Closing the knowledge gap on the composition of the asbestos bodies.

Asbestos bodies (AB) form in the lungs as a result of a biomineralization process initiated by the alveolar macrophages in the attempt to remove asbestos. During this process, organic and inorganic material deposit on the foreign fibers forming a Fe-rich coating. The AB start to form in months, thus quickly becoming the actual interface between asbestos and the lung tissue. Therefore, revealing their composition, and, in particular, the chemical form of Fe, which is the major component of the AB, is essential to assess their possible role in the pathogenesis of asbestos-related diseases. In this work we report the result of the first x-ray diffraction measurements performed on single AB embedded in the lung tissue samples of former asbestos plant workers. The combination with x-ray absorption spectroscopy data allowed to unambiguously reveal that Fe is present in the AB in the form of two Fe-oxy(hydroxides): ferrihydrite and goethite. The presence of goethite, which can be explained in terms of the transformation of ferrihydrite (a metastable phase) due to the acidic conditions induced by the alveolar macrophages in their attempt to phagocytose the fibers, has toxicological implications that are discussed in the paper.

Pleural mesothelioma and lung cancer: the role of asbestos exposure and genetic variants in selected iron metabolism and inflammation genes.

Two of the major cancerous diseases associated with asbestos exposure are malignant pleural mesothelioma (MPM) and lung cancer (LC). In addition to asbestos exposure, genetic factors have been suggested to be associated with asbestos-related carcinogenesis and lung genotoxicity. While genetic factors involved in the susceptibility to MPM were reported, to date the influence of individual genetic variations on asbestos-related lung cancer risk is still poorly understood. Since inflammation and disruption of iron (Fe) homeostasis are hallmarks of asbestos exposure affecting the pulmonary tissue, this study aimed at investigating the association between Fe-metabolism and inflammasome gene variants and susceptibility to develop LC or MPM, by comparing an asbestos-exposed population affected by LC with an "asbestos-resistant exposed population". A retrospective approach similar to our previous autopsy-based pilot study was employed in a novel cohort of autoptic samples, thus giving us the possibility to corroborate previous findings obtained on MPM by repeating the analysis in a novel cohort of autoptic samples. The protective role of HEPH coding SNP was further confirmed. In addition, the two non-coding SNPs, either in FTH1 or in TF, emerged to exert a similar protective role in a new cohort of LC exposed individuals from the same geographic area of MPM subjects. No association was found between NLRP1 and NLRP3 polymorphisms with susceptibility to develop MPM and LC. Further research into a specific MPM and LC "genetic signature" may be needed to broaden our knowledge of the genetic landscape attributed to result in MPM and LC.

A genetic variant of NLRP1 gene is associated with asbestos body burden in patients with malignant pleural mesothelioma.

The presence of asbestos bodies (ABs) in lung parenchyma is considered a histopathologic hallmark of past exposure to asbestos fibers, of which there was a population of longer fibers. The mechanisms underlying AB formation are complex, involving inflammatory responses and iron (Fe) metabolism. Thus, the responsiveness to AB formation is variable, with some individuals appearing to be poor AB formers. The aim of this study was to disclose the possible role of genetic variants of genes encoding inflammasome and iron metabolism proteins in the ability to form ABs in a population of 81 individuals from North East Italy, who died after having developed malignant pleural mesothelioma (MPM). This study included 86 genetic variants distributed in 10 genes involved in Fe metabolism and 7 genetic variants in two genes encoding for inflammasome molecules. Genotypes/haplotypes were compared according to the number of lung ABs. Data showed that the NLRP1 rs12150220 missense variant (H155L) was significantly correlated with numbers of ABs in MPM patients. Specifically, a low number of ABs was detected in individuals carrying the NLRP1 rs12150220 A/T genotype. Our findings suggest that the NLRP1 inflammasome might contribute in the development of lung ABs. It is postulated that the NLRP1 missense variant may be considered as one of the possible host genetic factors contributing to individual variability in coating efficiency, which needs to be taken when assessing occupational exposure to asbestos.

