Renal replacement therapy in Japan: better outcome than in the USA.
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Humans↗
Biomedical subjects
E Friedman
Publications and source records attributed to E Friedman.
Adenovirus-mediated gene transfer to ciliated airway epithelia requires prolonged incubation time.
The efficiency of adenovirus-mediated gene transfer to airway epithelia will be an important factor in determining whether recombinant adenoviruses can be developed as vectors for transferring cystic fibrosis transmembrane conductance regulator (CFTR) cDNA to patients with cystic fibrosis. Current understanding of the biology of CF lung disease suggests that vectors should express transgene in mature, ciliated airway epithelia. We evaluated the efficiency of adenovirus-mediated gene transfer to primary cultures of normal and CF human airway epithelia. Our studies showed that the airway cells developed from an undifferentiated epithelium with markers characteristic of basal cells and a surface covered by short microvilli 3 days after seeding to a mature epithelium whose apical surface was covered with cilia by 10 to 14 days. The ability of adenovirus vectors to express a reporter gene and to correct defective cyclic AMP-stimulated Cl- transport in CF epithelia was correlated inversely with the state of differentiation. However, the inefficiency of adenovirus-mediated gene transfer could be partially corrected when the contact time between vector and epithelium was prolonged. After prolonged contact, we observed complete correction of the CF Cl- transport defect in differentiated CF airway epithelia in culture and of the Cl- transport defect in the nasal epithelia of mice homozygous for the deltaF508 mutation. The fact that gene transfer to airway epithelia required prolonged incubation with vector contrasts with the rapid infection observed in cell models such as 293 and HeLa cells, which are commonly used to study adenovirus infection. Gene transfer observed after prolonged incubation may result from mechanisms different from those that mediate infection of 293 cells. These observations suggest that interventions that either increase the contact time or alter the epithelium or the vector may be required to facilitate gene transfer to ciliated respiratory epithelia.
Adenoviridae↗
Hypothalamic-pituitary-adrenocortical activity and response to cognitive behavior therapy in unmedicated, hospitalized depressed patients.
OBJECTIVE: Surprisingly little research supports the hypothesis that depressions characterized by objective measures of neurobiological dysregulation respond poorly to psychotherapy. Moreover, relevant studies testing this hypothesis have been compromised by low rates of neurobiological abnormality in outpatient samples. The authors therefore investigated response to cognitive behavior therapy in relation to pretreatment measures of hypothalamic-pituitary-adrenocortical (HPA) activity in hospitalized, yet unmedicated, patients. METHOD: The subjects were 29 unmedicated, hospitalized patients with major depression (DSM-III-R and Schedule for Affective Disorders and Schizophrenia/Research Diagnostic Criteria), nonpsychotic/nonbipolar subtype. After a 7- to 14-day evaluation, urinary free cortisol levels and dexamethasone suppression tests (DSTs) were obtained. Patients were treated for an average of 3 weeks with intensive individual cognitive behavior therapy. Response was assessed in relation to clinical severity of illness and pretreatment HPA parameters. RESULTS: Response to inpatient cognitive behavior therapy was inversely associated with pretreatment urinary free cortisol concentrations, although not strongly correlated with DST results. Overall, 12 (92%) of 13 cortisol suppressors on the DST who had normal urinary free cortisol concentrations responded to treatment, compared with only seven (44%) of the 16 patients characterized by nonsuppression of cortisol and/or elevated urinary free cortisol excretion. The relation between response to cognitive behavior therapy and HPA activity was not explained by clinical measures of symptom severity. CONCLUSIONS: Results are consistent with the hypothesis that patients with increased HPA function are less responsive to psychotherapy and, hence, might require somatic interventions. It is proposed that the negative impact of hypercortisolism on neurocognitive function mediates this relationship.
Adolescent↗
Medulloblastoma in a 7-year-old girl.
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Brain↗
Familial Albright's hereditary osteodystrophy with hypoparathyroidism: normal structural Gs alpha gene.
Albright's hereditary osteodystrophy (AHO) is a characteristic skeletal phenotype, including short stature, obesity, round face, and brachydactyly. AHO appears in patients with pseudohypoparathyroidism (PHP) who have resistance to PTH and in their eumetabolic family members who have pseudopseudohypoparathyroidism (PPHP). The differential diagnosis of AHO in families without PHP includes brachydactyly E, whose existence as a distinct entity has been questioned. We studied a patient with familial AHO who presented with hypocalcemia. To our surprise, PTH levels were low, and the response to PTH administration was normal. This is the first case of familial AHO with hypoparathyroidism. The proband's family included 22 affected subjects spanning 3 generations, who had variable degrees of AHO manifestations, with an autosomal dominant inheritance trait. The metacarpophalangeal pattern profile was typical of that of PHP-PPHP. As deficient activity and inactivating mutations of Gs alpha were described in PHP as well as in PPHP, we measured the biological activity of Gs in family members, which was normal. To exclude subtle abnormalities in the Gs alpha gene, we sequenced the entire coding region of Gs alpha in the propositus, which was normal. We conclude that hypocalcemia should be adequately evaluated even in the presence of familial AHO, and that familial AHO can occur with a normal coding structural Gs alpha gene. Identification of the molecular defect in familial AHO without PHP will shed light on the pathogenesis of AHO in general.
