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Biomedical subjects

D Peters

Publications and source records attributed to D Peters.

At least 37 records · Page 2Linked to original sources
PubMed2000

Increased glomerular deposits of von Willebrand factor in chronic, but not acute, rejection of primate renal allografts.

BACKGROUND: In our previously described primate renal allograft model, T cell ablation leads to long-term graft survival. The role of endothelial cell alteration in chronic rejection was examined in our model. METHODS: Renal transplants were performed in rhesus monkeys using a T cell- depleting immunotoxin, FN18-CRM9. Sections from 10 rejected kidneys (5 acute and 7 chronic rejection) were examined after immunohistochemical staining for expression of endothelium-related proteins [von Willebrand factor (vWF), CD62P, and CD31], fibrinogen, and a macrophage marker (CD68). Glomerular staining for each antigen was graded on a semiquantitative scale. RESULTS: Intense staining for vWF was consistently observed in glomerular endothelium, subendothelium, and mesangium in all kidneys removed due to chronic rejection. vWF staining was weak in kidneys showing acute rejection. The difference in glomerular staining was statistically significant. Staining for vWF in extraglomerular vessels was nearly identical in kidneys showing acute and chronic rejection. Expression of CD62P was increased in extraglomerular vessels in allografts with chronic rejection, but the glomeruli showed little or no staining. There was no significant difference in the glomerular staining for CD62P or CD31 in organs showing acute and chronic rejection. Fibrinogen staining of glomerular mesangium was seen in kidneys with chronic rejection. Macrophages (CD68+) infiltrating glomeruli were more numerous in kidneys showing chronic rejection. CONCLUSION: Increased glomerular deposition of vWF in renal allografts showing chronic rejection, without increased staining for CD62P or CD31, suggests increased constitutive secretion of vWF from endothelial cells as a component of the mechanism of chronic rejection in our model.

Acute Disease↗
PubMed2000

Novel potent ligands for the central nicotinic acetylcholine receptor: synthesis, receptor binding, and 3D-QSAR analysis.

In the past few years the focus on central acetylcholine receptors has shifted from compounds with affinity for muscarinic acetylcholine receptors (mAChR) to compounds with affinity for nicotinic acetylcholine receptors (nAChR). The therapeutic potential includes treatment of a variety of diseases, e.g., Alzheimer's disease, Parkinson's disease, and Tourette's syndrome. This work describes the synthesis of six novel series of potent ligands with nanomolar affinity for the alpha4beta2 nAChR subtype. Structure-activity relationship (SAR) was evaluated by the calculation of a 3D-QSAR model. 3D-QSAR analysis of the compounds using the GRID/GOLPE methodology resulted in a model of high quality (R(2) = 0.97, Q(2) = 0.81). The coefficient plots reveal that the steric interactions between the target and our compounds are of major importance for the affinity. Bulky substituents in the 6-position of the pyridine ring will reduce the affinity of the compounds, whereas bulky ring systems including a sp(3)-nitrogen will increase the affinity of the compounds.

Alkaloids↗
PubMed2000

Potentiation of CD3-induced expression of the linker for activation of T cells (LAT) by the calcineurin inhibitors cyclosporin A and FK506.

The activation of blood cells, including T cells, triggers intracellular signals that control the expression of critical molecules, including cytokines and cytokine receptors. We show that T-cell receptor (TCR) ligation increases the cellular level of the protein linker for activation of T cells (LAT), a molecule critical for T-cell development and function. T-cell activation increased LAT messenger RNA, as determined by reverse transcription-polymerase chain reaction and by Northern blotting. The TCR-induced increase in LAT expression involved the activation of the serine/threonine kinases PKC and MEK, because inhibitors of these kinases blocked the increase in LAT. Accordingly, the PKC activator phorbol myristate acetate up-regulated LAT expression. Strikingly, the calcineurin inhibitors cyclosporin A (CsA) and FK506 strongly potentiated TCR-induced LAT expression, suggesting that the activation of calcineurin following TCR ligation negatively regulates LAT expression. Accordingly, Ca(++ )ionophores, which can activate calcineurin by increasing intracellular Ca(++), blocked the TCR-induced increase in cellular LAT. CsA and FK506 blocked the Ca(++ )ionophores' inhibitory effect on LAT expression. Notably, CsA and FK506 preferentially up-regulated TCR-induced LAT expression; under the same conditions, these compounds did not increase the expression of 14 other molecules that previously had been implicated in T-cell activation. These data show that TCR-induced LAT expression involves the activation of the PKC-Erk pathway and is negatively regulated by the activation of calcineurin. Furthermore, the potentiation of TCR-induced LAT expression by CsA and FK506 suggests that the action of these agents involves up-regulating the cellular level of critical signaling molecules. These findings may have important therapeutic implications. (Blood. 2000;95:2733-2741)