Chronic renal failure in equine due to ascending pyelonephritis predisposed by cauda equina syndrome: case report / Insuficiência renal crônica em equino devido à pielonefrite ascendente predisposta por síndrome da cauda equina: relato de caso

Descreve-se o caso de uma égua, da raça Campeiro, utilizada como doadora de embriões, que apresentava quadros de cistite recorrente e incontinência urinária. Os sinais clínicos evoluíram para emagrecimento progressivo, anorexia, apatia e isolamento do plantel. Ao exame físico, foi identificada hipotonia da cauda, hipoalgesia da região perineal, flacidez retal e vesical, compatíveis com sinais relacionados à síndrome da cauda equina. Exames complementares laboratoriais, exame ultrassonográfico e necropsia confirmaram o diagnóstico de insuficiência renal crônica (IRC), a qual foi atribuida à pielonefrite ascendente. O exame de urocultura demonstrou crescimento de bactérias do gêneroStreptococcus sp. Este é um caso raro em equinos em que a disfunção de neurônio motor inferior propiciou o desenvolvimento de processo infeccioso no trato urinário, progredindo para um quadro crônico renal incompatível com a vida.(AU)

Descreve-se o caso de uma égua, da raça Campeiro, utilizada como doadora de embriões, que apresentava quadros de cistite recorrente e incontinência urinária. Os sinais clínicos evoluíram para emagrecimento progressivo, anorexia, apatia e isolamento do plantel. Ao exame físico, foi identificada hipotonia da cauda, hipoalgesia da região perineal, flacidez retal e vesical, compatíveis com sinais relacionados à síndrome da cauda equina. Exames complementares laboratoriais, exame ultrassonográfico e necropsia confirmaram o diagnóstico de insuficiência renal crônica (IRC), a qual foi atribuida à pielonefrite ascendente. O exame de urocultura demonstrou crescimento de bactérias do gênero Streptococcus sp. Este é um caso raro em equinos em que a disfunção de neurônio motor inferior propiciou o desenvolvimento de processo infeccioso no trato urinário, progredindo para um quadro crônico renal incompatível com a vida.(AU)

Metformin improves putative longevity effectors in peripheral mononuclear cells from subjects with prediabetes. A randomized controlled trial.

BACKGROUND AND AIMS: Prediabetes increases cardiovascular risk and is associated with excess mortality. In preclinical models, metformin has been shown to exert anti-ageing effects. In this study, we sought to assess whether metformin modulates putative effector longevity programs in prediabetic subjects. METHODS AND RESULTS: In a randomized, single-blind, placebo-controlled trial, 38 prediabetic subjects received metformin (1500 mg/day) or placebo for 2 months. At baseline and after treatment, we collected anthropometric and metabolic parameters. Gene and protein levels of SIRT1, mTOR, p53, p66Shc, SIRT1 activity, AMPK activation, telomere length, and SIRT1 promoter chromatin accessibility were determined in peripheral blood mononuclear cells (PBMCs). Plasma N-glycans, non-invasive surrogate markers of ageing, were also analysed. Compared to baseline, metformin significantly improved metabolic parameters and insulin sensitivity, increased SIRT1 gene/protein expression and SIRT1 promoter chromatin accessibility, elevated mTOR gene expression with concomitant reduction in p70S6K phosphorylation in subjects' PBMCs, and modified the plasma N-glycan profile. Compared to placebo, metformin increased SIRT1 protein expression and reduced p70S6K phosphorylation (a proxy of mTOR activity). Plasma N-glycans were also favourably modified by metformin compared to placebo. CONCLUSION: In individuals with prediabetes, metformin ameliorated effector pathways that have been shown to regulate longevity in animal models. ClinicalTrials. gov identifier: NCT01765946 - January 2013.

Neuropeptides in saliva of subjects with burning mouth syndrome: a pilot study.

OBJECTIVE: A neuropathic basis has been suggested for burning mouth syndrome (BMS) and an altered concentration of neuropeptides has been reported in lingual oral mucosa and saliva in this disease. The aims of this study were to compare the levels of nerve growth factor (NGF), substance P (SP) and degranulation products from mast cells and neutrophils in the saliva of BMS subjects with those of control subjects. MATERIAL AND METHODS: Salivary flow rate, protein concentration, NGF peptide and mRNA, SP, mast cells tryptase, neutrophil myeloperoxidase and calprotectin were analyzed in saliva of 20 BMS subjects and of 20 age- and gender-matched healthy subjects. RESULTS AND CONCLUSIONS: NGF peptide and tryptase activity were shown to be significantly and persistently higher in saliva of BMS subjects, with respect to control values. Conversely the salivary levels of SP were shown to be significantly lower, while neutrophil markers didn't show any change. We conclude that the neuropathic origin of the disease is confirmed at salivary level. Furthermore, the higher tryptase activity indicates a possible involvement of mast cells. The salivary neuropeptide concentration in BMS subjects, together with mast cell derived compounds, could be useful biomarkers for diagnosis and monitoring of this disease.

