Impfung gegen humane Papillomaviren (HPV) zur Prävention HPV 16/18 induzierter Zervixkarzinome und derer Vorstufen

Einleitung: Notwendige Voraussetzung für die Entstehung von Zervixkarzinomen ist eine persistierende Infektion mit humanen Papillomaviren (HPV). Die HPV-Typen 16 und 18 verursachen mit etwa 70% den überwiegenden Teil der Zervixkarzinome. Seit 2006/2007 stehen zwei Impfstoffe gegen HPV 16 und 18 zur Verfügung. Fragestellung: Wie effektiv ist die HPV-Impfung hinsichtlich der Reduktion von Zervixkarzinomen bzw. ihren Vorstufen (CIN)? Stellt die HPV-Impfung eine kosteneffektive Ergänzung zur derzeitigen Screeningpraxis dar? Gibt es Unterschiede bezüglich der Kosten-Effektivität zwischen den beiden verfügbaren Impfstoffen? Sollte aus gesundheitsökonomischer Perspektive eine Empfehlung für den Einsatz der HPV-Impfung gegeben werden? Falls ja, welche Empfehlungen bezüglich der Ausgestaltung einer Impfstrategie lassen sich ableiten? Welche ethischen, sozialen und juristischen Implikationen sind zu berücksichtigen? Methoden: Basierend auf einer systematischen Literaturrecherche werden randomisierte kontrollierte Studien zur Wirksamkeit der HPV-Impfungen für die Prävention von Zervixkarzinomen bzw. deren Vorstufen, den zervikalen intraepithelialen Neoplasien, identifiziert. Gesundheitsökonomische Modellierungen werden zur Beantwortung der ökonomischen Fragestellungen herangezogen. Die Beurteilung der Qualität der medizinischen und ökonomischen Studien erfolgt mittels anerkannter Standards zur systematischen Bewertung wissenschaftlicher Studien Ergebnisse: Bei zu Studienbeginn HPV 16/18 negativen Frauen, die alle Impfdosen erhalten haben, liegt die Wirksamkeit der Impfungen gegen HPV 16/18-induzierten CIN 2 oder höher bei 98% bis 100%. Nebenwirkungen der Impfung sind vor allem mit der Injektion assoziierte Beschwerden (Rötungen, Schwellungen, Schmerzen). Es gibt keine signifikanten Unterschiede für schwerwiegende unerwünschte Ereignisse zwischen Impf- und Placebogruppe. Die Ergebnisse der Basisfallanalysen der gesundheitsökonomischen Modellierungen reichen bei ausschließlicher Berücksichtigung direkter Kostenkomponenten von ca. 3.000 Euro bis ca. 40.000 Euro pro QALY (QALY = Qualitätskorrigiertes Lebensjahr), bzw. von ca. 9.000 Euro bis ca. 65.000 Euro pro LYG (LYG = Gewonnenes Lebensjahr). Diskussion: Nach den Ergebnissen der eingeschlossenen Studien sind die verfügbaren HPV-Impfstoffe wirksam zur Prävention gegen durch HPV 16/18 verursachte prämaligne Läsionen der Zervix. Unklar ist derzeit noch die Dauer des Impfschutzes. Hinsichtlich der Nebenwirkungen ist die Impfung als sicher einzustufen. Allerdings ist die Fallzahl der Studien nicht ausreichend groß, um das Auftreten sehr seltener Nebenwirkungen zuverlässig zu bestimmen. Inwieweit die HPV-Impfung zur Reduktion der Inzidenz und Mortalität des Zervixkarzinoms in Deutschland führen wird, hängt nicht allein von der klinischen Wirksamkeit der Impfstoffe ab, sondern wird von einer Reihe weiterer Faktoren wie der Impfquote oder den Auswirkungen der Impfungen auf die Teilnahmerate an den bestehenden Screeningprogrammen determiniert. Infolge der Heterogenität der methodischen Rahmenbedingungen und Inputparameter variieren die Ergebnisse der gesundheitsökonomischen Modellierungen erheblich. Fast alle Modellanalysen lassen jedoch den Schluss zu, dass die Einführung einer Impfung mit lebenslanger Schutzdauer bei Fortführung der derzeitigen Screeningpraxis als kosteneffektiv zu bewerten ist. Eine Gegenüberstellung der beiden verschiedenen Impfstoffe ergab, dass die Modellierung der tetravalenten Impfung bei der Berücksichtigung von QALY als Ergebnisparameter in der Regel mit einem niedrigeren (besseren) Kosten-Effektivitäts-Verhältnis einhergeht als die Modellierung der bivalenten Impfung, da auch Genitalwarzen berücksichtigt werden. In Sensitivitätsanalysen stellten sich sowohl die Schutzdauer der Impfung als auch die Höhe der Diskontierungsrate als wesentliche Einflussparameter der Kosten-Effektivität heraus. Schlussfolgerung: Die Einführung der HPV-Impfung kann zu einem verringerten Auftreten von Zervixkarzinomen bei geimpften Frauen führen. Jedoch sollten die Impfprogramme von weiteren Evaluationen begleitet werden, um die langfristige Wirksamkeit und Sicherheit beurteilen sowie die Umsetzung der Impfprogramme optimieren zu können. Von zentraler Bedeutung sind hohe Teilnahmeraten sowohl an den Impfprogrammen als auch - auch bei geimpften Frauen - an den Früherkennungsuntersuchungen. Da die Kosten-Effektivität entscheidend von der Schutzdauer, die bislang ungewiss ist, beeinflusst wird, ist eine abschließende Beurteilung der Kosten-Effektivität der HPV-Impfung nicht möglich. Eine langfristige Schutzdauer ist eine bedeutende Vorraussetzung für die Kosten-Effektivität der Impfung. Der Abschluss einer Risk-Sharing-Vereinbarung zwischen Kostenträgern und Herstellerfirmen stellt eine Option dar, um die Auswirkungen der Unsicherheit der Schutzdauer auf die Kosten-Effektivität zu begrenzen.

