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Biomedical subjects

S Greene

Publications and source records attributed to S Greene.

At least 19 recordsLinked to original sources
PubMed1997

Prolactin, epidermal growth factor or transforming growth factor-alpha activate a mammary cell-specific enhancer in mouse mammary tumor virus-long terminal repeat.

Mammary specific expression of elevated levels of mouse mammary tumor virus (MMTV) contributes to mammary carcinogenesis. Mechanisms which regulate provirus expression have not been completely defined. Using a MMTV-long repeat terminal (MMTV-LRT) directed chloramphenicol-acetyltransferase (CAT) reporter gene system and a human breast cancer cell line T47D, we demonstrate that prolactin (PRL), epidermal growth factor (EGF), or transforming growth factor-alpha (TGF-alpha) act on a mammary cell-specific enhancer at the extreme 5' end of the MMTV-LTR involving sequences -1094 through -858. PRL and either EGF or TGF-alpha exert concerted roles in this activation of these sequences. In contrast, using a plasmid construct lacking this mammary cell-specific enhancer, EGF or TGF-alpha, but not PRL, act synergistically with progesterone to induce CAT activity, indicating that the action of PRL on regulatory elements of the MMTV-LTR is restricted to this mammary cell-specific enhancer involving sequences -1094 through -858. A mobility shift assay was used to demonstrate that PRL, EGF or TGF-alpha induce nuclear factors (MP4, MAF, and MGF) which bind directly to this mammary cell-specific enhancer element.

Binding Sites↗
PubMed1996

A new therapeutic option for the treatment of pneumonia.

Patients with bacterial pneumonia often are treated empirically with parenteral broad-spectrum antimicrobials intended to cover potential gram-negative and gram-positive pathogens. However, beta-lactamase-mediated resistance has developed to many of these antimicrobials, particularly third-generation cephalosporins, and has led to the development of fourth-generation agents that are relatively beta-lactamase stable. The purpose of these studies was to compare the efficacy and safety of the fourth-generation agent, cefepime, with that of the third-generation agent, ceftazidime, in the treatment of hospitalized patients with moderate-to-severe bacterial pneumonia. A total of 336 (97 evaluable) patients were enrolled in an open-label study, and 99 (23 evaluable) patients were enrolled in a blinded study of patients with lower respiratory tract infections (LRTI) including pneumonia. Patients were randomized to receive either cefepime 1 g every 12 hours or ceftazidime 1 g every 8 hours given as an intravenous infusion over 30 minutes. Efficacy analysis included the evaluable patients while the safety analysis included all patients. The results in the open-label study were as follows: In patients with pneumonia, clinical response was satisfactory in 58 (85%) of 68 patients in the cefepime group and 21 (72%) of 29 patients in the ceftazidime group. Bacteriologic eradication occurred for 75 (93%) of 81 pathogens and 30 (94%) of 32 pathogens isolated from the 68 cefepime-treated patients and 29 ceftazidime-treated patients, respectively. The results in the blinded study were as follows: In patients with pneumonia, clinical response was satisfactory in 12 (80%) of 15 cefepime patients and in 7 (88%) of 8 ceftazidime patients, and the bacteriologic eradication rates were 85% (17/20 pathogens) and 73% (8/11 pathogens) isolated from the 15 cefepime-treated patients and the eight ceftazidime-treated patients, respectively. Among the most frequent adverse events in both groups were nausea, diarrhea, vomiting, and abdominal pain. Similar adverse events were noted in the 99 patients in the blinded study. These studies indicate that the efficacy and safety of cefepime administered at 1 g twice daily is comparable to that of ceftazidime administered at 1 g three times daily for treatment of hospitalized patients with pneumonia caused by susceptible pathogens.

Acute Disease↗
PubMed1995

Inhibition of dihydroorotate dehydrogenase by the immunosuppressive agent leflunomide.

Leflunomide [HWA 486 or RS-34821, 5-methyl-N-(4-trifluoromethylphenyl)-4-isoxazole carboximide] is an immunosuppressive agent effective in the treatment of rheumatoid arthritis. In spite of its clinical potential, its mechanism of action has not been elucidated. Recent studies suggest that leflunomide may interfere with the metabolism of pyrimidine nucleotides. In our studies, the active metabolite of leflunomide, RS-61980 (A77 1726, 2-hydroxyethylidene-cyanoacetic acid-4-trifluoromethyl anilide), was cytostatic towards a human T-lymphoblastoma cell line (A3.01). The inhibition of growth could be overcome completely by uridine. The other nucleosides, cytidine, adenosine and guanosine, did not overcome the effect of the compound. Since uridine is a precursor for the salvage synthesis of UMP, we propose that RS-61980 may be inhibiting the de novo pathway of UMP synthesis. Using human cells, the six enzymes catalyzing de novo UMP biosynthesis were tested for their sensitivity towards RS-61980. Only one of the enzymes, dihydroortate dehydrogenase (DHODH, EC 1.3.3.1) was inhibited by RS-61980 with a Ki value of 2.7 +/- 0.7 microM. The other five enzymes were not affected. The inhibition exhibited mixed-type kinetics towards both substrates, dihydroorotic acid and coenzyme Q. These results suggest that the molecular target of leflunomide action is DHODH. The immunomodulating activity may be related to the inhibition of UMP synthesis in proliferating lymphocytes.