Myeloperoxidase exerts microbicidal activity against Mycobacterium tuberculosis.

We investigated the antimycobacterial role of myeloperoxidase (MPO), one of the most abundant granule proteins in human neutrophils. Our data indicate that purified MPO, in the presence of hydrogen peroxide, exerts a consistent killing activity against Mycobacterium tuberculosis H37Rv and against a clinical isolate. The activity is time and dose dependent and requires the presence of chloride ions in the assay medium.

Contribuiçäo ao estudo da vascularizaçäo arterial do testículo de búfalos da raça Murrah / Contribuition to the study of the arterial vascularization of the testicle in buffalo

Estudamos o comportamento da artéria testicular, o número e a distribuiçäo dos vasos penetrantes em 30 pares de testículos de búfalos da raça Murrah (Bubalus bubalis), com idade entre 8 meses e 5 anos, procedentes da regiäo de Ilha Sonteira, no Estado de Säo Paulo, mediante a análise de moldes obtidos pela injeçäo de vinil, na artéria testicular e em seguida corrosäo do órgäo em ácido sulfúrico a 30 por cento. Encontramos mais freqüentemente (68,4 por cento) a artéria testicular cedendo dois ramos, o cranial e o caudal, com participaçäo equivalente de ambos os ramos na vascularizaçäo do órgäo (35,0 por cento), ou com predominância do ramo cranial (21,7 por cento) ou do ramo caudal (11,7 por cento). Em outros arranjos, a artéria testicular cede três ramos: o cranial, o médio e o caudal (20,0 por cento) ou ainda número variável de ramos craniais (4 a 7) e caudais (3 a 5) (11,6 por cento) para a vascularizaçäo arterial do testículo

Low density lipoprotein-apheresis decreases oxidized low density lipoproteins and monocyte adhesion to endothelial cells.

The mutual interaction between monocytes and low density lipoprotein (LDL) in atherogenesis prompted a test of the hypothesis that LDL-apheresis could reduce the adhesive properties of monocytes to endothelium; and therefore interfere with a key mechanism in atheroma formation. Five patients affected by heterozygous familial hypercholesterolemia were studied. All patients received LDL-apheresis treatment with selective adsorption of LDL-cholesterol on dextran-sulphate columns. Low density lipoprotein particles were isolated by sequential preparative ultracentrifugation and subfractionated by ion exchange high performance liquid chromatography. Thiobarbituric acid reacting products of lipid peroxidation were measured fluorometrically. Vitamin E was estimated by high performance liquid chromatographic technique. Monocytes were isolated from patients blood before and 1 day after LDL-apheresis by Percoll gradient. The blood samples for monocyte adhesion were drawn from control subjects for 2 consecutive days. The adhesion of monocytes to an endothelial monolayer was evaluated by assaying the peroxidase content of the adherent monocytes. Low density lipoprotein-apheresis reduced total cholesterol (-65%; p < 0.01), LDL-cholesterol (-75%; p < 0.01), triglycerides (-51%; p < 0.05), and fibrinogen (-28%; p < 0.01). With LDL-apheresis treatment, a reduction of 54% in oxidized LDLs was observed; vitamin E concentration significantly increased in LDLs (+ 14.2%; p < 0.05). The monocyte adhesion decreased by approximately 61% after apheresis; the variation became statistically significant (-65%; p < 0.01) when endothelial cells were stimulated by lipopolysaccaride.

Subcellular localization of the small GTPase Rab5a in resting and stimulated human neutrophils.

