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Biomedical subjects

S A Berry

Publications and source records attributed to S A Berry.

At least 19 recordsLinked to original sources
PubMed2001

Paris-Trousseau syndrome platelets in a child with Jacobsen's syndrome.

The thrombocytopenia in an infant with clinical features of Jacobsen's syndrome characterized by multiple congenital anomalies, cardiac defects, psychomotor retardation, and deletion of chromosome 11 at 11q23.3 has been evaluated. Study of his platelets in the electron microscope revealed giant alpha granules in his cells identical in appearance to those reported in the family with Paris-Trousseau syndrome. As a result, the Paris-Trousseau syndrome appears to be a variant of the Jacobsen syndrome, and the thrombocytopenia observed in all cases of chromosome 11q23.3 deletion due to dysmegakaryopoieses. Giant alpha granules are frequently observed in normal platelets during long-term storage and may form in Jacobsen and Paris-Trousseau platelets during prolonged residence in the bone marrow.

Abnormalities, Multiple↗
PubMed2001

Metabolic effects of rexinoids: tissue-specific regulation of lipoprotein lipase activity.

Hypertriglyceridemia is a frequent complication accompanying the treatment of patients with either retinoids or rexinoids, [retinoid X receptor (RXR)-selective retinoids]. To investigate the cellular and molecular basis for this observation, we have studied the effects of rexinoids on triglyceride metabolism in both normal and diabetic rodents. Administration of a rexinoid such as LG100268 (LG268) to normal or diabetic rats results in a rapid increase in serum triglyceride levels. LG268 has no effect on hepatic triglyceride production but suppresses post-heparin plasma lipoprotein lipase (LPL) activity suggesting that the hypertriglyceridemia results from diminished peripheral processing of plasma very low density lipoproteins particles. Treatment of diabetic rats with rexinoids suppresses skeletal and cardiac muscle but not adipose tissue LPL activity. This effect is independent of changes in LPL mRNA. In C2C12 myocytes, LG268 suppresses the level of cell surface (i.e., heparin-releasable) LPL activity without altering LPL mRNA. This effect is very rapid (t(1/2) = 2 h) and is blocked by the transcriptional inhibitor actinomycin D. These studies demonstrate that RXR ligands can have dramatic effects on the post-translational processing of LPL and suggest that skeletal muscle may be an important target of rexinoid action. In addition, these data underscore that the metabolic consequences of RXR activation are distinct from either retinoic acid receptor or peroxisome proliferator-activated receptor activation.

Animals↗
PubMed2000

Yin-yang 1 and glucocorticoid receptor participate in the Stat5-mediated growth hormone response of the serine protease inhibitor 2.1 gene.

A growth hormone-inducible nuclear factor complex (GHINF), affinity-purified using the growth hormone response element (GHRE) from the promoter of rat serine protease inhibitor 2.1, was found to contain Stat5a and -5b, as well as additional components. The ubiquitous transcription factor yin-yang 1 (YY1) is present in GHINF. An antibody to YY1 inhibited the formation of the GHINF.GHRE complex in an electrophoretic mobility shift assay. Furthermore, Stat5 was co-immunoprecipitated from rat hepatic nuclear extracts with antibodies to YY1. An examination of the GHRE shows that, in addition to two gamma-activated sites, it contains a putative YY1 binding site between the two gamma-activated sites, overlapping them both. Mutation of this putative YY1 site results in a decrease of GHINF.GHRE complex formation in an electrophoretic mobility shift assay and a corresponding decrease in growth hormone (GH) response in functional assays. The glucocorticoid receptor was also present in GHINF, and Stat5 co-immunoprecipitates with glucocorticoid receptor in hepatic nuclear extracts from rats treated with GH. GH activation of serine protease inhibitor 2.1 requires the unique sequence of the GHRE encompassing the recognition sites of several transcription factors, and the interaction of these factors enhances the assembly of the transcription complex.

Animals↗
PubMed2000

Inhibition of growth hormone action in models of inflammation.

