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Biomedical subjects

A George

Publications and source records attributed to A George.

At least 55 records · Page 3Linked to original sources
PubMed2000

Acquired aphasia in children after surgical resection of left-thalamic tumors.

Five children (three males, two females; four right-, one left-handed; age range 6 to 14 years) who developed aphasia after gross-total excision of left predominantly thalamic tumors are reported. Three patients had Broca aphasia, one had mixed transcortical aphasia, and one patient had conduction aphasia. In the months after surgery, three children improved while receiving radiation and/or chemotherapy, although none recovered completely. Two patients with malignant tumors developed worsening aphasia when the tumor recurred, and later died. Two of three patients tested had visuospatial difficulties in addition to language deficits. Attention and executive functioning were affected in three of three patients tested. Memory, verbal and/or visual functioning, were affected in four of four patients tested. Both patients who were tested showed transient right hemineglect. Two of two patients tested were probably apraxic. The wide range of deficits in these children highlights the importance of the thalamus and other subcortical structures in developing cognition.

Adolescent↗
PubMed2000

The use of the Panic and Agoraphobia Scale (P & A) in a controlled clinical trial.

BACKGROUND: A new 13-item scale has been developed for measuring severity of illness in patients with panic disorder and agoraphobia, the Panic and Agoraphobia Scale (P & A). The scale has five subscales covering the main factors that reduce quality of life in panic disorder patients (panic attacks, avoidance, anticipatory anxiety, disability and worries about health). The application of this scale in a double-blind placebo-controlled panic disorder trial is described. At the same time, the aim of the study was to compare the therapeutic effects of aerobic exercise with a treatment of well-documented efficacy. METHODS: Patients with Panic disorder (DSM-IV) were randomly assigned to three treatment modalities: running (n=45), clomipramine (n=15) or placebo (n=15). Treatment efficacy was measured with the Panic and Agoraphobia Scale (P & A) and other rating scales. RESULTS: According to the P & A and other scales, both exercise and clomipramine led to a significant decrease of symptoms in comparison to placebo treatment. Clomipramine was significantly more effective and improved anxiety symptoms significantly earlier than exercise. The evaluation of the P & A subscales revealed that exercise exerted its effect mainly reducing anticipatory anxiew and panic-related disability. CONCLUSIONS: The new Panic and Agoraphobia Scale was shown to be sensitive to differences between different panic treatments. Analysis of the scales five subscores may help to understand mechanisms of action of panic disorder treatments.

Agoraphobia↗
PubMed2000

Effect of L-carnitine supplementation on red blood cells deformability in hemodialysis patients.

Anemia is a serious problem in hemodialysis patients, the main cause of which is erythropoietin deficiency. After the discovery of recombinant human erythropoietin (rHuEpo) at the end of the last decade, the hematological profile of hemodialysis patients improved significantly but at considerable expense. The deformability of red blood cells (RBC) influences their microcirculation and tissue oxygen delivery along with their life span. We investigated the deformabilty of RBCs in 15 hemodialysis patients before and after three months on L-carnitine supplementation (30 mg/Kg body wt/dialysis session). We excluded from the study all patients who received blood transfusions three months before or during the study, patients who had hemorrhagic episodes, those with hyperparathyroidism or infections, and any who required surgical intervention during the study. The serum iron, folic acid and vitamin B-12 levels were kept normal during the duration of the study. The erythropoietin dose taken before the beginning of L-cartnitine supplementation was not changed. The deformability of RBCs before and after dialysis, prior to and following three months on L-carnitine was determined and compared to the deformability of RBCs from a control group. Hematocrit levels were measured before entry into the study and every month for three months. We found that the deformability of RBCs before the dialysis session was significantly greater than that found in the control group (t-test, p < 0.00001), and that there was a further increase after the end of the dialysis session. Three months following L-carnitine supplementation, we found a significant reduction of RBCs deformability (paired t-test, p < 0.004), and a significant increase in the hematocrit (ANOVA, p < 0.0001). We concluded that abnormalities in the deformability of RBCs improved after L-carnitine and that this was responsible for the increase in the hematocrit. This may allow a substantial reduction in rHuEpo dose.