The evidence that small GTPases of the Rab family are regulators of vesicle traffic which can influence various cell functions prompted us to investigate the potential role of one of these proteins, Rab5a, in human neutrophils. In this paper we show that a large amount of Rab5a is present in the cytosol of peripheral blood mature neutrophils. The remaining protein was found to be membrane and azurophilic granule associated. Upon neutrophil challenge with PMA for 10 min the amount of membrane-associated Rab5a was upregulated while the cytosolic content of the protein concomitantly decreased. These findings support the hypothesis that Rab5a could be involved in the mechanism of neutrophil activation by modulating the rate of endocytosis and/or vesicle fusion.

The arterial supply of the nodus sinuatrialis in bovine Gir

A irrigaçäo da área do nó sinoatrial foi estudada em 50 coraçöes de fêmeas de bovinos da raça Gir, após injeçäo das artérias coronárias com Neoprene-látex. A área nodal, com muita frequência (72 por cento dos casos) foi irrigada pela a. coronária esquerda, sendo 58 por cento pelo ramus circumflexus sinister e 14 por cento por outros ramos. O r. proximalis atrii sinistri irrigava a área nodal isoladamente (42 por cento) ou associado com o r. intermedius atrii dextri (2 por cento) ou com r. distalis dexter (2 por cento) ou com um colateral do r. ventricularis dexter (2 por cento). Numerosas anastomoses foram encontradas entre os ramos que irrigavam a área nodal. Pela primeira vez foi descrito, em coraçöes de bovinos, ramos átrio-ventriculares das artérias coronárias

Contribuiçäo ao estudo da vascularizaçäo arterial do testículo em jumentos da raça Pega / Contribution to the study of the arterial vascularization of the testicles in donkey of the Pega race

Estudou-se o comportamento da artéria testicular e seus ramos, bem como o número e distribuiçäo dos vasos penetrantes, em 30 pares de testículos de jumentos da raça pega, adultos e procedentes de várias regiöes do Estado de Minas Gerais, mediante a análise de esquemas de modelos obtidos por corrosäo após injeçäo de acetato de "vinyl". Observou-se que nestes animais essa artéria oferece quatro arranjos vasculares diferentes, de acordo com sua divisäo com predomínio de um ou outro dos vasos resultantes na irrigaçäo do órgäo. Quanto à distribuiçäo dos vasos penetrantes, por quadrante, em mediana, faz-se de maneira que nos testículos direitos o quadrante mais povoado é o craniomedial (17,0), sendo seguido pelos quadrantes caudomedial e craniolateral (15,5) e caudolateral (15,0). Por outro lado, nos testículos esquerdos o quadrante caudolateral mostra o maior número de vasos penetrantes (18,5), seguido pelos quadrantes craniolateral (17,0), craniomedial (16,0) e caudomedial (14,0). Identificou-se a presença de anastomoses que ocorrem entre a artéria testicular e seus ramos ou entre os diferentes colaterais cedidos pela própria artéria. Relativamente ao número total de vasos penetrantes, encontrou-se em mediana, 66,5 e 66,0 vasos para os testículos direitos e esquerdos, respectivamente, o que estatisticamente näo é significante ao nível de alfa=0,05, quando comparamos o número de vasos penetrantes dos testículos direitos e esquerdos

Vascularizaçäo arterial do testículo de suínos / Arterial blood supply of the testicle in pigs

