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B Harris

Publications and source records attributed to B Harris.

At least 37 records · Page 2Linked to original sources
PubMed1997

Cell fate specification and symmetrical/asymmetrical divisions in the developing cerebral cortex.

Two different modes of cell division are adopted by progenitor cells to generate the neurons and glia of the cerebral cortex: they either divide symmetrically to generate other progenitors or a pair of postmitotic cells or divide asymmetrically to generate both a progenitor and a postmitotic cell. In this study we used a lineage marker, the BAG retrovirus, in embryonic day 16 rats in combination with bromodeoxyuridine (BrdU) to identify patterns of cell generation in the cerebral cortex, and investigated the relationship between the phenotype of cells and the history of their lineages. The location, phenotype and birth order of clonally related cells were studied in the subsequent 3 weeks. Only pyramidal neurons and/or astrocytes formed discrete clusters in which several generations of family members were present, whereas nonpyramidal neurons were found exclusively in pairs or as single cells. Analysis of BrdU levels in these cells showed that nonpyramidal neurons were originally part of larger clones and were found dispersed in the neocortex because of tangential migration of their progenitors, dispersion of postmitotic cells, or death of clonal relatives. These results suggest that both symmetrical and asymmetrical division can be adopted by progenitor cells to generate cortical neurons and glial cells and that cell extrinsic events contribute to the isolation of nonpyramidal neurons.

Animals↗
PubMed1997

Ricin fusion toxin targeted to the human granulocyte-macrophage colony stimulating factor receptor is selectively toxic to acute myeloid leukemia cells.

Treatment failure of patients with acute myelogenous leukemia (AML) is frequently due to the development of multidrug resistance phenotype blasts. We have expressed a fusion protein consisting of human granulocyte-macrophage colony stimulating factor (GMCSF) fused to the N-terminus of a lectin-deficient ricin toxin B chain (RTB) in Spodoptera frugiperda insect cells. The fusion protein was purified by immunoaffinity chromatography and reassociated with chemically deglycosylated ricin toxin A chain (RTA). The resulting fusion toxin was found to react with antibodies to GMCSF, RTB and RTA and had the predicted molecular mass of 80 kDa. GMCSF-ricin bound poorly to asialofetuin (Kd = 10(6) M-1) and receptor negative cells indicating loss of lectin activity, but bound strongly to GMCSF receptor positive HL60 cells. Ligand displacement assays showed fusion toxin affinity 2.6-fold less than native GMCSF. Selective inhibition of protein synthesis was observed on receptor positive cells. Induction of apoptosis was also observed on receptor positive cells. Cells expressing multidrug resistance gene products (P-gp, Bcl2 and BclXL) were also sensitive to fusion toxin. These results suggest that GMCSF-ricin deserves further preclinical development.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1997

Magic--'A'.

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Australia↗
PubMed1997

Harlequin ichthyosis (ichq): a juvenile lethal mouse mutation with ichthyosiform dermatitis.

The harlequin ichthyosis (ichq) mouse mutation arose spontaneously in 1989 in a colony of BALB/cJ mice at The Jackson Laboratory. Affected mice developed thick skin due to formation of compact, orthokeratotic scales that fractured over articular surfaces, secondary to bending. Harlequin ichthyosis mice on the inbred BALB/cJ background died between 9 and 12 days of age. Onset of the clinical phenotype corresponded with emergence of hair fibers from follicles at 5 days of age. There was marked proliferation of the root sheaths of anagen hair follicles, limited to the region within the dermis. Sebaceous glands were present but small compared with those of littermate controls. Emerging hair fibers were surrounded by a thick, compact sheath of cornified cells. Mutant skin contained large mitochondria with lamellar-shaped, electron-dense structures at the ultrastructural level. Keratohyalin granules were smaller and less pleomorphic than those in control mice. Lamellar bodies were not evident in either mutant or littermate control mice. Using a panel of antibodies to evaluate changes in keratinocyte differentiation, mouse-specific keratin 6 was overexpressed in the suprabasilar, hyperplastic epidermis. Loricrin expression, within the cytoplasm of cells in the stratum granulosum, decreased rapidly postmortem, unlike that in normal mice where it was stable for over 24 hours postmortem. Filaggrin expression, within granules of cells in the stratum granulosum, was prominent, corresponding to hypergranulosis evident by light microscopy in mutant mouse skin. Skin grafts from harlequin ichthyosis mice grafted onto immunodeficient nude mice maintained the phenotype for the 10-week observation period. The mutant gene locus mapped to the proximal end of mouse chromosome 19 and is inherited as a fully penetrant autosomal recessive gene. The harlequin ichthyosis mouse mutation is very similar to human type 2 harlequin ichthyosis for which it may be a good model.

