RESUMO
Low birth weight and fetal thinness have been associated with non-insulin dependent diabetes mellitus (NIDDM) and insulin resistance in childhood and adulthood. It has been proposed that this association results from fetal programming in response to the intrauterine environment. An alternative explanation is that the same genetic influences alter both intrauterine growth and adult glucose tolerance. Fetal insulin secretion in response to maternal glycaemia plays a key role in fetal growth, and adult insulin secretion is a primary determinant of glucose tolerance. We hypothesized that a defect in the sensing of glucose by the pancreas, caused by a heterozygous mutation in the glucokinase gene, could reduce fetal growth and birth weight in addition to causing hyperglycaemia after birth. In 58 offspring, where one parent has a glucokinase mutation, the inheritance of a glucokinase mutation by the fetus resulted in a mean reduction of birth weight of 533 g (P=0.002). In 19 of 21 sibpairs discordant for the presence of a glucokinase mutation, the child with the mutation had a lower birth weight, with a mean difference of 521 g (P=0.0002). Maternal hyperglycaemia due to a glucokinase mutation resulted in a mean increase in birth weight of 601 g (P=0.001). The effects of maternal and fetal glucokinase mutations on birth weight were additive. We propose that these changes in birth weight reflect changes in fetal insulin secretion which are influenced directly by the fetal genotype and indirectly, through maternal hyperglycaemia, by the maternal genotype. This observation suggests that variation in fetal growth could be used in the assessment of the role of genes which modify either insulin secretion or insulin action.
Assuntos
Glucoquinase/genética , Recém-Nascido de Baixo Peso , Insulina/fisiologia , Mutação , Adulto , Peso ao Nascer/genética , Desenvolvimento Embrionário e Fetal , Feminino , Genótipo , Humanos , Recém-Nascido , Insulina/metabolismo , Secreção de InsulinaRESUMO
The current work presents a systematic study of two alloy compositions (RR3010 and CMSX-4) and two types of coatings: inward grown (pack) and outward grown (vapour) deposited aluminides, exposed to 98Na2SO4-2NaCl mixture. Grit blasting was used on some of the samples, prior to coating, to mimic in-service procedures and remove oxides from the surface prior to coating. Two-point bend tests were then performed on the coated samples, with and without applied salt at 550 °C for 100 hours. Samples were pre-strained at 0.6 pct strain to deliberately pre-crack the coating and then strained at 0.3 pct for the heat treatment. Exposure to 98Na2SO4-2NaCl under applied stress of vapour-aluminide coated samples of both alloys, revealed significant coating damage in the form of secondary cracks in the intermetallic-rich inter-diffusion zone, although only CMSX-4 exhibited cracks propagating further into the bulk alloy while RR3010 proved more resistant. The pack-aluminide coating proved more protective for both alloys, with cracks propagating only into the coating and never into the underlying alloy. In addition, grit blasting proved beneficial in reducing spallation and cracking for both types of coating. The findings were used to propose a mechanism based on thermodynamic reactions, to explain the crack width changes through the formation of volatile AlCl3 in the cracks.
RESUMO
INTRODUCTION: There is little published regarding the association between canine cardiovascular disease and the hepatic system. The objective of the study was to evaluate the relationship between hepatic parameters, survival, and disease stages of dogs with either dilated cardiomyopathy (DCM) or degenerative valvular disease (DVD). ANIMALS, MATERIALS, AND METHODS: Retrospective study analyzing hepatic parameters in dogs with DVD or DCM in American College of Veterinary Internal Medicine stage B or C and healthy control dogs. Associations between liver parameters, type and stage of disease, and survival were investigated. RESULTS: Ninety-nine dogs were included in the study: 61 DVD, 22 DCM, and 16 controls. Differences in liver parameter concentrations between DCM, DVD, and disease stages were found. Univariate analysis identified alanine aminotransferase (P < 0.001), aspartate aminotransferase (P = 0.02), and total bilirubin (P = 0.005) as predictors of mortality. In the multivariate analysis, total bilirubin remained an independent predictor of mortality. CONCLUSIONS: The observed differences between DCM, DVD, and disease stages are likely consistent with disease-specific hemodynamics and progression of disease. This and the role of total bilirubin as an independent predictor for mortality indicate that in dogs with DVD and DCM the cardiovascular-hepatic interaction might be of relevance for disease progression and outcome, as reported for humans with cardiac disease. Further studies into the role of hepatic function in canine cardiac disease are required.
