A comparison between monodisperse Tc-99m-labeled aerosol particles and Kr-81m for the assessment of lung function.

A quantitative method for study of the penetration and clearance of inhaled particles (5-micron Tc-99m-labeled polystyrene) in the human lung is described and compared with a Kr-81m technique for ventilation imaging. Volunteer healthy subjects and patients with chronic obstructive airway disease (COAD) were studied. Following inhalation of radioaerosol, data were recorded by a gamma-camera/computer system over a period of 6 hr. An aerosol penetration index (API) measures the proportion of aerosol reaching the peripheral region of the lung relative to that deposited in the larger central airways. A significant difference in the mean values of API for both groups was observed. Aerosol clearance rates from the whole lung and from central, intermediate and peripheral compartments of each lung field were studied. The healthy group showed a total clearance rate consistent with data from earlier work; the patients with COAD showed no clearance over the same period. Some healthy subjects were smokers, and differences in their penetration and clearance rates were evident, in spite of normal results from their conventional pulmonary function tests and Kr-81m ventilation studies. The aerosol technique, if carefully controlled, can be a more sensitive index for early lung abnormality than Kr-81m ventilation imaging.

Networking mass spectrometer data systems for improved productivity and electronic archiving of data.

Several Finngan-MAT mass spectrometer data systems were networked together to achieve the following two primary objectives: (1) to allow access to mass spectrometry data and data processing functions from remote locations without affecting simultaneous data acquisition at the instruments, and (2) to electronically archive mass spectrometry data at a central location on a high-capacity, fast-access device that allows rapid retrieval of archived data for all data processing operations at all locations. UNIX workstations, IBM PC/AT-compatible computers, and Data General Nova minicomputers were connected via Ethernet interfaces to allow rapid data transfer among all systems as well as X-Windows access to UNIX-based systems. Bridging techniques were used to isolate possible high-traffic areas of the network and to enable security measures for adequate protection of files. Additionally, serial connections were made through a Northern Telecom phone system to provide remote terminal access to the Data General Nova-based systems. Use of these connectivity techniques significantly improved productivity by allowing retrieval, processing, and printing of data from remote locations, such as office areas, without affecting data acquisition, processing, and printing performed simultaneously at the instruments. For archival purposes, data files are electronically stored on high-capacity magneto-optical disks for rapid retrieval. A highcapacity fixed disk is also available for centralized temporary data file storage. A Digital Equipment Corporation DECstation 2100 UNIX workstation was used as the file server for centralized data storage while being simultaneously utilized as the data system computer for one of the mass spectrometers. Utilization of this UNIX-based file server system in conjunction with Ethernet connectivity techniques provides a centralized, rapid-access, high-capacity, cost- and space-efficient method for electronic archival of mass spectrometry raw data recorded at all of the instruments.

Markers close to the dopamine D5 receptor gene (DRD5) show significant association with schizophrenia but not bipolar disorder.

Following the description of linkage of markers at chromosome 4p16 to bipolar disorder in several families [Blackwood et al., 1996], and the association of the alleles of a polymorphism closely linked to D5 dopamine receptor gene with schizophrenia [Williams et al., 1997], we have looked for linkage disequilibrium between a series of microsatellite markers from this region and major psychoses including schizophrenia, bipolar disorder, and unipolar major depressive disorder. A significant increase in the frequency of the 148 bp allele of DRD5 (P = 0.024) and the 244 bp allele of D4S615 (P = 0.001) was found in patients with schizophrenia (n = 158 DRD5; n = 133 D4S615), compared with patients with bipolar disorder (n = 270 DRD5; n = 107 D4S615), or controls without psychiatric illness (n = 437 DRD5; n = 309 D4S615). The frequency of the 148 bp allele of DRD5 was also increased in schizophrenia over unipolar major depressive disorder (n = 65). D4S615 was not typed in unipolar disorder. The estimated odds ratios confirmed that the 148 bp allele of DRD5 and the 244 bp allele of D4S615 conferred increased risk of schizophrenia. Estimated Haplotype (EH) analysis of 174 controls and 128 patients with schizophrenia who were typed for both markers confirmed the strong associations with these alleles but did not show evidence that the markers were in linkage disequilibrium with each other even though they lie approximately 150 kb apart. The data are consistent with an association between markers close to the D5 dopamine receptor and schizophrenia, but not bipolar disorder or unipolar major depression.

A preliminary study of the effect of a vibrating pad on bronchial clearance.

The effect of vibration (41.0 +/- 5.4 Hz; 2 mm amplitude) on the clearance of lung secretions was ascertained in 10 patients with chronic bronchitis who complained of difficulty in raising sputum. Vibration was applied to the back for one hour by an electrically driven pad while the patients reclined on a couch with the trunk at 45 degrees to the vertical. Each patient had randomized control and experimental runs of 5 hours' duration that were identical in all respects except for vibration. The rate of clearance of secretions from the lung was assessed by serial whole lung counts after inhaling monodispersed tracer particles tagged with a gamma-emitting radioisotope (technetium-99m) and by sputum production. The mean rates of clearance and of sputum production were slightly higher during the vibration runs than the control runs but the differences were not significant.

Enhanced clearance of secretions from the human lung after the administration of hypertonic saline aerosol.

