First report of Mycobacterium bovis in a muntjac deer.
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Animals↗
Biomedical subjects
A Harris
Publications and source records attributed to A Harris.
Cellular mechanisms of bone resorption in breast carcinoma.
The cellular mechanisms that account for the increase in osteoclast numbers and bone resorption in skeletal breast cancer metastasis are unclear. Osteoclasts are marrow-derived cells which form by fusion of mononuclear phagocyte precursors that circulate in the monocyte fraction. In this study we have determined whether circulating osteoclast precursors are increased in number or have an increased sensitivity to humoral factors for osteoclastogenesis in breast cancer patients with skeletal metastases (+/- hypercalcaemia) compared to patients with primary breast cancer and age-matched normal controls. Monocytes were isolated and cocultured with UMR 106 osteoblastic cells in the presence of 1,25 dihydroxyvitamin D3[1,25(OH)2D3] and human macrophage colony stimulating factor (M-CSF) on coverslips and dentine slices. Limiting dilution experiments showed that there was no increase in the number of circulating osteoclast precursors in breast cancer patients with skeletal metastases (+/- hypercalcaemia) compared to controls. Osteoclast precursors in these patients also did not exhibit increased sensitivity to 1,25(OH)2D3or M-CSF in terms of osteoclast formation. The addition of parathyroid hormone-related protein and interleukin-6 did not increase osteoclast formation. The addition of the supernatant of cultured breast cancer cell lines (MCF-7 and MDA-MB-435), however, significantly increased monocyte-osteoclast formation in a dose-dependent fashion. These results indicate that the increase in osteoclast formation in breast cancer is not due to an increase in the number/nature of circulating osteoclast precursors. They also suggest that tumour cells promote osteoclast formation in the bone microenvironment by secreting soluble osteoclastogenic factor(s).
Aged↗
An element in intron 1 of the CFTR gene augments intestinal expression in vivo.
The elements controlling the complex developmental and tissue-specific expression of the cystic fibrosis transmembrane conductance regulator (CFTR) gene lie outside the basal promoter region and have not been characterized. We previously identified a tissue-specific DNase I hypersensitive site (DHS) in intron 1 (185 + 10 kb) of the CFTR gene. Here we show that removal of the core element abolishes the activity of this DHS in transient transfection assays of reporter/enhancer gene constructs. We then compared expression from a 310 kb yeast artificial chromosome (YAC) that contains the entire CFTR gene with expression from the same YAC from which the DHS element had been deleted. Stable transfection of a human colon carcinoma cell line showed that transcription from the deleted YAC was reduced by approximately 60%. In transgenic mice, deletion of the intron 1 DHS had no effect on expression in the lung, but reduced expression in the intestine by approximately 60%. Thus, the regulatory element associated with the intron 1 DHS is tissue-specific and is required for normal CFTR expression levels in the intestinal epithelium in vivo.
Animals↗
Identification of MUC1 proteolytic cleavage sites in vivo.
Mucins are high molecular weight glycoproteins that provide a protective layer on epithelial surfaces and are involved in cell-cell interactions, signaling, and metastasis. The identification of several membrane-tethered mucins, including MUC1, MUC3, MUC4, and MUC12, has incited interest in the processing of these mucins and the mechanisms that govern their release from the cell surface. MUC1 consists of an extracellular subunit and a membrane-associated subunit. The two moieties are produced from a single precursor polypeptide by an early proteolytic cleavage event but remain associated throughout intracellular processing and transport to the cell surface. We identified the MUC1 proteolytic cleavage site and showed it to be identical in pancreas and colon cell lines and not to be influenced by the presence of heavily glycosylated tandem repeats. The MUC1 cleavage site shows homology with sequences in other cell-surface-associated proteins and may represent a common mechanism for processing of these molecules.
Amino Acid Sequence↗
Optical trirefringence in photonic crystal waveguides.
We demonstrate that 2D photonic crystals can possess optical trirefringence in which there are six field orientations for which linear incident light is not perturbed on reflection or transmission. Such a property is rigorously forbidden in homogeneous nonmagnetic dielectrics which can possess only optical birefringence. We experimentally demonstrate this phenomena in silicon-based mesostructures formed from photonic crystal waveguides embedded in a Fabry-Perot cavity. Multirefringence is controlled by the presence of submicron dielectric patterning and is well explained by an exact scattering matrix theory.
Journal Article↗
The sheep genome contributes to localization of control elements in a human gene with complex regulatory mechanisms.
