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Biomedical subjects

C Li

Publications and source records attributed to C Li.

At least 307 records · Page 17Linked to original sources
PubMed2000

Mortality associated with HIV infection in rural Rakai District, Uganda.

OBJECTIVE: To assess mortality impact of HIV in rural Uganda. METHODS: An open cohort of 19983 adults aged 15-59 years, in Rakai district was followed at 10 month intervals for four surveys. Sociodemographic characteristics and symptomatology/disease conditions were assessed by interview. Deaths among residents and out-migrants were identified household census. Mortality rates were computed per 1000 person years (py) and the rate ratio (RR) of death in HIV-positive/HIV-negative subjects, and the population attributable fraction (PAF) of death were estimated according to sociodemographic characteristics. Mortality associated with potential AIDS defining symptoms and signs was assessed. RESULTS: HIV prevalence was 16.1%. Mortality was 132.6 per 1000 py in HIV-infected versus 6.7 per 1000 py in uninfected subjects, and 73.5% of adult deaths were attributable to HIV infection. Mortality increased with age, but the highest attributable risk of HIV associated deaths were observed in persons aged 20-39 years (PAF > 80%) and in women. HIV associated mortality was highest in the better educated (PAF > or = 75%) and among government employees (PAF > or = 82%). Of the HIV-positive subjects 40.5% reported no illness < 10 months preceding death, symptoms were poor predictors of death (sensitivity 1.6-38.8%), and only 9.1% met the World Health Organization clinical definition of AIDS. Infant mortality rates in babies of HIV-infected and uninfected mothers were 209.4 and 97.7 per 1000, respectively. CONCLUSION: HIV is taking substantial toll in this population, particularly among the younger better educated adults, and infants. Symptomatology or the World Health Organization definition of AIDS are poor predictors of death.

Adolescent↗
PubMed2000

Analyzing high-density oligonucleotide gene expression array data.

We have developed methods and identified problems associated with the analysis of data generated by high-density, oligonuceotide gene expression arrays. Our methods are aimed at accounting for many of the sources of variation that make it difficult, at times, to realize consistent results. We present here descriptions of some of these methods and how they impact the analysis of oligonucleotide gene expression array data. We will discuss the process of recognizing the "spots" (or features) on the Affymetrix GeneChip(R) probe arrays, correcting for background and intensity gradients in the resulting images, scaling/normalizing an array to allow array-to-array comparisons, monitoring probe performance with respect to hybridization efficiency, and assessing whether a gene is present or differentially expressed. Examples from the analyses of gene expression validation data are presented to contrast the different methods applied to these types of data.

Base Sequence↗
PubMed2000

The Finland-United States investigation of non-insulin-dependent diabetes mellitus genetics (FUSION) study. II. An autosomal genome scan for diabetes-related quantitative-trait loci.

Type 2 diabetes mellitus is a complex disorder encompassing multiple metabolic defects. We report results from an autosomal genome scan for type 2 diabetes-related quantitative traits in 580 Finnish families ascertained for an affected sibling pair and analyzed by the variance components-based quantitative-trait locus (QTL) linkage approach. We analyzed diabetic and nondiabetic subjects separately, because of the possible impact of disease on the traits of interest. In diabetic individuals, our strongest results were observed on chromosomes 3 (fasting C-peptide/glucose: maximum LOD score [MLS] = 3.13 at 53.0 cM) and 13 (body-mass index: MLS = 3.28 at 5.0 cM). In nondiabetic individuals, the strongest results were observed on chromosomes 10 (acute insulin response: MLS = 3.11 at 21.0 cM), 13 (2-h insulin: MLS = 2.86 at 65.5 cM), and 17 (fasting insulin/glucose ratio: MLS = 3.20 at 9.0 cM). In several cases, there was evidence for overlapping signals between diabetic and nondiabetic individuals; therefore we performed joint analyses. In these joint analyses, we observed strong signals for chromosomes 3 (body-mass index: MLS = 3.43 at 59.5 cM), 17 (empirical insulin-resistance index: MLS = 3.61 at 0.0 cM), and 19 (empirical insulin-resistance index: MLS = 2.80 at 74.5 cM). Integrating genome-scan results from the companion article by Ghosh et al., we identify several regions that may harbor susceptibility genes for type 2 diabetes in the Finnish population.

