Pharmacokinetics of neoral before and after total gastrectomy in a renal transplant patient.
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Area Under Curve↗
Biomedical subjects
M Martin
Publications and source records attributed to M Martin.
Radiation-induced oral mucositis in mice: strain differences.
The present study was initiated to investigate strain differences in oral mucosal radiosensitivity in mice with regard to induction of clinically manifest ulceration. Mouse ventral tongue epithelium was used as an established animal model for radiobiological studies of radiation-induced mucositis. Mice from two different strains, C3H/Neu (n = 40) from the Dresden colony, and B6D2F1 (n = 50) from the Harlan/Winkelmann UK colony were subjected to irradiation of tongue mucosa. Graded single doses were applied to a 3 x 3 mm2 test field in the centre of the lower tongue with 25 kV X-rays in order to generate full dose-effect curves for acute mucosal ulceration, as a clinically relevant reaction. For both groups, dose-effect curves were computed by logit analysis; comparison of the curves was by maximum-likelihood chi2 test. In addition, the time course of ulceration, i.e. latent time and individual ulcer duration, was analysed. In both mouse strains, a well-defined dose effect was observed. The ED50 values, i.e. the doses at which ulceration is expected in 50% of the animals irradiated, and their standard deviation sigma, calculated by logit analysis, can be used to describe radiosensitivity. The ED50 was 11.0 +/- 3.4 Gy (95% confidence interval (7.2; 15.4), P for dose dependence: 0.014) and 13.4 +/- 3.6 Gy (95% confidence interval (10.6; 16.1), P for dose dependence: 0.0002) in C3H and BDF1 mice, respectively. Hence, oral mucosa in BDF1 mice was found to be marginally more radioresistant (P = 0.1). The latent time to ulceration, i.e. the time between irradiation and first diagnosis of ulcer, was 11.6 +/- 0.2 days (mean +/- SEM, n = 18) in C3H mice and 5.6 +/- 0.1 days (n = 27) in BDF1 mice (P = 0.0001). Both were independent of dose (PC3H = 0.94, PBDF1 = 0.33) and hence were calculated for all responding animals of the respective strain. Ulcer duration was 2.8 +/- 0.2 days and 2.4 +/- 0.1 days in C3H and B6 mice, respectively, and was also independent of dose (PC3H = 0.25, PBDF1 = 0.99), but was dependent on the mouse strain (P = 0.036). In conclusion, no statistically significant difference in oral mucosal radiosensitivity was observed between the mouse strains. This, however, may be attributed to the small number of animals used per dose group. The time course data, with a shorter latency and ulcer duration in BDF1 mice, are in good accordance with the higher proliferation rates reported for oral mucosa in this mouse strain.
Animals↗
Reliability and validity of a modified gait scoring system and its use in assessing tibial dyschondroplasia in broilers.
1. The gait scoring system for broilers developed by Kestin et al. (Veterinary Record, 131: 190-194, 1992) has been widely used to evaluate leg problems. The many factors and measures associated with this scale have empirically established its external (biological) validity. However, published test-retest (within-observer) reliabilities are poor, and inter-observer reliabilities are unknown. We evaluated several modifications to this scale aimed at improving its objectivity and reliability. 2. Eighteen naïve observers scored a standardised video of birds exhibiting varying degrees of lameness, either using Kestin et al.'s system, or our modified system. 3. Test-retest reliability (0.906) for Kestin et al.'s system was higher than previously reported. Inter-rater reliability was also good (0.892). The modified system offered significantly better test-retest (0.948) and inter-rater reliabilities (0.943), without incurring costs in terms of time taken or difficulty of use. The systems were consistent, assigning individual birds the same score on average. 4. It is concluded that the modified system offers the advantages of reduced error within and between studies. 5. In a second experiment, we used our modified scoring system to examine the relationship between tibial dyschondroplasia (TD) and gait score in 267 selected broilers. 6. Neither the presence nor severity of TD affected gait score, suggesting that, at least in this strain of broilers, other leg problems like slipped tendons or torsional deformities had more influence on gait impairment than did TD.
Animals↗
Can beta blockers be safely initiated at home in patients with heart failure?
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Adrenergic beta-Antagonists↗
A breast cancer family from Spain with germline mutations in both the BRCA1 and BRCA2 genes.
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Adult↗
Cytotoxic T lymphocyte antigen 4 and CD28 modulate cell surface raft expression in their regulation of T cell function.
