Biomedical subjects
Publications and source records attributed to L K Pickering.
Rotaviruses have proven to be major causes of pediatric diarrheal disease morbidity and mortality worldwide. The past several years have yielded substantial new insights into these viruses, their epidemiology, and the mechanisms of host resistance to them. These insights have in turn resulted in development of several candidate rotavirus vaccine strains, bringing closer the possibility of effective protection of young children from rotavirus disease.
The relation between in vitro production of HeLa cell cytotoxin by strains of Shigella and clinical symptomatology was determined for 35 travelers from the United States who developed shigellosis in Guadalajara, Mexico. There were 25 patients with Shigella sonnei, eight with Shigella flexneri, one with Shigella boydii, and one with Shigella dysenteriae. These strains were evaluated for in vitro production of cytotoxin. The amount of cytotoxin did not correlate with the number of stools passed, the severity of abdominal pain, or the presence of nausea or vomiting. However, patients with strains of Shigella that produced more cytotoxic activity were more likely to have fever (P less than .02) and occult blood in their stools (P less than .004). The cytotoxicity produced by 30 (86%) strains could not be neutralized with rabbit antiserum to purified, formaldehyde-treated Shiga toxin from S. dysenteriae type 1 strain 60 R; the cytotoxicity of five (14%) of the strains was partially neutralized. When only nonneutralizable cytotoxin was considered, the presence of fecal leukocytes (P less than .04), as well as of occult blood (P less than .002) and fever (P less than .02), correlated with the amount of cytotoxin. The amount of nonneutralizable cytotoxin produced by shigella strains was related to the clinical findings. This cytotoxic activity was infrequently attributable to "Shiga toxin".
We measured the cytotoxic activity of 119 strains of Shigella by using a quantitative [3H]thymidine-labeled HeLa cell assay. We assayed 13 strains of Shigella dysenteriae 1; 18 strains of S. dysenteriae types 2 and 3; and 88 strains of Shigella sonnei, Shigella flexneri, and Shigella boydii. Strains of S. dysenteriae 1 demonstrated high levels of cytotoxicity (geometric mean, 10(5.04) CD50/mg of protein; range, 10(3.95)-10(6.10). Cytotoxic activities of the non-type 1 strains of S. dysenteriae and of the other Shigella serogroups were approximately 1/1,000 that of the S. dysenteriae 1 strains (range, 10(1.09)-10(3.11) CD50/mg of protein). Neutralization of cytotoxicity by using rabbit antiserum to purified Shiga toxin revealed that in all strains of S. dysenteriae 1, greater than or equal to 99.5% of cytotoxic activity was attributable to Shiga toxin. In contrast, 88 of the other Shigella strains produced only nonneutralizable cytotoxic activity. Six of 18 strains of non-type 1 S. dysenteriae and 12 of 88 strains from other Shigella serogroups produced both Shiga toxin and nonneutralizable toxin.
Limited pharmacokinetic data for cefoperazone are available from the parturient. Because cefoperazone has a dual excretory pattern, primarily via the biliary system and secondarily via the kidney, pregnancy-induced physiologic alterations can influence its deposition and clearance. Twelve term parturients receiving cefoperazone prophylaxis after cesarean section were selected for study. After 2 g of cefoperazone was administered for 1 h intravenously, serial blood samples were assayed by high-pressure liquid chromatography. Plasma protein binding of cefoperazone was studied in vitro. The mean peak cefoperazone concentration +/- standard deviation was 169.9 +/- 60.4 micrograms/ml. The mean half-life was 152 min. Total serum clearance was 80.8 +/- 30.8 ml/min. The steady-state volume of distribution was 14.2 +/- 6.0 liters. All subjects had detectable trough levels at the end of the dosage interval, with a mean value of 6.5 +/- 5.2 micrograms/ml. Protein binding of cefoperazone for parturients was 74.3 +/- 10.9%, compared with 87.7 +/- 3.2% in nonpregnant controls (P less than 0.05). These data suggest that cefoperazone deposition can be greatly influenced by pregnancy. However, unlike several other new antimicrobial agents whose excretions are mainly renal, the cefoperazone half-life and thus trough concentration for the parturient more closely resemble that for the nonpregnant subject.
