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Biomedical subjects

T Smith

Publications and source records attributed to T Smith.

At least 37 records · Page 2Linked to original sources

Pharmacokinetics of enrofloxacin in the red pacu (Colossoma brachypomum) after intramuscular, oral and bath administration.

The intramuscular (i.m.), oral (p.o.), and bath immersion disposition of enrofloxacin were evaluated following administration to a cultured population of red pacu. The half-life for enrofloxacin following i.m. administration was 28.9 h, considerably longer than values calculated for other animals such as dogs, birds, rabbits, and tortoises. The 4 h maximum concentration (Cmax) of 1.64 micrograms/ml, following a single 5.0 mg/kg dosing easily exceeds the in vitro minimum inhibitory concentration (MIC) for 20 bacterial organisms known to infect fish. At 48 h post i.m. administration, the mean plasma enrofloxacin concentration was well above the MIC for most gram-negative fish pathogens. The gavage method of oral enrofloxacin administration produced a Cmax of 0.94 microgram/mL at 6-8 h. This Cmax was well above the reported in vitro MIC. A bath immersion concentration of 2.5 mg/L for 5 h was used in this study. The Cmax of 0.17 microgram/mL was noted on the 2 hour post-treatment plasma sample. Plasma concentrations of enrofloxacin exceeded published in vitro MIC's for most fish bacterial pathogens 72 h after treatment was concluded. Ciprofloxacin, an active metabolite of enrofloxacin, was detected and measured after all methods of drug administration. It is possible and practical to obtain therapeutic blood concentrations of enrofloxacin in the red pacu using p.o., i.m., and bath immersion administration. The i.m. route is the most predictable and results in the highest plasma concentrations of the drug.

Administration, Oral

Analysis of multiple Plasmodium falciparum infections in Tanzanian children during the phase III trial of the malaria vaccine SPf66.

In the first phase III efficacy trial of the malaria vaccine SPf66 in Africa, MOIs in SPf66- and placebo-vaccinated children were analyzed by polymerase chain reaction-restriction fragment length polymorphism of the Plasmodium falciparum merozoite surface antigen 2 (MSA2). MOIs were significantly reduced in asymptomatic vaccine recipients compared with those in asymptomatic placebo recipients; however, no differences were observed among symptomatic children in the vaccine and control groups. These results show that immunization with SPf66 modulates the course of naturally occurring infections, as reflected by reduced MOIs. In placebo recipients, however, there was a significant negative correlation between numbers of infecting genotypes, as identified by MSA2, and morbidity. Asymptomatic placebo recipients had an average of 5 concurrent infections, whereas children with clinical cases had an average of 3.4 infections. These data provide further evidence that premunition from concurrent infections is important in immunity against clinical malaria. No such effect of multiple infections was found in the vaccinated group.

Animals

Spatial and temporal variation in abundance of Anopheles (Diptera:Culicidae) in a malaria endemic area in Papua New Guinea.

Abundance of anophelines in 10 villages in the Wosera area of Papua New Guinea was monitored during 1990-1993. Of 85,197 anophelines collected in 1,276 paired indoor and outdoor landing catches, 40.4% were Anopheles koliensis Owen, 36.7% An. punctulatus Donitz, 14.3% An. karwari (James), 4.9% An. farauti s.l. Laveran, 3.1%, An, longirostris Brug, and 0.7% An. bancroftii Giles. Maps of average indoor biting rates were produced using a Bayesian conditional autoregressive model which allowed for heterogeneities in sampling effort over time and space. Differences in spatial distributions among species were observed among and within villages and were related to the distribution of larval habitats and vegetation. Abundance of An. punctulatus and An. koliensis decreased with distance from the main waterway and probably from a sago swamp forest at 6 villages in North Wosera. Abundance of An. punctulatus was associated negatively with those of An. farauti s.l., An. longirostris, and An. bancroftii. The latter 3 species also had relatively low ratios of indoor-to-outdoor biting rates, and earlier biting times than An. punctulatus. Human blood indices of at least 0.79 were observed for all species except An. bancroftii. Abundance of all 6 species was correlated temporally with recent rainfall, but An. koliensis, An. karwari, and An. longirostris showed greater temporal variability than the other species. An punctulatus and An. koliensis tended to occur together in time and space (index of association, I = 0.85). Weaker associations were seen between An. farauti s.l. and An. longirostris (I = 0.44) and An. koliensis and An. karwari (I = 0.34). The most frequently collected species occurred together and were concentrated near the Amugu river; the remaining species tended to occur together but in different parts of the Wosera area. The importance of understanding ecological requirements of the different Anopheles vectors and their association with key household and landscape features are discussed in relation to malaria transmission and control.