The radioaerosol method was used to measure the effect of saline aerosol on the rate of clearance of secretions from the lung. Two trial runs were done in each of 7 patients with chronic obstructive lung disease (mean +/- SD ratio of 1-sec forced expiratory volume for forced vital capacity, 50 +/- 15 per cent), a control run and a saline run. In both runs, 5.0 +/- 0.7-micron polystyrene particles tagged with 99mTc were inhaled under controlled conditions by the patients, and their subsequent clearance was monitored for 6 hours by whole lung counters. Scanning was also done with a gamma rectilinear scanner. The saline run was identical to the control run except that 30 min after inhaling the radioaerosol the patient inhaled an aerosol of hypertonic (1.21 M) saline for 11 min from an ultrasonic nebulizer. Although the initial distribution of the radioaerosol along the airways was the same in both runs, whole lung clearance during the first 50 min was twice as fast after the inhalation oft he hypertonic saline aerosol as in the control (P less than 0.01). The mean weight of sputum produced was higher (P less than 0.05) in the saline run. The number of coughs in the 2 runs was the same.

Oestrone sulphate, adipose tissue, and breast cancer.

Oestrone sulphate, the oestrogen in highest concentration in the plasma, may play a role in the induction and growth of breast cancers. By enzymolysis and radioimmunoassay, oestrone sulphate concentrations were measured in 3 biological fluids. High concentrations of the conjugate (up to 775 nmol/l) were detected in breast cyst fluids from some premenopausal women, the concentrations in blood plasma (0.91-4.45 nmol/l) being much lower. Concentrations in the plasmas from postmenopausal women with (0.23-4.63 nmol/l) or without (0.18-1.27 nmol/l) breast cancer were still lower. Oestrone sulphate concentration in cow's milk or cream (0.49-0.67 nmol/l) was also low: dietary intake in these fluids is probably of little consequence. The capacity of breast tissues for hydrolysis of oestrone sulphate was examined in two ways: In tissue slices incubated with 85 pM (3H) oestrone sulphate solution at 37 degrees C, cancers (131-412 fmol/g tissue/hr) and adipose tissues (23-132 fmol/g tissue/hr) hydrolysed significantly more sulphate than did benign tissues (1-36 fmol/g tissue/hr). In tissue homogenates incubated with 5-25 microM [3H] oestrone sulphate at 37 degrees much higher capacities for hydrolysis (nmol/g tissue/hr) were demonstrated with a Km of 2-16.5 microM: cancers (34-394) and benign tissues (9-485) had significantly higher sulphatase activities than adipose tissues (9-39). On a protein basis, however, the sulphatase activities in the 3 tissues were comparable. It is concluded that oestrone sulphate is present in breast cysts and blood plasma and that in vitro, the conjugated hormone can be hydrolysed by breast tissues. The biological significance of these findings in vivo remains to be established.

The effect of sodium 2-mercapto-ethane sulphonate and hypertonic saline aerosols on bronchial clearance in chronic bronchitis.

1 The efficacy of a mucolytic agent, 2-mercapto-ethane sulphonate, administered in the form of an aerosol was evaluated in a group of eleven patients with chronic bronchitis in a controlled, double-blind, crossover study. 2 Saline aerosol isotonic (1.21M, 7.1%) to the drug was used as a placebo. 3 Approximately 1 ml drug/placebo was inhaled by the patients twice a day for 3 days and a final dose was given on the mornings of the drug/placebo trial runs. 4 There was no improvement in this group of patients in lung function or subjective well being attributable to the drug. 5 The viscosity of sputum, dry macromolecular weight and N-acetyl neuraminic acid/fucose ratio remained unaltered throughout the study. 6 An enhancement of tracheobronchial clearance was obtained following the administration of either placebo (31%) or drug aerosols (24%) Statistical significance (P less than 0.01) was only achieved for the placebo and was attributed to an increase in sputum volume.

Effect of lung function and mode of inhalation on penetration of aerosol into the human lung.

The method using radioactive tracer particles has been applied to study the effect of the mode of inhalation of aerosols on the depth of deposition in the lungs of 50 patients with airways obstruction. The findings show that the penetration of particles is directly related to: (1) volume inspired per breath (VI); (2) forced expiratory volume in one second (FEV1); and inversely related to (3) flow rate during inhalation (V). In mathematical terms, alveolar deposition (%) = 40-3 (VI)+10-98 (FEV1)--0-75 (V)+40-4; for this regression F = 4-41 and P less than 0-01.

No demonstrable effect of S-carboxymethylcysteine on clearance of secretions from the human lung.

The mucolytic efficacy of S-carboxymethylcysteine has been assessed in a double-blind crossover trial in 16 patients with chronic obstructive bronchitis. No significant difference was found between drug and placebo after four or seven days' treatment in the rate of clearance of secretions from the lung. This was measured by external counting of previously inhaled polystyrene tracer particles tagged with technetium-99m (99mTc). Lateral scans across the right chest after inhaling the aerosol showed equal penetration of particles towards the periphery of the lung in drug and placebo runs; this indicated that the airways had not been cleared of mucus by the drug. There was no significant difference between drug and placebo runs in the number of coughs or the weight and radioactive content of sputum voided or raised at the end of the run by chest percussion and postural drainage. Ventilatory capacity was not significantly changed nor was there any subjective improvement in the patients as a result of taking the drug.

Identifying genes within microdissected genomic DNA: isolation of brain expressed genes from a translocation region associated with inherited mental illness.

An improved protocol has been developed for physical enrichment of cDNA sequences by hybridization to genomic DNA. When applied to microdissection recombinants derived from a translocation breakpoint region associated with inherited mental illness, a single cycle of the procedure permitted enriched cDNAs to be visualized directly by agarose gel electrophoresis. Hybridization screening of a library of clones derived from the enriched cDNAs, employing the genomic resource as a probe, led to the identification of six novel gene fragments. This general approach to the isolation of regionally encoded genes could be applied to any subchromosomal interval as a first step towards global transcription map construction.