A school outbreak of hepatitis A in southwestern Ontario.
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Child↗
Biomedical subjects
S Davies
Publications and source records attributed to S Davies.
Cholera toxin-sensitive and insensitive signaling via surface Ig.
We have observed that a 2-h pretreatment of murine B cells with cholera toxin (CT) renders the B cell incapable of receiving an activation signal via surface Ig as measured by cell volume increase and entry into the S phase of the cell cycle. In contrast, CT pretreatment does not inhibit the delivery of a signal by IL-4, as measured by increase in cell volume. In fact, CT pretreated B cells are able to respond to anti-Ig in the presence of IL-4, as measured by both an increase in cell size and entry into S suggesting that IL-4 overcomes the effects of CT on normal B cell activation. Despite blocking the anti-Ig-mediated entry into the cell cycle, CT was not able to interfere with the induction of nonresponsiveness by anti-Ig in normal B cells or with the delivery of growth-inhibitory signal to the B cell lymphoma WEHI-231. These results suggest that there are two signaling pathways mediated by cross-linking of surface Ig: one pathway sensitive and the other insensitive to modulation by CT.
Animals↗
A controlled family history study of prepubertal major depressive disorder.
First-degree (N = 195) and second-degree (N = 785) adult relatives of prepubertal children with major depression (N = 48), children with nonaffective psychiatric disorders (N = 20), and normal children (N = 27) were assessed by the Family History-Research Diagnostic Criteria method (FH-RDC), except for the adult informant (usually the mother), who was directly interviewed. Compared with normal controls, prepubertal children with major depressive disorder (MDD) had significantly higher familial rates of psychiatric disorders in both first- and second-degree relatives, especially MDD, alcoholism, and "other" (mostly anxiety) diagnoses. Relatives of children in the nonaffective psychiatric control (PC) group had low rates of alcoholism, high rates of other (anxiety) disorder diagnoses, and intermediate rates of MDD (accounted for by those children with separation anxiety). This suggests that prepubertal onset of major depression may be especially likely in families with a high aggregation of affective disorders when these families also have a high prevalence of alcoholism, and that a proportion of children without affective disorder but with separation anxiety disorder in this study were at high risk for the development of affective illness later in life. These results support the validity of prepubertal-onset depressive illness as a diagnostic category, and are consistent with high familial rates of MDD and other psychiatric disorders found in family studies of adolescent and early-onset adult probands with major affective disorders, and with studies of the offspring of parents with major affective disorders. Within the child MDD group substantial heterogeneity was found. Low familial rates of MDD were associated with suicidality and comorbid conduct disorder in the child probands. The highest familial rates of MDD, approximately threefold those in the normal controls, and all the bipolar relatives, were found in the families of prepubertal probands with MDD who never had a concrete suicidal plan or act and who were without comorbid conduct disorder. A useful nosological continuum in which to classify prepubertal MDD may be to place at one end those patients with comorbid conduct disorder and at the other end those patients with manifestations related to bipolarity, including hypomania, mania, and psychotic subtype.
Adult↗
Modulation of ceroid accumulation in macrophages in vitro.
Mouse resident peritoneal macrophages (MPM) cultured with artificial lipoprotein consisting of cholesteryl linoleate complexed with bovine serum albumin (CL/BSA) rapidly accumulate ceroid in the form of rings. Experiments with various phenolic radical scavenger antioxidants and derivatives showed that the radical scavengers which are strongly lipophilic, and possess a free (i.e. non-esterified) phenolic hydroxyl group are inhibitors of ceroid ring formation. Time-course experiments with MPM and CL/BSA in which either or both of the components of the artificial lipoprotein have been oxidised before feeding showed that such oxidation accelerated ceroid accumulation, and suggested that oxidation of the lipoprotein is rate-determining in ceroid accumulation. Copper appeared to be a good catalyst for this. Agents able to activate the respiratory burst production of reactive oxygen species appeared to have no accelerating effect on ceroid accumulation from CL/BSA by MPM in a time-course. A novel method has been attempted for quantitating ceroid in MPM by means of its autofluorescence, using a Fluorescence-activated Cell Sorter (FACS). The results from FACS agree qualitatively with those from alcohol-xylene treatment followed by oil-red-o staining (AX/ORO). MPM cultured with CL/BSA for up to 4 days showed a 2.7-4.6-fold increase in mean fluorescence (at wavelengths greater than 490 nm) over MPM cultured with cholesteryl oleate/BSA (CO/BSA), with CL/BSA/butylated hydroxytoluene (CL/BSA/BHT), with CL/BSA/probucol, and with no artificial lipoprotein. The implications of the findings with respect to human atherosclerosis are discussed.
