Biomedical subjects

C Wang

Publications and source records attributed to C Wang.

At least 631 records · Page 35Linked to original sources

PubMed1998

Dissection of de novo membrane insertion activities of internal transmembrane segments of ATP-binding-cassette transporters: toward understanding topological rules for membrane assembly of polytopic membrane proteins.

The membrane assembly of polytopic membrane proteins is a complicated process. Using Chinese hamster P-glycoprotein (Pgp) as a model protein, we investigated this process previously and found that Pgp expresses more than one topology. One of the variations occurs at the transmembrane (TM) domain including TM3 and TM4: TM4 inserts into membranes in an N(in)-C(out) rather than the predicted N(out)-C(in) orientation, and TM3 is in cytoplasm rather than the predicted N(in)-C(out) orientation in the membrane. It is possible that TM4 has a strong activity to initiate the N(in)-C(out) membrane insertion, leaving TM3 out of the membrane. Here, we tested this hypothesis by expressing TM3 and TM4 in isolated conditions. Our results show that TM3 of Pgp does not have de novo N(in)-C(out) membrane insertion activity whereas TM4 initiates the N(in)-C(out) membrane insertion regardless of the presence of TM3. In contrast, TM3 and TM4 of another polytopic membrane protein, cystic fibrosis transmembrane conductance regulator (CFTR), have a similar level of de novo Nin-Cout membrane insertion activity and TM4 of CFTR functions only as a stop-transfer sequence in the presence of TM3. Based on these findings, we propose that 1) the membrane insertion of TM3 and TM4 of Pgp does not follow the sequential model, which predicts that TM3 initiates N(in)-C(out) membrane insertion whereas TM4 stops the insertion event; and 2) "leaving one TM segment out of the membrane" may be an important folding mechanism for polytopic membrane proteins, and it is regulated by the N(in)-C(out) membrane insertion activities of the TM segments.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1998

Arylaminobenzoate block of the cardiac cyclic AMP-dependent chloride current.

The cystic fibrosis transmembrane conductance regulator (CFTR) Cl- channel has been identified in the cardiac muscle of a number of mammalian species, including humans. The goal of this study was to begin quantifying the structural requirements necessary for arylaminobenzoate block of the CFTR channel. The cardiac cAMP-dependent Cl- current (ICl) was measured using the whole-cell arrangement of the patch-clamp technique in guinea pig ventricular myocytes during stimulation of protein kinase A with forskolin. At drug concentrations below the IC50 value for channel block, reduction of ICl by the arylaminobenzoates occurred in a strongly voltage-dependent manner with preferential inhibition of the inward currents. At higher drug concentrations, block of both the inward and outward ICl was observed. Increasing the length of the carbon chain between the benzoate and phenyl rings of the arylaminobenzoates resulted in a marked increase in drug block of the channel, with IC50 values of 47, 17, and 4 microM for 2-benzylamino-5-nitro-benzoic acid, 5-nitro-2-(2-phenylethylamino)-benzoic acid, and 5-nitro-2-(3-phenylpropylamino)-benzoic acid (NPPB), respectively. Increasing the carbon chain length further with the compound 5-nitro-2-(4-phenylbutylamino)-benzoic acid, caused no additional increase in the potency of drug block (IC50 = 4 microM). Inhibition of ICl by the arylaminobenzoates was modulated by the pH of the external solution; increasing the pH from 7.4 to 10.0 greatly weakened NPPB block, whereas decreasing the pH to 6.4 enhanced block. In addition, block of ICl was observed during intracellular dialysis of NPPB, and this action was not affected by raising the external pH.

Animals↗

PubMed1998

Oral immunization of macaques with attenuated vaccine virus induces protection against vaginally transmitted AIDS.