Adult↗
PubMed2000

Increased psychological responses and divergent neuroendocrine responses to m-CPP and ipsapirone in patients with panic disorder.

In patients with panic disorder and /or agoraphobia (PDA) an increased sensitivity of central 5-HT2C receptors and a decreased responsiveness of 5-HT1A receptors has been postulated. In the present study, neuroendocrine challenges were performed using oral doses of the non-selective 5-HT2C agonist m-chlorophenylpiperazine (m-CPP) (0.4 mg/kg), the selective 5-HT1A antagonist ipsapirone (0.3 mg/kg), and placebo in 40 patients with PDA and 12 healthy controls in order to compare 5-HT2C and 5-HT1A-specific psychobehavioural and neuroendocrine response patterns. At baseline, all psychobehavioural variables and the plasma concentration of noradrenaline (NE) were significantly increased in the patient group compared to the controls. The administration of m-CPP or ipsapirone was followed by comparable psychological symptoms and, in 55% of all patients, panic attacks. In comparison to the control subjects, patients were characterized by significantly higher psychological reactions to both challenge agents and a significantly higher NE response to m-CPP. In the patient group, there was also a trend towards an increased cortisol response after administration of m-CPP and a decreased cortisol and hypothermia response after administration of ipsapirone compared to the control group. The neuroendocrine findings of our study support earlier reports of opposite changes in the responsiveness of 5-HT2C and 5-HT1A-related receptors in PDA patients. The behavioural hypersensitivity to both, m-CPP and ipsapiron, shows that the provocation of anxiety and other psychological symptoms might be influenced by

Adolescent↗
PubMed2000

The non-collagenous dentin matrix proteins are involved in dentinogenesis imperfecta type II (DGI-II).

Dentinogenesis Imperfecta type II (DGI-II) is a localized form of mesodermal dysplasia of the dentin affecting both the primary and permanent dentitions. This is an autosomal-dominant disease in which there is a disorder in dentin mineralization. Several studies have localized DGI-II to human chromosome 4 in the region 4q 12-21. Many ECM genes-such as OPN, DMP1, DMP2, DMP3 (DSPP), and BSP-have been mapped to the same locus. Biochemical studies indicated that dentin phosphophoryn (DMP2) might be a candidate gene in DGI-II. In this study, we have used histological and RFLP analyses of tissues from a DGI-II-affected patient, as compared with two normal controls, to determine if DMP1, 2, or 3 was linked to DGI-II. The histology of the affected tooth was very different in the DGI-II patient as compared with the normals. In particular, the dentinal tubules in the DGI-II patient were very irregular, which could be the result of perturbations in the process of dentin formation. Patient and control DNA samples were digested with EcoRI or PstI and Southern-hybridized with the DMP1, DMP2, and DMP3 cDNAs. Few differences in the restriction pattern were observed between affected and normal samples for DMP1 and DMP3-3' region (phosphophoryn-like sequences) probes. On the other hand, DMP2 showed a dramatic shift in the restriction pattern in DGI-II. This study suggests that the different restriction enzyme digestion profiles of the DNA from the DGI-II patient, as probed by DMP2, might be related to the defective mineralization of dentin in DGI-II.

Chromosomes, Human, Pair 4↗
PubMed1999

Bruton's tyrosine kinase deficiency in macrophages inhibits nitric oxide generation leading to enhancement of IL-12 induction.

We show that macrophages of X-linked immunodeficient mice with a mutant nonfunctional Bruton's tyrosine kinase produce less NO than wild-type macrophages in response to a variety of stimuli. Induction of the inducible NO synthase (iNOS) protein, the transcription factor IFN regulatory factor-1 involved in iNOS expression, and the transcription factor STAT-1 involved in regulating IFN regulatory factor-1 induction are all poorer in X-linked immunodeficient than in wild-type macrophages. On the other hand, induction of IL-12 is higher in X-linked immunodeficient than in wild-type macrophages. Macrophage IL-12 induction is enhanced by iNOS inhibitors such as aminoguanidine and thiocitrulline and is inhibited by NO generation via sodium nitroprusside. There is relative enhancement of IFN-gamma production by immune T cells from mice immunized under aminoguanidine cover. Our data thus suggest that Bruton's tyrosine kinase participates in signaling for iNOS induction via IFN regulatory factor-1 in macrophages and that NO is an inhibitor of IL-12 induction.