Animals↗
PubMed1997

Clinical aspects of recurrent postpartum thyroiditis.

BACKGROUND: Postpartum thyroiditis (PPT), characterized by transient hyperthyroidism and transient hypothyroidism, occurs in 5-9% of women. It is accompanied by the presence of circulating antithyroid peroxidase antibodies (TPOAb) which have been associated with an increase in depressive symptomatology compared with TPOAb-negative women. AIM: To assess the frequency and nature of the syndrome in patients studied in detail after more than one pregnancy, as there are only sparse data on recurrence of PPT. METHOD: Fifty-four patients were identified who had participated in at least two of three detailed postpartum studies of thyroid and psychiatric function during the past 12 years in the Caerphilly and Cardiff regions of South Wales. They included two women who had had three pregnancies. All patients had been followed monthly postpartum for at least six months, and 44 had been followed for 12 months. RESULTS: Of the 13 patients who developed PPT after their first pregnancy, nine had a recurrence of dysfunction after a further pregnancy and four remained TPOAb positive. Of the 24 women who were euthyroid anti-TPO positive after the first pregnancy, six developed thyroid dysfunction after a subsequent delivery, 14 remained antibody positive and euthyroid, while four underwent seroconversion and were antibody negative. The control group of 17 women were antibody negative after the first pregnancy; 16 remained negative after a further pregnancy and one became anti-TPO positive. The severity of PPT was slightly, but not significantly worse after the second recorded pregnancy (67% hypothyroid versus 44% hypothyroid). Neither the maximum anti-TPO titre following the first pregnancy, nor the rise in titre during this period were predictive of outcome after a subsequent pregnancy. Data from 26 women showed that recurrent depression was seen in 15.4%; a further six were depressed after the first pregnancy only, and two during a further postpartum period. CONCLUSION: There was a 70% chance of developing recurrent PPT after a first attack, and a 25% risk even in women who were only anti-TPO positive without thyroid dysfunction during the first postpartum period. The recurrence of postpartum depression was not related to thyroid function. Patients noted to have thyroid dysfunction or just to be euthyroid but anti-TPO positive after pregnancy should be assessed carefully after a subsequent pregnancy.

Autoantibodies↗
PubMed1997

Fatal Erysipelothrix rhusiopathiae septicemia in a captive Pacific white-sided dolphin (Lagenorhyncus obliquidens).

One male of a group of seven Pacific white-sided dolphins (Lagenorhynchus obliquidens) died after a brief period of nonspecific clinical signs. Four beluga whales (Delphinapterus leucas) and four harbor seals (Phoca vitulina) were managed in the same water system. Gross examination of the dolphin revealed only moderately enlarged mesenteric lymph nodes. Histopathology revealed small to massive numbers of gram-positive bacilli, usually intravascular, in all tissues. Bacteria were both extracellular and present in macrophages, monocytes, and neutrophils. Aerobic bacterial culture of lung, liver, kidney, and spleen yielded pure cultures of Erysipelothrix rhusiopathiae. Based on clinical course, histopathology, and bacteriology, a diagnosis of acute erysipelas septicemia was made. None of the other cetaceans or pinnipeds exhibited clinical signs.

Animals↗
PubMed1996

Preproricin expressed in Nicotiana tabacum cells in vitro is fully processed and biologically active.

