Biomedical subjects

J Alexander

Publications and source records attributed to J Alexander.

At least 163 records · Page 9Linked to original sources

PubMed1999

Gabapentin as add-on therapy in children with refractory partial seizures: a 12-week, multicentre, double-blind, placebo-controlled study. Gabapentin Paediatric Study Group.

PURPOSE: To evaluate the efficacy and safety of gabapentin (Neurontin; GBP) as add-on therapy for refractory partial seizures in paediatric patients aged 3-12 years. METHODS: After a 6-week baseline period, 247 patients (54 centres) entered a 12-week double-blind phase and were randomized to receive either GBP (t.i.d., titrated to 23-35 mg/kg/ day) or placebo. Seizure activity and type were recorded daily. Efficacy variables included Response Ratio (RRatio), responder rate, and percentage change in frequency (PCH) for all partial seizures; PCH and RRatio for individual types of partial seizures; and investigator and parent/guardian global assessments of seizure frequency and patient well-being. RESULTS: RRatio for all partial seizures was significantly lower (better) for GBP-treated patients (p = 0.0407). Responder rate favored GBP, but the difference between treatment groups was not statistically significant. Median PCH for all partial seizures for the GBP treatment group (-17.0%) was better than that for the placebo group (-6.5%). Median PCH for specific seizure types showed GBP to be most effective in controlling complex partial seizures (-35%) and secondarily generalized seizures (-28%) when compared with placebo (-12%, +13%, respectively). A greater percentage of GBP-treated patients exhibited improvement according to investigator and parent/guardian global assessments, with a statistically significant difference observed in the parent/guardian global assessment of seizure-frequency reduction (p = 0.046). Three GBP patients and one placebo patient were seizure free during the double-blind treatment period. GBP was well tolerated. CONCLUSIONS: GBP was effective and well tolerated as an add-on therapy for partial seizures in paediatric patients with previously drug-resistant seizures.

Acetates↗

PubMed1999

The drinking water chlorination by-products 3,4-dichloro-5-hydroxy-2[5H]-furanone(mucochloric acid) and 3-chloro-4-(dichloromethyl)-5-hydroxy-2[5H]-furanone do not induce preneoplastic or neoplastic intestinal lesions in F344 rats, balb/ca mice or C57bl/6J-min mice.

Epidemiological studies indicate an association between exposure to chlorinated drinking water and risk of intestinal cancer. In order to study this experimentally, we have examined the effects of 3,4-dichloro-5-hydroxy-2[5H]-furanone (mucochloric acid, MCA) and 3-chloro-4-(dichloromethyl)-5-hydroxy-2[5H]-furanone (MX), mutagenic and genotoxic compounds in drinking water, on aberrant crypt foci and tumours in the intestines of male F344 rats and Balb/cA mice, and C57BL/6J-Min (multiple intestinal neoplasia)/+ mice of both sexes, in six independent experiments. In some experiments the effects of MCA and MX on aberrant crypt foci induced by the colon carcinogens 1,2-dimethylhydrazine or its metabolite azoxymethane were also studied. Neither MCA nor MX alone induced aberrant crypt foci or intestinal tumours when given in drinking water. With this route of exposure neither MCA nor MX, when given in combination with 1,2-dimethylhydrazine or azoxymethane, had any effect on the induction or growth of the aberrant crypt foci. Drinking water exposure of MX did not affect the number or growth of aberrant crypt foci or intestinal tumours in the Minl+ mice. When administered intrarectally MCA had a weak inducing effect on aberrant crypt foci in the colons of Balb/cA mice. Exposure to MCA and MX intrarectally apparently promoted the growth of aberrant crypt foci both in rats and mice, increasing the crypt multiplicity, aberrant crypts/aberrant crypt foci. Based on an overall evaluation of these experiments, the intestinal tract, at least in rats and mice, seems not to be a main target organ for effects of MCA or MX on preneoplastic or neoplastic development.

1,2-Dimethylhydrazine↗

PubMed1999

Determination of resonance frequency of the respiratory system in respiratory distress syndrome.