Utilizando 30 pares de testículos de suínos, com idade compreendida entre 6 a 10 meses, procedentes do Campus Administrativo de Pirassununga, da Universidade de Säo Paulo e da Seara Industrial de Xanxerê S. A., Santa Catarina, estudou-se a vascularizaçäo arterial mediante análise de moldes da artéria testicular, obtidos pela injeçäo de vynil. Na vascularizaçäo do órgäo, a artéria testicular forneceu: (a) em 50,0 por cento das preparaçöes, número variável de ramos laterais e mediais, ocorrendo em 31,7 por cento, predominância dos ramos laterais; (b) em 43,3 por cento um ramo medial e outro lateral, havendo em 30 por cento das peças, predomínio do ramo medial; (c) em 6,7 por cento dos moldes, os ramos ventral e dorsal, notando-se predomínio do ramo ventral, na vascularizaçäo do órgäo. Nas preparaçöes em que a artéria testicular fornecia número variável de ramos laterais e mediais, observou-se em mediana e nos quadrantes dorsolateral, dorsomedial, ventrolateral e ventromedial, respectivamente, 27,0; 26,0; 38,0; 28,0 vasos penetrantes quanto da predominância dos laterais 24,0; 24,0; 30,0; 33,0 no caso do predomínio dos mediais. Quando a artéria testicular cedeu dois ramos, o medial e o lateral, os valores foram, respectivamente, 25,0; 24,0; 35,0; 28,0 com predominância do medial e de 33,0; 33,5; 38,0; 37,5 com predominância do lateral. Quando emitiu os ramos dorsal e ventral, verificou-se, respectivamente 30,5; 24,5; 26,5 e 28,0 quando da predominância do ventral. Observou-se em 30 preparaçöes (50 por cento) ramos laterais ou mediais cedendo vasos penetrantes a quadrantes opostos ao destino principal do vaso que lhe deu origem. Foi verificada a presença de ramos adicionais, específicos, originados da artéria testicular antes desta ceder os ramos lateral e medial, e os ramos ventral e dorsal. Foram identificadas em 95 por cento das preparaçöes, anastomoses entre a artéria testicular e seus ramos principais e colaterais, bem como dos ramos adicionais. A ocorrência se deu com maior frequência na face caudal do órgäo sob a albugínea e ainda entre ramos da artéria testicular e epididimários. Näo houve diferença significativa no número total de vasos penetrantes dos testículos direito e esquerdo, ao nível de P>0,05

The excretory system of the liver in wild animals. VI. Biliary ducts of the great anteater (Myrmecophaga tridactyla)

Neste trabalho säo sistematizadas as vias bilíferas do tamanduá bandeira (Myrmecophaga tridactyla). Os resultados demonstram: o ductos choledocus, livre de afluentes, origina-se da uniäo do ramus principalis dexter e do ramus principalis sinister. O ramus principalis dexter é invariavelmente composto pelo ramus lateralis lobi dextri e pelo ramus medialis lobi dextri, enquanto o ramo pincipalis sinister está composto pelo ramus lateralis lobi sinistri, ramus medialis lobi sinistri e ramus lobi quadrati

Intestinal transit time is delayed by artificial sphincters after massive enterectomy in dogs.

Artificial sphincters were created in three groups of dogs after the resection of 87.5 percent of the intestine in each animal. Intestinal transit time was measured after 6 weeks by observing the passage of a radiopaque medium through the animals' intestinal tracts. No statistically significant differences were found between the intestinal transit times of dogs with one artificial sphincter and control animals. In dogs with two artificial sphincters there was a delay in the radiologically monitored intestinal transit time that was statistically significant compared with that of the control group.

Artificial sphincters as surgical treatment for experimental massive resection of small intestine.

A modification of the technique of Schiller, DiDio, and Anderson was adopted by extending removal of the longitudinal layer of the muscular coat to the entire perimeter of a segment of the small intestine in dogs, resulting in the construction of artificial sphincters, to assist animals undergoing enterectomy. The creation of one or two artificial sphincters prolonged the survival of dogs undergoing massive resection of the small intestine (87.5 percent of the total length).

[Topographic and histological study of the sinoatrial node in the Jaffarabadi buffalo (Babalus bubalis Linnaeus, 1758)]. / Etude topographique et histologique du noeud sinusal, chez le buffle (Bubalus bubalis Linnaeus, 1758) de race Jaffarabadi

A topographic and histologic study of the sinuatrial node was made in the hearts of 12 buffalo of the Jaffarabadi breed, 8 adults (5 females and 3 males) and 4 term fetuses (3 female and 1 male). The nodal tissue was localized at the junction of the vena cava superior with the right atrium, occupying, more precisely, the entire extent of the terminal groove, the dihedral cavoatrial angle and the first part of the auricular surface of the junction, which is contiguous with this angle. This structure contains cells with single or double nuclei, round or oval in shape, surrounded by a light halo, with scattered chromatin and a well-defined nucleolus, acidophilic cytoplasm containing, in comparison with the common myocardium, few sinuous myofibrils with transverse striations and a larger amount of glycogen. We also observed arteries of small and medium caliber, with veins and nerves accompanying the nodal mass, while the nerve ganglia were situated opposite the sinuatrial node.