The chimeric simian-human immunodeficiency virus SHIVKU-1, bearing the envelope of human immunodeficiency virus type 1 (HIV-1), causes fulminant infection with subtotal loss of CD4(+) T cells followed by development of AIDS in intravaginally inoculated macaques and thus provides a highly relevant model of sexually transmitted disease caused by HIV-1 in human beings. Previous studies using this SHIV model had shown that the vpu and nef genes were important in pathogenesis of the infection, and so we deleted portions of these genes to create two vaccines, DeltavpuDeltanefSHIV-4 (vaccine 1) and DeltavpuSHIVPPc (vaccine 2). Six adult macaques were immunized subcutaneously with vaccine 1, and six were immunized orally with vaccine 2. Both viruses caused infection in all inoculated animals, but whereas vaccine 1 virus caused only a nonproductive type of infection, vaccine 2 virus replicated productively but transiently for a 6- to 10-week period. Both groups were challenged 6 to 7 months later with pathogenic SHIVKU-1 by the intravaginal route. All four unvaccinated controls developed low CD4(+) T-cell counts (<200/microliter) and AIDS. The 12 vaccinated animals all became infected with SHIVKU-1, and two in group 1 developed a persistent productive infection followed by development of AIDS in one. The other 10 have maintained almost complete control over virus replication even though spliced viral RNA was detected in lymph nodes. This suppression of virus replication correlated with robust antiviral cell-mediated immune responses. This is the first demonstration of protection against virulent SHIV administered by the intravaginal route. This study supports the concept that sexually transmitted HIV disease can be prevented by parenteral or oral immunization.

AIDS Vaccines↗

PubMed1998

CD4(+) cytotoxic T-lymphocyte activity against macrophages pulsed with bovine herpesvirus 1 polypeptides.

Bovine herpesvirus 1 (BHV-1) induces immune suppression, but the mechanisms for suppression are not well identified. We examined the induction and activity of BHV-1-specific cytolytic CD4(+) T lymphocytes (CTL) by stimulating peripheral blood mononuclear cells (PBMC) of cattle immunized with attenuated live BHV-1. Cytolytic effector cells were primarily CD4(+) T lymphocytes and lysed autologous, but not allogeneic, macrophages infected with BHV-1 or pulsed with BHV-1 polypeptides. Apoptosis of BHV-1-expressing target cells was observed in CD4(+) CTL assays by terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL) analysis. To determine if apoptosis was mediated by a perforin- or Fas-mediated pathway, EGTA, a known selective inhibitor of the perforin pathway, was used. EGTA did not inhibit CD4(+)-T-cell-mediated cytotoxic activity, but it did limit the NK cell cytotoxicity of virus infected cells. These findings support the concept that CD4(+) CTL lyse macrophages pulsed with BHV-1 polypeptides through a Fas-mediated lytic pathway by inducing apoptosis in the target cells. The prominent cytotoxicity mediated by CD4(+) CTL suggests a mechanism of selective removal of viral antigen-associated antigen-presenting cells.

Animals↗

PubMed1998

Molecular mechanism governing heme signaling in yeast: a higher-order complex mediates heme regulation of the transcriptional activator HAP1.

Apart from serving as a prosthetic group in globins and enzymes, heme is a key regulator controlling a wide range of molecular and cellular processes involved in oxygen sensing and utilization. To gain insights into molecular mechanisms of heme signaling and oxygen sensing in eukaryotes, we investigated the yeast heme-responsive transcriptional activator HAP1. HAP1 activity is regulated precisely and tightly by heme. Here we show that in the absence of heme, HAP1 forms a biochemically distinctive higher-order complex. Our data suggest that this complex contains HAP1 and four other cellular proteins including Hsp82 and Ydj1. The formation of this complex is directly correlated with HAP1 repression in the absence of heme, and mutational or heme disruption of the complex correlates with HAP1 activation, suggesting that this complex is responsible for heme regulation of HAP1 activity. Further, we determined HAP1 domains required for heme regulation: three domains-the dimerization domain, the heme domain, and the HRM7 (heme-responsive motif 7) domain-cooperate to form the higher-order complex and mediate heme regulation. Strikingly, we uncovered a novel function for the HAP1 dimerization domain: it not only allows dimerization but also provides critical functions in heme regulation and transcriptional activation. Our studies provide significant insights into the molecular events leading to heme activation of HAP1 and may shed light on molecular mechanisms of various heme-controlled biological processes in diverse organisms.

Animals↗

PubMed1998

Tumor-specific PAX3-FKHR transcription factor, but not PAX3, activates the platelet-derived growth factor alpha receptor.

