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Biomedical subjects

E Friedman

Publications and source records attributed to E Friedman.

At least 73 records · Page 4Linked to original sources
PubMed2000

Lack of efficacy of riluzole in the treatment of peripheral neuropathic pain conditions.

OBJECTIVE: To assess the efficacy, tolerability, and safety of riluzole in the treatment of peripheral neuropathic pain conditions. BACKGROUND: Both basic and clinical research has demonstrated that drugs with sodium channel and NMDA antagonism can be effective in alleviating neuropathic pain. Riluzole, a drug currently used for treatment of ALS, possesses these properties. It was hypothesized that riluzole would be effective in reducing the pain in subjects with peripheral neuropathic pain. METHODS: Two randomized, placebo-controlled, crossover studies were performed at two sites. Study 1 compared 100 mg/day of riluzole (the currently recommended dosage for treatment of ALS) versus placebo, and Study 2 compared 200 mg/day of riluzole versus placebo. Each treatment phase (both studies) was 2 weeks long, separated by 2-week wash-out periods. Outcome measures included change in the score on a 100-mm pain intensity visual analog scale, the Neuropathic Pain Scale, allodynia, hyperalgesia, and preference for study treatment phase. RESULTS: Twenty-two subjects completed Study 1, and 21 subjects completed Study 2. Four subjects (two from each study) discontinued the study because of intolerable side effects. No statistical difference was found for any study outcome measure between riluzole and placebo for either study. In Study 1, pain intensity was more likely to increase than decrease with riluzole (mean treatment difference 8.7 mm; 95% CI -19.5 to +2.1 mm). In Study 2, very slight pain reduction was observed with riluzole compared with placebo (mean treatment difference 1.4 mm; 95% CI -5.1 to +8.0 mm). In both studies, the majority of subjects chose "no change" in pain on the category relief scale after placebo and riluzole treatment phases. On study completion, no treatment preference was reported by 76% of the subjects in Study 1 and by 61% of the subjects in Study 2. CONCLUSIONS: Doses of riluzole at (100 mg) or above (200 mg) those used for the treatment of ALS were not effective in alleviating peripheral neuropathic pain.

Adult↗
PubMed2000

IGFBP-3 mediates TGF beta 1 proliferative response in colon cancer cells.

Many human tumor cells are resistant to growth inhibition by TGF beta 1. Resistance may be caused by mutations in TGFbeta receptors or in other components of the TGF beta signal transduction systems, or by knockout of the retinoblastoma (Rb) gene, which in fibroblasts converts cellular response to TGF beta 1 from growth inhibition to growth stimulation. Our earlier studies showed such a switch in response to TGF beta 1 occurred in 45% of colon cancers but without deletion of Rb. We now show that insulin-like growth factor binding protein 3 (IGFBP-3) mediates the TGF beta 1-induced proliferation of 3 metastatic or highly aggressive colon carcinoma cell lines. TGF beta 1 increases IGFBP-3 abundance while phosphorothiolated antisense oligonucleotides to IGFBP-3 block the growth-promoting effect of TGF beta 1 in each of 3 lines.IGFBP-3 induces carcinoma cell growth in a dose-dependent and time-dependent manner in vitro. IGFBP-3 may confer a selective growth advantage on tumor cells in vivo because levels of mature IGFBP-3 were elevated at least 2-fold in 7 of 10 resected colon cancers compared with adjacent normal tissue.

Adenocarcinoma↗
PubMed2000

Mirk protein kinase is a mitogen-activated protein kinase substrate that mediates survival of colon cancer cells.

