Potential of caveolae in the therapy of cardiovascular and neurological diseases.

Caveolae are membrane micro-domains enriched in cholesterol, sphingolipids and caveolins, which are transmembrane proteins with a hairpin-like structure. Caveolae participate in receptor-mediated trafficking of cell surface receptors and receptor-mediated signaling. Furthermore, caveolae participate in clathrin-independent endocytosis of membrane receptors. On the one hand, caveolins are involved in vascular and cardiac dysfunction. Also, neurological abnormalities in caveolin-1 knockout mice and a link between caveolin-1 gene haplotypes and neurodegenerative diseases have been reported. The aim of this article is to present the rationale for considering caveolae as potential targets in cardiovascular and neurological diseases.

Role of human hydroxysteroid (17beta) dehydrogenase type 1 (HSD17B1) in steroid-dependent diseases in females –novel indications for HSD17B1 inhibitors. Phenotypic analysis of transgenic mice overexpressing human HSD17B1.

Hormone-dependent diseases, e.g. cancers, rank high in mortality in the modern world, and thus, there is an urgent need for new drugs to treat these diseases. Although the diseases are clearly hormone-dependent, changes in circulating hormone concentrations do not explain all the pathological processes observed in the diseased tissues. A more inclusive explanation is provided by intracrinology – a regulation of hormone concentrations at the target tissue level. This is mediated by the expression of a pattern of steroid-activating and -inactivating enzymes in steroid target tissues, thus enabling a concentration gradient between the blood circulation and the tissue. Hydroxysteroid (17beta) dehydrogenases (HSD17Bs) form a family of enzymes that catalyze the conversion between low active 17-ketosteroids and highly active 17beta-hydroxysteroids. HSD17B1 converts low active estrogen (E1) to highly active estradiol (E2) with high catalytic efficiency, and altered HSD17B1 expression has been associated with several hormone-dependent diseases, including breast cancer, endometriosis, endometrial hyperplasia and cancer, and ovarian epithelial cancer. Because of its putative role in E2 biosynthesis in ovaries and peripheral target tissues, HSD17B1 is considered to be a promising drug target for estrogen-dependent diseases. A few studies have indicated that the enzyme also has androgenic activity, but they have been ignored. In the present study, transgenic mice overexpressing human HSD17B1 (HSD17B1TG mice) were used to study the effects of the enzyme in vivo. Firstly, the substrate specificity of human HSD17B1 was determined in vivo. The results indicated that human HSD17B1 has significant androgenic activity in female mice in vivo, which resulted in increased fetal testosterone concentration and female disorder of sexual development appearing as masculinized phenotype (increased anogenital distance, lack of nipples, lack of vaginal opening, combination of vagina with urethra, enlarged Wolffian duct remnants in the mesovarium and enlarged female prostate). Fetal androgen exposure has been linked to polycystic ovary syndrome (PCOS) and metabolic syndrome during adulthood in experimental animals and humans, but the genes involved in PCOS are largely unknown. A putative mechanism to accumulate androgens during fetal life by HSD17B1 overexpression was shown in the present study. Furthermore, as a result of prenatal androgen exposure locally in the ovaries, HSD17B1TG females developed ovarian benign serous cystadenomas in adulthood. These benign lesions are precursors of low-grade ovarian serous tumors. Ovarian cancer ranks fifth in mortality of all female cancers in Finland, and most of the ovarian cancers arise from the surface epithelium. The formation of the lesions was prevented by prenatal antiandrogen treatment and by transplanting wild type (WT) ovaries prepubertally into HSD17B1TG females. The results obtained in our non-clinical TG mouse model, together with a literature analysis, suggest that HSD17B1 has a role in ovarian epithelial carcinogenesis, and especially in the development of serous tumors. The role of androgens in ovarian carcinogenesis is considered controversial, but the present study provides further evidence for the androgen hypothesis. Moreover, it directly links HSD17B1-induced prenatal androgen exposure to ovarian epithelial carcinogenesis in mice. As expected, significant estrogenic activity was also detected for human HSD17B1. HSD17B1TG mice had enhanced peripheral conversion of E1 to E2 in a variety of target tissues, including the uterus. Furthermore, this activity was significantly decreased by treatments with specific HSD17B1 inhibitors. As a result, several estrogen-dependent disorders were found in HSD17B1TG females. Here we report that HSD17B1TG mice invariably developed endometrial hyperplasia and failed to ovulate in adulthood. As in humans, endometrial hyperplasia in HSD17B1TG females was reversible upon ovulation induction, triggering a rise in circulating progesterone levels, and in response to exogenous progestins. Remarkably, treatment with a HSD17B1 inhibitor failed to restore ovulation, yet completely reversed the hyperplastic morphology of epithelial cells in the glandular compartment. We also demonstrate that HSD17B1 is expressed in normal human endometrium, hyperplasia, and cancer. Collectively, our non-clinical data and literature analysis suggest that HSD17B1 inhibition could be one of several possible approaches to decrease endometrial estrogen production in endometrial hyperplasia and cancer. HSD17B1 expression has been found in bones of humans and rats. The non-clinical data in the present study suggest that human HSD17B1 is likely to have an important role in the regulation of bone formation, strength and length during reproductive years in female mice. Bone density in HSD17B1TG females was highly increased in femurs, but in lesser amounts also in tibias. Especially the tibia growth plate, but not other regions of bone, was susceptible to respond to HSD17B1 inhibition by increasing bone length, whereas the inhibitors did not affect bone density. Therefore, HSD17B1 inhibitors could be safer than aromatase inhibitors in regard to bone in the treatment of breast cancer and endometriosis. Furthermore, diseases related to improper growth, are a promising new indication for HSD17B1 inhibitors.