Animals

Development of a human lymphoblastoid cell line constitutively expressing human CYP1B1 cDNA: substrate specificity with model substrates and promutagens.

An AHH-1 TK+/- cell derivative was developed that stably expresses human cytochrome P4501B1 (CYP1B1) cDNA in an extrachromosomal vector which confers resistance to 1-histidinol and co-expresses NADPH cytochrome P450 oxidoreductase (OR). The CYP1B1-expressing cell line was designated h1B1/OR. Microsomes prepared from CYP1B1 cDNA expressing cells exhibit elevated levels of 7-ethoxy-resorufin deethylase (EROD), 7-ethoxy-4-trifluoromethyl-coumarin deethylase (EFCD), benzo(alpha)pyrene hydroxylase (BPH), bufuralol 1'-hydroxylase, testosterone hydroxylase activities and spectrally quantifiable cytochrome P450. CYP1B1-containing microsomes did not contain detectable coumarin 7-hydroxylase, p-nitrophenol hydroxylase, lauric acid hydroxylase, (S)-mephenytoin 4'-hydroxylase or diclofenac 4'-hydroxylase activities. Kinetic parameters for selected substrates were compared among CYP1B1 and the two additional members of the CYP1 family, CYP1A1 and CYP1A2. For BPH and EFCD, the rank order of rates of substrate metabolism were CYP1A1 > CYP1B1 > CYP1A2. For EROD, the rank order of substrate metabolism was CYP1A1 > CYP1A2 > CYP1B1. For both EROD and EFCD the apparent K(m) values for CYP1B1 were more similar to CYP1A1 than to CYP1A2. In order to begin to characterize the promutagen activating ability of CYP1B1, the mutagenicity of selected chemicals was examined in h1B1/OR cells; there was increased sensitivity (CYP1B1-expressing relative to control cells) to the mutagenicity of benzo(a)pyrene, cyclopenta(c,d)pyrene, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone and aflatoxin B1 (AFB). CYP1B1, expressed in this system, appears to be particularly efficient at activating AFB.

Aflatoxin B1

Ovarian morphology and endocrine characteristics of female sheep fetuses that are heterozygous or homozygous for the inverdale prolificacy gene (fecX1).

The Inverdale gene (fecX1), located on the X chromosome, is a major gene affecting the ovulation rate of sheep. At each ovulation, ewes heterozygous (I+) for the fecX1 gene ovulate, on average, one more egg than noncarriers (++), whereas ewes that are homozygous (II) for this gene are infertile and have "streak" ovaries. Since formation of the ovary occurs in fetal life, it is possible that the fecX1 gene influences ovarian development before birth. The aims of this study were to examine the effects of the fecX1 gene on germ cell development, follicular formation and growth, and plasma gonadotropin concentrations at 5 different days of gestation (i.e., Days 40, 90, 105, 120, and 135) and also in adult life. The results suggest that one copy of the X-linked mutation in female fetuses leads to a retardation of germ cell development at Days 40 and 90 of gestation. However, from Day 105 of gestation, follicular formation and growth appear normal. By contrast, in females with two copies of the X-linked mutation, germ cell development and follicular formation appear normal, but thereafter follicular growth from the primary stage of development is impaired. During fetal life the plasma concentrations of FSH and LH, although not measurable at Day 40, were similar between all the genotypes at Day 105, 120, and 135 of gestation. The only exception was for LH at Day 90 in the I+ and II animals: in ewes with these genotypes the plasma concentrations of LH were similar but significantly lower (p < 0.01) than in the ++ genotype. In adult animals the plasma concentrations of FSH and LH were not different between the ++ and I+ genotypes, reflecting similar levels of ovarian follicular activity. However, in adult II animals, the plasma concentrations of FSH and LH were significantly higher (both p < 0.01) than in the ++ and I+ genotypes, reflecting the absence of normal secondary and antral follicles. In summary, these data show that the fecX1 gene affects ovarian development before birth and that the nature of the effect is influenced by whether the female fetus is a homozygous or heterozygous carrier of the X-linked mutation.