Coreceptors CD28 and cytotoxic T lymphocyte antigen (CTLA)-4 have opposing effects on TcR/CD3 activation of T cells. While CD28 enhances and CTLA-4 inhibits activation, the underlying molecular basis of these effects has yet to be established. In this context, ganglioside and cholesterol enriched membrane microdomains (rafts, GEMs) serve as centers of signaling in T cells. Although CD28 can promote TcR/raft colocalization, evidence is lacking on whether the surface expression of membrane rafts can be targeted by CTLA-4 in its modulation of T cell responses. In this study, we demonstrate that both CD28 and CTLA-4 profoundly alter the surface expression of membrane rafts during T cell activation. While CD28 increased expression and the number of peripheral T cells induced to express surface rafts in response to TcR ligation, CTLA-4 potently inhibited both TcR and TcR x CD28 induced raft expression on the surface of T cells. Consistent with this, CD28 increased the presence of the linker of activated T cells (LAT) in purified membrane rafts, while CTLA-4 coligation effectively blocked this increase. Further, the reversal of the CTLA-4 block with CD3/CD28 ligation was accompanied by an increase in surface raft expression and associated LAT. Our observations demonstrate for the first time that CTLA-4 targets the release of rafts to the surface of T cells, and provides a mechanism for the opposing effects of CD28 and CTLA-4 on costimulation.
Abatacept↗
Gluconeogenesis from glutamine and lactate in the isolated human renal proximal tubule: longitudinal heterogeneity and lack of response to adrenaline.
Recent studies in vivo have suggested that, in humans in the postabsorptive state, the kidneys contribute a significant fraction of systemic gluconeogenesis, and that the stimulation of renal gluconeogenesis may fully explain the increase in systemic gluconeogenesis during adrenaline infusion. Given the potential importance of human renal gluconeogenesis in various physiological and pathophysiological situations, we have conducted a study in vitro to further characterize this metabolic process and its regulation. For this, successive segments (S1, S2 and S3) of human proximal tubules were dissected and incubated with physiological concentrations of glutamine or lactate, two potential gluconeogenic substrates that are taken up by the human kidney in vivo, and glucose production was measured. The effects of adrenaline, noradrenaline and cAMP, a well established stimulator of gluconeogenesis in animal kidney tubules, were also studied in suspensions of human renal proximal tubules. The results indicate that the three successive segments have about the same capacity to synthesize glucose from glutamine; by contrast, the S2 and S3 segments synthesize more glucose from lactate than the S1 segment. In the S2 and S3 segments, lactate appears to be a better gluconeogenic precursor than glutamine. The addition of cAMP, but not of adrenaline or noradrenaline, led to the stimulation of gluconeogenesis from lactate and glutamine by human proximal tubules. These results indicate that, in the human kidney in vivo, lactate might be the main gluconeogenic precursor, and that the stimulation of renal gluconeogenesis observed in vivo upon adrenaline infusion may result from an indirect action on the renal proximal tubule.
Animals↗
Structural basis for the interaction of the free SH2 domain EAT-2 with SLAM receptors in hematopoietic cells.
The T and natural killer (NK) cell-specific gene SAP (SH2D1A) encodes a 'free SH2 domain' that binds a specific tyrosine motif in the cytoplasmic tail of SLAM (CD150) and related cell surface proteins. Mutations in SH2D1A cause the X-linked lymphoproliferative disease, a primary immunodeficiency. Here we report that a second gene encoding a free SH2 domain, EAT-2, is expressed in macrophages and B lympho cytes. The EAT-2 structure in complex with a phosphotyrosine peptide containing a sequence motif with Tyr281 of the cytoplasmic tail of CD150 is very similar to the structure of SH2D1A complexed with the same peptide. This explains the high affinity of EAT-2 for the pTyr motif in the cytoplasmic tail of CD150 but, unlike SH2D1A, EAT-2 does not bind to non-phosphorylated CD150. EAT-2 binds to the phosphorylated receptors CD84, CD150, CD229 and CD244, and acts as a natural inhibitor, which interferes with the recruitment of the tyrosine phosphatase SHP-2. We conclude that EAT-2 plays a role in controlling signal transduction through at least four receptors expressed on the surface of professional antigen-presenting cells.
Adaptor Proteins, Signal Transducing↗
Identification of tumor-infiltrating macrophages as the killers of tumor cells after immunization in a rat model system.
