Biomedical subjects
A Chu
Publications and source records attributed to A Chu.
Intraepidermal animal-type melanoma.
Animal-type melanoma is a rare variant of melanoma in humans.1 Its name is derived from its histological appearance, which is similar to that described in melanomas occurring in white or gray horses.2 All tumors are dermally located, and characterized by a proliferation of deeply pigmented elongated or rounded cells, showing moderate atypia and a low mitotic rate. In some tumors, secondary infiltration of the epidermis has been noted. More than half of the patients are younger than 30 years, and prognosis seems to be much better than that expected for a superficial spreading or nodular melanoma of the same size. We report the first case of animal-type melanoma in situ.
Estrogen-metabolizing gene COMT polymorphism synergistic APOE epsilon4 allele increases the risk of Alzheimer disease.
Alzheimer disease (AD) is a polygenic multifactorial disorder. Several studies suggested that the neuroprotective effect of estrogen was based on an APOE-dependent mechanism. The goals of the current study were to determine if the genes involved in estrogen metabolism were linked to the risk of AD and find out if there was an interaction between estrogen-metabolizing gene polymorphisms and the APOE epsilon4 allele in the risk of prevalent AD. We investigated 66 patients with AD and 86 age- and gender-matched normal subjects. The polymorphisms of APOE and estrogen-metabolizing genes CYP17, CYP1A1 and COMT were examined. No association was found between each estrogen-metabolizing gene polymorphism and AD. However, the COMT HH genotype and APOE epsilon4 allele had a synergistic effect on the risk of AD. Taking subjects with epsilon4-epsilon4-/HH- as reference, the risk of developing AD in subjects with one epsilon4 allele (epsilon4+epsilon4-/HH-) was 2.6 (95% confidence interval, CI, 0.7- 9.1); however, the risk in subjects with both HH and one epsilon4 (epsilon4+epsilon4-/HH+) increased to 3.6 (95% CI 1.2-10.6). The subjects with homozygous epsilon4 still had the highest risk in developing AD (odds ratio 6.6, 95% CI 0.6-69.6). The p value of the linear trend test for this regression model was 0.004. It is possible that a high metabolism of estrogen by COMT may have reduced the protective effect of estrogen in AD. Further studies to clarify this interaction may improve our understanding of the generic risks for AD.
Multiple mechanisms promote the inhibition of classical nuclear import upon exposure to severe oxidative stress.
In growing HeLa cells, severe stress elicited by the oxidant hydrogen peroxide inhibits classical nuclear import. Oxidant treatment collapses the nucleocytoplasmic Ran concentration gradient, thereby elevating cytoplasmic GTPase levels. The Ran gradient dissipates in response to a stress-induced depletion of RanGTP and a decreased efficiency of Ran nuclear import. In addition, oxidative stress induces a relocation of the nucleoporin Nup153 as well as the nuclear carrier importin-beta, and docking of the importin-alpha/beta/cargo complex at the nuclear envelope is reduced. Moreover, Ran, importin-beta and Nup153 undergo proteolysis upon oxidative stress. Caspases and the proteasome degrade Ran and importin-beta; however, ubiquitination of these transport factors is not observed. Inhibition of caspases in stressed cells alleviates the mislocalization of importin-beta, but does not restore the Ran concentration gradient or classical import. In summary, inhibition of classical nuclear import by hydrogen peroxide is caused by a combination of multiple mechanisms that target different components of the transport apparatus.
Tobramycin and gentamycin elution analysis between two in situ polymerizable orthopedic composites.
