Bone Health, Osteoporosis and Fracture Risk in Neurofibromatosis 1 - An Emphasis on Osteoclasts

Neurofibromatosis 1 (NF1) is an autosomal dominant hereditary syndrome, affecting skin, neural tissues and skeleton. Hallmarks of NF1 include benign cutaneous neurofibroma tumors, pigmentation lesions on the skin and in the iris, learning disabilities and predisposition to selected malignancies. Low bone mineral density (BMD) and osteopenia/osteoporosis are common in NF1. Osteoporosis is a systemic disorder characterized by low bone mineral density and increased fracture risk. Treatment of osteoporosis aims to prevent falls and decrease fracture risk. Osteoporosis is diagnosed in adults by measuring BMD and evaluating clinical risk factors of the patient. Bone turnover is a process of old bone resorbed by osteoclasts and new bone formed by osteoblasts. Multinuclear osteoclasts are derived from osteoclast progenitors, which can be isolated from peripheral blood. Osteoclast progenitors were isolated from 17 NF1 patients and healthy controls, and cultured in vitro to osteoclasts. NF1 osteoclasts are hyperactive, displaying increased differentiation and resorption capacity, abnormal morphology and tolerance to serum deprivation compared to control osteoclasts. These findings expanded the study to evaluate the effects of bisphosphonates, drugs designed to treat osteoporosis, in osteoclasts derived from blood samples of 20 NF1 and control persons. The number of control osteoclasts was expectedly reduced after bisphosphonate treatment. However, NF1 osteoclasts tolerated the apoptotic effect of alendronate, zoledronic acid and clodronate in vitro compared to controls. NF1-related osteoporosis was found in ~20 % of the patients, and selected laboratory parameters were measured. Patients with NF1 have increased levels of serum CTX and PINP, reflecting increased bone turnover in vivo. BMD decreases progressively in NF1 as evaluated in 19 NF1 patients 12 years after their initial BMD measurement. Patients with NF1-related osteopenia often progress to osteoporosis. This was found in patients aged 37-76.

The Roots of Neurofibromas in Neurofibromatosis 1 — A Question of Multipotency, Differentiation and Hiding

Neurofibromatosis type 1 (NF1) is an autosomal dominant cancer predisposition syndrome that affects about 1 in 3500 individuals worldwide. NF1 is caused by mutations in the NF1 gene that encodes the tumor suppressor protein neurofibromin, an inactivator of the Ras oncogene. The hallmarks of NF1 include pigmentary lesions of the skin, Lisch nodules of the iris and cutaneous neurofibromas. Cutaneous neurofibromas are benign tumors composed of all the cell types of normal peripheral nerve. The traditional view of neurofibroma development has been that cutaneous neurofibromas arise from the disruption of the small nerve tributaries of the skin and subsequent proliferation of the resident cells. The second hit mutation in the NF1 gene has been considered as a prerequisite for neurofibroma development. The second hit is detectable in a subpopulation of primary Schwann cells cultured from neurofibromas. This thesis challenges the traditional concept of neurofibroma development. The results show that cutaneous neurofibromas are intimately associated with hair follicular structures and contain multipotent precursor cells (NFPs), suggesting that neurofibromas may arise from the multipotent cells which reside in hair follicles. Furthermore, this study presents that neurofibroma-derived Schwann cells that harbor bi-allelic inactivation in the NF1 gene express HLA class II genes and may act as nonprofessional antigen presenting cells. The CD4- and FoxP3-positive cells detected in cutaneous neurofibromas suggest that these cells may represent regulatory T cells (Tregs) which interact with HLA II –positive cells and aid the tumor cells in hiding from the immune system and are thus mediators of immune tolerance. This thesis also investigated neurofibroma development in the oral cavity and the use of different biomarkers to characterize cellular differentiation in neurofibromas. The results revealed that oral neurofibromas are not rare, but they usually appear as solitary lesions contrary to multiple cutaneous neurofibromas and present high heterogeneity within and between tumors. The use of class III beta-tubulin as a marker for neuronal differentiation led to an unexpected finding showing that multiple cell types express class III beta-tubulin during mitosis. The increased understanding of the multipotency of tumor cells, cellular differentiation and ability to hide from immune system will aid in the development of future treatments. Specifically, targeting Tregs in NF1 patients could provide a novel therapeutic approach to interfere with the development of neurofibromas.