Animals

Doxycycline reduces early neurologic impairment after cerebral arterial air embolism in the rabbit.

BACKGROUND: Previous studies indicate leukocytes play a role in the pathogenesis of cerebral arterial air embolism. Because doxycycline inhibits numerous leukocyte activities, the authors hypothesized doxycycline would decrease neurologic impairment after cerebral arterial air embolism. METHODS: New Zealand White rabbits anesthetized with methohexital received either intravenous saline (n = 7) or 10 mg/kg doxycycline (n = 7) 1 h before administration of 100 microl/kg of air into the internal carotid artery. Somatosensory-evoked potentials (SSEPs) were recorded at 30-min intervals for the next 2 h. After the final recording, the anesthetic was discontinued, and animals recovered. Animals were neurologically evaluated 4 h after air embolism on a scale of 0 (normal) to 99 (coma) points. RESULTS: At 4 h, doxycycline animals had lesser neurologic impairment (46 +/- 23; median, 41) than animals that received saline (77 +/- 20; median, 81); P = 0.007. SSEP amplitude was greater in the doxycycline group at 60, 90, and 120 min after air embolism; P = 0.001, 0.006, 0.026, respectively. SSEP amplitudes at 30, 60, 90, and 120 min inversely correlated with 4 h neurologic impairment; tau = -0.43, -0.75, -0.85, -0.79, respectively. CONCLUSIONS: Doxycycline decreased electrophysiologic and neurologic abnormalities after cerebral air embolism. Because groups could be distinguished electrophysiologically as soon as 1 h after air embolism and because SSEP amplitude inversely correlated with neurologic impairment, doxycycline appears to inhibit a key early (approximately 1 h) process in the pathophysiology of cerebral air embolism.

Animals

Video colpography: a new technique for secondary cervical screening.

OBJECTIVE: To assess the diagnostic accuracy of a new technique of cervical imaging and to consider its potential as a secondary cervical screening method. DESIGN: A prospective cross-sectional study with each case acting as its own control, comparing video colpography with colposcopy. SETTING: University of Birmingham colposcopy clinics, City Hospital and Birmingham Women's Hospital. PARTICIPANTS: Fifty women referred for colposcopy. INTERVENTIONS: The women had a video colpogram recording made prior to colposcopy. MAIN OUTCOME MEASURES: The proportion of technically suitable colpograms obtained and the level of agreement between colposcopist and video screener. RESULTS: The images were satisfactory or good in 94% cases, and there was a very high level of agreement between colposcopist and video screener (kappa = 0.79). If the technique had been used in a primary health care setting as a secondary screening method for women with low grade cervical smear abnormalities, 61% would have avoided referral for colposcopy. CONCLUSIONS: Video colpography is an accurate, portable and quick method of cervical imaging. It combines the simplicity of a video camera with the versatility of computerised digital imaging and has great potential in the fields of teaching, audit and screening of low grade smear abnormalities.

Colposcopy

Association of mercury resistance with antibiotic resistance in the gram-negative fecal bacteria of primates.

Gram-negative fecal bacterial from three longitudinal Hg exposure experiments and from two independent survey collections were examined for their carriage of the mercury resistance (mer) locus. The occurrence of antibiotic resistance was also assessed in both mercury-resistant (Hgr) and mercury-susceptible (Hgs) isolates from the same collections. The longitudinal studies involved exposure of the intestinal flora to Hg released from amalgam "silver" dental restorations in six monkeys. Hgr strains were recovered before the installation of amalgams, and frequently these became the dominant strains while amalgams were installed. Such persistent Hgr strains always carried the same mer locus throughout the experiments. In both the longitudinal and survey collections, certain mer loci were preferentially associated with one genus, whereas other mer loci were recovered from many genera. In general, strains with any mer locus were more likely to be multiresistant than were strains without mer loci; this clustering tendency was also seen for antibiotic resistance genes. However, the association of antibiotic multiresistance with mer loci was not random; regardless of source, certain mer loci occurred in highly multiresistant strains (with as many as seven antibiotic resistances), whereas other mer loci were found in strains without any antibiotic resistance. The majority of highly multiresistant Hgr strains also carried genes characteristic of an integron, a novel genetic element which enables the formation of tandem arrays of antibiotic resistance genes. Hgr strains lacking antibiotic resistance showed no evidence of integron components.