Agammaglobulinaemia Tyrosine Kinase↗
PubMed1999

Delayed clearance of filarial infection and enhanced Th1 immunity due to modulation of macrophage APC functions in xid mice.

Bruton's tyrosine kinase (Btk) mutant CBA/N mice show delayed clearance of injected microfilaria (mf) compared with wild-type CBA/J mice. Anti-mf T cells from CBA/N mice make relatively more IFN-gamma than those from CBA/J mice. The anti-mf T cell proliferative responses are also greater in CBA/N mice. This CBA/N immune phenotype is not restricted to filarial Ags, because immunization with pure proteins also yields T cell responses of greater proliferative magnitude skewed away from Th2 cytokines in CBA/N compared with CBA/J mice. The increased magnitude of CBA/N T cell proliferative responses is reflected in increases in both precursor frequencies and clonal burst sizes of responding Ag-specific T cells, and is independent of the source of re-stimulating APCs. Transfer of CBA/J peritoneal resident cells (PRCs) into CBA/N mice before pure protein immunization leads to a wild-type immune phenotype in the recipient CBA/N mice, with a reduction in the proliferative response and a relative decrease in the IFN-gamma produced. When wild-type PRC subpopulations are similarly transferred, the wild-type immune phenotype is transferred by macrophages rather than by B cells. Transfer of wild-type PRCs into CBA/N mice before injection of mf also causes similar changes in the anti-mf T cell responses and enhances the clearance of mf. Thus, Btk is involved in critical macrophage APC functions regulating priming of T cells, and can modulate these responses in pathophysiologically relevant fashion in vivo.

Agammaglobulinaemia Tyrosine Kinase↗
PubMed1999

MHC class I-restricted presentation of maleylated protein binding to scavenger receptors.

Pathways for loading exogenous protein-derived peptides on MHC class I are thought to be present mainly in monocyte-lineage cells and to involve phagocytosis- or macropinocytosis-mediated antigenic leakage into either cytosol or extracellular milieu to give peptide access to MHC class I. We show that maleylation of OVA enhanced its presentation to an OVA-specific MHC class I-restricted T cell line by both macrophages and B cells. This enhanced presentation involved uptake through receptors of scavenger receptor (SR)-like ligand specificity, was TAP-1-independent, and was inhibited by low levels (2 mM) of ammonium chloride. No peptide loading of bystander APCs by maleylated (maleyl) OVA-pulsed macrophages was detected. Demaleylated maleyl-OVA showed enhanced MHC class I-restricted presentation through receptor-mediated uptake and remained highly sensitive to 2 mM ammonium chloride. However, if receptor binding of maleyl-OVA was inhibited by maleylated BSA, the residual presentation was relatively resistant to 2 mM ammonium chloride. Maleyl-OVA directly introduced into the cytosol via osmotic lysis of pinosomes was poorly presented, confirming that receptor-mediated presentation of exogenous maleyl-OVA was unlikely to involve a cytosolic pathway. Demaleylated maleyl-OVA was well presented as a cytosolic Ag, consistent with the dependence of cytosolic processing on protein ubiquitination. Thus, receptor-specific delivery of exogenous protein Ags to APCs can result in enhanced MHC class I-restricted presentation, suggesting that the exogenous pathway of peptide loading for MHC class I may be a constitutive property dependent mainly on the quantity of Ag taken up by APCs.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1999

Presence of pentoxifylline during T cell priming increases clonal frequencies in secondary proliferative responses and inhibits apoptosis.

