Y-linked inheritance of non-syndromic hearing impairment in a large Chinese family.
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Audiometry↗
Biomedical subjects
Y Shen
Publications and source records attributed to Y Shen.
Novel ghrelin analogs with improved affinity for the GH secretagogue receptor stimulate GH and prolactin release from human pituitary cells.
OBJECTIVE: Ghrelin, a recently identified 28-amino acid peptide is a potent GH secretagogue (GHS) produced predominantly by the stomach. Ghrelin stimulates GH secretion through binding to the GHS receptor in the hypothalamus and pituitary. In addition to the GH-releasing action, ghrelin has been found to be a powerful orexigenic factor. To assess the direct in vitro effects of ghrelin on human pituitary hormone secretion we have produced a panel of novel ghrelin analogs (molecular weight, 3323-3384; human native ghrelin, 3371) with enhanced affinity for the human GHS receptor (IC(50) 0.38-1.09 nM; human ghrelin, 1.2-2.2 nM). METHODS: The peptidic analogs were tested for their effect on GH secretion using dispersed human fetal pituitaries (21 to 23 weeks of gestation) and cultured GH- and prolactin (PRL)-secreting adenomas. The expression of the GHS receptor in normal (fetal and adult) human pituitary tissues, GH- and PRL-cell adenomas was established using RT-PCR. RESULTS: The effects of ghrelin, its analogs and GH-releasing hormone (GHRH) alone or in combination on GH and PRL secretion were compared at various concentrations. The ghrelin analogs stimulated GH release by 35-60% from human fetal pituitary cells (1-10 nM; P<0.05) and by 50-75% from cultured pituitary adenomas (10 nM; P<0.05). This releasing effect was dose-dependent, achieving maximal stimulation with analog concentrations at 100 nM. Human ghrelin was less potent as compared with its analogs in stimulating human GH, in keeping with the improved binding affinity of the analogs for the GHS-1a receptor. The ghrelin analogs and GHRH had comparable effects on GH secretion from both normal and adenomatous cells, and in combination produced an additive stimulatory effect on GH (150%; P<0.0001). In contrast, ghrelin and its analogs induced a comparable increase in PRL release ranging between 25 and 40% (P<0.05) from fetal cells and 30 and 70% (P<0.001) from cultured PRL-cell and mixed GH-PRL adenomas. CONCLUSIONS: Our results have demonstrated for the first time that ghrelin analogs with enhanced affinity for the GHS receptor are potent stimulators of GH secretion from human pituitary cells, and thus may possess potential clinical therapeutic benefits.
Adenoma↗
[Report on the 89th Scientific Assembly and Annual Meeting of the Radiological Society of North America--cone beam artifact and helical artifact on the MDCT helical scan].
Because MDCT use narrow cone beam x-ray, to quantitatively evaluate cone beam artifact and helical artifact is very important with different x-ray beam width (detector configuration) . The both effect (helical artifact and cone beam artifact) was confirmed on the MDCT helical scan. It does not have cone beam artifact in the Isocenter or using center detector row for conventional scan, but helical artifact basically does not depend position of x-y plane. From quantitative evaluation of cone beam artifact, helical scan has fewer cone beam artifact than conventional scan on the 200 mm position of x-y plane: the cone beam artifact index is 11.76 (8 x 2.5mm conventional scan with most edge detector row) , 6.86 (8 x 2.5mm helical pitch 0.625) and 4.9 (8 x 2.5mm helical pitch 1.675). From phantom experiment, it was concluded that cone beam angle more contribute cone beam artifact than increasing slice numbers. And it was concluded that helical scan has fewer cone beam artifact than conventional scan, because helical scan use multi detector row information and special recon algorithm with cone beam correction on the GE LightSpeed MDCT scanner.
Artifacts↗
Nanoscale proteomics.
