The PROP1 2-Base Pair Deletion Is a Common Cause of Combined Pituitary Hormone Deficiency

Combined pituitary hormone deficiency (CPHD) has an incidence of approximately 1 in 8000 births. Although the proportion of familial CPHD cases is unknown, about 10% have an affected first degree relative. We have recently reported three mutations in the PROP1 gene that cause CPHD in human subjects. We report here the frequency of one of these mutations, a 301–302delAG deletion in exon 2 of PROP1, in 10 independently ascertained CPHD kindreds and 21 sporadic cases of CPHD from 8 different countries. Our results show that 55% (11 of 20) of PROP1 alleles have the 301–302delAG deletion in familial CPHD cases. Interestingly, although only 12% (5 of 42) of the PROP1 alleles of our 21 sporadic cases were 301–302delAG, the frequency of this allele (in 20 of 21 of the sporadic subjects given TRH stimulation tests) was 50% (3 of 6) and 0% (0 of 34) in the CPHD cases with pituitary and hypothalamic defects, respectively. Using whole genome radiation hybrid analysis, we localized the PROP1 gene to the distal end of chromosome 5q and identified a tightly linked polymorphic marker, D5S408, which can be used in segregation studies. Analysis of this marker in affected subjects with the 301–302delAG deletion suggests that rather than being inherited from a common founder, the 301–302delAG may be a recurring mutation.

The PROP1 2-Base Pair Deletion Is a Common Cause of Combined Pituitary Hormone Deficiency

Combined pituitary hormone deficiency (CPHD) has an incidence of approximately 1 in 8000 births. Although the proportion of familial CPHD cases is unknown, about 10% have an affected first degree relative. We have recently reported three mutations in the PROP1 gene that cause CPHD in human subjects. We report here the frequency of one of these mutations, a 301-302delAG deletion in exon 2 of PROP1, in 10 independently ascertained CPHD kindreds and 21 sporadic cases of CPHD from 8 different countries. Our results show that 55% (11 of 20) of PROP1 alleles have the 301-302delAG deletion in familial CPHD cases. Interestingly, although only 12% (5 of 42) of the PROP1 alleles of our 21 sporadic cases were 301-302delAG, the frequency of this allele (in 20 of 21 of the sporadic subjects given TRH stimulation tests) was 50% (3 of 6) and 0% (0 of 34) in the CPHD cases with pituitary and hypothalamic defects, respectively. Using whole genome radiation hybrid analysis, we localized the PROP1 gene to the distal end of chromosome 5q and identified a tightly linked polymorphic marker, D5S408, which can be used in segregation studies. Analysis of this marker in affected subjects with the 301-302delAG deletion suggests that rather than being inherited from a common founder, the 301-302delAG may be a recurring mutation.

Investigation of the response to the enterobacterial common antigen after typhoid vaccination

Antibodies against the Salmonella typhi enterobacterial common antigen (ECA) and the O and H antigens were investigated in sera from healthy male subjects who had been previously vaccinated with the typhoid vaccine. No serological response to ECA was observed. Sera from subjects not previously vaccinated presented titers of ECA hemagglutinins which quantitatively were related to the presence ofH titers, but not to O agglutinins but with no statistical significance. The results are discussed in relation to the possible protective immunological mechanisms in typhoid fever.

Experimental schistosomiasis in the Common Marmoset Callithrix jacchus

In order to evaluate Callithrix jacchus as an animal model for mansoni schistosomiasis, a group of 10 male animals were once percutaneously exposed to 250 cercariae of the Schistosoma mansoni SLM (São Lourenço da Mata) strain. Animals were periodically bled for measuring serum level of enzymes and proteins and for blood cell counting. When comparing pre-infection to post-infection values, a significant increase was found for alkaline phosphatase at 15 to 120 days p.i., differential counts of eosinophil at 45 and 60 days, and total protein and global eosinophil counts at 120 days. No Schistosoma mansoni eggs were found in stools. Adult worms of small size were recovered from five animals. At day 120, the number of Schistosoma mansoni eggs/g of tissue was 0-289.7 (liver), 0-30.1 (large intestine) and 0-171.4 (small intestine). These findings lead us to classify Callithrix jacchus as a non-permissive host to the SLM strain of Schistosoma mansoni.

