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1.  Phase II trial of docetaxel, cisplatin and 5FU chemotherapy in locally advanced and metastatic penis cancer (CRUK/09/001) 
British Journal of Cancer  2013;109(10):2554-2559.
Background:
Penis cancer is rare and clinical trial evidence on which to base treatment decisions is limited. Case reports suggest that the combination of docetaxel, cisplatin and 5-flurouracil (TPF) is highly active in this disease.
Methods:
Twenty-nine patients with locally advanced or metastatic squamous carcinoma of the penis were recruited into a single-arm phase II trial from nine UK centres. Up to three cycles of chemotherapy were received (docetaxel 75 mg m−2 day 1, cisplatin 60 mg m−2 day 1, 5-flurouracil 750 mg m−2 per day days 1–5, repeated every 3 weeks). Primary outcome was objective response (assessed by RECIST). Fourteen or more responses in 26 evaluable patients were required to confirm a response rate of 60% or higher (Fleming-A'Hern design), warranting further evaluation. Secondary endpoints included toxicity and survival.
Results:
10/26 evaluable patients (38.5%, 95% CI: 20.2–59.4) achieved an objective response. Two patients with locally advanced disease achieved radiological complete remission. 65.5% of patients experienced at least one grade 3/4 adverse event.
Conclusion:
Docetaxel, cisplatin and 5FU did not reach the pre-determined threshold for further research and caused significant toxicity. Our results do not support the routine use of TPF. The observed complete responses support further investigation of combination chemotherapy in the neoadjuvant setting.
doi:10.1038/bjc.2013.620
PMCID: PMC3833214  PMID: 24169355
penis cancer; chemotherapy; metastatic; locally advanced
2.  A prospective study of chemotherapy-induced febrile neutropenia in the South West London Cancer Network. Interpretation of study results in light of NCAG/NCEPOD findings 
British Journal of Cancer  2010;104(3):407-412.
Background:
Chemotherapy-induced febrile neutropenia is a medical emergency complicating the treatment of many cancer patients. It is associated with considerable morbidity and mortality, as well as impacting on healthcare resources.
Methods:
A prospective study of all cases of chemotherapy-induced febrile neutropenia in the South West London Cancer Network was conducted over a 4-month period. Factors including demographics, treatment history, management of febrile neutropenia and outcome were recorded.
Results and conclusi:
Our results reflect those of the recent National Chemotherapy Advisory Group (NCEPOD, 2008)/National Confidential Enquiry into Patient Outcomes and Death reports (NCAG, 2009) and highlight the need for network-wide clinical care pathways to improve outcomes in this area.
doi:10.1038/sj.bjc.6606059
PMCID: PMC3049562  PMID: 21179036
neutropenic sepsis; chemotherapy; infection; febrile neutropenia
3.  A phase I/II trial of sorafenib and infliximab in advanced renal cell carcinoma 
British Journal of Cancer  2010;103(8):1149-1153.
There is clinical evidence to suggest that tumour necrosis factor-α (TNF-α) may be a therapeutic target in renal cell carcinoma (RCC). Multi-targeted kinase inhibitors, such as sorafenib and sunitinib, have become standard of care in advanced RCC. The anti-TNF-α monoclonal antibody infliximab and sorafenib have differing cellular mechanisms of action. We conducted a phase I/II trial to determine the safety and efficacy of infliximab in combination with sorafenib in patients with advanced RCC.
Eligible patients were systemic treatment-naive or had received previous cytokine therapy only. Sorafenib and infliximab were administered according to standard schedules. The study had two phases: in phase I, the safety and toxicity of the combination of full-dose sorafenib and two dose levels of infliximab were evaluated in three and three patients, respectively, and in phase II, further safety, toxicity and efficacy data were collected in an expanded patient population.
