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D J Williams
Publications and source records attributed to D J Williams.
Mechanisms for the elimination of potentially lytic complement-fixing variable surface glycoprotein antibody-complexes in Trypanosoma brucei.
Live antibody-coated Trypanosoma brucei parasites remove variable surface glycoprotein (VSG)-antibody complexes from their surface upon warming to 37 degrees C and evade antibody-activated complement lysis by both protein synthesis-dependent and protein synthesis-independent mechanisms. The protein synthesis-dependent process follows antibody-mediated trypanosome agglutination, whereas the protein synthesis-independent mechanism can occur in the absence of trypanosome agglutination. The latter process leads to a more rapid elimination of complement-fixing VSG-antibody complexes.
In vitro activation and detection of antibody-secreting cells from Trypanosoma congolense-infected cattle.
B cells from the peripheral blood and spleen of Trypanosoma congolense-infected cattle and from the peripheral blood of an uninfected cohort were analysed for ability to secrete antibody and for expression of surface antigens before and after in vitro culture with interleukin-2, lipopolysaccharide and pokeweed mitogen. Antibody-secreting cells (ASC) were only detected in lymphocytes from peripheral blood after in vitro stimulation. The frequency of ASC was greater in cultures of lymphocytes from infected cattle than from the uninfected cohort. The frequency of ASC was positively correlated with the number of B cells expressing the transferring receptor but not with the expression of the CD5 antigen.
Acute hypernatraemia during bicarbonate-buffered haemodialysis.
Five patients on maintenance haemodialysis were exposed to varying degrees of hypernatric dialysate, leading to acute hypernatraemia (plasma sodium concentrations 158 mmol/l to 179 mmol/l). With the exception of one patient, who developed pulmonary oedema, symptoms were minimal and in each case hypernatraemia was corrected without residual complications. The hypernatric dialysate resulted from a granular and less soluble batch of sodium bicarbonate powder. The extra effort required to dissolve the powder caused CO2 to be shaken out of solution, producing sodium carbonate and raising the pH. Mixing calcium from the 'acid' concentrate with excess carbonate in the 'bicarbonate' concentrate led to rapid precipitation of calcium carbonate on the conductivity monitoring cells. Dialysate conductivity was incorrectly sensed as low by the coated conductivity cells, so that an increasing amount of 'acid' concentrate, with its accompanying electrolytes, was delivered to the patient. When the granular powder was ground to a fine powder, passed through a 125 microns sieve and gently dissolved, the machine operated normally. We recommend that sodium bicarbonate powder is supplied with a sieve size no greater than 125 microns, kept dry to prevent the formation of large crystals, and dissolved gently.
A search for candidate viruses in type 1 diabetic pancreas using the polymerase chain reaction.
In order to investigate a possible viral aetiology for Type 1 diabetes the polymerase chain reaction (PCR) technique was used. Pancreatic tissue from Type 1 diabetic subjects was examined for the presence of a panel of common viruses. Primers specific for mumps, measles, cytomegalovirus, and Epstein Barr virus, as well as primers located in a highly conserved region of the enterovirus genome which are capable of detecting all of the following family members: Coxsackie B, echovirus, polio, mengovirus, and encephalomyocarditis virus were used to screen 18 Type 1 diabetic subjects of whom 3 had proven insulitis, 12 Type 2 diabetic subjects and 18 non-diabetic controls. Epstein Barr virus was detected in two Type 1 (13%), two Type 2 (22%), and three of the normal nondiabetic pancreases (20%), and the DNA sequences confirmed by direct sequencing. Cytomegalovirus was detected in one of the normal pancreases only and no evidence of any of the other viruses was found. It is concluded that the Type 1 diabetic pancreatic samples studied did not show persistence of infection with any of the above viruses. Non-persistent acute infection of the pancreas by the above viruses cannot be excluded in the aetiology of Type 1 diabetes from this study.
Occipital contrecoup in a case of Hallervorden-Spatz disease.