Immunization can prevent tumor growth, but the effector cells directly responsible for tumor cell killing in immunized hosts remain undetermined. The present study compares tumor grafts that progress in naive syngeneic rats with the same grafts that completely regress in hosts preimmunized with an immunogenic cell variant. The progressive tumors contain only a few macrophages that remain at the periphery of the tumor without direct contact with the cancer cells. These macrophages do not kill tumor cells in vitro. In contrast, tumors grafted in immunized hosts and examined at the beginning of tumor regression show a dramatic infiltration with mature macrophages, many of them in direct contact with the cancer cells. These macrophages are strongly cytotoxic for the tumor cells in vitro. In contrast to macrophages, tumor-associated lymphocytes are not directly cytotoxic to the tumor cells, even when obtained from tumor-immune rats. However, CD4(+) and CD8(+) T cells prepared from the regressing tumors induce tumoricidal activity in splenic macrophages from normal or tumor-bearing rats and in macrophages that infiltrate progressive tumors. These results strongly suggest that the main tumoricidal effector cells in preimmunized rats are macrophages that have been activated by adjacent tumor-immune lymphocytes.
Animals↗
Differential induction of endotoxin tolerance by lipopolysaccharides derived from Porphyromonas gingivalis and Escherichia coli.
Exposure of mononuclear phagocytes to enterobacterial LPS induces a state of transient hyporesponsiveness to subsequent LPS exposure, termed endotoxin tolerance. In the present study, LPS derived from the oral periodontal pathogen, Porphyromonas gingivalis, was compared with that derived from the enterobacterium, Escherichia coli, for the ability to induce endotoxin tolerance. Pretreatment of the human macrophage cell line, THP-1, with E. coli LPS resulted in a severe reduction in the levels of IL-1beta, IL-6, and TNF-alpha upon secondary stimulation. In contrast, pretreatment of THP-1 cells with P. gingivalis LPS resulted in a mitigation of IL-1beta, but not IL-6 and TNF-alpha production upon subsequent exposure to P. gingivalis LPS: primary or secondary stimulation with < or =100 ng/ml P. gingivalis LPS resulted in comparable levels of IL-6 and TNF-alpha, while stimulation of THP-1 cells with > or =1 microg/ml P. gingivalis LPS induced a significant enhancement in IL-6 and TNF-alpha levels upon secondary exposure. To identify possible mechanisms for these differences, changes in the expression of molecules involved in the LPS-signaling pathway were assessed. Pretreatment of THP-1 cells with E. coli LPS resulted in a significant reduction in surface Toll-like receptor 4 (TLR4) expression and an inability to degrade I-kappaB-alpha or I-kappaB-beta proteins upon secondary stimulation. In contrast, pretreatment of THP-1 cells with P. gingivalis LPS resulted in a significant enhancement of both CD14 and TLR2, while maintaining the ability to degrade I-kappaB-beta only upon secondary stimulation. Thus, E. coli and P. gingivalis LPS differentially affect CD14 and TLR expression as well as secondary LPS-associated responses.
Animals↗
The context of uncertainty modulates the subcortical response to predictability.
Implicit motor learning tasks typically involve comparisons of subject responses during a sequence versus a random condition. In neuroimaging, brain regions that are correlated with a sequence are described, but the temporal relationship of sequence versus nonsequence conditions is often not explored. We present a functional magnetic resonance imaging (fMRI) study describing activation related to sequential predictability in an implicit sensorimotor learning task and the history (context) dependence of these effects. Participants regarded four squares displayed horizontally across a screen and pressed a button when any one of the four targets was illuminated in a particular color. A repeating spatial sequence with varying levels of predictability was embedded within a random color presentation. Both the right dorsolateral prefrontal cortex (R DLPFC) and right caudate displayed a positive correlation to increasing predictability, whereas the left posterior parietal cortex (L PPC) displayed a negative correlation. However, the activation changes within the caudate were significant when transitioning from high predictability to low predictability but not for the reverse case, suggesting a sensitivity not only to predictability but to order effects as well. These results support the hypothesized relationship between basal ganglia and visuomotor sequential learning, but demonstrate the importance of context upon sequence learning.
Adult↗
CD84 functions as a homophilic adhesion molecule and enhances IFN-gamma secretion: adhesion is mediated by Ig-like domain 1.