Growth hormone (GH) action is attenuated during the hepatic acute-phase response (APR). To understand this attenuation, we asked whether GH and cytokine-signaling pathways intersect during an APR. In hypophysectomized rats treated with lipopolysaccharide (LPS), accumulation of activated signal transducer and transcription activator 5 (Stat5) in hepatic nuclei in response to GH and its binding to a GH response element (GHRE) from the serine protease inhibitor (Spi) 2.1 promoter are diminished in a time-dependent manner. Similarly, accumulation of activated Stat3 in hepatic nuclei in response to LPS and its binding to a high-affinity sis-inducible element (SIE) are also diminished by the simultaneous administration of GH. In functional assays with primary hepatocytes, LPS-stimulated monocyte-conditioned medium (MoCM) inhibits the GH response of Stat5-dependent Spi 2.1 reporter activity but induces Stat3-dependent Spi 2.2 reporter activity, as in an APR. Similar results are obtained when hepatocytes are treated with either tumor necrosis factor-alpha (TNF-alpha) or interleukin (IL)-1beta. TNF-alpha, IL-1beta, and IL-6 also inhibit GH-induced Spi 2.1 mRNA expression in hepatocytes. Thus inhibition of the GH signaling pathway during an APR results in reduced expression of GH-responsive genes.

Acute-Phase Reaction↗
PubMed2000

Growth hormone action in hypothyroid infant rats.

In neonatal rats, expression of serine protease inhibitors 2.1 and 2.3 mRNA peaks on d 2 of life and declines shortly thereafter, coinciding with levels of circulating GH. To evaluate the role of GH in this increase and to test the hypothesis that GH is active in perinatal life, we studied GH action in a model of GH deficiency. Maternal/neonatal hypothyroidism with consequent GH deficiency was induced by methimazole administration to pregnant dams. The resultant hypothyroid neonates were treated at d 2 or 7 of age with GH or saline for 1 h before exsanguination. In d-7 neonates, but not at d 2, GH administration resulted in significant serine protease inhibitors 2.1 and 2.3 mRNA induction. This treatment did not result in increased production of either GH receptor or IGF-I mRNA at either age. There was a slight GH-independent increase in GH receptor and IGF-I mRNA expression by d 7. Electromobility shift assays using hepatic nuclear extracts from these neonates and the GH response element from the serine protease inhibitor 2.1 promoter showed signal transducer and activator of transcription 5 (Stat5) binding in response to GH in extracts from d-7 rats only. Immunoblots of these extracts showed twice as much Stat5 in the nuclei of d-7 treated neonates compared with d-2 treated neonates. We conclude that there is apparent insensitivity to GH treatment in d-2 neonates that remits by d 7 and that this remission correlates with increased abundance of GH receptor and Stat5.

Animals↗
PubMed2000

Hepatic growth hormone signaling in the late gestation fetal rat.

The role of GH in the developing fetus is poorly understood. Several studies have demonstrated a limited role for GH in late fetal life. In fact, few data are available regarding GH signal transduction in the late gestation fetus. We therefore focused on a comparison of hepatic GH signaling in near-term fetal rats [embryonic day 19 (E19)] and adult rats using a combination of in vitro studies employing hepatocytes in primary culture and in vivo studies. We found that GH receptor (GHr) binding was comparable in fetal liver and adult liver. The long isoform of the GHr underwent tyrosine phosphorylation in response to GH stimulation of E19 fetal hepatocytes in a manner similar to that seen in cultured adult hepatocytes. Furthermore, downstream signaling via the Janus kinase-2 tyrosine kinase, STAT1 (signal transducer and activator of transcription), and STAT5 was also intact in both, as demonstrated by the tyrosine phosphorylation of these signaling proteins. To confirm the relevance of these findings to the in vivo situation, GH was directly administered by ip injection to E 19 fetal and adult rats. In both cases, tyrosine phosphorylation of STAT5 was markedly and rapidly induced. Finally, transfection of E19 fetal hepatocytes with GH-responsive reporter elements [Spi2.1(-275/+85)-CAT and 8xGHRE-TKCAT] demonstrated intact transcriptional regulation. Our data indicate that GHr abundance and activity as well as downstream GH signaling are similar in the late gestation fetal rat and in the adult and that these mechanisms appear capable of supporting physiological GH functions in the developing liver.

