, rest 201Tl SPET had a higher sensitivity (82% vs 53%, P = 0.07) and showed a trend towards higher accuracy and specificity (77% vs 58%, and 71% vs 64%, respectively) as compared with low-dose dobutamine echocardiography. In conclusion, these findings suggest that when severely reduced global function is present, rest 201Tl SPET evaluation of viability is more accurate than low-dose dobutamine echocardiography for the identification of patients who will benefit most from revascularization.

Adrenergic beta-Agonists↗

Hemostatic function in young subjects with central obesity: relationship with left ventricular function.

This study was designed to evaluate coagulation and fibrinolysis activity and their relationship with left ventricular function in young obese subjects with central fat distribution. We assessed coagulation and fibrinolysis activity by evaluation of factor VII activity, fibrinogen and plasminogen, plasminogen activator inhibitor (PAI), and tissue plasminogen activator antigen basally (tPA1) and after venous occlusion (tPA2). These measures were evaluated in young (< 40 years) obese subjects with central fat distribution (n = 19) and in comparable lean subjects (n = 20). Blood glucose, triglycerides, total and high-density lipoprotein (HDL) cholesterol, apolipoprotein (apo) A1 and apo B, fasting immunoreactive insulin, and lipoprotein(a) levels were also measured by current methods. Left ventricular ejection fraction (LVEF) and peak filling rate (PFR) determined by radionuclide angiocardiography and left ventricular mass (LVM) and LVM indexed for body height (LVM/H) determined by echocardiographic study were calculated. Central obesity was evaluated by the waist to hip ratio (WHR) according to the criteria of the Italian Consensus Conference of Obesity. Factor VII (P < .001), fibrinogen (P < .001), plasminogen (P < .001), PAI activity (P < .001), tPA1 (P < .02), fasting blood glucose (P < .01), apo B (P < .02), and immunoreactive insulin (P < .01) were significantly higher in obese than in lean subjects. In contrast, HDL cholesterol (P < .01), tPA2 (P < .01), LVEF (P < .001), and PFR (P < .02) were significantly lower in obese than in lean subjects. In all subjects, WHR correlated directly with fibrinogen and inversely with tPA2; LVEF correlated inversely with tPA1, PAI, and fibrinogen; and PFR correlated inversely with factor VII activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

Importance of left ventricular systolic function in the assessment of left ventricular diastolic function with Doppler transmitral flow velocity recording.

To study the effect of left ventricular systolic function on the Doppler transmitral flow velocity pattern, Doppler echocardiographic variables were correlated with hemodynamic indexes in 11 control subjects and 58 patients with heart disease. All underwent cardiac catheterization performed with use of a Millar micromanometer. The time constant of left ventricular isovolumetric pressure decrease and left ventricular end-diastolic myocardial stiffness was calculated. The 58 patients were classified into two groups according to ejection fraction: group I (n = 30; ejection fraction greater than 55%) and group II (n = 28; ejection fraction less than 50%). Compared with the control subjects, patients in group I had impairment only of left ventricular relaxation (time constant 47 +/- 9 vs. 38 +/- 3 ms; p less than 0.01), whereas patients in group II had, in addition to impaired left ventricular relaxation (time constant 52 +/- 11 vs. 38 +/- 3 ms; p less than 0.01), increased preload, increased pulmonary capillary pressure (12 +/- 8 vs. 5 +/- 3 mm Hg; p less than 0.01) and increased myocardial stiffness (2,018 +/- 980 vs. 1,050 +/- 218 g/cm2; p less than 0.01). In group I, there was a significant partial correlation coefficient between the time constant and deceleration half-time (r = 0.54). In group II, a strong correlation existed between myocardial stiffness and peak atrial filling velocity (r = -0.71) and between myocardial stiffness and the ratio of peak atrial to peak rapid filling velocity (r = -0.71).(ABSTRACT TRUNCATED AT 250 WORDS)

Blood Flow Velocity↗

Thickening of the infarcted wall by collagen injection improves left ventricular function in rats: a novel approach to preserve cardiac function after myocardial infarction.