Assuntos
Cardiomiopatia Dilatada , Doenças do Cão , Doenças das Valvas Cardíacas , Humanos , Cães , Animais , Cardiomiopatia Dilatada/veterinária , Estudos Retrospectivos , Bilirrubina , Doenças das Valvas Cardíacas/veterináriaRESUMO
This study looks at the difference between the macroscopic and microscopic appearances of the anterior cruciate ligament (ACL) in a sample of 55 consecutive patients admitted for routine total knee replacement for osteoarthritis. At the time of surgery the macroscopic appearance of the ACL was classified as normal, moderately damaged (fissured) or completely ruptured. The excised ACL was sent for histological examination and grading. The macroscopic appearance of the ACL at surgery was compared to the severity of disease on microscopic examination. At surgery, 31 ACLs were found to be macroscopically normal: 22 of these (71%) showed moderate to severe disease on microscopic assessment. Thus a macroscopically normal ACL does not necessarily imply histological integrity. This has clinical implications in other areas of knee surgery including Unicompartmental Knee Replacement which require a fully functional intact ACL.
Assuntos
Ligamento Cruzado Anterior/patologia , Osteoartrite do Joelho/patologia , Idoso , Idoso de 80 Anos ou mais , Lesões do Ligamento Cruzado Anterior , Estudos de Coortes , Feminino , Humanos , Instabilidade Articular/diagnóstico , Masculino , Pessoa de Meia-Idade , Osteoartrite do Joelho/complicaçõesRESUMO
Miniature parallel bioreactors are becoming increasingly important as tools to facilitate rapid bioprocess design. Once the most promising strain and culture conditions have been identified a suitable scale-up basis needs to be established in order that the cell growth rates and product yields achieved in small scale optimization studies are maintained at larger scales. Recently we have reported on the design of a miniature stirred bioreactor system capable of parallel operation [Gill et al. (2008); Biochem Eng J 39:164-176]. In order to enable the predictive scale-up of miniature bioreactor results the current study describes a more detailed investigation of the bioreactor mixing and oxygen mass transfer characteristics and the creation of predictive engineering correlations useful for scale-up studies. A Power number of 3.5 for the miniature turbine impeller was first established based on experimental ungassed power consumption measurements. The variation of the measured gassed to ungassed power ratio, P(g)/P(ug), was then shown to be adequately predicted by existing correlations proposed by Cui et al. [Cui et al. (1996); Chem Eng Sci 51:2631-2636] and Mockel et al. [Mockel et al. (1990); Acta Biotechnol 10:215-224]. A correlation relating the measured oxygen mass transfer coefficient, k(L)a, to the gassed power per unit volume and superficial gas velocity was also established for the miniature bioreactor. Based on these correlations a series of scale-up studies at matched k(L)a (0.06-0.11 s(-1)) and P(g)/V (657-2,960 W m(-3)) were performed for the batch growth of Escherichia coli TOP10 pQR239 using glycerol as a carbon source. Constant k(L)a was shown to be the most reliable basis for predictive scale-up of miniature bioreactor results to conventional laboratory scale. This gave good agreement in both cell growth and oxygen utilization kinetics over the range of k(L)a values investigated. The work described here thus gives further insight into the performance of the miniature bioreactor design and will aid its use as a tool for rapid fermentation process development.
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Reatores Biológicos , Fermentação , Microbiologia Industrial/métodos , Miniaturização/instrumentação , Oxigênio/metabolismo , Biomassa , Reatores Biológicos/economia , Técnicas de Cultura de Células/instrumentação , Técnicas de Cultura de Células/métodos , Meios de Cultura , Desenho de Equipamento/métodos , Escherichia coli/genética , Escherichia coli/metabolismo , Eletrodos Seletivos de Íons , Cinética , Miniaturização/métodos , Modelos Biológicos , Oxigênio/análise , Oxigenases/genética , Oxigenases/metabolismo , Proteínas Recombinantes de Fusão , Torque , TransdutoresRESUMO
Mutations in the hepatocyte nuclear factor-1alpha (HNF1alpha) gene have recently been shown to cause maturity-onset diabetes of the young (MODY). We have examined 15 U.K. MODY families for mutations in the coding region of the HNF-1alpha gene. Eight different mutations, three frameshift (P291fsinsC, P379fsdelCT, and A443fsdelCA) and five missense mutations (P129T, R131W, R159W, P519L, and T620I), were identified in eleven families (73%). The previously reported mutation P291fsinsC was found in four pedigrees. A screen of a further 32 probands with early onset (<40 years of age) NIDDM showed the mutation in two additional families. This common mutation was present on at least three different haplotypes, suggesting that its high frequency is due to recurrent mutation rather than a founder effect. We have demonstrated that mutations in the HNF-1alpha gene are a common cause of MODY in U.K. families and result in early onset NIDDM with a progressive clinical course. Mutation-based genetic counseling can now be considered for the majority of patients with MODY.