The t(2;13) chromosomal translocation occurs at a high frequency in alveolar rhabdomyosarcoma, a common pediatric tumor of muscle. This translocation results in the production of a chimeric fusion protein derived from two developmentally regulated transcription factors, PAX3 and FKHR. The two DNA binding modules, the paired domain and the homeodomain, of PAX3 are fused in frame to the transactivation domain of FKHR. Previously, tumor-specific PAX3-FKHR has been shown to bind to DNA sequences normally recognized by wild-type PAX3 and to exhibit relatively enhanced transcriptional activity. The DNA binding sites used to demonstrate that PAX3-FKHR is a more potent transcriptional activator than PAX3 have included recognition sequences for the paired domain of PAX3. In this report, we demonstrate the ability of PAX3-FKHR to activate the product of a growth control gene, platelet-derived growth factor alpha receptor (PDGFalphaR), by recognizing a paired-type homeodomain binding site located in the PDGFalphaR promoter. PAX3 alone cannot mediate transcriptional activation of this promoter under the conditions tested. This provides the first evidence that chromosomal translocation results in altered target gene specificity of PAX3-FKHR and suggests a transcriptional target that may play a significant role in oncogenic activity and rhabdomyosarcoma development.

Animals↗

PubMed1998

Acute and chronic increases in excitability in rat hippocampal slices after perinatal hypoxia In vivo.

We have previously shown that hypoxia induces both acute and chronic epileptogenic effects that are age dependent. Global hypoxia (3-4% O2) induces seizure activity in the developing brain [postnatal day (P)10-12] but not at younger or older ages. Adult rats with prior seizures induced by hypoxia at P10 show increased seizure susceptibility to chemical convulsants compared with controls. In the present study, we tested the hypothesis that acute and chronic epileptogenic effects of hypoxia are demonstrable in hippocampus both in vivo and in vitro. Depth electrode recordings confirmed the presence of ictal activity within hippocampus in P10 rats during global hypoxia. Hippocampal slices prepared from P10 pups killed at 10 min after recovery from hypoxia showed evidence of increased excitability. Extracellular field recordings revealed that the amplitude and duration of long-term potentiation (LTP) was increased significantly in area CA1 of hippocampal slices removed from hypoxic pups. In addition, extracellular recordings within areas CA1 and CA3 showed significantly longer afterdischarge durations in response to kindling stimuli in slices from hypoxic pups compared with controls. To evaluate whether there were also long-term changes in hippocampal excitability, hippocampal slices were prepared from adult rats that had underwent hypoxia at P10 and compared with slices from adult litter-mate controls. A Mg2+-free medium was superfused to induce epileptiform activity within the slices. Extracellular recordings from stratum pyramidale of area CA1 showed that Mg2+-free media induced significantly more frequent ictal discharges in slices from previously hypoxic rats compared with controls. These results provide evidence that the naturally occurring stimulus of hypoxia can result in both acute and chronic changes in the excitability of the CA1 neuronal network. These results parallel our previous in vivo studies demonstrating that global hypoxia acutely increases excitability in the immature brain and that hypoxia during the age window approximately P10 results in long-lasting increases in seizure susceptibility within hippocampus. Our results suggest that the age-dependent epileptogenic effects of hypoxia are in part mediated by a direct and permanent effect on neuronal excitability within hippocampal neuronal networks.

Aging↗

PubMed1998

Influence of pituitary disease on sexual development and functioning.

Pituitary disorders may have a major effect on sexual development and function. This review describes the regulation of normal reproductive hormonal function in the fetus, infant, adolescent and adult. The effects of pituitary insufficiency and pituitary adenomas on sexual development, reproductive function and sexuality in men and women are discussed.

Adolescent↗

PubMed1998

Kallikrein gene delivery attenuates hypertension and cardiac hypertrophy and enhances renal function in Goldblatt hypertensive rats.

