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Biomedical subjects

J R Harrison

Publications and source records attributed to J R Harrison.

At least 19 recordsLinked to original sources
PubMed2006

Impaired cortical bone acquisition and osteoblast differentiation in mice with osteoblast-targeted disruption of glucocorticoid signaling.

To determine the role of endogenous glucocorticoids in bone, we previously developed transgenic mice in which a 2.3 kb fragment of the Col1a1 promoter drives 11beta-hydroxysteroid dehydrogenase 2 expression in mature osteoblasts. This transgene should inactivate glucocorticoids upstream of all receptor signaling pathways. In the present study, we show that femoral cortical bone area and thickness were approximately 10-15% lower in transgenic mice than in wild-type littermates. Femur length was unchanged, indicating that bone elongation was not affected in this model. Expression of osteocalcin mRNA, pOBCol2.3-GFP (a green fluorescent protein marker of mature osteoblasts), and the formation of mineralized nodules were impaired in ex vivo transgenic primary calvarial cultures. The extent of crystal violet staining in bone marrow cultures, indicative of the number of adherent stromal cells, was also decreased. These data suggest that endogenous glucocorticoids are required for cortical bone acquisition and full osteoblast differentiation. It appears that blocking glucocorticoid signaling in vivo leads to a decrease in the commitment and/or expansion of progenitors entering the osteoblast lineage.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed2006

Mandibular phenotype of p20C/EBPbeta transgenic mice: Reduced alveolar bone mass and site-specific dentin dysplasia.

CCAAT enhancer binding proteins (C/EBP) comprise a family of basic-leucine zipper transcription factors that regulate cellular differentiation and function. To determine the role of C/EBP transcription factors in osteoblasts and odontoblasts, we generated a transgenic (TG) mouse model with Co1a1 (pOBCol3.6) promoter-targeted expression of a FLAG-tagged dominant negative C/EBP isoform, p20C/EBPbeta (previously LIP). Two of the four transgenic lines presented with abnormalities in the developing incisors, including breakage, overgrowth, and malocclusion. Histological examination revealed that the amount of alveolar bone was reduced in TG compared to wild-type (WT) mice. By microcomputed tomography (microCT), the bone volume fraction of the mandible was reduced at the level of the first and third molars, demonstrating a severe mandibular osteopenia. The lingual dentin morphology of TG incisors differed dramatically from WT. Labial dentin (enamel side) showed normal thickness and tubular dentin structure, whereas the lingual dentin was thinner (25-30% of WT at the alveolar crest) with an amorphous globular structure characteristic of dentin dysplasia. FLAG immunostaining was seen in both lingual and labial odontoblasts, indicating that the site-specific defect was not due to a lack of labial transgene expression. Northern blot analysis demonstrated reduced osteocalcin expression in TG mandibles, while bone sialoprotein was increased, consistent with prior results in calvariae and long bones. Dental sialophosphoprotein, a marker of the odontoblast lineage whose absence causes dentin dysplasia, was modestly reduced in TG mice by Northern blot and in situ hybridization analysis. By fluorescence microscopy, pOBCol2.3-GFP, a marker of the odontoblast lineage, was expressed in both labial and lingual odontoblasts, although GFP-marked lingual odontoblasts were more flattened than WT cells. Moreover, GFP-positive processes in the lingual dentin tubules were truncated and less organized than those in WT dentin. MicroCT analysis showed reduced tissue density in the lingual dentin. These data suggest that C/EBP transcription factors may be involved in the regulation of odontoblast polarization and dentin matrix production.

Alveolar Bone Loss↗
PubMed2005

Ill-health retirement: national rates and updated guidance for occupational physicians.