Ricin, the highly toxic glycoprotein expressed in the endosperm of castor seeds, is composed of a galactose-binding lectin B chain (RTB) disulfide linked to a RNA N-glycosidase A chain (RTA). Chemically modified ricin has been conjugated to monoclonal antibodies and used for targeted therapy of cancer and autoimmune diseases. Replacement of chemically coupled molecules with a genetically engineered targeted ricin would improve homogeneity and yield and permit structural changes in the fusion toxin to be introduced readily by oligonucleotide-directed mutagenesis. Previous methods of expression of ricin fusion proteins have been limited to expression of RTA or RTB moieties alone or expression of incompletely processed toxin in Xenopus laevis oocytes. In the present study, we introduced the cDNA encoding preproricin into cultured tobacco cells via Agrobacterium tumefaciens-mediated gene transfer. Yields of ricin in soluble cell extracts were 1 microg/g in cells or, approximately, 0.1% of the total soluble protein. The ricin was partially purified by P2 monoclonal antibody anti-RTB affinity chromatography. The RTA and RTB immunoreactive material migrated on SDS-PAGE at 65 kDa under nonreducing conditions and at 32-35 kDa under reducing conditions. The tobacco ricin bound to immobilized asialofetuin as avidly as castor bean ricin, suggesting intact sugar binding. Tobacco ricin inhibited rabbit reticulocyte lysate protein translation similar to castor bean ricin (IC50 of 3 x 10(-12) M for tobacco ricin and 1 x 10(-11) M for castor bean ricin). The human cutaneous T cell lymphoma cell line HUT102 showed similar sensitivity to tobacco ricin when compared to castor bean ricin (IC50 = 9 x 10(-13) and 2 x 10(-12) M, respectively). The efficiency of gene transfer, reasonable levels of expression, and full post-translational processing indicate that this expression system is suitable for production of ricin fusion toxins for therapeutic applications.

Agrobacterium tumefaciens↗
PubMed1996

The clinical spectrum of postpartum thyroid disease.

The clinical and biochemical features of postpartum thyroid disease were analysed in 152 antithyroid peroxidase antibody-positive (anti-TPO+ve) women and compared with 239 anti-TPO-ve age-matched control postpartum women. All were assessed monthly for up to 12 months postpartum. Seventy three anti-TPO+ve women developed postpartum thyroiditis (PPT): 19.2% hyperthyroid alone, 49.3% hypothyroid alone, and 31.5% characterized by hyper- followed by hypothyroidism. None of the antibody-negative women developed any thyroid dysfunction. A significant increase in many of eleven symptoms of hypothyroidism and some of eight symptoms of hyperthyroidism compared to control women was observed in all anti-TPO+ve women, independent of thyroid status. This was particularly seen in women who later developed PPT when they were euthyroid, but was also observed in euthyroid anti-TPO+ve women who showed no decline of thyroid function during the postpartum period. Although PPT is usually transient, this condition, and the euthyroid antibody-positive state, may be associated with significant symptomatology, including an increased incidence of minor to moderate depression. Early recognition of this syndrome by antenatal screening of thyroid antibodies may contribute to improved management of women during the postpartum period.

Adult↗
PubMed1996

Cardiff puerperal mood and hormone study. III. Postnatal depression at 5 to 6 weeks postpartum, and its hormonal correlates across the peripartum period.

BACKGROUND: We assessed associations of mood at 5-6 weeks postpartum with peripartum saliva cortisol and progesterone profiles. METHOD: A prospective study involved 120 primiparous women free of major marital, socioeconomic and health problems, who collected saliva twice daily from 2 weeks before delivery to day 35 postpartum. This allowed intensive characterisation of cortisol and progesterone profiles. At the conclusion of the study, mood was assessed according to standard criteria. RESULTS: Seven women developed major depression according to DSM-III-R criteria. No associations emerged between progesterone and mood at 5 to 6 weeks. Lower levels of evening cortisol in the immediate peripartum period, were associated with postnatal depression. CONCLUSION: The study provides no support for the treatment strategy of progesterone augmentation following delivery, as a prophylactic against postnatal depression. The HPA axis and its associations with postnatal mood warrants further investigation.

Adolescent↗
PubMed1996

Aspects of perinatal psychiatric illness.

BACKGROUND: In view of the current changes in the National Health Service, it was considered an opportune time to review the literature on perinatal psychiatric illness. METHOD: A systematic review was undertaken of relevant articles on MEDLINE, ClinPsych and Excerpta Medica Psychiatry. RESULTS: Sixty-eight articles were used in the review. CONCLUSIONS: Developments in the field of perinatal psychiatry include a greater understanding of the nosology and aetiology of the conditions, the effect of maternal illness on the child, as well as transcultural factors. The perspective of the individual sufferer has been somewhat ignored. New treatments with both pharmacotherapy and hormones are emerging, but perhaps the greatest current challenge is to adapt our management strategies to community care.