Animals↗
Gentamicin alters membrane structure as shown by freeze-fracture of liposomes.
Freeze-fracture has been used to examine the effects of gentamicin on membrane structure in liposomes of different anionic phospholipids combined with a neutral phospholipid, phosphatidylcholine. The molar ratios of neutral: anionic lipid were 1:1 (high anionic lipid ratio) and 4:1 (low anionic lipid) and the liposomes were incubated with 0.1 mM (low) and 1 mM (high) gentamicin. With the anionic phospholipid phosphatidylinositol bisphosphate, an identifiable disruption of the membrane bilayer was observed as well as aggregation of liposomes leading to membrane fusion. These effects occurred both at low gentamicin concentration and low anionic lipid content of the liposomes; these responses were not inhibited by 1 mM Ca2+. With the other anionic lipids tested (phosphatidylserine, phosphatidylinositol and phosphatidylinositol monophosphate), only aggregation and fusion of liposomes was observed and this effect only occurred at high gentamicin concentration and high anionic lipid content. Further, 1 mM Ca2+ inhibited the responses of these other anionic lipids to gentamicin. The results demonstrate the unique character of the interaction between gentamicin and phosphatidylinositol bisphosphate and provide further support for the hypothesis that a specific binding to this lipid is a key step in the ototoxic action of aminoglycoside antibiotics. They also suggest that such an interaction in vivo might cause alterations to the structure and properties of cell membranes in the inner ear.
Calcium↗
The effect of gentamicin-induced hair cell loss on the tight junctions of the reticular lamina.
Freeze fracture has been used to examine junctional complexes within the gentamicin damaged guinea pig organ of Corti during the period of structural reorganisation associated with hair cell loss. When examined up to 28 days after a regime of chronic gentamicin administration, no significant alterations to the pattern or nature of the complex tight junctions associated with the hair cell apex could be detected. In contrast, marked abnormalities of the junctions between adjacent supporting cells, and evidence of formation of new gap junctions on the lateral membranes of Deiter's cell was seen. The use of lanthanum as an electron dense tracer in thin sections also showed that no breakdown of permeability barriers occurred in the reticular lamina. These results support the concept of a controlled response by the organ of Corti, with conservation of the tight junction of the hair cell and maintenance of permeability barriers. Early changes to the membranes of the stereocilia and lateral cisternae of the outer hair cells were also identified. These may indicate direct effects of gentamicin upon membrane structure.
Animals↗
An improved method for the treatment of data from DNA strand break measurements using filter elution techniques with an internal standard.
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Animals↗
Cell killing and DNA damage in Chinese hamster V79 cells treated with hydrogen peroxide.
Hydrogen peroxide induces lesions in cells similar to those from ionizing radiation, by a Fenton-type production of hydroxyl radicals. At 4 degrees C significant levels of DAN single-strand breaks (ssb) could be measured using the alkaline elution technique, after a 20-min incubation with 10(-5) mol dm-3 H2O2. Only at higher concentrations of H2O2 (greater than 10(-4) mol dm-3) where the levels of ssb measured corresponded to that induced by more than 18 Gy of X-rays, was any significant cell killing detected in a clonogenic assay. Cell killing was observed to coincide with the measurement of significant levels of DNA double-strand breaks (dsb) using the filter elution technique at pH 9.6. This suggests that dsb and not ssb are important as regards hydroxyl-radical-induced cell kill, as found for ionizing radiation. The correlation of induced dsb with lethal events showed that the predicted lethal effect of the H2O2-induced dsb was approximately 5 times less than that of X-ray-induced dsb. This is compared with data previously obtained which showed differences in the lethality of dsb with the quality of radiation (Prise et al. 1987).
Animals↗
The irradiation of V79 mammalian cells by protons with energies below 2 MeV. Part I: Experimental arrangement and measurements of cell survival.
The relative biological effectiveness (RBE) has been determined for protons with mean energies of 1.9, 1.15 and 0.76 MeV, from measurements of the survival of V79 Chinese hamster cells. The cells are supported as a monolayer and are swept through a beam of scattered protons produced using a 4 MeV Van de Graaff accelerator. An estimation of the dose and unrestricted linear energy transfer (LET) variation within the sensitive volume of the cells is given for the three proton energies. The RBEs for cell survival (relative to 250 kVp X-rays) at the 10 per cent survival level are 1.6, 1.9 and 3.36 for protons with track-average LETs of 17, 24 and 32 keV microns-1 respectively, and the data suggest that protons are most effective at about 40-50 keV microns-1. It is shown that the proton RBEs can be reconciled with those of other light ions if plotted against z*2/beta 2 (where z* is the effective charge and beta is the relative velocity) rather than against LET.