Age Factors↗
PubMed2000

Stable and unstable transgene integration sites in the human genome: extinction of the Green Fluorescent Protein transgene in K562 cells.

In gene transfer experiments including gene therapy studies, expression of the integrated transgenes in host cells often declines with time. The molecular basis of this phenomenon is not clearly understood. We have used the Green Fluorescent Protein (GFP) gene as both a selectable marker and a reporter to study long-term transgene integration and expression in K562 cells. Cells transfected with plasmids containing the GFP gene coupled to the HS2 or HS3 enhancer of the human beta-globin Locus Control Region (LCR) or the cytomegalovirus (CMV) enhancer were sorted by either fluorescence-activated-cell-sorting (FACS) alone or FACS combined with drug selection based on a co-integrated drug resistance gene. The two groups of selected cells were subsequently cultured for long periods up to 250 cell generations. Comparison of long-term GFP transgene integration and expression in these two groups of cells revealed that the K562 genome contains two types of transgene integration sites: i) abundant unstable sites that permit transcription but not long-term integration of the transgenes and thus eliminate the transgenes in 60-250 cell generations and ii) rare stable sites that permit both efficient transcription and long-term stable integration of the transgenes for at least 200 cell generations. Our results indicate that extinction of GFP expression with time is due at least in part to elimination of the gene from the host genome and not entirely to transcriptional silencing of the gene. However, long-term, stable expression of the transgene can be achieved in cells containing the transgene integrated into the rare, stable host sites.

Binding Sites↗
PubMed2000

VIP innervation: sharp contrast in fetal sheep and baboon adrenal glands suggests differences in developmental regulation.

Immunocytochemical technique and light microscopy were used to ascertain the relationship between vasoactive intestinal polypeptide (VIP) and tyrosine hydroxylase in fetal sheep and fetal baboon adrenal cortices and medullae at 85% of gestation. VIP immunostaining was extremely robust in fetal sheep adrenal cortical neurofibers and cells while weak in fibers and nonexistent in cells of fetal baboon. Also, tyrosine hydroxylase-immunopositive cells, present throughout the adrenal cortices of both fetal sheep and baboons, were heavily innervated by VIP-immunoreactive neurofibers in fetal sheep, but not in fetal baboons. Adrenal cortical VIP-immunopositive fibers occurred in greater (P<0.05) frequency in fetal sheep than in fetal baboons (14.82+/-3.10 vs. 0.84+/-0.26 fibers/field), were larger in diameter (2.93+/-0.34 vs. 0.93+/-0.07 microm) and ran for longer distances in the plane of section (127.85+/-5.16 vs. 74.53+/-4.93 microm). VIP immunogenicity in cells (ganglion and chromaffin) and fibers was robust in fetal adrenal medulla of sheep while nonexistent in baboons. VIP fibers in fetal sheep medulla were smaller in diameter compared to fetal sheep cortex (1.22+/-0.13 vs. 2.93+/-0.34 microm, P<0.05), but not compared to extrinsic nerve fibers (1.30+/-0.09 microm). We hypothesize that in fetal sheep of this age, medullary neurofibers derive primarily from extrinsic sources while cortical fibers arise from cortical ganglion cells. We conclude that at 85% of gestation the potential for VIP neural control of paracrine (e.g., glucocorticoid/catecholamine) interactions in both adrenal cortex and medulla is much greater in fetal sheep compared to fetal baboons.

Adrenal Cortex↗
PubMed2000

Preparation of a protected triamino analogue of cholic acid and sequential incorporation of amino acids in solution and on a solid support.