Fase menstrual na data da cirurgia para câncer de mama: resultados tardios e taxas de sobrevida assintomática

Objetivo: verificar se existem diferenças nas taxas de sobrevida para as portadoras de carcinoma de mama, em função da fase do ciclo menstrual vivida pela paciente na data da cirurgia. Pacientes e Métodos: pesquisa retrospectiva de 451 mulheres com câncer de mama, em pré-menopausa, das quais foram selecionados 130 casos com idade entre 26 e 52 anos e acompanhados em seguimento mínimo de 60 meses. Foram operadas 68 na fase folicular e 62 na fase lútea. Foram também analisados os dados referentes ao estádio clínico das neoplasias, ao eventual comprometimento axilar e às determinações quantitativas dos receptores hormonais de estrógenos e de progesterona. Resultados: o seguimento das 130 pacientes demonstrou que 64,6% tiveram sobrevida assintomática após cinco anos e 43% superaram os dez anos. Dividindo os casos em dois subgrupos, segundo o dia da cirurgia executada, as taxas de sobrevida foram diferentes, caindo para 58,8% aos cinco e 36,7% aos dez anos, quando operadas na fase folicular e subindo para 70,9% e 50%, aos 5 e 10 anos respectivamente, durante a fase lútea. Conclusões: neste estudo, as pacientes operadas durante a fase lútea mostraram taxas mais altas de sobrevida do que aquelas operadas na fase folicular. Todavia, os índices foram inferiores aos proporcionados pelos fatores prognósticos clássicos de estado axilar e diâmetro tumoral.

Anatomical and functional characteristics of the pelvic floor in nulliparous women submitted to three-dimensional endovaginal ultrasonography: case control study and evaluation of interobserver agreement

PURPOSE: To determine anatomical and functional pelvic floor measurements performed with three-dimensional (3-D) endovaginal ultrasonography in asymptomatic nulliparous women without dysfunctions detected in previous dynamic 3-D anorectal ultrasonography (echo defecography) and to demonstrate the interobserver reliability of these measurements. METHODS: Asymptomatic nulliparous volunteers were submitted to echo defecography to identify dynamic dysfunctions, including anatomical (rectocele, intussusceptions, entero/sigmoidocele and perineal descent) and functional changes (non-relaxation or paradoxical contraction of the puborectalis muscle) in the posterior compartment and assessed with regard to the biometric index of levator hiatus, pubovisceral muscle thickness, urethral length, anorectal angle, anorectal junction position and bladder neck position with the 3-D endovaginal ultrasonography. All measurements were compared at rest and during the Valsalva maneuver, and perineal and bladder neck descent was determined. The level of interobserver agreement was evaluated for all measurements. RESULTS: A total of 34 volunteers were assessed by echo defecography and by 3-D endovaginal ultrasonography. Out of these, 20 subjects met the inclusion criteria. The 14 excluded subjects were found to have posterior dynamic dysfunctions. During the Valsalva maneuver, the hiatal area was significantly larger, the urethra was significantly shorter and the anorectal angle was greater. Measurements at rest and during the Valsalva maneuver differed significantly with regard to anorectal junction and bladder neck position. The mean values for normal perineal descent and bladder neck descent were 0.6 cm and 0.5 cm above the symphysis pubis, respectively. The intraclass correlation coefficient ranged from 0.62-0.93. CONCLUSIONS: Functional biometric indexes, normal perineal descent and bladder neck descent values were determined for young asymptomatic nulliparous women with the 3-D endovaginal ultrasonography. The method was found to be reliable to measure pelvic floor structures at rest and during Valsalva, and might therefore be suitable for identifying dysfunctions in symptomatic patients.