CD84 is a member of the CD2 subset of the Ig superfamily of cell surface molecules. Its cytoplasmic tail binds to Src homology 2 domain-containing protein 1A (signaling lymphocytic activation molecule-associated protein), a protein encoded by the X-linked lymphoproliferative disease gene. It is preferentially expressed on B lymphocytes, monocytes, and platelets. We show that it is also expressed on thymocytes and T cells. CD84 was positive on CD4-CD8- thymocytes, and its expression decreased with cell maturation. It is expressed on mature T cells preferentially on CD45RO+. To identify the CD84 ligand, we generated a soluble Ig fusion protein containing the human CD84 extracellular domains (CD84-Ig). Because receptor-ligand interactions occur between several members of this subfamily, we assayed CD84-Ig binding with all members of the CD2 family. CD84-Ig bound to CD84-transfected cells, whereas no binding was detected with cells expressing other CD2 subfamily receptors, showing that CD84 binds to itself. Anti-CD84 mAbs recognizing epitopes wholly within domain 1 of CD84 blocked the binding of the CD84-Ig fusion protein to CD84-transfected cells and platelets. Data from CD84 domain human/mouse chimeras further revealed that only the first extracellular domain of the molecule is involved in the ligand receptor recognition. The CD84-CD84 interaction was independent of its cytoplasmic tail. Finally, concurrent ligation of human CD84 with mAbs or CD84-Ig and CD3 enhanced IFN-gamma secretion in human lymphocytes. Thus, CD84 is its own ligand and acts as a costimulatory molecule.
Animals↗
Altered emotional behavior in PACAP-type-I-receptor-deficient mice.
PAC1 (pituitary adenylate cyclase activating polypeptide type I receptor) is a G-protein-coupled receptor that binds the strongly conserved neuropeptide PACAP (pituitary adenylate cyclase activating polypeptide) with a thousandfold higher affinity than the related peptide VIP (vasoactive intestinal peptide). PAC1 shows strong expression in brain areas which have been implicated in the emotional control of behavior, such as the amygdala, the hypothalamus, the locus coeruleus and the periaqueductal gray. To assess whether PAC1-mediated signaling has an impact on emotional behavior, we analysed two different mutant mouse lines with an ubiquitous or a forebrain-specific inactivation of PAC1 in several testing paradigms modelling general locomotor activity and anxiety-related behavior. We clearly demonstrate that mice with a ubiquitous but not with a forebrain-specific deletion of PAC1 exhibit elevated locomotor activity and strongly reduced anxiety-like behavior. We could not observe any gross alteration in circadian rhythmicity nor any enhanced sensitivity towards ethanol in the mutant mice. We previously demonstrated that PAC1 plays a crucial role in contextual fear conditioning. Therefore the finding that PAC1-deficient mice exhibit reduced anxiety is quite exciting, since the receptor and hence its ligand PACAP seem to be important for both, innate and learned fear.
Animals↗
High-dose tamoxifen added to concurrent biochemotherapy with decrescendo interleukin-2 in patients with metastatic melanoma.
BACKGROUND: In vitro cell culture data and preclinical models suggest that tamoxifen modulates tumor cell sensitivity to a wide range of therapeutic agents. In the current study, the authors examined whether high-dose tamoxifen (HDT) improved the overall and complete response in patients with metastatic melanoma who were treated with concurrent biochemotherapy. METHODS: Forty-nine patients were treated with a biochemotherapy regimen of dacarbazine, vinblastine, cisplatin, decrescendo interleukin-2, interferon-alpha-2b, and tamoxifen. The study had a 2-step design, beginning with a tamoxifen dose escalation from 40 mg to 320 mg (17 subjects) to evaluate safety and tolerability, followed by Phase II accrual of 32 patients to HDT (320 mg) to assess clinical efficacy. Efficacy was compared with a similar modified biochemotherapy regimen with low-dose tamoxifen (LDT). Pharmacokinetic studies were performed to determine in vivo tamoxifen levels. RESULTS: Tamoxifen dose escalation was completed without any reported dose-limiting toxicity. The overall response rate in the HDT group was 50% (95% confidence interval, 33.2%-66.8%), with a complete response rate of 6% and a median survival of 9.5 months. The overall response rate was not improved and the complete response and survival appeared inferior compared with that of patients recently treated with concurrent biochemotherapy and LDT. Serum tamoxifen levels were found to correlate with the dose administered, with a mean of 0.9 microM at the 40-mg dose to 4.6 microM at the 320-mg dose. Ultrafiltered protein-free sera demonstrated low (< 0.01 microM) concentrations of tamoxifen. CONCLUSIONS: The addition of HDT to a regimen of concurrent biochemotherapy did not appear to improve response rates or overall survival, despite reaching the targeted plasma concentration. Unknown drug interactions or high protein binding of tamoxifen may account for the lack of clinical effectiveness.
Adolescent↗
Association among physical activity level, cardiorespiratory fitness, and risk of musculoskeletal injury.