Acceptable safety was reported for the first three patients (infliximab 5 mg kg−1) in phase 1. Sorafenib 400 mg twice daily and infliximab 10 mg kg−1 were administered to a total of 13 patients (three in phase 1 and 10 in phase 2). Adverse events included grade 3 hand–foot syndrome (31%), rash (25%), fatigue (19%) and infection (19%). Although manageable, toxicity resulted in 75% of the patients requiring at least one dose reduction and 81% requiring at least one dose delay of sorafenib. Four patients were progression-free at 6 months (PFS6 31%); median PFS and overall survival were 6 and 14 months, respectively.
Sorafenib and infliximab can be administered in combination, but a significant increase in the numbers of adverse events requiring dose adjustments of sorafenib was observed. There was no evidence of increased efficacy compared with sorafenib alone in advanced RCC. The combination of sorafenib and infliximab does not warrant further evaluation in patients with advanced RCC.
doi:10.1038/sj.bjc.6605889
PMCID: PMC2967062  PMID: 20842130
renal cell carcinoma; sorafenib; infliximab
6.  The longer term outcome of children born to mothers with epilepsy 
Objectives: To determine the prevalence of cognitive delay and possible associated dysmorphic features in children exposed to antiepileptic drugs (AEDs) in utero.
Design: Retrospective study of children born to mothers with epilepsy.
Setting: Regional epilepsy clinics in Liverpool and Manchester, UK.
Participants: Children aged between 6 months and 16 years born to mothers with epilepsy.
Main outcome measures: Structured interviews, hospital records, clinical examination, and psychometric tests (Wechsler) were used to assess exposure and intelligence quotient (IQ). Blinded assessment of photographs was used to score children with characteristic dysmorphic features.
Results: A total of 249 children aged 6 and over were studied: 41 were exposed to sodium valproate, 52 to carbamazepine, 21 to phenytoin, 49 to polytherapy, and 80 were unexposed. Mean verbal IQ was significantly lower in the valproate group compared to unexposed and other monotherapy groups. Multiple regression analysis showed that both valproate exposure and frequent tonic-clonic seizures in pregnancy were significantly associated with a lower verbal IQ despite adjusting for other confounding factors. There was a significant negative correlation between dysmorphic features and verbal IQ in children exposed to valproate.
Conclusions: This study identifies valproate as a drug carrying potential risks for developmental delay and cognitive impairment and is the first to suggest that frequent tonic-clonic seizures have a similar effect. Our results need to be interpreted with caution given their retrospective nature. Women with epilepsy need careful counselling about individual risk benefit of AED treatment before pregnancy.
doi:10.1136/jnnp.2003.029132
PMCID: PMC1738809  PMID: 15491979
7.  Expression, self-assembly, and antigenicity of a snow mountain agent-like calicivirus capsid protein. 
Journal of Clinical Microbiology  1995;33(6):1452-1455.
Virus-like particles were produced in insect cells infected with a recombinant baculovirus containing the capsid gene of MX virus, a Mexican strain of human calicivirus. These recombinant MX (rMX) particles were morphologically similar to recombinant Norwalk virus (rNV) particles as observed under an electron microscope and contained a single capsid protein with a molecular weight of 57,000, which was slightly smaller than that of rNV. This protein was immunoprecipitated by sera from volunteers infected with the Snow Mountain agent, but it reacted weakly with sera from volunteers infected with NV. This protein did not react with hyperimmune antisera from animals immunized with rNV in the rNV antigen enzyme immunoassay (EIA). Seroresponses were detected from volunteers infected with Snow Mountain agent and Hawaii agent when the rMX particles were used as antigen in an EIA. This EIA also detected an immune response in the sera of child from whom the MX virus was isolated, and a high prevalence of antibody to MX virus was found in the sera of a cohort of Mexican children.
PMCID: PMC228194  PMID: 7650166
8.  Evaluation of the molecular epidemiology of an outbreak of multiply resistant Shigella sonnei in a day-care center by using pulsed-field gel electrophoresis and plasmid DNA analysis. 
Journal of Clinical Microbiology  1993;31(8):2152-2156.