Genetic diversity of bovine viral diarrhoea virus (BVDV) from Peru and Chile

Twenty-five BVDV strains, detected in serum from persistently infected cattle from Peru (n=15) and Chile (n=10) were genetically characterized. The phylogenetic analysis based on the 5' UTR showed that all 25 strains belonged to genotype 1. Twenty-three of the strains could further be subdivided into subtype 1b, and two out of ten Chilean strains into subtype 1a. In conclusion, in total 23 out of 25 strains analyzed were of genotype 1, subtype 1b. This is the predominant BVDV subtype in many countries all over the world, including USA. The close homology with previously described strains reflects the influence of livestock trade on the diversity of BVDV circulating within and between countries and continents. Peru and Chile have imported large numbers of cattle from USA and Europe, mostly with insufficient or lacking health documentation.

Participação da excreção renal de cálcio, fósforo, sódio e potássio na homeostase em cães sadios e cães com doença renal crônica

Na doença renal crônica (DRC) a manutenção da homeostase de água e sódio é o primeiro problema a ser contornado pelo organismo e com o agravamento das lesões renais surgem outros problemas graves relacionados à homeostase de cálcio e fósforo. O presente estudo tem por escopo avaliar a excreção renal de cálcio, fósforo, sódio e potássio, e o perfil sérico destes eletrólitos em cães normais e em cães com DRC naturalmente adquirida. Foram avaliados três grupos de cães adultos, machos ou fêmeas, de raças variadas. Animais normais compuseram o grupo controle (G1) e os cães com DRC foram distribuídos em dois grupos de acordo com os estágios de comprometimento da função renal (G2 e G3, respectivamente, estágios 1-2 e estágios 3-4, descritos pela IRIS 2006 staging CKD). Os cães do G3 apresentaram aumento das concentrações séricas de cálcio ionizado e fósforo, além de diminuição da concentração sérica de sódio. Quanto à excreção renal dos eletrólitos analisados, os animais dos grupos G1 e G2 apresentaram diminuição de carga filtrada e aumento de excreção fracionada, mas as excreções urinárias não variaram significativamente. Os resultados são indicativos de que os rins de cães com DRC podem manter a excreção urinária dos eletrólitos em valores se melhantes aos dos normais. O mecanismo envolve aumento da excreção fracionada na medida em que haja diminuição da filtração glomerular. Esse processo de compensação, entretanto, pode perder a eficiência nos estágios mais avançados da enfermidade no que se refere à manutenção das concentrações séricas de fósforo e sódio.

Serum intact parathyroid hormone levels in cats with chronic kidney disease

Chronic kidney disease (CKD) is frequently observed in cats and it is characterized as a multisystemic illness, caused by several underlying metabolic changes, and secondary renal hyperparathyroidism (SRHPT) is relatively common; usually it is associated with the progression of renal disease and poor prognosis. This study aimed at determining the frequency of SRHPT, and discussing possible mechanisms that could contribute to the development of SRHPT in cats at different stages of CKD through the evaluation of calcium and phosphorus metabolism, as well as acid-base status. Forty owned cats with CKD were included and divided into three groups, according to the stages of the disease, classified according to the International Renal Interest Society (IRIS) as Stage II (n=12), Stage III (n=22) and Stage IV (n=6). Control group was composed of 21 clinically healthy cats. Increased serum intact parathyroid hormone (iPTH) concentrations were observed in most CKD cats in all stages, and mainly in Stage IV, which hyperphosphatemia and ionized hypocalcemia were detected and associated to the cause for the development of SRHPT. In Stages II and III, however, ionized hypercalcemia was noticed suggesting that the development of SRHPT might be associated with other factors, and metabolic acidosis could be involved to the increase of serum ionized calcium. Therefore, causes for the development of SRHPT seem to be multifactorial and they must be further investigated, mainly in the early stages of CKD in cats, as hyperphosphatemia and ionized hypocalcemia could not be the only factors involved.