Adaptor Proteins, Signal Transducing↗
PubMed2000

Activity of voriconazole against Candida albicans and Candida krusei isolated since 1984.

With the recent dramatic rise in fluconazole use, there has been an increase in Candida species resistant to that agent. This has led to the clinical development of newer triazoles such as voriconazole that have greater potency and a broader spectrum of activity. We therefore hypothesized that fluconazole-resistant Candida albicans and Candida krusei would be susceptible to voriconazole. Susceptibility testing was performed on 205 isolates of C. albicans collected from 1984 to 1995, and on C. albicans and C. krusei that were identified as fluconazole resistant since 1995. The anti fungal agents used were amphotericin B, 5-flucytosine, itraconazole, ketoconazole, fluconazole and voriconazole. Three C. albicans and 26 C. krusei isolates had a minimum inhibitory concentration (MIC) >/=20 mg/l and were defined as fluconazole resistant. Of these, 28 isolates were susceptible to </=2.5 mg/l voriconazole, with a mean MIC of 0.78 mg/l. The mean amphotericin B MIC for these same strains was 0.98 mg/l. Only one isolate of C. krusei was relatively resistant to voriconazole with a MIC of 5 mg/l. Of these 29 isolates, there were ten amphotericin-resistant strains of C. krusei (MIC>2 mg/l) but all were susceptible to </=2.5 mg/l voriconazole. The higher potency of voriconazole may be useful in the treatment of fluconazole- and amphotericin-resistant C. albicans and C. krusei.

Antifungal Agents↗
PubMed2000

Location of mutations within the PKD2 gene influences clinical outcome.

BACKGROUND: Since the cloning of the gene for autosomal dominant polycystic kidney disease type 2 (PKD2), approximately 40 different mutations of that gene have been reported to be associated with the disease. The relationship between the PKD2 genotype and phenotype, however, remains unclear. METHODS: Detailed clinical information was collected for PKD2 families in which the underlying mutation had been identified. Logistic regression analysis was employed to assess the influence of age and sex on hypertension, hematuria, renal calculi, and urinary tract infections, and a clinical phenotype score was computed. Patients were then grouped according to the relative location of their mutation within the cDNA sequence, and differences in the mean phenotypic score between groups were tested for statistical significance by means of a multiple pairwise t-test. RESULTS: While phenotypic scores for each mutational group revealed a considerable degree of intragroup variability, the variability in phenotypic scores was significantly higher between mutational groups than within groups. A group-wise comparison of the mean phenotypic scores confirmed the observation of significant nonlinear variation in disease severity, with high- and low-scoring mutational groups interspersed along the gene sequence. CONCLUSION: The identification of groups of mutations in the PKD2 gene, which differ significantly with respect to clinical outcome, is to our knowledge the first description of a genotype/phenotype correlation in autosomal dominant polycystic kidney disease. It also provides evidence against complete loss of function of the mutant PKD2 gene product.

Analysis of Variance↗
PubMed2000

Using a computer-based clinical management system to improve effectiveness of a homeopathic service in a fundholding general practice.