Aging↗
PubMed1999

Olanzapine safety and efficacy in patients with borderline personality disorder and comorbid dysthymia.

BACKGROUND: Numerous medications have been tested in patients with borderline personality disorder (BPD) and/or schizotypal personality disorder (SPD). Although many of the medications tested have been demonstrated to be useful, no clear main treatment for BPD has emerged. Despite the efficacy of some of the medicines, acceptability and side effects have proven to be barriers to the use of medication. Therefore, an open-label olanzapine trial utilizing objective ratings was performed. METHODS: Patients suffering from BPD and dysthymia were included in an 8-week, open-label study of olanzapine monotherapy. The first 4 weeks of the trial allowed for flexible dosing; during the last 4 weeks, olanzapine dose was held constant. Patients were rated on Hopkins Symptoms Checklist 90 (SCL-90), Brief Psychiatric Rating Scale (BPRS), Global Assessment of Function (GAF), Barratt Impulsivity Scale (BIS 11), and Buss-Durkee Hostility Inventory (BDHI). RESULTS: Eleven patients completed at least 2 weeks; nine of the patients finished the entire trial. There was a robust and statistically significant reduction in the five global ratings. Within the global ratings, symptoms of psychoticism, depression, interpersonal sensitivity, and anger were among the symptoms to be reduced. No movement disorder symptoms were noted for any of the patients. CONCLUSIONS: In this open-label pilot study, patients treated with olanzapine showed statistically significant reduction in self-rated and clinician-rated scales. Symptoms associated with BPD and dysthymia were among those to be substantially reduced. Further studies to explore olanzapine's efficacy versus placebo, as well as comparison to other potential treatments for BPD, are important next steps.

Adult↗
PubMed1999

Definition of a high affinity growth hormone DNA response element.

Rat liver contains a growth hormone inducible nuclear factor complex, GHINF, that binds to the growth hormone response element (GHRE) of the serine protease inhibitor (Spi) 2.1 gene. GHINF contains Stat5 and binds to paired gamma-activated sites (GAS) within the GHRE, but poorly to either one alone. By analysis of the sequence of various GAS sites that bind the GHINF complex (based on the GHRE 3' GAS motif), we demonstrate that a 13 nucleotide high affinity DNA recognition sequence (haGHRE) for GHINF complex binding is (ANTTC)C/T(N)A/G(GAA)A/T(A)/T. One copy of the haGHRE will replace the requirement for two GAS elements present in the wild type promoter in supporting a GH response in primary hepatocyte culture. Mutation of the native Spi 2.1 from a paired GAS site to a single haGHRE does not appreciably change its affinity for binding to the GHINF complex, nor does it alter its sensitivity to GH concentration.

Animals↗
PubMed1999

Clozapine and other 5-hydroxytryptamine-2A receptor antagonists alter the subcellular distribution of 5-hydroxytryptamine-2A receptors in vitro and in vivo.