Aniline Compounds↗
PubMed1995

Predictive value of precore hepatitis B virus mutations in spontaneous and interferon-induced hepatitis B e antigen clearance.

We previously reported two mutually exclusive mutations in the precore region of hepatitis B virus: M1 (T-1856, proline-serine substitution at codon 15) and M2 (A-1896, stop codon at codon 28). This study was conducted to determine if the presence of precore mutants affect spontaneous or interferon (IFN)-induced hepatitis B e antigen (HBeAg) clearance. Sera from 201 hepatitis B e antigen positive Chinese patients (including 106 who participated in a controlled trial of IFN therapy) with chronic hepatitis B virus (HBV) infection were analyzed by direct sequencing of HBV DNA after amplification by polymerase chain reaction (PCR) assay. Forty-three (21%) patients had M1 (T-1856), and 20 patients (10%) had M2 (A-1896). During a follow-up period of 1 to 7 years, 75%, 28%, and 26% of those with M2 (A-1896), M1 (T-1856), and wild type sequence respectively, cleared HBeAg (P < .0001). Eighteen (67%) of 27 patients with wild-type sequence but none of 10 patients who had M1 (T-1856) in their initial samples developed M2 (A-1896) after loss of HBeAg (P < .0001). Sustained antiviral response was achieved in 55%, 0%, and 17% of interferon-treated patients who had M2 (A-1896), M1 (T-1856), and wild-type sequence, respectively, initially (P = .04). However, patients with M2 (A-1896) were also more likely to have elevated pretreatment aminotransferase levels (P = .02). In summary, HBeAg-positive Chinese patients with M2 (A-1896) were mor likely to clear HBeAg, and to do so earlier.(ABSTRACT TRUNCATED AT 250 WORDS)

Base Sequence↗
PubMed1994

Mutations in the pre-core region of hepatitis B virus serve to enhance the stability of the secondary structure of the pre-genome encapsidation signal.

We conducted a large-scale survey to determine the frequency and clinical significance of mutations in the pre-core region of hepatitis B virus (HBV). Sera from 263 patients with chronic HBV infection were analyzed by direct sequencing of PCR-amplified HBV DNA. Four major missense/nonsense mutations (M) were found: (M1) C-->T at nucleotide position 1856, Pro-->Ser at codon 15; (M2) G-->A at position 1896, Trp-->stop at codon 28; (M3) G-->A at position 1898, Gly-->Ser at codon 29; and (M4) G-->A at position 1899, Gly-->Asp at codon 29. The commonest conserved mutation was M0: T-->C at position 1858, Pro-->Pro at codon 15. We found that M1 and M2 were mutually exclusive, M3 was only found in association with M1, and M4 was predominantly found in association with M2. All patients with M1 but none of those with M2 had M0. The invariable coexistence of certain mutations in codon 15 and codons 28 and 29 and the mutual exclusion of other mutations in these two noncontiguous regions is related to the stem-loop structure of the pre-genome encapsidation sequence located in the precore/core region. M2 and M4 enhance the stability of the stem by providing two additional paired sites. M1 destroys an existing base pair. However, M1 only occurred in the presence of M0, which provides an extra paired site, and 50% of patients with M1 had M3, a compensatory mutation that restores base pairing at this site. Our data support the proposed secondary structure of the pre-genome encapsidation sequence. The primary function of the mutations in the pre-core region is to enhance stability of this secondary structure to ensure perpetuation of viral replication.

Base Sequence↗
PubMed1994

Detection of precore hepatitis B virus mutants in asymptomatic HBsAg-positive family members.

Precore hepatitis B virus mutants have been detected mainly in HBeAg-negative patients with active liver disease. We previously reported two novel mutations: M1 (C-to-T change at nucleotide 1856 [proser at codon 15]) and M3 (G-to-A change at nucleotide 1898 [gly-ser at codon 29]) in addition to two well-described mutations: M2 (G-to-A change at nucleotide 1896 [trp-stop at codon 28]); and M4 (G-to-A change at nucleotide 1899 [gly-asp at codon 29]) in Chinese patients. The aims of this study were to determine (a) the prevalence of precore HBV mutations in asymptomatic carriers and (b) whether family members share the same mutated sequence as the index patients. Fifty-three index patients and 89 HBsAg-positive family members were studied by means of direct sequencing of polymerase chain reaction-amplified hepatitis B virus DNA. M0, a conserved mutation (T-to-C at nucleotide 1858, codon 15), was detected in 81% and 12% family members of index patients with and without M0, respectively (p < 0.0001). The clustering of M0 indicates that most subjects were infected through intrafamilial transmission. M1 was detected in all the family members of patients with M1 but in none of the family members of patients with wild-type or M2 sequences (p < 0.0001). M2 was detected in 25%, 0% and 15% of family members of patients with M2, M1 and WT sequences, respectively (p = 0.19). M3 was detected in five and M4 in four family members.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1993

NIH appointment due.