Accurate diagnosis of rotavirus is important in both clinical and research situations. A total of 100 stool specimens from children with diarrhea were tested for rotavirus by electron microscopy. These specimens were then coded and tested for rotavirus by four procedures: a monoclonal antibody-based enzyme immunoassay (EIA) (Pathfinder; Kallestad Laboratories, Inc., Austin, Tex.), two polyclonal antibody-based EIAs (Rotazyme II; Abbott Laboratories, North Chicago, Ill.; and an EIA performed with reagents from the National Institutes of Health, Bethesda, Md. [NIH reagent EIA]), and a latex agglutination (LA) assay (Rotalex; Medical Technology Corp., Somerset, N.J.). The sensitivity of the monoclonal antibody EIA (95%) was superior to those of the polyclonal antibody EIAs (73% for Rotazyme II and 57% for the NIH reagent EIA) and the LA assay (61%). The specificity of the LA assay (98%) was slightly better than those of the other systems (88 to 96%). The positive and negative predictive values of the monoclonal antibody EIA (93 and 96%, respectively) were better than those of Rotazyme II (82 and 80%, respectively), the LA assay (96 and 76%, respectively), and the NIH reagent EIA (93 and 74%, respectively). The visual readings of the monoclonal antibody EIA correlated better with the spectrophotometric optical density readings than did the visual readings of the polyclonal antibody EIAs; however, the agreement of both with electron microscopy results was poor when 1+ or plus-minus readings were observed. The monoclonal antibody EIA is more sensitive and predictive than other rotavirus detection systems and second only to the LA assay in specificity in detecting rotavirus in stool specimens.
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Hypernatremic dehydration was induced in rabbits during a 3- to 5-day period resulting in mean plasma sodium concentrations of 187 meq/liter. The animals were then rehydrated during a 4-h period by intravenous administration of a 2.5% glucose or fructose solution. The water content of four regions of brain sample showed a significant (P less than 0.05) increase in brain water content above normal in the rehydrated groups. Brain water content was significantly (P less than 0.01) greater in those animals with seizures compared with those without seizures, suggesting the importance of water intoxication in the pathogenesis of seizure activity. Changes in muscle Na, K, Cl, and water content were not similar to those of brain, indicating that muscle content of these substances was not an accurate reflection of the brain content specific time. The incidence of seizures was significantly (P less than 0.05) greater when glucose solution was used for rehydration (49%) compared with the use of fructose solution (25%). The mechanism(s) by which fructose resulted in a lower incidence of seizures is not known. The frequency of seizure activity was directly proportional to the rate of administration of intravenous solutions utilized to correct hypernatremia. In addition, the specific carbohydrate of the solution appeared to play an important role in the pathophysiology of the development of seizures.
A scarcity of pharmacokinetic data are available on cefotaxime in the obstetric patient. Fifteen patients received either 1 or 2 gm of cefotaxime after cesarean section. After intravenous administration of the designated dose, serial blood samples were analyzed for cefotaxime and its active metabolite, desacetyl cefotaxime (DCTX), by high-pressure liquid chromatography. The mean (+/- SD) peak concentrations of cefotaxime were 14.1 +/- 7.9 micrograms/ml and 40.0 +/- 32.5 micrograms/ml for the 1- and 2-gm dosage regimens, respectively. Detectable trough concentrations were 0.87 +/- 0.24 and 1.0 +/- 0.26, respectively, with many values falling below the sensitivity limits of the assay (0.5 micrograms/ml). The mean peak concentrations of DCTX for the two doses were 5.5 +/- 1.9 micrograms/ml and 10.9 +/- 6.2 micrograms/ml, respectively. Measurable trough levels for DCTX were more frequently identified, than for cefotaxime, at the end of the dosing interval due to an extended half-life as compared to its parent compound. Pharmacokinetic parameters of cefotaxime demonstrated large volumes of distribution and high clearance rates. Our data suggest altered pharmacokinetics of this agent in the obstetric patient when compared to previous studies in nonpregnant patients. This may be important in the seriously ill gravida where dosage adjustments in cefotaxime administration may be needed.
We used an enzyme-linked immunosorbent assay system to compare prevalence and levels of systemic and local antibody to Giardia lamblia in different populations. Serial blood and milk samples were collected simultaneously from lactating women in Texas and Mexico. IgG antibody to G. lamblia was present in 118 (77%) of 153 sera from 27 Mexican mothers but in only 51 (24%) of 214 sera obtained from 28 Texan mothers (P less than .001). Sera positive for IgG antibody to G. lamblia revealed antibody levels that were significantly higher in Mexico than in Texas (0.325 +/- 0.076 vs. 0.219 +/- 0.079 optical density units). Secretory IgA antibody to G. lamblia was found in 121 (79%) of 153 milk samples in the Mexican population, but in only 33 (15%) of 214 samples in the Texan population (P less than .001). The levels of secretory antibody to G. lamblia also were higher in the Mexican population. The study documents a widely different antibody response to G. lamblia in individuals living in different areas. As antibodies to G. lamblia can be acquired by infants transplacentally or through breast-feeding, this difference might be important in the relative protection against giardial infection.
Human milk contains factors that protect suckling infants against enteropathogen-induced diarrhea. One nonspecific protective factor found in human milk is a small molecular weight material that protects suckling mice from death due to the heat-stable enterotoxin of Escherichia coli. This study demonstrated that cow's milk and most formulas derived from cow's milk also contain a factor(s) that can protect against heat-stable enterotoxin of E. coli in suckling mice.