In this study, we demonstrate that clozapine and other atypical antipsychotic drugs induce a paradoxical internalization of 5-hydroxytryptamine-2A receptors in vitro and a redistribution of 5-hydroxytryptamine-2A receptors in vivo. We discovered that clozapine, olanzapine, risperidone and the putative atypical antipsychotic drug MDL 100,907 all induced 5-hydroxytryptamine-2A receptor internalization in fibroblasts stably expressing the 5-hydroxytryptamine-2A receptor in vitro. Two 5-hydroxytryptamine-2A antagonists (mianserin and ritanserin), which have been demonstrated to reduce negative symptoms in schizophrenia, also caused 5-hydroxytryptamine-2A receptor internalization. Four different drugs, each devoid of 5-hydroxytryptamine-2A antagonist activity, had no effect on the subcellular distribution of 5-hydroxytryptamine-2A receptors in vitro. Treatment of rats for seven days with clozapine induced an increase in intracellular 5-hydroxytryptamine-2A receptor-like immunoreactivity in pyramidal neurons, while causing a decrease in labeling of apical dendrites in the medial prefrontal cortex. This redistribution of 5-hydroxytryptamine-2A receptors in pyramidal neurons was also seen when rats were chronically treated with another atypical antipsychotic drug, olanzapine. The typical antipsychotic drug haloperidol, however, did not induce a redistribution of 5-hydroxytryptamine-2A receptors in pyramidal neurons in the medial prefrontal cortex. Taken together, these results demonstrate that several atypical antipsychotic drugs with high 5-hydroxytryptamine-2A receptor affinities induce a redistribution of 5-hydroxytryptamine-2A receptors both in vivo and in vitro. It is conceivable that the loss of 5-hydroxytryptamine-2A receptors from the apical dendrites of pyramidal neurons is important for the beneficial effects of atypical antipsychotic drugs and other 5-hydroxytryptamine-2A antagonists in schizophrenia.

3T3 Cells↗
PubMed1999

Increased placental iron regulatory protein-1 expression in diabetic pregnancies complicated by fetal iron deficiency.

Placental transferrin receptor (TfR) protein expression is increased in diabetic pregnancies that are complicated by low fetal iron stores, suggesting regulation of placental iron transport by fetoplacental iron status. In cell culture, iron homeostasis is regulated by coordinate stabilization of TfR mRNA and translation inactivation of ferritin mRNA by iron regulatory proteins (IRP-1 and -2) which bind to iron-responsive elements (IREs) on the respective mRNAs. Concentrations of IRP-1, IRP-2 and TfR mRNA were measured in 10 placentae obtained from diabetic and non-diabetic human pregnancies with a wide range of fetoplacental iron status. IRP-1 activity was present in human placenta and correlated closely with TfR mRNA concentration (r=0.82; P=0.007). IRP-2 activity and protein were not detected. In a second experiment, placentae were collected from 12 diabetic pregnancies, six with low fetal cord serum ferritin and placental non-heme iron concentrations, and six with normal iron status. IRP-1 activity and TfR Bmax for diferric transferrin were greater in the iron-deficient group (P<0.05). IRP-1 activity correlated inversely with cord serum ferritin (r=0.75; P<0.01) and placental non-heme iron (r=0.61; P=0.05) concentration. Placental IRP-1 activity is directly related to TfR mRNA concentration and is more highly expressed in iron-deficient placentae. The study provides direct in vivo evidence for IRP regulation of TfR expression in the human placenta.

Animals↗
PubMed1999

CBFA1 mutation analysis and functional correlation with phenotypic variability in cleidocranial dysplasia.

Cleidocranial dysplasia (CCD) is a dominantly inherited skeletal dysplasia caused by mutations in the osteoblast-specific transcription factor CBFA1. To correlate CBFA1 mutations in different functional domains with the CCD clinical spectrum, we studied 26 independent cases of CCD and a total of 16 new mutations were identified in 17 families. The majority of mutations were de novo missense mutations that affected conserved residues in the runt domain and completely abolished both DNA binding and transactivation of a reporter gene. These, and mutations which result in premature termination in the runt domain, produced a classic CCD phenotype by abolishing transactivation of the mutant protein with consequent haploinsufficiency. We further identified three putative hypomorphic mutations (R391X, T200A and 90insC) which result in a clinical spectrum including classic and mild CCD, as well as an isolated dental phenotype characterized by delayed eruption of permanent teeth. Functional studies show that two of the three mutations were hypomorphic in nature and two were associated with significant intrafamilial variable expressivity, including isolated dental anomalies without the skeletal features of CCD. Together these data show that variable loss of function due to alterations in the runt and PST domains of CBFA1 may give rise to clinical variability, including classic CCD, mild CCD and isolated primary dental anomalies.