Air pollution and emergency admissions for cardiorespiratory diseases in Lisbon (Portugal)

Daily records of hospital admissions due to cardiorespiratory diseases and levels of PM10, SO2, CO, NO, NO2, and O3 were collected from 1999-2004 to evaluate the relationship between air pollution and morbidity in Lisbon. Generalised additive Poisson regression models were adopted, controlling for temperature, humidity, and both short and long-term seasonality. Significant positive associations, lagged by 1 or 2 days, were found between markers of traffic-related pollution (CO and NO2) and cardiocirculatory diseases in all age groups. Increased childhood emergency admissions for respiratory illness were significantly correlated with the 1-day lagged SO2 levels coming from industrial activities.

Genetic variation among pathogens causing "Helminthosporium" diseases of rice, maize and wheat

Twenty isolates of four fungal species, agents of "Helminthosporium" diseases in cereals, were collected from different regions: nine Bipolarisoryzae isolated from rice (Oryza sativa), seven B.sorokiniana from wheat (Triticum aestivum), two B. maydis, and two Exserohilumturcicum from maize (Zea mays). The strains were compared by PCR-RFLP and RAPD analysis. Size polymorphism among the isolates in the ITS region comprising the 5.8 S rDNA indicated genetic differences among the isolates, while a UPGMA phenogram constructed after the digestion of this region with restriction enzymes showed inter- and intra-specific polymorphism. The RAPD profiles indicated an expressive level of polymorphism among different species, compared with a low level of polymorphism among isolates of the same species. A UPGMA phenogram grouped the isolates according to the species and their host plant. RAPD profiles did not reveal polymorphism that directly correlated climatic factors with geographic source of the isolates of B. sorokiniana, and B. oryzae. Teleomorphic species revealed high similarity with their correspondent anamorphs.

