Cadmium, chromium, and copper induce polychromatocyte micronuclei in carp (Cyprinus carpio L.).
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Animals↗
Biomedical subjects
R Zhang
Publications and source records attributed to R Zhang.
Scanning for MODY5 gene mutations in Chinese early onset or multiple affected diabetes pedigrees.
Mutation of HNF-1beta gene has been reported in early onset diabetes or MODY families and this gene has been defined as MODY5 gene. The aim of our study was to examine whether HNF-1beta mutation contribute to early onset or multiple affected diabetes pedigrees in Chinese. Molecular scanning of HNF-1beta gene promoter region, nine exons and flanking introns was performed in 154 unrelated probands from early onset and multiple affected diabetes Chinese pedigrees. The family members of probands with mutations or variants and 58 nondiabetics were also examined. Clinical examinations of renal morphology, renal function and beta-cell function were performed in the HNF-1beta gene mutation carriers and family members. Mutation of HNF-1beta gene causing the substitution S36F was found in two subjects of an early onset diabetic family. One carrier has early onset diabetes, renal function impairment and renal cyst, while the other has impaired glucose tolerance only. This is the first case of MODY5 gene mutation diabetes found in the Chinese. Three HNF-1beta variants were identified and no significant differences in allele frequencies for these variants were detected between the nondiabetic and diabetic groups. Nucleotide 66 of intron 8 of HNF-1beta gene was G in the Chinese population rather than A as noted in the GenBank sequence. These results suggest that HNF-1beta gene mutations may be associated with nondiabetic renal dysfunction and diabetes in Chinese, but they are responsible for only a small percentage of early onset or multiple affected diabetes pedigrees including MODY.
Adenine↗
Response durations encode nociceptive stimulus intensity in the rat medial prefrontal cortex.
We examined whether the medial prefrontal cortex (mPFC) encodes nociceptive stimulus intensity by applying mechanical pressure stimulation, for 2 s at 50, 100, or 300 g constant force (gf) to the tails of urethane-anesthetized rats. In a total of 1208 neurons sampled, 242 (20.0%) were responsive to mechanical stimuli. One hundred thirteen of the 242 (46.7%) were mechanical high threshold neurons (nociceptive specific neurons, NS; threshold >or=100 gf), and 35 (14.5%) exhibited a graded increase in excitator responses to a stepwise increase in stimulus intensity (wide dynamic range-like neurons, WDR-L). These 148 response discharges persisted during stimulation followed by post-stimulus discharges. The nociceptive response duration of NS neurons, but not discharge frequency, was reduced dose-dependently by intraventricular injection of morphine (0.3, and 30 microg/3 microl). Different doses of morphine may set the stimulus intensity at relatively different brain activity levels. Thus, the NS neurons used the response duration as a sensory transduction code. In WDR-L neurons, the response duration, but not always the firing frequency, was linearly related to stimulus intensity. The WDR-L neurons in the mPFC encoded stimulus intensity with response duration, although the coding method is not likely to be the same as that of sensory discriminating WDR cells in the primary somatosensory cortex. Both types of mPFC neurons encode nociceptive (absolute or relative) stimulus intensity and transform the information into the temporal duration of the next stage of pain-related modulation in animal behavior.
Action Potentials↗
Allogenic donor splenocytes pretreated with antisense peptide against B7 prolong cardiac allograft survival.
The interaction of T cell CD28/CTLA-4 receptors with B7 on antigen-presenting cells (APCs) represents an important co-stimulatory pathway in T cell activation or anergy. Our previous study indicated that recipients immunized with allogenic donor immature dendritic cells (DCs) or resting B cells could induce specific immune tolerance and prolong allograft survival. A possible mechanism for this observation is that the expression of B7 molecules is either at a low level or lacking on these cells. The present study investigates whether blockade of B7 molecules on donor splenocytes with a B7 antisense peptide (B7AP), i.e. a peptide analogue of the CD28-binding region, could induce specific immune tolerance and prolong allograft survival in the recipients. Both the lymphocyte proliferation reaction and the mice pinna cardiac allograft experiment were performed to evaluate the role of B7AP in inducing specific immune tolerance in recipients in vitro and in vivo. The results showed that 56.65% and 20.52% of C57BL/6 splenocytes expressed B7.1 and B7.2 molecules, respectively, on their cell surface. There were no significant changes of the B7 expression on such splenocytes after being treated by the B7AP (53.28% and 19.06%, respectively). B7AP inhibited the mixed lymphocyte reaction by up to 38.4% and a dose-response correlation was observed for inhibition. The recipients (BALB/c) immunized with B7AP-pretreated C57BL/6 splenocytes induced a specific immune hypo-response (43%versus control) and notably prolonged survival of the C57BL/6 cardiac allograft by up to 20.3 days. In contrast to the normal saline group (average: 8.6 days) and FTD(10) control peptide group (<4 days), the cardiac allograft survival of the test group was extended for an additional 11.7 days. These results strongly support the notion that immunization with donor splenocytes, which had been pretreated with B7AP, induced specific immune tolerance and prolonged allograft survival in the recipients.
