Focus on genetic modifiers of polyglutamine diseases / 中华神经科杂志

Polyglutamine (PolyQ) diseases are a group of clinically and genetically heterogeneous neurodegenerative diseases, due to an expanded CAG repeat in a coding region of the respective genes leading to neurodegenerative phenotypes by selective neuronal loss. Overall, only part of variance (50%-70%) in age at onset is explained by (CAG)n length, suggesting genetic modifying factors independent of (CAG)n size may contribute to clinical heterogeneity. Here, the research history of genetic modifiers in polyQ diseases is reviewed, and the major findings and current research status are discussed.

O efeito do calor e do frio na mortalidade não-acidental da população residente nas regiões metropolitanas brasileiras ao longo do período de 2000-2014: estudo de série temporal / Heat and cold effect on non-accidental mortality of the population living in brazilian metropolitan regions over the period 2000-2014: time series study

O aumento do risco relativo de mortalidade por diversas causas é associado a temperatura ambiente extremas. Fatores a nível individual e comunitários podem influenciar esta associação podendo aumentar ou diminuir seus efeitos. Estes podem ser variáveis ao longo do tempo, o que poderia fazer esta associação oscilar ao longo dos anos. Esta tese investigou os efeitos a curto prazo da temperatura ambiente na mortalidade da população geral e idosos do Brasil, bem como a modificação desta associação ao longo do tempo. O primeiro manuscrito verificou quais modificadores de efeito modulam a associação temperatura-mortalidade a curto prazo. O segundo manuscrito verificou se houve mudança na associação temperatura-mortalidade ao longo de três períodos sequenciais. Foi analisado mortalidade não-acidental da população geral e idosa, e para estes foi subdividido em causas circulatórias, respiratórias e outras causas. Ambos os estudos utilizaram um modelo aditivo generalizado combinado com distributed lag non-linear models e período de defasagem de 21 dias para estimar a associação temperatura-mortalidade para cada região metropolitana, grupo e período. Os estudos incluíram um teste de heterogeneidade entre os locais e estimativas combinadas para Brasil e regiões geográficas via metanálise. Modelos de metarregressão incluindo fatores a nível do local foram utilizados para análise de possíveis modificadores da associação. Os resultados do primeiro manuscrito evidenciam um efeito do frio e do calor na mortalidade não-acidental da população geral e idosa, bem como para mortalidade cardiovascular, respiratória e outras causas dos idosos do Brasil, principalmente nas regiões metropolitanas e geográficas do Sudeste e Sul do Brasil, sendo geralmente as baixas temperaturas as promotoras de maiores riscos relativos de óbitos. Os fatores geográficos foram os responsáveis por explicar a maior parte da heterogeneidade entre os locais, com destaque para amplitude da temperatura média. Os resultados do segundo manuscrito exibem estimativas pontuais de risco relativo de mortalidade associado ao frio e ao calor diferentes a cada quinquênio, sendo esta flutuação de padrões distintos conforme tipo de causa e região brasileira. A heterogeneidade da associação temperatura-mortalidade entre os locais cresceu ao longo dos períodos para todos os grupos. Nos grupos mortalidade não-acidental e circulatório, nos três períodos, a amplitude da temperatura é a variável que melhor explica esta heterogeneidade. No grupo respiratório a amplitude diária da temperatura foi forte explicador nos dois primeiros períodos. Os resultados desta tese sugerem efeito da temperatura ambiente sobre a mortalidade no Brasil, com maior foco nas regiões Sul e Sudeste. Assim, planejamento de ações com foco de adaptação as temperaturas extremas tanto altas quanto baixas são necessárias e de imediato foco nas regiões Sul e Sudeste.

