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Biomedical subjects

C H King

Publications and source records attributed to C H King.

At least 19 recordsLinked to original sources
PubMed1992

Age-targeted chemotherapy for control of urinary schistosomiasis in endemic populations.

Severity of urinary tract morbidity increases with intensity and duration of Schistosoma haematobium infection. We assessed the ability of yearly drug therapy to control infection intensity and reduce S. haematobium-associated disease in children 5-21 years old in an endemic area of Kenya. In year 1, therapy resulted in reduced prevalence (66% to 22%, P < 0.001) and intensity of S. haematobium infection (20 to 2 eggs/10 mL urine), with corresponding reductions in the prevalence of hematuria (52% to 19%, P < 0.001). There was not, however, a significant first-year effect on prevalence of urinary tract abnormalities detected by ultrasound. Repeat therapy in years 2 and 3 resulted in significant regression of hydronephrosis and bladder abnormalities (41% to 6% prevalence, P < 0.01), and further reductions in proteinuria. Repeat age-targeted therapy was associated with decreased prevalence of infection among young children (< 5 yr) entering into the targeted age group. Two years after discontinuation of therapy, intensity of S. haematobium infection and ultrasound abnormalities remained suppressed, but hematuria prevalence began to increase (to 33% in 1989). Reinstitution of annual therapy in 1989 and 1990 reversed this trend. We conclude that annual oral therapy provides an effective strategy for control of morbidity due to S. haematobium on a population basis, both through regression of disease in treated individuals, and prevention of infection in untreated subjects.

Adolescent↗
PubMed1991

Protease priming of neutrophil superoxide production. Effects on membrane lipid order and lateral mobility.

Phagocyte superoxide (O2-) response is primed by a variety of physiologic compounds including the neutrophil secretory proteases cathepsin G and elastase. To study whether protease priming of neutrophil O2- response is related to changes in membrane physical state, we examined enzyme effects on the order and lateral mobility of lipid probes in intact neutrophil membranes. Exposure to cathepsin G (5 micrograms/ml) or elastase (10 micrograms/ml) caused a significant decrease in fluorescence anisotropy of the probe trimethylammonium diphenylhexatriene in neutrophil plasma membranes (0.279 to 0.256 for cathepsin G, 0.274 to 0.256 for elastase, p less than 0.02 for both), indicating a decrease in phospholipid chain order in the surface membrane bilayer. Cathepsin G and elastase also caused significant increases in membrane lipid lateral mobility as measured by excimer formation of the fluorescent probe 1-pyrenedecanoic acid (for cathepsin G, a 107% increase, and for elastase, a 44% increase in excimer/monomer fluorescence ratio, p less than 0.001). Enzyme effects on membrane structure were dependent on intact proteolytic activity, and were cell specific; the proteases had no effect on lipid order or lateral mobility in liposomes. In corollary studies, the possible association between the physical state of the polymorphonuclear leukocyte membrane and O2- generation was analyzed with the membrane modifying compounds, linoleic acid, ethanol, and cholesterol. Cell exposure to linoleic acid (1 microM) caused a significant decrease in lipid order and an increase in lipid lateral mobility along with increased O2- production to N-formyl-Met-Leu-Phe (fMLP) (191%) and phorbol myristate acetate (PMA) (39%), p less than 0.02 for each. 3 mM ethanol also augmented O2- response to fMLP (31%) and PMA (48%) and caused a significant decrease in lipid order, but did not affect lipid lateral mobility. Treatment with cholesteryl hemisuccinate (100 micrograms/ml) resulted in increased lipid order and decreased lipid lateral mobility, as well as decreased neutrophil superoxide response to fMLP (-61%, p less than 0.001) and PMA (-50%, p less than 0.02). We then examined whether modulation of membrane physical state may explain the mechanism of action of a known priming agent by studying the effects of low concentrations of a diacylglycerol. Cells treated with 10 microM 1-oleoyl-2-acetyl-sn-glycerol had a greater than 8-fold increase in superoxide response to fMLP (p less than 0.001) while demonstrating a significant decrease in lipid order (0.289 to 0.281, p less than 0.01) and a 50% increase in lipid lateral mobility (p less than 0.001).(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1991

Structural and functional analysis of the human neutrophil 1-15 antigen, an Mr 65,000 to 70,000 activation-associated membrane proteinase.