OBJECTIVES: We determined whether collagen implantation could thicken the infarcted left ventricular (LV) wall and improve LV function. BACKGROUND: We hypothesized that thickening the infarcted wall by using collagen might result in some benefits that are similar to what previously had been reported when the infarcted wall was thickened with cells. METHODS: Fischer rats with one-week-old myocardial infarcts were injected with collagen or saline (100 microl) into the scar (n = 12 each group). Six weeks later, LV angiograms, hemodynamics, and regional myocardial blood flow were assessed. The hearts were processed for measurements of postmortem LV volume and histology. RESULTS: Collagen injection significantly increased scar thickness (719 +/- 26 microm) compared with the saline-treated group (440 +/- 34 microm, p = 2.6 x 10(-6)). By LV angiography, stroke volume was significantly larger in the collagen-treated group (163 +/- 8 microl) than in the saline-treated group (129 +/- 6 microl, p = 0.005), and LV ejection fraction was also greater in the collagen-treated group (48.4 +/- 1.8%) than in the saline-treated group (40.7 +/- 1.0%, p = 0.002). Analysis of regional wall motion demonstrated paradoxical systolic bulging in 5 of 10 saline-treated rats that averaged 20.3 +/- 2.6% of the LV diastolic circumference, but in none of the 11 collagen-treated rats (p = 0.012). The LV end-diastolic and end-systolic volumes were 319 +/- 12 microl and 190 +/- 7 microl in the saline-treated group, respectively. There was a trend for larger LV end-diastolic volumes (343 +/- 23 microl), but smaller end-systolic volumes (180 +/- 16 microl) in the collagen-treated group. CONCLUSIONS: This study shows that collagen injection thickens an infarct scar and improves LV stroke volume and ejection fraction, and prevents paradoxical systolic bulging after myocardial infarction.

Animals↗

The long-term effect of recombinant methionyl human leptin therapy on hyperandrogenism and menstrual function in female and pituitary function in male and female hypoleptinemic lipodystrophic patients.

Lipodystrophy patients are hypoleptinemic and insulin resistant. Women have enlarged polycystic ovaries, hyperandrogenism, and amenorrhea. We have determined the role of correction of hypoleptinemia on these metabolic and neuroendocrine parameters. Ten females and 4 males with generalized lipodystrophy were treated with recombinant methionyl human leptin (r-metHuLeptin) in physiologic doses in an open-labeled study for a period of 12 and 8 months, respectively. In the female group, serum free testosterone decreased from 39.6 +/- 11 to 18.9 +/- 4.5 ng/dL (P < 0.01) and serum sex hormone binding globulin increased from 14 +/- 2.5 to 25 +/- 4.8 nmol/L (P < 0.02). Luteinizing hormone (LH) responses to LH releasing hormone were more robust after therapy and significantly changed in the youngest group of 3 female patients (P < 0.01). Ovarian ultrasound showed a polycystic ovarian disease pattern in all patients and did not change after therapy. Eight of the 10 patients had amenorrhea prior to therapy and all 8 developed normal menses after therapy. In the male group, serum testosterone tended to increase from 433 +/- 110 to 725 +/- 184 ng/dL (P = 0.1) and sex hormone binding globulin also increased from 18.25 +/- 2.6 to 27 +/- 1.7 nmol/L (P < 0.04) following r-metHuLeptin therapy. Serum LH response to LH releasing hormone did not show significant changes. Five additional hypoleptinemic male subjects with minimal metabolic abnormalities underwent normal pubertal development without receiving r-metHuLeptin therapy. In both genders, insulin-like growth factor increased significantly and there were no differences in growth hormone, thyroid, or adrenal hormone levels following r-metHuLeptin therapy. Glycemic parameters significantly improved after r-metHuLeptin therapy in both groups. Hypoglycemic medications were discontinued in 7 of 12 patients and dramatically reduced in 5 patients. r-metHuLeptin therapy plays an important role in insulin sensitivity. In females, it plays an additional role in normalizing menstrual function. This is likely to occur both from increasing insulin sensitivity and from restoring LH pulsatility. The persistent hypoleptinemic state in these subjects did not inhibit pubertal development.