This case report describes the unusual complications of a simple fall in a person with a profound neurological disorder, Hallervorden-Spatz disease. The fall produced a laceration of the forehead, skull fractures and severe occipital contrecoup contusions. Such contrecoup contusions are rare and may be a feature of this case because of the abnormal limb rigidity displayed in Hallervorden-Spatz disease. The mechanisms of injury are discussed.
In vitro and in vivo inhibition of rat vascular smooth muscle cell migration and proliferation by a 2-aminochromone U-86983.
Vascular smooth muscle cell migration and proliferation are the primary events that govern neointimal thickening and thus they determine the extent to which delayed restenosis occurs after percutaneous transluminal coronary angioplasty. In this study, the in vitro and in vivo smooth muscle cell antichemotactic and antiproliferative properties of a 2-aminochromone, 2-(4-morpholinyl)-8-(3-pyridinylmethoxy)-4H-1-benzopyran-4-one (U-86983), were examined. Migration and proliferation of early-passage rat vascular smooth muscle cells were inhibited by U-86983 in a concentration-dependent manner (IC50S, approximately 10 microM and 3.5 microM, respectively). Longer-term studies showed that the proliferation of smooth muscle cells was inhibited by U-86983 for at least 7 days and was fully reversible on removal of the drug. In addition, the effect of U-86983 on neointimal formation was examined in rats subjected to left common carotid artery balloon dilatation injury. Continual (2-week) i.v. administration of U-86983 (216 mg kg-1 day-1) resulted in a mean plasma drug concentration of 2.39 micrograms/ml (blood level, approximately 3.5 microM) and a 42% (P = .003) reduction in the neointima/media ratio of the injured artery. In agreement with the in vitro reversibility results, administration of U-86983 for only 2, 4 or 7 days did not affect significantly the neointimal thickness measured at 14 days, which indicated that the stimuli for smooth muscle cell migration and/or proliferation were still present 1 week after injury.(ABSTRACT TRUNCATED AT 250 WORDS)
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Secretion of co-stimulatory cytokines by monocytes and macrophages during infection with Trypanosoma (Nannomonas) congolense in susceptible and tolerant cattle.
Bovine macrophages and monocytes were cultured in vitro and analyzed for their capacity to secrete co-stimulatory cytokines. To this end, the culture medium was titrated on suboptimally stimulated murine thymocytes. A low residual release by normal monocytes was noted which usually remained below the detection limit of the assay. These cells could be induced to secrete high titres following activation with bacterial lipopolysaccharide. When harvested from animals infected with Trypanosoma congolense, the cells released high titres spontaneously. This increase in co-stimulatory cytokine secretion was noted in both peripheral blood monocytes and splenic macrophages and was amplified by addition of indomethacin. The activation was transient, and the titres had dropped to pre-infection values at the end of the experiment. At that time, the monocytes were, however, still able to respond to external stimuli. Addition of neutralizing anti-transforming growth factor beta antibodies did not influence the thymocyte co-stimulatory activity of the supernatants. High levels of co-stimulatory cytokine secretion were noted with monocytes from both the susceptible Boran breed and the tolerant N'Dama breed. Early in infection, at Day 10 post infection, the production by the N'Dama monocytes was 16 times higher than the production by the Boran monocytes. Later in the infection, the titres were similar in both breeds.
Pathophysiology of transient cranial diabetes insipidus during pregnancy.