Animals

Phylogeny of mercury resistance (mer) operons of gram-negative bacteria isolated from the fecal flora of primates.

Nine polymorphic mer loci carried by 185 gram-negative fecal bacterial strains from humans and nonhuman primates are described. The loci were characterized with specific intragenic and intergenic PCR primers to amplify distinct regions covering approximately 80% of the typical gram-negative mer locus. These loci were grouped phylogenetically with respect to each other and with respect to seven previously sequenced mer operons from gram-negative bacteria (the latter designated loci 1, 2, 3, 6, 7, 8, and delta 8 by us here for the purpose of this analysis). Six of the mer loci recovered from primates are similar either to these previously sequenced mer loci or to another locus recently observed in environmental isolates (locus 4), and three are novel (loci 5, 9, and 10). We have observed merC, or a merC-like gene, or merF on the 5' side of merA in all of the loci except that of Tn501 (here designated mer locus 6). The merB gene was observed occasionally, always on the 3' side of merA. Unlike the initial example of a merB-containing mer locus carried by plasmid pDU1358 (locus 8), all the natural primate loci carrying merB also had large deletions of the central region of the operon (and were therefore designated locus delta 8). Four of the loci we describe (loci 2, 5, 9, and 10) have no region of homology to merB from pDU1358 and yet strains carrying them were phenylmercury resistant. Two of these loci (loci 5 and 10) also lacked merD, the putative secondary regulator of operon expression. Phylogenetic comparison of character states derived from PCR product data grouped those loci which have merC into one clade; these are locus 1 (including Tn21), locus 3, and locus 4. The mer loci which lack merC grouped into a second clade: locus 6 (including Tn501) and locus 2. Outlying groups lacked merD or possessed merB. While these mer operons are characterized by considerable polymorphism, our ability to discern coherent clades suggests that recombination is not entirely random and indeed may be focused on the immediate 5' and 3' proximal regions of merA. Our observations confirm and extend the idea that the mer operon is a genetic mosaic and has a predominance of insertions and/or deletions of functional genes immediately before and after the merA gene. chi sites are found in several of the sequenced operons and may be involved in the abundant reassortments we observe for mer genes.

Animals

Molecular characterization of murine humoral immune response to botulinum neurotoxin type A binding domain as assessed by using phage antibody libraries.

To produce antibodies capable of neutralizing botulinum neurotoxin type A (BoNT/A), the murine humoral immune response to BoNT/A binding domain (H(C)) was characterized at the molecular level by using phage antibody libraries. Mice were immunized with BoNT/A H(C), the spleens were harvested, and single-chain Fv (scFv) phage antibody libraries were constructed from the immunoglobulin heavy and light chain variable region genes. Phage expressing BoNT/A binding scFv were isolated by selection on immobilized BoNT/A and BoNT/A H(C). Twenty-eight unique BoNT/A H(C) binding scFv were identified by enzyme-linked immunosorbent assay and DNA sequencing. Epitope mapping using surface plasmon resonance in a BIAcore revealed that the 28 scFv bound to only 4 nonoverlapping epitopes with equilibrium constants (Kd) ranging from 7.3 x 10(-8) to 1.1 x 10(-9) M. In a mouse hemidiaphragm assay, scFv binding epitopes 1 and 2 significantly prolonged the time to neuroparalysis, 1.5- and 2.7-fold, respectively, compared to toxin control. scFv binding to epitopes 3 and 4 showed no protection against neuroparalysis. A combination of scFv binding epitopes 1 and 2 had an additive effect on time to neuroparalysis, which increased to 3.9-fold compared to the control. The results suggest that there are two "productive" receptor binding sites on H(C) which lead to toxin internalization and toxicity. Blockade of these two epitopes with monoclonal antibodies may provide effective immunoprophylaxis or therapy against BoNT/A intoxication.

Amino Acid Sequence

Seizure resulting from a venlafaxine overdose.