Animals↗
Atomic resolution imaging of a carbon nanotube from diffraction intensities.
Atomic imaging of three-dimensional structures has required a crystal in diffraction or a lens in electron imaging. Whereas diffraction achieves very high resolution by averaging over many cells, imaging gives localized structural information, such as the position of a single dopant atom. However, lens aberrations limit electron imaging resolution to about 1 angstrom. Resolution is reduced further by low contrast from weakscattering or from the limitations on electron dose for radiation-sensitive molecules. We show that both high resolution and high contrast can be achieved by imaging from diffraction with a nanometer-sized coherent electron beam. The phase problem is solved by oversampling and iterative phase retrieval. We apply this technique to image a double-wall carbon nanotube at 1-angstrom resolution, revealing the structure of two tubes of different helicities. Because the only requirement for imaging is a diffraction pattern sampled below the Nyquist frequency, our technique has the potential to image nonperiodic nanostructures, including biological macromolecules, at diffraction intensity-limited resolutions.
Journal Article↗
A reversible hydrogel membrane for controlling the delivery of macromolecules.
Glucose-sensitive hydrogel membranes have been synthesized and characterized for their rate-of-delivery of macromolecules. The mechanism for changing this rate is based on variable displacement of the affinity interaction between dextran and concanavalin A (con A). Our main objective was to characterize the diffusion of model proteins (insulin, lysozyme, and BSA) through the membrane, in response to changes in environmental glucose concentrations. Membranes were constructed from crosslinked dextrans to which con A was coupled via a spacer arm. Changes in the porosity of the resulting hydrogel in the presence of glucose led to changes in the diffusion rate observed for a range of proteins. Gels of specified thickness were cast around to nylon gauze support (pore size, 0.1 mm) to improve mechanical strength. Diffusion of proteins through the gel membrane was determined using a twin-chamber diffusion cell with the concentrations being continuously monitored using a UV-spectrophotometer. Changes in the transport properties of the membranes in response to glucose were explored and it was found that, while 0.1M D-glucose caused a substantial, but saturateable, increase in the rates of diffusion of both insulin and lysozyme, controls using glycerol or L-glucose (0.1M) had no significant effect. Sequential addition and removal of external glucose in a stepwise manner showed that permeability changes were reversible. As expected, diffusion rates were inversely proportional to membrane thickness. A maximum increase in permeability was observed at pH 7.4 and at 37 degrees C. The results demonstrate that this hydrogel membrane functions as a smart material allowing control of solute delivery in response to specific changes in its external environment.
Anti-Bacterial Agents↗
Clinical studies in patients with solid tumors using a second-generation antisense oligonucleotide (GEM 231) targeted against protein kinase A type I.