Efforts to develop a liquid chromatography (LC)/mass spectrometry (MS) technology for ultra-sensitive proteomics studies (i.e., nanoscale proteomics) are described. The approach combines high-efficiency nanoscale LC (separation peak capacity of approximately 10(3); 15-microm-i.d. packed capillaries with flow rates of 20 nL min(-1), the optimal separation linear velocity) with advanced MS, including high-sensitivity and high-resolution Fourier transform ion cyclotron resonance MS, to perform both single-stage MS and tandem MS (MS/MS) proteomic analyses. The technology enables broad protein identification from nanogram-size proteomics samples and allows the characterization of more abundant proteins from sub-picogram-size samples. Protein identification in such studies using MS is demonstrated from <75 zeptomole of a protein. The average proteome measurement throughput is approximately 50 proteins h(-1) using MS/MS during separations, presently requiring approximately 3 h sample(-1). Greater throughput (approximately 300 proteins h(-1)) and improved detection limits providing more comprehensive proteome coverage can be obtained by using the "accurate mass and time" tag approach developed in our laboratory. This approach provides a dynamic range of at least 10(6) for protein relative abundances and an improved basis for quantitation. These capabilities lay the foundation for studies from single or limited numbers of cells.
Amino Acid Sequence↗
Global structure and dynamics of human apolipoprotein CII in complex with micelles: evidence for increased mobility of the helix involved in the activation of lipoprotein lipase.
Apolipoprotein CII (apoCII), a surface constituent of plasma lipoproteins, is the activator for lipoprotein lipase (LPL) and is therefore central for lipid transport in blood. The three-dimensional structure of (13)C-, (15)N-enriched human full-length apoCII in complex with sodium dodecyl sulfate (SDS) micelles is reported. In addition to the structure determination, (15)N-relaxation measurements have been performed at two magnetic fields to characterize the dynamics of the backbone of apoCII in the complex. The relaxation data also provided global structural constraints, viz. the orientation of helices in the complex. In addition, global constraints were derived from the fact that apoCII helices are attached to the surface of the SDS micelle and that the hydrophobic moments of each helix faces the interior of the micelle. These three categories of global constraints, together with the local classical NMR constraints, were sufficient to define the 3D structure of the apoCII-SDS micelle complex. To our knowledge, this presents the first example in which the global structure of a protein-SDS micelle complex has been determined. The C-terminal helix of apoCII is known to be responsible for the activation of LPL. This helix is distinguished from the other helices by a higher degree of internal motion on the nanosecond time scale as shown by the relaxation data. The overall structure and the internal dynamics, combined with previous mutation data, give important clues toward a possible mechanism for the activation of LPL by apoCII.
Amino Acid Sequence↗
Glycoprotein Ib-IX-V.
Glycoprotein (GP) Ib-IX-V is a remarkable platelet adhesion receptor of the leucine-rich repeat family. It has evolved to fulfil its major function of initiating platelet aggregation (thrombus formation) at high-shear stress in flowing blood. In addition to binding von Willebrand factor (vWF) in subendothelial matrix or plasma to trigger platelet aggregation, GPIb-IX-V also binds counter-receptors, alphaMbeta2 (Mac-1) on neutrophils or P-selectin on activated platelets or endothelial cells. GPIb-IX-V ligands also include alpha-thrombin, clotting factors XI/XIIa, and high-molecular-weight kininogen. Interactions involving GPIb-IX-V are therefore central to vascular processes of thrombosis and inflammation, and the receptor is under intense scrutiny as a potential therapeutic target.
Animals↗
Dimensional complexity and spectral properties of the human sleep EEG. Electroencephalograms.
OBJECTIVE: The relevance of the dimensional complexity (DC) for the analysis of sleep EEG data is investigated and compared to linear measures. METHODS: We calculated DC of artifact-free 1 min segments of all-night sleep EEG recordings of 4 healthy young subjects. Non-linearity was tested by comparing with DC values of surrogate data. Linear properties of the segments were characterized by estimating the self-similarity exponent alpha based on the detrended fluctuation analysis which quantifies the persistence of the signal and by calculating spectral power in the delta, theta, alpha and sigma bands, respectively. RESULTS: We found weak nonlinear signatures in all sleep stages, but most pronounced in sleep stage 2. Strong correlations between DC and linear measures were established for the self-similarity exponent alpha and delta power, respectively. CONCLUSIONS: The dimensional complexity of the sleep EEG is influenced by both linear and nonlinear features. It cannot be directly interpreted as a nonlinear synchronization measure of brain activity, but yields valuable information when combined with the analysis of linear measures.