AIM: To measure tidal volume delivery produced by high frequency oscillation (HFO) at a range of frequencies including the resonance frequency. METHODS: Eighteen infants with respiratory distress syndrome were recruited (median gestation 28.7 weeks). Each was ventilated at frequencies between 8 and 30 Hertz. Phase analysis was performed at various points of the respiratory cycle. HFO was provided by a variable speed piston device. Resonance frequency was determined from the phase relation between the cyclical movements of the piston and pressure changes at the airway opening. Tidal volume was measured using a jacket plethysmograph. RESULTS: The results were most reproducible when analysis was performed at the end of inspiration (within 1 Hz in nine out of 10 cases). Comparison between tidal volume delivery at 10 Hz and resonance frequency was made in 10 subjects. Delivery was significantly higher at resonance than at 10 Hertz (mean percentage increase 92%, range 9-222%). CONCLUSIONS: These preliminary findings suggest that there is improved volume delivery at resonance frequency.

Airway Resistance↗

PubMed1999

New simple methods for isolating baroreceptor regions of carotid sinus and aortic depressor nerves in rats.

We developed new methods for isolating in situ baroreceptor regions of carotid sinus and aortic depressor nerves in halothane-anesthetized rats. After ligation of the root of the external carotid artery, the internal carotid and pterygopalatine arteries were embolized with two ball bearings of 0.8 mm in diameter. Bilateral carotid sinus pressures were changed between 60 and 180 mmHg in 20-mmHg steps lasting 1 min each. The sigmoidal steady-state relationship between aortic and carotid sinus pressures in 11 rats indicated the maximum gain of the carotid sinus baroreflex to be -2. 99 +/- 0.75 at 120 +/- 5 mmHg. An in situ isolation of the baroreceptor area of the right aortic depressor nerve could be made by ligation of the innominate, common carotid, and subclavian arteries in 9 rats. Pressure imposed on the subclavian baroreceptor was altered between 40 and 180 mmHg in 20-mmHg steps lasting 1 min each. The sigmoidal steady-state relationship between the aortic depressor nerve activity and imposed pressure showed that the baroreceptor gain peaked at 118 +/- 4 mmHg. We established an easy approach to the rat baroreflex and baroreceptor research.

Animals↗

PubMed1999

Simultaneous identification of static and dynamic vagosympathetic interactions in regulating heart rate.

We earlier reported that stimulation of either one of the sympathetic and vagal nerves augments the dynamic heart rate (HR) response to concurrent stimulation of its counterpart. We explained this phenomenon by assuming a sigmoidal static relationship between nerve activity and HR. To confirm this assumption, we stimulated the sympathetic and/or vagal nerve in anesthetized rabbits using large-amplitude Gaussian white noise and determined the static and dynamic characteristics of HR regulation by a neural network analysis. The static characteristics approximated a sigmoidal relationship between the linearly predicted and the measured HRs (response range: 212.4 +/- 46.3 beats/min, minimum HR: 96.0 +/- 28.4 beats/min, midpoint of operation: 196.7 +/- 31.3 beats/min, maximum slope: 1.65 +/- 0.51). The maximum step responses determined from the dynamic characteristics were 7.9 +/- 2.9 and -14.0 +/- 4.9 beats. min-1. Hz-1 for the sympathetic and the vagal system, respectively. Because of these characteristics, changes in sympathetic or vagal tone alone can alter the dynamic HR response to stimulation of the other nerve.

Acoustic Stimulation↗

PubMed1999

Neuronal uptake affects dynamic characteristics of heart rate response to sympathetic stimulation.