To demonstrate potential therapeutic effects of kallikrein gene delivery, we delivered adenovirus (Ad.CMV-cHK) carrying the human tissue kallikrein gene into two-kidney, one-clip Goldblatt hypertensive rats. A single intravenous injection of the recombinant adenovirus caused a delay of blood pressure increase that began 1 day after injection and continued for 24 days. A maximal blood pressure reduction was observed in rats receiving kallikrein gene delivery compared with control rats receiving Ad.CMV-LacZ (160+/-5 versus 186+/-7 mm Hg, n=6, P<.01). The expression of human tissue kallikrein mRNA was identified in the kidney, heart, aorta, and liver of rats receiving kallikrein gene delivery. Immunoreactive human kallikrein levels were measured in rat serum and urine in a time-dependent manner. Adenovirus-mediated kallikrein gene delivery caused a significant reduction in the left ventricular mass and cardiomyocyte size, as well as an increase in renal blood flow, urine flow, glomerular filtration rates, electrolyte output, and urine excretion. Enhanced renal responses were accompanied by significant increases in urinary kinin, nitrite/nitrate, and cyclic GMP levels. These findings show that the expression of human tissue kallikrein via gene delivery has protective effects against renovascular hypertension and cardiovascular and renal dysfunction.

Adenoviridae↗

PubMed1998

Soluble ecto-domain mutant of thyrotropin (TSH) receptor incapable of binding TSH neutralizes the action of thyroid-stimulating antibodies from Graves' patients.

A soluble form of the amino-terminal extracellular (ecto-) domain of the human TSH receptor was generated. This protein was capable of binding TSH and autoimmune antibodies found in Graves' patients. A deletion mutant of the ectodomain lacking nine amino acids in the C-terminal region lost its ability to interact with TSH but retained binding to Graves' IgGs. In cells expressing recombinant TSH receptors, cotreatment with the mutant protein blocked the cAMP production induced by stimulating antibodies from all Graves' patients tested but was without effect on TSH action. The ability to dissociate the actions of TSH and Graves' IgGs provides a tool with which to study the mechanisms underlying Graves' disease and the possibility of neutralizing the undesirable effects of thyroid-stimulating antibodies without altering the normal responses to TSH.

Autoantibodies↗

PubMed1998

Spontaneous expression of inducible nitric oxide synthase in the hypothalamus and other brain regions of aging rats.

Our laboratory has demonstrated that aging in Brown-Norway rats is associated with decreased LH pulse amplitude and reduced GnRH and LH responsiveness to excitatory amino acids (EAA), presumably through the NMDA receptor (NMDAR). Nitric oxide (NO) is a neurotransmitter postulated to be involved in hypothalamic synaptic events required for normal GnRH regulation through the activation of neuronal nitric oxide synthase (nNOS). Paradoxically, excessive stimulation of nNOS by NMDAR or the expression of inducible nitric oxide synthase (iNOS) can lead to supraphysiological levels of NO acting as effector of apoptosis with resultant decreased regional neuronal function. The aims of this study were to determine: 1) whether aging in the preoptic area/medial basal hypothalamus is associated with altered NO synthesis; 2) the possible roles of the NMDAR/nNOS cascade and iNOS in this process; and 3) whether alterations in the levels of NOS isoforms are specific to this region of the brain. Brown Norway male rats (N = 5) at ages 1 (immature), 3 (adult), and 24 (old) months, were used for measuring NMDARs in hypothalamic membranes by the binding of a (3H)-NMDAR ligand. Another series of the same age groups of rats (N = 9) were used to determine by Western blot the contents of NMDAR, nNOS, and iNOS in the hypothalamus, and only iNOS in the frontal and parietal cortex, and cerebellum. NOS activity was measured in the hypothalamus by the arginine/citrulline assay. A significant decrease of NMDA analog binding was found in the hypothalamus from old rats as compared with adult (-66%) and immature animals (-57%), accompanied by a reduction in NMDAR content (-34% and -46%, respectively). NOS activity in the hypothalamus was 67% and 100% higher in old rats as compared with the other two groups, although no significant differences were observed in nNOS content. However, hypothalamic iNOS increased 3.8- and 7.6-fold in old rats, as compared with adult and immature, respectively. This increase in hypothalamic iNOS was paralleled by a rise of iNOS in other brain regions of old rats as compared respectively to adult and immature animals: 3.9- and 12.8-fold, in the frontal cortex; 2.8- and 2.5-fold, in the parietal cortex; and 3.1- and 4.8-fold, in the cerebellum. These results show that aging in this rat model is associated with high NO synthesis in the hypothalamus and other regions of the brain, which is independent of the NMDAR/nNOS cascade. We speculate that increased brain levels of iNOS may lead to neurotoxicity, which may be involved in GnRH impaired pulsatile secretion, as well as acting as a possible inducer of age associated neuronal loss in cognitive related brain areas.