Effect of organic amendments on sclerotial germination, mycelial growth, and Sclerotium rolfsii-induced diseases

The addition of organic residues to soil is an option to control some soil-borne diseases. Benzaldehyde and powders of kudzu (Pueraria lobata), velvetbean (Mucuna deeringiana), and pine-bark (Pinus elliottii and P. taeda) added to soil could reduce certain soil-borne diseases. This study evaluated the effects of benzaldehyde and the dried powders of kudzu, velvetbean, and pine-bark as soil amendments on germination and formation of sclerotia, on mycelial growth of Sclerotium rolfsii, on plant survival, and disease incidence. The data showed that high amounts of benzaldehyde (0.4 ml kg-1 of soil) and velvetbean (100 g kg-1) inhibited S. rolfsii mycelial growth and sclerotium germination. However, low amounts of benzaldehyde (0.1 ml kg-1), kudzu (25 g kg-1), and pine-bark (25 g kg-1) stimulated mycelial growth and sclerotium germination. Kudzu (25-100 g kg-1) and velvetbean (25-100 g kg-1) inhibited the formation of sclerotia. Nevertheless, benzaldehyde at 0.2 and 0.4 ml kg-1 stimulated the formation of sclerotia. Kudzu (50 and 100 g kg-1) and pine-bark (50 g kg-1) favored the colonization of sclerotia by Trichoderma sp. The numbers of soybean (Glycine max) plants were higher and diseased plants were lower than the non-amend soil in the following treatments: kudzu (50 and 100 g kg-1), velvetbean (50 and 100 g kg-1), and pine-bark (50 g kg-1). Disease severity on tomato (Lycopersicon esculentum) plants was low in soil treated with kudzu or velvetbean (30 and 35 g kg-1) and pine-bark (35 g kg-1). Dried powders of kudzu, velvetbean, or pine-bark added to soil can reduce disease by reducing pathogen inoculum.

Berry polyphenol absorption and the effect of northern berries on metabolism, ectopic fat accumulation, and associated diseases

The prevalence of obesity and type 2 diabetes has increased at an alarming rate in developed countries. It seems in the light of current knowledge that metabolic syndrome may not develop at all without NAFLD, and NAFLD is estimated to be as common as metabolic syndrome in western population (23 % occurrence). Fat in the liver is called ectopic fat, which is triacylglycerols within the cells of non-adipose tissue. Serum alanine aminotransferase (ALT) values correlate positively with liver fat proportions, and increased activity of ALT predicts type 2 diabetes independently from obesity. Berries, high in natural bioactive compounds, have indicated the potential to reduce the risk of obesity-related diseases. Ectopic fat induces common endocrine excretion of adipose tissue resulting in the overproduction of inflammatory markers, which further induce insulin resistance by multiple mechanisms. Insulin resistance inducing hyperinsulinemia and lipolysis in adipocytes increases the concentration of free fatty acids and consequently causes further fat accumulation in hepatocytes. Polyphenolic fractions of berries have been shown to reverse inflammatory reaction cascades in in vitro and animal studies, and moreover to decrease ectopic fat accumulation. The aim of this thesis was to explore the role of northern berries in obesity-related diseases. The absorption and metabolism of selected berry polyphenols, flavonol glycosides and anthocyanins, was investigated in humans, and metabolites of the studied compounds were identified in plasma and urine samples (I, II). Further, the effects of berries on the risk factors of metabolic syndrome were studied in clinical intervention trials (III, IV), and the different fractions of sea buckthorn berry were tested for their ability to reduce postprandial glycemia and insulinemia after high-glucose meal in a postprandial study with humans (V). The marked impact of mixed berries on plasma ALT values (III), as well as indications of the positive effects of sea buckthorn, its fractions and bilberry on omental adiposity and adhesion molecules (IV) were observed. In study V, sea buckthorn and its polyphenol fractions had a promising effect on potprandial metabolism after high-glucose meal. In the literature review, the possible mechanisms behind the observed effects have been discussed with a special emphasis on ectopic fat accumulation. The literature review indicated that especially tannins and flavonoids have shown potential in suppressing diverse reaction cascades related to systemic inflammation, ectopic fat accumulation and insulin resistance development.