Genes that show complex tissue-specific and temporal control by regulatory elements located outside their promoters present a considerable challenge to identify the sequences involved. The rapid accumulation of genomic sequence information for a number of species has enabled a comparative phylogenetic approach to find important regulatory elements. For some genes, which show a similar pattern of expression in humans and rodents, genomic sequence information for these two species may be sufficient. Others, such as the cystic fibrosis transmembrane conductance regulator (CFTR) gene, show significant divergence in expression patterns between mouse and human, necessitating phylogenetic approaches involving additional species. The ovine CFTR gene has a temporal and spatial expression pattern that is very similar to that of human CFTR. Comparative genomic sequence analysis of ovine and human CFTR identified high levels of homology between the core elements in several potential regulatory elements defined as DNase I hypersensitive sites in human CFTR. These data provide a case for the power of an artiodactyl genome to contribute to the understanding of human genetic disease.
Animals↗
Detector sensitivity influences blood flow sampling in scanning laser Doppler flowmetry.
PURPOSE: To establish the effect of photodiode sensitivity on the DC (brightness) value and the resultant blood flow measurements of retina and rim tissue using a scanning laser Doppler flowmeter (SLDF). METHODS: The sample consisted of one eye of each of 15 healthy subjects (mean age 27.8 +/- 6.1 years). Using the Heidelberg Retina Flowmeter (HRF), three 10-deg images of the superior temporal retina and three further images of the superior temporal rim were acquired for each of five DC bands: band 1: 30-70; band 2: 70-110; band 3: 110-150; band 4 150-190; band 5: 190-230. Retinal blood volume, flow and velocity were determined for each image using a 10 x 10 pixel square grid located at a predetermined location on the retina and rim for each subject. Following image acquisition, the DC values corresponding to each pre-assigned retinal or rim location were determined. The mean and standard deviation were determined for the blood flow parameters within each DC band for each subject in both locations. Analysis of variance was used to identify significant change in the data as a function of the DC value (P<0.05). RESULTS: Analysis of variance revealed that retinal blood flow measures acquired within DC band 5 resulted in significantly lower measures of blood flow and velocity (P=0.035 and P=0.049 respectively) than at lower DC values. Band 5 values of flow, volume and velocity in the neuroretinal rim were also significantly low (P=0.016, P= 0.003 and P=0.026 respectively). Peak neuroretinal rim blood flow was recorded when the DC value was between 70 and 110. For blood flow measurement at the retina and neuroretinal rim the DC value should not exceed 190. CONCLUSION: Photodiode sensitivity as indicated by the DC value affects measurements of ocular blood flow using the HRF.
Adult↗
Effect of dorzolamide timolol combination versus timolol 0.5% on ocular bloodflow in patients with primary open-angle glaucoma.
PURPOSE: Addition of dorzolamide to timolol in primary open-angle glaucoma shows augmented reduction of intraocular pressure. It is unknown as yet if addition of dorzolamide will alter hemodynamics. METHODS: Fifteen patients with primary open-angle glaucoma were placed on a medication-dependent 1-week to 4-week washout that included maintenance on timolol. After washout, baseline measurements were taken (timolol). They were studied after a month on timolol or dorzolamide-timolol (Cosopt; Merck, Inc, Whitehouse Station, New Jersey), with the second drug preceded by another month of timolol maintenance and second baseline measurements. At each visit, visual function, intraocular pressure, and ocular hemodynamics were monitored, including indocyanine green and fluorescein angiography and color Doppler imaging. RESULTS: Cosopt significantly reduced intraocular pressure (14.7 to 13.4 mm Hg, P <.05) and increased arteriovenous passage time (superior temporal artery) of fluorescein dye (2.13 to 1.76 seconds, P =.01) but had no effect on visual function. CONCLUSIONS: When compared with timolol in primary open-angle glaucoma, Cosopt augments ocular tension reduction and reduces the amount of time required for blood to pass through the superior retinal vasculature.
Adrenergic beta-Antagonists↗
Ocular perfusion and age-related macular degeneration.
PURPOSE: To review the role of ocular perfusion in the pathophysiology of age-related macular degeneration (AMD), the leading cause of irreversible blindness in the industrialized world. METHODS: Medline search of the literature published in English or with English abstracts from 1966 to 2000 was performed using various combinations of relevant key words. RESULTS: Vascular defects have been identified in both nonexudative and exudative AMD patients using fluorescein angiographic methods, laser Doppler flowmetry, indocyanine green angiography, and color Doppler imaging. CONCLUSION: Although these studies lend some support to the vascular pathogenesis of AMD, it is not possible to determine if the choroidal perfusion abnormalities play a causative role in nonexudative AMD, if they are simply an association with another primary alteration, such as a primary RPE defect or a genetic defect at the photoreceptor level, or if they are more strongly associated with one particular form of this heterogeneous disease. Further study is warranted.
