Valproic acid and augmentation of fetal hemoglobin in individuals with and without sickle cell disease.
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Anemia, Sickle Cell↗
Biomedical subjects
L Chang
Publications and source records attributed to L Chang.
Characterization of a negative response DNA element in the upstream region of the cellular retinoic acid-binding protein-I gene of the mouse.
A negative, regulatory DNA element from the mouse cellular retinoic acid-binding protein I gene promoter was identified. This DNA element, located approximately 1 kilobase upstream from the transcription initiation site of this gene, contained a pair of direct repeats (DRs) separated by 4 base pairs (DR4, TGACCTTTGGGGACCT). By examining a series of reporters deleted or mutated within this DR4 region, it was concluded that the core sequence of this DR4, including both repeats and the spacer, was required for suppressive activity in the mouse embryonal carcinoma cell line P19. From gel retardation experiments, it was concluded that both repeated sequences were essential for specific protein binding, but the spacer sequence was not as critical. Specific residues required for protein binding to this DR4 were identified. In P19 cells, retinoic acid induced the binding of nuclear factors to DR4 and suppressed the activities of the reporters containing this DR4. Co-expression of retinoic acid receptor beta or thyroid hormone receptor beta1 (T3Rbeta1) significantly inhibited the expression of this reporter in P19 cells. Gel retardation with in vitro-synthesized nuclear receptors demonstrated specific binding of this DR4 by T3Rbeta1 monomers, homodimers, or heterodimers of T3Rbeta1/retinoid receptor X beta. A biological function of DR4 in crabp-I gene regulation in P19 cells was suggested.
Animals↗
A prevalent missense substitution that modulates activity of prostatic steroid 5alpha-reductase.
Prostate cancer is the most common serious cancer diagnosed in men in the United States. This disease is also characterized by a striking racial/ethnic variation in incidence: highest in African-Americans, intermediate in Caucasians, slightly lower in Latinos, and lowest in Asians. Ample biochemical and epidemiological evidence suggests a role for androgens, particularly testosterone and dihydrotestosterone, in prostate cancer etiology. We have analyzed a candidate gene for prostate cancer, SRD5A2, encoding prostatic steroid 5alpha-reductase type II, which converts testosterone into the more bioactive dihydrotestosterone, for mutations. We report here one amino acid substitution, V89L, which replaces valine at codon 89 with leucine. This substitution is a "germline" (constitutional) DNA polymorphism, and it is common, panethnic, and reduces in vivo steroid 5alpha-reductase activity. This substitution is particularly common among Asians and may explain the low risk for prostate cancer in this population.
3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
Histones in transit: cytosolic histone complexes and diacetylation of H4 during nucleosome assembly in human cells.
The organization and acetylation of nascent histones prior to their stable incorporation into chromatin were examined. Through sedimentation and immunoprecipitation analyses of HeLa cytosolic extracts, two somatic non-nucleosomal histone complexes were detected: one containing nascent H3 and H4, and a second containing H2A (and probably H2B) in association with the nonhistone protein NAP-1. The H3/H4 complex has a sedimentation coefficient of 5-6S, consistent with the presence of one or more escort proteins. H4 in the cytosolic H3/H4 complex is diacetylated, fully in accord with the acetylation state of newly synthesized H4 in chromatin. The diacetylation of nascent human H4 is therefore completed prior to nucleosome assembly. As part of our studies of the nascent H3/H4 complex, the cytoplasmic histone acetyltransferase most likely responsible for acetylating newly synthesized H4 was also investigated. HeLa histone acetyltransferase B (HAT B) acetylates H4 but not H3 in vitro, and maximally diacetylates H4 even in the presence of sodium butyrate. Human HAT B acetylates H4 exclusively on the lysine residues at positions 5 and 12, in complete agreement with the highly conserved acetylation pattern of nascent nucleosomal H4 (Sobel et al., 1995), and has a native molecular weight of approximately 100 kDa. Based on our findings a model is presented for the involvement of histone acetylation and NAP-1 in H2A/H2B deposition and exchange, during nucleosome assembly and chromatin remodeling in vivo.
Acetylation↗
cDNA sequence analysis and expression of kappa-bungarotoxin from Taiwan banded krait.
