Biomedical subjects

J M Peters

Publications and source records attributed to J M Peters.

At least 19 recordsLinked to original sources

PubMed2006

Peroxisome proliferator activated receptor gamma in colonic epithelial cells protects against experimental inflammatory bowel disease.

INTRODUCTION: Peroxisome proliferator activated receptor gamma (PPARgamma) is expressed in epithelial cells, macrophage, and T and B lymphocytes. Ligand induced activation of PPARgamma was reported to attenuate colitis activity but it is not clear whether this protection is mediated by epithelial or leucocyte PPARgamma. METHODS: Mice with targeted disruption of the PPARgamma gene in intestinal epithelial cells, generated using a villin-Cre transgene and floxed PPARgamma allele and designated PPARgamma(DeltaIEpC), were compared with littermate mice having only the PPARgamma floxed allele with no Cre transgene that expressed PPARgamma in the gut, designated PPARgamma(F/F). Colitis was induced by administering dextran sodium sulphate (DSS) and the two mouse lines compared for typical symptoms of disease and expression of inflammatory cytokines. RESULTS: PPARgamma(DeltaIEpC) mice displayed reduced expression of the PPARgamma target genes ADRP and FABP in the gut but were otherwise normal. Increased susceptibility to DSS induced colitis, as defined by body weight loss, colon length, diarrhoea, bleeding score, and altered histology, was found in PPARgamma(DeltaIEpC) mice in comparison with PPARgamma(F/F) mice. Interleukin (IL)-6, IL-1beta, and tumour necrosis factor alpha mRNA levels in colons of PPARgamma(DeltaIEpC) mice treated with DSS were higher than in similarly treated PPARgamma(F/F) mice. The PPARgamma ligand rosiglitazone decreased the severity of DSS induced colitis and suppressed cytokine production in both PPARgamma(F/F) and PPARgamma(DeltaIEpC) mice. CONCLUSIONS: These studies reveal that PPARgamma expressed in the colonic epithelium has an endogenous role in protection against DSS induced colitis and that rosiglitazone may act through a PPARgamma independent pathway to suppress inflammation.

Animals↗

PubMed2006

PPARbeta/delta selectively induces differentiation and inhibits cell proliferation.

Peroxisome proliferator-activated receptor (PPAR) beta-null mice exhibit exacerbated epithelial cell proliferation and enhanced sensitivity to skin carcinogenesis, suggesting that ligand activation of PPARbeta will inhibit keratinocyte proliferation. By using of a highly specific ligand (GW0742) and the PPARbeta-null mouse model, activation of PPARbeta was found to selectively induce keratinocyte terminal differentiation and inhibit keratinocyte proliferation. Additionally, GW0742 was found to be anti-inflammatory due to inhibition of myeloperoxidase activity, independent of PPARbeta. These data suggest that ligand activation of PPARbeta could be a novel approach to selectively induce differentiation and inhibit cell proliferation, thus representing a new molecular target for the treatment of skin disorders resulting from altered cell proliferation such as psoriasis and cancer.

Animals↗

PubMed2006

Intracranial penetration of a halo pin causing an epileptic seizure.

A 71-year-old man with ankylosing spondylitis and an unstable fracture of the 6th and 7th cervical vertebrae was managed with a halo vest. Eight weeks following application the halo had shifted because of a loose pin. The patient's only complaint at the time was a headache but this was followed two days later by a seizure. An MR scan of the brain showed a swollen cortex under the right dorsal pin as a result of a perforation of the internal lamina by the pin. The halo was removed and anti-epileptic medication commenced. The patient had no further seizures.

Aged↗

PubMed2004

Provision for children with developmental co-ordination disorder (DCD): audit of the service provider.