The increase in the relative risk of mortality from various causes is associated with extreme ambient temperatures. Factors at the individual and community level can influence this association and may increase or decrease its effects. These can be variable over time, which could cause this association to fluctuate over the years. This thesis investigated the short-term effects of ambient temperature on mortality in the general population and the elderly in Brazil, as well as the modification of this association over time. The first manuscript verified which effect modifiers modulate the short-term association of temperature and mortality. The second manuscript verified whether there was a change in the association between temperature and mortality over three sequential periods. Non-accidental mortality of the general and elderly population was analyzed, and for these it was subdivided into circulatory, respiratory and other causes. Both studies used a generalized additive model combined with distributed lag non-linear models and a lag of 21 days, to estimate the temperature-mortality association for each metropolitan region, group and period. The studies included a test of heterogeneity between locations and combined estimates for Brazil and geographic regions via meta-analysis. Meta-regression models including factors at the local level were used to analyze possible modifiers of the association. The results of the first manuscript show an effect of cold and heat on non-accidental mortality in the general and elderly population, as well as for cardiovascular, respiratory and other causes of the elderly in Brazil, especially in the metropolitan and geographic regions of the Southeast and South of Brazil. Brazil, with low temperatures being generally the promoters of higher relative risks of death. The geographical factors were responsible for explaining most of the heterogeneity between the locations, with emphasis on the amplitude of the average temperature. The results of the second manuscript show specific estimates of the relative risk of mortality associated with cold and heat differently every five years, with this fluctuation of different patterns according to the type of cause and the Brazilian region. The heterogeneity of the temperature-mortality association between sites increased over the periods for all groups. In the non-accidental and circulatory mortality groups, in the three periods, the temperature amplitude is the variable that best explains this heterogeneity. In the respiratory group, the daily temperature range was a strong factor in the first two periods. The results of this thesis suggest the effect of ambient temperature on mortality in Brazil, with a greater focus on the South and Southeast regions. Thus, action planning with a focus on adaptation to extreme temperatures, both high and low, is necessary and immediately focus on the South and Southeast regions.

Association between incidence of fatal intracerebral hemorrhagic stroke and fine particulate air pollution

OBJECTIVE@#Few studies investigating associations between fine particulate air pollution and hemorrhagic stroke have considered subtypes. Additionally, less is known about the modification of such association by factors measured at the individual level. We aimed to investigate the risk of fatal intracerebral hemorrhage (ICH) incidence in case of PM (particles ≤ 2.5 μm in aerodynamic diameter) exposure.@*METHODS@#Data on incidence of fatal ICH from 1 June 2012 to 31 May 2014 were extracted from the acute stroke mortality database in Shanghai Municipal Center for Disease Control and Prevention (SCDC). We used the time-stratified case-crossover approach to assess the association between daily concentrations of PM and fatal ICH incidence in Shanghai, China.@*RESULTS@#A total of 5286 fatal ICH cases occurred during our study period. The averaged concentration of PM was 77.45 μg/m. The incidence of fatal ICH was significantly associated with PM concentration. Substantial differences were observed among subjects with diabetes compared with those without; following the increase of PM in lag2, the OR (95% CI) for subjects with diabetes was 1.26 (1.09-1.46) versus 1.05 (0.98-1.12) for those without. We did not find evidence of effect modification by hypertension and cigarette smoking.@*CONCLUSIONS@#Fatal ICH incidence was associated with PM exposure. Our results also suggested that diabetes may increase the risk for ICH incidence in relation to PM.

Mutation analysis of a Chinese pedigree of Leber hereditary optic neuropathy with only male patients / 中华实验眼科杂志