Aging↗

PubMed1998

Spontaneous germ cell apoptosis in humans: evidence for ethnic differences in the susceptibility of germ cells to programmed cell death.

Spontaneous death of certain classes of germ cells has been shown to be a constant feature of normal spermatogenesis in a variety of mammalian species, including the human. Recent studies on various animal models have demonstrated that apoptosis is the underlying mechanism of germ cell death during normal spermatogenesis. Withdrawal of gonadotropins and/or testosterone further accelerates the germ cell apoptosis. We examined the involvement of apoptosis in the spontaneous loss of germ cells in men. Testicular samples obtained at autopsy from 5 Chinese and 9 non-Hispanic Caucasian men were analyzed. To identify individual germ cells undergoing apoptosis, we used a modified terminal deoxynucleotidyl transferase-mediated deoxy-UTP nick end labeling technique that detects germ cell apoptosis with high sensitivity and specificity. Testicular sections from all 14 subjects exhibited spontaneous occurrence of germ cell apoptosis involving spermatogonia, spermatocytes, and spermatids (apoptotic indexes, 1.6 +/- 0.4 2.5 +/- 0.6, and 5.5 +/- 1.2, respectively). The incidence of spermatogonial (2.8 +/- 0.8 vs. 1.0 +/- 0.2) as well as spermatid (9.3 +/- 2.1 vs. 8.4 +/- 0.9) apoptosis was higher in Chinese than in Caucasian men. A higher incidence of spermatocyte apoptosis was also noted for Chinese (4.4 +/- 1.4) compared to Caucasian (1.9 +/- 0.4) men, but the difference was not statistically significant. These results suggest that germ cell death during normal spermatogenesis in men occurs via apoptosis and provide evidence for ethnic differences in the inherent susceptibility of germ cells to programmed cell death. Our data may also help to explain the greater efficacy of testosterone-induced spermatogenic suppression to azoospermia observed in Asian compared to non-Asian men.

Adult↗

PubMed1998

Suppression of spermatogenesis in man induced by Nal-Glu gonadotropin releasing hormone antagonist and testosterone enanthate (TE) is maintained by TE alone.

GnRH antagonists plus testosterone (T) suppress LH and FSH levels and inhibit spermatogenesis to azoospermia or severe oligozoospermia. High-dose T treatment alone has been shown to be an effective male contraceptive (contraceptive efficacy rate of 1.4 per 100 person yr). Combined GnRH antagonist and T induces azoospermia more rapidly and at a higher incidence than T alone; this combination has therefore been proposed as a prototype male contraceptive. However, because GnRH antagonists are expensive to synthesize and difficult to deliver, it would be desirable to rapidly suppress sperm counts to low levels with GnRH antagonist plus T and maintain azoospermia or severe oligozoospermia with T alone. In this study, 15 healthy men (age 21-41 yr) with normal semen analyses were treated with T enanthate (TE) 100 mg im/week plus 10 mg Nal-Glu GnRH antagonist sc daily for 12 weeks to induce azoospermia or severe oligozoospermia. At 12-16 weeks, 10 of 15 subjects had zero sperm counts, and 14 of 15 had sperm counts less than 3 x 10(6)/mL. The 14 who were suppressed on combined treatment were maintained on TE alone (100 mg/week im) for an additional 20 weeks. Thirteen of 14 subjects in the TE alone phase had sperm counts maintained at less than 3 x 10(6)/mL for 20 weeks. Ten remained persistently azoospermic or had sperm concentration of 0.1 x 10(6)/mL once during maintenance. Mean LH and FSH levels in the subjects were suppressed to 0.4+/-0.2 IU/L and 0.5+/-0.2 IU/L in the induction phase, which was maintained in the maintenance phase. The 1 subject who failed to suppress sperm counts during induction had serum LH and FSH reduced to 0.3 and 0.5 IU/L, respectively. The subject who failed to maintenance had LH and FSH suppressed to 1.0 and 0.2 IU/L, respectively, during the induction phase but these rose to 1.6 and 2.1 IU/L, respectively, during maintenance. Failure to suppress or maintain low sperm counts may be related to incomplete suppression of serum LH and FSH levels. We conclude that sperm counts suppressed with GnRH antagonist plus T can be maintained with relatively low dose TE treatment alone. This concept should be explored further in the development of effective, safe, and affordable hormonal male contraceptives.

