Biomedical subjects
Publications and source records attributed to M King.
Intrauterine retention of fetal bone is a rare complication of abortion that can cause secondary infertility by an unknown mechanism. We report such a case in which menstrual fluid prostanoids were measured to elucidate the possible pathophysiology. The pattern of prostanoid increases was similar to that seen in intrauterine device users.
A series of CCRF-CEM sublines selected for extreme resistance to methotrexate has been shown previously to exhibit cross resistance to a number of agents belonging to the multidrug resistance phenotype (J.Natl.Cancer Inst.1989; 81, 1250-1254). The role of the mdr1 gene and its product (P-glycoprotein) in this atypical pattern of multidrug resistance has now been investigated. Southern and Northern analyses failed to demonstrate any amplification, rearrangement or over-expression of the mdr1 gene in the drug-resistant cells. Similarly, monoclonal antibodies MRK16 and JSB1 revealed no increase in the amount of P-glycoprotein present. By contrast, monoclonal antibody C219 detected a 170 kDa protein in all sublines, and in highest concentration in the most resistant cells. The results raise the possibility that a novel, C219-reactive protein may mediate resistance to both methotrexate and members of the multidrug resistance family.
Monocyte and macrophage Fc gamma receptors are important components in the recognition of IgG-coated cells and IgG-containing immune complexes. Two proteins have been identified on human peripheral blood monocytes that can function as Fc gamma receptors, Fc gamma RI (70 Kd) and Fc gamma RII (40 Kd). We studied the role of Fc gamma RI and Fc gamma RII on human monocytes by examining their binding of IgG-sensitized cells (human IgG anti-D-coated RBCs and rabbit IgG-sensitized sheep RBCs) and their binding of human trimeric IgG. To examine the function of monocyte Fc gamma RII, we used an anti-Fc gamma RII monoclonal antibody (MoAb) that competes for the Fc gamma RII ligand binding site. Preincubation of monocytes with saturating concentrations of anti-Fc gamma RII MoAb did not alter the recognition of IgG (anti-D)-sensitized human RBCs by monocytes. Furthermore, ligand-binding studies demonstrated that anti-Fc gamma RII antibody altered neither the number nor the affinity of monocyte-binding sites for human IgG trimer. Anti-Fc gamma RII inhibited monocyte binding of rabbit IgG-sensitized sheep RBCs, but only at low ionic strength or temperature when increased numbers of monocyte Fc gamma RII were expressed. At low ionic strength and 4 degrees C, anti-Fc gamma RII also partially inhibited monocyte binding of human trimeric IgG. Thus, monocyte Fc gamma RII does not appear to recognize IgG-sensitized RBCs or trimeric IgG at physiologic temperatures and ionic strength. The data suggest that Fc gamma RI is the primary Fc gamma receptor on monocytes involved in the binding of IgG (anti-D)-sensitized erythrocytes and low mol wt complexes of IgG.
The effect of varying particle size on the site of deposition of inhaled particles in the human lung was measured in 11 young healthy male subjects. The simultaneous inhalation of two chemically inert, radiolabelled particles, differing in size but in no other respect, controlled for all other variables including airways geometry, breathing pattern and posture. Under conditions of quiet respiration the larger particles (3.5 microns) were preferentially deposited in the upper rather than the lower zones of the lungs as compared with the smaller particles (1.1 microns). Furthermore, the penetrance of the larger particles beyond the mucociliary escalator was greater for 3.5 microns particles in all lung zones and particularly at the apex. These findings may be of significance in the pathogenesis of those diseases induced by the inhalation of particles, vapours or fumes.
Locus of control scales have been used to measure 'effectiveness' or personal control in patients with eating disorders. A locus of control of behaviour scale was used in a community sample of women with a spectrum of eating pathology from bulimia nervosa to chronic dieting as well as in a comparison group of non-dieters. This scale appeared to add nothing over and above general measures of psychopathology as assessed by the Clinical Interview Schedule and the Symptom Rating Test, or more specific measures such as the Eating Attitudes Test.
Twenty-two men, who had been forcibly sexually assaulted, participated in a study to determine the circumstances of the attacks and the effects on the victims. The immediate and long-term responses were very similar to those described in female victims of rape.
2,4-Diaminoquinazoline analogs of folate were assessed as antileishmanial agents and as dihydrofolate reductase inhibitors. Against Leishmania major in human macrophages in vitro, two compounds with tertiary amines attached directly to the quinazoline ring were remarkably active. The 50% effective doses were in the picogram per milliliter range (12 to 91 pg/ml), and the in vitro therapeutic indices were approximately 10(5). These compounds were 1,000 times more active on an absolute basis and had a 100 times more favorable therapeutic index than any compound previously tested in this model. Antileishmanial activity was not correlated with activity against Leishmania mexicana promastigote reductase, which suggests that folate utilization in general, rather than reductase activity specifically, was being inhibited.
