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Biomedical subjects

D Zhu

Publications and source records attributed to D Zhu.

At least 19 recordsLinked to original sources
PubMed2003

CMT with pyramidal features. Charcot-Marie-Tooth.

To determine whether Charcot-Marie-Tooth (CMT) with pyramidal features is genetically distinct from other dominantly inherited axonal neuropathies, the authors examined all chromosomal loci and genes for axonal CMT. Two families were identified with an axonal CMT phenotype with distal wasting, weakness, pes cavus, sensory loss, and mild pyramidal signs (including extensor plantar responses, mild increase in tone, and preserved or increased reflexes but no spastic gait). Linkage studies excluded CMT2A, 2B, 2D, 2E, and 2F; ALS4; and HMN2. There were no mutations in the PMP22, MPZ/Po, or EGR2 genes.

Adolescent↗
PubMed2002

Co-activation of the phosphatidylinositol-3-kinase/Akt signaling pathway by N-methyl-D-aspartate and TrkB receptors in cerebellar granule cell neurons.

Neuroprotective concentrations of N-methyl-D-aspartate (NMDA) promote survival of cerebellar granule cell neurons against glutamate excitotoxicity through a TrkB receptor-mediated brain-derived neurotrophic factor (BDNF) autocrine loop. However, the intracellular signaling pathway(s) are not clear. Our results show that PI-3 kinase/Akt is activated by either NMDA or BDNF displaying differential kinetics. BDNF and NMDA increased Akt phosphorylation within 5 minutes but maximal activation by NMDA was observed at 3 hours. Akt phosphorylation was completely blocked by the PI-3 kinase inhibitor LY294002. NMDA-mediated activation of Akt was completely blocked by MK-801 and partially blocked by the TrkB receptor inhibitor, K252a, indicating the requirement of TrkB receptors for maximal activation by NMDA. In contrast, BDNF-induced Akt phosphorylation was abolished by K252a, but not by the addition of MK-801. Therefore, the PI-3 kinase/Akt pathway is co-activated by NMDA and TrkB receptors. The kinetics of BDNF and NMDA-mediated activation of PI-3 kinase/Akt suggests that they have different roles in intraneuronal time-related events.

Animals↗
PubMed2002

Autosomal dominant juvenile amyotrophic lateral sclerosis and distal hereditary motor neuronopathy with pyramidal tract signs: synonyms for the same disorder?

Autosomal dominant juvenile amyotrophic lateral sclerosis (ALS) is a rare disorder and so far only one family has been reported. Genetic linkage studies mapped the disease locus to chromosome 9q34 (ALS4). The diagnosis of ALS in this family is based on the clinical signs with almost exclusively lower motor neurone pathology in combination with less prominent pyramidal tract signs. Atypical features include normal life expectancy, the absence of bulbar involvement and the symmetrical distal distribution of atrophy and weakness. We performed a molecular genetic study in three families that we had diagnosed as having distal hereditary motor neuronopathy, i.e. distal spinal muscular atrophy or spinal Charcot-Marie-Tooth syndrome, and found linkage to the ALS4 locus. The clinical phenotype in these three families, of different geographic origin (Austria, Belgium and England), is strikingly similar to the autosomal dominant juvenile ALS family except for a younger onset age in two of the distal hereditary motor neuronopathy families. These data suggest that ALS4 and distal hereditary motor neuronopathy with pyramidal tract signs may be one and the same disorder.

Adolescent↗
PubMed2002

The pattern of estradiol and progesterone differs in serum and tissue of benign and malignant ovarian tumors.