Blood Flow Velocity↗
Simultaneous management of blood flow and IOP in glaucoma.
Factors other than intraocular pressure (IOP) elevation must be involved in initiation and progression of glaucoma. An additional element in disease causation may be ischemia in the retina and optic nerve head. Ischemic damage to neurons in the CNS is similar mechanistically and histopathologically to changes seen in glaucoma. Further, glaucoma patients with normal IOP show clear evidence for cerebral and ocular ischemia. Aging and atherosclerosis reduce the ability of the eye to autoregulate blood flow when ocular perfusion pressure changes: the dependence of blood flow on perfusion pressure links ischemia to IOP. Consequently, neuroprotective treatments for glaucoma should be designed to both reduce IOP and improve ocular nutrient delivery.
Aging↗
Timolol increased retrobulbar flow velocities in untreated glaucoma eyes but not in ocular hypertension.
PURPOSE: To investigate retrobulbar blood flow velocities and the effects of topical timolol treatment in eyes with newly detected, previously untreated open angle glaucoma or ocular hypertension. METHODS: Fifteen eyes with open angle glaucoma (OAG) and 12 eyes with ocular hypertension (OH), in the same number of patients, all untreated and newly detected, were examined with colour Doppler imaging of retrobulbar vessels before and after 1 month of topical timolol treatment (0.5% Timoptic BID). RESULTS: Baseline central retinal artery end diastolic velocity was lower (48%, p=0.0002) and resistive index higher (7.6%, p=0.018) in the OAG group than in the OH group. In the glaucoma group mean end diastolic velocity increased by 41%, (p=0.006) while resistive index decreased by 5.8%, (p=0.02) on treatment, while no significant changes were seen in the OH group. Blood flow velocities in the ophthalmic artery did not change with treatment. Baseline IOP and IOP reduction did not differ between OAG and OH group. CONCLUSION: Peripheral resistance to blood flow was found to be increased in untreated glaucoma eyes as compared to a similar group of eyes with ocular hypertension. Timolol treatment diminished resistance significantly in the glaucoma group, but not in the ocular hypertension group. Thus the two groups responded differently to timolol treatment. The reaction to IOP lowering treatment could indicate defective autoregulation in the glaucoma group.
Adrenergic beta-Antagonists↗
Chronic systemic administration of salmeterol to rats promotes pulmonary beta(2)-adrenoceptor desensitization and down-regulation of G(s alpha).
1. The aim of the present study was to examine the effects of chronic infusion of the long-acting agonist salmeterol on pulmonary beta(2)-adrenoceptor function in Sprague-Dawley rats in vivo and to elucidate the molecular basis of any altered state. 2. Systemic administration of rats with salmeterol for 7 days compromised the ability of salmeterol and prostaglandin E(2) (PGE(2)), given acutely by the intravenous route, to protect against ACh-induced bronchoconstriction when compared to rats treated identically with vehicle. 3. beta(1)- and beta(2)-adrenoceptor density was significantly reduced in lung membranes harvested from salmeterol-treated animals, which was associated with impaired salmeterol- and PGE(2)-induced cyclic AMP accumulation ex vivo. 4. Three variants of G(s alpha) that migrated as 42, 44 and 52 kDa peptides on SDS polyacrylamide gels were detected in lung membranes prepared from both groups of rats but the intensity of each isoform was markedly reduced in rats that received salmeterol. 5. The activity of cytosolic, but not membrane-associated, G-protein receptor-coupled kinase was elevated in the lung of salmeterol-treated rats when compared to vehicle-treated animals. 6. The ability of salmeterol, administered systemically, to protect the airways of untreated rats against ACh-induced bronchoconstriction was short-acting (t(off) approximately 45 min), which contrasts with its long-acting nature when given to asthmatic subjects by inhalation. 7. These results indicate that chronic treatment of rats with salmeterol results in heterologous desensitization of pulmonary G(s)-coupled receptors. In light of previous data obtained in rats treated chronically with salbutamol, we propose that a primary mechanism responsible for this effect is a reduction in membrane-associated G(s alpha). The short-acting nature of salmeterol, when administered systemically, and the reduction in beta-adrenoceptor number may be due to metabolism to a biologically-active, short-acting and non-selective beta-adrenoceptor agonist.
Acetylcholine↗
Delta4, an endothelial specific notch ligand expressed at sites of physiological and tumor angiogenesis.