Animals↗
Non-linear dose-effect curve for DNA double-strand breaks by low LET radiation: the effect of eluting buffer composition on the measurement of breaks by the filter elution technique.
Chinese hamster V79 cells were irradiated with 250 kVp X-rays and analysed for the presence of DNA double-strand breaks using filter elution. Changing the pH of the elution and lysis buffers from pH 9.6 to 7.2 leads to a decreased rate of elution of the DNA from the filters and a small difference in the dose-effect relationship obtained. In both cases the dose-effect curves were non-linear. When cells are irradiated with 238Pu alpha-particles a difference in the rate of elution of the DNA is also observed between the two pH values, although the dose-effect curves are linear. These findings suggest that there may be qualitative differences in the types of lesions being induced by low-LET radiation and being scored as dsb in the filter elution assay at pH 9.6. However, carrying out elution at pH 7.2 does not eliminate the nonlinear response measured after X-irradiation.
Alpha Particles↗
Survey of blood lead and plasma aluminium concentrations in patients of a renal unit.
Blood lead and plasma aluminium concentrations have been measured in patients with end-stage chronic renal failure treated by haemodialysis (HD) or by continuous ambulatory peritoneal dialysis (CAPD) and in a control group of non-dialysed patients with chronic renal failure (CRF). Data on a group of subjects with normal renal function is included for comparison. We have found significantly increased mean blood lead and plasma aluminium concentrations in all patients with chronic renal failure compared to a group with normal renal function. All blood lead concentrations were within the accepted safe exposure range of less than 1.8 mumol/l (380 micrograms/l]. There were significant differences among the patient groups: home HD, 0.60 +/- 0.25 mumol/l (124 +/- 52 micrograms/l); hospital HD, 0.39 +/- 0.31 mumol/l (81 +/- 64 micrograms/l); CAPD, 0.32 +/- 0.17 mumol/l (66 +/- 35 micrograms/l); CRF, 0.38 +/- 0.20 mumol/l (79 +/- 41 micrograms/l); normal, 0.24 +/- 0.11 mumol/l (50 +/- 23 micrograms/l). Correction of the blood lead results for haemoglobin accentuates these differences (i.e. hospital HD, 4.61 +/- 3.25 nmol/g (0.96 +/- 0.67 micrograms/g); CRF, 3.05 +/- 1.46 nmol/g (0.63 +/- 0.30 micrograms/g); normal, 1.65 +/- 0.70 nmol/g (0.34 +/- 0.14 micrograms/g). Plasma aluminium concentrations show a similar pattern: home HD, 1.09 +/- 0.70 mumol/l (29.4 +/- 18.9 micrograms/l); hospital HD, 0.81 +/- 0.58 mumol/l (21.9 +/- 15.7 micrograms/l); CAPD, 0.34 +/- 0.34 mumol/l (9.2 +/- 9.2 micrograms/l); CRF, 0.18 +/- 0.09 mumol/l (4.9 +/- 2.4 micrograms/l); normal, 0.09 +/- 0.07 mumol/l (2.4 +/- 1.9 micrograms/l).(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Regional lung microvascular permeability using dual isotope scintigraphy.
We have extended the dual isotope probe technique of Basran et al. for the measurement of pulmonary microvascular permeability (PMVP) to include gamma camera data acquisition and functional imaging of the plasma protein accumulation index (PPA) throughout the lung fields. The study group consisted of 11 patients with possible increased PMVP following the drainage of a pleural effusion or the evacuation of air from a pneumothorax, and 11 control patients. The PPA was calculated (1) for probe data, (2) on a pixel by pixel basis for the camera data, the results being stored in a functional image and (3) for four pixel x four pixel regions of interest positioned over the lung fields using the functional image and raw data as a guide. Functional images of the control group showed uniformly low PPAs throughout the lung fields. Nine of the eleven patients in the effusion/pneumothorax group showed discrete areas of increased PPA on the functional images. In the effusion/pneumothorax group, the re-expanded lung four pixel x four pixel ROI PPA values were significantly higher than the nonexpanded lung ROI values (p less than 0.001). The re-expanded lung ROI values were also significantly higher than the mean of the left and right lung ROIs in the control group (p less than 0.01). Five of the eleven patients in the effusion/pneumothorax group had probe PPAs that differed significantly from zero. We believe that probe positioning problems in the absence of sufficient clinical guidelines were largely responsible for there being no overall significant difference in the probe PPAs between the two study groups.
Adult↗
Phase and amplitude analysis of exercise digital left ventriculograms in patients with coronary disease.