Outbreaks of diarrhea in child day-care centers (DCC) are common. This study was undertaken to evaluate the molecular epidemiology of an outbreak of diarrhea due to Shigella sonnei. This outbreak involved 25 of 52 (48%) DCC children and 14 of 132 (11%) teachers and household contacts. S. sonnei isolates from nine children and five contacts were characterized by antimicrobial susceptibility, plasmid content, plasmid DNA restriction fragment pattern, and pulsed-field gel electrophoresis (PFGE) of total genomic DNA; 33 isolates from Houston, Tex., Chicago, Ill., and Mexico City, Mexico, also were studied. All outbreak isolates were resistant to ampicillin and trimethoprim-sulfamethoxazole and shared five to six plasmids ranging from 3.3 to 70 MDa. A total of 8 of 12 temporally associated nonoutbreak Houston isolates had plasmid profiles and restriction fragment patterns similar to those of the outbreak strain, despite possessing different antibiotic susceptibility patterns. PFGE demonstrated identical DNA patterns among outbreak isolates and similar or identical patterns among temporally associated sporadic Houston isolates with plasmid profiles similar to that of the outbreak strain. All other nonoutbreak strains from Houston, Chicago, and Mexico had plasmid profiles, restriction fragment patterns, and PFGE patterns different from those of the outbreak strain. DCC outbreak isolates could be distinguished from most sporadic isolates by antimicrobial susceptibility testing, but plasmid analysis and PFGE could not differentiate common-source isolates from sporadic isolates in the same location during the same time period, indicating that isolates present in the community were genetically similar to those producing outbreaks in the DCC.
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PMCID: PMC265713  PMID: 8396589
9.  Identification by DNA sequence analysis of a new plasmid-encoded trimethoprim resistance gene in fecal Escherichia coli isolates from children in day-care centers. 
In our ongoing studies of trimethoprim resistance (Tmpr) in day-care centers (DCC), we have shown a high rate of fecal colonization with Tmpr Escherichia coli and, using total plasmid content analysis, have shown that this is due to a diversity of strains. In the present study, we analyzed 367 highly Tmpr (MIC, greater than or equal to 2,000 micrograms/ml) isolates of E. coli from 72 children over a 5-month period and found at least 83 distinct plasmid patterns, indicating that at least 83 strains were involved. Several strains were particularly common in a given DCC, including one found in 61% of children with Tmpr E. coli; these common strains usually persisted within a DCC for several months. Colony lysates were hybridized with gene probes for dihydrofolate reductases (DHFR) types I, II, III, V, and VII; 21% hybridized under stringent conditions, and all of these were with type I (17%) or type V (4%) probes. Tmpr was cloned from a probe-negative Tmpr transconjugant, and an intragenic probe was prepared from this clone. Approximately 21% of the Tmpr E. coli strains (76 isolates) in the DCC were found to have this new gene, 74 of which were in one DCC. The DNA sequence of this gene was determined, and the predicted amino acid sequence was shown to have between 32% and 39% identity with the amino acid sequences for types I, III, V, VI, and VII and the partial sequence of type IV and approximately 26% identity with types IX and X DHFR. This confirms the uniqueness of this gene, which has tentatively been named dhfrxii, and its translation product, DHFR type XII.
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PMCID: PMC192037  PMID: 1416855
10.  Characterization of serum antibody responses to natural rotavirus infections in children by VP7-specific epitope-blocking assays. 
Journal of Clinical Microbiology  1992;30(5):1056-1061.
Knowledge of the immune response to rotavirus is crucial for vaccine development. We compared an epitope-blocking assay (EBA) that uses VP7-specific monoclonal antibodies with neutralization assays (NAs) with polyclonal antisera for detecting serum antibody responses after natural rotavirus infection in children. Twenty-six serum pairs from children living in an orphanage with and without symptoms during two rotavirus outbreaks were evaluated for VP7 type 1-, 2-, 3-, and 4-specific antibody responses. In the first outbreak, which was caused by a VP7 type 3 strain, homotypic antibody responses were detected in 11 of 11 symptomatic children by NA and in 10 of 11 symptomatic children by EBA. Heterotypic antibody responses were detected more frequently (12 of 15 children) by NA than by EBA, and the heterotypic epitope-blocking antibody responses occurred in children older than 14 months of age. Antibody responses in asymptomatic children were more commonly detected by EBA than by NA. EBA results from the sera of children in the second outbreak indicated that it was caused by VP7 type 4, whereas NA results suggested it was caused by VP7 type 3. Our results confirm that EBA is a sensitive and specific method for determining VP7 type-specific immune responses after natural rotavirus infections.