Vicilinas de sementes de leguminosas selvagens:purificação, caracterização, efeito de deletério e mecanismo de ação para bruquídeos e para fungos fitopatogênicos

Globulins fractions of legume seeds of Crotalaria pallida, Erytrina veluntina and Enterolobium contortisiliquum were isolated and submitted to assays against serine, cysteine and aspartic proteinases, as also amylase present in midgut of C. maculatus and Z. subfasciatus. Hemagglutination assays indicated presence of a lectin in E. veluntina globulin fractions. This lectin had affinity to human erythrocytes type A, B and O. Vicilins were purified by chromatography on Sephacryl S-300 followed of a chromatography on Sephacryl S-200, which was calibrated using protein markers. Vicilins from C. pallida (CpV) and E. veluntina (EvV) seeds had a molecular mass of 124.6 kDa and E. contortisiliquum a molecular mass of 151kDa. Eletrophoresis in presence of SDS showed that CpV was constituted by four subunities with apparent molecular mass of 66, 63, 57 and 45 kDa, EvV with three subunities with apparent molecular mass of 45kDa and EcV four subunities, two with 37.1 kDa and two with 25.8 kDa. Non denaturantig eletrophoresis displayed single bands with high homogeneity, where CpV had lower acidic behavior. All vicilins are glycoproteins with carbohydrate contents at 1 to1.5%. Bioassays were done to detect deleterious effects of vicilins against C. maculatus and Z. subfasciatus larvae. CpV, EvV and EcV exhibited a WD50 of 0.28, 0.19 and 1.03%; LD50 0.2, 0.26, and 1.11% respectively to C. maculatus. The dose responses of CpV, EvV and EcV to Z. subfasciatus were: WD50 of 0.12, 0.14, 0.65% and LD50 of 0.09, 0.1, and 0.43% respectively. The mechanism of action of these proteins to bruchids should be based on their properties of bind to chitin present in mid gut of larvae associated with the low digestibility of vicilin. In assays against phytopatogenous fungus, only EcV was capable of inhibit F. solani growth at concentrations of 10 and 20 µg and its action mechanism should be also based in the affinity of EcV to chitin present in the fungi wall

CCR2 and CCR5 genes polymorphisms in women with cervical lesions from Pernambuco, Northeast Region of Brazil: a case-control study