Efficiency of phylloplane bacteria in controlling aerial tomato diseases under field conditions

The capacity of two bacteria isolated from the tomato phylloplane to control late blight (Phytophthora infestans) was investigated in the field, and compared against the effectiveness of spraying with the fungicide chlorothalonil (1.5 g a.i. L-1) or water (control). A 55% reduction in late blight intensity was observed in the leaves of the middle of the plant and 62% in those of the upper leaves when using the antagonist UFV-STB 6 (Novosphingobium capsulatum) as compared to the control. Isolate UFV-IEA 6 (Bacillus cereus) was able to reduce disease intensity by 55%, but only in the upper leaves of the tomato plants. Treatment with isolate UFV-STB 6 also led to a significant reduction in the percentage of fruits with late blight symptoms. The results demonstrate the potential of these two bacteria in controlling this disease.

Management of crotalaria and pigeon pea for control of yam nematode diseases

Management of plant-parasitic nematodes with the use of nematicides has not been recommended for small farmers that grow yam in the Northeastern region of Brazil, due to its high cost and residue toxicity. The use of plants with antagonistic effect to nematodes and green manure which improves soil chemical, physical and biological characteristics can be a viable and low cost alternative to control parasitic nematodes. This work aimed to evaluate the effect of crotalaria (Crotalaria juncea) and pigeon pea (Cajanus cajan) plants on the control of yam nematodes. Three experiments were carried out. The first was conducted under in vitro conditions to evaluate the nematostatic and nematicide effect of extracts from fresh and dry matter of the above ground parts of crotalaria, pigeon pea, and the combination of both. The second experiment was carried out under greenhouse conditions to evaluate the effect of soil amendment with crotalaria, pigeon pea, and the combination of both in the infectivity of Scutellonema bradys, using tomato plants as the host plant. The third experiment was conducted under field conditions to evaluate the effect of crotalaria, pigeon pea, and the combination of both, cultivated between yam planting rows and incorporated to soil surface, on yam nematodes. The aqueous extract obtained form fresh matter of crotalaria had a nematicide effect of 100% for S. bradys. Extracts from dry matter of both crotalaria and pigeon pea did not have any nematicide effect, but had a nematostatic effect. Incorporation of crotalaria to soil inhibited infectivity of S. bradys in tomato seedlings. These results showed that planting crotalaria alone or in combination with pigeon pea, between the yam planting rows, is an efficient method for controlling S. bradys and Rotylenchulus reniformis associated with yams. Crotalaria can be used for controlling these plant-parasitic nematodes in soil.

Evolution in the profile of thyroid cancer cases treated in an oncology reference service: what changed in the last 20 years

Objective: To evaluate the characteristics of thyroid carcinoma cases treated at a reference hospital for cancer between 2008 and 2010.Methods: we studied 807 cases and analyzed the following clinicopathologic variables: symptoms, risk factors, diagnostic tests, staging, histological type, treatment performed and complications.Results: Females were more affected, with 660 cases (82%). The average age at diagnosis was 44.5 years. Prior exposure to ionizing radiation was reported by 22 (3%) patients, a family history of thyroid cancer by 89 (11%), and 289 (36%) individuals reported other types of cancer in the family. The fine needle aspiration biopsy was the main parameter for surgical indication and was suggestive of carcinoma in 463 patients (57%). Papillary carcinoma was the most common histological type, with 780 cases (96.6%). There were 728 (90%) total thyroidectomies, 43 (5.3%) reoperations or partial thyroidectomies followed by totalization, 23 (2.8%) extended thyroidectomies and only 13 (1.6%) partial thyroidectomies (lobectomy with isthmectomy). Neck dissection associated with thyroidectomy was done in 158 patients (19.5%). We observed a predominance of tumors classified as T1 in 602 (74.6%) patients. Transient hypocalcemia was the most frequent complication.Conclusion: The results show that the worldwide increase in the incidence of thyroid cancer has changed the profile of patients seen at a referral service. In addition, there were changes in the type of surgical treatment used, with increased use of total thyroidectomy in relation to partial and subtotal ones, and decreased use of elective neck dissections.