Adult↗

PubMed1998

Graded testosterone infusions distinguish gonadotropin negative-feedback responsiveness in Asian and white men--a Clinical Research Center study.

Recently, multicenter clinical trials to determine male contraceptive efficacy disclosed that testosterone-induced suppression of spermatogenesis to azoospermia occurred in about 90% of Asian but only 60-70% of white men. To test whether there are ethnic differences in the sensitivity of gonadotropin secretion to suppression by testosterone, we administered constant infusions of testosterone at 0, 7, 14, and 28 mg/1.7 m2 x 24 h i.v. for 48 h to 9 Asian and 8 white normal male volunteers (22-42 yr old). During the last 8 h of each infusion dose, 10-min frequent blood sampling was carried out for later LH and FSH measurements by sensitive fluoroimmunoassays. Analyses of LH secretory pulses showed that LH pulse width, height, area, and total area under the curve (LH concentration vs. time) were significantly more suppressed in Asians than in whites during the lowest infusion dose of testosterone. With increasing testosterone dose, the suppression of pulsatile LH secretion was not different in the two ethnic groups. In contrast to pulsatile LH secretion, the responsiveness of pulsatile FSH secretion to exogenous testosterone infusion was not different between the two ethnic groups. At baseline, Asian men had a significantly higher mean number of FSH pulses and mean incremental pulse heights than did white men. Serum inhibin B levels were not distinguishable in the two ethnic groups, but the FSH profiles were quantifiably more irregular (higher approximate entropy) in the Asian volunteers. Our data suggest that, compared with white men, Asian men respond earlier and with more marked suppression of pulsatile LH secretion to ramped testosterone infusions. The elevated basal serum FSH concentrations (and more irregular FSH release pattern) observed in Asian men may suggest a small relative decrease in spermatogenic reserve and/or gonadal negative feedback. Whether these differences contribute to the observed differences in suppression of spermatogenesis in Asians vs. non-Asians in male contraceptive studies is not yet known.

Adult↗

PubMed1998

Comparative rates of androgen production and metabolism in Caucasian and Chinese subjects.

Clinically apparent prostate cancer occurs more commonly among Caucasians living in Western countries than in Chinese in the Far East. Prior studies demonstrated diminished facial and body hair and lower levels of plasma 3 alpha-androstanediol glucuronide and androsterone glucuronide in Chinese than in Caucasian men. Based upon these findings, investigators postulated that Chinese men could have diminished 5 alpha-reductase activity with a resultant decrease in prostate tissue dihydrotestosterone levels and clinically apparent prostate cancer. An alternative hypothesis suggests that decreased 3 alpha-androstanediol glucuronide and androsterone glucuronide levels might reflect reduced production of androgenic ketosteroid precursors as a result of genetic or environmental factors. The present study examined 5 alpha-reductase activity, androgenic ketosteroid precursors, and the influence of genetic and environmental/dietary factors in groups of Chinese and Caucasian men. We found no significant differences in the ratios of 5 beta-:5 alpha-reduced urinary steroids (a marker of 5 alpha-reductase activity) between Chinese subjects living in Beijing, China, and Caucasians living in Pennsylvania. To enhance the sensitivity of detection, we used an isotopic kinetic method to directly measure 5 alpha-reductase activity and found no difference in testosterone to dihydrotestosterone conversion ratios between groups. Then, addressing the alternative hypothesis, we found that the Caucasian subjects excreted significantly higher levels of individual and total androgenic ketosteroids than did their Chinese counterparts. To distinguish genetic from environmental/dietary factors as a cause of these differences, we compared Chinese men living in Pennsylvania and a similar group living in Beijing, China. We detected a reduction in testosterone production rates and total plasma testosterone and sex hormone-binding levels, but not in testosterone MCRs in Beijing Chinese as a opposed to those living in Pennsylvania. Comparing Pennsylvania Chinese with their Caucasian counterparts, we detected no significant differences in total testosterone, free and weakly bound testosterone, sex hormone-binding globulin levels, and testosterone production rates. Taken together, these studies suggest that environmental/dietary, but not genetic, factors influence androgen production and explain the differences between Caucasian and Chinese men.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗

PubMed1998

Comparative pharmacokinetics of three doses of percutaneous dihydrotestosterone gel in healthy elderly men--a clinical research center study.