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Administrative Personnel↗
PubMed1990

The use of a single non-timed urine collection in the calculation of fractional lithium clearance.

The fractional clearance of lithium (CLLi/CLCR) calculated in 15 normal healthy adults from a single morning urine aliquot collection, together with a single venous blood sample (FQ) was compared with the average CLLi/CLCR obtained from three timed consecutive urine collections with mid-point blood sampling (FABC). Lithium had been ingested 15-18 h prior to the collection of these samples. Mean CLLi/CLCR was similar (FQ, 0.186, FABC, 0.177), with a highly significant correlation in each individual of CLLi/CLCR measured by either method (r = 0.97, P less than 0.0001). Proximal tubular reabsorption of sodium using lithium clearance may be calculated from a single urine and blood sample.

Adult↗
PubMed1989

Ciprofloxacin (intravenous/oral) versus ceftazidime in lower respiratory tract infections.

The efficacy and safety of intravenous ciprofloxacin was compared with intravenous ceftazidime in 80 hospitalized patients with lower respiratory tract infection. There were 40 patients in each treatment group. Patients and physicians were blinded to the randomized scheme for treatment groups until patient consent was obtained. The 37 evaluable ciprofloxacin-treated patients received 200 mg every 12 hours intravenously as initial therapy and 29 completed their course receiving oral ciprofloxacin. The 34 evaluable ceftazidime-treated patients received 1 to 2 g intravenously every eight to 12 hours. The two groups did not differ with respect to patient age, infection severity, and admitting diagnosis. Clinical outcomes were similar with greater than 95 percent of treatments in each group being successful. Headache was the most commonly reported complaint (four patients) in the ciprofloxacin group. Three patients experienced substantial increases in serum theophylline concentrations while receiving ciprofloxacin. The predominant pathogens isolated were Haemophilus influenzae and Pseudomonas aeruginosa, and susceptibility rates for all organisms were similar for both drugs. The mean peak serum concentration at steady state while receiving intravenous ciprofloxacin was 2.3 micrograms/ml, and the mean trough concentration was 0.5 micrograms/ml. Patients randomly assigned to ciprofloxacin therapy received 2.6 fewer days of intravenous antibiotic therapy than those receiving ceftazidime. This 80-patient comparative trial demonstrates that ciprofloxacin and ceftazidime are similar in efficacy and safety when treating gram-negative lower respiratory tract infections. There appears to be potential for cost-reducing benefits through decreased length of intravenous therapy and earlier hospital discharge.

Administration, Oral↗
PubMed1987

Comparison of two tests to recognize or exclude 5 alpha-reductase deficiency in prepubertal children.

Plasma testosterone (T, nmol/l) and dihydrotestosterone (DTH, nmol/l) were measured in 54 children and young adults with male pseudohermaphroditism (46XY, no defect of steroid biosynthesis) 4 h after im injection of testosterone propionate (25 mg/m2, group 1, N = 18), or before and 2, 4 and 6 days after hCG (5000 IU/m2 im, group 2, N = 36). The response to hCG was also studied in 5 control children (unilateral cryptorchidism, group 3) and that to testosterone propionate in a gonadectomized child with confirmed 5 alpha-reductase deficiency. Mean T (133.1 +/- 14.0, SEM) and DHT (17.1 +/- 2.6) in group 1 were higher than in group 2 (17.3 +/- 2.1 and 2.9 +/- 0.4), but there was not significant difference in the T/DHT ratios (group 1: 10.7 +/- 2.0; group 2: 7.2 +/- 0.6). Following testosterone-propionate, there was a negative correlation of T with age (r = -0.723). After hCG, T and DHT were lower in the prepubertal children than in those under 2 or over 10 years, and the T/DHT-ratio rose with age. Two children from group 1 had a T/DHT-ratio above 18, but urinary aetiocholanolone/androsterone (Ae/A) ratios were normal. In the child with 5 alpha-reductase deficiency, the T/DHT ratio was 60, and the urinary Ae/A ratio high. We concluded that the two tests are suitable for confirming or excluding 5 alpha-reductase deficiency in prepubertal children, in whom basal DHT is too low for evaluation, but that physiological age-related changes in 5 alpha-reductase activity have to be taken into consideration.

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