New perspectives on the melanocortins and their cardiovascular effects: Potential implications for the treatment of cardiovascular diseases with melanocortin analogues

The melanocortin peptides, including melanocyte-stimulating hormones, α-, β- and γ-MSH, are derived from the precursor peptide proopiomelanocortin and mediate their biological actions via five different melanocortin receptors, named from MC1 to MC5. Melanocortins have been implicated in the central regulation of energy balance and cardiovascular functions, but their local effects, via yet unidentified sites of action, in the vasculature, and their therapeutic potential in major vascular pathologies remain unclear. Therefore, the main aim of this thesis was to characterise the role of melanocortins in circulatory regulation, and to investigate whether targeting of the melanocortin system by pharmacological means could translate into therapeutic benefits in the treatment of cardiovascular diseases such as hypertension. In experiments designed to elucidate the local effects of α-MSH on vascular tone, it was found that α-MSH improved blood vessel relaxation via a nitric oxide (NO)-dependent mechanism without directly contracting or relaxing blood vessels. Furthermore, α-MSH was shown to regulate the expression and function of endothelial NO synthase in cultured human endothelial cells via melanocortin 1 receptors. In keeping with the vascular protective role, pharmacological treatment of mice with α-MSH analogues displayed therapeutic efficacy in conditions associated with vascular dysfunction such as obesity. Furthermore, α-MSH analogues elicited marked diuretic and natriuretic responses, which together with their vascular effects, seemed to provide protection against sodium retention and blood pressure elevation in experimental models of hypertension. In conclusion, the present results identify novel effects for melanocortins in the local control of vascular function, pointing to the potential future use of melanocortin analogues in the treatment of cardiovascular pathologies.

Main diseases of pejerrey (Odontesthes bonariensis) in central Argentina

Argentina's central region includes an important area covered by shallow pampean lakes and dams. In these environments, fishing of pejerrey Odontesthes bonariensis Valenciennes, 1835 (Pisces, Atherinopsidae), the most important fresh-water fish of the country, is a relevant social activity and also a considerable economic resource. The main diseases found in this species were studied from 1992 to 2003 in the provinces of Córdoba, La Rioja and Santa Fe (30º and 35º S, 61º and 67º W). Most cases were registered in high temperature months. Lernaea sp and Aeromonas hydrophila were the etiological agents most frequently found. The trophic characteristics of the aquatic environments enhanced disease processes and caused massive death of O. bonariensis, due to complex hydrochemical interactions.

Role of the canonical transient receptor potential channel 2 (TRPC2) in thyroid cell function

Kalciumjonen reglerar flera processer i celler såsom transkribering av gener, celldelning, cellernas rörlighet och celldöd. Därför har cellerna utvecklat många mekanismer för att reglera den intracellulära kalciumkoncentrationen. Kalciumkanaler spelar en viktig roll i denna regleringsprocess. TRPC-kanalerna (eng. canonical transient receptor potential) är en familj av jonkanaler med sju medlemmar (TRPC1-7) vars regleringsmekanismer och fysiologiska roller är varierande. TRPC2-kanalens fysiologiska signifikans, samt hur kanalen regleras, är dåligt karakteriserad. För första gången, rapporterar vi närvaron av TRPC2 kanalen i råttans sköldkörtelceller samt primära sköldkörtelceller från råtta. Hos gnagare har TRPC2 antagits vara exklusivt uttryckt i det vomeronasala organet. För att undersöka den fysiologiska betydelsen av kanalen, har vi utvecklat stabila celler med nedreglerat TRPC2 (shTRPC2) m.h.a. shRNA-teknik. Nedreglering av TRPC2 resulterade i stora skillnader i flera viktiga cellulära funktioner och i regleringen av sköldkörtelcellernas cellsignalering. Nedreglering av TRPC2 orsakade minskad agonist-beroende frigivning av kalcium från det endoplasmatiska nätverket, samt minskat agonist-beroende inflöde av extracellulärt kalcium, men ökade det basala kalciuminflödet. Uttrycket av PKCβ1 och PKCδ, SERCA-aktiviteten och kalciumhalten i det endoplasmatiska nätverket minskade i shTRPC2 celler. Kommunikation mellan kalcium- och cAMP-signalering påvisades vara TRPC2-beroende, vilket visades reglera uttrycket av TSH-receptorn. Vi undersökte också betydelsen av TRPC2 kanalen i reglering av sköldkörtelcellers proliferation, migration, vidhäftning och invasion; processer som alla var dämpade i shTRPC2 celler. Samamnfattningsvis påvisade dessa resultat en ny och viktig fysiologisk betydelse för TRPC2 kanalerna.