Twenty-five men, 60-80 yr old, participated in a pharmacokinetic study to compare three doses (16, 32, and 64 mg/day, n = 8 or 9 in each group) of 5alpha-dihydrotestosterone (DHT) gel (0.7% hydroalcoholic gel with 2.3 g gel delivering 16 mg DHT) applied daily over one upper arm (16 mg); both arms and shoulders (32 mg); and bilateral arms, shoulders, and upper abdomen (64 mg), respectively. Multiple blood samples for the pharmacokinetic profile for DHT and testosterone (T) were drawn over a 24-h period before application, after first application, and after 14 days of daily application of DHT gel. Additional blood samples for DHT, T, and estradiol were obtained 24 h after application on days 3, 5, 7, and 11 and after discontinuation of DHT gel for 3, 5, 7, and 14 days (days 17, 19, 21, and 28 after first instituting treatment). No skin irritation was observed in any of the subjects. Before treatment, mean serum DHT and T levels were not different among the three dose groups. The serum DHT levels increased gradually after gel application on the first day, reaching a plateau between 12-18 h. During the 14 days of daily application of DHT gel, the mean baseline DHT levels reached steady state by day 2 or 3 and were elevated considerably above baseline. Mean serum DHT levels varied between 8-11, 12-17, and 14-24 nmol/L in the 16-, 32-, and 64-mg groups, respectively. The area under curve (AUC) of serum DHT levels over 24 h on day 14 were 6.0-, 6.9-, and 16.1-fold above pretreatment levels for the three doses. Concomitant with the increase in serum DHT levels, the AUC produced by endogenous serum T levels decreased to 75, 56, and 36% of baseline after 14 days of 16, 32, and 64 mg/day DHT gel. Similar patterns of decreases in AUC of serum estradiol levels were found. The calculated mean total androgen levels (T + DHT) rose with DHT gel application in all groups (P < 0.0001) on both days 1 and 14. We conclude that the three doses of DHT gel tested might provide adequate androgen replacement in hypogonadal men at the low, middle, and high physiological androgen (T + DHT) range.

Administration, Cutaneous↗

PubMed1998

[Mutation of p53 gene and genomic instability in testicular tumors].

BACKGROUND: During the past decade, studies of human cancer have begun to yield molecular information on the identify of the multiple genetic changes in the development and progression of tumorigenesis. We investigated alterations of p53 and genomic instability in testicular tumors. MATERIALS AND METHODS: Polymerase chain reaction (PCR) single-strand conformation polymorphism was performed for analysis from exons 5 to 8 of p53 gene in 22 cases and PCR-microsatellite instability analysis using 8 microsatellite markers were conducted in 19 cases of testicular tumor. RESULTS: No mutations were noted for exons 5 to 8 of the p53 gene. Differences in unrelated microsatellites for tumor and corresponding normal DNA were detected in 5 of 19 (26.3%) cases examined. Alterations noted in more than 2 microsatellites were observed in 3 of 19 (15.8%) and categorized as replication error (RER) phenotype. Two of 7 (28.6%) seminomatous and 1 of 12 (8.3%) non-seminomatous testicular tumors patients showed RER. Two of 16 (12.5%) stage T1-3N0M0 and 1 of 3 (33.3%) stage T1-3N1-3M0-1 showed RER. CONCLUSIONS: Alterations in microsatellite instability may be involved in the development of testicular tumor.

DNA Replication↗

PubMed1998

[A study on the effectiveness of hepatitis B vaccine among the vaccinated population].

In order to identify the effect of hepatitis B vaccine in a vaccinated population, 5890 persons from 1890 families in 13 counties/cities in Henan province were chosen for investigation under multistage cluster systematic sampling. All subjects were bled for HBsAg, anti-HBs and anti-HBc by RIA. The positive rate of HBsAg was significantly lower in vaccinates than in that non-vaccinates. There was no protective effect in those who only vaccinated for one dose. It was preferable to receive vaccination before the age of two years. If 70% of hepatitis B vaccine coverage was reached among those younger than 5 years old, the positive rate of HBsAg could reduce to 1% or even lower. Results showed that it was important to ensure an earlier and full course vaccination with high coverage.

Adolescent↗