RESUMO
BACKGROUND: Dental caries in the expanding elderly, predominantly-dentate population is an emerging public health concern. Elderly individuals with heavily restored dentitions represent a clinical challenge and significant financial burden for healthcare systems, especially when their physical and cognitive abilities are in decline. Prescription of higher concentration fluoride toothpaste to prevent caries in older populations is expanding in the UK, significantly increasing costs for the National Health Services (NHS) but the effectiveness and cost benefit of this intervention are uncertain. The Reflect trial will evaluate the effectiveness and cost benefit of General Dental Practitioner (GDP) prescribing of 5000 ppm fluoride toothpaste and usual care compared to usual care alone in individuals 50 years and over with high-risk of caries. METHODS/DESIGN: A pragmatic, open-label, randomised controlled trial involving adults aged 50 years and above attending NHS dental practices identified by their dentist as having high risk of dental caries. Participants will be randomised to prescription of 5000 ppm fluoride toothpaste (frequency, amount and duration decided by GDP) and usual care only. 1200 participants will be recruited from approximately 60 dental practices in England, Scotland and Northern Ireland and followed up for 3 years. The primary outcome will be the proportion of participants receiving any dental treatment due to caries. Secondary outcomes will include coronal and root caries increments measured by independent, blinded examiners, patient reported quality of life measures, and economic outcomes; NHS and patient perspective costs, willingness to pay, net benefit (analysed over the trial follow-up period and modelled lifetime horizon). A parallel qualitative study will investigate GDPs' practises of and beliefs about prescribing the toothpaste and patients' beliefs and experiences of the toothpaste and perceived impacts on their oral health-related behaviours. DISCUSSION: The Reflect trial will provide valuable information to patients, policy makers and clinicians on the costs and benefits of an expensive, but evidence-deficient caries prevention intervention delivered to older adults in general dental practice. TRIAL REGISTRATION: ISRCTN: 2017-002402-13 registered 02/06/2017, first participant recruited 03/05/2018. Ethics Reference No: 17/NE/0329/233335. Funding Body: Health Technology Assessment funding stream of National Institute for Health Research. Funder number: HTA project 16/23/01. Trial Sponsor: Manchester University NHS Foundation Trust, Oxford Road, Manchester, M13 9WL. The Trial was prospectively registered.
Assuntos
Cárie Dentária , Fluoretos , Cremes Dentais , Idoso , Análise Custo-Benefício , Inglaterra , Humanos , Pessoa de Meia-Idade , Qualidade de Vida , EscóciaRESUMO
In cultured hepatocytes, as in vivo, mono-2-ethylhexyl phthalate (MEHP) and its straight chain analogues mono-n-hexyl phthalate (MnHP) and mono-n-octyl phthalate (MnOP) each cause accumulation of lipid but only MEHP produces significant induction of peroxisomal fatty acid oxidizing enzymes. To elucidate the mechanisms underlying this lipid accumulation we investigated the effects of these phthalates and the drug clofibric acid on fatty acid metabolism in suspensions of isolated hepatocytes. The effects were found to be markedly dependent on the nutritional state of the animals from which the hepatocytes were isolated. In hepatocytes isolated from animals fasted overnight, or animals fed ab libitum but killed at approximately 2.30 p.m., MEHP, MnHP, MnOP and clofibric acid each caused a marked rapid stimulation of fatty acid oxidation and the synthesis of triglycerides in hepatocytes when incubated in Hanks saline. Export of very low density lipoprotein (VLDL) from the cells was either unchanged or somewhat reduced. In contrast, in hepatocytes isolated from rats fed ad libitum but killed at approximately 9.30 a.m. MEHP and clofibric acid did not alter fatty acid oxidation or triglyceride synthesis, while MnOP and MnHP increased triglyceride synthesis but decreased fatty acid oxidation. The effects of fasting were largely abolished by incubations of the cells in a complete tissue culture medium (Liebowitz L-15). The results suggest that MEHP and its straight chain analogues can, either as the free acid or the CoA ester, mimic the action of fatty acids in the allosteric regulation of fatty acid metabolism.