Background Leber hereditary optic neuropathy (LHON) is a maternally inherited disorder characterized by a bilateral acute or subacute painless central visual loss in young adults,predominately in males.So far no one theory can completely explain all clinical manifestations of LHON.Objective This study was to investigate whether there is a linkage between X-chromosomal and mitochondrial mutation in the inheritance of a Chinese LHON pedigree with only male patients.Methods This study was approved by Ethic Committee of Affiliated First Hospital of Zhengzhou University and followed by Declaration of Helsinki.A Chinese LHON pedigree was included in Anyang city from January 2008 to August 2016.Periphery blood of 5-10 ml was collected from 4 sufferers,13 maternal members and 10 non-maternal members for DNA extraction and PCR sequencing.The gene scanning and genotyping analysis were performed by ABI-PRISM 3100 genetic analyzer and Genotyper 3.7 software,and linkage analysis was carried out with Linkage software for the calculation of logarithm of odds (LOD).Mitochondrial DNA (mtDNA) sequence,fluorescence-based Genescan for X-chromosomal sequence were analyzed in the propositus and haplotype was evaluated.Results A total of 5 generations and 71 families were included in the pedigree,with 6 male sufferers,30 maternal members and 41 non-maternal members.The visual acuity was ≤0.10,and the central visual field defection,the optic nerve flushing was found in the acute phase,different levels of the optic nerve fibers atrophy were found in the chronic phase;visual evoked potential (VEP) amplitude was low and peak latency were found in the male patients,and no any ocular abnormality was seen in the maternal members,meeting a maternally inherited characteristics,with the penetranee of 20％.The three primnary mutations were not been found in this family bv PCR sequencing,mtDNA sequencing appeared 31 variation of loci in the proband,including a known G3635A mutation,as well as an unknown ND5 A12340G missense mutation and ND4 T11809C synonymous mutation as well as 28 polymorphism of locus,and the proband was mitochondrial haplotype F1.The maternal families were mutation carriers of G3635A and AI2340G loci,while the same mutation was not found in the normal family members and 107 controls.The maximum two point parametric LOD score was 1.46(θ=0.0) for marker DXS1060,1oeated at Xp22.3,and the two-point and multipoint non-parametric linkage analysis were significant (all at P＞0.05).Conclusions The ND5 A12340G and ND1 G3635A mutations coexist in this LHON family,and the ND5 A12340G mutation is a newly reported mutation.There is no evidence for an X-linked modifiers loci in this Chinese LHON family.

Optimization of modifiers and process for changing superficial hydrophilicity of Indigo Naturalis / 中草药

Objective: To discuss the interaction between modifier and Indigo Naturalis by selecting the modifier that enhancing the superficial hydrophilicity of I. naturalis, then the best powder modification technique was selected to prepare the hydrophilic decoction pieces of I. naturalis, which can suit for decoction. Methods: In this paper, the contact angle was used to select the modifier, thermal stability was studied by different drying temperatures; Mechanism and thermal stability were studied according to the microstructure of alcohols, I. naturalis, and indirrubin preliminarily. Best technique was chosen by single factor experiment and uniform design. Results: Alcohols could enhance the superficial hydrophilicity of I. naturalis comparing to the normal one, the acts of -OH and -CH3 were different, and generally, the modifying effect of longer carbochain and polyhydroxy-alcohol was better. The best modifier was ethanol, the optimum modifying technique was 19% ethanol and grinding for 23 min. Conclusion: Above all, alcohols can enhance the superficial hydrophilicity of I. naturalis, the use of ethanol as modifier and the modifying process are reliable and suitable, and hydrophilic decoction pieces of I. naturalis can be prepared successfully.

Beta talasemia intermedia: características clínicas y estudio molecular. Serie de casos clínicos / Beta thalassemia intermedia: clinical characteristics and molecular analysis. Case series

La beta talasemia intermedia es una hemoglobinopatía de amplio espectro clínico, que surge de la presencia de una o dos mutaciones en el gen HBB, asociada a modificadores genéticos secundarios y/o terciarios. Analizamos las características clínicas y de laboratorio de 29 pacientes con beta talasemia intermedia, evaluados en un período de 23 años. La edad mediana fue de 10,8 años (rango: 0,34-60,4). El 100% de los pacientes mostró anemia microcítica hipocrómica, y solo el 17,2% presentó esplenomegalia y requerimiento transfusional esporádico. El análisis molecular de los pacientes detectó 3 con los dos genes HBB afectados; 2 con un gen HBB afectado y genes alfa cuadriplicados/triplicados; 23 con un gen HBB afectado y genes alfα triplicados; y 1 con dos genes HBB afectados y polimorfismos de genes gama. La correcta identificación de estos pacientes aseguró un adecuado consejo genético y la implementación de controles clínicos regulares.