Recently, studies in our laboratory involving the use of a Gaussian white noise technique demonstrated that the transfer function from sympathetic stimulation frequency to heart rate (HR) response showed dynamic characteristics of a second-order low-pass filter. However, determinants for the characteristics remain to be established. We examined the effect of an increase in mean sympathetic stimulation frequency and that of a blockade of the neuronal uptake mechanism on the transfer function in anesthetized rabbits. We found that increasing mean sympathetic stimulation frequency from 1 to 4 Hz significantly (P < 0.01) decreased the dynamic gain of the transfer function without affecting other parameters, such as the natural frequency, lag time, or damping coefficient. In contrast, the administration of desipramine (0.3 mg/kg iv), a neuronal uptake blocking agent, significantly (P < 0.01) decreased both the dynamic gain and the natural frequency and prolonged the lag time. These results suggest that the removal rate of norepinephrine at the neuroeffector junction, rather than the amount of available norepinephrine, plays an important role in determining the low-pass filter characteristics of the HR response to sympathetic stimulation.

Adrenergic Uptake Inhibitors↗

PubMed1999

Leishmania species: models of intracellular parasitism.

Leishmania species are obligate intracellular parasites of cells of the macrophage-dendritic cell lineage. Indeed, the ability to survive and multiply within macrophages is a feature of a surprising number of infectious agents of major importance to public health, including Mycobacterium tuberculosis, Mycobacterium leprae, Listeria monocytogenes, Salmonella typhimurium, Toxoplasma gondii and Trypanosoma cruzi. The relationship between such organisms and their host cells is particularly intriguing because, not only are macrophages capable of potent microbicidal activity, but in their antigen-presenting capacity they can orchestrate the developing immune response. Thus, to initiate a successful infection parasites must gain entry into macrophages, and also withstand or circumvent their killing and degradative functions. However, to sustain a chronic infection, parasites must also subvert macrophage-accessory-cell activities and ablate the development of protective immunity. The leishmanias produce a wide spectrum of disease in mice, and as such they have provided excellent models for studying problems associated with intracellular parasitism. In recent years, largely using these organisms, we have made enormous progress in elucidating the mechanisms by which successful intracellular infection occurs. Furthermore, characterization of immunological pathways that are responsible for resistance or susceptibility to Leishmania has given rise to the Th1/Th2 paradigm of cellular/humoral dominance of the immune response.

Animals↗

PubMed1999

Measuring geographic atrophy in advanced age-related macular degeneration.

PURPOSE: To present a method developed for measuring areas of geographic atrophy (GA) in advanced age-related macular degeneration, METHODS: A microfilm reader projected the 30 degrees fundus photograph of the macula. Retinal landmarks, atrophic areas, and spared areas within the atrophy were traced, without access to drawings of other years. The total atrophic area was calculated, as was the atrophy within a four-disc-area circle entered on the estimated foveal center. The configuration of the atrophy was documented. RESULTS: Avoidable sources of discrepancy included variability in peripapillary atrophy seen on the photograph, and variability seen in the extent of the field. Reproducibility studies found a median absolute difference of 0.19 Macular Photocoagulation Study disc areas (DA) in total atrophy between repeat drawings, with 75% of repeat drawings having a difference of less than 0.33 DA. For central atrophy measures, there was a median difference of 0.08 DA, with 75% of pairs having a difference of less than 0.18 DA. Features making the definition of borders of GA difficult include the presence of drusen and pigmentary alteration, a fundus in which choroidal vessels are easily visible, and variation in the appearance of GA within a single area of atrophy. CONCLUSIONS: This method provides a reliable means of measuring the size of atrophic areas in GA and will be useful for measuring longitudinal change. It may be difficult to determine whether central spared areas are present, and correlation with visual acuity and macular perimetry may be helpful.

Aged↗

PubMed1999

Water chlorination and birth defects.

Chlorination of drinking water that contains organic compounds leads to the formation of by-products, some of which have been shown to have mutagenic or carcinogenic effects. As yet, too little is known about the possible teratogenic effects on the human fetus. We linked the Norwegian waterwork registry, containing 1994 data on chlorination practice and color (an indicator for natural organic matter), with the Medical Birth Registry for 1993-1995. The proportion of the population exposed to chlorination and a weighted mean color number in drinking water was computed for each municipality. Among 141,077 births, 2,608 (1.8%) had birth defects. In a comparison between exposed (high color; chlorination) and reference groups (low color; no chlorination), the adjusted odds ratio was 1.14 (0.99-1.31) for any malformation, 1.26 (0.61-2.62) for neural tube defects, and 1.99 (1.10-3.57) for urinary tract defects. This study provides further evidence of the role of chlorination of humic water as a potential cause of birth defects, in a country with relatively low levels of chlorination byproducts.