We have prepared a triamine derivative of cholic acid with protecting groups on the amines that allow sequential amide formation. The triamine was formed from 3 alpha,7 alpha, 12 alpha-trihydroxycholan-24-ol with good stereoselectivity. Sequential removal of the amine protecting groups and amide formation was achieved in high-yielding steps and was performed in solution and on a solid support.

Amides↗
PubMed2000

Histological studies of pedicle skin formation and its transformation to antler velvet in red deer (Cervus elaphus).

Deer antlers and their antecedent pedicles are made up of two components, interior osseocartilage and exterior integument. In a previous study, we described that histogenesis of the interior osseocartilage proceeds through four ossification stages. These are intramembranous (IMO), transition (OPC), pedicle endochondral (pECO), and antler endochondral (aECO). In the present study, we used histological techniques to examine pedicle skin formation and its transformation to antler velvet. The results showed that pedicle skin initiated from the apex of a frontal lateral crest and was formed through three distinctive stages. These stages are 1) compression of the subcutaneous loose connective tissue at the OPC stage, 2) stretching of the undulated epidermis at the early pECO stage, and 3) neogenesis of the skin and its associated appendages at the mid pECO stage. Transformation into antler velvet, which occurs at the late pECO stage, is mainly associated with alteration in the skin appendages. This alteration includes the loss of arrector pili muscle and sweat glands, and the gain of the large bi- or multi-lobed sebaceous glands. These results suggest that pedicle skin expansion occurs to release the mechanical tension created by underlying forming antlerogenic tissue, initially in response to it by mechanical stretch, and then by neogenesis of skin. In turn, the stretched pedicle skin may exert mechanical pressure on the underlying antlerogenic tissue causing it to change in ossification type. Antler velvet generation may be accomplished by both mechanical stimulation and chemical induction from the underlying pECO stage antlerogenic tissue. If this hypothesis is correct it is likely that mechanical stimulation would drive skin formation and chemical induction then determine skin type. Furthermore, asynchronous transformation of the interior and exterior components during pedicle formation and antler generation may result from the delayed chemical induction and the way antler velvet initially generates. The results from both mitotic cell labelling of the basal layer and ultrastructure of the basement membrane of the apical skin in the study support these hypotheses.

Aging↗
PubMed2000

Effects of norethisterone acetate addition to estradiol in long term HRT.

OBJECTIVE: The aim of this study was to evaluate the efficacy and tolerability of hormone replacement therapy (HRT) among postmenopausal women living in the Lund area of Southern Sweden and to analyze treatment effects in different types or routes of HRT administration, as well as to compare with unopposed estrogen therapy. METHOD: in an ongoing, large population-based, prospective cohort study, this interim analysis included 3900 women. Of them, 693 postmenopausal women were eligible in the present analyses as they continued to use one of the four commercial HRT products for at least 2-3 years, i.e. continuous oral estradiol (E(2)) 2 mg+norethisterone acetate (NETA) 1 mg (CON-O), sequential oral estradiol 2 mg + norethisterone acetate 1 mg (CYC-O), sequential transdermal estradiol 50 microg + norethisterone acetate 250 microg (CYC-TRANS) and estradiol monotherapy. These women completed one generic questionnaire and one specific 'hormonal' questionnaire, as well as a personal interview pertaining to socio-demographics, detailed status of HRT use, and therapeutic efficacy and untoward side-effects by HRT. RESULTS: comparing the three combined E(2)+NETA groups with E(2) monotherapy, the beneficial effects on sexual desire and emotional well-being were significantly less in the combined groups than in E(2) monotherapy group. There was no significant difference regarding the negative side-effects between the groups. No significant difference was found between CON-O and CYC-O groups either in positive effects or in negative side-effects. A higher prevalence of positive effects was found in CYC-TRANS group than that in CYC-O group, especially in amelioration of sleep and urinary symptoms. Higher odd ratios of negative effects by HRT, such as irregular bleeds, weight gain, food craving and skin disorders were also found in CYC-TRANS group. CONCLUSION: in long-term HRT administration, the addition of a progestogen in HRT could compromise the beneficial effects of estradiol, particularly, the effects on women's emotional well being and psychosexual functioning. Administration of NETA continuously and sequentially had similar therapeutic efficacy and tolerability. More marked positive effects, such as improving of sleep and urinary symptoms, as well as nuisance side-effects, i.e. irregular bleeds, weight gain, food craving and skin disorders were encountered by the women using sequential transdermal regimen