BACKGROUND: Advising on ill-health retirement is an important role of most practising occupational physicians. In recent years, the eligibility criteria and process for gaining early retirement benefits have changed in many pension schemes in the UK. AIM: To investigate the variation in rates of retirement due to ill-health in National Health Service (NHS) Trusts and Local Authorities and to update previously published guidance on ill-health retirement with specific reference to pension schemes with eligibility criteria that include permanence of incapacity due to ill-health. METHODS: Rates of retirement were calculated for 222 NHS Trusts and 132 Local Authorities with more than 1500 employees. Literature searches and consensus statements by the authors. RESULTS: Rates of retirement were widely distributed in the NHS Trusts and Local Authorities. The median rates of retirement were 2.11 (IQR 1.37-2.91)/1000 active members and 4.10 (IQR 3.01-6.10)/1000 employees, respectively (P<0.001). Difficulties in the doctor-patient relationship and in ascertaining the true functional ability of some patients were identified. CONCLUSION: There continues to be marked variation in rates of early retirement due to ill-health within and between organizations that warrants further investigation. The general and specific guidance that appears as an appendix in Supplementary data to this paper should help occupational physicians to make equitable recommendations when assessing applications for early retirement benefits and fitness to work.

Disability Evaluation↗
PubMed2002

Urine amino and organic acids analysis in developmental delay or intellectual disability.

OBJECTIVES: To determine the proportion of urine amino and organic acids screening tests (UMS) undertaken for patients referred with developmental delay or intellectual disability (DD/ID), and within the group with DD/ID, to determine the diagnostic yield, the proportion of diagnoses with a therapy and the associated recurrence risks. METHODS: A retrospective review of request forms and results of UMS, in individuals older than 28 days, referred to the Women's and Children's Hospital, North Adelaide, between 1 January 1992 and 31 December 1998 was carried out. Urine was analysed by ion exchange chromatography (amino acids), gas chromatography/mass spectrometry (organic acids), colorimetric assay (orotic acid) and stable isotope-dilution mass spectrometry (trimethylamine). RESULTS: A total of 3316 samples were received, 1447 being from patients with DD/ID. A diagnosis was determined for 1.8% of all referrals. For patients with DD/ID, the diagnostic yield was 1.1%, with a similar yield for isolated DD/ID and DD/ID with other features (9/828 vs 7/619; chi2 = 0.006; P = 0.93). Specific therapies were available for 69% of diagnoses associated with DD/ID and 87.5% had known Mendelian or mitochondrial inheritance. CONCLUSION: Urine metabolic screening is an important part of the evaluation of children with DD/ID as it can enable families to make reproductive decisions and children to receive appropriate therapy early.

Amino Acids↗
PubMed2002

Gastro-oesophageal reflux disease in obesity: pathophysiological and therapeutic considerations.

Gastro-oesophageal reflux disease (GERD) is common in obese patients. Apart from the physical discomfort and the economic burden, GERD may increase morbidity and mortality through its association with oesophageal carcinoma. The pathophysiology of GERD differs between obese and lean subjects. First, obese subjects are more sensitive to the presence of acid in the oesophagus. Second, hiatal hernia, capable of promoting GERD by several mechanisms, is more prevalent among the obese. Third, obese subjects have increased intra-abdominal pressure that displaces the lower oesophageal sphincter and increases the gastro-oesophageal gradient. Finally, vagal abnormalities associated with obesity may cause a higher output of bile and pancreatic enzymes, which makes the refluxate more toxic to the oesophageal mucosa. The altered body composition associated with obesity affects the pharmacokinetics of drugs. There are no data regarding the efficacy of any of the drugs used for GERD treatment. The dosages of cimetidine and ranitidine should be calculated according to the patient's ideal body weight, not their actual weight. Of the operative procedures used for weight loss, Roux-en-Y gastric bypass was found to be most effective for GERD, while gastric banding was associated with a high prevalence of reflux. This review outlines the pathophysiology and the treatment of GERD in obesity with emphasis on the therapeutic considerations in this population of patients.

Body Composition↗
PubMed2001

Hepatic angiosarcoma: an unusual cause of congestive heart failure.

Hepatic angiosarcoma is a rare form of liver cancer. The history, physical examination, and liver biopsy are nonspecific. As a result, diagnosis of angiosarcoma can be challenging. We report the case of an elderly woman with congestive heart failure caused by a hepatic angiosarcoma. The massive tumor burden created extensive arteriovenous shunting and a high-cardiac-output state.

Aged↗
PubMed2001

Chronic intermittent intestinal obstruction from a seat belt injury.