Degree of disability, pain levels, muscle strength, and electromyographic function in patients with Hansen's disease with common peroneal nerve damage

INTRODUCTION: This study evaluated the degree of disability, pain levels, muscle strength, and electromyographic function (RMS) in individuals with leprosy. METHODS: We assessed 29 individuals with leprosy showing common peroneal nerve damage and grade 1 or 2 disability who were referred for physiotherapeutic treatment, as well as a control group of 19 healthy participants without leprosy. All subjects underwent analyses of degree of disability, electromyographic tests, voluntary muscle force, and the Visual Analog Pain Scale. RESULTS: McNemar's test found higher levels of grade 2 of disability (Δ = 75.9%; p = 0.0001) among individuals with leprosy. The Mann-Whitney test showed greater pain levels (Δ = 5.0; p = 0.0001) in patients with leprosy who had less extension strength in the right and left extensor hallucis longus muscles (Δ = 1.28, p = 0.0001; Δ = 1.55, p = 0.0001, respectively) and dorsiflexion of the right and left feet (Δ = 1.24, p = 0.0001; Δ = 1.45, p = 0.0001, respectively) than control subjects. The Kruskal-Wallis test showed that the RMS score for dorsiflexion of the right (Δ = 181.66 m·s-2, p = 0.001) and left (Δ = 102.57m·s-2, p = 0.002) feet was lower in patients with leprosy than in control subjects, but intragroup comparisons showed no difference. CONCLUSIONS: Leprosy had a negative influence on all of the study variables, indicating the need for immediate physiotherapeutic intervention in individuals with leprosy. This investigation opens perspectives for future studies that analyze leprosy treatment with physical therapeutic intervention.

Common variable immunodeficiency and isosporiasis: first report case

We report a severe case of diarrhea in a 62-year-old female HIV-negative patient from whom Giardia lamblia and Isospora belli were isolated. Because unusual and opportunistic infections should be considered as criteria for further analysis of immunological status, laboratory investigations led to a diagnosis of common variable immunodeficiency (CVID). This is the first reported case of isosporiasis in a patient with CVID and illustrates the importance of being aware of a possible link, particularly in relation to primary immunodeficiency.

Nanomateriais manufaturados : avaliação de segurança através da caracterização dos seus efeitos genéticos