Administration, Cutaneous↗
PubMed2000

Purification, cDNA cloning and function assessment of BmK abT, a unique component from the Old World scorpion species.

A new neurotoxic component named BmK abT was purified from the venom of Chinese scorpion Buthus martensi Karsch. The molecular weight of BmK abT was determined to be 7212 Da on a mass spectrum. The minimum lethal dose of BmK abT was tested to be about 1.5 microg per mouse by intracerebroventricular injection, and the dose induced significant paralysis effect on cockroach was about 5 microg by i.p. injection. The partial amino acid sequence indicated that it was a distinctive polypeptide in the scorpion neurotoxin family. Thereafter, the whole amino acid sequence of mature BmK abT was deduced from cDNA sequence by 5'- and 3'-rapid amplification of cDNA ends. Finally, it was defined to be composed of 63 residues with amidation at the C-terminal residue. By sequence comparison, BmK abT was found to be most similar to Ts VII, a beta-toxin from the New World scorpion. The patch-clamp recording on DRG neurons, unexpectedly, showed this toxin could prolong the action potential and increase the amplitude of the peak Na+ currents, which are the typical characters of alpha-toxin. These results suggested that BmK abT was a new toxic component found in the Old World scorpion species structurally similar to beta-toxins, but functionally similar to alpha-toxins.

Action Potentials↗
PubMed2000

A Pro250Arg substitution in mouse Fgfr1 causes increased expression of Cbfa1 and premature fusion of calvarial sutures.

Pfeiffer syndrome is a classic form of craniosynostosis that is caused by a proline-->arginine substitution at amino acid 252 (Pro252Arg) in fibroblast growth factor receptor 1 (FGFR1). Here we show that mice carrying a Pro250Arg mutation in Fgfr1, which is orthologous to the Pfeiffer syndrome mutation in humans, exhibit anterio-posteriorly shortened, laterally widened and vertically heightened neurocraniums. Analysis of the posterior and anterior frontal, sagittal and coronal sutures of early post-natal mutant mice revealed premature fusion. The sutures of mutant mice had accelerated osteoblast proliferation and increased expression of genes related to osteoblast differentiation, suggesting that bone formation at the sutures is locally increased in Pfeiffer syndrome. Of note, dramatically increased expression of core-binding transcription factor alpha subunit type 1 (Cbfa1) accompanied premature fusion, suggesting that Cbfa1 may be a downstream target of Fgf/Fgfr1 signals. This was confirmed in vitro, where we demonstrate that transfection with wild-type or mutant Fgfr1 induces Cbfa1 expression. The induced expression was also observed using Fgf ligands (Fgf2 and Fgf8). These studies provide direct genetic evidence that the Pro252Arg mutation in FGFR1 causes human Pfeiffer syndrome and uncovers a molecular mechanism in which Fgf/Fgfr1 signals regulate intramembraneous bone formation by modulating Cbfa1 expression.

Acrocephalosyndactylia↗
PubMed2000

Conserved molecular mechanism for the stage specificity of the mosquito vitellogenic response to ecdysone.