The mechanism by which enteropathogenic Escherichia coli (EPEC) cause disease remains to be defined. We studied EPEC and non-EPEC strains of E. coli from stool specimens obtained from infants and adults for production of Shiga-like cytotoxin. Although it was common for healthy infants and adults to have cytotoxin-producing E. coli as part of the fecal flora, Shiga-like cytotoxin was detected more commonly and in greater amounts among EPEC than among other fecal E. coli. These results suggest a role for Shiga-like cytotoxin in the pathogenesis of EPEC-related gastroenteritis.
Limited pharmacokinetic data exist on cefoxitin, a semisynthetic cephamycin antibiotic, in the obstetric patient. Thirteen normotensive and five subjects with severe pregnancy-induced hypertension were identified within the first two postpartum days after cesarean section. After a 2 gm intravenous infusion, serial samples of blood were obtained and analyzed for cefoxitin by high-pressure liquid chromatography. Peak cefoxitin concentrations after infusion were 53.3 +/- 18.6 and 50.8 +/- 25.2 micrograms/ml for the normotensive and pregnancy-induced hypertensive groups, respectively. The only significant difference in pharmacokinetic parameters between these groups was a higher serum trough concentration of cefoxitin in the patients with pregnancy-induced hypertension as compared to the normotensive group. Because of diminished trough levels in our study patients, attention may need to be given to the adjustment of dosages in postpartum women with serious infections.
The comparative bioavailability of chloramphenicol from intravenous succinate, oral palmitate, and oral base preparations was studied in a crossover manner in 12 adult patients. Chloramphenicol was administered at a dose of 1 Gm every 6 hours, and blood samples were collected at steady state. For the succinate study, total urine output was also collected. The bioavailability of active chloramphenicol from the succinate preparation averaged 85.8 +/- 42.3 and 78.8 +/- 50.1 per cent of the free base and palmitate forms, respectively. This lower availability appeared to be due to variable excretion of unchanged succinate in the urine, averaging 27 +/- 11 per cent of the dose. Regardless of dosage form or route of administration, plasma chloramphenicol concentrations remained in the therapeutic range (5 to 25 mg/liter) for the entire dosage interval, implying that no change needs to be made when changing dosage form or route of administration. The interpatient variability, however, supports the need for monitoring of plasma chloramphenicol concentrations, especially in newborn infants, persons with liver disease, or those receiving other medications that alter chloramphenicol metabolism.
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We prospectively evaluated excretion of Giardia lamblia in children in day care centers in Houston by conducting two prevalence studies of 600 children enrolled in 30 DCC, day care centers, and an 18-month longitudinal study in 82 children in one center. In the two prevalence surveys, Giardia cysts were identified in 72 (21%) and 67 (26%) children, respectively, who provided stool specimens. Trophozoites were found in 15 (4%) and 8 (3%), respectively. There was no correlation between the frequency of recent diarrheal episodes and the finding of Giardia. Stool specimens containing cysts were significantly (P less than 0.0001) more frequent in the 13- to 30-month-old children than in children younger than 12 months. Children attending day care centers for more than 3 months were more likely to be excreting Giardia than those attending for less than 3 months. In the longitudinal study, cysts were detected in stool specimens from 27 (33%) of the 82 children at least once during the survey. Twelve children had Giardia cysts in weekly stool specimens for a mean of 6.2 +/- 1.2 months and trophozoites for 3.3 +/- 1.2 months. The number of enteric symptoms observed in children and the classification of nutritional status based on monthly height and weekly weight measurements did not differ significantly when infected and noninfected children were compared. Asymptomatic Giardia excretion in children younger than 36 months is common and appears to be well tolerated.
The neutralizing activity (NA) of supernates of colostral samples collected postpartum from 55 women and tested against a 50% cytopathic dose of purified toxins A and B of Clostridium difficile was evaluated in Y1 adrenal cells. Thirty-one (56%) of the samples had NA against one or both toxins. Samples of breast milk were collected postpartum from five women-three had colostral NA and two did not. All milk specimens from the three women with colostral NA had NA titers of 1:1-1:4 throughout the study (609 days in one case). Samples from the two women without colostral NA did not exhibit NA during a 60-day follow-up period. In suckling mice either toxin plus human milk with in vitro NA elicited significantly less fluid accumulation than did toxin plus diluent or toxin plus milk without in vitro NA (P less than .025 to P less than .05). Twelve (63%) of 19 milk samples with in vitro NA against toxin A and 15 (65%) of 23 with in vitro NA against toxin B inhibited fluid accumulation caused by the corresponding toxin. In vitro NA against toxin A appeared to reside in the secretory IgA fraction of one milk sample assessed by immune precipitation. The results suggest that human milk may protect newborn infants against toxins A and B of C. difficile.