GEM 231 is a second-generation antisense oligonucleotide targeted against the RIalpha regulatory subunit of cAMP-dependent protein kinase type I (PKA-I). Excessive expression of PKA-I is associated with cell proliferation and transformation, and increased levels of secreted extracellular PKA (ECPKA) are found in the serum of cancer patients. Preclinical studies have demonstrated single-agent antitumor activity of GEM 231 in a variety of human cancer xenograft models, and additive or synergistic antitumor activity has been observed with taxane and/or camptothecin-based combinations. Based on prior safety (MTD) data demonstrating dose-dependent, reversible, and cumulative transaminitis, and high peak plasma concentration (Cmax)-dependent changes in activated partial thromboplastin time (aPTT) with GEM 231 2-h twice-weekly infusions, an alternative schedule of GEM 231 given as a single agent was evaluated in patients with advanced solid tumors. Fourteen patients (median age approximately 60 yrs) with advanced solid malignancies received a total of 78 weeks of therapy. GEM 231 was infused via a CADD pump at 80 mg/m2/day (d) for 3 d/wk (n = 1), then for 5 d/wk at 80 (n = 3), 120 (n = 8), and 180 mg/m2/d (n = 2). One cycle was defined as 4 weeks of therapy. Apparent dose dependency for the occurrence of transaminitis was readily reversible. At 180 mg/m2/d, 2 of 2 patients had cycle 1 dose-limiting toxicity (DLT) transaminitis. One patient treated at 120 mg/m2/d experienced grade 3 transaminase elevations after 8 weeks of therapy, but when serum transaminase values rapidly improved he resumed treatment at 80 mg/m2/d for 6 weeks until tumor progression was documented. Another patient at 120 mg/m2/d developed grade 3 esophagitis after 3 weeks, limiting further dosing. One patient (lung cancer) demonstrated stable disease for 9 weeks. Overall, plasma aPTT was minimally prolonged and changes were transient, peaked at the end of each infusion, and were not associated with spontaneous bleeding. A constitutive symptom (e.g., low-grade fatigue) was common, cumulative, and reversible following discontinuation of therapy. Serum ECPKA was measured by enzymatic assay and Western blotting from blood drawn at the beginning and end of each infusion. Serum ECPKA levels demonstrated a trend to decline with the treatment. In addition to single agent schedules, combination trials were undertaken to assess safety and possible interaction of GEM 231 with taxanes (paclitaxel, docetaxel), given once every 3 weeks (one cycle). While trials using the 2-h twice-weekly GEM 231 infusions are ongoing, preliminary results from both studies show that it is safe to combine paclitaxel or docetaxel with GEM 231. Overall, it is also feasible to administer GEM 231 in combination with taxane or nontaxane chemotherapy (e.g., camptothecins). Phase I combination studies are currently underway to further explore the clinical, pharmacokinetic, and biologic profile of GEM 231 with chemotherapy.
Antineoplastic Agents↗
Single nucleotide polymorphism discrimination assisted by improved base stacking hybridization using oligonucleotide microarrays.
Efficiencies of mismatch discrimination using size-varied capture probes were examined at various hybridization temperatures. The probes were 17, 15, 13, 11, 9, and 7 nucleotides long and contained single-base mismatches at their 3' ends. The optimal signal intensity and efficiency of base stacking hybridization on mismatch discrimination were observed for capture probes with a melting temperature (Tm) value of 36 degrees C, in the detection of DNA sequence variations at 40 degrees C. We employed asymmetric PCR to prepare single-stranded target DNA labeled with a fluorescent dye, and the PCR product was hybridized on the DNA microarray with no further purification. Our efforts have enhanced the sensitivity and simplified the procedures of base stacking hybridization on mismatch discrimination. As a model experiment, this improved technology was used to identify plasmid templates of human leukocyte antigen (HLA)-A alleles 2601, 2902, and 0206 on oligonucleotide microarrays. It is now possible to apply this simple, rapid, sensitive, and reliable base stacking hybridization technology to detect DNA sequence variations on microarrays in clinical diagnosis and other applications.
Alleles↗
Diagnostic utility of somatosensory and motor evoked potentials in a patient with thoracic outlet syndrome.
OBJECTIVE: To evaluate the utility of somatosensory and motor evoked potentials in the diagnosis of neurogenic thoracic outlet syndrome (TOS). MATERIALS AND METHODS: In a female patient with progressive weakness and sensory disturbance, ulnar nerve somatosensory evoked potentials (SSEP), and intraoperative motor evoked potential (MEP) were performed. RESULTS: The SSEPs demonstrated no significant change in latency of major peaks at rest and after abduction of the shoulder. Diminishment of amplitude was noted after dynamic position of the arm. The MEPs demonstrated no significant change in latency after dynamic position. Diminishment of amplitude was noted after the dynamic position. The amplitude returned to normal after repositioning the arm. CONCLUSIONS: Electrophysiologic study is helpful in the diagnosis of neurogenic TOS. Reduced amplitude of cortical SSEP and myogenic MEP is expected during dynamic position of the affected arm.
Adult↗
Microfabrication technology: organized assembly of carbon nanotubes.
Nanoscale structures need to be arranged into well-defined configurations in order to build integrated systems. Here we use a chemical-vapour deposition method with gas-phase catalyst delivery to direct the assembly of carbon nanotubes in a variety of predetermined orientations onto silicon/silica substrates, building them into one-, two- and three-dimensional arrangements. The preference of nanotubes to grow selectively on and normal to silica surfaces forces them to inherit the lithographically machined template topography of their substrates, allowing the sites of nucleation and the direction of growth to be controlled.