Abnormalities, Drug-Induced↗

PubMed1998

Leishmania mexicana cysteine proteinase-deficient mutants have attenuated virulence for mice and potentiate a Th1 response.

Leishmania mexicana mutants lacking cysteine proteinase genes cpa (delta cpa), cpb (delta cpb), or both cpa and cpb (delta cpa/cpb) have been generated by targeted gene disruption. Delta cpa mutants produce a disease phenotype in BALB/c mice close to that of wild-type L. mexicana, but delta cpb mutants are much less infective, producing very slowly growing small lesions, and delta cpa/cpb double mutants do not induce lesion growth. Immunologic analysis of Ab isotype during infection and splenocyte IFN-gamma, IL-2, and IL-4 production following stimulation with Leishmania Ag or Con A indicates that there was a significant shift from a predominantly Th2-associated immune response in mice infected with wild-type L. mexicana to a Th1-associated response in mice inoculated with delta cpb or delta cpa/cpb. Significantly, delta cpa altered the balance of the immunologic response to a lesser extent than did the other mutants. Similar disease outcomes and switches in the Th1/Th2 balance were also observed when other L. mexicana-susceptible mouse strains were infected with the mutants. BALB/c and C57BL/6 mice vaccinated with delta cpa/cpb and CBA/Ca mice vaccinated with delta cpb or delta cpa/cpb were subsequently more resistant, to varying degrees, than were untreated mice to infection with wild-type parasites, as measured by development of lesions and parasite burden. These data implicate leishmanial cysteine proteinases not only as parasite virulence factors but also in modulation of the immune response and provide strong encouragement that cysteine proteinase-deficient L. mexicana mutants are candidate attenuated live vaccines.

Animals↗

PubMed1998

Lipid vesicle size determines the Th1 or Th2 response to entrapped antigen.

Understanding the factors that control the differential induction of Th1 and Th2 responses is a key immunologic objective with profound implications for vaccination and immunotherapy of infectious and autoimmune diseases. Using Ag formulated in lipid vesicles prepared from nonionic surfactants, we describe a novel mechanism influencing the balance of the Th1 or Th2 response. Our results indicate that inoculation of BALB/c mice with vesicles with a mean diameter > or = 225 nm preferentially induces Th1 responses, as characterized by increased titers of IgG2a in plasma and elevated IFN-gamma production by lymph node cells. However, preparation of the same quantity of Ag in vesicles with mean diameter of < or = 155 nm induces a Th2 response, as identified by IgG1 in the absence of IgG2a production and increased lymph node IL-5 production. Although large (> or = 225 nm) vesicles could induce IL-12 production, smaller vesicles (< or = 155 nm) could not. However, small vesicles did induce higher levels of IL-1beta production by macrophages than larger vesicles. The role of IL-12 in this response was confirmed in IL-12-deficient mice, whose spleen cells failed to produce IFN-gamma following in vivo priming with Ag prepared in large vesicles. Our results therefore indicate that macrophages respond to endocytosis of large or small vesicles by producing different patterns of cytokines that can subsequently direct the immune response toward a Th1 or a Th2 phenotype.

Animals↗

PubMed1998

Liquid chromatographic determination of myocardial interstitial epinephrine.

This study describes a high-performance liquid chromatographic method with electrochemical detection (HPLC-ED) for monitoring of epinephrine (Epi) in the myocardial interstitial space. The in vitro detection limit for Epi was 200 fg in a 50-microl injection. Using a cardiac dialysis technique, 60-microl dialysates were sampled from the myocardial interstitial space (6-min fractions). After an alumina procedure, the dialysate Epi concentration was measured using the HPLC-ED system. Although the basal Epi concentration was undetectable, local administration of desipramine increased Epi concentration of the dialysate to 38.1+/-18.5 pg/ml. This system affords a new possibility for estimating myocardial interstitial Epi level.