To help public health practitioners promote physical activities with a low risk of injury, this study determined the relation among type and duration of physical activity, cardiorespiratory fitness, and musculoskeletal injury in a sample of adults enrolled in the Aerobics Center Longitudinal Study. Subjects included 4,034 men and 967 women who underwent a baseline physical examination between 1970 and 1985 and who returned a mailed follow-up survey in 1986. At baseline, a treadmill graded exercise test was used to measure cardiorespiratory fitness. At follow-up, subjects reported injuries and type and duration of physical activity in the preceding 12 months. Polytomous logistic regression was used to estimate the association among physical activity type and duration, cardiorespiratory fitness, and injury. The risk of sustaining an activity-related injury increased with higher duration of physical activity per week and cardiorespiratory fitness levels. Results suggest that cardiorespiratory fitness may be a surrogate for unmeasured components of physical activity, such as exercise intensity. Among walkers, increasing duration of activity per week was not associated with an increased risk of injury. Results suggest that, for most adults, walking is a safe form of physical activity associated with a lower risk of injury than running or sport participation.
Adult↗
Impairment of mossy fiber long-term potentiation and associative learning in pituitary adenylate cyclase activating polypeptide type I receptor-deficient mice.
The pituitary adenylate cyclase activating polypeptide (PACAP) type I receptor (PAC1) is a G-protein-coupled receptor binding the strongly conserved neuropeptide PACAP with 1000-fold higher affinity than the related peptide vasoactive intestinal peptide. PAC1-mediated signaling has been implicated in neuronal differentiation and synaptic plasticity. To gain further insight into the biological significance of PAC1-mediated signaling in vivo, we generated two different mutant mouse strains, harboring either a complete or a forebrain-specific inactivation of PAC1. Mutants from both strains show a deficit in contextual fear conditioning, a hippocampus-dependent associative learning paradigm. In sharp contrast, amygdala-dependent cued fear conditioning remains intact. Interestingly, no deficits in other hippocampus-dependent tasks modeling declarative learning such as the Morris water maze or the social transmission of food preference are observed. At the cellular level, the deficit in hippocampus-dependent associative learning is accompanied by an impairment of mossy fiber long-term potentiation (LTP). Because the hippocampal expression of PAC1 is restricted to mossy fiber terminals, we conclude that presynaptic PAC1-mediated signaling at the mossy fiber synapse is involved in both LTP and hippocampus-dependent associative learning.
Animals↗
Oral health status of kindergarten children in a medium-sized German town near the Czech border.
A cohort examination was performed to investigate the oral health status of 215 kindergarten children in a medium-sized German town near the Czech border. Despite an extensive campaign involving information events and discussions, only 130 of these children could be recruited to participate in the study. They showed a mean caries rate of 50%, which was up to 60% among the 6-year-olds. These findings clearly fall short of the WHO goals for 2000 and indicate that the geographic area covered by the study has a significant oral health deficit. The study also showed a particularly high prevalence of carious defects in a small number of children. The posterior occlusal relations were normal in 90.8 percent of cases. Deformations of the os maxillare (open bite due to finger sucking) were found in 20% of the 4 year group, in 2.3% of the 5 year group, and in 13% of the 6 year group.
Child↗
Characterization of SH2D1A missense mutations identified in X-linked lymphoproliferative disease patients.
X-linked lymphoproliferative disease (XLP) is a primary immunodeficiency characterized by extreme susceptibility to Epstein-Barr virus. The XLP disease gene product SH2D1A (SAP) interacts via its SH2 domain with a motif (TIYXXV) present in the cytoplasmic tail of the cell-surface receptors CD150/SLAM, CD84, CD229/Ly-9, and CD244/2B4. Characteristically, the SH2D1A three-pronged interaction with Tyr(281) of CD150 can occur in absence of phosphorylation. Here we analyze the effect of SH2D1A protein missense mutations identified in 10 XLP families. Two sets of mutants were found: (i) mutants with a marked decreased protein half-life (e.g. Y7C, S28R, Q99P, P101L, V102G, and X129R) and (ii) mutants with structural changes that differently affect the interaction with the four receptors. In the second group, mutations that disrupt the interaction between the SH2D1A hydrophobic cleft and Val +3 of its binding motif (e.g. T68I) and mutations that interfere with the SH2D1A phosphotyrosine-binding pocket (e.g. C42W) abrogated SH2D1A binding to all four receptors. Surprisingly, a mutation in SH2D1A able to interfere with Thr -2 of the CD150 binding motif (mutant T53I) severely impaired non-phosphotyrosine interactions while preserving unaffected the binding of SH2D1A to phosphorylated CD150. Mutant T53I, however, did not bind to CD229 and CD224, suggesting that SH2D1A controls several critical signaling pathways in T and natural killer cells. Because no correlation is present between identified types of mutations and XLP patient clinical presentation, additional unidentified genetic or environmental factors must play a strong role in XLP disease manifestations.
Amino Acid Sequence↗