The cDNAs encoding kappa-bungarotoxin was constructed from the cellular RNA isolated from the venom glands of Bungarus multicinctus by reverse transcription-polymerase chain reaction. A high degree of nucleotide sequence homology was observed between kappa-bungarotoxin and other kappa-neurotoxins. The kappa-bungarotoxin was subcloned into the expression vector pET32a(+) and transformed into BL21(DE3) E. coli strain. The recombinant toxin was expressed as a fusion protein. Recombinant kappa-bungarotoxin was separated from the fused protein by cleavage with CNBr and purified by reversed phase high performance liquid chromatography. In addition to kappa-bungarotoxin, the cDNA fragment encoding kappa3-bungarotoxin was also found in the cDNA mixtures prepared from the cellular RNA of the venom glands of the same snake. This result suggests that the venom glands of Taiwanese B. multicinctus should secrete at least two kinds of kappa-neurotoxins.
Amino Acid Sequence↗
Repetitive sigmoid stimulation induces rectal hyperalgesia in patients with irritable bowel syndrome.
BACKGROUND & AIMS: Only a fraction of patients with irritable bowel syndrome (IBS) show hypersensitivity to rectal distention. The current study sought to determine if repetitive high-pressure stimulation of sigmoid mechanoreceptors modulates perception of rectal pain and discomfort. METHODS: In 14 patients with IBS and 11 healthy controls, perception thresholds for discomfort and pain during rectal sensory tracking and verbal descriptor ratings of the perceived intensity of a rectal tonic stimulus were obtained before and after repetitive high-pressure mechanical sigmoid stimulation. Gastrointestinal and psychological symptoms were assessed by questionnaires. RESULTS: Despite heterogeneity in baseline rectal sensitivity in patients with IBS, after sigmoid stimulation, 100% of patients, regardless of baseline sensitivity, developed rectal hyperalgesia manifested by at least two of the following three criteria: lowered thresholds for pain and discomfort and increased viscerosomatic referral and lower abdominal discomfort outlasting the experimental stimulation. This pattern of responses was not observed in any of the healthy controls. CONCLUSIONS: In patients with IBS, repetitive stimulation of sigmoid splanchnic afferents results in the development of central sensitization manifested as hyperalgesia and increased viscerosomatic referral during rectal distention and as spontaneous rectosigmoid hyperalgesia in the absence of applied stimuli. Repetitive sigmoid contractions may induce rectosigmoid hyperalgesia in patients with IBS.
Adult↗
Self- and peer-ratings of female and male roles and attributes.
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Adolescent↗
Endocrine abnormalities in ovulatory women with polycystic ovaries on ultrasound.
Polycystic-appearing ovaries (PAO) on ultrasound have been described in a variety of endocrinopathies and also occur in ovulatory women. By some investigators this is merely referred to as 'PCO' (polycystic ovaries). Although there is controversy in this regard, we do not consider women with PAO/PCO who have no known endocrine disturbance to have polycystic ovary syndrome (PCOS) and therefore prefer not to use the term 'PCO' which is often equated with PCOS. We studied 15 ovulatory women with normal-appearing (NAO) ovaries on ultrasound and 15 matched ovulatory women with PAO/PCO. Compared to ovulatory women, 25 other women were studied who were considered to have PCOS. Of these, 15 were overweight and 10 were of normal weight. All the PCOS women had serum concentrations of luteinizing hormone (LH), testosterone, unbound testosterone, androstenedione and dihydroepiandrosterone sulphate (DHEAS) which were significantly higher (P < 0.01) than values in the normal women, regardless of ovarian morphology. These values were similar in the two groups of ovulatory women with NAO and PAO/PCO. Fasting insulin was elevated in women with PCOS with increased body weight (P < 0.01) and was higher than in ovulatory women with NAO and PAO/PCO and than in women of normal weight with PCOS. Serum insulin-like growth factor (IGF)-I and binding protein (BP)-3 were similar in all groups but serum IGFBP-1 was significantly (P < 0.01) lower in those women with PCOS with increased body weight, compared to all other groups. Compared to values in ovulatory women with NAO, serum IGFBP-1 was also significantly (P < 0.05) lower in women with PAO/PCO and those women with PCOS of normal weight. These lower values were similar in women with PAO/PCO and in normal weight women with PCOS. On an individual basis, an elevation of at least one serum androgen value was found in 33% of women with PAO/PCO. These data confirm that increased body weight accentuates the metabolic alterations in PCOS, but suggest that subtle endocrine disturbances, similar to those that are found in PCOS, may be uncovered in up to a third of ovulatory women with PAO/PCO. It appears that a disturbance of the IGF/IGFBP-1 axis is common and apparently closely associated with alterations in ovarian morphology.