Adult↗
Carcinoid tumors frequently display genetic abnormalities involving chromosome 11.
Carcinoid tumors are neuroendocrine neoplasms that are encountered either sporadically or as part of a familial syndrome, most notably-multiple endocrine neoplasia type 1 (MEN1). The MEN1 gene localizes to chromosome 11 (11q13) and presumably functions as a tumor suppressor gene. The molecular mechanisms underlying carcinoid tumor development and their clonal composition remain largely unknown. To establish whether carcinoid tumors develop via a mechanism similar to other MEN1-associated tumors, and indirectly determine their clonal composition, we analyzed 36 sporadically occurring carcinoid tumors with 16 chromosome 11 microsatellite markers, mostly from around the MEN1 region for loss of heterozygosity (LOH). Twenty one tumors (58%) displayed LOH of at least three markers, five lost almost an entire allele and the rest displayed a discontinuous pattern. Similar, but less extensive analysis was also carried out for 10 additional carcinoid tumors from Brazil, 6 of the 10 showed LOH with at least one marker. Overall, 36 of 46 tumors (78%) displayed LOH. In addition, 20 of 46 (43%) tumors exhibited a pattern of genomic instability. Thus, the majority of sporadically occurring carcinoid tumors are monoclonal whose tumorigenesis involves inactivation of a tumor suppressor gene on chromosome 11 and DNA mismatch repair genes mutations.
Adolescent↗
The great health policy debate of 2010.
Moderator: Good evening. Tonight I will be moderating a debate on the Health Care System Salvage and Coverage Overhaul Act of 2010 (Senate Bill 1, with companion legislation in the House). The bill is awaiting final congressional action, and the issue is considered so important that all 14 major television networks are carrying this debate live, along with many radio networks and at least 1,873 Internet/World Wide Web sites. As you know, S.B. 1 would provide immediate federal aid to the 1,000 hospitals and health care systems that are currently in bankruptcy; extend government-subsidized coverage to the estimated 90 million Americans who lack it; return to the federal government a wide range of health care regulatory and payment activities that had been transferred to the states; and prohibit certain types of health care enterprises and services, chiefly proprietary delivery and managed care systems. At the moment, the chances of its passage are too close to call. Arguments in support of S.B. 1 will be presented tonight by Sen. Joseph P. Kennedy II, Democrat of Massachusetts; arguments in opposition to the bill will be presented by Sen. George W. Bush, Republican of Texas; and the view of the Independent Party will be presented by former Kansas Senator Nancy Kassebaum, who also speaks as chairman of the National Nonpartisan Commission to Save American Health Care. Senator Kennedy will begin.
Forecasting↗
Myenteric ganglionic 5-hydroxytryptamine(1P) signal transmission is mediated via Go protein.
The role of G proteins in mediating the signal transduction of the guinea pig myenteric ganglionic 5-hydroxytryptamine (5-HT)1P receptors was examined. Stimulation of ganglionic membranes with 5-HT in the presence of [35S]GTPgammaS or [alpha 32P]GTP increased guanine nucleotide binding to G(alpha)o but not to G(alpha)s, G(alpha)i or G(alpha)q in a concentration-dependent fashion. Pertussis toxin pretreatment markedly reduce this 5-HT induced response. Similarly, the 5-HT1P receptor-mediated slowly developing and long-lasting depolarizing response is potentiated by GTPgammaS and is inhibited by GDPbetaS or pertussis toxin. The activation of G(alpha)o by 5-HT also was mimicked by the 5-HT1P agonist, 5-hydroxyindalpine and was blocked by the selective 5-HT1P antagonist, N-acetyl-5-hydroxytryptophyl-5-hydroxytryptophan amide. These data provide compelling evidence to suggest that transmembrane signaling for the 5-HT1P receptors in isolated myenteric ganglia is transduced by the trimeric Go protein.
Animals↗
Protein kinase C beta 1 and protein kinase C beta 2 activate p57 mitogen-activated protein kinase and block differentiation in colon carcinoma cells.