A controlled analysis of the attitudes of doctors and homosexual men to male homosexuality is reported. Not surprisingly the homosexual men held the most liberal attitudes which served as a yard-stick against which the doctors' attitudes could be assessed. The implications of these data, collected before the AIDS era, are discussed in terms of the current needs of homosexual patients.
The manufacture of a polyester vascular prosthesis in the southern hemisphere is a new development in the global dissemination of this maturing technology. Hence the recent introduction of the Barone Microvelour arterial graft from Argentina has highlighted the need for a comparative in vitro and in vivo study to compare its structure and performance with that of existing commercial products. Following a series of laboratory tests and implantations as a thoracoabdominal bypass in dogs, the Barone Microvelour has been identified as a strong graft constructed after the style of early weft-knitted designs. It provides an equivalent sequence and rate of healing to that of other polyester knitted grafts.
Chronic cigarette smoke exposure is well known to cause mucus hypersecretion in experimental animals, but the alterations in mucus rheology have not been described. We studied mucus hypersecretion and viscoelasticity changes in nine tracheostomized beagle dogs exposed to cigarette smoke. The dogs were trained to stand quietly in a harness, and smoke was delivered via a cuffed tracheostomy tube. A 35-cm3 bolus was introduced to the inspiratory line each 20 s, using unfiltered 70-mm cigarettes (20 mg tar, 1.2 mg nicotine). Each dog smoked 10 cigarettes per day over 2.5 h, 5 days per week. Two dogs were exposed for 6 months; 7 dogs were exposed for 10 months. Five dogs served as sham-smoking controls. Mucus was collected twice weekly without drugs by resting a cytology brush on the lower trachea for 2-5 min. The rheological properties of the mucus samples were determined by magnetic rheometry, which yields elasticity and viscosity as a function of frequency. The mucus was also weighed, and the galactose content was determined by phenolsulfuric acid assay. The mucus collection rate served as an index of tracheal mucus flux, and the galactose assay as a marker of mucous glycoprotein content. The tracheal mucus linear velocity (TMV) was determined periodically under xylazine analgesia by observing charcoal particle transport bronchoscopically. Eight of 9 smoking dogs developed mucus hypersecretion (flux greater than 2 X control) versus 1 of 5 controls (p less than .01). TMV did not change significantly in 10 months of exposure. In the first 2-4 months of smoking, the elasticity and viscosity of the mucus both decreased (mean at 4 months = 42% control, p less than .001), as did the galactose content (mean at 4 months = 48% control, p less than .01). At this stage, according to model studies, the mucus should have been more easily clearable by ciliary action. After 6 months, the viscoelasticity returned toward the initial control level, while the galactose content remained low, suggesting an alteration in the nature of the mucous glycoprotein.
We investigated the role of the viscoelastic and adhesive properties of mucus gel simulants on the clearance of mucus by simulated cough. Mucus-like gels with widely varying viscoelastic properties were prepared from polysaccharides crosslinked with sodium borate. Cough was simulated by opening a solenoid valve connecting a model trachea to a pressurized tank. The clearance of gels lining the model trachea was quantified by observing marker particle transport. Viscosity elastic modulus, relaxation time and yield stress were measured with a steady-shear viscoelastometer. Spinnability (thread formation) was determined with a filancemeter. Adhesivity (surface tension) was measured by the platinum ring technique. The viscoelastic and adhesive properties of the mucus gel simulants spanned the ranges observed for bronchial secretions from patients with COPD. The relationship between simulated cough clearance and the viscoelastic and adhesive properties of the gels was analyzed by stepwise linear regression of the non-zero data matrix. The major independent variable relating to clearance was viscosity. Secondary, but highly significant dependences, were also found for spinnability and adhesivity. Elastic modulus, relaxation time and yield stress had no independent effect on cough clearance over the investigated range. The results indicate that, in the absence of airway surface liquid, cough-type clearance relates primarily with mucus gel viscosity. For a given viscosity, clearance is also impaired by spinnability, i.e. the capacity of the mucus to form threads. At constant viscosity and spinnability, clearance is further impaired by an increase in the adhesivity of the mucus. The negative dependence of each of these physical factors can be rationalized in terms of their inhibitory effect on wave formation in the mucus lining layer during high velocity airflow interaction.
Using a simulated cough machine, we analyzed the effect of adding tensio-active liquids as sol phase simulant on the clearance of gel mucus simulant by cough. Polysaccharides crosslinked with sodium tetraborate were used at different concentration as gel mucus simulant. A drop of gel mucus simulant was deposited either directly on the model trachea or on a sol phase layer simulant (2% sodium dodecyl sulfate in water). The clearance of the mucus simulants was quantified by observing the movement of marker particles in the gel layer. The viscoelastic properties of gel mucus simulants were determined by using a viscoelastometer (SEFAM). The adhesive properties were analyzed by means of the platinum ring technique. The wettability of the mucus simulants was quantified by the automatic measurement of the contact angle of the drop of gel on the model trachea. We found that the addition of a sol phase significantly decreased by about 50% the adhesivity and wettability of the gel mucus simulants. This decrease was associated with a marked enhancement of cough clearance, whatever the viscoelastic properties of the gel mucus simulants. These results suggest that the sol phase is essential in bronchial respiratory mucus clearance by the cough mechanism.