Previous studies with the anti-neutrophil/antichymotrypsin mAb 1-15 have identified an activation-associated, chymotrypsin-like activity within the membrane fraction of isolated human neutrophils (PMN). In the present study, the molecular and biochemical characteristics of mAb 1-15 Ag/proteinase were determined. On casein/acrylamide sizing gels, PMN membrane preparations were found to contain an Mr 58,000 to 84,000 band of Ca2(+)-dependent proteinase activity. Reducing and nonreducing SDS-PAGE of mAb 1-15-affinity-purified membrane proteins demonstrated specific recovery of an enzymatically active Mr 65,000 to 70,000 chymotrypsin-like Ag. The presence of a distinct membrane serine esterase of isoelectric point 6.3/Mr 65,000 to 70,000 was confirmed in active site-labeling experiments with the serine proteinase inhibitor [3H]diisopropylfluorophosphate (DFP). Substrate-affinity chromatography with phe-Sepharose or FMLP-Sepharose provided partial purification of enzyme activity among Mr 65,000 to 70,000 FMLP- or phe-binding proteins. Enzyme inhibition was obtained by incubation with mAb 1-15, DFP, N-carbobenzoxyl-phe-chlormethyl ketone, or PMSF, but not tosyl-amide-phenylethylchlormethyl ketone, bestatin, aprotinin, or phosphoramidon. In HPLC analysis, [3H]DFP labeled proteinase was found to comigrate with one of three FMLP-affinity-labeled membrane peaks, but unlike the FMLP surface receptor the DFP-labeling membrane proteinase was not modified by endoglycosidase F. We conclude that the mAb 1-15 Ag, which appears to play a role in PMN activation, is a distinct, active, Mr 65,000 to 70,000 serine proteinase with affinity for substrate sites containing aromatic amino acids.

Antibodies, Monoclonal↗
PubMed1991

Cytokine- and LPS-induced synthesis of interleukin-8 from human mesangial cells.

The cytokine neutrophil-activating peptide-1/interleukin-8 (NAP/IL-8) activates neutrophils (PMN) and elicits selective diapedesis of PMN into the extracellular space. The glomerular mesangial cell (MC) is a specialized pericyte that controls glomerular filtration and synthesizes and responds to a variety of cytokines. Because of its location within the glomerulus, the MC is in a pivotal position to orchestrate events underlying immune injury. Since immune-injured glomeruli have been shown to produce NAP/IL-8 activity in vitro, we assessed whether lipopolysaccharide (LPS)- or cytokine-activated MC might be a source of this activity. Pure human MC, devoid of monocyte/macrophage and fibroblast contamination, were grown by explant from collagenase-treated glomeruli. Human recombinant interleukin-1 alpha (IL-1 alpha, 20 ng/ml), IL-1 beta (50 ng/ml), tumor necrosis factor alpha (TNF, 100 ng/ml) and lipopolysaccharide (LPS, 10 micrograms/ml) stimulated release of a neutrophil chemotactic factor from cultured MC. Both concentrated (fivefold) and unconcentrated MC supernatants stimulated directed neutrophil migration under agarose at a level similar to that of the bacterial chemotactic factor, FMLP. In contrast, unstimulated MC-conditioned media and IL-1 alpha, IL-1 beta. TNF and LPS in medium alone did not directly induce PMN migration. Molecular sizing studies using sequential membrane ultrafiltration identified significant TNF-stimulated, MC-derived chemotactic activity in the 3000 to 10000 kD fraction. An anti-NAP/IL-8 monoclonal antibody, 46E5, significantly inhibited PMN chemotaxis stimulated by TNF-stimulated, MC-conditioned media in a dose-dependent manner.(ABSTRACT TRUNCATED AT 250 WORDS)

Cells, Cultured↗
PubMed1991

Effects of cytochalasin D and methylamine on intracellular growth of Legionella pneumophila in amoebae and human monocyte-like cells.