This research analyzed Tobramycin and Gentamycin elution characteristics for two antibiotic-impregnated bone composites: PMMA-based Simplex P and the novel, hybrid, bioactive, CORTOSS. Experimental results were correlated with composite hydrophilicity and antibiotic phase partitioning behaviors. The phase partitioning experiment was conducted to understand antibiotic solubility in aqueous environments. By comparing experimental results with calculated data, antibiotic release behavior was predicted. Total Tobramycin elution percentages from CORTOSS and Simplex P were 12.5 and 6.4%, respectively. Total Gentamycin elution percentages from CORTOSS and Simplex P were 6.95 and 10.17%, respectively. Phase partitioning data indicate 100% of Tobramycin remains in aqueous phases, being extremely hydrophilic. This is supported by its calculated theoretical value (log P = - 7.32). Results suggest that Tobramycin elution can be attributed to composite hydrophilicity as well as its high degree of hydrophilicity. Fifteen percent of Gentamycin distributes in hydrophobic phases (log P = - 4.22). Despite a lower Gentamycin hydrophilicity, its release was affected by its complexation with polar salts in the leaching buffer, thereby increasing its elution potential, making it appreciably water soluble. CORTOSS is more hydrophilic; therefore the migration of aqueous liquids into the polymer network of CORTOSS facilitates greater antibiotic elution compared with hydrophobic Simplex P.
Transcription factor 1 and beta-cell function in glucose-tolerant subjects.
AIMS: Although beta-cell dysfunction and insulin resistance are observed in patients with Type 2 diabetes, beta-cell dysfunction plays a crucial role in the development of the disease. Mutations of transcription factor 1 (TCF1, or hepatocyte nuclear factor-1alpha) affect beta-cell function. We examined the impact of amino acid polymorphisms of this gene on beta-cell function in 60 glucose-tolerant Caucasians. METHODS: Insulin sensitivity index (ISI) and 1st and 2nd phase insulin responses (1stIR, 2ndIR) were measured using the hyperglycaemic clamp. The genotypes were determined from genomic DNA and their impact on beta-cell function was investigated. RESULTS: Among three polymorphisms (I27L, A98V, and S487N), significant impact on beta-cell function was found in the I27L polymorphism. Univariate analyses revealed differences for the I27L polymorphism in both 1stIR (P = 0.0052) and 2ndIR (P = 0.0432). Multivariate analysis revealed that the I27L polymorphism (P = 0.0124) with ISI accounted for 32% of the variation in 1stIR and had a marginal impact on 2ndIR (P = 0.0343), accounting for 52% of the variation with ISI and age. By dissecting out the impact of other covariate(s), the I27L polymorphism independently explained 12% of the variation in 1stIR and 6% of the variation in 2ndIR. CONCLUSION: The I27L polymorphism of TCF1 is an independent determinant of beta-cell function by affecting both 1st and 2nd phase insulin response. This polymorphism could play a role in the pathogenesis of Type 2 diabetes. A large-scale association study (approx. 2000 subjects) will be required to demonstrate the genetic susceptibility of this polymorphism to Type 2 diabetes.
The inter-relationship between isotretinoin/acne and depression.
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Measurement in vivo of proliferation rates of slow turnover cells by 2H2O labeling of the deoxyribose moiety of DNA.
We describe here a method for measuring DNA replication and, thus, cell proliferation in slow turnover cells that is suitable for use in humans. The technique is based on the incorporation of (2)H(2)O into the deoxyribose (dR) moiety of purine deoxyribonucleotides in dividing cells. For initial validation, rodents were administered 4% (2)H(2)O in drinking water. The proliferation rate of mammary epithelial cells in mice was 2.9% per day and increased 5-fold during pregnancy. Administration of estradiol pellets (0-200 microg) to ovariectomized rats increased mammary epithelial cell proliferation, according to a dose-response relationship up to the 100 microg dose. Similarly, proliferation of colon epithelial cells was stimulated in a dose-response manner by dietary cholic acid in rats. Bromodeoxyuridine labeling correlated with the (2)H(2)O results. Proliferation of slow turnover cells was then measured. Vascular smooth muscle cells isolated from mouse aorta divided with a half-life in the range of 270-400 days and die-away values after (2)H(2)O wash-out confirmed these slow turnover rates. The proliferation rate of an adipocyte-enriched fraction from mouse adipose tissue depots was 1-1.5% new cells per day, whereas obese ad libitum-fed obob mice exhibited markedly higher fractional and absolute proliferation rates. In humans, stable long-term (2)H(2)O enrichments in body water were achieved by daily (2)H(2)O intake, without toxicities. Labeled dR from fully turned-over blood cells (monocytes or granulocytes) exhibited a consistent amplification factor relative to body (2)H(2)O enrichment ( approximately 3.5-fold). The fraction of newly divided naive-phenotype T cells after 9 weeks of labeling with (2)H(2)O was 0.056 (CD4(+)) and 0.043 (CD8(+)) (replacement rate <0.1% per day). In summary, (2)H(2)O labeling of dR in DNA allows safe, convenient, reproducible, and inexpensive measurement of cell proliferation in humans and experimental animals and is well suited for slow turnover cells.