In the mosquito Aedes aegypti, the adult female becomes competent for a vitellogenic response to ecdysone after previtellogenic development. Here, we show that betaFTZ-F1, the nuclear receptor implicated as a competence factor for stage-specific responses to ecdysone during Drosophila metamorphosis, serves a similar function during mosquito vitellogenesis. AaFTZ-F1 is expressed highly in the mosquito fat body during pre- and postvitellogenic periods when ecdysteroid titers are low. The mosquito AaFTZ-F1 transcript nearly disappears in mid-vitellogenesis when ecdysteroid titers are high. An expression peak of HR3, a nuclear receptor implicated in the activation of betaFTZ-F1 in Drosophila, precedes each rise in mosquito FTZ-F1 expression. In in vitro fat body culture, AaFTZ-F1 expression is inhibited by 20-hydroxyecdysone (20E) and superactivated by its withdrawal. Following in vitro AaFTZ-F1 superactivation, a secondary 20E challenge results in superinduction of the early AaE75 gene and the late target VCP gene. Electrophoretic mobility-shift assays show that the onset of ecdysone-response competence in the mosquito fat body is correlated with the appearance of the functional AaFTZ-F1 protein at the end of the previtellogenic development. These findings suggest that a conserved molecular mechanism for controlling stage specificity is reiteratively used during metamorphic and reproductive responses to ecdysone.

Aedes↗
PubMed2000

A neonatal lethal mutation in FGFR3 uncouples proliferation and differentiation of growth plate chondrocytes in embryos.

We have generated the first mouse model of fibro-blast growth factor receptor 3 (Fgfr3) with the K644E mutation, which accurately reflects the embryonic onset of a neonatal lethal dwarfism, thanatophoric dysplasia type II (TDII). Long-bone abnormalities were identified as early as embryonic day 14, during initiation of endochondral ossification. Increased expression of PATCHED: (PTC:) was observed, independent of unaltered expression of parathyroid hormone-related peptide (PTHrP) receptor and Indian Hedgehog (IHH:), suggesting a new regulatory role for Fgfr3 in embryos. We demonstrate that the mutation enhances chondrocyte proliferation during the early embryonic skeletal development, in contrast to previous reports that showed decreased proliferation in postnatal-onset dwarf mice with activating Fgfr3 mutations. This suggests that signaling through Fgfr3 both promotes and inhibits chondrocyte proliferation, depending on the time during development. In contrast, suppressed chondrocyte differentiation was observed throughout the embryonic stages, defining decreased differentiation as the primary cause of retarded longitudinal bone growth in TDII. This model was successfully crossed with a cartilage-specific CRE: transgenic strain, excluding the lung as the primary cause of lethality.

Amino Acid Substitution↗
PubMed2000

Studies of the synthesis and thermochemistry of coordinatively unsaturated chelate complexes (eta 5-C5Me5)IrL2 (L2 = TsNCH2CH2NTs, TsNCH2CO2, CO2CO2).

A comparative synthetic, structural, and thermochemical study on a series of chelate complexes containing the fragment (eta 5-C5Me5)Ir [(eta 5-C5Me5)Ir(TsNCH2CH2NTs) (1), (eta 5-C5Me5)Ir(TsNCH2CO2) (2), (eta 5-C5Me5)Ir(CO2CO2) (3)] was performed to clarify the roles of carboxylato and sulfonamido ligands. Whereas 1 and 2 are monomeric in solution and in the solid state, 3 appears to exist as an oligomer or polymer, (3)n, which can be broken up by addition of a ligand L such as a phosphine, CO, or 2-methoxypyridine to form (eta 5-C5Me5)Ir(L)(CO2CO2) (6). The synthesis of (3)n from [(eta 5-C5Me5)IrCl(mu-Cl)]2 required the use of silver oxalate in CH3CN, but if other solvents were used, the bridging oxalato complex (eta 5-C5Me5)IrCl(mu-eta 2-eta 2-C2O4)ClIr(eta 5-C5Me5) (7) was obtained and identified by X-ray diffraction. Enthalpies for reaction of THF-soluble monomers 1 and 2 with PMe3 were determined to be -28.7(0.5) and -28.5(0.4) kcal mol-1, respectively. The oligomerization behavior of 3 may be a result of reduced sigma- or pi-donation of carboxylato ligands compared to N-tosylamido ligands, because the values for nu CO in oxalato and bissulfonamido complexes 6-CO and (eta 5-C5Me5)Ir(CO)(TsNCH2CH2NTs) (4-CO) were 2064 and 2042 cm-1, respectively.