Assuntos
Dietilexilftalato/toxicidade , Metabolismo dos Lipídeos , Fígado/metabolismo , Ácidos Ftálicos/toxicidade , Animais , Células Cultivadas , Clofibrato/farmacologia , Dietilexilftalato/análogos & derivados , Lipoproteínas/biossíntese , Fígado/efeitos dos fármacos , Masculino , Microcorpos/efeitos dos fármacos , Microcorpos/metabolismo , Oxirredução , Ácido Palmítico , Ácidos Palmíticos/metabolismo , Ratos , Ratos Endogâmicos , Triglicerídeos/metabolismoRESUMO
The effects, over periods from 3 days to 9 months of administration, of diets containing di-2-ethylhexyl phthalate are very similar to those observed in rats administered diets containing hypolipidemic drugs such as clofibrate. Changes occur in a characteristic order commencing with alterations in the distribution of lipid within the liver, quickly followed by proliferation of hepatic peroxisomes and induction of the specialized P-450 isoenzyme(s) catalyzing omega oxidation of fatty acids. There follows a phase of mild liver damage indicated by induction of glucose-6-phosphatase activity and a loss of glycogen, eventually leading to the formation of enlarged lysosomes through autophagy and the accumulation of lipofuscin. Associated changes are found in the kidney and thyroid. The renal changes are limited to the proximal convoluted tubules and are generally similar to changes found in the liver. The effects on the thyroid are more marked. Although the levels of thyroxine in plasma fail to about half normal values, serum triiodothyronine remains close to normal values while the appearance of the thyroid varies, very marked hyperactivity being noted 7 days after commencement of treatment, this is less marked at 14 days, but even after 9 months treatment there is clear cut evidence for hyperactivity with colloid changes which indicate this has persisted for some time. Straight chain analogs of di-2-ethylhexyl phthalate, di-n-hexyl phthalate and di-n-oxtyl phthalate differ entirely in their short-term effects on the liver and kidney but have similar effects on the thyroid. The short-term in vivo hepatic effects of the three phthalate esters can be reproduced in hepatocytes in tissue culture. All three phthalate esters, as well as clofibrate, have early marked effects on the metabolism of fatty acids in isolated hepatocytes. The nature of these changes is such as to increase storage of lipid in the liver. A hypothesis is presented to explain the progress from these initial metabolic effects to the final formation of liver tumors.
Assuntos
Fígado/patologia , Ácidos Ftálicos/toxicidade , Glândula Tireoide/patologia , Animais , Células Cultivadas , Feminino , Rim/efeitos dos fármacos , Rim/patologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Ratos , Ratos Endogâmicos , Relação Estrutura-Atividade , Glândula Tireoide/efeitos dos fármacos , Glândula Tireoide/metabolismoRESUMO
Groups of male Wistar albino rats were administered diets containing sufficient fenofibrate to ensure intakes of either 200, 60 or 13 mg/kg/day or sufficient clofibrate to ensure an intake of 400 mg/kg/day. Four rats from each experimental group and 6 control rats were killed, 3, 7, 14 and 28 days, 8, 12 and 20 weeks and 6, 9, 12 and 18 months after commencement of treatment. At all time points livers were subjected to histological, electron microscopic and biochemical examination, the other major abdominal organs were removed for histological examination. A more extensive necropsy was carried out on rats killed after 12 and 18 months. The major alterations were observed in the liver, although there were also morphological changes in the thyroid, pancreas and kidney after prolonged treatment. The hepatic changes followed a distinct time course. Within 24 h of offering diets containing the compounds to the rats there was accumulation of small droplets of lipid, induction of peroxisomal enzymes and of the specific cytochrome P-450 catalysing omega-hydroxylation of fatty acids and an increase in the number of mitotic figures. More slowly developing changes were loss from the centrilobular zone of fat, glycogen and of glucose 6-phosphatase activity. Here maximal changes were observed after 14 days of treatment. A still more slowly developing change was accumulation of enlarged lipid-loaded lysosomes, which was maximal at 26 weeks, accompanied by the development of lipofuscin bodies. Finally, in animals treated for 12 months or more there was evidence for increasing cell turnover as indicated by an increased number of mitotic figures, more dark cells and induction of serum alanine transaminase. The last 2 groups of changes were not observed in rats treated with 13 mg/kg/day of fenofibrate. In general the degree of change in rats treated with 400 mg/kg/day of clofibrate was similar to those found in rats treated with 60 mg/kg/day of fenofibrate.
Assuntos
Fenofibrato/toxicidade , Hipolipemiantes/toxicidade , Fígado/efeitos dos fármacos , Propionatos/toxicidade , Animais , Clofibrato/toxicidade , Sistema Enzimático do Citocromo P-450/análise , Relação Dose-Resposta a Droga , Retículo Endoplasmático/efeitos dos fármacos , Rim/efeitos dos fármacos , Metabolismo dos Lipídeos , Fígado/metabolismo , Fígado/patologia , Lisossomos/efeitos dos fármacos , Masculino , Microcorpos/efeitos dos fármacos , Ratos , Ratos Endogâmicos , Fatores de TempoRESUMO
Eastern encephalomyelitis virus was isolated from the brain of 2 calves with encephalomyelitis. Using the isolant from 1 of these calves, the disease was reproduced in a clinically normal calf. Histopathologic features conformed with those described for eastern encephalomyelitis in the horse.