Genome-wide multipoint linkage analyses of multiplex schizophrenia pedigrees from the oceanic nation of Palau.
The oceanic nation of Palau has been geographically and culturally isolated over most of its 2000 year history. As part of a study of the genetic basis of schizophrenia in Palau, we genotyped five large, multigenerational schizophrenia pedigrees using markers every 10 cM (CHLC/Weber screening set 6). The number of affected/unaffected individuals genotyped per family ranged from 11/21 to 5/5. Thus the pedigrees varied in their information for linkage, but each was capable of producing a substantial LOD score. We fitted a simple dominant and recessive model to these data using multipoint linkage analysis implemented by Simwalk2. Predictably, the most informative pedigrees produced the best linkage results. After genotyping additional markers in the region, one pedigree produced a LOD = 3.4 (5q distal) under the dominant model. Seven of nine schizophrenics in the pedigree, mostly 3rd-4th degree relatives, share a 15-cM, 7-marker haplotype. For a different pedigree, another promising signal occurred on distal 3q, LOD = 2.6, for the recessive model. For two other pedigrees, the best LODs were modest, slightly better than 2.0 on 5q and 9p, while the fifth pedigree produced no noteworthy linkage signal. Similar to the results for other populations, our results suggest there are multiple genes conferring liability to schizophrenia even in the small population of Palau (roughly 21,000 individuals) in remote Oceania.
A high-resolution radiation hybrid map of the human genome draft sequence.
We have constructed a physical map of the human genome by using a panel of 90 whole-genome radiation hybrids (the TNG panel) in conjunction with 40,322 sequence-tagged sites (STSs) derived from random genomic sequences as well as expressed sequences. Of 36,678 STSs on the TNG radiation hybrid map, only 3604 (9.8%) were absent from the unassembled draft sequence of the human genome. Of 20,030 STSs ordered on the TNG map as well as the assembled human genome draft sequence and the Celera assembled human genome sequence, 36% of the STSs had a discrepant order between the working draft sequence and the Celera sequence. The TNG map order was identical to one of the two sequence orders in 60% of these discrepant cases.
Fatty acid binding protein 2 and insulin resistance.
BACKGROUND: An A54T polymorphism of the fatty acid binding protein 2 (FABP2) gene was found to be associated with insulin resistance in nondiabetic Pima Indians. Design This is a cross-sectional study to examine the role of this polymorphism in insulin resistance in 71 healthy and normotensive Caucasian subjects with normal glucose tolerance. Insulin sensitivity (%S, ISI(M), ISI(S)) and beta-cell function (%B, dI/dG, 1stPHS, 2ndPHS) were estimated based on published models. Their genotypes were determined using a polymerase chain reaction-restriction fragment length polymorphism assay. The relationship between genotypes and phenotypes was examined. RESULTS: After genotyping, we identified 34 AA, 32 AT and five TT subjects. The TT subjects were pooled together with the AT subjects during the analysis due to their low number. No difference was noted in gender distribution, clinical features, or fasting lipid profile between the two genotypic groups (AA vs. AT/TT). The AT/TT group had lower %S and ISI(S) than the AA group (P = 0.0118 and P = 0.0170, respectively). The difference in ISI(M) was marginal (P = 0.0544). However, no difference was noted in beta-cell function between the two groups. Multivariate analysis revealed that this polymorphism was an independent but modest determinant for %S (P = 0.0149), ISI(M) (P = 0.0489) and ISI(S) (P = 0.0175). It independently contributed 6.04% (95% CI, 0.02-20.53%), 4.28% (95% CI, 0.08-17.63%) and 4.94% (95% CI, 0.01-18.75%) of the variation of %S, ISI(M) and ISI(S), respectively. CONCLUSIONS: We demonstrated that the A54T polymorphism at the FABP2 locus is a risk factor for insulin resistance in a Caucasian population.