We have cloned a novel gene mirk (minibrain-related kinase) encoding a protein kinase that enables colon carcinoma cells to survive under certain stress conditions. Mirk is a mitogen-activated protein kinase substrate but is down-regulated by activated extracellular signal-regulated kinases (erks) in vivo. Mirk contains a PEST region characteristic of rapidly turned over proteins and is broken down to a Mr 57,000 form only in the nucleus. In each of three colon carcinoma cell lines, mirk levels were increased 20-fold when erk activation was blocked by the MEK inhibitor PD98059 in serum-free medium. Addition of IGF-I to activate erks blocked this increase. Mirk was stably overexpressed in two colon carcinoma cell lines to attain levels seen in colon cancers. Each of five mirk transfectants proliferated when switched to serum-free medium and regained rapid growth when serum was restored, whereas five vector control transfectants and three kinase-dead mutant mirk transfectants did not. mirk mRNA levels were elevated in several types of carcinomas, and mirk protein was detected in each of seven colon carcinoma cell lines. mirk was expressed at a higher protein level in Western blots from three of eight colon cancers compared with paired normal colon tissue, suggesting that mirk plays a role in the evolution of a subset of colon cancers. mirk is not mutated in colon carcinomas. Mirk may mediate tumor cell survival in mitogen-poor environments or early in colon cancer development before many autocrine growth factors have been induced.

Amino Acid Sequence↗
PubMed2000

In utero cocaine-induced dysfunction of dopamine D1 receptor signaling and abnormal differentiation of cerebral cortical neurons.

Monoamines modulate neuronal differentiation, and alteration of monoamine neurotransmission during development produces specific changes in neuronal structure, function, and pattern formation. We have previously observed that prenatal exposure to cocaine in a clinically relevant animal model produces increased length of pyramidal neuron dendrites in the anterior cingulate cortex (ACC) postnatally. We now report that cocaine administered intravenously to pregnant rabbits at gestational stages preceding and during cortical histogenesis results in the early onset of hypertrophic dendritic outgrowth in the embryonic ACC. Confocal microscopy of DiI-labeled neurons revealed that the atypical, tortuous dendritic profiles seen postnatally in ACC-cocaine neurons already are apparent in utero. No defects in neuronal growth were observed in visual cortex (VC), a region lacking prominent dopamine innervation. In striking correlation with our in vivo results, in vitro experiments revealed a significant enhancement of spontaneous process outgrowth of ACC neurons isolated from cocaine-exposed fetuses but no changes in neurons derived from visual cortex. The onset of modified growth in vivo is paralleled by reduced D(1A) receptor coupling to its G-protein. These data suggest that the dynamic growth of neurons can be regulated by early neurotransmitter signaling in a selective fashion. Prenatal onset of defects in dopamine receptor signaling contributes to abnormal circuit formation and may underlie specific cognitive and behavioral dysfunction.

Aging↗
PubMed2000

Activation of extracellular signal-regulated protein kinases is associated with a sensitized locomotor response to D(2) dopamine receptor stimulation in unilateral 6-hydroxydopamine-lesioned rats.

Evidence indicates that mitogen-activated protein kinase (MAPK) pathways play a crucial role in the neurobiology of the nervous system. In the present study, dopamine receptor-mediated regulation of extracellular signal-regulated kinases (ERKs) was examined in rats in which the nigrostriatal dopaminergic pathway was unilaterally lesioned by 6-hydroxydopamine (6-OHDA). Subcutaneous injections of the D(2) receptor agonist quinpirole significantly increased tyrosine-phosphorylated ERK1/2 in lesioned striatum, whereas the D(1) receptor agonist SKF38393 failed to activate ERKs. Quinpirole-induced phosphorylation of ERK1/2 was seen as early as 3 min and peaked at 15 min after the challenge. In parallel, striatal ERK kinase activity, measured by the in vitro kinase assay, was increased 2.5-fold on the lesioned side after the administration of quinpirole. Immunohistochemical examination of brain sections after quinpirole administration revealed significant increases in ERK1/2 immunostaining in perinuclear and intranuclear areas of striatal neurons. This increase was much more pronounced on the lesioned than the intact side. Furthermore, quinpirole-induced contralateral rotation was decreased by 48.7 and 50.7%, respectively, when the striatal ERK pathway was selectively inhibited by a single intrastriatal injection of the MAPK/ERK kinase inhibitor PD098059 or after a continuous 7 d intrastriatal infusion of ERK1/2 antisense oligodeoxynucleotide. The results demonstrate, for the first time, that the ERK signaling pathway is activated in denervated striatum in response to stimulation of D(2) dopamine receptors and that the resulting imbalance in striatal ERK activity contributes, at least in part, to neuronal plasticity that underlies D(2) dopamine receptor-mediated contralateral rotation in unilateral 6-OHDA denervated rats.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed2000

Prenatal diagnosis of a novel COL1A1 mutation in osteogenesis imperfecta type I carried through full term pregnancy.