BACKGROUND: The aim of this study was to conduct an audit of parent/carer satisfaction with the service provided for children presenting with movement difficulties [developmental co-ordination disorder (DCD)/dyspraxia] at the out-patient physiotherapy clinic of a specialist tertiary referral paediatric hospital. METHOD: A postal questionnaire was used to obtain objective and subjective data on the service offered. Factual information on aspects such as waiting time for first appointment, type of intervention offered, etc. was checked against clinical records. Satisfaction with the service was assessed using ratings and open-ended comment. RESULTS: Forty-five families completed the questionnaire. The results showed that the service was generally rated highly. The opportunity to discuss the child's problems and its implications was considered valuable. Among families offered 1 : 1 intervention, a statistically significant correlation emerged between the number of sessions attended and perceived effectiveness. Among families offered a home programme, perceived effectiveness was related to the number of times per week the child practised the programme. CONCLUSIONS: This study showed that many children from mainstream schools with co-ordination problems continued to find it difficult to obtain a clear diagnosis. Once a referral and assessment had been achieved, however, parents/carers were shown to be satisfied with the package offered by this service provider.

Adolescent↗

PubMed2003

Environmental tobacco smoke and absenteeism related to respiratory illness in schoolchildren.

Household environmental tobacco smoke (ETS) exposure accounts for substantial morbidity among young children, but the ETS-associated morbidity burden among school-age children is less well defined. Illness-related school absenteeism is a measure of a broad spectrum of adverse effects of ETS exposure in school-age children. The authors investigated the relations between ETS exposure, asthma status, and illness-related school absenteeism in a cohort of 1,932 fourth-grade schoolchildren from 12 southern California communities during January-June 1996. Incidence rates and adjusted relative risks of illness-related absences were determined by using an active surveillance system. The effects of ETS exposure on absenteeism were assessed by using stratified incidence rates and Poisson regression to adjust for sociodemographic factors. ETS exposure was associated with an increased risk of respiratory-illness-related school absences (relative risk (RR) = 1.27, 95% confidence interval (CI): 1.04, 1.56). Children living in a household with two or more smokers were at increased risk of such absences (RR = 1.75, 95% CI: 1.33, 2.30). Children's asthma status affected their response to ETS. Compared with unexposed children without asthma, children with asthma were at increased risk of respiratory-illness-related school absences when exposed to one (RR = 2.35, 95% CI: 1.49, 3.71) or two or more (RR = 4.45, 95% CI: 2.80, 7.07) household smokers. Children without asthma also had an increased risk if exposed to two or more smokers (RR = 1.44, 95% CI: 1.04, 2.00). Therefore, ETS exposure is associated with increased respiratory-related school absenteeism among children, especially those with asthma.

Absenteeism↗

PubMed2001

The role of Kupffer cell oxidant production in early ethanol-induced liver disease.

Considerable evidence for a role of Kupffer cells in alcoholic liver disease has accumulated and they have recently been shown to be a predominant source of free radicals. Several approaches including pharmacological agents, knockout mice, and viral gene transfer have been used to fill critical gaps in understanding key mechanisms by which Kupffer cell activation, oxidant formation, and cytokine production lead to liver damage and subsequent pathogenesis. This review highlights new data in support of the hypothesis that Kupffer cells play a pivotal role in hepatotoxicity due to ethanol by producing oxidants via NADPH oxidase.

Adenoviridae↗

PubMed2001

Respiratory effects of relocating to areas of differing air pollution levels.

We studied 110 children (59 boys and 51 girls, who were 10 yr of age at enrollment and 15 yr of age at follow-up) who had moved from communities participating in a 10-yr prospective study of respiratory health (The Children's Health Study [CHS]) to determine whether changes in air quality caused by relocation were associated with changes in annual lung function growth rates. The subjects were given health questionnaires and underwent spirometry in their homes across six western states, according to a protocol identical to evaluations performed annually on the CHS cohort in school. Changes in annual average exposure to particulate matter with a mean diameter of 10 microm (PM(10)) were associated with differences in annual lung function growth rates for FEV(1), maximal midexpiratory flow, and peak expiratory flow rate. As a group, subjects who had moved to areas of lower PM(10) showed increased growth in lung function and subjects who moved to communities with a higher PM(10) showed decreased growth in lung function. A stronger trend was found for subjects who had migrated at least 3 yr before the follow-up visit than for those who had moved in the previous 1 to 2 yr. We conclude that changes in air pollution exposure during adolescent growth years have a measurable and potentially important effect on lung function growth and performance.