Estudo da ocorrência de litíase renal e ureteral em gatos com doença renal crônica

Investigou-se a ocorrência de nefrolitíase e/ou ureterolitíase em 72 gatos portadores de doença renal crônica (DRC), classificados predominantemente no estágio II, segundo os critérios designados pela IRIS - International Renal Interest Society. Destes pacientes, 47 (65,27%) apresentaram litíase renal e ou ureteral. Não houve diferença estatística entre o grupo de estudo (DRC com cálculo) e o grupo controle (DRC sem cálculo) em relação à idade (p=0,274). Apesar disso, os pacientes portadores de nefrolitíase e/ou ureterolitíase apresentaram maiores indícios de lesão renal, caracterizados por diferenças estatisticamente relevantes da densidade urinária (p=0,013) e pelo menor tamanho dos rins direito (p=0,009) e esquerdo (p=0,048). Encontrou-se similaridade entre os grupos em relação a outros parâmetros, tais como as concentrações plasmáticas de cálcio total, cálcio ionizado, fósforo, sódio, potássio e paratormônio intacto (PTHi). Os valores das concentrações séricas de ureia e bicarbonato diferiram entre os grupos, com valores de p=0,039 e p=0,037, respectivamente. Além disso, foi mensurada a pressão arterial, que se manteve inalterada na comparação entre o grupo de estudo e o grupo controle. Os resultados obtidos reforçam a necessidade de acompanhamento ultrassonográfico de todos os pacientes portadores de DRC, mesmo daqueles assintomáticos ou em estágios iniciais da doença.

Pulsed corona discharge as an advanced oxidation process for degradation of organic

Advanced oxidation processes (AOPs) have been studied and developed to suffice the effective removal of refractory and toxic compounds in polluted water. The quality and cost of wastewater treatment need improvements, and electric discharge technology has a potential to make a significant difference compared to other established AOPs based on energy efficiency. The generation of active oxidant species such as ozone and hydroxyl radicals by high voltage discharge is a relatively new technology for water treatment. Gas-phase pulsed corona discharge (PCD), where a treated aqueous solution is dispersed between corona-producing electrodes free of the dielectric barriers, was developed as an alternative approach to the problem. The short living radicals and ozone formed in the gas phase and at the gas-liquid interface react with dissolved impurities. PCD equipment has a relatively simple configuration, and with the reactor in an enclosed compartment, it is insensitive towards gas humidity and does not need the gas transport. In this thesis, PCD was used to study and evaluate the energy efficiency for degrading various organic compounds, as well as the chemistry of the oxidation products formed. The experiments investigate the aqueous oxidation of phenol, humic substances, pharmaceutical compounds (paracetamol, ibuprofen, indomethacin, salicylic acids, -estradiol), as well as lignin degradation and transformation to aldehydes. The study aims to establish the influence of initial concentration of the target pollutant, the pulsed discharge parameters, gas phase composition and the pH on the oxidation kinetics and the efficiency. Analytical methods to measure the concentrations of the target compounds and their by-products include HPLC, spectrophotometry, TOC and capillary electrophoresis. The results of the research included in this summary are presented in the attached publications and manuscripts accepted for publication. Pulsed corona discharge proved to be highly effective in oxidizing each of the target compounds, surpassing the closest competitor, conventional ozonation. The increase in oxidation efficiencies for some compounds in oxygen media and at lower pulse repetition frequencies shows a significant role of ozone. The role of the ·OH radicals was established in the surface reactions. The main oxidation products, formation of nitrates, and the lignin transformation were quantified. A compound specific approach is suggested for optimization of the PCD parameters that have the most significant impact on the oxidation energy efficiency because of the different characteristics and responses of the target compound to the oxidants, as well as different admixtures that are present in the wastewater. Further studies in the method’s safety (nitration and nitrosation of organic compounds, nitrite and nitrate formation enhancement) are needed for promoting the method.

Att tala om det osägbara : Nicolaus Cusanus cirkulära filosofi i verket De coniecturis med särskild hänsyn till Nelson Pikes tankar om unio mystica