Adult↗
Comparison of fludarabine-containing salvage chemotherapy regimens for relapsed/refractory acute myelogenous leukemia.
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Acute Disease↗
Immune biology of macaque lymphocyte populations during mycobacterial infection.
Immune responses of lymphocyte populations during early phases of mycobacterial infection and reinfection have not been well characterized in humans. A non-human primate model of Mycobacterium bovis bacille Calmette-Guerin (BCG) infection was employed to characterize optimally the immune responses of mycobacteria-specific T cells. Primary BCG infection induced biphasic immune responses, characterized by initial lymphocytopenia and subsequent expansion of CD4+, CD8+ and gammadelta T cell populations in the blood, lymph nodes and the pulmonary compartment. The potency of detectable T cell immune responses appears to be influenced by the timing and route of infection as well as challenge doses of BCG organisms. Systemic BCG infection introduced by intravenous challenge induced a dose-dependent expansion of circulating CD4+, CD8+ and gammadelta T cells whereas, in the pulmonary compartment, the systemic infection resulted in a predominant increase in numbers of gammadelta T cells. In contrast, pulmonary exposure to BCG through the bronchial route induced detectable expansions of CD4+, CD8+ and gammadelta T cell populations in only the lung but not in the blood. A rapid recall expansion of these T cell populations was seen in the macaques reinfected intravenously and bronchially with BCG. The expanded alphabeta and gammadelta T cell populations exhibited their antigen specificity for mycobacterial peptides and non-peptide phospholigands, respectively. Finally, the major expansion of T cells was associated with a resolution of active BCG infection and reinfection. The patterns and kinetics of CD4+, CD8+ and gammadelta T cell immune responses during BCG infection might contribute to characterizing immune protection against tuberculosis and testing new tuberculosis vaccines in primates.
Animals↗
Collagen platelet receptor polymorphisms integrin alpha2beta1 C807T and GPVI Q317L and risk of ischemic stroke.
Several polymorphisms of integrin alpha2beta1 and glycoprotein (GP) VI that may modify platelet-collagen interactions or subsequent signaling have been described. We conducted a case-control study involving 180 stroke patients and 172 controls to determine whether the alpha2 C807T and GPVI Q317L polymorphisms were associated with an increased risk of ischemic stroke. We found no statistically significant differences in the distribution of alpha2 C807T and GPVI Q317L in patients and controls overall or after stratification by etiological subtype. The GPVI 317QQ genotype was found to be over-represented in a subgroup of patients >/=60 years compared to corresponding controls. However, this association did not remain significant after adjustment for other cardiovascular risk factors. Our results do not support a role for the integrin alpha2 C807T and GPVI Q317L polymorphisms in the development of first-ever ischemic stroke. However, larger studies are required to confirm this.
Aged↗
Chinese SF-36 Health Survey: translation, cultural adaptation, validation, and normalisation.
STUDY OBJECTIVE: To develop a self administered Chinese (mainland) version of the Short-Form Health Survey (SF-36) for use in health related quality of life measurements in China. DESIGN: A three stage protocol was followed including translation, tests of scaling construction and scoring assumptions, validation, and normalisation. SETTING: 1000 households in 18 communities of Hangzhou. PARTICIPANTS: 1688 respondents recruited by multi-stage mixed sampling. MAIN RESULTS: The assumption of equal intervals was violated for the vitality and mental health scales. The recoded item values were used to calculate scale scores. The clustering and ordering of item means was the same as that of the source and other two Chinese versions. The items in each scale had similar standard deviations except those in the physical functioning, boduily pain, social functioning scales. The item hypothesised scale correlations were identical for all except the social functioning and vitality scales. Convergent validity and discriminant validity were satisfactory for all except the social functioning scale. Cronbach's alpha coefficients ranged from 0.72 to 0.88 except 0.39 for the social functioning scale and 0.66 for the vitality scale. Two weeks test-retest reliability coefficients ranged from 0.66 to 0.94. Factor analysis identified two principal components explaining 56.3% of the total variance. The Chinese SF-36 could distinguish known groups. CONCLUSIONS: This study suggested that the Chinese (mainland) version of the SF-36 functioned in the general population of Hangzhou, China quite similarly to the original American population tested. Caution is recommended in the interpretation of the social functioning and vitality scales pending further studies.
