Immunoregulation during toxoplasmosis.
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Animals↗
Biomedical subjects
J Alexander
Publications and source records attributed to J Alexander.
A double-blind trial of gabapentin monotherapy for newly diagnosed partial seizures. International Gabapentin Monotherapy Study Group 945-77.
BACKGROUND: Gabapentin is widely approved as add-on therapy for epilepsy treatment for partial seizures with and without secondary generalization. To investigate the efficacy of gabapentin administered as monotherapy in patients with newly diagnosed partial epilepsy, a randomized double-blind trial was performed. METHODS: Eligible patients were randomized to receive one of three masked doses of gabapentin (300, 900, or 1,800 mg/day) or open-label carbamazepine (600 mg/day) and kept daily seizure diaries throughout the study. After titration, patients entered a 24-week evaluation phase. Patients were required to exit the study if they experienced an exit event, defined as a total of three simple or complex partial seizures, one generalized tonic-clonic (GTC) seizure, or status epilepticus. Patients could be withdrawn for lack of efficacy, adverse events, or noncompliance. Kaplan-Meier statistics were used to estimate the probability that patients would continue in the study without having an exit event. RESULTS: Time to exit event was longer for patients on 900 mg/day (n = 72) or 1,800 mg/day (n = 74) of gabapentin than for patients receiving 300 mg/day (n = 72; p = 0.0395 and 0.0175, respectively). The most clinically relevant measure of retention on treatment (exit event plus adverse event withdrawal rate) was similar for carbamazepine (n = 74) and 1,800 mg/day gabapentin (54% versus 57%) but was lower (better) for 900 mg/day gabapentin (44%). No unexpected new adverse events emerged with gabapentin monotherapy. CONCLUSIONS: Gabapentin at 900 or 1,800 mg/day is effective and safe as monotherapy for patients with newly diagnosed partial epilepsy.
Acetates↗
Adenocarcinoma in an isolated ileal sleeve 30 years after periureteral wrap.
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Adenocarcinoma↗
Derivation of HLA-A11/Kb transgenic mice: functional CTL repertoire and recognition of human A11-restricted CTL epitopes.
Transgenic mice expressing chimeric human (alpha1 and alpha2 HLA-A11 domains) and murine (alpha3, transmembrane, and cytoplasmic H-2Kb domains) class I molecules were derived. These mice were used as a model system to study the immunogenicity of human CTL epitopes and also to examine the aspects of Ag processing differences of mice vs man. Immunization of these mice with seven known HLA-A11-restricted CTL epitopes emulsified in IFA resulted in vigorous specific CTL responses. A larger panel of 45 A11-binding peptides was used to examine the relationship between immunogenicity in the HLA-A11/Kb transgenic mice and HLA-A11 binding capacity. Twenty-one of 28 (75%) peptides with high binding affinities (50% inhibitory concentration (IC50), 2-50 nM) and 7 of 13 (54%) intermediate binding peptides (IC50, 50-500 nM range) were immunogenic. In parallel, 19 of these peptides were used for in vitro primary immunizations of PBMC derived from HLA-A11 healthy human donors. It was found that 8 of 8 peptides that were able to elicit CTL in primary human in vitro cultures were also immunogenic in HLA-A11/Kb mice. Finally, HLA-A11/Kb transgenic mice were found to generate an A11/Kb restricted CTL response following immunization with influenza virus A/PR/8/34, suggesting that, at least to some extent, A11 epitopes are generated by transgenic mice as a result of natural in vivo processing and presentation.
Animals↗
SCID mice reconstituted with IL-4-deficient lymphocytes, but not immunocompetent lymphocytes, are resistant to cutaneous leishmaniasis.
To characterize the roles of lymphoid- and non-lymphoid-derived IL-4 during cutaneous infection with Leishmania mexicana, the disease was monitored in SCID mice reconstituted with splenocytes from either immunocompetent BALB/c mice or IL-4-deficient BALB/c mice. Whereas following s.c. infection with L. mexicana no lesion growth was observed in BALB/c IL-4(-/-) mice and lesion growth was significantly inhibited in SCID mice, rapid initial lesion growth occurred in both SCID IL-4(+/+) and SCID IL-4(-/-) reconstituted mice. However, after 3 to 4 wk of infection, lesions in SCID IL-4(-/-) but not SCID IL-4(+/+) reconstituted mice began to heal. This paralleled a developing Th1-like phenotype and parasite clearance in the former group and a developing Th2-like phenotype in the latter group. Lesion sites from the healing SCID IL-4(-/-) mice expressed the inducible nitric oxide synthase, whereas the SCID IL-4(+/+) mice with progressive disease did not. These findings indicate that non-lymphocyte-derived IL-4 may play a role in initiating lesion growth following cutaneous infection with L. mexicana, but the presence of lymphocyte-derived IL-4 is essential for disease progression, and in its absence, lesions heal due to a developing Th1 phenotype.