A cloned and axenically cultured strain of Hartmannella vermiformis was used as a model to study intracellular multiplication of Legionella pneumophila in amoebae. The growth of L. pneumophilia in both H. vermiformis and a human monocyte-like cell line (U937) was investigated with cytoskeletal and metabolic inhibitors. L. pneumophila replicated only intracellularly in these cellular models, and electron microscopy showed ultrastructural similarities in the initial phase of multiplication. Treatment of amoebae with an inhibitor of microfilament-dependent phagocytosis (cytochalasin D, 0.5 or 1.0 micrograms/ml) did not inhibit intracellular growth of L. pneumophila; however, intracellular multiplication was inhibited by treatment of U937 monocytes with the same concentrations of cytochalasin D. Methylamine (10 to 100 mM), an inhibitor of adsorptive pinocytosis, inhibited the replication of L. pneumophila in amoebae in a dose-dependent manner. All doses of methylamine tested (10 to 50 mM) inhibited growth of L. pneumophila in U937 monocytes. Cytochalasin D and methylamine had no effect on the multiplication of L. pneumophila in culture medium or on the viability of amoebae or U937 monocytes. Intracellular replication of L. pneumophila in H. vermiformis may be accomplished by a cytochalasin D-independent mechanism, such as adsorptive pinocytosis. In contrast, both cytochalasin D- and methylamine-sensitive mechanisms may be essential for the intracellular multiplication of L. pneumophila in U937 monocytes.

Analysis of Variance↗
PubMed1991

Ultrastructural localization of a protective 68,000 molecular weight antigen in Schistosoma mansoni.

Vaccination with SMW 68, an Mr 68,000 glycoprotein of Schistosoma mansoni, induces significant protection in mice against challenge schistosome infection. This resistance occurs without the use of adjuvants and without sensitizing animals to granuloma formation. Likewise, passive transfer of monoclonal antibody (MAb) 31-3B6 against SMW 68 confers partial protection against challenge infection. As a first step in understanding how the immune response to this molecule leads to resistance, SMW 68 was localized in three developmental stages of the parasite by immunoelectron microscopy using MAb 31-3B6 and polyclonal antisera raised against purified SMW 68. In cercariae and schistosomula, MAb 31-3B6 bound electron-dense granules within the head gland and similar granules in the preacetabular glands. In adult worms, SMW 68 or related antigens were found to be widely distributed in tissues. Binding of specific antisera was most pronounced in the gut and tegument of male worms, but less so in subtegumental muscles. We conclude that SMW 68 is presented to the immune system in various ways during parasite development. The protective protein or epitope is excreted, and presented on the surface and in the cytoplasm at various stages of the life cycle. The relationship of the location of this protein to its role in protective immunity is discussed.

Animals↗
PubMed1991

Chemotherapy-based control of schistosomiasis haematobia. IV. Impact of repeated annual chemotherapy on prevalence and intensity of Schistosoma haematobium infection in an endemic area of Kenya.

To determine the effect of repeated, annual, age-targeted therapy on prevalence and intensity of Schistosoma haematobium infection in an endemic area, we treated all available, infected, school-age children (n = 2, 493) in the Msambweni area of Coast Province, Kenya with a randomized protocol of oral metrifonate (10 mg/kg for three doses each year) or praziquantel therapy (40 mg/kg as a single dose each year) for a period of one to three years. During 1984-1987, 1, 101 children completed three years of therapy, 550 received two years, and 842 received a single year. Annual followup revealed significant long-term suppression of S. haematobium infection in the targeted school-age population. Both cross-sectional analysis and study of individual outcomes suggested maximal suppression of infection after two years of therapy. Suppression lasted more than two years after cessation of treatment, and was associated with reduced community transmission (gauged by decreased prevalence among new study entrants and decreasing negative-to-positive conversion on annual parasitologic examinations). Comparison of metrifonate and praziquantel outcomes indicated greater suppression of infection and longer infection-free intervals for some subgroups given praziquantel. We conclude that annual population-based therapy targeted to schoolchildren has direct and indirect beneficial effects for endemic communities. In some specific situations, repeat therapy may not suppress transmission, and reduced drug efficacy may be observed after one to three years, suggesting the need for additional non-drug control measures in highly endemic villages.

Adolescent↗
PubMed1990

Castanospermine-glucosides as selective disaccharidase inhibitors.

Castanospermine (CS) is a potent but non-selective inhibitor of many glycohydrolases including the intestinal disaccharidases. Several CS-glucosides were synthesized to investigate the effect of an attached glucopyranosyl residue on the potency and selectivity of CS toward inhibition of intestinal disaccharidases. 8 alpha-glucosyl-CS and 7 alpha-glucosyl-CS were nearly as potent against sucrase activity as CS (IC50 values = 30, 40, and 20 nM respectively) but were 1/50 or less as potent as CS against lactase and trehalase activities. 8 beta-glucosyl-CS was 1/20 to 1/140 as potent as CS and 1 alpha-glucosyl-CS was 1/57 to 1/1500 as potent as CS against disaccharidase activities. 1 alpha-glc-CS was less selective than CS, whereas the other CS-glucosides were more selective. 7 alpha-glc-CS and 8 alpha-glc-CS were the most sucrase selective and were particularly ineffective against trehalase and lactase activities. 8 beta-glc-CS was similar to CS except for relatively weaker trehalase inhibition. In summary, selectivity toward certain disaccharidases was achieved by glucosylation of CS hydroxyls. However, a simple structural comparison of the CS-glucoside to a disaccharide substrate did not reliably predict which disaccharidase would be more inhibited by the CS-glucoside.