Most patients with intestinal obstruction have had previous surgery. Rarely, the development of adhesions and resulting small bowel obstruction is attributed to previous intra-abdominal trauma. We present the case of a young man, without a history of surgery, who had been a restrained driver in a motor vehicle crash. Seven years later, the patient had an intermittent partial small bowel obstruction that recurred over the next 5 years. We review the pathophysiology and epidemiology of similar occurrences, as well as diagnostic options.

Abdominal Injuries↗
PubMed2000

Treatment of late-onset nonketotic hyperglycinaemia: effectiveness of imipramine and benzoate.

We report a patient with late-onset nonketotic hyperglycinaemia managed with a sequential approach to drug therapy in placebo-controlled therapeutic trials. Partial response to low-protein diet and sodium benzoate and dramatic response to imipramine are demonstrated, with parental scores on the Developmental Behavioural Checklist falling from the 86th centile before treatment to normal with combined benzoate and imipramine therapy.

Benzoates↗
PubMed2000

Involvement of CCAAT enhancer binding protein transcription factors in the regulation of prostaglandin G/H synthase 2 expression by interleukin-1 in osteoblastic MC3T3-E1 cells.

Interleukin-1 (IL-1) stimulates prostaglandin production in bone by a rapid and transient activation of prostaglandin G/H synthase 2 (PGHS-2) gene expression. In osteoblastic MC3T3-E1 cells, IL-1 caused a transient increase in PGHS-2 messenger RNA (mRNA), which peaked at 2 h. IL-1 caused a 2- to 4-fold activation of a 371-base pair (bp) murine PGHS-2 promoter/luciferase construct in stable transfectants. This response mapped to a proximal promoter element(s) located between -150 and -40 bp. This region contains a putative CCAAT enhancer binding protein (C/EBP) site (centered at -135 bp), which shows enhanced binding of C/EBPbeta and C/EBPdelta by mobility shift analysis after IL-1 treatment. A transient cotransfection approach was used to examine the effects of C/EBPbeta and C/EBPdelta overexpression. IL-1 caused a maximal 3- to 7-fold stimulation of PGHS-2 promoter activity after 2.5 h. Overexpression of murine C/EBPbeta and C/EBPdelta caused a dose-dependent increase in basal and IL-1-stimulated luciferase activity. C/EBPdelta caused a greater enhancement of basal and IL-1-stimulated promoter activity than C/EBPbeta, suggesting that C/EBPdelta is a stronger transactivator. Overexpression of p20C/EBPbeta, a dominant negative inhibitor of C/EBP function, blocked the stimulation of PGHS-2 promoter activity by IL-1 and blocked the ability of overexpressed C/EBPbeta and C/EBPdelta to increase basal and IL-1-stimulated promoter activity. Mutagenesis of the C/EBP site reduced, but did not abolish, the stimulation of PGHS-2 promoter activity by IL-1 and blunted the effect of overexpressed C/EBPdelta on basal and IL-1-stimulated promoter activity. These results suggest an essential role for C/EBPbeta and C/EBPdelta in the induction of PGHS-2 gene expression by IL-1 in osteoblastic cells.

Animals↗
PubMed1999

Molecular modeling studies on G-quadruplex complexes of telomerase inhibitors: structure-activity relationships.

Inhibition of the ability of the enzyme telomerase to add telomeric repeats to the end of chromosomes is a novel target for potential anticancer therapy. This paper examines the hypothesis that compounds possessing a planar aromatic chromophore inhibit telomerase via stabilization of, and binding to, a folded guanine quadruplex structure. Two series of telomerase inhibitors have been designed based on the 2,6-disubstituted amidoanthracene-9,10-dione and 3,6-disubstituted acridine chromophores in order to investigate structure-activity relationships between biological activity and substituent group size. The relative binding energies between these compounds and the folded human telomere DNA quadruplex were determined using molecular simulation methods, involving explicitly solvated structures. The results obtained are in excellent agreement with the biological activity as measured in vitro using a modified TRAP assay and in general agreement with the ranking order of binding enthalpies found in isothermal titration calorimetry studies. This broad agreement provides strong support for the hypothesis that guanine quadruplexes are the primary target for telomerase inhibitors with extended planar chromophores.

Acridines↗
PubMed1998

Parathyroid hormone induces interleukin-6 heterogeneous nuclear and messenger RNA expression in murine calvarial organ cultures.