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Proteínas de Ligação a DNA , Diabetes Mellitus Tipo 2/etiologia , Mutação/genética , Proteínas Nucleares , Fatores de Transcrição/genética , Adolescente , Adulto , Idoso , Criança , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/genética , Família , Haplótipos , Fator 1 Nuclear de Hepatócito , Fator 1-alfa Nuclear de Hepatócito , Fator 1-beta Nuclear de Hepatócito , Humanos , Pessoa de Meia-Idade , Linhagem , Polimorfismo Genético/genética , Reino Unido/epidemiologiaRESUMO
Colorectal tumorigenesis in familial adenomatous polyposis (FAP) results from somatic mutation of either the normal APC allele or another growth control gene in epithelial cells bearing a germline APC defect. The rate at which tumors develop is therefore dependent on the somatic mutation frequency; it is not known whether this is normal or elevated in FAP. We aimed to quantify stem cell somatic mutation in FAP, comparing it with hereditary nonpolyposis colorectal cancer (HNPCC) and Crohn's disease (CD). Stem cell somatic mutation frequency was studied in 47 FAP patients, 5 HNPCC patients, and 13 CD patients, all younger than 49 years, by quantifying crypt-restricted loss of O-acetyltransferase activity in sections of morphologically normal colonic mucosa from individuals heterozygous for this monogenically inherited polymorphism. Median stem cell somatic mutation frequency was significantly higher in FAP than HNPCC (4.2 x 10(-4) v 1.4 x 10(-4), Mann-Whitney U, P < .02). The level in CD (4.0 x 10(-4)) was similar to FAP. Mutated crypts occurred in groups more frequently in FAP (22%) than HNPCC (12%) or CD (10%), suggesting an increase in stem cell division associated with crypt fission in FAP. We conclude that stem cell somatic mutation frequency is raised in non-neoplastic colorectal mucosa in FAP. This is probably related to increased stem cell proliferation and contributes to the high rate of tumor formation in this condition.
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Polipose Adenomatosa do Colo/patologia , Mucosa Intestinal/patologia , Mutação , Células-Tronco/patologia , Polipose Adenomatosa do Colo/genética , Adolescente , Adulto , Idoso , Criança , Colo/patologia , Neoplasias Colorretais Hereditárias sem Polipose/patologia , Doença de Crohn/patologia , Feminino , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Reação do Ácido Periódico de Schiff , Reto/patologiaRESUMO
The clinical course of chronic myeloid leukaemia (CML) is characterised by a chronic phase followed by an acute phase or blast crisis. Lymphoid transformation accounts for 20-30% of such events, with the majority of cases being of B cell origin. Extramedullary transformation occurs in approximately 10% of cases. We report a case of T cell lymphoblastic transformation in CML presenting as an extramedullary mass after allogeneic stem cell transplant. This case supports the growing evidence that CML arises in the pluripotent stem cell.
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Transformação Celular Neoplásica , Transplante de Células-Tronco Hematopoéticas , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Linfócitos T/patologia , Adulto , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/terapia , Masculino , Transplante HomólogoRESUMO
A case of an ulcerating rheumatoid nodule of the vulva in a 76 year old woman with rheumatoid arthritis complicated by Felty's syndrome is reported. The patient presented with a mass in the vulval region. On clinical examination, she had an ulcerated mass associated with inguinal lymphadenopathy. These findings resulted in a clinical diagnosis of invasive carcinoma of the vulva and an excision biopsy was carried out. On microscopic examination, the lesion showed the characteristic features of a rheumatoid nodule with ulceration of overlying epidermis. Adjacent vessels showed inflammation and fibrinoid necrosis of their walls suggestive of a vasculitis. Awareness of the possibility of ulceration in rheumatoid nodules may facilitate diagnosis and avert unduly aggressive treatment.