1-Deoxynojirimycin↗
PubMed1990

Chemotherapy-based control of schistosomiasis haematobia. II. Metrifonate vs. praziquantel in control of infection-associated morbidity.

To determine the relative efficacy of metrifonate and praziquantel in controlling urinary tract morbidity due to Schistosoma haematobium infection, a random allocation treatment trial was performed among 1,813 school age S. haematobium-infected children from the Msambweni area of Coast Province, Kenya. Following baseline examination for infection, hematuria, proteinuria, and ultrasonographic urinary tract abnormalities, oral treatment with either metrifonate (10 mg/kg, repeated at 4 month intervals) or praziquantel (1 dose of 40 mg/kg) was given to infected subjects. Prevalence of morbidity was reassessed 12 months later for each treatment group. Results indicated equivalent patient improvement in response to either regimen: prevalence of hematuria fell from 75% to 17% after either praziquantel or metrifonate therapy. Similarly, prevalence of proteinuria was significantly reduced from 73% to 29% (metrifonate) or 27% (praziquantel) after therapy. Metrifonate and praziquantel caused similar reductions in bladder granulomata and bladder thickening; however, no reduction in hydronephrosis was noted with either drug. Analysis of outcomes in population subgroups defined by age, sex, pretreatment intensity of infection, or severity of pretreatment morbidity showed no consistent advantage for either drug. In this endemic area, both agents provide effective control of morbidity due to urinary schistosomiasis.

Adolescent↗
PubMed1990

Association of reduced antibody response to "SMW68" (an affinity purified schistosomal antigen) with hepatosplenomegaly in Egyptian schoolchildren infected with Schistosoma mansoni.

Studies of the pathogenesis of schistosomal infections have revealed that the occurrence of disease is so strongly related to host responses to parasite products, that schistosomiasis can be considered as an immunological disease. Further, numerous genetic and environmental factors may modify the host resistance or susceptibility to disease. To test whether hepatosplenic patients manifest different immune capabilities, and the effects of intensity of infection on immune responses; we evaluated anti-SMW68 and anti-crude antigens (SWAP & SEA) antibody levels in 100 children aged 9-15, having light and moderate S. mansoni infection (80-360 eggs/gm of stool). In this group, anti-SMW67 antibody levels (determined by ELISA) were significantly higher in those with lower levels of infection (P less than 0.001). Furthermore, the hepatosplenic patients showed a lower anti-SMW68 antibody levels than those with intestinal schistosomiasis. (P less than 0.05). We conclude that the worm burden and so the resultant morbidity may be influenced by the immune capabilities of the host. Whether enhanced antibody response to SMW68 represents acquired protective humoral immunity remains to be determined.

Adolescent↗
PubMed1989

Intensity of Schistosoma mansoni infection in a human population is inversely correlated with antibody response to SmW68, a protective parasite antigen.

Vaccination with SmW68, a Schistosoma mansoni surface antigen, significantly protects mice against challenge infection. To investigate the vaccine potential of SmW68 in clinical schistosomiasis, human antibody response to SmW68 was studied as a function of intensity of infection in a chronically infected Egyptian population. In 85 serum samples obtained randomly from families in El Gazairy (population 1,310), antibody to SmW68 (determined by ELISA) was found to increase significantly with age, reaching a plateau at 15-19 y, 1-5 y after peak prevalence and intensity of infection. Among infected individuals (n = 54), antibody response showed a significant inverse correlation (r = -.28, P less than .04) with intensity of infection. In isotype analysis, a higher IgM but not IgG response was significantly associated with low parasite burden. These studies demonstrate that significant antibody response to SmW68 could occur in chronically infected humans. Whether parasite burdens suppress circulating levels of antibody to SmW68 or whether enhanced antibody response to SmW68 represents acquired protective humoral immunity remains to be determined.