Naive T cells appear to be primed by specific Ag to differentiate into either effectors or memory cells. We have been analyzing the factors involved in this differential commitment in the priming of alloresponsive human T cells in vitro and have shown that the presence of a phosphodiesterase inhibitor, pentoxifylline (POX), during priming results in a decrease in the primary response and enhancement in the secondary proliferative response. We now show that the POX-mediated effect can be mimicked by dibutyryl cAMP. The secondary response enhancement is due to the effects of POX on the T cells rather than the APCs, because even fixed APCs can prime T cells in the presence of POX. POX affects T cells directly by increasing clonal frequency rather than the burst size of the secondary responders. The known inhibition of IL-2 production by POX is not responsible for this effect, because exogenous IL-2 supplementation does not block it. The presence of POX during priming alters the outcome of T cell activation, resulting in a lower frequency of cells expressing IL-2R alpha (CD25) and a decrease in their subsequent apoptosis, and this antiapoptotic effect is consistent with the enhanced commitment of T cells to secondary responsiveness by POX.

Adjuvants, Immunologic↗
PubMed1999

Preventing deadly conflict: the critical role of leadership.

This article emerged from the work of the Carnegie Commission on Preventing Deadly Conflict, Washington, DC. The commission addressed several fundamental questions: (1) What are the problems posed by deadly conflict, and why is outside help often necessary to deal with these problems? (2) How can disputes be resolved peaceably? (3) Which strategies work best? (4) Who can do what to implement these preventive strategies? Borrowing from the model of preventive medicine, the commission detailed a repertoire of the most promising political, economic, military, and social tools and strategies that can be mobilized by the international community to assist vulnerable societies in the development of sustainable and equitable arrangements for managing diversity and resolving disputes peacefully. From a comparative examination of intransigent and destructive intergroup conflicts, the commission found that the failure to prevent conflict is most often not a failure of foreknowledge or capacity but of political will. Effective political leadership is often the critical variable for successful prevention. This article seeks to illustrate how the social and behavioral sciences may be usefully applied to the problems encountered by leaders when confronted by the challenges of preventing deadly conflict.

Behavioral Sciences↗
PubMed1999

Expression of an immunoglobulin heavy chain transgene in macrophage as well as lymphocyte lineages in vivo.

A rearranged immunoglobulin heavy chain (IgH) transgene-encoded protein is expressed in macrophage lineage cells, in addition to B and T lineages, in transgenic mouse bone marrow. Peripheral macrophages also express transgenic IgH protein. Mature T cells express lower levels than immature thymocytes. Almost all B220+ cells in the bone marrow express transgenic IgH protein, and this early expression in the B lineage is accompanied by a reduction of cell frequency even in the early B220+ CD43+ BP-1- stages, although it is more prominent in BP-1+ pre-B cells. Thus, an IgH transgene can be expressed not only in lymphoid but also in myeloid cells, although its developmental effects are restricted to the B cell lineage.

Animals↗
PubMed1999

Serial determination of tumor necrosis factor-alpha content in rat sciatic nerve after chronic constriction injury.

Wallerian degeneration, induced after injury to a peripheral nerve, is associated with upregulation of proinflammatory cytokines, which are suggested to contribute to the development of lesion-induced neuropathic pain. In chronic constrictive injury (CCI), an animal model of injury-induced painful mononeuropathy, inhibition of synthesis, release, or function of the cytokine tumor necrosis factor-alpha (TNF) results in reduced pain-associated behavior. Here, changes of TNF content in rat sciatic nerves after CCI (days 0, 0.5, 1, 3, 7 and 14) were investigated by enzyme-linked-immunoassay. Low levels of TNF were already detectable in control nerves. Concentrations increased rapidly after CCI, with a maximum (2.7-fold) at 12 h, and remained elevated on a lower level until day 3. Baseline levels were reached again at day 14. These results indicate that TNF is produced at an early time point in the cascade of events resulting in Wallerian degeneration and hyperalgesia following peripheral nerve injury. Given that only prophylactic treatment with TNF inhibitors efficiently reduces hyperalgesia in CCI, TNF seems to contribute to the initiation of neuropathic pain in this model.

Animals↗
PubMed1999

Subclinical hyperthyroidism and hyperkinetic behavior in children.