Adolescent↗

Impact of combined mycophenolate mofetil and low-dose calcineurin inhibitor therapy on renal function, cardiovascular risk factors, and graft function in liver transplant patients: preliminary results of an open prospective study.

As liver transplantation (LT) is now being performed with excellent 1-year graft survival rates of 85% to 90%, attention has been shifted to reducing long-term complications of calcineurin inhibitors (CNI). We randomized LT patients (2:1) who displayed renal dysfunction under CNI treatment to either mycophenolate mofetil (MMF) (1000 mg twice a day) followed by stepwise reduction of CNI (n = 21; Tac trough levels <4 ng/mL, CsA trough levels <50 ng/mL); or continue their current CNI dose (n = 11; control group). Three months after study entry, we observed significantly decreased mean values in the CNI reduction group of serum creatinine (1.88 +/- 0.36 versus 1.58 +/- 0.33 mg/dL, P < .001) and BUN (39.2 +/- 11.8 versus 29.9 +/- 9.59 mg/dL, P < .001) with a significantly increased GFR (51.4 +/- 10.8 versus 61.6 +/- 14.1 mL/min, P < .001). Improved renal function in these long-term LT recipients (5.6 +/- 3.6 years posttransplant; range, 2 to 13 years) suggests at least a partial reversibility of CNI-induced renal damage. Furthermore, we found an improved lipid profile as well as a significantly decreased mean systolic (140 +/- 19 versus 130 +/- 14 mm Hg, P < .01) and diastolic (82 +/- 9 to 74 +/- 8 mm Hg, P < .001) blood pressure 3 months after introduction of MMF therapy. Additionally, transaminases significantly improved in the CNI reduction group within this time period (ALT 37.9 +/- 25.9 versus 25.2 +/- 13.2, P < .05). MMF and CNI-reduced immunosuppressive regimens may improve long-term patient survival, suggesting a broad application within the liver transplant setting.

Aged↗

Acute changes in renal function following extracorporeal shock wave lithotripsy in patients with a solitary functioning kidney.

Twelve consecutive patients with a solitary functioning kidney were treated for renal stone by extracorporeal shock wave lithotripsy (ESWL*) with the modified Dornier HM3 lithotriptor and studied for 3 days after treatment. Urinary excretion of electrolytes, N-acetyl-beta-glucosaminidase (NAG), alkaline phosphatase, kallikrein, glycosaminoglycans, albumin and beta 2-microglobulin, and clearances of creatinine, inulin and para-aminohippuric acid were determined, as were serum levels of creatinine, urea, beta 2-microglobulin and aldosterone, and plasma renin activity. Urinary flow rate, free water clearance, and urinary excretion of NAG, kallikrein and beta 2-microglobulin were significantly increased 0 to 24 hours after ESWL. The urinary excretions of alkaline phosphatase, albumin and glycosaminoglycans were unchanged. Glomerular filtration rate was significantly decreased and effective renal plasma flow was unchanged. Filtration fraction was stable. Serum lactic dehydrogenase increased significantly after ESWL and remained high through the period of observation. Serum levels of creatinine, beta 2-microglobulin and aldosterone were unaltered. A decrease in plasma renin activity immediately after treatment is explained by the water immersion and the extracellular volume expansion during treatment.

Female↗

Selective in vivo growth of lymphocyte function- associated antigen-1-positive murine myeloma cells. Involvement of function-associated antigen-1-mediated homotypic cell-cell adhesion.