PMCID: PMC265223  PMID: 1374761
11.  Comparative in vitro activities of amoxicillin-clavulanic acid, cefuroxime, cephalexin, and cephalothin against trimethoprim-resistant Escherichia coli isolated from stools of children attending day-care centers. 
Antimicrobial Agents and Chemotherapy  1990;34(11):2047-2049.
A high prevalence of fecal colonization with trimethoprim-resistant Escherichia coli was found in diapered children attending day-care centers in Houston, Tex. In the present study, 100 isolates of E. coli resistant to multiple antibiotics, including trimethoprim (100%), sulfisoxazole (100%), streptomycin (94%), and ampicillin (87%), were obtained over a 5-month period from stool samples of diapered children attending four day-care centers and tested for their susceptibilities to amoxicillin-clavulanic acid, cefuroxime, cephalexin, and cephalothin. The MICs for 50 and 90% of strains tested were 16 and 32 micrograms/ml, respectively, for amoxicillin-clavulanic acid, 4 and 16 micrograms/ml, respectively, for cefuroxime, 4 and 64 micrograms/ml, respectively, for cephalexin, and 32 and greater than 64 micrograms/ml, respectively, for cephalothin. Although all three oral beta-lactams tested were generally active at concentrations likely to be achieved in urine, cefuroxime and cephalexin were more potent and are thus more likely to be inhibitory at the concentrations needed for systemic infections.
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PMCID: PMC171996  PMID: 2073095
12.  Risk factors for fecal colonization with trimethoprim-resistant and multiresistant Escherichia coli among children in day-care centers in Houston, Texas. 
In a previous study, we found fecal colonization with multiresistant Escherichia coli exhibiting high-level trimethoprim resistance in 19% of diapered children attending six day-care centers in Houston, Tex. To examine the potential risk factors associated with this finding, we conducted cross-sectional studies among 203 children attending 12 day-care centers, 51 children attending a well-child clinic (controls), and 64 medical students. The prevalence of fecal colonization with trimethoprim-resistant E. coli among children attending day-care centers (30%) was higher (P less than 0.001) than among control children (6%) or medical students (8%). The prevalence of colonization among the children attending the 12 centers ranged from 0 to 59% and was correlated with the number of diapered children enrolled (r = 0.73; P less than 0.01). In a case control study among the day-care center children, significant risk factors were an age of less than 12 months and attendance at a center with an enrollment of over 40 diapered children (odds ratios of 2.2 and 3.5, respectively); ethnicity, duration of attendance, and prior antibiotic administration were not associated with colonization. Plasmid analysis of 60 of the day-care center strains revealed 22 profiles, each of which was unique to a given day-care center. Transmission and carriage of trimethoprim-resistant strains for as long as 6 months was documented in one center studied on three occasions. Given the documented transmission of enteric pathogens among diapered children attending day-care centers and their spread into family members, it is likely that day-care centers are an important community reservoir of plasmid-associated antibiotic-resistant E. coli.
PMCID: PMC175994  PMID: 2201257
13.  Giemsa staining for cysts and trophozoites of Pneumocystis carinii. 
Journal of Clinical Pathology  1989;42(4):432-434.
Although Giemsa staining has been routinely used for the detection of trophozoites and intracystic bodies in smears of bronchoalveolar lavage fluid (BAL) from patients with Pneumocystis carinii pneumonia, it does not normally stain the cyst wall. For detection of the cysts other stains such as toluidine Blue 'O' and methenamine silver must be used as well. Sulphation of smears before staining with Giemsa allows cysts to be visualised, thus enabling a single stain to be used to show all the stages of BAL or sputum, which is particularly useful, considering the increase in the prevalence of P carinii pneumonia in conjunction with the spread of AIDS.