OBJECTIVE: We investigated the possible mechanisms underlying transient cranial diabetes insipidus during pregnancy. DESIGN AND PATIENTS: A woman who developed clinical diabetes insipidus during the third trimester of pregnancy was studied through a total of three pregnancies and postpartum. MEASUREMENTS: Plasma AVP, urine and plasma osmolality, urine volume and specific gravity were measured during water deprivation tests and hypertonic saline infusion. Plasma and urine osmolality were measured after subcutaneous injection of AVP. The water deprivation and AVP test were repeated after proven inhibition of urinary PGE2 with aspirin. Serum vasopressinase activity was measured during one of the pregnancies affected with diabetes insipidus and compared with that obtained between 26 and 38 weeks from 13 normal pregnancies. RESULTS: The patient was found to have cranial diabetes insipidus which responded to low dose intranasal 1-desamino-8-D-arginine vasopressin. Inhibition of PGE2 with aspirin did not enhance urine concentrating ability or the response to a test dose of subcutaneous AVP. Plasma levels of vasopressinase remained within the physiological range for normal pregnancy. CONCLUSIONS: These studies indicate that subclinical cranial diabetes insipidus may be unmasked in late pregnancy. This effect is not related to AVP resistance resulting from PGE2 production or excessive vasopressinase activity, but may be due to a combination of physiological vasopressinase secretion with reduced AVP secretory capacity and reduction in the thirst threshold that accompanies normal pregnancy. We relate these findings to a previously described group of women with transient diabetes insipidus during pregnancy who had impaired liver function.
Antibody responses to invariant antigens of Trypanosoma congolense in cattle of differing susceptibility to trypanosomiasis.
Five trypanotolerant N'Dama (Bos taurus) and five susceptible Boran (Bos indicus) cattle were challenged by tsetse flies infected with Trypanosoma congolense IL 13-E3. These animals had experienced five previous infections with T. congolense, each terminated by drug therapy. Immunoblotting and ELISA were used to determine isotype and specificity of antibody responses to trypanosome invariant antigens. Both IgM and IgG1 were elicited, but the IgG1 responses were directed against a greater diversity of antigens. A 69 kD antigen was the major invariant antigen which elicited IgM antibodies in both breeds, but the N'Damas also responded with high levels of specific IgG1. Analysis of isotypic responses to whole trypanosome extract also revealed lower levels of IgG1 and higher levels of IgM in the Borans than in the N'Damas, suggesting that a dysfunction in the switch from IgM to IgG might occur in infected Boran cattle. A 33 kD antigen appeared to elicit only IgG1. Sera from all five N'Damas and the two Borans which were most resistant to the disease reacted with this antigen prior to and following re-infection. Furthermore, during the primary T. congolense infection in the same animals, anti-33 kD antibodies were detectable in all five trypanotolerant N'Damas, but in none of the five susceptible Borans. Thus, the presence of antibodies to the 33 kD antigen of T. congolense appeared to be associated with a capacity to control the disease.
Antibody responses to a 33 kDa cysteine protease of Trypanosoma congolense: relationship to 'trypanotolerance' in cattle.
A cysteine protease of Trypanosoma congolense (congopain) elicited IgG1 antibodies in those cattle which exhibited a degree of resistance to disease during experimental infections (Authié et al. 1992, 1993). The aim of the present study was to investigate further the association between anti-congopain antibodies and resistance to trypanosomiasis, and to provide a lead into the mechanisms responsible for the differential responses to congopain in cattle. Isotype characteristics and kinetics of the antibody response to congopain were studied in three N'Dama (trypanoresistant) and three Boran (susceptible) cattle during primary infection with T. congolense ILNat 3.1. In both groups an IgM response to congopain was elicited, thus demonstrating that congopain is antigenic in both types of cattle. Most of the IgM appeared to be incorporated into immune complexes. IgG was detected as free antibody; IgG1 but not IgG2 was detected. All three N'Dama, but none of the three Boran cattle, mounted a significant IgG response to congopain. Sera from 70 primary-infected cattle belonging to five breeds of differing susceptibility were tested for their reactivity to congopain. High levels of IgG to congopain were observed in the two trypanotolerant breeds, whereas the three susceptible breeds had lower levels of these antibodies. Crosses between N'Dama and Boran cattle, which exhibit an intermediate susceptibility, had intermediate levels of antibodies. Thus, the results from experimental infections confirmed our initial observations. However, under natural tsetse challenge, repeated infections and trypanocidal treatments in Zebu cattle stimulated as high anti-congopain antibody levels as in non-treated trypanotolerant taurine cattle.
Directional movement of variable surface glycoprotein-antibody complexes in Trypanosoma brucei.