Beta thalassemiaintermediaisaquantitative haemoglobinopathy covering a broad clinical spectrum, that results from the presence of one or two HBB gene mutations associated with secondary and/or tertiary genetic modifiers. We analyze the clinical and laboratory features of 29 patients with beta thalassemia intermedia, assessed over a period of 23 years. Median age was 10.8 years (range: 0.34-60.4). Hypochromic microcytic anemia was seen in 100% of the patients, while only 17.2% had splenomegaly and occasional transfusion requirement. The molecular analysis of patients detected: 3 with two HBB affected genes; 2 with one HBB affected gene and alpha quadruplicate/triplicate genes; 23 with one HBBaffected gene and alpha triplicate genes and 1 with two HBB affected genes and polymorphisms of gamma genes. The adequate identification of these patients enables us to give appropriate genetic counseling and implementation of regular clinical follow up

Optimization of the entrapment efficiency and release of ambroxol hydrochloride alginate beads.

The objective of the current study was to optimize the composition of alginate beads to produce ambroxol hydrochloride alginate beads with optimum specifications. The study employed beads based on sodium alginate solution (2% w/v) as the main component with calcium chloride solution as crosslinking agent as the prototype beads. The beads were prepared by syringe method. The effect of viscosity modifiers on the morphology, entrapment efficiency and drug release was studied. The prototype beads were spherical semitransparent with entrapment efficiency (EE) of 23%. Incorporation of polyvinylpyrrolidone (PVP) as a viscosity modifier produced spherical semitransparent beads with higher EE values compared with the prototype. Addition of carboxymethyl cellulose (CMC) produced oval opaque beads which have larger size and higher EE values compared with the prototype beads or those containing PVP only. Replacement of CMC with hydroxypropyl methyl cellulose (HPMC) produced semitransparent spherical beads with significant increase in the EE. Monitoring the drug release rate from different beads, the all the tested beads were able to retain the drug in the stomach condition. In the intestinal conditions the release rate depended on the composition of the beads with prototype beads librating most of its contents in the first 15 minutes. Formulations containing either CMC or HPMC were able to retard the drug release in the intestinal phase. In conclusion the study developed beads with optimum entrapment and release of ambroxol hydrochloride.

SUMO Expression and Regulation in Oxidative Stress in Cultured Human Lens Epithelial Cells / 中国医科大学学报

Objective To observe the expression of small ubiquitin?related modifiers(SUMO)protein in normal cultured human lens epithelial cells(SRA01/04)and discuss regulation effects of SUMO protein on oxidative stress induced by high glucose. Methods The expression and local?ization of SUMO 1,2/3,4 was detected in normal cultured SRA01/04 cells through immunocytochemistry. The mRNA expression levels of SUMO 1?4 were examined by RT?PCR after the SRA01/04 cells treated with high glucose media at different concentrations and time points. Samples were grouped by medium concentrations(glucoses 5.5 mmol/L,12.5 mmol/L,25 mmol/L,50 mmol/L respectively for 24 h)and by treatment time(0 h, 6 h,12 h and 24 h respectively). After highly efficient transfection of GFP?SUMO2 into SRA01/04 cells,the survival and apoptotic rates of transfect?ed and un?transfected cells treated with high glucose was detected by CCK8 method and AV/PI double staining flow cytometry. Results The immu?nocytochemistry results showed that SUMO1,2/3,4 proteins were mainly located in the nucleus of SRA01/04 cells and part of SUMO2/3 was in the cytoplasm. RT?PCR results showed that compared with the low?glucose group,the mRNA expression of SUMO1?4 was increased along the increas?ing glucose concentration in the high?glucose group(P<0.05). Compared with 0 h,the mRNA expression of SUMO1?4 was enhanced at 6 h,12 h and 24 h(P<0.05)in the high?glucose group treated at 50 mmol/L concentration. Compared with the un?transfected cells,the survival rate was in?creased and the apoptotic rate was decreased in GFP?SUMO2 transfected cells in oxidative stress induced by high glucose(P<0.05). Conclusion SUMO protein was positively expressed in SRA01/04 cells and the expression of SUMO mRNA was affected by oxidative stress induced by high glu?cose.