Animals↗

PubMed1998

Termination of peripheral tolerance to a T cell epitope by heteroclitic antigen analogues.

Treating mice with an immunodominant T cell epitope from moth cytochrome c (MCC(88-103)) can induce T cell unresponsiveness under certain conditions of administration. In this report, we determined whether T cell tolerance to MCC(88-103) in adult animals can be overcome by immunization with cross-reactive analogues of the tolerizing Ag. A panel of analogues of the tolerogen were tested for their capacity to terminate the tolerant state following in vivo immunization. As analyzed by their stimulatory capacity for a representative MCC(88-103)-specific T cell clone, this panel covered a wide range of cross-reactivity, including nonantigenic, antagonistic, weakly, and strongly antigenic peptides. Interestingly, only heteroclitic analogues, as measured in vitro by their enhanced antigenicity for the T cell clone that was specific for MCC(88-103), were capable of breaking tolerance. Thus, an immune response to the cross-reactive, heteroclitic analogues of tolerized self Ags may represent a mechanism by which Ag molecular mimicry operates.

Animals↗

PubMed1998

Rescue of Caenorhabditis elegans pharyngeal development by a vertebrate heart specification gene.

Development of pharyngeal muscle in nematodes and cardiac muscle in vertebrates and insects involves the related homeobox genes ceh-22, nkx2.5, and tinman, respectively. To determine whether the nematode and vertebrate genes perform similar functions, we examined activity of the zebrafish nkx2.5 gene in transgenic Caenorhabditis elegans. Here, we report that ectopic expression of nkx2.5 in C. elegans body wall muscle can directly activate expression of both the endogenous myo-2 gene, a ceh-22 target normally expressed only in pharyngeal muscle, and a synthetic reporter construct controlled by a multimerized CEH-22 binding site. nkx2.5 also efficiently rescues a ceh-22 mutant when expressed in pharyngeal muscle. Together, these results indicate that nkx2.5 and ceh-22 provide a single conserved molecular function. Further, they suggest that an evolutionarily conserved mechanism underlies heart development in vertebrates and insects and pharyngeal development in nematodes.

Amino Acid Sequence↗

PubMed1998

The immunology of canine leishmaniosis: strong evidence for a developing disease spectrum from asymptomatic dogs.

Asymptomatic mixed breed dogs (49) from a region of high incidence of visceral leishmaniosis in Portugal were examined for the presence of Leishmania-specific cellular immunity using a proliferation assay and humoral immunity using an indirect antibody fluorescent test (IFAT) and an ELISA. The results were compared directly with 25 mixed breed dogs permanently residing in a non-endemic region (Scotland). Unlike similar studies in humans from non-endemic areas, there was no evidence of any immunological response against leishmanial antigen whatsoever from the latter group of animals. Of the 49 dogs from Portugal, however, 20 had demonstrable parasite-specific cellular immunity. Depending on the assay and criteria used to measure a positive humoral response, 11, 16 or 24 dogs had a Leishmania-specific humoral response with the ELISA being the most sensitive assay system. While 16, 12 or 8 of the dogs had clearly only a cellular response (depending on which criterion was used to constitute a true antibody response) and 7, 8 or 12 had only humoral response, other 4, 8 or 12 of the dogs had both cellular and humoral responses. This study clearly demonstrates that the infection rate of canine leishmaniosis is not only higher than previously thought using serological tests alone but that the response to infection is already highly polarised in many asymptomatic dogs. It is postulated that an individual dog's position within the immunological spectrum is likely to indicate how the disease will progress.

Animals↗

PubMed1998

[Mercury exposure from dental amalgam. Risk assessment and clinical evaluation].