Adolescent↗
Evidence for linkage and association of the markers near the LPL gene with hypertension in Chinese families.
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Adult↗
Crystallographic findings on the internally uncoupled and near-rigor states of myosin: further insights into the mechanics of the motor.
Here we report a 2.3-A crystal structure of scallop myosin S1 complexed with ADP.BeF(x), as well as three additional structures (at 2.8-3.8 A resolution) for this S1 complexed with ATP analogs, some of which are cross-linked by para-phenyl dimaleimide, a short intramolecular cross-linker. In all cases, the complexes are characterized by an unwound SH1 helix first seen in an unusual 2.5-A scallop myosin-MgADP structure and described as corresponding to a previously unrecognized actin-detached internally uncoupled state. The unwinding of the SH1 helix effectively uncouples the converter/lever arm module from the motor and allows cross-linking by para-phenyl dimaleimide, which has been shown to occur only in weak actin-binding states of the molecule. Mutations near the metastable SH1 helix that disable the motor can be accounted for by viewing this structural element as a clutch controlling the transmission of torque to the lever arm. We have also determined a 3.2-A nucleotide-free structure of scallop myosin S1, which suggests that in the near-rigor state there are two conformations in the switch I loop, depending on whether nucleotide is present. Analysis of the subdomain motions in the weak actin-binding states revealed by x-ray crystallography, together with recent electron microscopic results, clarify the mechanical roles of the parts of the motor in the course of the contractile cycle and suggest how strong binding to actin triggers both the power stroke and product release.
Adenosine Diphosphate↗
Misfolded loops decrease the effective rate of DNA hairpin formation.
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DNA, Single-Stranded↗
Early alterations in the collagen meshwork and lesions in the ankles are associated with spontaneous osteoarthritis in guinea-pigs.
OBJECTIVE: The purpose of this study was to evaluate matrix changes in knee cartilage prior to development of surface disruptions and to examine the ankle for evidence of osteoarthritis (OA)-like lesions. DESIGN: Guinea-pig ankles and knees were examined histologically or viewed with polarization microscopy to reveal changes in orientation of the collagen fibers. RESULTS: The medial femoral condyles were virtually free of histologic changes at 3 months of age. Changes were present by 6 months. Medial tibial plateau histologic changes were seen at 3 months which became more pronounced with age. Alterations in the collagen meshwork corresponding to areas of proteoglycan (PG) loss were noted in animals with an intact articular surface as early as 3 months. Histologic changes were noted in the ankles as early as 3 months of age which included surface disruptions, cell loss and loss of PG staining. Only knee joint composite histology scores were significantly elevated at 3 months while both knee and ankle scores were significantly elevated at 6 months. Knee and ankle joint scores were not different from each other at 6 months. CONCLUSIONS: Alterations in the orientation of the collagen network of the cartilage correlated with Safranin-O loss suggesting that alterations in collagen:PG interactions play a role in the early phases of the OA process and precede frank histologic changes in the articular surface. The results in this study report for the first time OA-like lesions occurring spontaneously in articular cartilage of the ankle in the guinea-pig.
Aging↗
A randomised, double blind, placebo controlled study of celecoxib, a selective cyclooxygenase 2 inhibitor, on duodenal polyposis in familial adenomatous polyposis.