Polymorphisms in chemokine receptors play an important role in the progression of cervical intraepithelial neoplasia (CIN) to cervical cancer (CC). Our study examined the association of CCR2-64I (rs1799864) and CCR5-Δ32 (rs333) polymorphisms with susceptibility to develop cervical lesion (CIN and CC) in a Brazilian population. The genotyping of 139 women with cervical lesions and 151 women without cervical lesions for the CCR2-64I and CCR5-Δ32 polymorphisms were performed using polymerase chain reaction-restriction fragment length polymorphism. The individuals carrying heterozygous or homozygous genotypes (GA+AA) for CCR2-64I polymorphisms seem to be at lower risk for cervical lesion [odds ratio (OR) = 0.37, p = 0.0008)]. The same was observed for the A allele (OR = 0.39, p = 0.0002), while no association was detected (p > 0.05) with CCR5-Δ32 polymorphism. Regarding the human papillomavirus (HPV) type, patients carrying the CCR2-64I polymorphism were protected against infection by HPV type 16 (OR = 0.35, p = 0.0184). In summary, our study showed a protective effect of CCR2-64I rs1799864 polymorphism against the development of cervical lesions (CIN and CC) and in the susceptibility of HPV 16 infection.

Un aporte a la comprensión de las estrategias emergentes en las organizaciones a través del concepto de improvisación y la metáfora musical

Este trabajo se inscribe en uno de los grandes campos de los estudios organizacionales: la estrategia. La perspectiva clásica en este campo promovió la idea de que proyectarse hacia el futuro implica diseñar un plan (una serie de acciones deliberadas). Avances posteriores mostraron que la estrategia podía ser comprendida de otras formas. Sin embargo, la evolución del campo privilegió en alguna medida la mirada clásica estableciendo, por ejemplo, múltiples modelos para ‘formular’ una estrategia, pero dejando en segundo lugar la manera en la que esta puede ‘emerger’. El propósito de esta investigación es, entonces, aportar al actual nivel de comprensión respecto a las estrategias emergentes en las organizaciones. Para hacerlo, se consideró un concepto opuesto —aunque complementario— al de ‘planeación’ y, de hecho, muy cercano en su naturaleza a ese tipo de estrategias: la improvisación. Dado que este se ha nutrido de valiosos aportes del mundo de la música, se acudió al saber propio de este dominio, recurriendo al uso de ‘la metáfora’ como recurso teórico para entenderlo y alcanzar el objetivo propuesto. Los resultados muestran que 1) las estrategias deliberadas y las emergentes coexisten y se complementan, 2) la improvisación está siempre presente en el contexto organizacional, 3) existe una mayor intensidad de la improvisación en el ‘como’ de la estrategia que en el ‘qué’ y, en oposición a la idea convencional al respecto, 4) se requiere cierta preparación para poder improvisar de manera adecuada.

Innovación social: una reflexión sobre los beneficios en su implementación en el Estado colombiano.

La innovación social es un tipo de innovación que promueve la búsqueda de soluciones enfocadas a los problemas que se presentan en la sociedad. Estas soluciones generan además un valor agregado que ayudan al crecimiento del país. En Colombia este tipo de iniciativas han empezado a tener una gran importancia y han empezado a promover condiciones de vida más favorables y justas que buscan generar un beneficio a la sociedad y contribuir al desarrollo del país. A partir de la historia de la innovación social, ejemplos y grandes literatos en la administración y la sociología, comprenderemos la importancia de la innovación en nuestro país.

Molecular analysis of Papillomavirus-induced cutaneous tumors in equids

Papillomavirus associated tumors are well recognized entities in humans as well as in animals. Here is reviewed the current understanding of human papillomavirus (HPV) associated cancers to better understand the oncogenic mechanisms of Equine papillomavirus (EcPV) and Bovine Papillomavirus (BPV) in horses. In the first part of this study the interactions between Equine papillomavirus 2 (EcPV-2) and cell cycle proteins are discussed. EcPV-2 has been recognized as the cause of genital squamous cell carcinomas (SCCs) in horses, but the exact mechanism of carcinogenesis is not fully understood. The aim of the first part of this study is to assess the expression of cell cycle proteins p53, p16, pRB and Cyclin D1 in a series of equine SCCs and papillomas. Results confirm the role of EcPV-2 in the pathogenesis of genital SCCs. Moreover, in a small subset of ocular SCCs, EcPV-2 was detected for the first time. By immunohistochemistry, p53 was mostly expressed in ocular SCCs with a suprabasal localization. Regarding p16, overexpression was associated with increased mitotic index but not with viral infection. Investigation on pRB and Cyclin D1 proteins did not show significant correlation with other variables. The second part of this study is focused on the carcinogenetic mechanisms of BPV in equine sarcoids. The aim of the second part of this study was to characterize the typical histomorphological features of equine sarcoids, assess the expression of cell cycle proteins and Ki-67 proliferation index. Our results confirm that the typical histological features of sarcoids cannot be used to correctly classify the clinical types. Moreover, in a subset of sarcoids low pRB-Cyclin D1 scores were associated with simultaneous high p16 expression. The Ki-67 proliferation index confirm the low proliferative activity of sarcoids, except for tumors displaying a fascicular pattern. Finally, a subset of sarcoids recurred after excision.