Adult↗
Frontotemporal dementia and early Alzheimer disease: differentiation with frontal lobe H-1 MR spectroscopy.
PURPOSE: To evaluate cerebral biochemical abnormalities in patients with frontotemporal dementia and Alzheimer disease and to determine whether proton (hydrogen-1) magnetic resonance (MR) spectroscopy can help differentiate among these two patient groups and healthy (control) subjects. MATERIALS AND METHODS: MR imaging and H-1 MR spectroscopy were performed in 14 patients with frontotemporal dementia, 12 with probable Alzheimer disease (Alzheimer), and 11 healthy (control) elderly subjects. Spectra were acquired from midfrontal and temporoparietal gray matter with a double spin-echo sequence (repetition time, 3,000 msec; echo time, 30 msec). Results were expressed in metabolite concentrations corrected for the presence of cerebrospinal fluid. RESULTS: In frontotemporal dementia patients, the frontal lobe showed reduced N-acetyl compounds (-28%) and glutamate plus glutamine (-16%), suggestive of neuron loss, and increased myo-inositol (MI) (+19%), suggestive of increased glial content. In three frontotemporal dementia patients, a lactate peak was present in the frontal lobe. In Alzheimer patients, no statistically significant abnormalities were observed in the frontal region, but MI was elevated (+8%) in the temporoparietal region. With use of linear discriminant analysis of MR spectroscopy data alone, 92% of the frontotemporal dementia patients were correctly differentiated from the Alzheimer patients and control subjects. The overall accuracy for discrimination among all three groups was 84%. CONCLUSION: H-1 MR spectroscopy demonstrated biochemical abnormalities in patients with frontotemporal dementia and aided differentiation between patients with frontotemporal dementia and Alzheimer disease.
Aged↗
Assessment of CSF levels of tau protein in mildly demented patients with Alzheimer's disease.
CSF levels of tau protein are increased in many patients with Alzheimer's disease (AD). Studies disagree on whether the increase is found in moderate or severe AD to a greater extent than in mild AD, and in two reports there was an inverse correlation between tau levels and cognitive scores. To readdress this question, we measured CSF tau in a group of mildly impaired patients with AD (Mini-Mental State Examination [MMSE] scores > or =20/30) and compared their tau levels with those in age-comparable normal and neurologic controls. We found that the mean level of CSF tau was significantly increased in the AD group compared with the controls, and 29 of 36 patients with AD had levels that exceeded a cutoff determined in a previous study. CSF tau levels did not correlate with MMSE scores. These findings and those of previous studies show that elevated CSF tau levels are found in most patients with AD, occur early in the course of dementia, and may be useful in supporting the diagnosis of AD.
Aged↗
Metabolite abnormalities in progressive multifocal leukoencephalopathy by proton magnetic resonance spectroscopy.
OBJECTIVE: To evaluate progressive multifocal leukoencephalopathy (PML) lesions using proton magnetic resonance spectroscopy (1H MRS). DESIGN: CSF polymerase chain reaction (PCR) detection for JC viral (JCV) DNA; MRI and localized 1H MRS in the PML lesions, normal-appearing contralateral brain regions (CONTRA), and in matched brain regions of normal subjects. SETTING: University-affiliated medical center. PATIENTS OR PARTICIPANTS: 20 AIDS patients with clinical diagnosis of PML, 16 had tissue and/or CSF evidence of JCV infection; 20 age-matched normal subjects. MAIN OUTCOME MEASURES: Metabolites from 1H MRS: N-acetyl aspartate (NA), creatine (CR), choline-containing compounds (CHO), myoinositol (MI), glutamine/glutamate (GLX), lactate, and lipids. RESULTS: CSF PCR for JCV DNA showed 86% sensitivity. MRI showed characteristic demyelinating lesions; commonest locations were frontal lobe and cerebellum. 1H MRS in the lesions showed decreased NA (-35%; p < 0.0001) and CR (-18%; p = 0.003), increased CHO (+28%; p = 0.0005), occasional increased MI, and excess lactate (15/20 lesions) and lipids (18/20). In the CONTRA, MRS showed trends for increased CR (+15%), CHO (+15%), MI (+13%), and lower GLX (-9%; p = 0.02). Six patients, studied longitudinally (4-18 months), showed progressive spectroscopic changes; two patients with longest survival showed the highest MI. CONCLUSIONS: These MRS findings are consistent with neuropathologic observations of neuronal loss, cell membrane and myelin breakdown, and increased glial activity in PML lesions. The CONTRA abnormalities may be due to remote effects of PML or direct HIV-1 infection. 1H MRS may be useful for characterization and follow-up evaluation of PML lesions.