Modifiers of TGF-beta1 effector function as novel therapeutic targets of pulmonary fibrosis

Pulmonary fibrosis is a fatal progressive disease with no effective therapy. Transforming growth factor (TGF)-beta1 has long been regarded as a central mediator of tissue fibrosis that involves multiple organs including skin, liver, kidney, and lung. Thus, TGF-beta1 and its signaling pathways have been attractive therapeutic targets for the development of antifibrotic drugs. However, the essential biological functions of TGF-beta1 in maintaining normal immune and cellular homeostasis significantly limit the effectiveness of TGF-beta1-directed therapeutic approaches. Thus, targeting downstream mediators or signaling molecules of TGF-beta1 could be an alternative approach that selectively inhibits TGF-beta1-stimulated fibrotic tissue response while preserving major physiological function of TGF-beta1. Recent studies from our laboratory revealed that TGF-beta1 crosstalk with epidermal growth factor receptor (EGFR) signaling by induction of amphiregulin, a ligand of EGFR, plays a critical role in the development or progression of pulmonary fibrosis. In addition, chitotriosidase, a true chitinase in humans, has been identified to have modulating capacity of TGF-beta1 signaling as a new biomarker and therapeutic target of scleroderma-associated pulmonary fibrosis. These newly identified modifiers of TGF-beta1 effector function significantly enhance the effectiveness and flexibility in targeting pulmonary fibrosis in which TGF-beta1 plays a significant role.

A role of radioprotective agents in cancer therapeutics: a review.

In the field of medicine or dentistry, cancer is one of the most common causes for death of the individual worldwide, in which oral cancer accounts for about 10% of it. One of the most important treatment modalities for cancer includes radiotherapy. During radiotherapy, exposure of the normal tissue to these ionizing radiations, results in mutagenesis and cell death. Several modalities and clinical approaches have been made to reduce these early and late complications of the radiotherapies and one among them is, by the means of pharmacological agents. Many experimental and clinical studies have given rise to new concepts of chemical and molecular pharmacological agents that could be effective in protection and treatment of radiation damage to surrounding normal tissues. Clinical Significance: To reduce the significant complications in irradiated patients, the clinical implication of these radioprotective agents have emerged as potential drugs and with anti-tumour effect in the radiotherapy of various cancers including oral carcinomas.

Biologic response modifiers

Biotherapy, often called biological therapy or immunotherapy, aims at supporting and helping in the treatment of human disease without chemical drugs and invasive therapies, by restoring the natural immune system. It is also used to reduce certain side effects that may be caused by some treatments against cancer, autoimmune diseases, or other diseases. Biotherapy employs substances called biological response modifiers (BRMs). The term BRM is often used synonymously with the terms immunomodulator and immunostimulant. BRMs are agents that modify the host's response to pathogens with resultant beneficial prophylactic or therapeutic effects. The use of BRMs had rapidly expanded since the introduction of the first diagnostic antibodies. They are now employed in oncology, autoimmune diseases, inflammatory diseases, and transplantation medicine. BRMs used in biological therapy include interferones, interleukins, colony-stimulating factors, monoclonal antibodies, differentiation agents, tyrosine kinase inhibitor, tumor necrosis factor, vaccines, and nonspecific immunomodulating agents. BRMs are widely accepted in the treatment of certain types of cancer and rheumatoid arthritis, while others are being tested in research studies. This article reviewed the clinical use and side effects of BRMs in cancer and other diseases.

Floating microspheres: a review

Gastric emptying is a complex process, one that is highly variable and that makes in vivo performance of drug delivery systems uncertain. A controlled drug delivery system with prolonged residence time in the stomach can be of great practical importance for drugs with an absorption window in the upper small intestine. The main limitations are attributed to the inter- and intra-subject variability of gastro-intestinal (GI) transit time and to the non-uniformity of drug absorption throughout the alimentary canal. Floating or hydrodynamically controlled drug delivery systems are useful in such applications. Various gastroretentive dosage forms are available, including tablets, capsules, pills, laminated films, floating microspheres, granules and powders. Floating microspheres have been gaining attention due to the uniform distribution of these multiple-unit dosage forms in the stomach, which results in more reproducible drug absorption and reduced risk of local irritation. Such systems have more advantages over the single-unit dosage forms. The present review briefly addresses the physiology of the gastric emptying process with respect to floating drug delivery systems. The purpose of this review is to bring together the recent literature with respect to the method of preparation, and various parameters affecting the performance and characterization of floating microspheres.