Animals↗
Mechanisms of innate resistance to Toxoplasma gondii infection.
The interaction of protozoan parasites with innate host defences is critical in determining the character of the subsequent infection. The initial steps in the encounter of Toxoplasma gondii with the vertebrate immune system provide a striking example of this important aspect of the host-parasite relationship. In immuno-competent individuals this intracellular protozoan produces an asymptomatic chronic infection as part of its strategy for transmission. Nevertheless, T. gondii is inherently a highly virulent pathogen. The rapid induction by the parasite of a potent cell-mediated immune response that both limits its growth and drives conversion to a dormant cyst stage explains this apparent paradox. Studies with gene-deficient mice have demonstrated the interleukin-12 (IL-12)-dependent production of interferon gamma (IFN-gamma) to be of paramount importance in controlling early parasite growth. However, this seems to be independent of nitric oxide production as mice deficient in inducible nitric oxide synthase (iNOS) and tumour necrosis factor receptor were able to control early growth of T. gondii, although, they later succumbed to infection. Nitric oxide does, however, seem to be important in controlling persistent infection; treating chronic infection with iNOS metabolic inhibitors results in disease reactivation. Preliminary evidence implicates neutrophils in effector pathways against this parasite distinct from that described for macrophages. Once initiated, IL-12-dependent IFN-gamma production in synergy with other proinflammatory cytokines can positively feed back on itself to induce 'cytokine shock'. Regulatory cytokines, particularly IL-10, are essential to down-regulate inflammation and limit host pathology.
Animals↗
[Genetic and environmental factors in colorectal cancer. Mutations in the familial adenomatous polyposis gene].
The incidence of colon cancer has increased during the last 30 years in Norway and is now the second most common newly diagnosed type of cancer in women and the third in men. Familial adenomatous polyposis, hereditary colorectal cancer, is caused primarily by inactivation of the tumour suppressor gene adenomatous polyposis coli (APC). The protein coded for by this gene has a possible role in cell-cell signalling or adhesion by binding to catenins which bind to the cell adhesion molecule E-cadherin, or in anchoring the cytoskeleton. Both germ-line and somatic APC gene mutations result in a truncated protein, due to introduction of a stop codon. The positions of the germ-line mutations seem to correlate with the seriousness of polyposis. The food mutagen PhIP causes specific mutations in the Apc gene in rats, and is a possible environmental mutagen also in humans. The Min mouse with mutated Apc-gene is a good model for studies of both induction and prevention of inherited and sporadic intestinal cancer.
Adenomatous Polyposis Coli↗
Binding of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) to protein- and low molecular weight thiols and its role in ring hydroxylation.
The N-oxidized species of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) have been shown to react with thiols. We have previously characterized a glutathione conjugate of PhIP linked via the C2 of PhIP with apparent loss of the amino group, in rat hepatocytes and PhIP exposed rats. This metabolite was possibly formed from 1-methyl-2-nitro-6-phenylimidazo[4,5-b]pyridine (nitro-PhIP). Upon reacting nitro-PhIP with rat albumin, both in the presence and absence of a reducing system, four products were observed after enzymic proteolysis. One of them was markedly increased after 2-mercaptoethanol treatment of the protein. This adduct was linked to a cysteine-S via C2 of PhIP. Using N2-acetoxy-PhIP as a starting material, an unstable protein adduct was observed which degraded to 50% of the original concentration (t 1/2) after 3 days. This is compatible with the finding that serum PhIP adducts decline rapidly in PhIP exposed rats. Unstable adducts were also formed following the reaction of N2-acetoxy-PhIP with glutathione or cysteine. Based on mass spectroscopy and UV spectra analysis, the suggested structures were RS(-S-)-(H)N2-PhIP. In all cases a degradation product identified as 5-hydroxy-PhIP was formed as characterized by mass spectrometry and NMR spectroscopy. 5-hydroxy-PhIP and its glucuronyl derivative were also observed in rat hepatocytes incubated in vitro with PhIP. In bile of PhIP-exposed rats, only the glucuronyl derivative was observed. Depletion of glutathione reduced the amount excreted in bile and experiments with microsomes indicate that hydroxylation directly at the 5 position is not mediated by cytochrome P-450 mono-oxygenase system. This indicates that 5-hydroxy-PhIP may be formed from N-acetoxy-PhIP via binding to thiols also in cells.
Animals↗
Differential T cell signaling induced by antagonist peptide-MHC complexes and the associated phenotypic responses.