Adolescent↗

PubMed2001

Influence of conjugated linoleic acid on body composition and target gene expression in peroxisome proliferator-activated receptor alpha-null mice.

The mechanisms underlying the beneficial effects of conjugated linoleic acid (CLA) are unknown, but one hypothesis is that they are mediated by the nuclear receptor, peroxisome proliferator-activated receptor (PPARalpha). In this work, the effect of dietary CLA on body weight gain, body composition, serum lipids and tissue specific PPAR target gene expression was examined in PPARalpha-null mice. Male wild-type or PPARalpha-null mice were fed either a control diet or one containing 0.5% CLA for a period of 4 weeks. Weight gain in wild-type and PPARalpha-null mice fed CLA was similar, and significantly less than controls. Whole body fat content was lower in wild-type and PPARalpha-null mice while whole body protein content was increased in both genotypes fed CLA compared to controls. Serum triglycerides were lowered in both genotypes as a result of dietary CLA. While CLA feeding resulted in specific activation of PPARalpha in liver, alterations in liver, adipose and muscle mRNAs were also found that were independent of PPARalpha genotype including those encoding uncoupling proteins (UCPs), mitochondrial fatty acid oxidizing enzymes, and fatty acid transporter. These results demonstrate that despite specific activation of PPARalpha-dependent gene expression, the influence of CLA on body composition appears to be independent of PPARalpha. Further, CLA causes increased levels of mRNAs encoding lipid metabolizing and mitochondrial uncoupling proteins that likely contribute to the mechanisms underlying reduced fat/increased lean body mass resulting from consumption of dietary CLA.

Animals↗

PubMed2001

Adaptive increase in pyruvate dehydrogenase kinase 4 during starvation is mediated by peroxisome proliferator-activated receptor alpha.

Pyruvate dehydrogenase kinase isoform 4 (PDK4) is upregulated by starvation in many tissues of the body during starvation. This causes inactivation of the pyruvate dehydrogenase complex which blocks pyruvate oxidation and conserves lactate and alanine for gluconeogenesis. Enhanced PDK4 expression may be caused by the increase in free fatty acids that occurs during starvation. Free fatty acids can activate peroxisome proliferator-activated receptor alpha (PPARalpha), and activation of PPARalpha can promote PDK4 expression. This model is supported by the findings reported here that WY-14,643, a synthetic PPARalpha activator, increases PDK4 expression in wild-type mice but not in PPARalpha-null mice. Starvation likewise increases the expression of PDK4 in tissues of wild-type mice but not in tissues of PPARalpha-null mice. These findings document the functional importance of PPARalpha for PDK4 expression during starvation and suggest an important role for elevated free fatty acids in the induction.

Animals↗

PubMed2001

Impaired skin wound healing in peroxisome proliferator-activated receptor (PPAR)alpha and PPARbeta mutant mice.

We show here that the alpha, beta, and gamma isotypes of peroxisome proliferator-activated receptor (PPAR) are expressed in the mouse epidermis during fetal development and that they disappear progressively from the interfollicular epithelium after birth. Interestingly, PPARalpha and beta expression is reactivated in the adult epidermis after various stimuli, resulting in keratinocyte proliferation and differentiation such as tetradecanoylphorbol acetate topical application, hair plucking, or skin wound healing. Using PPARalpha, beta, and gamma mutant mice, we demonstrate that PPARalpha and beta are important for the rapid epithelialization of a skin wound and that each of them plays a specific role in this process. PPARalpha is mainly involved in the early inflammation phase of the healing, whereas PPARbeta is implicated in the control of keratinocyte proliferation. In addition and very interestingly, PPARbeta mutant primary keratinocytes show impaired adhesion and migration properties. Thus, the findings presented here reveal unpredicted roles for PPARalpha and beta in adult mouse epidermal repair.