Adult↗
PubMed1996

Preoperative endovascular embolization of craniospinal hemangioblastomas.

PURPOSE: To determine whether hemangioblastomas, highly vascular tumors requiring surgery that is potentially complicated by excessive bleeding, can be embolized safely by using interventional techniques that furnish a more avascular surgical field. METHODS: Nine hemangioblastomas involving either the cerebellum or the spinal cord were embolized preoperatively. In each case the feeding artery was selectively catheterized with a microcatheter and the hypervascular tumor nidus was devascularized with polyvinyl alcohol particles. RESULTS: Two patients who had undergone recent attempts as surgical resection at another institution had repeat surgery after endovascular embolization rendered the tumor nidus avascular. At surgery, the tumor was completely removed in one case and markedly debulked in the other. In all nine cases, blood loss after embolization was reported to be less than expected by experienced surgeons. In addition, manipulation and removal of the tumor was reported to be subjectively easier in these embolized tumors. The embolization procedure caused no permanent complications; however, one patient with a posterior fossa hemangioblastoma and hydrocephalus worsened clinically within 12 hours of embolization. This event was thought to be caused by obstructive hydrocephalus resulting from tumor swelling. Emergency craniotomy, ventricular decompression, and surgical resection of the tumor produced complete resolution of the signs and symptoms. CONCLUSIONS: Our results indicate that preoperative embolization of hemangioblastomas is a safe procedure that is useful in aiding surgical resection of these highly vascular tumors.

Adolescent↗
PubMed1995

Synthesis of novel imidazobenzodiazepines as probes of the pharmacophore for "diazepam-insensitive" GABAA receptors.

The syntheses of a series of novel imidazobenzodiazepines and their affinities for diazepam sensitive (DS) and diazepam insensitive (DI) GABAA receptors are described. Imidazobenzodiazepines belong to one of the very few chemical families which exhibit high to moderate potency for DI GABAA receptors. Although imidazobenzodiazepines such as Ro 15-4513, 20, are the most potent DI GABAA receptor ligands described to date, their selectivity for DI versus DS GABAA receptors is only marginal. Previous structure-activity relationship (SAR) studies of imidazobenzodiazepines have indicated that the 3- and 8-positions are critical for high-affinity binding to DI GABAA receptors (J. Med. Chem. 1993, 36, 479-490. J. Med. Chem. 1993, 36, 1001-1006. J. Med. Chem. 1993, 36, 1820-1830). In order to determine why the ester function is critical to high affinity at the DI site, we have synthesized several derivatives which have substituents other than an ester at the C(3) position including 3-alkyl-, 3-alkylketo-, 3-alkyl ether, and 3-dialkylamino-substituted imidazobenzodiazepines. The SAR analysis of these compounds when combined with that of several pyrazoloquinolinones indicates that interactions at H1 and L1 as well as interactions at H2 anti to the imidazole N(2) and at a lipophilic pocket (labeled LDi) about the 3-position are required in order for imidazobenzodiazepines to exhibit selectivity and high affinity for DI GABAA receptors. Furthermore, the imidazobenzodiazepines substituted with an electron-donating group (alkoxy function) at position 8 revealed that the change of the substituent at C(8) from an electron-withdrawing to a donating function did not substantially alter either ligand affinity or selectivity for DI GABAA receptors. Thus, a pharmacophore is proposed for DI GABAA receptor ligands, which is characterized by the requirement of a lipophilic pocket LDi about the C(3) position of imidazobenzodiazepines. Using this model, two pyrazoloquinolinone derivatives were designed and synthesized. Their affinities and selectivities for DI GABAA receptors are consistent with those predicted by the DI GABAA receptor pharmacophore. In addition, examination of the in vitro binding data of 3-alkyl ether analogs confirms that the anti conformation of the ester group at the C(3) position of imidazobenzodiazepines (Ro15-4513, 20 series) is preferred at both DI and DS GABAA receptors. This constitutes the first evidence (other than molecular modeling) to support the auxillary involvement of H2 at the DI site and is important with regard to the synthesis of other DI GABAA receptor selective ligands in the future.(ABSTRACT TRUNCATED AT 400 WORDS)

Affinity Labels↗