The transport of mucus gel simulant (MGS) in a constricted simulated cough machine, using blood plasma as a serous layer simulant (SLS), was investigated. MGS was prepared from locust bean gum solutions crosslinked with varying amounts of added borate to produce gels of varying spinnability (filance). The model trachea was a plexiglass channel of rectangular cross-section with the plane bottom surface. The upper surface included a sinusoidal protrusion which provided a flow convergence with minimum gaps of 6, 4 and 2 mm. Experiments for mucus transport were conducted for these minimum gaps, as well as for the non-convergent case (12 mm gap). Miniaturization of sample quantity was achieved by keeping the MGS layer depth constant (0.5 or 1 mm) but reducing the zone of loading from 13.4 cm to 1 cm, thus reducing the sample requirement to as little as 0.2 ml. MGS transport was determined as the minimum displacement of a line of marker dye placed in the MGS layer at the point of minimum constriction gap. It was shown that in all cases (dry as well as with SLS), MGS transport increased as the minimum constriction gap between the plane and the convergent top surface decreased. This increase was further enhanced if an SLS of lesser viscosity was used. It was also found that the transport of MGS increased as the depth of MGS layer increased or as the filance decreased in both non-constricted and constricted cases. The relationship between MGS transport and filance was maintained even in the presence of an SLS layer.
Promastigotes of Leishmania mexicana amazonensis WR 669 clone 4 were made resistant to antimony in the form of Pentostam (sodium stibogluconate) by exposure to media containing increasing concentrations of Sb. The dose of Sb expected to kill 50% of promastigotes and amastigotes of the parent sensitive clone (WR 669) and the resistant clone (WR 669R) was determined by exposure of suspensions in physiologic salt solution for 3 hr. The approximate Ed50s in microgram Sb/ml were: 10,000 for WR 669R promastigotes; 7,000 for WR 669R amastigotes; 200 for WR 669 promastigotes; and 150 for WR 669 amastigotes. Thus, Sb resistance and Sb sensitivity expressed by promastigote clones are also expressed by their respective amastigotes. Studies with 125Sb-Pentostam showed that WR 669R amastigote resistance was not due to altered Sb uptake over 1 hr. When amastigotes pretreated with Pentostam were incubated with 14C labeled metabolic precursors, susceptibility to Sb was correlated with inhibition of glycolytic enzymes and of fatty acid beta-oxidation.
RFLP haplotypes at the phenylalanine hydroxylase (PAH) locus were determined in 45 nuclear Caucasian families from Switzerland and Scotland. The RFLPs at the PAH locus are highly informative, and prenatal diagnosis is possible in 85% of the families studied. The data were combined with the profiles previously observed in the Danish population, in order to study the variation in RFLP haplotype distribution among European populations. A total of 22 different haplotypes were observed in Denmark, Switzerland, and Scotland. Fifteen and 19 haplotypes are associated with the normal (non-PKU) and with the mutant chromosomes, respectively. The haplotype distribution and the allele frequency of normal chromosomes remain constant between Denmark, Switzerland, and Scotland. However, both the haplotype distribution and allele frequencies of mutant chromosomes show significant variation between the three countries. Our results suggest there may be additional mutations in the PAH gene that cause PKU.
Tracheobronchial mucociliary function in dogs that underwent left upper sleeve lobectomy was compared with that of dogs that underwent left lung autotransplantation or allotransplantation (n = 5 each). Proximal airway clearance was measured by observing the movement of carbon particles through a bronchoscope. Preoperative and postoperative clearance rates for the right lungs in these dogs were unchanged. Although preoperative clearance rates in the transplanted left lungs were comparable with those of the right lungs, these left lungs were unable to clear the carbon particles during a 15-minute observation period 3 weeks postoperatively. In contrast, preoperative and postoperative clearance rates for the dogs that underwent sleeve resection were unchanged for both lungs. Mucus rigidity was studied by microrheometry and was found to be significantly increased postoperatively for samples collected from the autotransplanted and allotransplanted lungs than for samples collected from the untreated right lungs. These changes in mucus were noted for forces representing both normal ciliary beat and coughing. Viscoelastic properties of mucus were not significantly altered after sleeve lobectomy. Microscopic study showed squamous cell metaplasia and relative disappearance of bronchial glands distal to the anastomosis in all transplanted lungs. These changes were less pronounced in the sleeve resected bronchi. We conclude that changes in rheologic characteristics of mucus can impair mucociliary clearance and may be related to denervation after lung transplantation. Bronchial devascularization may have an additional effect of altering mucosal structures and function in the early postoperative period after lung transplantation. These effects are avoided by preserving peribronchial tissue in sleeve resection.
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