Certain changes in TCR contact residues have been shown to have profound effects on the capacity of a peptide Ag to stimulate a T cell response. Although some of these changes apparently lead to a complete loss of the ability to interact with the TCR, others result in partial agonist activity (e.g., cytokine production without proliferation) or antagonist activity (i.e., the capacity to inhibit the engagement to the TCR by Ag). We show MHC class II-restricted antagonist activity was associated with a differential pattern of early tyrosine phosphorylation events that was characterized by a preponderance of phosphorylation of low molecular mass TCRzeta and the failure to phosphorylate Zap-70. These early tyrosine phosphorylation patterns are the same as those previously described for partial agonists. Thus, a partial agonist phenotype such as anergy induction cannot be ascribed in a causal manner to this pattern of tyrosine phosphorylation. We further extend the studies of signal transduction elicited by agonist and antagonist peptides by characterizing differential recruitment of Zap-70 associated with TCRzeta isoforms and differential phosphorylation of p120 proto-oncogene c-Cbl. Another early event following TCR engagement by Ag, down-modulation of the TCR, was studied with antagonist peptides. We show that antagonist peptides do not cause TCR down-modulation. This failure may represent a mechanism by which antagonists inhibit antigen-mediated stimulation of T cells.
Amino Acid Sequence↗
Occult choroidal neovascularization in age-related macular degeneration. A natural history study.
OBJECTIVE: To explore morphological and vision changes in untreated eyes with subfoveal choroidal neovascularization (CNV) that have poorly demarcated boundaries. DESIGN: Analysis of photographs of untreated patients with poorly demarcated occult CNV participating in a prospective clinical trial evaluating laser treatment compared with observation. SETTING: Two tertiary retinal referral centers. PATIENTS: Symptomatic individuals with poorly demarcated subfoveal occult CNV associated with age-related macular degeneration. MAIN OUTCOME MEASURES: Change in size of lesion, development of classic CNV, change in vision, and development of subretinal fibrosis. RESULTS: During follow-up (9-12 months), 32% of the occult choroidal neovascular lesions more than doubled their original size. Classic CNV developed in 52% of eyes that started without it. The median loss in visual acuity was 2.5 lines. Eyes with classic CNV or subretinal blood or both at baseline developed subretinal fibrosis more frequently and lost more visual acuity, but not to a statistically significant degree. CONCLUSIONS: The morphological changes of eyes with subfoveal occult CNV in which the boundaries are poorly demarcated in variable; the presence of subretinal blood or a component of classic CNV may influence the prognosis for further loss of vision.
Aged↗
Aberrant results due to incorrect use of the Bayer Glucometer 4 meter.
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Blood Glucose↗
Nitric oxide treatment of severe hypoxemia after liver transplantation in hepatopulmonary syndrome: case report.
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Child, Preschool↗
A bilaminar record base for a complete overdenture with severe hard tissue undercuts: a clinical report.
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Adult↗
Effects of a homoanatoxin-a-containing extract from Oscillatoria formosa (Cyanophyceae/cyanobacteria) on neuromuscular transmission.
Experimental investigations were carried out with cultured and lyophilized material of the toxigenic strain Oscillatoria NIVA-CYA 92. This organism is classified as Phormidium formosum (Boryex Gom.) Anagnet kom. Aqueous extracts of the algal material, containing the bioactive secondary amine alkaloid 2-(propan-1-oxo-1-yl)-9-azabicyclo(4,2,1)non-2ene (homoanatoxin-a) in an amount of 2.57 micrograms/mg lyophilized material, were tested for acute in vivo toxicity in mice, and for toxicity on neuromuscular transmission by means of electrophysiological methods on the isolated phrenic-nerve hemidiaphragm from rat and in the frog rectus abdominis assay. Acute toxic effects in mice were observed by i.p. and oral (by gavage) administration. Lethal doses were in the range 112-225 and 1125-2250 mg of freeze-dried algal material per kg body weight (i.e. 288-578 and 2890-5780 micrograms homoanatoxin-a/ kg body weight), respectively. The nerve-initiated muscle contractions in the rat diaphragm were blocked by about 0.125 mg cyanophyte material per ml bath solution (i.e. 0.32 microgram homoanatoxin-a/ml or 1.8 microM), but muscle contractions, although slightly reduced, could still be elicited by direct electrical stimulation of the muscle. The compound action potentials recorded from the main phrenic-nerve trunk were not affected. An additive blocking effect on partly curarized preparations was observed and cholinesterase inhibition by physostigmine (eserine) transiently augmented the muscle twitch contraction in preparations partly blocked by the extract. Intracellular recordings from single muscle fibers of homoanatoxin-a-treated rat hemidiaphragm disclosed a partial depolarization and a decrease in the endplate potential to subthreshold level simultaneously with a decrease and then complete disappearance of the miniature endplate potentials. The neuromuscular transmission block was reversed by washing. The extract produced muscle contractions in the frog rectus abdominis assay. Homoanatoxin-a in the algal material was readily absorbed from the gastrointestinal tract in mice. Blockade of the neuromuscular transmission of the respiratory muscle may partly explain the acute toxic effects observed in mice. Thus, the main target of the homoanatoxin-a action at the mammalian neuromuscular junction was traced to the postsynaptic nicotinic acetylcholine receptor channel complex, where it reduced the sensitivity to the transmitter substance.