Journal Article↗
The thyroid hormone receptor and the insulator protein CTCF: two different factors with overlapping functions.
Thyroid hormones and thyroid hormone receptors (TRs) confer a fundamental regulation of critical genes involved in metabolism, differentiation, and development. A similar role is attributed to the highly conserved zinc-finger factor CTCF. Furthermore, a potential role in tumour suppression has been attributed to CTCF. In addition to promoter regulation, CTCF has also been shown to be involved in chromatin insulation or enhancer blocking. In several cases, binding sites for TR and for CTCF have been found next to each other. Functionally, these sites mediate synergistic repression or induction dependent on the type of binding site and on the presence or absence of thyroid hormone. Here we discuss functional similarities between TR and CTCF and their roles within these composite elements.
Animals↗
Research on the microstructure of insect cuticle and the strength of a biomimetic preformed hole composite.
The insect cuticle is a typical natural composite with excellent strength, stiffness, and fracture toughness. Scanning electron microscope observation of the microstructure of Hydrophilidae (an insect) cuticle showed several unique plies and structural characteristics, which may provide available information to the design of advanced composites. The microstructure found in the vicinity of pore canals in the insect cuticle was used for the design of the composite laminate with a hole. Compared with the composite laminate with a normally drilled hole, it was found that the strength of the specially designed composite laminate increases markedly, which is of important significance to the design of high-performance composites.
Animals↗
Effective gene therapy for medullary thyroid carcinoma using recombinant adenovirus inducing tumor-specific expression of interleukin-12.
No satisfactory treatment of metastatic medullary thyroid carcinoma (MTC) is available. Cell-specific gene therapy offers a new approach. We have constructed a recombinant replication-defective adenoviral vector expressing murine interleukin-12 (mIL-12), driven by a modified CALC-I promoter (TCP). This vector (AdTCPmIL-12) includes two separate cassettes encoding mIL-12 p35 or p40 subunit controlled by TCP inserted in the E1 region of adenovirus type 5. In vitro and in vivo reporter gene expression using TCP revealed its cell-specific activity. AdTCPmIL-12-infected rat MTC (rMTC) cells produced high amounts of functional mIL-12 cells in vitro, while other cell lines infected with AdTCPmIL-12 did not. AdTCPmIL-12-transduced rMTC cells completely lost their tumorigenicity in syngenic WAG/Rij rats. Direct injection of 1 x 10(9) plaque forming units of AdTCPmIL-12 into subcutaneous rMTC tumors in WAG/Rij rats caused tumor regression in over 60% of animals within 20 days. Rats cured of tumors did not develop tumors after re-injection of naive rMTC cells, demonstrating lasting immunity. Treatment with AdTCPmIL-12 of one tumor resulted in regression of an established tumor at a distant site. Moreover, intratumoral or intravenous injection of AdTCPmIL-12 did not induce evident toxicity. These results indicate AdTCPmIL-12 can contribute to effective and less toxic gene therapy of MTC.
Adenoviridae↗
An effective immunization and cancer treatment with activated dendritic cells transduced with full-length wild-type p53.
P53-based immunization is an attractive approach to cancer immunotherapy due to the accumulation of p53 protein in tumor, but not in normal cells. However, it was not known whether immune response against self-protein (p53) could be generated in vivo. Mouse dendritic cells (DCs) were transduced with adenoviral construct containing murine full-length wild-type p53 (Ad-p53). Repeated immunizations with these cells protected 60% of mice against challenge with MethA sarcoma cells bearing point mutations in p53 gene. Activation of DCs via ligation of CD40 significantly improved the results of immunization: all mice were protected against MethA sarcoma. The treatment of MethA tumor-bearing mice with activated Ad-p53-transduced DCs showed complete tumor rejection in four out of six mice. The specificity of antitumor immune response was confirmed by CTL assay. The analysis of phenotype and function of DCs demonstrated that the effect of CD40 ligation on these cells was enhanced by their infection with Ad-p53. The level of neutralizing anti-adenovirus antibody was moderately elevated in these mice. No signs of autoimmune reaction were evident during detailed pathological evaluation of treated mice. These data demonstrate that activated Ad-p53-infected DCs are able to break tolerance to this protein and can be used in immunotherapy of cancer.