O esvaziamento gástrico é um processo complexo, com elevada variabilidade e responsável pela incerteza do desempenho dos medicamentos in vivo. Dessa forma, os sistemas de liberação modificada de fármacos, com tempo de residência prolongado no estômago, em especial, considerando aqueles fármacos com janela de absorção na porção superior do intestino delgado, apresentam fundamental importância. As principais limitações relativas à absorção do fármaco são, no geral, atribuídas à variabilidade inter e intra-paciente do tempo de trânsito gastro-intestinal (GI) e da não-uniformidade da absorção do fármaco na extensão do canal alimentar. Assim, justifica-se a utilização dos sistemas flutuantes ou hidrodinâmicos de liberação de fármacos. Vários medicamentos gastrorretentivos estão disponibilizados no mercado e incluem comprimidos, cápsulas, pílulas, filmes laminados, microesferas flutuantes, grânulos e pós. As microesferas flutuantes apresentam maior destaque em função da distribuição granulométrica uniforme dessas formulações de dose múltipla. Como resultado, a absorção do fármaco apresenta maior reprodutibilidade e os riscos associados à irritação local são reduzidos. Tais sistemas apresentam maior vantagem quando comparado às formulações de dose única. A presente revisão tem como objetivo apresentar as publicações recentes referentes aos métodos de preparação, os vários parâmetros que afetam o desempenho e a caracterização das microesferas flutuantes. Além disso, o presente trabalho aborda a fisiologia do processo de esvaziamento gástrico no que se refere aos sistemas flutuantes de liberação de fármacos.

Hb E/beta-thalassaemia: a common & clinically diverse disorder.

Haemoglobin E-beta thalassaemia (Hb E/β-thalassaemia) is the genotype responsible for approximately one-half of all severe beta-thalassaemia worldwide. The disorder is characterized by marked clinical variability, ranging from a mild and asymptomatic anaemia to a life-threatening disorder requiring transfusions from infancy. The phenotypic variability of Hb E/β-thalassaemia and the paucity of long-term clinical data, present challenges in providing definitive recommendations for the optimal management of patients. Genetic factors influencing the severity of this disorder include the type of beta-thalassaemia mutation, the co-inheritance of alpha-thalassaemia, and polymorphisms associated with increased production of foetal haemoglobin. Other factors, including a variable increase in serum erythropoietin in response to anaemia, previous or ongoing infection with malaria, previous splenectomy and other environmental influences, may be involved. The remarkable variation, and the instability, of the clinical phenotype of Hb E beta-thalassaemia suggests that careful tailoring of treatment is required for each patient, and that therapeutic approaches should be re-assessed over-time.

Biological response modifiers: Current use and future prospects in cancer therapy.

Over the past few decades, considerable success has been achieved in the field of cancer treatment with biological response modifiers (BRM), which are agents that improve the body's ability to fight cancer by immunostimulation. Biological agents, such as interferons and interleukins, provide nonspecific active immunity, whereas the monoclonal antibodies provide passive immunity. Apart from this, other biological agents, such as antiangiogenic agents, matrix metalloprotease inhibitors, tyrosine kinase inhibitors, and tumor vaccines, are also increasingly being used in cancer treatment. Hematopoietic factors, such as granulocyte colony-stimulating factor, are used to increase the general immunity and prevent opportunistic infection. BRM are basically used alone or as adjuvants to cancer chemotherapeutic agents. This review sheds light on the current use and the future development of cancer immunotherapy. Search strategy included Pubmed, using the terms "Biological response modifiers in cancer" citations relevant to the topic were screened.