Epidemiological studies have indicated a relationship between gonadal steroid hormones and ovarian cancer. A production of both estradiol and progesterone by ovarian cancers has been demonstrated. The local steroid concentrations and the putative relation to histopathological and clinical condition were investigated herein. Ovarian tissue, ovarian tumor cyst fluid, ovarian vein samples and peripheral serum concentrations of estradiol and progesterone in pre- and post-menopausal women, subdivided into groups with normal ovaries, benign, borderline and malignant ovarian tumors, were quantitatively assessed. Both ovarian tissue concentrations of estradiol and progesterone were more than 100-fold higher than in serum. Based on differences in concentrations between different ovarian tumor groups, the data is not coherent with the previously suggested increased production of estradiol and progesterone in ovarian cancer tissue, since post-menopausal women with ovarian cancer presented lower median tissue hormone levels, most pronounced between malignant and benign tumors; median (25 and 75 percentile) estradiol; 9.40 (6.67-15.50) vs 16.44 (12.49-23.20), p=0.02 and progesterone; 308 (240-575) vs 957 (553-1143) pmol/g wet weight, p<0.01, n=81. Lower concentrations of estradiol, but not progesterone, were found in ovarian cancer tissue, ovarian cyst fluid and peripheral serum in patients with FIGO stages 3 and 4 than in stages 1 and 2. The novel finding of a large ovarian tissue to serum difference of both estradiol and progesterone indicates an important role of ovarian tissue concentrations in tumor biology and raises the question of adequate doses of anti-hormonal therapy in women with ovarian cancer.

Cyst Fluid↗
PubMed2001

Transplant coronary artery disease: a novel model independent of cellular alloimmune response.

BACKGROUND: Allograft coronary atherosclerosis (TxCAD) is the leading cause of death after the first year after transplantation. TxCAD is believed to be a form of chronic rejection of the cardiac allografts. This study was undertaken to determine whether TxCAD could develop in the absence of a cellular alloimmune response. METHODS AND RESULTS: Inbred lean Zucker rats (>26 generations) served as donors and recipients of the cardiac grafts. Donor hearts were explanted at 60 or 90 days. Explanted hearts were processed for coronary artery histological analysis. Cytokine expression was determined by reverse transcription-polymerase chain reaction, and the presence of T cells within the explanted hearts was evaluated by immunohistochemistry. Forty-six transplantations were made, and TxCAD developed in all but one of the transplanted hearts. Overall, one third of the vessels examined were affected by TxCAD, and in roughly half of these vessels, the disease was severe. Native hearts were free of atherosclerosis. Interleukin-2 was absent from the transplanted hearts, and T cells were present in minimal amounts (<1 per low-power field). CONCLUSIONS: TxCAD developed in the absence of a cellular alloimmune response in these genetically similar donors and recipients. The observed TxCAD was significant and comparable to what is found in rat allografting models.

Animals↗
PubMed2001

Contrasting molecular pathology of colorectal carcinoma in Egyptian and Western patients.

Colorectal carcinoma is uncommon in Egypt, but a high proportion of cases occurs before age 40 years and in the rectum. We compared the molecular pathology of 59 representative Egyptian patients aged 10-72 to Western patients with sporadic, young-onset, or hereditary non-polyposis colorectal cancer syndrome (HNPCC)-associated carcinoma and found significant differences. Most Egyptian cancers were rectal (51%) and poorly differentiated (58%). High levels of microsatellite instability (MSI-H) were frequent (37%) and attributable in some cases (36%) to methylation of the promoter of the hMLH1 mismatch repair gene, but no MSI-H cancer had loss of hMSH2 mismatch repair gene product of the type seen with germline hMSH2 mutation in HNPCC. K-ras mutation was uncommon (11%). In subset analyses, high frequencies of MSI-H in rectal carcinomas (36%) and p53 gene product overexpression in MSI-H cancers (50%) were found. MSI-H and K-ras mutation in Egyptians under age 40 were unusual (17% and 0%, respectively), and schistosomiasis was associated with MSI and K-ras mutation. Cluster analysis identified 2 groups: predominantly young men with poorly differentiated mucinous and signet-ring cell colorectal carcinoma lacking K-ras mutation; older patients who had well- or moderately differentiated adenocarcinoma often with MSI-H, K-ras mutation and schistosomiasis. Our findings show that the molecular pathology of colorectal cancer in older as well as younger Egyptians has unique differences from Western patients, and schistosomiasis influences the molecular pathogenesis of some tumours.