Adult↗
Distinct expression patterns and biological activities of two isoforms of the mouse orphan receptor TR2.
An alternatively spliced variant of a testis-specific nuclear orphan receptor TR2-11 was identified and designated as TR2-11-t. As a result of retaining intron 5 of this gene, TR2-11-t mRNA encoded a truncated receptor with the complete ligand-binding domain deleted. Protein expression of both isoforms was confirmed using a prokaryotic expression system. In the mouse, the expression of the two TR2 isoforms was elevated in the testis with distinct profiles beginning at puberty. TR2-11 expression increased at postnatal day 18, peaked between day 20 and day 24 and remained at high levels throughout adulthood, whereas TR2-11-t expression was elevated transiently at postnatal day 24. Among separated primary germ cells and established testicular cell lines, TR2-11 was expressed highly in meiotic and postmeiotic germ cells and weakly in a Leydig cell line and a germ cell line, but not expressed in a Sertoli cell line. In contrast, TR2-11-t was expressed at a much lower level in all the testicular cell types examined. In adult testes blocked at germ cell development by vitamin A depletion or hypophysectomy, TR2-11 expression was dramatically reduced whereas TR2-11-t was highly elevated. Based upon the RNA expression patterns of these isoforms, it was suggested that TR2-11 was specific to meiotic and postmeiotic germ cells whereas TR2-11-t was enriched in early germ cell populations such as premeiotic cells. The biological activities of TR2-11 and TR2-11-t on a direct repeat 5-type retinoic acid (RA) response element (RARE)-containing reporter gene was examined in Cos cells. TR2-11 repressed RA induction of this reporter whereas TR2-11-t enhanced RA induction of the same reporter, and the opposite biological effects of these isoforms were dose-dependent. Gel-shift experiments provided evidence for a direct interaction of TR2-11, but not TR2-11-t, with DNA fragments containing this RARE. Opposite roles of TR2-11 and TR2-11-t on RA induction of promoters containing this particular RARE are suggested.
Amino Acid Sequence↗
Regulation of the mouse cellular retinoic acid-binding protein-I gene by thyroid hormone and retinoids in transgenic mouse embryos and P19 cells.
The regulation of mouse cellular retinoic acid-binding protein-I (CRABP-I) gene expression by the retinoids and thyroid hormones was examined, by using a beta-galactosidase (lacZ) reporter gene and a CRABP-I specific antibody, in transgenic mouse embryos and a mouse embryonal carcinoma cell line P19. The CRABP-lacZ reporter gene expression recapitulated the expression pattern of endogenous CRABP-I in the developing central nervous system. In mid-gestation mouse embryos the expression of both the transgene and the endogenous protein was elevated under the condition of hypovitaminosis A, suggesting that depletion of retinoic acid (RA) induced CRABP-I expression in embryos. Consistently, this reporter was suppressed by RA in P19 cells. In co-transfection experiments it was demonstrated that the expression of RAR beta, RAR gamma or RXR alpha suppressed this reporter expression. In experiments designed to alter the thyroid hormone status in animals it was demonstrated that both the reporter gene and the endogenous CRABP-I expression were reduced by triiodothyronine injection and were elevated in a hypothyroidic condition induced by feeding with iodine-deficient diet supplemented with 6-propyl-2-thiouracil. In co-transfection experiments it was also demonstrated that the expression of T3R beta suppressed the reporter expression in P19 cells. It was concluded that RA had a suppressive effect on CRABP-I gene expression in embryos and P19 cells and the effect could be mediated through RAR beta, RAR gamma or RXR alpha. A role of thyroid hormones in CRABP-I gene expression and vitamin A metabolism in animals is discussed.
Animals↗
[Observation of EGG parameters during -6 degrees head-down bedrest for 21 days].