Journal Article↗
PubMed2000

Mechanical stress-induced heat shock protein 70 expression in vascular smooth muscle cells is regulated by Rac and Ras small G proteins but not mitogen-activated protein kinases.

-Previous studies have documented that acute elevation in blood pressure results in heat shock protein (hsp) 70-mRNA expression followed by hsp70-protein production in rat aortas. In this article, we provide evidence that mechanical forces evoke rapid activation of heat shock transcription factor (HSF) and hsp70 accumulation. In our study, Western blot analysis demonstrated that hsp70-protein induction peaked between 6 and 12 hours after treatment with cyclic stain stress (60 cycles/minute, up to 30% elongation). Elevated protein levels were preceded by hsp70-mRNA transcription, which was associated with HSF1 phosphorylation and activation stimulated by mechanical forces, suggesting that the response was regulated at the transcriptional level. Conditioned medium from cyclic strain-stressed vascular smooth muscle cells (VSMCs) did not result in HSF-DNA-binding activation. Furthermore, mitogen-activated protein kinases (MAPKs), including extracellular signal-regulated kinases, c-Jun NH(2)-terminal protein kinases or stress-activated protein kinases, and p38 MAPKs, were also highly activated in response to cyclic strain stress. Inhibition of extracellular signal-regulated kinase and p38-MAPK activation by their specific inhibitors (PD 98059 and SB 202190) did not influence HSF1 activation. Interestingly, VSMC lines stably expressing dominant-negative rac (rac N17) abolished hsp-protein production and HSF1 activation induced by cyclic strain stress, whereas a significant reduction of hsp70 expression was seen in ras N17-transfected VSMC lines. Thus, our findings demonstrate that cyclic strain stress-induced hsp70 expression is mediated by HSF1 activation and regulated by rac and ras GTP-binding proteins. Induction of hsp70 could be important in maintaining VSMC homeostasis during vascular remodeling in response to hemodynamic stimulation.

Animals↗
PubMed2000

Lack of obesity and normal response to fasting and thyroid hormone in mice lacking uncoupling protein-3.

Uncoupling protein-3 (UCP3) is a mitochondrial protein that can diminish the mitochondrial membrane potential. Levels of muscle Ucp3 mRNA are increased by thyroid hormone and fasting. Ucp3 has been proposed to influence metabolic efficiency and is a candidate obesity gene. We have produced a Ucp3 knockout mouse to test these hypotheses. The Ucp3 (-/-) mice had no detectable immunoreactive UCP3 by Western blotting. In mitochondria from the knockout mice, proton leak was greatly reduced in muscle, minimally reduced in brown fat, and not reduced at all in liver. These data suggest that UCP3 accounts for much of the proton leak in skeletal muscle. Despite the lack of UCP3, no consistent phenotypic abnormality was observed. The knockout mice were not obese and had normal serum insulin, triglyceride, and leptin levels, with a tendency toward reduced free fatty acids and glucose. Knockout mice showed a normal circadian rhythm in body temperature and motor activity and had normal body temperature responses to fasting, stress, thyroid hormone, and cold exposure. The base-line metabolic rate and respiratory exchange ratio were the same in knockout and control mice, as were the effects of fasting, a beta3-adrenergic agonist (CL316243), and thyroid hormone on these parameters. The phenotype of Ucp1/Ucp3 double knockout mice was indistinguishable from Ucp1 single knockout mice. These data suggest that Ucp3 is not a major determinant of metabolic rate but, rather, has other functions.

Adipose Tissue, Brown↗