Reliability of Covariates in Baseline Survey of a Cohort Study: Epidemiological Investigation on Cancer Risk Among Residents Who Reside Near the Nuclear Power Plants in Korea / 예방의학회지

OBJECTIVES: We evaluated the reliability of the possible covariates of the baseline survey data collected for the Epidemiological Investigation on Cancer Risk Among Residents Who Reside Near the Nuclear Power Plants in Korea. METHODS: Follow-up surveys were conducted for 477 participants of the cohort at less than 1 year after the initial survey. The mean interval between the initial and follow-up surveys was 282.5 days. Possible covariates were identified by analyzing the correlations with the exposure variable and associations with the outcome variables for all the variables. Logistic regression analysis with stepwise selection was further conducted among the possible covariates to select variables that have covariance with other variables. We considered that these variables can be representing other variables. Seven variables for the males and 3 variables for the females, which had covariance with other possible covariates, were selected as representative variables. The Kappa index of each variable was calculated. RESULTS: For the males, the Kappa indexes were as follow; family history of cancer was 0.64, family history of liver diseases in parents and siblings was 0.56, family history of hypertension in parents and siblings was 0.51, family history of liver diseases was 0.50, family history of hypertension was 0.44, a history of chronic liver diseases was 0.53 and history of pulmonary tuberculosis was 0.36. For females, the Kappa indexes were as follow; family history of cancer was 0.58, family history of hypertension in parents and siblings was 0.56 and family history of hypertension was 0.47. CONCLUSIONS: Most of the possible covariates showed good to moderate agreement.

VEGFA polymorphisms and cardiovascular anomalies in 22q11 microdeletion syndrome: a case-control and family-based study

Microdeletion 22q11 in humans causes velocardiofacial and DiGeorge syndromes. Most patients share a common 3Mb deletion, but the clinical manifestations are very heterogeneous. Congenital heart disease is present in 50-80 percent of patients and is a significant cause of morbidity and mortality. The phenotypic variability suggests the presence of modifiers. Polymorphisms in the VEGFA gene, coding for the vascular endothelial growth factor A, have been associated with non-syndromic congenital heart disease, as well as with the presence of cardiovascular anomalies in patients with microdeletion 22q11. We evaluated the association of VEGFA polymorphisms c.-2578C>A (rs699947), c.-1154G>A (rs1570360) and c.-634C>G (rs2010963) with congenital heart disease in Chilean patients with microdeletion 22q11. The study was performed using case-control and family-based association designs. We evaluated 122 patients with microdeletion 22q11 and known anatomy of the heart and great vessels, and their parents. Half the patients had congenital heart disease. We obtained no evidence of association by either method of analysis. Our results provide further evidence of the incomplete penetrance of the cardiovascular phenotype of microdeletion 22ql 1, but do not support association between VEGFA promoter polymorphisms and the presence of congenital heart disease in Chilean patients with this syndrome.

Determinación y estandarización de plomo en sangre en operarios de estaciones de servicio del Estado Mérida / Blood lead determination and standardization in petrol station workers in the State of Merida

En este trabajo se ha determinado el contenido de plomo (Pb) en sangre en operarios de estaciones de servicio de la ciudad de Mérida (Venezuela) y en un grupo de personas no expuestas ocupacionalmente. Las muestras de sangre provenientes de sujetos de ambos sexos n=21 (controles) y n=65 (personal expuesto) fueron procesadas por absorción atómica con atomización electrotérmica (ETAAS). Las concentraciones obtenidas de 15,27±9,62 y 83,74±28,95 µg/L para los grupos denominados como control y expuesto respectivamente, muestran diferencias altamente significativas que evidencian una exposición directa al Pb, por cuanto los valores del grupo expuesto ocupacional son más de 5 veces superiores a los del grupo control. Los resultados obtenidos también muestran que valores iguales o superiores a 54,79 µg/L son indicadores de exposición directa al Pb, permitiendo establecer valores de tolerancia entre los intervalos de 24,89 y 112,69 µg/L. Estos valores de referencia se encuentran por debajo de lo descripto por Burguera y cols. (1997), lo cual podría atribuirse al reemplazo gradual de la gasolina con plomo, en los últimos años, que ha llevado a una disminución de un 27% en los niveles de plomo en sangre, en comparación con un estudio similar realizado en esta misma ciudad en el año 1997.