Foot rot and other foot diseases of goat and sheep in the semiarid region of northeastern Brazil

This paper reports the occurrence and epidemiology of outbreaks of foot rot and other foot diseases in goats and sheep in the semiarid region of Paraíba, northeastern Brazil. Four farms were inspected for the presence of foot lesion in sheep and goats and for environmental conditions, general hygiene, pastures, and disease control measures. The prevalence of foot lesions was 19.41% (170/876) in sheep and 17.99% (52/289) in goats, ranging between 5.77% and 33.85% in different farms. Foot rot was the most common disease, affecting 12.1% of the animals examined (141/1165), but with significantly higher (p<0.05) prevalence in sheep (13.69%) than in goats (7.27%). The frequency of malignant foot rot was also significantly lower (p<0.05) in goats (9.53%) than in the sheep (40.83%). On one farm, Dorper sheep showed significantly higher (p<0.05) prevalence of foot rot (17.5%) than Santa Inês sheep (6.79%), and the number of digits affected was also higher in the former. Dichelobacter nodosus and Fusobacterium necrophorum were isolated from cases of foot rot. White line disease was found in 3.95% of the animals, sole ulcers in 1.29%, foot abscess in 1.03% and hoof overgrowth in 0.5%. The high rainfall at the time of occurrence, grazing in wetlands, clay soils with poor drainage, presence of numerous stony grounds, closure of the flocks in pens at night, and introduction of affected animals were considered predisposing factors for the occurrence of foot diseases.

Pathological findings in fetuses of goats and cattle poisoned by Sida carpinifolia (Malvaceae)

In Brazil, the consumption of Sida carpinifolia by livestock has been associated with neurological diseases linked to lysosomal storage disorders. This paper describes the pathological findings in two caprine fetuses from dams that were experimentally poisoned with S. carpinifolia. The goats were orally dosed with 10 and 13g/kg of a paste of green chopped S. carpinifolia for 30 days and were observed for an additional 15 days period after the last dosage with the plant; thereafter they were euthanized and necropsied. The dams showed only slight clinical signs. The study also includes the findings in one bovine fetus from a naturally S. carpinifolia poisoned cow which showed mild incoordination, generalized tremors, staggering, and frequent falls. The cow was euthanized and necropsied. While there were no significant histopathological changes in the goats, in the cow vacuolation of Purkinje neurons of the cerebellum, pancreatic acinar cells, and thyroid follicular cells were observed. The main microscopic changes observed in the caprine and bovine fetuses were vacuolation in the epithelium of renal tubules, thyroid follicular cells, and Purkinje neurons of the cerebellum. Transmission electron microscopy of sections from CNS of the cow and its fetus revealed vacuoles containing fine granular material surrounded by membrane. Lectin-histochemistry of CNS sections from goat fetuses marked lightly to sWGA lectins, WGA, and Con-A.