In my dissertation called Speaking of the unsayable: The circular philosophy of Nicholas of Cusa in his work De coniecturis, I presuppose an internal (conceptual) relation between the personal experience of God of Nicholas of Cusa (1401-64) in 1438 and, on the other hand, his philosophy. I hence try to describe the precise character of this relation. Referring to the Norwegian scholars Egil Wyller and Viggo Rossvær, I assume that there is a circularity in Cusanus’ philosophy which appears as self-references (= a sentence refers to itself: A is explained by B and B is explained by A). Wyller finds three phases in the thought of Cusanus (1. De docta ignorantia I-III, 2. De coniecturis I-II, 3. all subsequent works). Rossvær finds it impossible to presuppose certain phases, as the philosophy of Cusanus continuously proceeds and remains open to new ideas. As Cusanus however treats his experience of God far more consciously in his second work De coniecturis than in De docta ignorantia, I find it possible to distinguish between the earlier Cusanus (De docta ignorantia including his earlier works) and the later Cusanus (De coniecturis, about 1444, as well as the following works). Cusanus creates a philosophy of language in outline expressed in De coniecturis, in which he presents two concepts of necessity, i.e. absolute necessity and logical, or reasonable, necessity. These are interrelated in the sense that the mind, or the self, logically affirms the absolute, or unsayable, necessity, which shows itself in the mind and which the mind affirms conjecturally. The endeavour conceptually to understand absolute necessity implies intuitive (or intellectual) contemplation, or vision (investigatio symbolica), in which the four mental unities (the absolute, the intellectual, the rational and the sensuous) work together according to the rules described in De coniecturis. In De coniecturis Cusanus obviously turns from a negative concept of the unsayable to a paradigmatic, which implies that he looks for principles of speaking of the unsayable and presents the idea of a divine language (divinaliter). However, he leaves this idea behind after De coniecturis, although he continues to create new concepts of the unsayable and incomprehensible. The intellectual language of absolute seeing is expressed in the subjunctive, i.e. conditionally. In order to describe the unsayable, Cusanus uses tautologies, the primary one of which is a concept of God, i.e. non aliud est non aliud quam non aliud (the non-other is non-other than the nonother). Wyller considers this the crucial point of the philosophy of Cusanus (De non aliud), described by the latter as the definition of definitions, i.e. the absolute definition. However, this definition is empty regarding its content. It demonstrates that God surpasses the coincidence of opposites (coincidentia oppositorum) and that he is “superunsayable” (superineffabilis), i.e. he is beyond what can be conceived or said. Nothing hence prevents us from speaking of him, provided that he is described as unsayable (= the paradigmatic concept of the unsayable). Here the mode of seeing is decisive. Cusanus in this context (and especially in his later literary production) uses modalities which concern possibility and necessity. His aim is to conduct any willing reader ahead on the way of life (philosophia mentalis). In De coniecturis II he describes the notion of human self-consciousness as the basis of spiritual mutuality in accordance with the humanistic tradition of his time. I mainly oppose the negatively determined concept of Christian mysticism presented by the German philosopher Kurt Flasch and prefer the presentation of Burkhard Mojsisch of the translogical and conjectural use of language in De coniecturis. In particular, I take account of the Scandinavian research, basically that of Johannes Sløk, Birgit H. Helander, Egil Wyller and Viggo Rossvær, who all consider the personal experience of God described by Cusanus a tacit precondition of his philosophy.

In vitro and in vivo studies demonstrate non-mutagenicity of the herbicide metolachlor

The herbicide metolachlor was evaluated for genotoxic potential. Metolachlor did not induce micronuclei in mice, however at 40 mg/kg it significantly decreased the percentage of polychromatic erythrocytes, which is a cytotoxic effect. Metolachlor did not induce chromosomal aberrations in human lymphocytes in vitro, but 2.0 mug/ml culture medium resulted in cytotoxicity, decreasing the mitotic index significantly. The indirect exposure test was carried out by adding plasma from metolachlor-pretreated rats to the human lymphocyte cultures. There was no indication of clastogenicity by metolachlor metabolites. On the other hand, plasma of cyclophosphamide-pretreated rats had a significant clastogenic effect

Application of isotope-selective non-dispersive infrared spectrometry for the evaluation of the 13C-urea breath test: comparison with three concordant methods