Animals↗

PubMed2001

Cohesin cleavage by separase required for anaphase and cytokinesis in human cells.

Cell division depends on the separation of sister chromatids in anaphase. In yeast, sister separation is initiated by cleavage of cohesin by the protease separase. In vertebrates, most cohesin is removed from chromosome arms by a cleavage-independent mechanism. Only residual amounts of cohesin are cleaved at the onset of anaphase, coinciding with its disappearance from centromeres. We have identified two separase cleavage sites in the human cohesin subunit SCC1 and have conditionally expressed noncleavable SCC1 mutants in human cells. Our results indicate that cohesin cleavage by separase is essential for sister chromatid separation and for the completion of cytokinesis.

Anaphase↗

PubMed2001

Population study of benign rolandic epilepsy: is treatment needed?

Forty-three of 79 children (54%) with benign rolandic epilepsy from a regional population were treated with antiepileptic drugs (AED); 36 (46%) were not. Physician advice was a major determinant of treatment choice. AED significantly reduced generalized seizures (p = 0.001) but did not reduce partial seizures. After 4 to 14 years and >900 seizures, all patients were in remission without medication or injury. Physicians may confidently offer a no-AED treatment strategy.

Anticonvulsants↗

PubMed2001

Peroxisome proliferator-activated receptor-alpha regulates lipid homeostasis, but is not associated with obesity: studies with congenic mouse lines.

Considerable controversy exists in determining the role of peroxisome proliferator-activated receptor-alpha (PPARalpha) in obesity. Two purebred congenic strains of PPARalpha-null mice were developed to study the role of this receptor in modulating lipid transport and storage. Weight gain and average body weight in wild-type and PPARalpha-null mice on either an Sv/129 or a C57BL/6N background were not markedly different between genotypes from 3 to 9 months of age. However, gonadal adipose stores were significantly greater in both strains of male and female PPARalpha-null mice. Hepatic accumulation of lipids was greater in both strains and sexes of PPARalpha-null mice compared with wild-type controls. Administration of the peroxisome proliferator WY-14643 caused hepatomegaly, alterations in mRNAs encoding proteins that regulate lipid metabolism, and reduced serum triglycerides in a PPARalpha-dependent mechanism. Constitutive differences in serum cholesterol and triglycerides in PPARalpha-null mice were found between genetic backgrounds. Results from this work establish that PPARalpha is a critical modulator of lipid homeostasis in two congenic mouse lines. This study demonstrates that disruption of the murine gene encoding PPARalpha results in significant alterations in constitutive serum, hepatic, and adipose tissue lipid metabolism. However, an overt, obese phenotype in either of the two congenic strains was not observed. In contrast to earlier published work, this study establishes that PPARalpha is not associated with obesity in mice.

Animals↗

PubMed2001

The casein kinase I family: roles in morphogenesis.

Wnt signals play important roles in development and oncogenesis and are transduced through at least two pathways: a canonical beta-catenin-dependent and a beta-catenin-independent cascade. Casein kinase I (CKI) is required in both invertebrates and vertebrates to transduce canonical Wnt signals. However, its role in the beta-catenin-independent pathway was unknown. During vertebrate embryogenesis, the beta-catenin-independent cascade is thought to control cell movements and has been postulated to be analogous to the Drosophila planar cell polarity pathway, which signals through the JNK cascade. Here, we report that blocking CKI function inhibits embryonic morphogenesis and activates JNK in cell lines. These studies suggest that CKI might also act in the beta-catenin-independent pathway and indicate a role for CKI during convergence extension in early vertebrate development.

3T3 Cells↗

PubMed2001

The casein kinase I family in Wnt signaling.