The cytokine, interleukin-6 (IL-6), is produced by osteoblasts and may in part mediate parathyroid hormone (PTH)-stimulated bone resorption. The goals of the present study were: (1) to examine PTH induction of IL-6 expression in 7-day-old mouse calvarial organ cultures; (2) to assess the role of intracellular signaling pathways in this model; and (3) to determine whether PTH regulates IL-6 expression by a transcriptional mechanism. Northern blot analysis of calvarial RNA showed that PTH(1-34) at 0.1-100 nmol/L induced IL-6 mRNA at 0.5 h with a peak at 2 h. Forskolin at 10 micromol/L and 8-bromocyclic-AMP at 3 mmol/L also induced IL-6 mRNA with a peak at 2 h. Phorbol myristate acetate induced IL-6 expression, whereas ionomycin and PTH(3-34) amide, an N-terminal-truncated PTH analog that has reduced ability to activate the cAMP-PKA pathway, were much less effective. PMA pretreatment of calvariae greatly blocked IL-6 mRNA induction by a subsequent dose of PMA and decreased induction by PTH and forskolin to a much lesser extent. A reverse-transcriptase polymerase chain reaction (RT-PCR) assay was used to measure IL-6 heterogeneous nuclear RNA (hnRNA) and mRNA. A 5' primer spanning exons 1 and 2 and a 3' primer complementary to exon 5 of the murine IL-6 gene were used to detect IL-6 mRNA as a 638 bp product. A 5' primer corresponding to intron 4 of the murine IL-6 gene and the 3' primer were used to detect IL-6 hnRNA as a 370 bp product. RT-PCR of total calvarial RNA showed that the induction of IL-6 hnRNA by PTH and other agonists was similar to their induction of IL-6 mRNA. These data support the conclusion that PTH transcriptionally induces IL-6 gene expression in murine calvarial organ cultures mainly through the cAMP-PKA signaling pathway.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1998

AccuStat whole blood fingerstick test for Helicobacter pylori infection: a reliable screening method.

Helicobacter pylori antibody testing is accurate for diagnosing untreated patients. Rapid serum testing is as accurate as formal enzyme-linked immunosorbent assay (ELISA) testing. As whole blood fingerstick tests may become the diagnostic method of choice if they are of similar accuracy, 51 patients were studied who had not taken antibiotics, bismuth, sucralfate, or proton pump inhibitors. Concordance between C-14 Urea Breath Testing and HM-CAP ELISA testing served as the study standard for H. pylori diagnosis. Rapid antibody testing was performed with the AccuStat whole blood (Boehringer Mannheim, Mannheim, Germany) and FlexSure HP (Smith Kline Diagnostics, San Jose, CA) serum tests. Antral biopsy for CLO testing and histological evaluation with thiazine staining were available for 18 (35.3%) and 20 patients (39.2%), respectively. Nineteen of 50 patients (38%) were infected. (One patient had discordant tests and was excluded.) FlexSure HP and AccuStat were each positive in 18 (36%) and 19 patients (38%) with sensitivity, specificity, and positive and negative predictive values of 89.5% and 89.5%, 96.8% and 93.5%, 94.4% and 89.5%, and 93.8% and 93.5%, respectively. There were two false-negative FlexSure HP and AccuStat tests and three false-positive tests--1 FlexSure and 2 AccuStat results. CLO test and histology concurred in every case tested. We conclude that both rapid antibody tests are accurate and suitable for screening patients not previously treated for H. pylori infection. Since the AccuStat has preserved diagnostic strength, is less costly, takes less time, and is less labor intensive, whole blood testing is the screening test of choice.

Adult↗
PubMed1998

Interleukin-1 represses COLIA1 promoter activity in calvarial bones of transgenic ColCAT mice in vitro and in vivo.