UNLABELLED: Problems which the development attempts to address. This study's overall objectives were to determine whether: * The aims of collaboration between General Practitioner (GPs) and a homeopath can be made explicit and service delivery optimised by using computer-based data collection in a multi-disciplinary primary care team that includes a homeopathic practitioner. * Outcomes of the homeopathic service can be evaluated in a practical way, which allows quality assurance through rapid audit cycles. METHOD: The primary care team (PCT) explored the problems of developing a rational and quality assured complementary therapy service in a series of meetings in an NHS practice where complementary therapists are members of the PCT. This led to the defining of data-collection structures and processes needed. The researchers designed and supervised their implementation and evaluation through a series of action research cycles. A database was designed which allowed the clinicians to track interventions and outcomes using the Measure Your Own Medical Outcome Profile (MYMOP). Critical incidents were brought to fortnightly clinical meetings and methods were continually adapted as problems arose and new options emerged at six-weekly audit meetings. RESULTS: GPs tended to refer patients who do not fit easily into biomedical disease categories. Patients referred tend to self-rate themselves as experiencing notably poor wellbeing. MYMOP has to be used skillfully with homeopathic patients, especially where psychological distress is identified as one of their main complaints. CONCLUSIONS: It is possible to introduce rigour and reflectiveness when providing a homeopathic service in general practice by assessing the needs of patient and practitioners, agreeing intake guidelines, developing referral processes, implementing audit cycles. Clear lines of communication can be established and a patient-centred outcome measure can be introduced into the treatment cycle.

Database Management Systems↗
PubMed1999

Model for estimation of human exposure to copper in drinking water.

A model denominated Consumption Habit Exposure Model, (CHEM), was developed for the calculation of human individual acute and chronic exposure to copper in drinking water. The model can estimate daily exposure of individuals as well as the maximum concentration of copper which individuals ingest during a 24-h period. The CHEM model requires carrying out a water consumption habit questionnaire and measuring the minimum and maximum concentration of copper in homes, as well as minimum and random copper concentration at work and study places. The case study employed was a representative sample of the population of Santiago, Chile. The validation of the model was established with reference to the application in a limited number of homes of the composite proportional method, (CPS), used to measure human chronic ingestion of contaminants from drinking water. It was found that 4.5% of the sampled population is exposed daily to one cup of water or more at the maximum copper concentration available at the tap. The probabilities that the different age groups are exposed to one cup or more of water at cMAX during 1 day are greater for the 20-64-year-old group, followed by the 64-year-old group, and then by the younger age groups in descending order. Ingestion of copper from drinking water by the population of Santiago is on average 9.0% of the World Health Organization recommendations for minimum total ingestion of copper for adults, assuming that 100% of the copper contained in drinking water is absorbed.

Adolescent↗
PubMed1999

Sonochemical treatment of natural ground water at different high frequencies: preliminary results.

Naturally occurring ground water polluted by highly volatile chlorinated compounds, with 1,2-dichloroethane as the main contaminant, was sonicated with high frequency ultrasound (361, 620 and 1086 kHz) in order to investigate if results from studies performed with single model compounds in water can be applied to a natural ground water. It was shown that the treated highly volatile halogenated hydrocarbons are almost completely destroyed by ultrasound in natural ground water within 60 min. It also transpired that the naturally occurring inorganic components and gases in the ground water play an important role.

Fresh Water↗
PubMed1999

Effects of cold water immersion on the symptoms of exercise-induced muscle damage.

Cryotherapy is an effective treatment for acute sports injury to soft tissue, although the effect of cryotherapy on exercise-induced muscle damage is unclear. The aim of this study was to assess the effects of cold water immersion on the symptoms of exercise-induced muscle damage following strenuous eccentric exercise. After performing a bout of damage-inducing eccentric exercise (eight sets of five maximal reciprocal contractions at 0.58 rad x s(-1)) of the elbow flexors on an isokinetic dynamometer, 15 females aged 22.0+/-2.0 years (mean +/- s) were allocated to a control group (no treatment, n = 7) or a cryotherapy group (n = 8). Subjects in the cryotherapy group immersed their exercised arm in cold water (15 degrees C) for 15 min immediately after eccentric exercise and then every 12 h for 15 min for a total of seven sessions. Muscle tenderness, plasma creatine kinase activity, relaxed elbow angle, isometric strength and swelling (upper arm circumference) were measured immediately before and for 3 days after eccentric exercise. Analysis of variance revealed significant (P < 0.05) main effects for time for all variables, with increases in muscle tenderness, creatine kinase activity and upper arm circumference, and decreases in isometric strength and relaxed elbow angle. There were significant interactions (P<0.05) of group x time for relaxed elbow angle and creatine kinase activity. Relaxed elbow angle was greater and creatine kinase activity lower for the cryotherapy group than the controls on days 2 and 3 following the eccentric exercise. We conclude that although cold water immersion may reduce muscle stiffness and the amount of post-exercise damage after strenuous eccentric activity, there appears to be no effect on the perception of tenderness and strength loss, which is characteristic after this form of activity.