OBJECTIVES: Lymphocyte function-associated antigen-1 (LFA-1) expression on multiple myeloma cells and its potential role in myeloma biology have been the subject of conflicting literature reports. In this study we used the 5T experimental mouse model to analyze the involvement of LFA-1 in myeloma cell bone marrow homing, survival, and growth. MATERIALS AND METHODS: The 5T33MM vitro (5T33MMvt) myeloma line was used. LFA-1 and intercellular adhesion molecule-1 (ICAM-1) expression were analyzed by flow cytometry. A small molecule antagonist of LFA-1/ICAM interactions, BIRT 377, was used to block LFA-1 in vitro. Transendothelial migration was assessed by measuring migration through Transwells coated with bone marrow endothelial cells. Immediate in vivo homing was analyzed by tracing 51Cr-labeled cells. Invert microscopic cell counting was used to analyze homotypic cell adhesion. Cell cycle analysis was used to analyze apoptosis. S+G(2)/M phase analysis and 3H-thymidine incorporation were used to assess proliferation. Cells were separated into LFA-1(+) and LFA-1(-) fraction by magnetic activated cell sorting. RESULTS: 5T33MMvt cells had a heterogeneous LFA-1 expression and all cells were positive for the LFA-1 ligand ICAM-1. LFA-1 inhibition with BIRT 377 did not affect transendothelial migration of the 5T33MMvt cells; however, it did result in cell cluster scattering, indicating LFA-1 involvement in homotypic cell-cell adhesion. No effect was observed on apoptosis, but the percentage of cells in S+G(2)/M phase was decreased by 39%. 3H-thymidine incorporation confirmed this effect on 5T33MMvt cell proliferation (38% reduction). When 5T33MMvt cells were injected into animals, all myeloma cells isolated at the end stage of the disease were LFA-1(+) in contrast to the situation before injection. LFA-1(+) and LFA-1(-) MM cells had similar in vivo bone marrow homing capacities. Mice injected with LFA-1(+) 5T33MMvt cells developed myeloma (5/5) within 12 weeks after injection. In contrast, LFA-1(-) recipients did not develop the disease (0/5), even 1 year after tumor inoculation. CONCLUSIONS: Our data suggest that LFA-1-mediated homotypic cell-cell adhesion is involved in myeloma cell proliferation and raises the possibility that this interaction may have a crucial role in in vivo myeloma cell growth. LFA-1 does not appear to play a role in the bone marrow homing of these cells.

Animals↗

Human taste cortical areas studied with functional magnetic resonance imaging: evidence of functional lateralization related to handedness.

Whole-brain functional magnetic resonance imaging was used to detect local hemodynamic changes reflecting cortical activation in five left handed and five right handed human subjects during bilateral stimulation of the tongue with various tastes. Activation was found bilaterally in the insula and the perisylvian region. These regions correspond to the primary taste cortical areas identified with electrophysiological recordings in monkeys and suggested from former clinical observations in human subjects. Moreover, a unilateral projection was described for the first time in the inferior part of the insula of the dominant hemisphere, according to the subject's handedness.

Adult↗

Early changes in left ventricular volume and function are predictors for long-term remodeling in patients with acute transmural myocardial infarction and preserved systolic function.

BACKGROUND: We sought to describe the degree of long-term left ventricular (LV) remodeling after acute transmural myocardial infarction with preserved LV systolic function, and to evaluate whether Doppler echocardiographic parameters in the early phase could predict this process. METHODS: A total of 60 patients without heart failure and with LV ejection fraction > or = 0.40 (mean 0.48 +/- 0.054), were followed up with Doppler echocardiographic examinations at baseline, 3 months, and 1 and 2 years. RESULTS: There was a significant increase in LV end-diastolic volume index of 7% (P =.006) and LV end-systolic volume index of 8% (P =.03), and no change in ejection fraction. This remodeling was confined to 7 patients (12%) with a significant increase in LV end-diastolic volume index above 20 mL/m(2). There was also a significant increase in the deceleration time of both the early mitral filling wave (Delta early mitral filling wave = 58 milliseconds, P <.0005) and the diastolic forward component of pulmonary venous flow (Delta diastolic forward component of pulmonary venous flow = 61 milliseconds, P <.0005), and a shift in filling pattern with increasing prevalence of abnormal relaxation. Changes in end-diastolic volume index were predicted by baseline early mitral filling wave less than 100 milliseconds, but the most powerful predictors of 2-year remodeling were volume changes at 3 months. CONCLUSION: Twelve percent of patients with Q-wave infarction and ejection fraction > or = 0.40 experienced significant LV dilatation at 2 years, and this late remodeling was partly related to baseline filling characteristics.