Adenoviridae↗
Renal and cardiovascular considerations for the nonpharmacological and pharmacological therapies of obesity-hypertension.
Obesity-associated hypertension is a common disease that involves a complex pathogenesis. Failure to control hypertension (HTN) in obese subjects provides a great threat to their renal and cardiovascular functions. The treatment of obesity-associated HTN is often difficult, and requires nonpharmacological and/or pharmacological approaches. Weight reduction is the cornerstone of the therapies of obesity-HTN, as it reverses the multiple components of its pathogenesis. When weight loss cannot be sustained or fails, pharmacological means should then be used. Angiotensin-converting enzyme inhibitors (ACEI) are the drug of choice: they can reduce blood pressure, protect the kidney and heart, and improve the metabolic abnormalities in obese subjects. Angiotensin-2 type-1 receptor blockers have a renoprotective benefit similar to ACEI, and they provide an important alternative to the use of ACEI. Diuretics are very effective in African-American obese hypertensives, but small doses should be used to avoid adverse effects on metabolic profiles. Long-acting calcium channel blockers are also effective and have the advantage of no adverse metabolic effects. Nondihydropyridine calcium channel blockers may provide additional renal and cardiovascular protective effects. The beta-adrenergic receptor blockers can cause further weight gain and metabolic abnormalities in obese subjects; therefore, careful monitoring is needed. There are few clinical data that support the efficacy and benefit of centrally acting alpha-2 agonists and alpha-adrenergic receptor antagonists in the treatment of obesity-HTN.
Cardiovascular Physiological Phenomena↗
Modeling of nonlinear physiological systems with fast and slow dynamics. II. Application to cerebral autoregulation.
Dynamic autoregulation of cerebral hemodynamics in healthy humans is studied using the novel methodology of the Laguerre-Volterra network for systems with fast and slow dynamics (Mitsis, G. D., and V. Z. Marmarelis, Ann. Biomed. Eng. 30:272-281, 2002). Since cerebral autoregulation is mediated by various physiological mechanisms with significantly different time constants, it is used to demonstrate the efficacy of the new method. Results are presented in the time and frequency domains and reveal that cerebral autoregulation is a nonlinear and dynamic (frequency-dependent) system with considerable nonstationarities. Quantification of the latter reveals greater variability in specific frequency bands for each subject in the low and middle frequency range (below 0.1 Hz). The nonlinear dynamics are prominent also in the low and middle frequency ranges, where the frequency response of the system exhibits reduced gain.
Adult↗
Evaluating interactions of amphoteric molecules with phospholipid membrane using immobilized artificial membrane chromatography.
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Chemical Phenomena↗
Survival by time of day of hemodialysis in an elderly cohort.
CONTEXT: Patients with end-stage renal disease (ESRD) typically undergo hemodialysis (HD) during the morning or afternoon, with time of treatment generally based on space availability or patient preference. No studies have investigated variation in patient survival as a function of the time of day when they receive dialysis. OBJECTIVE: To investigate the association of elderly patients' HD treatment shift with their continued survival, controlling for well-established HD-related mortality risk factors. DESIGN, SETTING, AND PARTICIPANTS: An 11-year follow-up cohort study conducted among 242 ESRD patients aged 60 years or older who underwent HD at 58 dialysis facilities in Georgia either during a morning shift (n = 167) or an afternoon shift (n = 75) and who completed baseline (1988) [corrected] and follow-up (1991) interviews. MAIN OUTCOME MEASURE: Mortality from all causes occurring through July 7, 1999, as verified by death-certificate reviews, and compared by morning vs afternoon-shift HD. RESULTS: Morning-shift HD patients survived significantly longer than afternoon-shift patients (median survival, 941 days vs 470 days; P<.001). A Cox proportional hazards model indicated that the morning shift was protective (relative risk, 0.71; 95% confidence interval, 0.53-0.95) independent of age, race, sex, body mass index, functional status, diabetic ESRD, cardiovascular comorbidity, weekly hours of dialysis, and months of dialysis. CONCLUSIONS: Possible explanations for differential survival in association with morning vs afternoon dialysis include salutary effects of sleep in the morning or less efficient biochemical exchange during afternoon dialysis. Results from this cohort study may warrant prospective observational studies and randomized clinical trials that systematically alter the time of day at which HD is administered.
Aged↗