Prenatal diagnosis was performed in a family where the father has osteogenesis imperfecta (OI) type I, with a novel mutation in the COL1A1 gene: a C to T change at position c3076 (c.3076C-->T) leading to a change of arginine at codon 848 to a stop codon (R848X). Prenatal diagnosis by chorionic villous sampling (CVS) was performed during the fourth pregnancy, and revealed that the fetus is a carrier of the same COL1A1 mutation. The possibility of phenotypic variability was discussed with the parents. They elected to carry the pregnancy to term, and a male child with mild OI was born. This is the first reported case where OI was diagnosed prenatally, and the parents opted to carry the pregnancy to term. It illustrates the potential use of DNA-based analysis for early prenatal diagnosis of OI, and the complexities of genetic counselling.

Adult↗
PubMed2000

Mutation analysis of the MEN1 gene in Israeli patients with MEN1 and familial isolated hyperprolactinemia.

Multiple endocrine neoplasia type 1 (MEN-1) is characterized by hyperfunction and tumor formation of the parathyroids, anterior pituitary and endocrine pancreas. We carried out exon-specific, PCR-based DNA sequencing of the coding exons of the MEN1 gene in 8 Israeli MEN1 patients: 4 familial and 4 sporadic. We similarly analyzed Israeli families with a unique phenotype of isolated hyperprolactinemia (HPRL). Four mutations were detected in 4 MEN1 patients: C to T alteration at nucleotide 2608 resulting in R108X, and three intronic insertions/deletions (a 13 basepair (bp) deletion and a 1 bp insertion both in intron 1, and a 2 bp insertion in intron 3) leading to exonic frame shifts as they encompass the splice junctions. An additional patient exhibited a compound mutation: a G to T change at position 7614 resulting in E463X, and insertion/deletion of 9 bp at position 7622-7630 resulting in EAE466-468X. Haplotype analysis showed no segregation of phenotype with 11q13 markers in 4 familial HPRL, and no men 1 germline mutations were detected in three representative individuals, from 3 families. Our results confirm that men 1 gene germline mutations occur in the majority of patients with clinically diagnosed MEN1, and that familial HPRL is a genetically distinct disorder.

Adolescent↗
PubMed2000

Mutational analyses of BRCA1 and BRCA2 in Ashkenazi and non-Ashkenazi Jewish women with familial breast and ovarian cancer.

In Ashkenazi (East European) Jews, three predominant mutations in BRCA1 (185delAG and 5382insC) and BRCA2 (6174delT) account for the majority of germline mutations in high-risk breast and/or ovarian cancer families. Among non-Ashkenazi Jews, the 185delAG, Tyr978Ter, and a handful of "private" mutations have been reported anecdotally within both genes. In this study we attempted to determine the spectrum of BRCA1 and BRCA2 mutations in high-risk Jewish individuals, non-carriers of any of the predominant Jewish mutations. We employed multiplex PCR and denaturing gradient gel electrophoresis (DGGE) analysis for BRCA2, and combined denaturing high performance liquid chromatography (DHPLC) and protein truncation test (PTT) for BRCA1, complemented by DNA sequencing. We screened 47 high-risk Jewish individuals, 26 Ashkenazis, and 21 non-Ashkenazis. Overall, 13 sequence alterations in BRCA1 and eight in BRCA2 were detected: nine neutral polymorphisms and 12 missense mutations, including five novel ones. The novel missense mutations did not co-segregate with disease in BRCA1 and were detected at rates of 6.25% to 52.5% in the general population for BRCA2. Our findings suggest that except for the predominant mutations in BRCA1 and BRCA2 in Jewish individuals, there are only a handful of pathogenic mutations within these genes. It may imply novel genes may underlie inherited susceptibility to breast/ovarian cancer in Jewish individuals.