When HD3 colon carcinoma cells differentiate to fluid-transporting, enterocytic-like cells, they down-regulate their protein kinase C (PKC) beta levels 5-10-fold and lose two responses to basic fibroblast growth factor (FGF): proliferation and the ability to activate p57 mitogen-activated protein (MAP) kinase. HD3 cells were transfected with expression plasmids for the splice variants PKC-beta 1 and PKC-beta 2 and the empty vector for a control. Each of two PKC-beta 1 and each of two PKC-beta 2 transfectant clones exhibited elevated levels of Ca(2+)-and phosphatidylserine-dependent PKC activity. Both PKC-beta 1 transfectant clones had elevated levels of PKC-beta 1 protein compared with the PKC-beta 2 transfectants or controls, whereas both PKC-beta 2 transfectant clones had elevated levels of PKC-beta 2 protein compared with PKC-beta 1 transfectants. Control transfectants had no detectable PKC-beta 2 protein. Similar levels of PKC-alpha were found in all lines. Each PKC-beta transfectant was less differentiated than the parental line and had regained proliferative response to basic FGF. Increased growth rates in athymic mice were seen for PKC-beta 2 and PKC-beta 1 transfectant cells. Immunocytochemistry of the sectioned tumors showed enhanced protein levels of PKC-beta 2 and PKC-beta 1, correlating increased levels of these isonzymes with increased growth. Increased myelin-basic protein (MBP) kinase activities of M(r) 44,000, 57,000, 63,000, 110,000, and 130,000 by in-gel kinase assay characterized each PKC-beta transfectant. Both Western blotting and immunoprecipitation studies from 35S-prelabeled cells with a pan-erk antibody showed no increase in protein abundance of MAP kinases of M(r) 44,000, 57,000, and 63,000, suggesting that elevated PKC-beta levels led to activation of the smaller three MAP and MBP kinases. Activation of p57 MAP kinase in each PKC-beta transfectant was demonstrated by immunoprecipitation with an antiphosphotyrosine monoclonal antibody and then by assay of the immunoprecipitates by in-gel kinase assay on MBP. p57 MAP kinase was distinguished from the M(r) 54,000 stress-activated protein kinases, which migrated more rapidly on SDS gels and could be detected by in-gel kinase assay on MBP only after cellular stress. Thus, expression of elevated levels of PKC-beta 1 and PKC-beta 2 in differentiated HD3 colon carcinoma cells blocked their differentiation, enabled them to proliferate in response to basic FGF like undifferentiated cells, increased their growth rate in athymic mice, and activated several MBP kinases, among them, p57 MAP kinase.
Alternative Splicing↗
Genetic analysis of function and dysfunction in the central nervous system.
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Animals↗
Taking money from dentists is as easy as....
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Canada↗
Constitutional and somatic mutations in the WT1 gene in Wilms' tumor patients.
Wilms' tumor development, like most tumors, involves multiple genetic alterations affecting diverse genes. Only one of these has thus far been identified, the Wilms' tumor 1 (WT1) gene on 11p13, which functions as a tumor suppressor gene. We assessed the involvement of the WT1 gene constitutionally and somatically in 26 Wilms' tumor patients. Of these, the clinical data suggest a constitutional pre-disposition in 12 bilateral cases and 7 cases with early onset. We employed Southern blot analysis and PCR-based markers for analyses of somatic allelic losses in chromosome bands 11p13, 11p15 and 16q and screened for point mutations in exons 2-10 of the WT1 gene with denaturing gradient gel electrophoresis (DGGE). Of the 12 cases with multiple tumors, 1 exhibited a constitutional 11p13 deletion and a somatic stop mutation in exon 4 of the WT1 gene and 2 harbored constitutional mutations in the WT1 gene: a pre-mature stop codon in exon 6 in a boy with bilateral cryptorchidism and bilateral Wilms' tumors and an intragenic deletion in a girl with bilateral WT. Three additional bilateral tumors displayed WT1 rearrangements or allelic losses with 11p13 markers. Four of 7 patients with an early onset of unilateral tumor had losses of 11p13, though no WT1 mutations were detected. Two of the remaining cases that did not show any somatic or constitutional 11p13 alterations had Beckwith-Wiedemann syndrome, known to involve the 11p15 region.
Alleles↗
Analysis of microsatellite repeats in pediatric brain tumors.
Tumorigenesis has been shown to proceed through a series of genetic alterations involving protooncogenes and tumor suppressor genes. However, investigation of genomic instability of microsatellites has disclosed a new mechanism for human carcinogenesis, which is involved not only in hereditary nonpolyposis colon cancer (HNPCC) but also in a number of other malignancies. To determine whether microsatellite instability is involved in pediatric brain tumors, we screened 15 such tumors using seven microsatellite marker loci on six chromosomes 4, 5, 9p, 9q, 11, 14, and 17. Using the polymerase chain reaction method, DNA samples from the tumors and from normal peripheral blood leukocytes from each patient were compared for the allelic pattern produced at each locus. Our preliminary results indicate loss of heterozygosity at the fatty acid binding protein (FABP) locus, located on chromosomal arm 4q28-q31, the only trinucleotide repeat in the panel of markers used, for 3 of 15 cases, suggesting the presence of previously unidentified sequences relevant to brain tumorigenesis at or in the vicinity of this locus. We did not observe any microsatellite instability in these samples, indicating that the mechanisms operating in HNPCC are not active in this subset of pediatric brain tumors.