Adolescent↗
PubMed1989

Induction of resistance to Schistosoma mansoni infection in mice by purified parasite paramyosin.

Freeze-thaw (FT)-disrupted schistosomula or their membrane extract induced significant resistance in mice to Schistosoma mansoni infection (34 and 25%, respectively) without the use of adjuvant. Antigens identified in schistosome extracts by sera from immunized animals were then evaluated for protective potential. Immunization with schistosomal antigens of 97 and 68-70 kD resulted in significant protection that was equivalent to that obtained by FT schistosomula. Since the 97-kD antigen was suggested to be parasite paramyosin, we used a biochemical technique to purify this muscle protein. Purified schistosome paramyosin ran as a single band on 10% SDS-PAGE and was recognized both by sera from mice immunized with FT schistosomula and a polyclonal antiserum raised against the 97-kD parasite protein. Preincubation of schistosome paramyosin with sera from mice immunized with FT schistosomula resulted in the removal of reactivity with the 97-kD protein in crude worm extracts. Paramyosin was identified by Western blotting to be in the tegument of schistosomula. The purified schistosome paramyosin resulted in significant protection in three separate experiments (24, 46, and 53%) without the use of adjuvant. Addition of BCG to paramyosin resulted in enhanced protection.

Animals↗
PubMed1989

Dose-finding study for praziquantel therapy of Schistosoma haematobium in Coast Province, Kenya.

To assess the efficacy of low dose praziquantel regimens in comparison with standard 40 mg/kg dosing in the treatment of urinary schistosomiasis, a random allocation dose-finding trial was performed in children and adults from a Schistosoma haematobium endemic region in Coast Province, Kenya. Following an initial screening, 280 individuals with greater than or equal to 50 eggs/10 ml urine were randomly assigned to receive either 10, 20, 30, or 40 mg/kg of the drug in a single oral dose. Two to three months later, cure rates of 26%, 68%, 78%, and 84% were found for the 10, 20, 30, and 40 mg/kg doses, respectively. The results of 10 mg/kg oral dosing were significantly worse than for all other doses in terms of cure rate and of post-treatment prevalence of morbidity. The 40 mg/kg dosing resulted in a significantly higher cure rate than the 20 mg/kg doses; nevertheless, there was no significant difference between 20 mg/kg and 40 mg/kg doses in terms of mean post-treatment intensity of infection or post-treatment prevalence of hematuria or proteinuria. For large-scale control programs, oral 20 mg/kg praziquantel therapy for urinary schistosomiasis may prove as effective as the standard oral 40 mg/kg dosing for control of infection-associated morbidity and reduction of parasite transmission.

Adolescent↗
PubMed1989

Effects of borehole wells on water utilization in Schistosoma haematobium endemic communities in Coast Province, Kenya.

To determine the impact of the introduction of borehole wells on water use patterns and the consequent risk of transmission of Schistosoma haematobium in 3 endemic villages in Kenya, we performed a survey (a 1:6 sample of affected households) to identify sources of water and types of water utilization before and after well introduction. Water usage was also determined in 2 unaffected neighboring villages not given borehole wells, but having continuous access to piped water from communal taps. Prior to borehole well construction, significantly more high-risk water use occurred in the borehole villages vs. comparison villages in terms of water gathered for cooking, drinking, dish washing, and bathing; residents of both types of villages preferred high-risk sources (marshes and ponds) for clothes washing. Following well introduction, there were significant declines in the use of high-risk water for drinking, cooking, and dish washing, but not for bathing or clothes washing. A higher proportion of individuals from the 3 borehole villages reported some type of continued contact with high-risk water sources. Despite well introduction and a 3 year chemotherapy program among school-aged children, a 21-28% incidence of infection persisted among children in the villages, suggesting minimal impact on transmission. Regular monitoring for S. haematobium infected snail sites showed no decline in the number or proportion of infected snails. Borehole well introduction can significantly alter some forms of water usage, but social and water quality factors may limit the ability of communal wells to reduce S. haematobium transmission.

Adult↗
PubMed1976

Counter-transference and counter-experience in the treatment of violence prone youth.

The constant confrontation inherent in therapeutic intervention with violence prone children, some of whome have committed homicide, is explored. Problems unique to work with these youths are discussed in terms of counter-transference issues for clinicians and counter-experience of teachers and child care workers. Suggestions for training and supervision are offered.

Adolescent↗