OBJECTIVE: To report a case of venlafaxine overdose. CASE SUMMARY: A 40-year-old woman with major depression took an overdose of venlafaxine in an apparent suicide attempt. After the ingestion of 26 venlafaxine 50-mg tablets, the patient experienced a witnessed generalized seizure. She was admitted to the medical intensive care unit, venlafaxine was discontinued, and no further sequelae were seen. DISCUSSION: To our knowledge, this is the first reported case of venlafaxine overdose that resulted in a generalized seizure. Based on nonoverdose pharmacokinetics and pharmacodynamics of venlafaxine and the potential risks of available interventions, no emergent therapy was instituted. CONCLUSIONS: The venlafaxine overdose in our patient resulted in a single episode of generalized seizure but elicited no further sequelae.

Adult

Intensive behavioral treatment for preschoolers with severe mental retardation and pervasive developmental disorder.

From archival records, we assessed outcomes achieved by preschoolers with both severe mental retardation and autistic features: (a) an experimental group (n = 11), which received intensive behavioral treatment, and (b) a comparison group (n = 10), which received minimal treatment. At intake (mean CA = 3.08 years), the groups did not differ significantly on any variable. At follow-up children in the experimental group obtained a higher mean IQ and evinced more expressive speech than did those in the comparison group. Behavior problems diminished in both groups. Results indicate that intensively treated children achieved clinically meaningful gains relative to the comparison group but remained quite delayed.

Autistic Disorder

Müllerian mixed tumors: CT characteristics with clinical and pathologic observations.

OBJECTIVE: This retrospective study analyzed the CT characteristics of mullerian mixed tumors. Clinical aspects, outcomes, and pathologic correlations were also evaluated. CONCLUSION: Müllerian mixed tumor is a rapidly growing aggressive tumor with a relatively poor prognosis. Uterine and metastatic masses showed central low attenuation. Metastatic masses often had irregular enhancement centrally and surface enhancement circumferentially. The tendency toward local and lymphatic spread and intraperitoneal seeding was greater than the tendency toward hematogenous metastases. CT was useful before surgery in defining the extent of disease and for follow-up clinical management in identifying metastases and assessing treatment effectiveness.

Aged

Primary parotid lymphoma: the effect of International Prognostic Index on outcome.

Since the reported survival and failure-free survival (FFS) of adults with primary parotid non-Hodgkin's lymphoma (NHL) is variable, we reviewed our experience of untreated adults with primary parotid NHL. Patients were eligible if they presented to the University of Texas M. D. Anderson Cancer Center Cancer between 1980 and 1995 with parotid enlargement and if the diagnosis of lymphoma was verified according the Working Formulation. Medical records were reviewed to determine Ann Arbor Stage (AAS), the International Prognostic Index (IPI) score, response to therapy, relapse, FFS, and survival. We identified 39 untreated adults with primary parotid NHL representing 1% of all lymphomas and 8.6% of all untreated parotid neoplasms. Three patients were excluded because of suboptimal therapy, leaving 36 patients eligible for outcome analysis. Of the 18 patients with low-grade NHL, two were treated with radiotherapy, eight with chemotherapy and radiotherapy, seven with chemotherapy only, and one with antibiotics. The complete remission (CR) rate was 94%, and with a median follow-up of 36 months for surviving patients the survival and failure-free survival (FFS) at 5 years were 94% and 78%, respectively. The 5-year FFS were not statistically different between patients with early (I or II) or advanced (III or IV) AAS (83% and 74%, respectively; p > 0.05) and favorable (0 or 1) or unfavorable (> 1) IPI scores (73% and 100%, respectively; p > 0.05). All 18 patients with intermediate-grade NHL were treated with doxorubicin-based chemotherapy which was followed by radiotherapy in six. The CR rate was 89%, and with a median follow-up of 51 months for surviving patients the survival and FFS at 10 years were 80% and 72%, respectively. In this group 10-year FFS was better in early than in advanced AAS (100% vs 0%, respectively; p = 0.01) and in favorable (0 or 1) than in unfavorable (> 1) IPI scores (86% vs 20%, respectively; p < 0.01). We conclude the the FFS of patients with low-grade NHL is 78% and not affected by AAS or IPI score. The FFS of patients with intermediate-grade NHL appears comparable with that of NHLs of other primary sites, being 86% for those with IPI < or = 1 and 20% for those with IPI 1. Patients with IPI > 1 should be entered on investigational protocols aiming to increase FFS.