BACKGROUND: Non-selective cyclooxygenase (COX) inhibitors (non-steroidal anti-inflammatory drugs) inhibit large bowel carcinogenesis in patients with familial adenomatous polyposis (FAP). Their role in the duodenum of these patients is less certain. The disease modifying activity of specific COX-2 inhibitors has not been explored in humans. PATIENTS AND METHODS: This was a randomised, double blind, placebo controlled study of celecoxib (100 mg twice daily (n=34) or 400 mg twice daily (n=32)) versus placebo (n=17), given orally twice daily for six months to patients with FAP. Efficacy was assessed qualitatively by blinded review of shuffled endoscopy videotapes comparing the extent of duodenal polyposis at entry and at six months and quantitatively by measurement of the percentage change in duodenal area covered by discrete and plaque-like adenomas from photographs of high and low density polyposis. RESULTS: Shuffled and blinded video review showed a statistically significant effect of 400 mg twice daily celecoxib compared with placebo treatment (p=0.033) with all five independent observers scoring a beneficial effect. Overall, patients taking celecoxib 400 mg twice daily showed a 14.5% reduction in involved areas compared with a 1.4% for placebo (p=0.436). However, patients with clinically significant disease at baseline (greater than 5% covered by polyps) showed a 31% reduction in involved areas with celecoxib 400 mg twice daily compared with 8% on placebo (p=0.049). CONCLUSIONS: A panel of five endoscopists found a significant reduction in duodenal polyposis after six months of treatment with celecoxib 400 mg twice daily. COX-2 inhibition may help this otherwise untreatable condition.
Adenomatous Polyposis Coli↗
OVX1, macrophage-colony stimulating factor, and CA-125-II as tumor markers for epithelial ovarian carcinoma: a critical appraisal.
BACKGROUND: Ovarian carcinoma remains the leading cause of death from gynecologic malignancy in Australia, the Netherlands, and the United States. CA-125-II, the most widely used serum marker, has limited sensitivity and specificity for detecting small-volume, early-stage disease. Therefore, a panel of three serum tumor markers-OVX1, CA-125-II, and macrophage-colony stimulating factor (M-CSF)-has been used to evaluate the sensitivity and specificity of multiple markers for the detection of early-stage ovarian carcinoma. METHODS: Preoperative serum levels of OVX1, CA-125-II, and M-CSF were measured in 281 patients with primary ovarian epithelial tumors of different histotypes. Among these tumors, 175 were malignant, 29 were of borderline malignancy, and 77 were benign. The three markers also were measured in sera from 117 apparently healthy women. Marker levels were considered abnormal at CA-125-II > 35 U/mL, OVX1 > 7.2 U/mL, and M-CSF > 3.5 ng/mL. RESULTS: Among 175 women with malignant ovarian tumors, at least one of the three serum markers was elevated in 85%, whereas CA-125-II was elevated in 80% (P = 0.008). In 58 patients with Stage I ovarian carcinoma, at least one of the three serum markers was elevated in 76%, whereas CA-125 levels were elevated in 66% (P = 0.04). For patients with borderline and benign tumors, a combination of the three antigens had slightly higher sensitivity compared with CA-125-II, but the differences were not statistically significant. Among 117 apparently healthy women, CA-125-II was elevated in 4%, and one of the three markers was positive in 17%. CONCLUSIONS: The sensitivity of a combination of three serum markers was significantly greater than the sensitivity of the CA-125-II assay alone in patients with primary ovarian epithelial tumors of different histotypes. This was true for all stages, including early-stage, potentially curable disease. When used as single markers, however, only the CA-125-II assay could distinguish invasive Stage I tumors from apparently healthy women.
Antigens, Tumor-Associated, Carbohydrate↗
Crystallization and preliminary X-ray study of the edema factor exotoxin adenylyl cyclase domain from Bacillus anthracis in the presence of its activator, calmodulin.
Edema factor from Bacillus anthracis is a 92 kDa secreted adenylyl cyclase exotoxin and is activated by the host-resident protein calmodulin. Calmodulin is a ubiquitous intracellular calcium sensor in eukaryotes and activates edema factor nearly 1000-fold upon binding. While calmodulin has many known effectors, including kinases, phosphodiesterases, motor proteins, channels and type 1 adenylyl cyclases, no structures of calmodulin in complex with a functional enzyme have been solved. The crystallization and initial experimental phasing of crystals containing a complex of edema factor adenylyl cyclase domain and calmodulin are reported here. The edema factor-calmodulin complex crystallizes in three different space groups. A native data set in the I222 space group has been collected to 2.7 A and the self-rotation function solution suggests three edema factor-calmodulin complexes in each asymmetric unit. Initial 4 A phases were obtained by selenomethionyl MAD in combination with two heavy-atom derivatives. These phases were successfully extended to 2.7 A using NCS averaging.
Adenylyl Cyclases↗