RESUMO - Os nanomateriais manufaturados (NMs), isto é, fabricados deliberadamente para fins específicos, apresentam propriedades físico-químicas únicas como a dimensão, área superficial ou funcionalização, que lhes conferem caraterísticas mecânicas, óticas, elétricas e magnéticas muito vantajosas para aplicações industriais e biomédicas. Efetivamente, a tecnologia baseada nos NMs, ou nanotecnologia, foi identificada como uma key enabling technology, impulsionadora do crescimento económico dos países industrializados, devido ao seu potencial para melhorar a qualidade e desempenho de muitos tipos de produtos e de processos. Contudo, a expansão da utilização de NMs contrasta com a insuficiente avaliação de risco para a saúde humana e para o ambiente, sendo considerados como um risco emergente para a saúde pública. As incertezas sobre a segurança dos NMs para a saúde pública advêm sobretudo de estudos epidemiológicos em humanos expostos a nanomateriais produzidos como consequência dos processos e atividades humanas e da poluição. Uma das principais preocupações relativamente aos efeitos adversos dos NMs na saúde humana é o seu potencial efeito carcinogénico, que é sugerido por alguns estudos experimentais, como no caso dos nanomateriais de dióxido de titânio ou dos nanotubos de carbono. Para avaliar em curto termo as propriedades carcinogénicas de um composto, utilizam-se frequentemente ensaios de genotoxicidade em linhas celulares de mamífero ou ensaios em modelos animais, em que se analisa uma variedade de lesões genéticas potencialmente relacionados com o processo de carcinogénese. No entanto, a investigação sobre as propriedades genotóxicas dos NMs não foi, até hoje, conclusiva. O presente estudo tem por objectivo principal caracterizar os efeitos genotóxicos associados à exposição a nanomateriais manufaturados, de forma a contribuir para a avaliação da sua segurança. Constituíram objectivos específicos deste estudo: i) avaliar a genotoxicidade dos NMs em três tipos de células humanas expostas in vitro: linfócitos humanos primários, linha celular de epitélio brônquico humano (BEAS-2B) e linha celular de adenocarcinoma epitelial de pulmão humano (A549); ii) avaliar a sua genotoxicidade num modelo de ratinho transgénico; iii) investigar alguns mecanismos de acção que poderão contribuir para a genotoxicidade dos nanomateriais, como a contribuição de lesões oxidativas para a genotoxicidade induzida pelos NMs in vitro, e a investigação da sua bioacumulação e localização celular in vivo. Foram analisados os efeitos genotóxicos associados à exposição a duas classes de NMs, dióxido de titânio e nanotubos de carbono de parede múltipla, bem como a um NM de óxido de zinco, candidato a ser utlilizado como controlo positivo de dimensão nanométrica. Os xx NMs utilizados foram previamente caracterizados com detalhe relativamente às suas características físico-químicas e também relativamente à sua dispersão em meio aquoso e no meio de cultura. A metodologia incluiu ensaios de citotoxicidade e de genotoxicidade in vitro, designadamente, ensaios de quebras no DNA (ensaio do cometa) e nos cromossomas (ensaio do micronúcleo) em células humanas expostas a várias concentrações de NMs, por comparação com células não expostas. Também foram realizados ensaios in vivo de quebras no DNA, quebras cromossómicas e ainda um ensaio de mutações em vários órgãos de grupos de ratinhos transgénicos LacZ, expostos por via intravenosa a duas doses de dióxido de titânio. Foi investigada a existência de uma relação dose-resposta após exposição das células humanas ou dos animais a NMs. A contribuição de lesões oxidativas para a genotoxicidade após exposição das células aos NMs in vitro foi explorada através do ensaio do cometa modificado com enzima. Realizaram-se estudos histológicos e citológicos para deteção e localização celular dos NMs nos órgãos-alvo dos ratinhos expostos in vivo. Os resultados demonstraram efeitos genotóxicos em alguns dos NMs analisados em células humanas. No entanto, os efeitos genotóxicos, quando positivos, foram em níveis reduzidos, ainda que superiores aos valores dos controlos, e a sua reprodutibilidade era dependente do sistema experimental utilizado. Para outros NMs, a evidência de genotoxicidade revelou-se equívoca, conduzindo à necessidade de esclarecimento através de ensaios in vivo. Para esse fim, recorreu-se a uma análise integrada de múltiplos parâmetros num modelo animal, o ratinho transgénico baseado em plasmídeo contendo o gene LacZ exposto a um NM de dióxido de titânio, NM-102. Embora tenha sido demonstrada a exposição e a acumulação do NM no fígado, não se observaram efeitos genotóxicos nem no fígado, nem no baço nem no sangue dos ratinhos expostos a esse NM. Neste estudo concluiu-se que algumas formas de dióxido de titânio e nanotubos de carbono de parede múltipla produzem efeitos genotóxicos em células humanas, contribuindo para o conjunto de evidências sobre o efeito genotóxico desses NMs. As diferenças observadas relativamente à genotoxicidade entre NMs do mesmo tipo, mas distintos em algumas das suas características físico-quimicas, aparentemente não são negligenciáveis, pelo que os resultados obtidos para um NM não devem ser generalizados ao grupo correspondente. Para além disso, a genotoxicidade equívoca verificada para o NM-102 em células humanas expostas in vitro, não foi confirmada no modelo in vivo, pelo que o valor preditivo da utilização dos ensaios in vitro para a identificação de NMs com efeitos genotóxicos (e portanto potencialmente carcinogénicos) ainda tem de ser esclarecido antes de ser possível extrapolar as conclusões para a saúde humana. Por sua vez, como a informação aqui produzida pelas metodologias in vitro e in vivo não reflete os efeitos de exposição continua ou prolongada, que poderá conduzir a efeitos genotóxicos distintos, esta xxi deverá ser complementada com outras linhas de evidência relativamente à segurança dos NMs. Perante a incerteza dos níveis de exposição real do organismo humano e do ambiente, a segurança da utilização dos NMs não pode ser garantida a longo prazo e, tendo em conta a elevada produção e utilização destes NMs, são prementes futuros estudos de monitorização ambiental e humana.