Adult↗
PubMed2000

Downregulation of p53 by sustained JNK activation during apoptosis.

In a previous study, we prepared short-chain fatty acid (SCFA) mixtures mimicking the composition of the digested fibers from wheat bran, oat bran, pectin, and cellulose and tested the products on U4 cells, a cell-line model for normal colonocytes. These SCFA mixes induced the cyclin-dependent kinase (cdk) inhibitors p21 and p27, which bound to cdk2/cyclin E and cdk4/cyclin D1 complexes, blocking their kinase activity and arresting cell growth. SCFAs from digested fiber may control intestinal crypt height in vivo by inducing apoptosis in growth-arrested cells at the top of the crypt. In the present study, we report that SCFA mixes induced apoptosis of U4 cells and unexpectedly caused both a sustained activation of the stress-activated protein kinase c-jun N-terminal kinase 1 (JNK1) and downregulation of the tumor suppressor protein p53. JNK1 bound to p53, and the amount of JNK1-bound p53 accurately reflected the amount of total cellular p53. After activation by SCFAs, JNK1 phosphorylated its bound p53. This phosphorylation is likely to have converted p53 into an apoptotic target because p53 breakdown correlated with caspase-3 activity, was inhibited by a caspase-3 inhibitor in a dose-dependent manner, and was inhibited by transfection of dominant-negative JNK1. Because JNK1 activation was sustained in SCFA-treated U4 cells, JNK1 can bind, phosphorylate, and release p53 for proteolysis and then continue this cycle until many p53 molecules have been phosphorylated. Loss of p53 protein was likely due to proteolysis and not to transcriptional changes because a sixfold decrease in p53 protein occurred within 3-24 h of SCFA treatment, whereas p53 mRNA levels were downregulated as much only after 2-3 d. SCFA mixes targeted p53 and possibly other cellular proteins for degradation during apoptosis by causing a sustained activation of JNKs.

Apoptosis↗
PubMed2000

Patients with double primary tumors in the breast and ovary- clinical characteristics and BRCA1-2 mutations status.

OBJECTIVE: The aim of this study was to define the prevalence, clinical characteristics, and BRCA1-2 mutation carrier status of ovarian cancer (OvC) patients with a previous primary malignancy in the breast (PPMBr). METHODS: The study population comprised 1240 consecutive Jewish Israeli women with pathologically confirmed epithelial OvC diagnosed between March 1, 1994, and December 31, 1997. Demographic and clinical data were obtained from medical files and from a detailed questionnaire taken through a nationwide epidemiological case-control study on OvC. Blood samples and tumor tissues were collected for analysis of the three predominant germline BRCA1-2 Jewish founder mutations (185delAG, 5382insC, and 6174delT). RESULTS: Fifty nine (4.7%) patients with OvC had a PPMBr. The median age at diagnosis of OvC was 60 years. The mean interval between the two diagnoses was 104 months (range 0-363 months). In the majority of the patients (n = 53), the diagnosis of breast cancer (BrC) preceded the OvC by more than 1 year. The ovarian tumors were diagnosed in 47% of the cases following investigation of patients' symptoms. In 41%, diagnosis was made as a consequence of check-up exams performed during the routine follow-up of BrC survivors. Patients with PPMBr were more likely to present with FIGO ovarian stage III-IV, compared to women with solitary OvC (73% vs 60. 3%, P < 0.05), and less likely to have borderline tumors (3.4% vs 17. 9%, P = 0.007). Family history of OvC/BrC was recorded in 26% of this group of patients compared to 10.5% among patients with solitary OvC (P = 0.003). Patients with PPMBr had an exceptionally high prevalence of BRCA1-2 mutations (57%), irrespective of family history. CONCLUSIONS: Patients with PPMBr present with more advanced disease and invasive-type epithelial ovarian tumors when compared to cases associated with solitary OvC. The rate of BRCA1-2 mutations in Jewish women with OvC who had PPMBr is at least twice as high as in Jewish women with OvC as the solitary disease.