Electrogastography (EGG) was recorded in 15 healthy volunteers before and after meal during 21 days head down tilt -6 degrees bed rest. The results showed that nausea, distension and pain in the abdomen and loss of appetite appeared at the beginning of bed rest and body weight decreased significantly (P < 0. 01) after bed rest; Low frequency (Bradygastria) proportion of EGG (<2.4cpm) increased apparently after 8 days of bedrest, and there was significant difference (P <0.05) between preprandial and postprandial bradygastria. The dynamic parameters of bradygastria declined significantly and the rhythm of bradygastria increased with duration of bedrest. It indicates that simulated weightlessness may cause decrease of gastric rhythm and gastric motility.
Aerospace Medicine↗
Barrier film protects skin of incontinent rats.
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Journal Article↗
Relationship of serum dehydroepiandrosterone (DHEA), DHEA sulfate, and 5-androstene-3 beta, 17 beta-diol to risk of breast cancer in postmenopausal women.
Laboratory evidence suggests a role for dehydroepiandrosterone (DHEA) and its metabolite 5-androstene-3 beta, 17 beta-diol (ADIOL) in mammary tumor growth. Serum DHEA also has been related to breast cancer in postmenopausal women, but the relationship of ADIOL to risk has not been evaluated previously. To assess the relationship of serum DHEA, its sulfate (DHEAS), and ADIOL with breast cancer risk in postmenopausal women, we conducted a prospective nested case-control study using serum from the Columbia, MO Breast Cancer Serum Bank. Cases included 71 healthy postmenopausal volunteers not taking replacement estrogens when they donated blood and who were diagnosed with breast cancer up to 10 years later (median, 2.9 years). Two randomly selected controls, who also were postmenopausal and not taking estrogens, were matched to each case on exact age, date (+/-1 year), and time (+/-2 h) of blood collection. Significant (trend P = 0.02) gradients of increasing risk of breast cancer were observed for increasing concentrations of DHEA and ADIOL, and women whose serum levels of these hormones were in the highest quartiles were at a significantly elevated risk compared to those in the lowest; their risk ratios were 4.0 [95% confidence interval (CI), 1.3-11.8) and 3.0 (95% CI, 1.0-8.6), respectively. The relationship of DHEAS to breast cancer was less consistent, but women whose serum DHEAS concentration was in the highest quartile also exhibited a significantly elevated risk ratio of 2.8 (95% CI, 1.1-7.4). Results of this prospective study support a role for the adrenal androgens, DHEA, DHEAS, and ADIOL, in the etiology of breast cancer.
Aged↗
Early computed tomography is rarely necessary in gallstone pancreatitis.
The role of early CT scanning in acute gallstone pancreatitis remains ill defined. The purpose of our study was to: 1) determine whether our previously identified admission prognostic factors for gallstone pancreatitis [white blood cell (WBC) count > or = 14.5 x 10(9)/L, blood urea nitrogen (BUN) > or = 12 mmol/L, Acute and Chronic Health Evaluation II score > or = 5, glucose > or = 150 mg/dL, and heart rate > or = 100 beats/min)] correlate with the severity of pancreatic inflammation on CT scan, and 2) to determine the utility of early CT scanning in the management of gallstone pancreatitis. Admission clinical and laboratory variables were collected prospectively. Early CT scan findings were graded using the Balthazar scoring system and subgrouped into mild-moderate (Balthazar grades A-C) or severe (grades D and E) by a radiologist blinded to the patients' clinical status. Ninety-seven patients underwent surgery during their initial hospitalization without preoperative CT scanning. Four had operative complications (4%). Forty-two patients underwent early CT scan (grade A, 19%; B, 5%; C, 21%; D, 10%; and E, 45%), but only four (all grade E) had surgery delayed because of necrotizing pancreatitis, abscess, or pseudocyst. All four had persistent abdominal pain. There was one (2.5%) operative complication in the CT group and no deaths. Admission WBC count > or = 14.5 x 10(9)/L and BUN > or = 12 mmol/L correlated with severe pancreatitis (grades D and E) on CT (P < .05). We conclude that in patients with gallstone pancreatitis, 1) admission WBC count > or = 14.5 x 10(9)/L and BUN > or = 12 mmol/L correlate with the severity of pancreatic inflammation on CT scan, and 2) CT scan findings rarely influence management decisions and CT is therefore unnecessary, except in the minority of patients with objective indications of severe or unresolving pancreatitis.
APACHE↗