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PMCID: PMC1141918  PMID: 2469702
14.  Diagnosis of Giardia lamblia infections by detection of parasite-specific antigens. 
Journal of Clinical Microbiology  1989;27(3):431-435.
Antigen detection methods may facilitate diagnosis of Giardia lamblia in stool specimens. As determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis and immunoblotting, G. lamblia cysts and trophozoites share several antigens, especially in the 65-kilodalton and 30- to 34-kilodalton regions. By using blind methods, we compared results obtained by counterimmunoelectrophoresis using cyst-immune rabbit serum and by enzyme-linked immunosorbent assay (ELISA) using trophozoite-immune rabbit serum with results obtained by microscopic examination of a preserved, concentrated, and permanently stained stool specimen. Results were similar when these three methods were used to examine 118 stool specimens from clinical microbiology laboratories (53 specimens with G. lamblia) and specimens from 239 day-care-center toddlers (39 specimens with G. lamblia). Compared with microscopy, we found, for counterimmunoelectrophoresis and ELISA, respectively: sensitivity, 88 versus 94%; specificity, 97 versus 95%; positive predictive value, 86 versus 76%; negative predictive value, 98 versus 97%; and concordance, 89%. The false-positive rate by ELISA was 24% (10 of 42) in day-care-center toddlers but only 3% (1 of 32) in healthy adults (P less than 0.04) as corroborated by microscopy. This discrepancy suggests that the ELISA may be more sensitive than microscopy, which is considered the reference standard, and that results may be dependent, in part, on the epidemiology of the infection in the study subjects.
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PMCID: PMC267335  PMID: 2715318
15.  Quantitative analysis and partial characterization of cytotoxin production by Salmonella strains. 
Infection and Immunity  1988;56(12):3089-3094.
The pathogenesis of the wide-spectrum human disease caused by Salmonella species is poorly understood. Cytotoxin production by other enteric pathogens has been increasingly investigated recently, and data are accumulating regarding the role of cytotoxins in enteric infections and hemolytic uremic syndrome. We studied the cytotoxic activity of 131 Salmonella strains of the major serotypes, including 94 strains of Salmonella enteritidis, 12 strains of Salmonella typhi, and 25 strains of Salmonella choleraesuis. Cytotoxicity was quantitatively determined in sonic extracts by a [3H]thymidine-labeled HeLa cell assay. All Salmonella strains examined showed some degree of cytotoxic activity. The geometric means +/- standard deviations of the amounts of cytotoxin produced (50% cytotoxic dose per milligram of bacterial protein) were 27 +/- 2 for S. typhi, 65 +/- 2 for S. enteritidis, and 117 +/- 2 for S. choleraesuis. Analysis of variance showed that the differences in cytotoxin production by the three species were significant (P less than 0.001). No significant differences were found between stool isolates and invasive strains of the same species. Neutralization studies showed that the cytotoxins produced by all Salmonella strains were immunologically distinct from Shiga toxin and the closely related Shiga-like toxins produced by Escherichia coli. DNA hybridization studies with DNA probes for Shiga-like toxins of types I and II showed no hybridization. In each species the cytotoxin was heat labile and sensitive to trypsin treatment, which indicated that its active component was probably protein in nature. Upon ultrafiltration with Amicon membranes and gel filtration chromatography, cytotoxic activity was found in the molecular weight range of 56,000 to 78,000. Our findings indicate that salmonellae produce cytotoxin(s) that may play a role in the manifestations of the various species.
PMCID: PMC259706  PMID: 3182072
16.  Clinical and biochemical significance of toxin production by Aeromonas hydrophila. 
Journal of Clinical Microbiology  1987;25(5):916-921.