Binding of antibody, antibody fragments (Fab and F(ab)2) and biotin molecules to variable surface glycoprotein (VSG) of Trypanosoma brucei was studied by both light microscopy and fluorescence activated cell sorter (FACS) analysis. Antibodies, antibody fragments and biotin molecules were distributed over the entire parasite surface after incubation at 0 degree C. Upon warming to 37 degrees C, surface bound Fab and F(ab)2 fragments showed different rates of clearance from the parasite surface. Clearance, which in both cases followed double exponential decay kinetics, resulted from a directional movement of VSG-bound antibody complexes from both the surface of the flagellum and the cell body towards the cellular site of active endocytosis, the flagellar pocket (FP), even in the absence of antibody-mediated crosslinking of VSG. Immunofluorescence on trypanosomes permeabilized after binding, clearance and internalization, indicated the location of small amounts of antibody intracellularly, between the nucleus and the flagellar pocket. However, if a cocktail of protease inhibitors was added to the medium, larger amounts of internalized antibody could be detected within vacuoles situated between the nucleus and the flagellar pocket. Movement of antibody-VSG complexes was reversibly inhibited at temperatures below 37 degrees C and by increasing the NaCl concentration in the medium to 200 mM.
Accuracy of a first-order model for estimating initial heparin dosage.
The accuracy of a first-order pharmacokinetic model for determining initial heparin infusion rates was studied, and factors that could affect the accuracy of the method were investigated. Patients who received an i.v. infusion of heparin for at least 24 hours for treatment of deep-vein thrombosis, pulmonary embolism (PE), or myocardial infarction were identified by retrospective chart review. A therapeutic dosage of heparin was defined by an activated partial thromboplastin time of 45-75 seconds. Heparin dosages were calculated by using estimated blood volume as the heparin volume of distribution, a desired steady-state heparin concentration of 0.30 units/mL, and an elimination rate constant of 0.832 hr-1. The difference between the calculated dosage and the actual therapeutic dosage was calculated. The differences for various patient subgroups were compared, and the estimated dosages were regressed against the actual dosages to determine their predictive value. Data for 49 patients were analyzed. The mean +/- S.E. difference between the actual and calculated dosages was 29.2 +/- 37.1 units/hr. No significant differences were evident according to sex or indication for therapy. Smokers and nonsmokers differed, as did obese and lean patients. The equation appeared to be more accurate in nonsmokers than smokers. The addition of 200 units/hr to the calculated dosage for patients with PE resulted in minor improvement in the predictive capacity of the equation. Moderate agreement was observed between the actual and calculated heparin dosages in non-smokers of various body weights.
Renal scintigraphy in acute scleroderma: report of three cases.
Scintigraphic findings in acute renal failure secondary to scleroderma are reported. In three patients, we have demonstrated severe reduction of renal perfusion with little or no parenchymal uptake of tracer and absent excretion. These findings are compatible with the known histological process of occlusive vasculopathy, and such scintigraphic findings at presentation may reflect a poor prognosis for renal recovery.
The misrepresentation of the human pelvis.
A representative series of illustrations of the human bony pelvis dating from the sixteenth century to the present is used to demonstrate the persistent misrepresentation in the orientation of the pelvis and in the nomenclature. Early erroneous concepts were probably strongly reinforced by publications of the Belgian anatomist Vesalius in the sixteenth century. In mounting the vertebrae on a vertical iron rod, he erased much of the sacral curvature and, as a consequence, the orientation of the rest of the pelvis was distorted. True versions of the pelvis were executed by Leonardo da Vinci before the time of Vesalius but these drawings were apparently among those that were lost for many years. A relatively small number of similarly accurate depictions of the bony pelvis have appeared down through the centuries and some of these are also included. A persistent error in many anatomical textbooks used today presents a modified inferior view of the pelvis as the "front view" and a nearly accurate front view as a "view from above." No definitive conclusion can be reached concerning the reason(s) for the remarkably long persistence of this error. The figures referenced are presented in the Gallery immediately following this article.