Inorganic mercury is absorbed in small amounts from dental amalgam fillings. Exposure can be calculated by measuring the level of mercury in the blood or urine (u-Hg). The average u-Hg in Norwegians is approximately 2-3 micrograms/g creatinine (approximately 1-2 nmol/mmol creatinine). Classic signs of mercury poisoning occur in a fraction of long-term exposed subjects with u-Hg > 100 micrograms/g creatinine (56 nmol/mmol creatinine). Subtle effects (e.g. enzymuria, altered selenium metabolism, and changes in tremor spectra) have been reported in humans at average levels of 20-35 micrograms/g creatinine (approximately 11-20 nmol/mmol creatinine). There is widespread concern about possible adverse effects of mercury from amalgam fillings. Data on exposure-response relationships make it less likely that low-level mercury exposure from amalgam fillings should cause symptoms or physical signs. Studies of the association between symptoms and amalgam fillings have been negative. Patients with symptoms allegedly caused by mercury from amalgam should undergo thorough medical examination. Based on the patient's symptoms and physical signs adequate time should be allowed for careful recording of medical history, physical examination and relevant laboratory tests.

Dental Amalgam↗

PubMed1998

Identification of Db- and Kb-restricted subdominant cytotoxic T-cell responses in lymphocytic choriomeningitis virus-infected mice.

Antiviral cytotoxic T-cells are critical for control of lymphocytic choriomeningitis virus (LCMV) infection in mice. In H-2b mice, the antiviral response is directed against three Db-restricted epitopes in the viral nucleoprotein (NP396-404) and glycoprotein (GP276-286 and GP33-41). Our present data revealed a clear hierarchy among these three epitopes, in which NP396-404 is immunodominant, followed by GP33-41 and GP276-286, respectively. In order to identify additional CTL epitopes in the LCMV nucleoprotein and glycoprotein, we used the motifs for Db2- and Kb-binding peptides, combined with MHC class I-binding assays. Out of 23 Db motif-fitting peptides, we identified 4 Db binders, one of which (GP92-101) turned out to be a new CTL epitope. Among 28 Kb motif-fitting peptides, 12 bound Kb, and one of these (NP205-212) was a CTL epitope. Both newly identified CTL peptides were recognized by LCMV-immune splenocytes after secondary in vitro stimulation. Both peptides bound their MHC class I molecules with intermediate affinity (470 and 170 nM for GP92-101 and NP205-212, respectively). Responses against these peptides were weaker than the responses against the three major epitopes. None of the high affinity binders were new epitopes, suggesting that high affinity binders are either immunodominant epitopes or no epitopes at all. Thus, analysis of 51 Kb and Db motif-fitting peptides yielded 2 new, subdominant epitopes. Immunization of C57BL/6 mice with these peptides, or vaccinia virus recombinants expressing these epitopes as minigenes, protected against chronic LCMV infection, demonstrating that immunization with subdominant epitopes can confer protection against chronic viral infection.

Amino Acid Sequence↗

PubMed1998

Screening mosaic F1 females for mutations affecting zebrafish heart induction and patterning.

The genetic pathways underlying the induction and anterior-posterior patterning of the heart are poorly understood. The recent emergence of the zebrafish model system now allows a classical genetic approach to such challenging problems in vertebrate development. Two large-scale screens for mutations affecting zebrafish embryonic development have recently been completed; among the hundreds of mutations identified were several that affect specific aspects of cardiac morphogenesis, differentiation, and function. However, very few mutations affecting induction and/or anterior-posterior patterning of the heart were identified. We hypothesize that a directed approach utilizing molecular markers to examine these particular steps of heart development will uncover additional such mutations. To test this hypothesis, we are conducting two parallel screens for mutations that affect either the induction or the anterior-posterior patterning of the zebrafish heart. As an indicator of cardiac induction, we examine expression of nkx2.5, the earliest known marker of precardiac mesoderm; to assess anterior-posterior patterning, we distinguish ventricle from atrium with antibodies that recognize different myosin heavy chain isoforms. In order to expedite the examination of a large number of mutations, we are screening the haploid progeny of mosaic F1 females. In these ongoing screens, we have identified four mutations that affect nkx2.5 expression as well as 21 that disrupt either ventricular or atrial development and thus far have recovered several of these mutations, demonstrating the value of our approach. Future analysis of these and other cardiac mutations will provide further insight into the processes of induction and anterior-posterior patterning of the heart.

Animals↗