Production of cytotoxin and enterotoxin by Aeromonas strains obtained from stools of 50 children in Mexico and Texas and from blood of 9 children with sepsis was determined. Results were correlated with clinical features of infected children as well as with biochemical traits of Aeromonas strains. Cytotoxin was produced by 40 of 42 Aeromonas strains (95%) isolated from stools of children with diarrhea, by all 8 isolates from stools of well children, and by all 9 isolates from children with sepsis. There was no difference in the quantities (amount of cytotoxin per milligram of protein required to kill 50% of the cells) of cytotoxin produced and in clinical manifestations among the groups. None of the isolates produced a toxin that could be neutralized by antiserum raised against Shiga toxin produced by Shigella dysenteriae 1 60R. Heat-labile-like enterotoxin (LT) was produced by 26 of 42 stool isolates (62%), while only 1 of the 42 isolates (2%) produced enterotoxinlike activity in suckling mice; 65% of the cytotoxin-producing strains also produced an LT-like material. All strains from blood produced LT-like material, and 2 of 6 (33%) produced activity in suckling mice. All strains produced hemolysin; 37 of 57 (65%) were Voges-Proskauer positive; 27 of 57 (47%) were lysine decarboxylase positive by API 20E strips, none were positive for lysine decarboxylose production by lysin-iron agar slants at 24 h, but 17 of 54 (31%) were positive at 48 h. There was no correlation between biochemical reactions and enterotoxin or cytotoxin production. There appears to be no correlation between toxin production by Aeromonas spp. and gastroenteritis.
PMCID: PMC266117  PMID: 3584426
17.  Pharmacokinetics of cefoperazone in the parturient. 
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.
PMCID: PMC180610  PMID: 3813513
18.  Detection of rotavirus in stool specimens with monoclonal and polyclonal antibody-based assay systems. 
Journal of Clinical Microbiology  1986;23(5):897-900.
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.
PMCID: PMC268745  PMID: 3519662
19.  Shiga-like cytotoxin production by enteropathogenic Escherichia coli serogroups. 
Infection and Immunity  1985;47(1):335-337.
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.
PMCID: PMC261520  PMID: 3880727
20.  Mezlocillin pharmacokinetics in pediatric oncology patients. 
The pharmacokinetics of mezlocillin were studied in 31 children (age, 2 to 19 years) with malignancies and normal renal and hepatic functions. Mezlocillin was administered intravenously over 30 min every 4 h at doses ranging from 12.2 to 125 mg/kg. Blood samples were obtained over one dosage interval at steady state. For all patients, the mean clearance was 0.21 +/- 0.11 liter/h per kg, the mean distribution volume was 0.26 +/- 0.13 liter/kg, and the mean elimination half-life was 0.97 +/- 0.51 h. Trough concentrations were 23.0 +/- 29.9 mg/liter before the dose was administered and 20.4 +/- 27.5 mg/liter at the end of the dosing interval. Peak concentrations averaged 245 +/- 90.4 mg/liter, and average concentrations for the dosing interval were 83.7 +/- 40.4 mg/liter. There were no apparent effects of sex, malignancy, age, or dose on either the kinetic parameters or plasma concentrations. Overall, the disposition parameters for mezlocillin in this patient group were comparable to those reported in adults.
PMCID: PMC185436  PMID: 6703685
21.  Survival and detection of rotaviruses on environmental surfaces in day care centers. 
Previously, we demonstrated that children in day care centers commonly experience diarrhea due to rotavirus, giardia, and bacterial pathogens. Multiple agents frequently coexist, and the environment is heavily contaminated with enteric bacteria during outbreaks. A study of environmental surface contamination with rotavirus was performed during three non-outbreak periods. Of 25 samples collected from environmental surfaces and teachers hands at a day care center, 4 (16%) were positive for rotavirus antigen when a fluorescence assay was used. We also examined the survival of two animal viruses, rotavirus SA-11 and poliovirus type 1, and bacteriophage 12 on similar environmental surfaces in a laboratory. Poliovirus type 1 and bacteriophage f2 were more resistant to drying than rotavirus SA-11 and could be recovered after a 90-min exposure on a dry surface. Rotavirus SA-11 could be detected for 30 min. All three viruses survived longer when they were suspended in fecal material than when they were suspended in distilled water. These data suggest that several agents, including rotavirus, can remain viable on contaminated surfaces long enough to be transmitted to susceptible children. This finding helps explain why rotavirus shows a mode of spread like that of parasitic and bacterial agents within day care center settings.