Echocardiography, Doppler↗

The structure and function of the helical heart and its buttress wrapping. IV. Concepts of dynamic function from the normal macroscopic helical structure.

Torrent-Guasp's model of the helical heart is presented, which includes the cardiac muscular structures that produce 2 simple loops and that start at the pulmonary artery and end in the aorta. These components include a horizontal basal loop that surrounds the right and left ventricles, changes direction through a spiral fold in the ventricular band to cause a ventricular helix produced by now obliquely oriented fibers, forming a descending and ascending segment of the apical loop with an apical vortex. These anatomic concepts are successively activated to produce a sequence of narrowing by the basal loop, shortening by the descending segment, lengthening by the ascending segment, and widening in the cardiac cycle that causes ventricular ejection to empty and suction to fill. The factors responsible for internal torsional movements for cardiac output and suction are defined, together with mechanisms responsible for electromechanical activity produced during sequential changes in contraction and relaxation properties. These interactions of mechanical structure and function are defined in relation to pressure-related cardiac events observed from aortic, left ventricular, and left atrial recordings.

Animals↗

[Monitoring kidney function during neonatal intensive care: comparison between Doppler ultrasound findings and renal function parameters].

33 neonates between 4th and 7th day of life were enrolled in the study. The data of renal Doppler sonography were compared to renal excretion parameters. In infants with respiratory distress a decrease of creatinine clearance as well as an increase of fractional sodium excretion were associated with reduced peak systolic flow velocity in the A. renalis. The results suggest the importance of the Doppler sonography in the monitoring of the renal function in the newborn intensive care.

Blood Flow Velocity↗

Deficiency of lymphocyte function-associated antigen 3 (LFA-3) in paroxysmal nocturnal hemoglobinuria. Functional correlates and evidence for a phosphatidylinositol membrane anchor.

Lymphocyte function-associated antigen 3 (LFA-3) is a widely distributed cell surface glycoprotein that binds to the T lymphocyte CD2 surface glycoprotein. This interaction mediates CTL-target cell conjugate formation and adhesion of thymocytes to thymic epithelial cells. CD2 is also the E rosette receptor of T lymphocytes and mediates rosetting with autologous E by binding to LFA-3. We describe deficient expression of LFA-3 on E from paroxysmal nocturnal hemoglobinuria (PNH) patients. PNH is an acquired defect affecting phosphatidylinositol-anchored membrane proteins, of which decay-accelerating factor (DAF) is most important in the clinical symptoms of PNH. LFA-3-negative, weakly positive, and positive populations were found among PNH E. There was a good correlation with DAF deficiency. PNH E exhibited decreased binding of 125I-CD2 and rosetting with a human T lymphoma cell line. PNH E readily incorporated purified LFA-3, restoring LFA-3 expression and the CD2 binding and rosetting activity to normal levels. The expression of DAF was not restored after the incorporation of purified LFA-3 into PNH E, showing that LFA-3 and DAF are different molecules. Phosphatidylinositol-specific phospholipase C (PIPLC) treatment of a B lymphoma cell line released 35% of the cell surface LFA-3 and 62% of DAF. LFA-3 on E was resistant to PIPLC. However, when LFA-3 purified from human E was reconstituted in sheep E or human E and subjected to PIPLC treatment, 40-50% of LFA-3 was released from the cell membrane. The results show that LFA-3 is attached to the cell membrane by a phosphatidylinositol glycolipid moiety, and confirm previous findings (37-41) that LFA-3 is a cell adhesion molecule that mediates adhesion by interacting with CD2 antigen.