Animals↗
Potent immunogenic short linear peptide constructs composed of B cell epitopes and Pan DR T helper epitopes (PADRE) for antibody responses in vivo.
Induction of humoral immune responses against protein antigen requires that two independent signals be delivered to B cells. It is currently assumed that simple monovalent synthetic peptides would not be effective immunogens for antibody responses because they would not be anticipated to effectively generate the necessary signals unless conjugated to a complex carrier system. In this study, the immunogenicity of short linear peptide constructs comprising Plasmodium vivax B cell epitopes (PVB) and non-natural Pan-DR T helper cell epitopes (PADRE) was assessed in mice and compared to other types of antigen constructs. The 33-residue PADRE-PVB linear constructs were highly immunogenic and induced responses comparable to those obtained with the multiple antigen peptides (MAP) constructs, both in terms of absolute titers and quality of antibody responses. The anti-PVB antibody responses were of long duration, composed mostly of IgG and reactive with intact sporozoites. The PADRE-PVB constructs were immunogenic when formulated in adjuvants such as Alum and Montanide ISA 51 underlining the relevance of these findings for vaccine development.
Adjuvants, Immunologic↗
What is the normal pattern of uterine involution? An investigation of postpartum uterine involution measured by the distance between the symphysis pubis and the uterine fundus using a paper tape measure.
OBJECTIVE: To describe normal postnatal uterine involution in a small sample of healthy primiparous women, and estimate the proportion who have a decline in the distance between the symphysis pubis and the uterine fundus (S-FD) slow enough to have the potentiality to trigger further clinical action, using currently accepted criteria for intervention. SETTING: A maternity unit in the south of England that has approximately 6000 deliveries per annum and the related community areas. METHODS: Daily measurement of the S-FD was carried out in 28 healthy women from within 18 hours of delivery until the uterine fundus was no longer palpable abdominally. Graphs showing the daily measurements and correlation coefficients were used to describe involution. The proportion of healthy women who would have been identified as healthy by the screening method was estimated (its specificity). FINDINGS: Considerable variability was found in the pattern of uterine involution that was experienced by the women who had a normal puerperium. The measurement of the S-FD has a low specificity with only 6 of the 28 women (21.4%; 95% CI 8.3% to 40.9% having had no episodes of the S-FD declining slowly (less than 1 cm over three days). There was a weak, positive correlation between the S-FD measurement on day one and the day on which the uterus ceased to be palpable (r = 0.426, P = 0.03). No relationship was found between method of baby feeding and the day on which the uterus ceased to be palpable. IMPLICATIONS FOR PRACTICE: The measurement of S-FD using a paper tape measure should not form part of routine postpartum assessment.
Adolescent↗
A comparison of vascularized and nonvascularized bone grafts for reconstruction of mandibular continuity defects.
PURPOSE: This study compared vascularized and nonvascularized bone grafts for the reconstruction of segmental defects of the mandible. PATIENTS AND METHODS: The results in 39 patients having vascularized bone grafts (38 fibulas and one iliac crest) and 29 patients having nonvascularized bone grafts (26 iliac crest [22 corticocancellous block grafts, four cancellous bone grafts in a tray] and three rib grafts) for segmental mandibular reconstruction were evaluated in terms of overall success rate, total number of surgeries performed, total blood loss, total number of hospital days, and total number of hours in the operating room. RESULTS: Of 39 vascularized bone grafts, two failed (95% success rate), whereas of 29 nonvascularized bone grafts, seven failed (76% success rate). Failure for the nonvascularized bone grafts was closely correlated to the length of the defect. Nonvascularized bone graft patients underwent an average of one more surgical procedure for total reconstruction than vascularized bone graft patients, including osseointegrated implants. However, vascularized bone graft patients spent a mean of over 14 additional days in the hospital for all of their reconstructive procedures and an additional 3 hours in the operating room as compared with nonvascularized bone graft patients. Blood loss was similar in both groups (1,100 mL). Only 20% to 24% of patients in each treatment group have completed reconstruction to include osseointegrated implants. CONCLUSIONS: The success rate for vascularized bone grafting is high and is the treatment of choice when primary reconstruction is required, when the patient has been previously irradiated, or when simultaneous replacement of soft tissue is required. Vascularized bone grafts are also the treatment of choice for mandibular replacements over 9 cm in length. Nonvascularized bone grafts create a better contour and bone volume for facial esthetics and subsequent implant insertion, and may be the treatment of choice for secondary reconstruction of defects less than 9 cm in length.
Adolescent↗