BRCA2 Protein↗
PubMed2000

The International Collaborative Study of Maternal Phenylketonuria: status report 1998.

UNLABELLED: The Maternal Phenylketonuria Study began in 1984 and during the intervening years, 572 pregnancies in hyperphenylalaninemic women and 99 controls and their outcomes have been evaluated. Among hyperphenylalaninemic women who delivered a live infant, only 15.9% were treated and in metabolic control preconceptually, however, another 18.4% were in control by 10 weeks. Compared to the results reported by Lenke and Levy in 1980, there is a marked improvement in outcome with treatment. Microcephaly was unusual in preconceptually treated pregnancies with well controlled phenylalanine restricted diets. Even in pregnancies that established control after conception but before the 8th week, congenital heart disease did not occur in the offspring, however, it did occur in 12% of pregnancies not achieving control until after 10 weeks of pregnancy. CONCLUSION: The recommended level of blood phenylalanine during pregnancy is 120-360 mumol/l. Best results were obtained by close cooperation between the attending obstetrician and a metabolic team experienced in the care of persons with phenylketonuria.

Adult↗
PubMed2000

Effect of hydrocortisone on platelet activating factor induced lung edema in isolated rabbit lungs.

The effect of hydrocortisone on platelet activating factor (PAF)-induced pulmonary edema is studied. Thirty four isolated and perfused rabbit lung preparations were used: eight control preparations, eight PAF preparations with two doses of PAF called low dose (LD = 0.5 microg/kg of rabbit weight) and high dose (HD = 1 microg/kg of rabbit weight). Eighteen preparations divided in three groups of six were pretreated with doses of 20, 200 and 2000 mg of hydrocortisone and later given the same doses of PAF as described above. Hydrocortisone significantly decreased (P < 0.05) the effect of PAF LD over the pulmonary arterial pressure (Ppa) in the 200 and 2000 mg groups (58 and 89% decrease, respectively) and it significantly decreased (P < 0.05) the effect of PAF HD over Ppa in all hydrocortisone pretreated groups (48, 70 and 96% decrease, respectively). Fluid filtration rate (FFR) increases mediated by PAF HD were significantly inhibited (P < 0.05) in the 200 and 2000 mg groups (64 and 96% decrease, respectively). We conclude that hydrocortisone inhibits the effect of PAF over the pulmonary circulation.

Animals↗
PubMed2000

Comparative genomic hybridization in inherited and sporadic ovarian tumors in Israel.

To gain an understanding of the molecular mechanisms of ovarian cancer, we analyzed 16 ovarian tumors from Jewish Israeli patients by comparative genomic hybridization: 12 invasive epithelial tumors (including three BRCA1 and one BRCA2 mutation carriers), 2 primary peritoneal carcinomatosis, 1 pseudomyxoma peritoneii tumor, and 1 sertoli cell tumor. We similarly analyzed 1 normal ovary from a BRCA1 mutation carrier, and 3 metastases. The most common abnormalities in epithelial tumors were amplification of 8q22.1-ter (8/12, 66.6%), 1q22-32.1 (5/12, 41.6%), 3q, 10p (4/12, 33.3% for each), and deletions of 9q (5/12, 41.6%) and 16q21-24 (4/12, 33.3%). All 3 BRCA1 mutation carriers and 2 of 8 sporadic cases displayed 9q deletion, and 2 of 3 BRCA1 mutation carriers, but none of the sporadic cases, had deletion of chromosome 19. The range of genetic changes in primary peritoneal tumors and epithelial ovarian cancers was similar, though the mean number of alterations in the former was less (3.5/tumor versus 8/tumor). Our preliminary results may indicate that inherited predisposition to ovarian cancer possibly entails preferential somatic deletions of chromosomes 9 and 19.

Aged↗
PubMed2000

Topical diclofenac patch relieves minor sports injury pain: results of a multicenter controlled clinical trial.