Animals↗
PubMed1999

Regulation of Spi 2.1 and 2.2 gene expression after turpentine inflammation: discordant responses to IL-6.

The rat serine protease inhibitor (Spi) 2 gene family includes both positive (Spi 2.2) and negative (Spi 2.1) acute phase reactants, facilitating modeling of regulation of hepatic acute phase response (APR). To examine the role of signal transducer and activation of transcription (STAT) proteins in the divergent regulation of these model genes after induction of APR, we evaluated the proximal promoters of the genes, focusing on STAT binding sites contained in these promoter elements. Induction of APR by turpentine injection includes activation of a STAT3 complex that can bind to a gamma-activated sequence (GAS) in the Spi 2.2 gene promoter, although the Spi 2.2 GAS site can bind STAT1 or STAT5 as well. To create an in vitro model of APR, primary hepatocytes were treated with combinations of cytokines and hormones to mimic the hormonal milieu of the whole animal after APR induction. Incubation of primary rat hepatocytes with interleukin (IL)-6, a critical APR cytokine, leads to activation of STAT3 and a 28-fold induction of a chloramphenicol acetyltransferase reporter construct containing the -319 to +85 region of the Spi 2.2 promoter. This suggests the turpentine-induced increase of Spi 2.2 is mediated primarily by IL-6. In contrast, although turpentine treatment reduces Spi 2.1 mRNA in vivo and IL-6 does not increase Spi 2.1 mRNA in primary rat hepatocytes, treatment of hepatocytes with IL-6 results in a 5. 4-fold induction of Spi 2.1 promoter activity mediated through the paired GAS elements in this promoter. Differential regulation of Spi 2.1 and 2.2 genes is due in part to differences in the promoters of these genes at the GAS sites. IL-6 alone fails to reproduce the pattern of rat Spi 2 gene expression that results from turpentine-induced inflammation.

Acute-Phase Reaction↗
PubMed1998

Serotonergic antagonist effects on trafficking of serotonin 5-HT2A receptors in vitro and in vivo.

The mechanism by which antagonists down-regulate 5-HT2A receptors in unknown. We here report that a variety of 5-HT2A antagonists induce a change in the subcellular distribution of 5-HT2A receptors both in vitro and in vivo. In a stably transfected NIH 3T3 cell-line, brief exposure to 1 muM clozapine caused a 2.5-fold increase in intracellular 5-HT2A-like immunoreactivity, as measured by confocal microscopy. Confirmatory studies utilizing a biotin-trap technique, demonstrated that the increase in intracellular immunoreactivity results from internalization of receptor from the cell surface. Exposure of transfected cells to other 5-HT2A receptor antagonists produced similar increases in intracellular 5-HT2A-like immunoreactivity. In vivo administration of clozapine (20 mg/kg, sc, X 7 days) caused a greater than twofold increase in intracellular immunoreactivity in cell bodies of cortical pyramidal neurons. Additionally, chronic clozapine administration was associated with decrease in labeling of apical dendrites on pyramidal cells. These results show that clozapine causes a change in subcellular distribution of 5-HT2A receptors in vitro and in vivo.

3T3 Cells↗
PubMed1998

Klippel-Trenaunay syndrome.

Patients with Klippel-Trenaunay (KT) syndrome have a complex constellation of anomalies that includes cutaneous capillary malformation (usually on an affected limb), abnormal development of the deep and superficial veins, and limb asymmetry, usually enlargement. Mixed vascular malformations may be present and include capillary, venous, arterial, and lymphatic systems. The records of 79 patients referred for vascular anomalies were reviewed and 49 were found to have the three "cardinal" anomalies of KT syndrome. Twenty-six females and 23 males had 46 affected legs (27 right legs), 23 affected arms (15 right), 21 affected trunks, and 10 affected heads. Thirty-six had only one affected quadrant, 8 had two, and 5 had three or more. Although 40 patients had increased limb girth, measurable length discrepancy was noted in only 17 individuals. Patients were evaluated using a noninvasive imaging strategy including color duplex ultrasonography, MRI, lymphoscintigraphy, and plain radiographs. Treatment included compression, pulsed-dye laser treatment, reduction of arteriovenous malformations, and orthopedic procedures for overgrowth. All KT cases in this series occurred sporadically. We speculate that KT syndromes may be due to a somatic mutation for a factor critical to vasculogenesis and angiogenesis in embryonic development.