Corticosterone exerts site-specific and state-dependent effects in prefrontal cortex and amygdala on regulation of adrenocorticotropic hormone, insulin and fat depots.
Chronic stress stimulates corticosterone secretion and recruits brain pathways that regulate energy balance (caloric acquisition and deposition) and facilitate hypothalamic-pituitary-adrenal responsiveness to new stressors. We implanted corticosterone or cholesterol bilaterally either near the central nucleus of the amygdala (CeA) or in the prefrontal cortex to determine whether high concentrations of the steroid act at either site, with or without chronic stress. Rats were adrenalectomized and treated systemically with low doses of corticosterone. Half were maintained at room temperature and the other half were exposed to 5 degrees C cold for 5 days before all rats were restrained. There was limited diffusion of corticosterone from brain implants. Corticosterone in prefrontal cortex, but not CeA, decreased plasma insulin and adrenocorticotropic hormone (ACTH) responses to acute restraint in both control and chronically cold stressed rats. Corticosterone implants near CeA decreased the weight of fat depots only in cold; corticosterone implants in prefrontal cortex were ineffective. We conclude that (i) corticosterone inhibits insulin and ACTH secretion by an action in prefrontal cortex but not CeA; (ii) high concentrations of corticosterone secreted during chronic stress alter metabolism through (autonomic) outputs of the CeA and prefrontal cortex in site- and variable-specific fashion; and (iii) the amygdala is a component of a stress-recruited, state-dependent pathway.
Heat-induced nuclear accumulation of hsc70s is regulated by phosphorylation and inhibited in confluent cells.
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Retrovesical gastrointestinal stromal tumor.
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Mycotic aneurysm and cerebral infarction resulting from fungal sinusitis: imaging and pathologic correlation.
SUMMARY: A 73-year-old man was admitted with invasive aspergillus of the sphenoid sinus. Endoscopic debridement of the sphenoid sinus was complicated by rupture of a mycotic cavernous carotid artery aneurysm with severe epistaxis. The aneurysm was closed emergently by endovascular coil placement. Subsequently, the mycotic aneurysm extended intradurally and caused fatal subarachnoid hemorrhage. The radiologic-pathologic data illustrate the mechanism of fungal mycotic aneurysm formation and growth. This case emphasizes the need for rapid diagnosis of potential fungal involvement of the central nervous system and suggests the necessity for aggressive treatment once fungal cerebrovascular involvement is identified.
A cholecystokinin-mediated pathway to the paraventricular thalamus is recruited in chronically stressed rats and regulates hypothalamic-pituitary-adrenal function.