Interleukin-1 (IL-1) inhibits collagen synthesis in osteoblastic cell lines and primary osteoblast-like cells. However, promoter elements regulating type I collagen A1 (COLIA1) expression in vivo and in organ culture may differ from those regulating expression in cell culture. We have examined the effects of IL-1 on reporter gene activity in neonatal transgenic mouse calvariae bearing COLIA1 promoter-chloramphenicol acetyltransferase (ColCAT) fusion genes. The parent construct, ColCAT 3.6, contains 3.5 kb of 5' flanking sequence and 115 bp of 5' untranslated region fused to the CAT reporter. In 48-h calvarial organ cultures, IL-1 repressed ColCAT 3.6 promoter activity and collagen synthesis in a dose-related manner, with a maximal inhibition of 40-65%. This repression was retained in 5' deletion constructs truncated to-1719 bp. The inhibition of transgene mRNA was blocked by cycloheximide, indicating a requirement for new protein synthesis. Pretreatment with indomethacin diminished the inhibitory effect of IL-1 on CAT activity and collagen synthesis, suggesting partial mediation by prostaglandins. Local in vivo injection of IL-1 (500 ng) decreased calvarial transgene mRNA after 8 h, an effect that was partially blocked by indomethacin. ColCAT transgenic mice represent a useful model for in vitro and in vivo assessment of COLIA promoter regulation by cytokines and other factors.

Animals↗
PubMed1996

Interleukin-4 inhibits prostaglandin G/H synthase-2 and cytosolic phospholipase A2 induction in neonatal mouse parietal bone cultures.

We have shown previously that prostaglandin (PG) production in 7-day-old neonatal mouse calvarial cultures is regulated largely by changes in prostaglandin G/H synthase-2 (PGHS-2) expression and to a lesser extent by changes in arachidonic acid (AA) release. In this study, we examined the effects of interleukin-4 (IL-4), and its interactions with other cytokines and with parathyroid hormone (PTH), on mRNA levels of PGHS-2, PGHS-1, and cytosolic phospholipase A2 (cPLA2) and on medium protaglandin E2 (PGE2) levels in calvarial cultures. IL-1 and tumor necrosis factor-alpha (TNF-alpha), both at 1-100 ng/ml, and PTH at 0.1-10 nM increased PGHS-2 and cPLA2 mRNA and medium PGE2 levels dose-dependently after 4 h of treatment. IL-6 and IL-11 at 1-100 ng/ml did not affect mRNA or PGE2 levels. IL-4 at 1-100 ng/ml decreased PGHS-2 and cPLA2 mRNA and PGE2 levels in control as well as IL-1, TNF-alpha, and PTH-stimulated cultures. The inhibition of PGHS-2 and cPLA2 mRNA expression by IL-4 (10 ng/ml) was present at 1 h, reached a maximum at 4 h, and persisted for 24 h. The effects were maintained in the presence of cycloheximide. IL-4 also decreased PGHS-2 protein levels in control and IL-1-stimulated cultures. PGHS-1 mRNA levels were not stimulated by any of the factors studied nor inhibited by IL-4. IL-4 partially inhibited control and PTH-stimulated 45Ca release from prelabeled mouse calvariae at 4 days. However, neither the inhibition of resorption by IL-4 nor the stimulation by IL-1 and PTH were altered by indomethacin (1 microM). We conclude that (1) IL-1, TNF-alpha, and PTH, but not IL-6 nor IL-11, can increase the expression of PGHS-2, cPLA2, and PGE2 production in cultured mouse calvariae; (2) IL-4 inhibits PGE2 production in both control and stimulated calvarial cultures by inhibiting PGHS-2 and cPLA2; and (3) IL-4 has an inhibitory effect on bone resorption which is independent of PG production.

Analysis of Variance↗
PubMed1995

Regulation of type I collagen gene expression in bone.

The regulation of COL1A1 gene expression in bone was studied by measuring the activity of type I collagen promoter fusion genes (ColCAT) in permanently transfected osteoblastic cells and calvariae from transgenic animals. The basal activity of ColCAT fusion genes in transfected cells is mediated by DNA sequences between -3.5 to -2.3 kb while expression in vivo requires sequences between -2.3 and -1.7 kb. Parathyroid hormone, 1,25-dihydroxyvitamin D3 and interleukin-1 decrease the activity of ColCAT fusion genes in osteoblastic cells and transgenic calvariae. Because there may be differences between the expression of ColCAT fusion genes in cultured cells and intact bone, it will be important to compare data obtained from transfected cells with an in vivo model such as calvariae from transgenic mice.

Animals↗