Aging and Alzheimer's disease: Searching for novel molecular cues

Tese de Doutoramento em Ciências da Saúde

A cost study of common surface finish systems for steel structures

This paper presents part of a study aimed at finding a suitable, yet cost-effective, surface finish for a steel structure subject to the car washing environment and corrosive chemicals. The initial, life cycle and average equivalent annual (AEAC) costs for surface finishing methods were calculated for a steel structure using the LCCC algorithm developed by American Galvanizers Association (AGA). The cost study consisted of 45 common surface finish systems including: hot-dip galvanization (HDG), metallization, acrylic, alkyd and epoxy as well as duplex coatings such as epoxy zinc and inorganic zinc (IOZ). The results show that initial, life cycle and AEAC costs for hot dip galvanization are the lowest among all the other methods, followed by coal tar epoxy painting. The annual average cost of HDG for this structure was estimated about €0.22/m2, while the other cost-effective alternatives were: IOZ, polyurea, epoxy waterborne and IOZ/epoxy duplex coating.

Color change using HSB color system of dental resin composites immersed in different common Amazon region beverages

The purpose of this study is to evaluate in vitro the color stability of composite resins when exposed to beverages with high coloring contents from the Amazon region. 240 samples from four different composite brands (Natural Look, Z350, 4Seasons and Opallis) of hue A3 were fabricated using an acrylic matrix. The samples were stored in distilled water at 37ºC for 24 hours. The initial color (T0) was registered using a Canon EOS Rebel XTi 10 mp camera, and then the samples were divided into four groups (n=15): G1 (coffee), G2 (açaí juice), G3 (energetic guaraná) and G4 (control - distilled water). The samples were exposed to solutions of DES (6hs) and RE (18hs) and placed in a double boiler under constant agitation, at 37ºC for 30 days. The samples were immersed in the coloring solutions for 15 minutes daily. After 7, 15 and 30 days, new photographic registers were made (T1, T2 and T3). The images were analyzed using Corel PHOTO-PAINT 12 software to identify the colors through the HSB system. The Kruskal-Wallis and t tests (p<0.05) demonstrated significant differences in color (hue, saturation and brightness). The results revealed that none of the tested composites showed color stability when exposed to coloring solutions, and that the Amazon region beverages (açaí juice and energetic guaraná) showed to be less coloring than coffee.

Common symptoms of Nepalese soft contact lens wearers: A pilot study

Aim: To determine the common symptoms in current soft contact lens (CL) wearers and theirassociation with other factors among Nepalese population.Methods: All the current CL wearers who started to wear soft CL in Nepal Eye Hospital between July 2007 and June 2012 were invited for the participation. Frequency of the ten most common symptoms, divided into never, occasionally, frequently and consistent were recorded. Association between degree of symptoms with other factors, e.g. age, gender, profession, cigarette smoking, ethnicity, level of education and duration and wearing modality of CL wear were analyzed.Results: Out of 129 subjects participated in this study, 67% were female; the mean age of the subjects was 23.9 ± 4.3 years. Ninety seven percent of them had at least one symptom occasionally or frequently or consistently. Discomfort was found in 88.4% of the total subjects.Other common symptoms were foreign body sensation in 73.6%, redness in 65.9%, reduced wearing time in 63.6% and dryness in 62.8%. Symptoms were found occasionally in the majority of subjects. Degree of symptoms was not associated with age, gender, profession, education status, ethnicity of subjects and duration or modality of lens wear (p > 0.05) but was positively associated with passive cigarette smoking (p < 0.001).Conclusion: Almost all of the Nepalese soft CL wearers had some types of symptoms at least occasionally. Discomfort was the most common symptom. Degree of symptoms was associated with the passive smoking but not with other factors like age, sex, profession and duration of lens wear.