In this work the lead (Pb) content in blood was determined in petrol station workers in the city of Merida-Venezuela and in a group of people not occupationally exposed. The blood samples coming from subjects of both sexes n=21 controls and n=65 exposed workers were processed by atomic absorption with electrothermal atomization (ETAAS). The 15.27±9.62 and 83.74±28.95 µg/L concentrations obtained for the group referred to as control and exposed respectively show highly significant differences that evidence a direct exposure to Pb, since the values of the occupationally exposed group are more than 5 times higher than those of the control group. The results obtained also show that values equal to or higher than 54.79 µg/L are indicative of direct exposure to Pb, making it possible to establish tolerance values between the 24.89 and 112.69 µg/L intervals. These reference values are below what was reported by Burguera et al (1997) which could be attributed to the gradual substitution of gasoline for lead that has originated a 27% decrease in lead levels in blood, if compared with a similar study carried out in the same city in 1997.

Proteomic approaches to post-translational modification by ubiquitin family proteins / 基础医学与临床

Post-translational modification by ubiquitin and ubiquitin-like modifiers(Ubls) is one of the most important mechanisms regulating a wide range of cellular processes in eukaryotes.Previous research showed that,through covalently modification by ubiquitin or ubls,the substrate proteins can be regulated in many different ways like stability,subcellular localization,enzymatic activity,protein-protein interaction and so on.Therefore,we believe,that ubiquitin and ubls play very important roles in cellular and biological processes by modifying plenty of proteins.To better understand the ubiquitin and ubls system,proteomic approaches have been developed to purify and identify more protein substrates.Large-scale idendification of ubiquitin/ubls-modification sites by mass spectrometry is particularly important for understanding the molecular mechanism and function of ubiquitin/ubls modification.Upto the present,more and more scientists are getting interested and participating in proteomics research of ubiquitin/Ubl modifications.This review summarizes the rencent results in this field.

Use of Human Skin Reconstructs Containing Melanocytes as a Model to Evaluate the Effect of Pigment Modifiers / 대한피부과학회지

BACKGROUND: Recently human skin reconstructs composed of keratinocytes and melanocytes have been developed. OBJECTIVE: We investigated whether human skin reconstructs containing melanocytes could be useful to test the efficacy of drugs that alter pigmentation. METHODS:Human skin reconstructs were made by culturing human keratinocytes and melanocytes on the top of de-epidermized dermis. Reagents that alter melanogenesis such as isobutyl methylxanthine, 1-oleoyl-2-acetyl-sn-glycerol, kojic acid were treated in the culture medium after 7 days of culture at the air-liquid interface. Macroscopic, histological, histochemical and immunohistochemical studies were performed. RESULTS: The effect of pigment modifiers was demonstrated in human skin reconstructs as expected from in vivo data on skin color, numbers of melanocytes and melanin content. CONCLUSION: These results indicate that this model is very useful to assess the efficacy of drugs that alter pigmentation.

Use of Human Skin Reconstructs Containing Melanocytes as a Model to Evaluate the Effect of Pigment Modifiers / 대한피부과학회지

BACKGROUND: Recently human skin reconstructs composed of keratinocytes and melanocytes have been developed. OBJECTIVE: We investigated whether human skin reconstructs containing melanocytes could be useful to test the efficacy of drugs that alter pigmentation. METHODS:Human skin reconstructs were made by culturing human keratinocytes and melanocytes on the top of de-epidermized dermis. Reagents that alter melanogenesis such as isobutyl methylxanthine, 1-oleoyl-2-acetyl-sn-glycerol, kojic acid were treated in the culture medium after 7 days of culture at the air-liquid interface. Macroscopic, histological, histochemical and immunohistochemical studies were performed. RESULTS: The effect of pigment modifiers was demonstrated in human skin reconstructs as expected from in vivo data on skin color, numbers of melanocytes and melanin content. CONCLUSION: These results indicate that this model is very useful to assess the efficacy of drugs that alter pigmentation.