Assuntos
Doenças dos Bovinos , Encefalomielite/veterinária , Animais , Encéfalo/patologia , Bovinos , Doenças dos Bovinos/patologia , Vírus da Encefalite Equina do Leste , Encefalomielite/patologiaRESUMO
Ten gray foxes seronegative for canine distemper virus were vaccinated with 1 of 3 commercial modified live-virus canine distemper vaccines. Of 5 foxes receiving vaccine A (chicken tissue culture origin), 4 developed significant titers (greater than or equal to 1:100) of neutralizing antibody to canine distemper virus and remained clinically normal after vaccination. Two of 3 foxes vaccinated with vaccine B (canine cell line origin) and both foxes receiving vaccine C (canine cell line origin) died of vaccine-induced distemper. Five unvaccinated control foxes died of distemper after a known occasion for contact transmission of virus from a fox vaccinated with vaccine B. The results suggested that the chicken tissue culture origin modified live-virus canine distemper vaccine is probably safe for normal adult gray foxes, whereas the canine cell origin vaccines are hazardous. The results of this study tended to corroborate anecdotal experiences of veterinarians who have observed that gray foxes frequently die from distemper soon after vaccination with modified live-virus canine distemper vaccines.
Assuntos
Vírus da Cinomose Canina/imunologia , Cinomose/etiologia , Raposas/imunologia , Vacinas Virais/efeitos adversos , Animais , Cães , Vacinas Atenuadas/efeitos adversosAssuntos
Ração Animal , Fusarium , Pneumonia Intersticial Atípica dos Bovinos/etiologia , Verduras , Animais , Bovinos , Doenças dos Bovinos/etiologia , Feminino , Doenças Transmitidas por Alimentos/etiologia , Doenças Transmitidas por Alimentos/veterinária , Masculino , Micotoxinas , Pneumonia Intersticial Atípica dos Bovinos/patologiaAssuntos
Vírus da Encefalite , Encefalomielite Equina/veterinária , Doenças dos Suínos/etiologia , Animais , Encéfalo/microbiologia , Encéfalo/patologia , Células Cultivadas , Efeito Citopatogênico Viral , Vírus da Encefalite/patogenicidade , Encefalomielite Equina/microbiologia , Encefalomielite Equina/patologia , Rim , Microscopia Eletrônica , Suínos , Doenças dos Suínos/microbiologia , Doenças dos Suínos/patologia , Cultura de VírusRESUMO
As a means of determining the role of protein kinase C in the signal transduction from novel growth factors and hormones, we investigated the effects of well-characterized agents on the phosphorylation state of protein kinase C itself. These studies show that agents that stimulate protein kinase C either directly (phorbol esters) or indirectly through phosphatidylinositol breakdown (platelet-derived growth factor) induce an increase in the phosphorylation state of the kinase. By contrast, epidermal growth factor, which does not stimulate protein kinase C in fibroblasts, does not increase the phosphorylation state of protein kinase C, but leads to a decrease. The data suggest that the phosphorylation state of protein kinase C is dynamically controlled and can be used to provide evidence of protein kinase C activation.
Assuntos
Proteína Quinase C/metabolismo , Células Cultivadas , Ativação Enzimática , Fator de Crescimento Epidérmico , Fibroblastos/enzimologia , Humanos , Fosforilação , Fator de Crescimento Derivado de Plaquetas , Acetato de TetradecanoilforbolRESUMO
Groups of male and groups of female Wistar albino rats were administered diets containing sufficient di(2-ethylhexyl) phthalate (DEHP) to ensure intakes of either 1000, 200, or 50 mg/kg/day. Four rats from each experimental group and six control rats of the same sex were killed 3, 7, 14, and 28 days and 9 months after commencement of treatment. At all time points the major abdominal organs were removed and subjected to histological examination. A more extensive necropsy was performed on those rats killed after 9 months of treatment. At all time points the livers of the rats were subjected to extensive histologic, electron microscopic, and biochemical examination. Changes could be grouped according to their time course. Two early and transient alterations were noticed. First, there were morphologic changes in the bile canaliculi of male rats treated with 1000 mg/kg/day of DEHP. Second, there was a burst of mitosis immediately after the start of administration of the compound. The time course of this mitotic burst varied; the increase in mitosis was greatest at 3 days in rats treated with 1000 mg/kg/day of DEHP and was smaller but more prolonged in rats treated with 200 or 50 mg/kg/day. Other changes, namely, a midzonal to periportal accumulation of fat, induction of peroxisomal enzymes, and induction of the P-450 isoenzyme also developed rapidly but were sustained throughout the study. The maximal change was usually attained within 7 days of commencement of treatment. More slowly developing changes were hypertrophy of the hepatocytes, centrilobular loss of glycogen, and a fall in glucose-6-phosphatase activity. Here maximal changes were not attained until 28 days after commencement of treatment. These three effects were clearly observed in rats treated with 200 or 1000 mg/kg/day of DEHP but were only marginally altered in rats treated with 50 mg/kg/day. Finally accumulation of lipid-loaded lysosomes assessed by light and electron microscopy and by assay of beta-galactosidase activity was only apparent in rats treated with DEHP for 9 months with 200 or 1000 mg/kg/day of DEHP. Changes in female rats were qualitatively similar to those observed in male rats. The alterations were, however, less pronounced than in male rats treated with an equal dose of DEHP and the degree of liver enlargement was much less because, although the initial hyperplasia was clearly apparent, there was a much smaller degree of hypertrophy.