Adolescent↗
PubMed2001

Passive immunization with Neisseria meningitidis PorA specific immune sera reduces nasopharyngeal colonization of group B meningococcus in an infant rat nasal challenge model.

To examine the protective efficacy of specific immune sera generated by meningococcal vaccine candidates against nasopharyngeal colonization, we developed an infant rat nasal colonization model for group B meningococcus. In this model, Sprague-Dawley infant rats were challenged intranasally in with host adapted, piliated Neisseria meningitidis group B strains H355 or H44/76 administered concurrently with iron dextran. Colonization was assessed by quantitative culture of nasal homogenates and expressed as log(10) colony forming units (c.f.u.) per nose. Three to five log(10) c.f.u. of N. meningitidis were routinely recovered from the nasal tissue up to 4 days post-challenge. Passive immunization (i.p.) of the infant rats with either PorA or whole cell antisera 24 h prior to homologous challenge resulted in a significant reduction of N. meningitidis colonization in the nasal tissues of these animals. These results demonstrate that this model can be utilized to evaluate the role of antibody to prevent the initial nasopharyngeal colonization by group B meningococcus.

Administration, Intranasal↗
PubMed2001

Dominant intermediate Charcot-Marie-Tooth neuropathy maps to chromosome 19p12-p13.2.

The hereditary disorders of peripheral nerve form one of the most common groups of human genetic diseases, collectively called Charcot-Marie-Tooth (CMT) neuropathy. Using linkage analysis we have identified a new locus for a form of CMT that we have called "dominant intermediate CMT" (DI-CMT). A genomewide screen using 383 microsatellite markers showed strong linkage to the short arm of chromosome 19 (maximum LOD score 4.3, with a recombination fraction (straight theta) of 0, at D19S221 and maximum LOD score 5.28, straight theta=0, at D19S226). Haplotype analysis performed with 14 additional markers placed the DI-CMT locus within a 16.8-cM region flanked by the markers D19S586 and D19S546. Multipoint linkage analysis suggested the most likely location at D19S226 (maximum multipoint LOD score 6.77), within a 10-cM confidence interval. This study establishes the presence of a locus for DI-CMT on chromosome 19p12-p13.2.

Charcot-Marie-Tooth Disease↗
PubMed2001

Electron-transfer reactivity and enzymatic activity of hemoglobin in a SP Sephadex membrane.

Hemoglobin can exhibit a direct electron-transfer reaction after being entrapped in a SP Sephadex membrane. A pair of stable and well-defined redox waves are obtained at a hemoglobin-SP sephadex modified pyrolytic graphite electrode. The anodic and cathodic peak potentials are located at -0.244 and -0.336 V (vs SCE), respectively. On the other hand, the peroxidase activity of the protein in the membrane is also greatly enhanced. The apparent Michaelis-Menten constant is calculated to be 1.9 mM, which shows a large catalytic activity of hemoglobin in the SP Sephadex membrane toward hydrogen peroxide (H2O2). According to the direct electron-transfer property and enhanced peroxidase activity of Hb in the membrane, a Hb/SP Sephadex membrane-based H2O2 biosensor is prepared, with a linear range approximately 5.0 x 10(-6) to 1.6 x 10(-4) mol/L.

Animals↗
PubMed2001

A new approach to 4-alkylthio-1,3-dithiole-2-thione: an unusual reaction of a zinc complex of 1,3-dithole-2-thione-4,5-dithiolate.

[see reaction]. A new and facile approach to 4-alkylthio-1,3-dithiole-2-thione starting from easily accessible reactants was described. This approach was based on the unusual reaction of a zinc complex of 1,3-dithiole-2-thione-4,5-dithiolate with electrophilic reagents in the presence of 3-picolyl chloride hydrochloride/or 4-picolyl chloride hydrochloride/or pyridine hydrochloride.