Delta-Notch signalling regulates cell-fate choices in a variety of tissues during development. We report the expression of Delta4 (D14) in arterial endothelium during mouse embryogenesis and in the endothelium of tumor blood vessels. The expression of D14 in the mouse begins at 8 dpc in the dorsal aortae, umbilical artery and the heart. Subsequent expression is restricted to smaller vessels and capillaries and is reduced in most adult tissues. However, it is high in the vasculature of xenograft human tumors in the mouse, in endogenous human tumors and is regulated by hypoxia. These data implicate D14 and the Notch signalling pathway in angiogenesis and suggest possible new targets for antiangiogenic tumor therapy.
Adaptor Proteins, Signal Transducing↗
Baastrup's disease correlating with diffuse lumbar paraspinal atrophy: a case report.
Baastrup's disease ("kissing spine") is an x-ray finding that has been considered a possible cause of low back pain (LBP) since the 1930s. Its etiology is unknown, and there are no reports of muscle or soft tissue changes associated with it. This case report concerns a 57-year-old man with chronic LBP, stiffness, and indurated skin over the back. He had classic sclerotic changes between the spinous processes on x-ray, which is consistent with Baastrup's disease. Computed tomography (CT) and electromyography were performed. CT showed profound fatty replacement of the paraspinal musculature. An electromyography report showed severe isolated paraspinal denervation. This case suggests that diffuse fatty replacement of the paraspinal muscles, perhaps due to a compartment syndrome or other vascular event, may have a role in the pathogenesis of Baastrup's disease.
Diagnosis, Differential↗
Intractable insomnia after cessation of treatment with thalidomide.
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Aged↗
[Beyond "successful aging: Rembrandt in his self-portraits].
The process of aging has been generally associated with cognitive dedine. However, some complex cognitive abilities, such as wisdom and judgement, have been suggested to improve with age. In the current study, the development of an advanced artistic ability is examined over the life span of Rembrandt H. van Rijn. Analysis of the paintings revealed the development of an old-age-style in the last portrait, characterised by uniformity of texture, facture, and lighting. The self-portrait painted in the last year of Rembrandt's life reflects a high degree of integration of artistic skill and experience gathered in the course of life, and hence reflects features of wisdom in the sence suggested by Baltes. The development of a mature "late" style can help to characterise the emergence of qualitatively different and advanced cognitive abilities in old age.
Aging↗
Effect of brimonidine tartrate on ocular hemodynamics in healthy volunteers.
While alpha2-adrenergic agonists, such as brimonidine tartrate, significantly reduce the intraocular pressure (IOP), the presence of vasoconstrictor postsynaptic alpha2 receptors on vascular smooth muscle raise the possibility that brimonidine could potentially compromise ocular blood flow. Consequently, the ocular hemodynamic effects of brimonidine were studied in normal subjects. Twelve healthy volunteers were included in this prospective, double-masked, placebo controlled, crossover-designed clinical trial. They received either brimonidine tartrate 0.2% or placebo b.i.d. for 2 weeks. Goldmann tonometry and color Doppler imaging (CDI) were performed at baseline, at 2 hr, 1 week, and 2 weeks after the treatment. Fundus angiography using a scanning laser ophthalmoscope was performed at baseline and 2 weeks after treatment to determine retinal arteriovenous passage time. Brimonidine lowered IOP at 2 hr, 1 week, and 2 weeks (p = 0.058, p = 0.031, and p = 0.022, respectively). Brimonidine did not affect the retrobulbar arterial velocities measured by CDI, nor retinal arteriovenous passage time. In conclusion, two-week treatment with brimonidine reduces IOP and does not reduce the bulk retinal or retrobulbar arterial perfusion in young healthy volunteers.
Administration, Topical↗
In vivo glycosylation of mucin tandem repeats.
The biochemical and biophysical properties of mucins are largely determined by extensive O-glycosylation of serine- and threonine-rich tandem repeat (TR) domains. In a number of human diseases aberrant O-glycosylation is associated with variations in the properties of the cell surface-associated and secreted mucins. To evaluate in vivo the O-glycosylation of mucin TR domains, we generated recombinant chimeric mucins with TR sequences from MUC2, MUC4, MUC5AC, or MUC5B, which were substituted for the native TRs of epitope-tagged MUC1 protein (MUC1F). These hybrid mucins were extensively O-glycosylated and showed the expected association with the cell surface and release into culture media. The presence of different TR domains within the chimeric mucins appears to have limited influence on their posttranslational processing. Alterations in glycosylation were detailed by fast atom bombardment mass spectrometry and reactivity with antibodies against particular blood-group and tumor-associated carbohydrate antigens. Future applications of these chimeras will include investigations of mucin posttranslational modification in the context of disease.
Amino Acid Sequence↗