PMCID: PMC239472  PMID: 6314896
22.  Virus-infected colostral cell cytokine stimulation of human leukocyte natural killer cytotoxicity. 
Infection and Immunity  1982;36(2):691-695.
Natural killer cytotoxicity is an important antiviral defense mechanism. Human peripheral blood mononuclear cells cultured with herpes simplex virus (HSV)-infected cells produced a cytokine. This substance stimulated adult natural killer cytotoxicity from 53.0 +/- 10.5% to 79.8% (P less than 0.01) against HSV-infected target cells. These data resulted in a calculated cytokine-dependent cellular cytotoxicity (CDCC) value of 65.8%. Cytokine production was not stimulated by uninfected cells and was independent of the presence or absence of antibodies to HSV in sera of donors and mononuclear cells. Cells from human colostrum also produced an HSV-stimulated cytokine which mediated CDCC by using both adult (19.8 +/- 3.9%) and neonatal (18.6 +/- 3.4%) mononuclear effectors cells. Colostral cell cytokine production was also independent of donor HSV serology. Not all colostral cultures produced the cytokine, and in general colostrum-stimulated CDCC was lower than peripheral blood leukocyte-stimulated CDCC. Colostral cell cytokine stimulation of neonatal natural killer cytotoxicity may account in part for the increased nonspecific resistance of breast-fed infants to viral infection.
PMCID: PMC351285  PMID: 6282758
23.  Amikacin pharmacokinetics in pediatric patients with malignancy. 
The pharmacokinetics of amikacin were evaluated in 50 pediatric patients (1 to 17 years of age) with malignancies and normal renal function. Dosage regimens of 5 mg/kg per dose were administered intravenously (i) over 30 min every 8 h, (ii) over 60 min every 8 h, and (iii) over 60 min every 6 h. Administration of amikacin over 30 min produced concentrations in serum of 29.3 +/- 5.7 micrograms/ml at the end of the infusion and subtherapeutic concentrations 4 h after the infusion. The regimen of 20 mg/kg per 24 h, divided into doses given every 6 h infused over 60 min, achieved concentrations in serum at the end of the infusion of 17.2 +/- 1.7 micrograms/ml and at 6 h of 1.2 +/- 0.3 microgram/ml. The serum half-life was 1.24 +/- 0.09 h, volume of distribution was 0.26 +/- 0.02 liter/kg, and total body clearance rate was 131 +/- 10 ml/min per 1.73 m2. No accumulation of amikacin was noted, and no significant side effects could be attributed to the drug. This study suggests that the optimal initial dosage regimen of amikacin in children is 20 mg/kg per 24 h administered in equal doses every 6 h over 60 min; however, optimal therapy requires individualization of dosage based on measured serum concentrations and susceptibility data on bacterial pathogens isolated.
PMCID: PMC352961  PMID: 533263
24.  Humoral immune response to the heat-labile enterotoxin of Escherichia coli in naturally acquired diarrhea and antitoxin determination by passive immune hemolysis. 
Infection and Immunity  1977;16(3):781-788.
Acute- and convalescent-phase sera from 132 students attending a university in rural Mexico were assayed for antibody against the heat-labile enterotoxin (LT) of Escherichia coli by neutralization of LT activity in the Y-1 adrenal cell assay and by passive immune hemolysis of LT-sensitized sheep erythrocytes. The two titration methods produced comparable results with respect to antitoxin responses detected. An inverse relationship was found between acute geometric mean antitoxin titer and the occurrence of diarrhea associated with LT-producing E. coli, especially in newly arrived students from the U.S.A. A significant correlation (P less than 0.00 5) was found between a rise in antitoxin titer detectable by the passive immune hemolysis technique and diarrhea with LT-producing E. coli isolated. Thus, humoral antitoxin titers appear to be a useful indicator of immune status with respect to enterotoxigenic (LT) E. coli diarrhea.
PMCID: PMC421030  PMID: 330395

Results 1-25 (27)