Journal Article↗
PubMed2001

African origin of modern humans in East Asia: a tale of 12,000 Y chromosomes.

To test the hypotheses of modern human origin in East Asia, we sampled 12,127 male individuals from 163 populations and typed for three Y chromosome biallelic markers (YAP, M89, and M130). All the individuals carried a mutation at one of the three sites. These three mutations (YAP+, M89T, and M130T) coalesce to another mutation (M168T), which originated in Africa about 35,000 to 89,000 years ago. Therefore, the data do not support even a minimal in situ hominid contribution in the origin of anatomically modern humans in East Asia.

Africa↗
PubMed2001

Growth factor-induced angiogenesis in vivo requires specific cleavage of fibrillar type I collagen.

The contribution of specific type I collagen remodeling in angiogenesis was studied in vivo using a quantitative chick embryo assay that measures new blood vessel growth into well-defined fibrillar collagen implants. In response to a combination of basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF), a strong angiogenic response was observed, coincident with invasion into the collagen implants of activated fibroblasts, monocytes, heterophils, and endothelial cells. The angiogenic effect was highly dependent on matrix metalloproteinase (MMP) activity, because new vessel growth was inhibited by both a synthetic MMP inhibitor, BB3103, and a natural MMP inhibitor, TIMP-1. Multiple MMPs were detected in the angiogenic tissue including MMP-2, MMP-13, MMP-16, and a recently cloned MMP-9-like gelatinase. Using this assay system, wild-type collagen was compared to a unique collagenase-resistant collagen (r/r), with regard to the ability of the respective collagen implants to support cell invasion and angiogenesis. It was found that collagenase-resistant collagen constitutes a defective substratum for angiogenesis. In implants made with r/r collagen there was a substantial reduction in the number of endothelial cells and newly formed vessels. The presence of the r/r collagen, however, did not reduce the entry into the implants of other cell types, that is, activated fibroblasts and leukocytes. These results indicate that fibrillar collagen cleavage at collagenase-specific sites is a rate-limiting event in growth factor-stimulated angiogenesis in vivo.

Allantois↗
PubMed2001

Immunogenicity of recombinant GA733-2E antigen (CO17-1A, EGP, KS1-4, KSA, Ep-CAM) in gastro-intestinal carcinoma patients.

Targeting the GA733 antigen (also known as CO17-1A, EGP, KS1-4, KSA, Ep-CAM) by monoclonal antibody CO17-1A or anti-idiotypic antibodies mimicking the CO17-1A or GA733 epitope has induced prolonged survival and specific immune responses to the antigen, respectively, in colorectal cancer (CRC) patients. In pre-clinical studies in mice and rabbits, recombinant baculovirus-derived GA733-2E antigen was superior to anti-idiotypic antibodies at modulating specific immune responses. Our aim was to evaluate the immunogenicity and potential toxicity of alum-precipitated GA733-2E in a phase I trial in patients with resected CRC or pancreatic cancer. Six patients with advanced pancreatic carcinoma and 6 with CRC Dukes' stage A, B or C received between 4 and 7 doses of alum-precipitated GA733-2E at 50, 200 or 800 microg/dose at monthly intervals. Antibody binding to GA733-2E or antigen-positive CRC cells was determined, as were antigen-specific proliferative, cytolytic T-lymphocyte and delayed-type hypersensitivity responses. Six of the 12 patients developed antigen-specific humoral immune responses after immunotherapy, and 8 developed cellular immune responses. The overall immune response rate, including patients with humoral and/or cellular immune responses, was 83%. Median overall survival of the CRC and pancreatic cancer patients was 39.8 and 11.2 months, respectively. Following 18 years of single-epitope targeting of the GA733 antigen, immunization of patients against multiple epitopes of the antigen frequently induces an immune response in the absence of significant toxicity, despite relatively widespread expression of this antigen on normal epithelial cells.