The aim of this work was to compare the performance of isotope-selective non-dispersive infrared spectrometry (IRIS) for the 13C-urea breath test with the combination of the 14C-urea breath test (14C-UBT), urease test and histologic examination for the diagnosis of H. pylori (HP) infection. Fifty-three duodenal ulcer patients were studied. All patients were submitted to gastroscopy to detect HP by the urease test, histologic examination and 14C-UBT. To be included in the study the results of the 3 tests had to be concordant. Within one month after admission to the study the patients were submitted to IRIS with breath samples collected before and 30 min after the ingestion of 75 mg 13C-urea dissolved in 200 ml of orange juice. The samples were mailed and analyzed 11.5 (4-21) days after collection. Data were analyzed statistically by the chi-square and Mann-Whitney test and by the Spearman correlation coefficient. Twenty-six patients were HP positive and 27 negative. There was 100% agreement between the IRIS results and the HP status determined by the other three methods. Using a cutoff value of delta-over-baseline (DOB) above 4.0 the IRIS showed a mean value of 19.38 (minimum = 4.2, maximum = 41.3, SD = 10.9) for HP-positive patients and a mean value of 0.88 (minimum = 0.10, maximum = 2.5, SD = 0.71) for negative patients. Using a cutoff value corresponding to 0.800% CO2/weight (kg), the 14C-UBT showed a mean value of 2.78 (minimum = 0.89, maximum = 5.22, SD = 1.18) in HP-positive patients. HP-negative patients showed a mean value of 0.37 (minimum = 0.13, maximum = 0.77, SD = 0.17). IRIS is a low-cost, easy to manage, highly sensitive and specific test for H. pylori detection. Storing and mailing the samples did not interfere with the performance of the test.

Endlich ein estnisches etymologisches Wörterbuch!

Kirjallisuusarvostelu

Neuroprotection by flavonoids

The high morbidity, high socioeconomic costs and lack of specific treatments are key factors that define the relevance of brain pathology for human health and the importance of research on neuronal protective agents. Epidemiological studies have shown beneficial effects of flavonoids on arteriosclerosis-related pathology in general and neurodegeneration in particular. Flavonoids can protect the brain by their ability to modulate intracellular signals promoting cellular survival. Quercetin and structurally related flavonoids (myricetin, fisetin, luteolin) showed a marked cytoprotective capacity in in vitro experimental conditions in models of predominantly apoptotic death such as that induced by medium concentrations (200 µM) of H2O2 added to PC12 cells in culture. Nevertheless, quercetin did not protect substantia nigra neurons in vivo from an oxidative insult (6-hydroxydopamine), probably due to difficulties in crossing the blood-brain barrier. On the other hand, treatment of permanent focal ischemia with a lecithin/quercetin preparation decreased lesion volume, showing that preparations that help to cross the blood-brain barrier may be critical for the expression of the effects of flavonoids on the brain. The hypothesis is advanced that a group of quercetin-related flavonoids could become lead molecules for the development of neuroprotective compounds with multitarget anti-ischemic effects.

CONDIÇÕES HIGIÊNICO-SANITÁRIAS DO QUEIJO DE LEITE DE CABRA "TIPO COALHO", ARTESANAL ELABORADO NO CURIMATAÚ PARAIBANO

Foram analisadas 20 amostras de queijo de leite de cabra" tipo coalho", elaborados de forma artesanal e armazenados durante 28 dias sob refrigeração a 10 ± 2 ºC, em intervalos de 0, 7, 14, 21 e 28 dias, tendo sido avaliados os seguintes parâmetros: contagem de bactérias aeróbias mesófilas (UFC/g) número mais provável de coliformes totais e fecais (NMP/g), contagem de bolores e leveduras (UFC/g) e contagem de Staphylococcus aureus (UFC/g). As contagens de bactérias aeróbias mesófilas variaram de 2,35 x 103 a 1,5 x 109 UFC/g; enquanto que o número de coliformes totais oscilaram entre 2,4 x 103 a 2,4 x 106 e 2,4 x 109 NMP/g. Por outro lado, a contagem de coliformes fecais a apresentou variações de 2,4 x 103 a 2,4 x 106 NMP/g e bolores e leveduras < 30 a 5,5 x 108 UFC/g. Durante o armazenamento não foi evidenciada a presença de Staphylococcus aureus, constatando-se a necessidade de reavaliar as técnicas utilizadas na manipulação e processamento artesanal do queijo elaborado.