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Nódulo Reumatoide/patologia , Doenças da Vulva/patologia , Idoso , Diagnóstico Diferencial , Feminino , Humanos , Úlcera/patologia , Neoplasias Vulvares/diagnósticoRESUMO
AIM: To assess the effectiveness of clinical audit in improving standards in histopathological reporting of mastectomy specimens. METHODS: Reports on mastectomy specimens containing tumour issued by non-specialist histopathologists in 1990, 1992, 1994, and 1996 were scored for their information content. There were 10 reports evaluated from each year. Before 1990 no reporting guidelines had been formulated within the department. The audits in 1992 and 1994 were performed after agreed written guidelines (including the establishment of six essential pieces of information), and in 1996 the specimens were reported using a proforma. RESULTS: There was a significant increase in information after the introduction of written guidelines but there was a reduction in information over time. In 1990 none of the 10 reports included all six pieces of mandatory information; in 1992 four of the reports contained all mandatory information; in 1994 only one report contained all mandatory information. The introduction of a proforma for reporting resulted in further significant improvement with all 10 reports in 1996 containing all mandatory information. CONCLUSIONS: Successive rounds of audit increases the standard of reporting in histopathology. There is a need for continuing monitoring of standards as these may deteriorate over time. Reporting complex specimens on a proforma has a significant beneficial effect on information content.
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Neoplasias da Mama/patologia , Mastectomia , Auditoria Médica , Prontuários Médicos/normas , Neoplasias da Mama/cirurgia , Feminino , Humanos , Guias de Prática Clínica como Assunto , País de GalesRESUMO
AIM: To determine interobserver and intra-observer agreement in the assessment of cytological grade and intraduct necrosis in pure duct carcinoma in situ (DCIS) of the breast. METHODS: Sixty unselected cases with illustrated diagnostic criteria were circulated to 19 practising histopathologists. RESULTS: Overall agreement was moderate for cytological grade in three categories: 71% agreement; weighted kappa (kappa w), 0.36; intraduct necrosis in three categories (absent, present, extensive): 76% agreement; kappa w, 0.57; and the Van Nuys classification system: 73% agreement; kappa w, 0.48. Agreement was no better among observers participating in the National External Quality Assurance Programme. Intra-observer agreement for cytological assessment (69.6% agreement; kappa w, 0.52) and intraduct necrosis (68.3% agreement; kappa w, 0.48) was moderate, suggesting that individual variation rather than precision of criteria contributes to the lack of agreement. CONCLUSIONS: Moderate agreement on observations can be achieved by non-specialist pathologists, with better agreement on necrosis than cytological grade. There was evidence of consistent individual bias towards over or under scoring cytological grade, which could be corrected with adequate and prompt feedback.
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Neoplasias da Mama/patologia , Carcinoma in Situ/patologia , Carcinoma Ductal de Mama/patologia , Feminino , Humanos , Variações Dependentes do Observador , Reprodutibilidade dos Testes , Estatística como AssuntoRESUMO
BACKGROUND: Sub-Saharan African countries have urged grassroots input to improve research capacity. In East Africa, MicroResearch is fostering local ability to find sustainable solutions for community health problems. At 5years, the following reports its progress. METHODS: The MicroResearch program had three integrated components: (1) 2-week training workshops; (2) small proposal development with international peer review followed by project funding, implementation, knowledge translation; (3) coaching from experienced researchers. Evaluation included standardized questions after completion of the workshops, 2013 online survey of recent workshop participants and discussions at two East Africa MicroResearch Forums in 2013. RESULTS: Between 2008 and 2013, 15 workshops were conducted at 5 East Africa sites with 391 participants. Of the 29 projects funded by MicroResearch, 7 have been completed; of which 6 led to changes in local health policy/practice. MicroResearch training stimulated 13 other funded research projects; of which 8 were external to MicroResearch. Over 90% of participants rated the workshops as excellent with 20% spontaneously noting that MicroResearch changed how they worked. The survey highlighted three local research needs: mentors, skills and funding - each addressed by MicroResearch. On-line MicroResearch and alumni networks, two knowledge translation partnerships and an East Africa Leaders Consortium arose from the MicroResearch Forums. CONCLUSION: MicroResearch helped build local capacity for community-directed interdisciplinary health research.