Aged↗
PubMed2001

Role of a JAK3-dependent biochemical signaling pathway in platelet activation and aggregation.

Here we provide experimental evidence that identifies JAK3 as one of the regulators of platelet function. Treatment of platelets with thrombin induced tyrosine phosphorylation of the JAK3 target substrates STAT1 and STAT3. Platelets from JAK3-deficient mice displayed a decrease in tyrosine phosphorylation of STAT1 and STAT3. In accordance with these data, pretreatment of human platelets with the JAK3 inhibitor WHI-P131 markedly decreased the base-line enzymatic activity of constitutively active JAK3 and abolished the thrombin-induced tyrosine phosphorylation of STAT1 and STAT3. Following thrombin stimulation, WHI-P131-treated platelets did not undergo shape changes indicative of activation such as pseudopod formation. WHI-P131 inhibited thrombin-induced degranulation/serotonin release as well as platelet aggregation. Highly effective platelet inhibitory plasma concentrations of WHI-P131 were achieved in mice without toxicity. WHI-P131 prolonged the bleeding time of mice in a dose-dependent manner and improved event-free survival in a mouse model of thromboplastin-induced generalized and invariably fatal thromboembolism. To our knowledge, WHI-P131 is the first anti-thrombotic agent that prevents platelet aggregation by inhibiting JAK3.

Animals↗
PubMed2001

A kinetic study on the interaction of deprotonated purine radical cations with amino acids and model peptides.

By use of pulse radiolysis techniques, the radical cations of purine nucleotides have been successfully produced by the SO4- ion oxidation. Time-resolved spectroscopic evidence is provided that the one-electron-oxidized radicals of dAMP and dGMP can be efficiently repaired by aromatic amino acids (including tyrosine and tryptophan) via electron transfer reaction. As a model peptide, Arg-Tyr-AcOH was also investigated with regard to its interaction with deprotonated purine radical cations. The rate constants of the electron transfer reactions were determined to be (1 approximately 5) x 10(8) dm(3) mol(-1) s(-1). These results suggest that the aromatic amino acids in DNA-associated proteins may play some role in electron transfer reactions through DNA.

Amino Acids↗
PubMed2001

Highly conserved regions of the immunodominant major surface protein 2 of the genogroup II ehrlichial pathogen Anaplasma marginale are rich in naturally derived CD4+ T lymphocyte epitopes that elicit strong recall responses.

Genogroup II ehrlichia, including the agent of human granulocytic ehrlichiosis, Ehrlichia phagocytophila, and the bovine pathogen Anaplasma marginale, express a markedly immunodominant outer membrane protein designated major surface protein 2 (MSP2). MSP2 is encoded by a multigene family, resulting in the expression of variant B cell epitopes. MSP2 variants are sequentially expressed in the repeated cycles of rickettsemia that characterize persistent A. marginale infection and control of each rickettsemic cycle is associated with development of a variant-specific IgG response. Importantly, these persistent rickettsemic cycles are controlled at levels 100-1000 times lower than those responsible for clinical disease during acute infection. Control of rickettsemia during persistence could result from an anamnestic Th lymphocyte response to conserved regions of MSP2 that enhances the primary Ab response against newly emergent variants. Comparison of MSP2 variants reveals conserved N and C termini flanking the central, surface-exposed hypervariable region that represents the variant B lymphocyte epitopes. We demonstrate MSP2-specific CD4(+) T lymphocyte recognition of epitopes common to several strains of A. marginale and the related pathogen A. ovis. Furthermore, T lymphocyte lines from three individuals identified six to nine overlapping peptides representing a minimum of four to seven dominant or subdominant epitopes in these conserved N and C termini. Immunodominant peptides induced high levels of IFN-gamma, a cytokine associated with protection against ehrlichia and needed for rapid generation of variant-specific IgG2. The presented data support the potential importance of a strong Th lymphocyte response to invariant MSP2 epitopes in controlling rickettsemia during persistent infection to subclinical levels.

Amino Acid Sequence↗