Common mental disorders among medical students

OBJECTIVE: Common mental disorders (CMD) have a high impact on interpersonal relationships and quality of life and are potential underlying causes for the development of more serious disorders. Medical students have been indicated as a risk population for the development of CMD. The aim of this study was to determine the frequency of CMD in undergraduate medical students and to identify related factors. METHODS: A cross-sectional study was performed in a sample population of medical students. CMD was identified according to the 20-item Self-Report Questionnaire. RESULTS: Two hundred and twenty-three students completed the questionnaire. The overall prevalence of CMD was 29.6% and its presence was independently associated with sleep disorders, not owning a car, not working and sedentary lifestyle. CONCLUSIONS: These findings indicate a high prevalence of CMD in the sample studied and are important for supporting actions to prevent mental disorders in future doctors and for reflecting on the curricula currently in use in medical schools.

The role of the mammalian DNA end-processing enzyme polynucleotide kinase 3'-phosphatase in spinocerebellar ataxia Type 3 pathogenesis

DNA strand-breaks (SBs) with non-ligatable ends are generated by ionizing radiation, oxidative stress, various chemotherapeutic agents, and also as base excision repair (BER) intermediates. Several neurological diseases have already been identified as being due to a deficiency in DNA end-processing activities. Two common dirty ends, 3'-P and 5'-OH, are processed by mammalian polynucleotide kinase 3'-phosphatase (PNKP), a bifunctional enzyme with 3'-phosphatase and 5'-kinase activities. We have made the unexpected observation that PNKP stably associates with Ataxin-3 (ATXN3), a polyglutamine repeat-containing protein mutated in spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph Disease (MJD). This disease is one of the most common dominantly inherited ataxias worldwide; the defect in SCA3 is due to CAG repeat expansion (from the normal 14-41 to 55-82 repeats) in the ATXN3 coding region. However, how the expanded form gains its toxic function is still not clearly understood. Here we report that purified wild-type (WT) ATXN3 stimulates, and by contrast the mutant form specifically inhibits, PNKP's 3' phosphatase activity in vitro. ATXN3-deficient cells also show decreased PNKP activity. Furthermore, transgenic mice conditionally expressing the pathological form of human ATXN3 also showed decreased 3'-phosphatase activity of PNKP, mostly in the deep cerebellar nuclei, one of the most affected regions in MJD patients' brain. Finally, long amplicon quantitative PCR analysis of human MJD patients' brain samples showed a significant accumulation of DNA strand breaks. Our results thus indicate that the accumulation of DNA strand breaks due to functional deficiency of PNKP is etiologically linked to the pathogenesis of SCA3/MJD.

Association between coronary artery atherosclerosis and the intima-media thickness of the common carotid artery measured on ultrasonography

OBJECTIVE: To assess whether the intima-media thickness of the common carotid artery of patients with coronary artery disease is greater than that of individuals without that disease. METHODS: Case-control prospective study of prevalence assessing the thickness of the intima and media layers of 29 patients with coronary artery disease and 29 individuals without that disease by using ultrasonography of the carotid arteries. Diabetic patients and those with peripheral artery and cerebral vasculopathies were excluded from the study. RESULTS: The mean age was 51±7.5 years. Fifty-five per cent of the patients were males. Acute myocardial infarction was present in 62%; cardiac catheterization in 72%; saphenous bypass in 5%; and coronary angioplasty in 24%. The intima-media thickness of the common carotid artery in case patients and in control patients was, respectively, 0.81±0.25 mm and 0.62±0.18 mm (P=0.001). CONCLUSION: Intima-media thickness of the common carotid artery was significantly greater in patients with coronary artery disease.

A curious herbal :containing five hundred cuts, of the most useful plants, which are now used in the practice of physick engraved on folio copper plates, after drawings taken from the life /by Elizabeth Blackwell. To which is added a short description of ye plants and their common uses in physick.

1737 v. 1 #1010