Chronic stress alters hypothalamic-pituitary-adrenal (HPA) responses to acute, novel stress. After acute restraint, the posterior division of the paraventricular thalamic nucleus (pPVTh) exhibits increased numbers of Fos-expressing neurons in chronically cold-stressed rats compared with stress-naive controls. Furthermore, lesions of the PVTh augment HPA activity in response to novel restraint only in previously stressed rats, suggesting that the PVTh is inhibitory to HPA activity but that inhibition occurs only in chronically stressed rats. In this study, we further examined pPVTh functions in chronically stressed rats. We identified afferent projections to the pPVTh using injection of the retrograde tracer fluorogold. Of the sites containing fluorogold-labeled cells, neurons in the lateral parabrachial, periaqueductal gray, and dorsal raphe containing fluorogold also expressed cholecystokinin (CCK) mRNA. We then examined whether these CCKergic inputs to the pPVTh were involved in HPA responses to acute, novel restraint after chronic stress. We injected the CCK-B receptor antagonist PD 135,158 into the PVTh before restraint in control and chronically cold-stressed rats. ACTH responses to restraint stress were augmented by PD 135,158 only in chronically stressed rats but not in controls. In addition, CCK-B receptor mRNA expression in the pPVTh was not altered by chronic cold stress. We conclude that previous chronic stress specifically facilitates the release of CCK into the pPVTh in response to acute, novel stress. The CCK is probably secreted from neurons in the lateral parabrachial, the periaqueductal gray, and/or the dorsal raphe nuclei. Acting via CCK-B receptors in pPVTh, CCK then constrains facilitated ACTH responses to novel stress in chronically stressed but not naive rats. These results demonstrate clearly that chronic stress recruits a new set of pathways that modulate HPA responsiveness to a novel stress.
Phototherapy with blue (415 nm) and red (660 nm) light in the treatment of acne vulgaris.
In this study we have evaluated the use of blue light (peak at 415 nm) and a mixed blue and red light (peaks at 415 and 660 nm) in the treatment of acne vulgaris. One hundred and seven patients with mild to moderate acne vulgaris were randomized into four treatment groups: blue light, mixed blue and red light, cool white light and 5% benzoyl peroxide cream. Subjects in the phototherapy groups used portable light sources and irradiation was carried out daily for 15 min. Comparative assessment between the three light sources was made in an observer-blinded fashion, but this could not be achieved for the use of benzoyl peroxide. Assessments were performed every 4 weeks. After 12 weeks of active treatment a mean improvement of 76% (95% confidence interval 66-87) in inflammatory lesions was achieved by the combined blue-red light phototherapy; this was significantly superior to that achieved by blue light (at weeks 4 and 8 but not week 12), benzoyl peroxide (at weeks 8 and 12) or white light (at each assessment). The final mean improvement in comedones by using blue-red light was 58% (95% confidence interval 45-71), again better than that achieved by the other active treatments used, although the differences did not reach significant levels. We have found that phototherapy with mixed blue-red light, probably by combining antibacterial and anti-inflammatory action, is an effective means of treating acne vulgaris of mild to moderate severity, with no significant short-term adverse effects.
Defining the atherogenicity of large and small lipoproteins containing apolipoprotein B100.
Apo-E-deficient apo-B100-only mice (APOE:(-/-)APOB:(100/100)) and LDL receptor-deficient apo-B100-only mice (LDLR:(-/-)APOB:(100/100)) have similar total plasma cholesterol levels, but nearly all of the plasma cholesterol in the former animals is packaged in VLDL particles, whereas, in the latter, plasma cholesterol is found in smaller LDL particles. We compared the apo-B100-containing lipoprotein populations in these mice to determine their relation to susceptibility to atherosclerosis. The median size of the apo-B100-containing lipoprotein particles in APOE:(-/-)APOB:(100/100) plasma was 53.4 nm versus only 22.1 nm in LDLR:(-/-)APOB:(100/100) plasma. The plasma levels of apo-B100 were three- to fourfold higher in LDLR:(-/-)APOB:(100/100) mice than in APOE:(-/-)APOB:(100/100) mice. After 40 weeks on a chow diet, the LDLR:(-/-)APOB:(100/100) mice had more extensive atherosclerotic lesions than APOE:(-/-)APOB:(100/100) mice. The aortic DNA synthesis rate and the aortic free and esterified cholesterol contents were also higher in the LDLR:(-/-)APOB:(100/100) mice. These findings challenge the notion that all non-HDL lipoproteins are equally atherogenic and suggest that at a given cholesterol level, large numbers of small apo-B100-containing lipoproteins are more atherogenic than lower numbers of large apo-B100-containing lipoproteins.