Assuntos
Dietilexilftalato/toxicidade , Fígado/efeitos dos fármacos , Ácidos Ftálicos/toxicidade , Administração Oral , Animais , Peso Corporal/efeitos dos fármacos , Catalase/metabolismo , Sistema Enzimático do Citocromo P-450/farmacologia , DNA/biossíntese , Feminino , Glicerolfosfato Desidrogenase/metabolismo , Hepatomegalia/induzido quimicamente , Fígado/enzimologia , Fígado/ultraestrutura , Neoplasias Hepáticas/induzido quimicamente , Neoplasias Hepáticas/metabolismo , Masculino , Neoplasias Experimentais/induzido quimicamente , Neoplasias Experimentais/metabolismo , Palmitoil-CoA Hidrolase/metabolismo , Ratos , Ratos Endogâmicos , Fatores SexuaisRESUMO
Cattle given intraruminal administration of 4-ipomeanol, a furanoterpenoid originally obtained from sweet potatoes infected with Fusarium solani (F. javanicum), developed a respiratory syndrome clinically and histologically indistinguishable from atypical interstitial pneumonia. There were edema and emphysema in the lungs and mediastinum. The maximum nonlethal oral dose of 4-ipomeanol was estimated to be between 7.5 and 9 mg/kg of body weight.
Assuntos
Pneumonia Intersticial Atípica dos Bovinos/induzido quimicamente , Terpenos/toxicidade , Verduras , Animais , Bovinos , Feminino , Furanos/toxicidade , Fusarium , Pulmão/patologia , Pneumonia Intersticial Atípica dos Bovinos/patologiaRESUMO
This study compares changes in the livers of rats treated with di(2-ethylhexyl) phthalate (DEHP) and its straight-chain analogs di(n-hexyl) phthalate (DnHP) and di(n-octyl phthalate (DnOP). Groups of rats were fed diets containing 20,000 ppm of one of these compounds. Subgroups were killed after 3, 10, and 21 days, and the livers were examined by histological, cytological, and biochemical methods. The results show considerable differences between the effects of the branched-chain phthalate ester DEHP and its straight-chain analogs. The major effects on the liver following administration of diets containing DEHP were midzonal and periportal accumulation of small droplets of lipid, hepatomegaly accompanied by an initial burst of mitosis, proliferation of hepatic peroxisomes and of smooth endoplasmic reticulum accompanied by induction of peroxisomal fatty acid oxidation, damage to the peroxisomal membranes as evidenced by increased leakage of catalase to the cytosol, and centrilobular loss of glycogen and falls in glucose-6-phosphatase activity and in low-molecular-weight reducing agents. In contrast, diets containing DnHP or DnOP induced accumulation of large droplets of fat around central veins leading, by 10 days, to mild centrilobular necrosis and a very slight induction of one peroxisomal enzyme and an increase in liver weight, but no significant changes in any other parameters which were affected by DEHP.
Assuntos
Dietilexilftalato/farmacologia , Fígado/efeitos dos fármacos , Ácidos Ftálicos/farmacologia , Administração Oral , Animais , Peso Corporal/efeitos dos fármacos , Ingestão de Alimentos/efeitos dos fármacos , Fígado/enzimologia , Fígado/patologia , Masculino , Tamanho do Órgão/efeitos dos fármacos , Ratos , Ratos Endogâmicos , Relação Estrutura-Atividade , Testículo/efeitos dos fármacosRESUMO
Treatment of rats with hypolipidaemic drugs or with the plasticizer di-2-ethyl hexyl phthalate caused significant alterations in the concentration of certain plasma proteins. Certain proteins showed dose-dependent increases, in other cases the plasma concentrations fell in treated animals. The changes were quite distinct from the changes in plasma proteins which occur during the acute-phase response to inflammatory agents. Some changes appeared specific to agents which produce peroxisome proliferation in liver, other alterations appeared associated with mild, but sustained, liver injury.