Antibodies, Monoclonal↗

Respiratory-related quality of life: relation to pulmonary function, functional exercise capacity, and sputum biophysical properties.

One of the difficulties in assessing mucoactive therapy is selecting clinical outcome variables that reflect the impact of clearing airway secretions on quality of life (QOL). Petty and colleagues developed a questionnaire designed to evaluate the clinical impact of mucoactive therapy in patients with chronic bronchitis (CB). We evaluated this questionnaire in a multicenter study of a mucolytic medication used in patients with CB and hypothesized that spirometry, exercise capacity, and sputum clearability changes would correlate with QOL changes. This was a multicenter trial in 159 patients with stable CB (111 completed the 16-week study). Spirometry, plethysmography, the 6-minute walk test (6MWT), and Petty score as a measure of QOL were assessed at each visit. Sputum was collected at each visit. Cough transportability was measured in a cough machine, and mucociliary transportability was measured on the frog palate. Cohesivity was measured in a filancemeter, interfacial tension by de Noüy ring, and wettability by contact angle analysis. Within the entire data set of 694 evaluations, there was no correlation between pulmonary function and QOL. There was an inverse correlation with distance covered in a 6MWT (R(2) = 0.041, p < 0.0001). Sputum CTR was directly correlated with QOL (R(2) = 0.027, p < 0.0001). Change from baseline (mean of first three visits) was computed and compared the change in the mean of values at the 8- and 12-week visits (n = 108 sets of data pairs). This was analyzed as a percentage of change for continuous measurements, and as QOL is normative, we calculated the absolute change in QOL. There was no relation between QOL and 6MWT changes. There was an inverse relation between change in forced expiratory volume in 1 second and QOL (R(2) = 0.092, p = 0.0021) as well as between forced vital capacity and QOL (R(2) = 0.05, p = 0.024). There was a direct relation between CTR and QOL (R(2) = 0.039, p = 0.048). The relation between QOL and 6-minute walk distance was expected but weak. The consistent relation between CTR and QOL (suggesting that improved CTR of sputum is associated with decreased QOL) is difficult to explain. A change in forced expiratory volume in 1 second and forced vital capacity did correlate with a change in QOL. There is a need for a good QOL tool to evaluate mucus clearance devices or medications. The Petty questionnaire was designed specifically for this task, but the effect on sputum properties by current mucoactive agents may be too small to elicit a significant change in the Petty score.

Analysis of Variance↗

Effects of I domain deletion on the function of the beta2 integrin lymphocyte function-associated antigen-1.

A subset of integrin alpha subunits contain an I domain, which is important for ligand binding. We have deleted the I domain from the beta2 integrin lymphocyte function-asssociated antigen-1 (LFA-1) and expressed the resulting non-I domain-containing integrin (DeltaI-LFA-1) in an LFA-1-deficient T cell line. DeltaI-LFA-1 showed no recognition of LFA-1 ligands, confirming the essential role of the I domain in ligand binding. Except for I domain monoclonal antibodies (mAbs), DeltaI-LFA-1 was recognized by a panel of anti-LFA-1 mAbs similarly to wild-type LFA-1. However, DeltaI-LFA-1 had enhanced expression of seven mAb epitopes that are associated with beta2 integrin activation, suggesting that it exhibited an "active" conformation. In keeping with this characteristic, DeltaI-LFA-1 induced constitutive activation of alpha4beta1 and alpha5beta1, suggesting intracellular signaling to these integrins. This "cross-talk" was not due to an effect on beta1 integrin affinity. However, the enhanced activity was susceptible to inhibition by cytochalasin D, indicating a role for the cytoskeleton, and also correlated with clustering of beta1 integrins. Thus, removal of the I domain from LFA-1 created an integrin with the hallmarks of a constitutively active receptor mediating signals into the cell. These findings suggest a key role for the I domain in controlling integrin activity.

Antibodies, Monoclonal↗