Adolescent↗
PubMed1998

Serotonin 5-HT2A receptors: molecular biology and mechanisms of regulation.

Serotonin 5-HT2A receptors are essential for a large number of physiological functions in the central nervous system and periphery. This review article summarizes our current knowledge of the molecular biology and mechanisms of regulation of 5-HT2A receptors. The mode of drug binding using data derived from molecular modeling and site-directed mutagenesis is described. The cellular and subcellular localization of 5-HT2A receptors is described, and the concentration of 5-HT2A receptors on apical dendrites of pyramidal neurons is emphasized. Various modes of regulation of 5-HT2A receptors are also summarized, including transcriptional, post-translational and mRNA editing processes. Finally, an integrated model of 5-HT2A receptor regulation that involves various protein kinases (protein kinase C, G-protein receptor kinases), arrestins, clathrin-coated vesicles, endosomes and lysosomes. The relevance of these pathways for antidepressant and antipsychotic drug actions is emphasized.

Animals↗
PubMed1997

Mosaicism for deletion 1p36.33 in a patient with obesity and hyperphagia.

We report on a 4-year-old girl with obesity and hyperphagia whose peripheral blood cytogenetic analysis showed mosaicism for a deletion of band 1p36.33. Terminal 1p deletions are rarely reported and this patient represents the first identified case of mosaicism. Given the subtlety of the cytogenetic abnormality and the possibility of mosaicism, the incidence of such deletions has probably been underestimated. While a characteristic phenotype associated with this karyotypic abnormality was described recently, the present report highlights the additional clinical findings of obesity and hyperphagia and the overlap of manifestations with Prader-Willi syndrome.

Child, Preschool↗
PubMed1997

Brain anomalies, retardation of mentality and growth, ectodermal dysplasia, skeletal malformations, Hirschsprung disease, ear deformity and deafness, eye hypoplasia, cleft palate, cryptorchidism, and kidney dysplasia/hypoplasia (BRESEK/BRESHECK): new X-linked syndrome?

Two half brothers (maternally related) had a similar syndrome of microhydrocephaly in both brothers and dilatation of the spinal canal with fusion of thalami in one brother. Primordial growth delay was noted in both brothers, with severe mental retardation in the surviving brother. Both had ectodermal dysplasia with scaling, hyperkeratosis, and generalized alopecia, but normal sweat and sebaceous glands. Skeletal anomalies included hemivertebrae with abnormal segmentation in one and scoliosis with polydactyly in the other. Ears were apparently low set, large, and protruding, with mixed hearing loss in the brother who survived. Eye anomalies included maldevelopment of one eye in Patient 1 and small optic nerves more noticeable on one side in Patient 2. Both had cryptorchidism and dysplastic/hypoplastic kidneys of varying severity that resulted in the early postnatal death of one sib. Manifestations present in only one or the other sib included submucous cleft palate, aganglionosis of the rectum and colon, agenesis of one testicle, and single umbilical artery. This syndrome has not been described previously and may be due to an X-linked mutation. The acronym BRESEK reflects the common findings, whereas BRESHECK denotes all manifestations of both patients: brain, retardation, ectodermal dysplasia, skeletal deformities, Hirschsprung disease, ear/eye anomalies, cleft palate/cryptorchidism, and kidney dysplasia/hypoplasia. In addition to an X-linked mutation, a contiguous gene deletion or maternal mosaicism of an autosomal dominant gene must be considered.

Abnormalities, Multiple↗