Adult↗
PubMed1999

Tissue tropism related to vector competence of Frankliniella occidentalis for tomato spotted wilt tospovirus.

The development of tomato spotted wilt tospovirus (TSWV) infection in the midgut and salivary glands of transmitting and non-transmitting thrips, Frankliniella occidentalis, was studied to elucidate tissue tropism and the virus pathway within the body of this vector. Immunohistological techniques used in this study showed that the midgut, foregut and salivary glands were the only organs in which virus accumulated. The first signals of infection, observed as randomly distributed fluorescent granular spots, were found in the epithelial cells of the midgut, mainly restricted to the anterior region. The virus subsequently spread to the circular and longitudinal midgut muscle tissues, a process which occurred late in the larval stage. In the adult stage, the infection occurred in the visceral muscle tissues, covering the whole midgut and foregut, and was abolished in the midgut epithelium. The infection of the salivary glands was first observed 72 h post-acquisition, and simultaneously in the ligaments connecting the midgut with these glands. The salivary glands of transmitting individuals appeared heavily or completely infected, while no or only a low level of infection was found in the glands of non-transmitting individuals. Moreover, the development of an age-dependent midgut barrier against virus infection was observed in second instar larvae and adults. The results show that the establishment of TSWV infection in the various tissues and the potential of transmission seems to be regulated by different barriers and processes related to the metamorphosis of thrips.

Animals↗
PubMed1999

Neuroprotection by a novel compound, NS521.

NS521 (1-(1-butyl)-4-(2-oxo-1-benzimidazolinyl)piperidine) belongs to a group of novel benzimidazolones, which exhibit neurotrophic-like activities. In vitro, NS521 rescued neuronal PC12 cells from death induced by serum and nerve growth factor deprivation. The survival effect of NS521 appeared to reflect a delay of the apoptotic process, because the extent of DNA fragmentation was attenuated transiently by NS521. NS521 did not preserve the neurites of the rescued cells, which, otherwise, appeared to be healthy and were able to regenerate when serum and nerve growth factor were added back to the culture. In vivo, NS521 provided significant protection against the delayed loss of hippocampal CA1 neurons in a gerbil model of transient global ischemia. A neuroprotective effect of NS521 in the peripheral nervous system also was observed in rats after transection of the sciatic nerve, where daily treatment with NS521 was found to inhibit retrograde degeneration of the transected nerve. The neuroprotective effect of NS521 is unlikely to be mediated through neurotrophin receptors, such as TrkA, because NS521 did not induce phosphorylation of the 44- and 42-kDa isoforms of mitogen-activated protein kinases (ERK1/2) in PC12 cells.

Animals↗
PubMed1998

Molecular characterization of tomato spotted Wilt virus defective interfering RNAs and detection of truncated L proteins.

Junction sites of 25 different defective interfering (DI) RNAs of tomato spotted wilt virus (TSWV) were characterized. The DI RNAs varied in size from 2.0 to 5.2 kilobases (kb) and contained a single internal deletion. The absence of DI RNAs smaller than 2 kb suggested a size constraint for the survival of TSWV DI RNAs. This hypothesis was reinforced by the finding of a dimeric DI RNA formed by two 1.6-long monomers linked head to tail. Three types of junction sites were found, one type originating from a simple deletion; the second type contained a few extra nucleotides of unknown origin; and the third type contained a stretch of three to five nucleotides, originally occurring at both sides of the deletion and of which one was deleted. In 19 of the 25 DI RNAs studied, the original reading frame was maintained, suggesting a selective preference of DI RNAs with translational potency. Truncated proteins encoded by these DI RNAs were indeed detected in the nucleocapsid preparations. Folding studies of the complete L RNA revealed that the calculated minimal energy of folding was at 16 degreesC lower than at 23 degrees, indicating a higher stability of this molecule at low temperatures. The results suggest an involvement of locally folded secondary structures in the process of deletion, rather than the requirement of certain sequences around the deletion point. The DI RNA generation in TSWV is essentially, as discussed, similar to the process of RNA recombination described in many viruses.

Base Sequence↗