Phase and amplitude analysis was applied to intravenous digital left ventriculograms to avoid the artefacts associated with image subtraction. Eight controls and 40 patients with known coronary artery disease underwent digital left ventriculography before and after a symptom limited supine bicycle exercise test. The resultant images were subjected to phase and amplitude analyses. In the control group there was no deterioration in left ventricular wall motion after exercise. In 30 of the 40 patients there was a deterioration in wall motion on exercise. This group contained all eight patients with three vessel disease and 12 of the 17 patients with two vessel disease. Ten patients showed no change in wall motion--five with one vessel disease and five with two vessel disease. Phase and amplitude analysis of digital left ventriculograms is a method of detecting exercise induced myocardial ischaemia that may help in the assessment of patients with coronary artery disease.
Coronary Disease↗
An 80-year-old man with acute abdominal pain. Small bowel obstruction due to midgut volvulus.
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Abdomen↗
Cell surface phenotype of mononuclear cells infiltrating bile ducts during acute and chronic liver allograft rejection.
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Acute Disease↗
Fluoxetine treatment of obsessive-compulsive disorder: an open clinical trial.
The selective serotonin reuptake blocker fluoxetine was administered to 49 patients with obsessive-compulsive disorder in a 12-week open clinical trial. A minimum adequate trial of at least 8 weeks of treatment was completed by 39 patients. Response rates were 62% (24/39) of adequately treated patients and 49% (24/49) of the whole sample. These uncontrolled findings suggest that fluoxetine is of significant benefit for a substantial proportion of obsessive-compulsive disorder patients. However, controlled trials comparing fluoxetine with placebo and other active agents are needed to confirm this, as are studies aimed to delineate fluoxetine's full dose range, optimal length of treatment and relapse rate following discontinuation.
Adult↗
Measurement of DNA damage and cell killing in Chinese hamster V79 cells irradiated with aluminum characteristic ultrasoft X rays.
Chinese hamster V79 cells were irradiated with 1.487 keV aluminum characteristic X rays produced using a cold-cathode discharge tube. Under aerobic conditions a relative biological effectiveness (RBE) of 2.18 for cell killing in comparison to 250-kVp X rays was measured using cells grown in suspension and irradiated on membrane filters. DNA damage in the form of single-strand (ssb) and double-strand breaks (dsb) was measured using the filter elution technique. The aerobic RBEs are 1.64 for dsb induction and 0.49 for ssb induction, consistent with the view that dsb are more closely related to cell kill than ssb. A reduced oxygen enhancement ratio (OER) for cell killing was measured for Al-K X rays, but the OER for dsb induction was similar to that measured for 250-kVp X rays. A curvilinear relationship between dsb induction and dose is observed, similar to that seen for 250-kVp X rays. This agrees with the concept that ultrasoft X rays produce critical lesions similar to hard X rays but with a greater efficiency per unit dose.
Animals↗
Comparison of the toxicity of orally administered L-triiodothyronine (T3) in rat and cynomolgus monkey.
Oral administration of L-triiodothyronine (L-T3) (0.015-1 mg/kg) for 30 days to mature rats or cynomolgus monkeys resulted in both species in a high mortality at 1 mg/kg (after 2 weeks of treatment) and a progressive loss in body weight. Dose-related elevations in plasma marker enzymes occurred, mainly after 1-2 weeks of treatment. The approximate no-effect dose for these changes was around 0.015-0.020 mg/kg for both rat and primate. The large elevations of leucine aminopeptidase (LAP) at 1 mg/kg L-T3 in monkey indicated hepatocellular toxicity although in the rat such large increases in alanine aminotransferase (ALT) and glutamate dehydrogenase (GLDH) were not seen. L-T3 also showed little toxicity to rat hepatocytes in vitro. High concentrations of L-T3 (7 x 10(-9) to 7 x 10(-7) M) had minimal effects on parameters of cell viability such as lactate dehydrogenase (LDH) leakage, chromium-51 release and [3H]leucine incorporation. Urinary enzymes in the rat showed a similar profile to those in plasma. Large rises in alkaline phosphatase (AKP) and N-acetyl glucosaminidase (NAG) at 1 mg/kg indicated possible proximal tubular damage although this was not supported histologically. Clinically, in both species L-T3 appeared more toxic to males than females but this was not supported histologically. The histological lesions observed were different in the 2 species. In the monkeys there was extensive lipid vacuolation of hepatocytes and changes in thyroid and adrenal cortex. In the rat there was fine, non-lipid vacuolation of hepatocytes and thyroid changes. In the rat, 2 previously unreported lesions were also noted. There were multinucleated cells in the renal distal tubular epithelium, and focal fibroplasia of serosal surfaces of abdominal viscera.
Acetylglucosaminidase↗