The authors report three children who exhibited developmental learning disabilities (DLDs) associated with behavioral disturbances, such as attention deficit, hyperactivity, and autistic features. The thyroid function tests performed as a part of routine endocrinologic evaluation of children with DLDs revealed a hormonal profile consistent with hyperthyroidism. These children had no systemic signs of hyperthyroidism. Treatment with neomercazole resulted in good control of their hyperkinetic behavior and subsequent improvement in language function attributable to an increased attention span, thereby facilitating speech therapy. Although routine screening of all children with DLDs for thyroid dysfunction may not be cost-effective, selective screening of children with familial attention-deficit hyperactivity disorder and those with attention-deficit and hyperactivity in association with DLDs and pervasive developmental disorders appears to be justified.

Antithyroid Agents↗
PubMed1999

Decreased neuroendocrine responses to meta-chlorophenylpiperazine (m-CPP) but normal responses to ipsapirone in marathon runners.

Several clinical studies suggest antidepressive and anxiolytic effects of regular aerobic exercise. To study the effects of exercise on central serotonergic receptor sensitivity, we performed neuroendocrine challenges using oral doses of meta-chlorophenylpiperazine (m-CPP, 0.4 mg/kg), ipsapirone (0.3 mg/kg) and placebo in 12 marathon runners and 12 healthy controls not practicing regular exercise. After administration of the nonselective serotonergic agonist m-CPP, which exerts a number of well-reproducible effects mainly by means of its action on 5-HT2C receptors, marathon runners showed a significantly reduced cortisol response in comparison to the control group. There was also a statistical trend toward a blunted prolactin response after m-CPP in the athlete group. In contrast, the increase of cortisol and the hypothermia observed after administration of the 5-HT1A agonist ipsapirone were of the same magnitude in both groups. The behavioral response to m-CPP or ipsapirone and the mean maximal increases of plasma adrenaline and noradrenaline did not differ between the marathon and the control group. In conclusion, exercise-induced downregulation of 5-HT2C receptors could play an important role in mediating the anxiolytic and antidepressive effects of exercise.

Adult↗
PubMed1999

Solubility parameter and oral absorption.

The solubility parameter (delta) for a series of structurally diverse compounds was determined using a group contribution method devised by Fedors, and then related to the degree of oral absorption. Solubility parameter values around 22.5 MPa1/2 were shown to be associated with compounds that were well absorbed, whereas, compounds with a high delta (30-40 MPa1/2) showed poor absorption. A correlation was also evident between the number of H-bonding acceptor groups in a compound and the extent of oral absorption. Surprisingly, when C Log P values were used in comparison, no obvious correlation existed. The conclusion from this work is that the solubility parameter may be a more reasonable predictor of absorption than using C Log P values.

Absorption↗
PubMed1999

Th1 dominance in the immune response to live Salmonella typhimurium requires bacterial invasiveness but not persistence.

Factors responsible for the predictable generation of Th1 or Th2 immune responses to microorganisms in vivo are not well characterized, although the ability of antigen presenting cells (APC) to provide co-stimulation, the kinetics of MHC-peptide ligand generation as well as the cytokine environment are all considered important factors for the differential Th1/Th2 priming of T cells. Our earlier findings of an IFN-gamma-dominant, Th1-type response to live Salmonella typhimurium (Stm) and a Th2-type response to killed Stm suggested that persistence of viable bacteria might be an important factor in the generation of IFN-gamma-dominant responses. Using genetically susceptible and resistant strains of mice to limit bacterial replication and persistence in vivo, we show that mice of the lty(r) genotype, capable of a 10-fold better clearance of Stm, mount an IFN-gamma-dominant immune response following immunization with live Stm similar to that in the lty(s) strain. Further, metabolically defective mutants of Stm, aroA and purA, when used in the live form, also elicit IFN-gamma-dominant immune responses similar to the wild-type Stm strain despite their inability to proliferate in vivo. While a laboratory strain of Escherichia coli, which is antigenically cross-reactive but non-invasive, elicits hardly any IFN-gamma in immune responses, an invasive strain of E. coil induces an IFN-gamma-dominant response. These data together indicate that, while entry of bacteria into macrophages is likely to be critical for the generation of IFN-gamma-dominant immune responses, their persistence is not.

Animals↗