Brain Neoplasms↗
Chronic fluoxetine or desmethylimipramine treatment alters 5-HT2 receptor mediated c-fos gene expression.
These studies examined the effects of a 21-day treatment regime with either the tricyclic antidepressant, desmethylimipramine (DMI), or the selective 5-HT uptake inhibitor, fluoxetine, on 5-HT2 receptors in rat brain, as assessed by selective agonist-mediated c-fos gene expression. Chronic, but not acute, treatment with fluoxetine (10 mg/kg, i.p. for 21 days) resulted in supersensitization of the response to an acute challenge (4 mg/kg, i.p.) with the selective 5-HT2 agonist, 2,5-dimethoxy-4-iodoamphetamine (DOI), both in frontal cortex and in hippocampus. Chronic treatment with DMI (10 mg/kg, i.p. for 21 days) resulted in a significant desensitization of the response to DOI. These findings are discussed in relation to the possible modes of action of these two clinically useful agents.
Amphetamines↗
The compromise and the afterthought. Medicare and Medicaid after 30 years.
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Anniversaries and Special Events↗
Colon goblet cells lose proliferative response to TGF alpha as they differentiate.
Two cell line models for colon goblet cells expressed 6- to 14-fold elevated levels of the EGF receptor, 3- to 5-fold levels of TGF alpha and 11- to 15-fold levels of amphiregulin compared with 2 cell lines which model colon enterocytic differentiation, suggesting a role for the EGF receptor and its ligands in goblet cell growth control. Two HT29 colon carcinoma sublines were used to model normal goblet cells at different stages of maturation. TGF alpha induced a 2-fold increase in growth of the HD8 subline but inhibited the growth of the more differentiated HD6 subline by 40%. EGF receptors were activated in each line by ligand, but signal transduction varied sharply. Both MAP kinase isoforms, p44 and p42, were markedly activated in HD8 cells for at least 20 min, while only a marginal activation was seen in HD6 cells. In contrast, the more differentiated HD6 cells showed an increase in 105 kDa MBP kinase activity with EGF treatment, while HD8 cells displayed constitutively elevated levels of this kinase. Thus, activated EGF receptors initiated different signalling pathways in model cell lines for colon goblet cells at different stages of maturation. TGF alpha protein levels have been shown by other investigators to be restricted to the top of the cylinder-like colonic crypt, where cells terminally differentiate and cease division, an unexpected location for an epithelial cell mitogen. Our data with model cell lines imply that normal colon goblet cells lose proliferative response to TGF alpha as they differentiate and the elevated levels of TGF alpha at the top of the colonic crypt in vivo serve to inhibit goblet cell growth.
Calcium-Calmodulin-Dependent Protein Kinases↗
Welcome to year 83.
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Health Care Reform↗
Platelet-derived growth factor-B increases colon cancer cell growth in vivo by a paracrine effect.
PDGF-B released from colon tumor cells regulated tumor growth in athymic mice in a paracrine manner by inducing blood vessel formation. A positive correlation was found between expression of PDGF B-chain in cells grown in vitro and the number of factor VIII-positive blood vessels in tumors induced by three classes of colon carcinoma cell lines. Elevated expression of PDGF-B was also correlated with tumor size. Each cell line had the same mutations in the colon cancer genes APC, DCC, and p53 and had wild type c-K-ras genes (Huang et al. [1994] Oncogene, 9:3701-3706.) eliminating the possibility that any differences in tumor blood vessel formation were due to mutations and/or deletions in these genes. Colon carcinoma cells released biologically active PDGF capable of stimulating the growth of NIH3T3 cells, which was inhibited by neutralizing antisera to PDGF-AB chains. An inverse correlation was found between induction of factor VIII-positive blood vessels and expression of vascular endothelial growth factor (VEGF), while no correlation was seen with expression of either TGF alpha or k-FGF. Basic fibroblast growth factor (FGF) expression was not detected in these tumor cells. TGF beta 1 was capable of inducing PDGF-B expression in the undifferentiated U9 colon carcinoma cell line, but this sensitivity was not seen in differentiated cells. In contrast, TGF beta 1 inhibited VEGF expression in both undifferentiated cells and differentiated colon cancer cells. Thus, TGF beta 1 has two roles in the growth of undifferentiated U9 colon carcinoma cells in vivo: direct stimulation of cell proliferation as we have showed in earlier studies, and an increase in angiogenesis by inducing PDGF-B.
Animals↗