Sports-related soft tissue injuries, such as sprains, strains, and contusions, are a common painful condition. Current treatment includes oral nonsteroidal anti-inflammatory drugs (NSAIDs), which have a high incidence of intolerable gastrointestinal side effects. Topically applied drugs have the potential to act locally in the soft tissues without systemic effects. This study assessed the efficacy and safety of topical diclofenac (NSAID) patch applied directly to the painful injury site for the treatment of acute minor sports injury pain. Adult subjects (N = 222) were recruited from two communities for a multicenter, randomized, placebo-controlled, parallel design study. All subjects had suffered a painful minor sports injury within the prior 72 hours of study entry. Either a diclofenac epolamine or placebo topical patch was applied directly to the skin overlying the painful injured site twice daily for 2 weeks. Measures of pain intensity were performed in a daily diary and at clinic visits on days 3, 7, and 14. Diclofenac patch was superior to placebo patch in relieving pain. Statistical significance was seen on clinic days 3 (P = 0.036) and 14 (P = 0. 048), as well as the daily diary pain ratings at days 3, 7, and 14 (P < or =0.044). No statistically significant differences were seen in any safety or side-effect measures with the diclofenac patch as compared to the placebo patch. Diclofenac epolamine patch is an effective and safe pain reliever for treatment of minor sports injury pain. The advantages of this novel therapy include its ease of use and lack of systemic side effects.

Administration, Topical↗
PubMed2000

The effects of agonist stimulation and beta(2)-adrenergic receptor level on cellular distribution of gs(alpha) protein.

This study examines the effects of adrenergic ligands, cholera toxin, forskolin, and varying levels of beta(2) adrenergic receptors (beta(2)AR) on the cellular distribution of Gs(alpha) subunits in CHO cells. Localization of Gs(alpha) was evaluated by confocal microscopy and beta(2)AR-mediated signalling was assessed by adenylyl cyclase (AC) activity. In cells expressing 0.2 pmol/mg protein beta(2)ARs (WT18), the localization of Gs(alpha) subunit was restricted to the plasma membrane region. Isoproterenol (ISO), cholera toxin or forskolin elicited redistribution of cellular Gs(alpha) so that Gs(alpha) appeared as intense spots throughout the plasma membrane as well as the cytoplasm. Exposure to a neutral beta(2)AR antagonist, alprenolol, prevented the ISO-stimulated Gs(alpha) translocation from peripheral to inner cytoplasm. In cells expressing high level of beta(2)ARs (8.2 pmol/mg) (WT4), basal and ISO-stimulated AC activities were significantly elevated when compared to the values detected in WT18 clone, suggesting a positive correlation between receptor expression and receptor-mediated signalling. Basal Gs(alpha) distribution in this group was similar to that observed in ISO-, cholera toxin-, or forskolin-stimulated WT18 clone. ISO, cholera toxin, or forskolin did not change the distribution of Gs(alpha) significantly when tested in WT4 clone. No difference in the cellular level of Gs(alpha) protein between WT18 and WT4 clones was detected. Alprenolol did not affect the distribution of Gs(alpha) in WT4 clone. ICI 118,551, a negative beta(2)AR antagonist, altered Gs(alpha) distribution from a dispersed basal pattern to a membrane-confined pattern. The latter appearance was similar to that observed in unstimulated WT18 clone. Taken together, these data suggest that: (1) enhanced beta(2)AR-Gs(alpha) coupling induced by agonist stimulation or by increased expression of beta(2)ARs remodel the cellular distribution of Gs(alpha); (2) the alteration in Gs(alpha) distribution induced by beta(2)AR overexpression provides evidence for agonist-independent interaction of beta(2)AR and Gs(alpha), that can be inhibited by a negative antagonist but not by a neutral antagonist; and (3) forskolin influences the activity state of Gs(alpha) that displays a Gs(alpha) distribution pattern comparable to that observed when Gs(alpha) is activated via beta(2)AR stimulation or directly by cholera toxin.

Adenylyl Cyclases↗