Adult

Interleukin-12 induces relapse in experimental allergic encephalomyelitis in the Lewis rat.

Acute, monophasic experimental allergic encephalomyelitis (EAE) in the Lewis rat shows pathological similarities to the human disease multiple sclerosis (MS). Rats that recover from EAE are essentially resistant to disease reinduction, unlike MS in which relapses are frequently associated with common bacterial and viral infections. As macrophage-derived interleukin (IL)-12 is a critical component of innate resistance to bacterial infection and appears to directly activate encephalitogenic T cells in vivo, the ability of this cytokine to reinduce paralysis in EAE was examined. Paralytic disease was exacerbated by intraperitoneal IL-12 administration and could be reinduced up to 1 week after recovery from the primary clinical episode. Concomitant with worsening of initial clinical signs and relapse was an increase in the ratio of macrophages to T cells in brain stem perivascular cuffs and the expression of inducible nitric oxide synthase in cells with both macrophage and microglial morphology. These findings suggest that IL-12 may contribute to macrophage-mediated disease exacerbation and relapse in patients with MS.

Animals

Assessing family planning service-delivery skills in Kenya.

This report demonstrates the use of Lot Quality Assurance Sampling (LQAS) to evaluate the technical competence of two cohorts of family planning service providers in Kenya trained with a new curriculum. One cohort had just finished training within two months of the study. The other cohort was the first group trained with the new curriculum about one year before the study. LQAS was adapted from industrial and other public health applications to assess both the individual competence of 30 service providers and the competence of each cohort. Results show that Cohorts One and Two did not differ markedly in the number of tasks needing improvement. However, both cohorts exhibited more tasks needing improvement in counseling skills as compared with physical examination skills or with all other skills. Care-givers who were not currently providing services accounted for most service-delivery problems. This result suggests that providers' use of their skills explains their ability to retain service-delivery skills learned in training to a greater degree than does the amount of time elapsed since they were trained. LQAS proved to be a rapid, easy-to-use empirical method for management decisionmaking for improvement of a family planning training curriculum and services.

Chi-Square Distribution

Interferon-alpha neutralizing antibodies in HIV and chronic HCV patients treated with natural-source human leukocyte-derived interferon-alpha n3.

Human leukocyte-derived IFN-alpha n3 (Alferon N Injection) was administered subcutaneously to treat 20 patients with asymptomatic human immunodeficiency virus type 1 (HIV-1) and 141 patients with chronic hepatitis C virus (HCV) infections. The treatment of HIV-1 and HCV patients, previously untreated with any IFN preparations, did not result in development of neutralizing antibodies to IFN-alpha n3. Among 69 HCV refractory patients who were unresponsive to previous treatment with rIFN-alpha 2b, 2 had neutralizing antibodies to rIFN-alpha 2b prior to IFN-alpha n3 therapy, with no or limited cross-reactivity to IFN-alpha n3. After retreatment with IFN-alpha n3, both patients had detectable neutralizing titers to IFN-alpha n3. Additionally, 2 other patients developed low and transient neutralizing titers to IFN-alpha n3. Interferon subtype specificity of these antibodies was tested against RP-HPLC purified fractions of IFN-alpha n3, as well as rIFN-alpha 2b and rIFN-alpha 8b. Sera from patients previously treated with rIFN-alpha 2b with high antibody titers to rIFN-alpha 2b strongly reacted with the natural IFN-alpha 2b, and to a limited extent with other iFN-alpha subtypes. Neutralizing activity against IFN-alpha 2b was significantly competed out by the presence of a small amount of other interferon subtypes present in IFN-alpha n3. One patient with prior presence of antibodies to IFN-alpha 2b developed a high antibody titer to IFN-alpha 8b with limited reactivity to IFN-alpha n3. Two of the HCV refractory patients with prior neutralizing antibodies to rIFN-alpha 2b responded to IFN-alpha n3 therapy. These data suggest that the presence of neutralizing antibodies to individual IFN-alpha species will not significantly diminish the biological activity and the clinical efficacy of multi-species IFN-alpha n3.

Antibodies