The canonical Wnt-signaling pathway is critical for many aspects of development, and mutations in components of the Wnt pathway are carcinogenic. Recently, sufficiency tests identified casein kinase Iepsilon (CKIepsilon) as a positive component of the canonical Wnt/beta-catenin pathway, and necessity tests showed that CKIepsilon is required in vertebrates to transduce Wnt signals. In addition to CKIepsilon, the CKI family includes several other isoforms (alpha, beta, gamma, and delta) and their role in Wnt sufficiency tests had not yet been clarified. However, in Caenorhabditis elegans studies, loss-of-function of a CKI isoform most similar to alpha produced the mom phenotype, indicative of loss-of-Wnt signaling. In this report, we examine the ability of the various CKI isoforms to activate Wnt signaling and find that all the wild-type CKI isoforms do so. Dishevelled (Dsh), another positive component of the Wnt pathway, becomes phosphorylated in response to Wnt signals. All the CKI isoforms, with the exception of gamma, increase the phosphorylation of Dsh in vivo. In addition, CKI directly phosphorylates Dsh in vitro. Finally, we find that CKI is required in vivo for the Wnt-dependent phosphorylation of Dsh. These studies advance our understanding of the mechanism of Wnt action and suggest that more than one CKI isoform is capable of transducing Wnt signals in vivo.

Adaptor Proteins, Signal Transducing↗

PubMed2001

Emi1 is a mitotic regulator that interacts with Cdc20 and inhibits the anaphase promoting complex.

We have discovered an early mitotic inhibitor, Emi1, which regulates mitosis by inhibiting the anaphase promoting complex/cyclosome (APC). Emi1 is a conserved F box protein containing a zinc binding region essential for APC inhibition. Emi1 accumulates before mitosis and is ubiquitylated and destroyed in mitosis, independent of the APC. Emi1 immunodepletion from cycling Xenopus extracts strongly delays cyclin B accumulation and mitotic entry, whereas nondestructible Emi1 stabilizes APC substrates and causes a mitotic block. Emi1 binds the APC activator Cdc20, and Cdc20 can rescue an Emi1-induced block to cyclin B destruction. Our results suggest that Emi1 regulates progression through early mitosis by preventing premature APC activation, and may help explain the well-known delay between cyclin B/Cdc2 activation and cyclin B destruction.

Adenosine Triphosphatases↗

PubMed2001

Securin is required for chromosomal stability in human cells.

Abnormalities of chromosome number are the most common genetic aberrations in cancer. The mechanisms regulating the fidelity of mitotic chromosome transmission in mammalian cells are therefore of great interest. Here we show that human cells without an hSecurin gene lose chromosomes at a high frequency. This loss was linked to abnormal anaphases during which cells underwent repetitive unsuccessful attempts to segregate their chromosomes. The abnormal mitoses were associated with biochemical defects in the activation of separin, the sister-separating protease, rendering it unable to cleave the cohesin subunit Scc1 efficiently. These results illuminate the function of mammalian securin and show that it is essential for the maintenance of euploidy.

Amino Acid Sequence↗

PubMed2001

Anaphase-promoting complex/cyclosome-dependent proteolysis of human cyclin A starts at the beginning of mitosis and is not subject to the spindle assembly checkpoint.

Cyclin A is a stable protein in S and G2 phases, but is destabilized when cells enter mitosis and is almost completely degraded before the metaphase to anaphase transition. Microinjection of antibodies against subunits of the anaphase-promoting complex/cyclosome (APC/C) or against human Cdc20 (fizzy) arrested cells at metaphase and stabilized both cyclins A and B1. Cyclin A was efficiently polyubiquitylated by Cdc20 or Cdh1-activated APC/C in vitro, but in contrast to cyclin B1, the proteolysis of cyclin A was not delayed by the spindle assembly checkpoint. The degradation of cyclin B1 was accelerated by inhibition of the spindle assembly checkpoint. These data suggest that the APC/C is activated as cells enter mitosis and immediately targets cyclin A for degradation, whereas the spindle assembly checkpoint delays the degradation of cyclin B1 until the metaphase to anaphase transition. The "destruction box" (D-box) of cyclin A is 10-20 residues longer than that of cyclin B. Overexpression of wild-type cyclin A delayed the metaphase to anaphase transition, whereas expression of cyclin A mutants lacking a D-box arrested cells in anaphase.

Amino Acid Sequence↗