Própolis do sudeste e nordeste do Brasil: influência da sazonalidade na atividade antibacteriana e composição fenólica

The composition and biological activities of propolis, a resinous hive product collected by honeybees from various plant sources, depends on various factors such as season and vegetation of the area. The aim of this study was to evaluate the influence of the seasonal effect on the ethanolic extracts of Brazilian propolis (EEP) type 6 and type 12, collected during 6 months in terms of antibacterial activity and phenolic composition. The antimicrobial properties were evaluated by MIC and MBC on S. mutans Ingbritt 1600 and the profile of chemical composition by UV-visible spectrophotometry, HPLC-RF and GC-MS. The results demonstrated that the season in which propolis is collected influences its chemical composition, resulting in modifications in its antibacterial activity.

Biological activities of lignoids from Amazon Myristicaceae species: Virola michelii, V. mollissima, V. pavonis and Iryanthera juruensis

This work revisits the fruits of Iryanthera juruensis and Virola pavonis and the leaves from V. michelii, as well as describing a study of the fruits of V. mollissima. In I. juruensis aryltetraline neolignan (1) and tetrahydrofuran neolignan (2), were found while from V. pavonis neolignans of benzofuran type (6-9), the tetrahydrofuran type (2, 11-13, 17) and the biphenyl type (10), in addition to diastereoisomers of the 8.O.4'-oxyneolignan type (14 and 15) and others were isolated. The V. mollissima accumulates the aryltetralone neolignan 4 and its seco derivative (5). The lignoids 1 and 2 obtained from I. juruensis arils possess antileishmanial activity against the promastigote form of Leishmania amazonensis.

Investigation of measles IgM-seropositive cases of febrile rash illnesses in the absence of documented measles virus transmission, State of São Paulo, Brazil, 2000-2004

Introdução: Revisar os casos de doenças febris exantemáticas com IgM reagente contra o sarampo, no estado de São Paulo, Brasil, durante os cinco anos seguidos a interrupção da transmissão do vírus do sarampo. Métodos: Nós revisamos 463 casos de doenças febris exantemáticas com IgM reagente contra o sarampo, no estado de São Paulo, Brasil, de 2000 a 2004. Indivíduos vacinados contra o sarampo 56 dias antes da coleta de amostra foram considerados expostos à vacina. Soros da fase aguda e de convalescença foram testados para a evidência de infecção de sarampo, rubéola, parvovírus B19 e herpes vírus 6. Na ausência de soroconversão para imunoglobulina G contra o sarampo, casos com IgM reagente contra o sarampo foram considerados falsos positivos em pessoas com evidência de outras infecções virais. Resultados: Entre as 463 pessoas com doenças febris exantemáticas que testaram positivo para anticorpos IgM contra o sarampo durante o período, 297 (64 por cento) pessoas foram classificadas como expostas à vacina. Entre os 166 casos não expostos à vacina, 109 (66 por cento) foram considerados falsos positivos baseado na ausência de soroconversão, dos quais 21 (13 por cento) tiveram evidência de infecção por vírus da rubéola, 49 (30 por cento) parvovírus B19 e 28 (17 por cento) infecção por herpes vírus humano 6. Conclusões: Após a interrupção da transmissão do vírus do sarampo é necessária exaustiva investigação dos casos com IgM reagente contra o sarampo, especialmente dos casos não expostos à vacina. Testes laboratoriais para etiologias das doenças febris exantemáticas ajudam na interpretação destes casos

Prevalência do HPV em mulheres rastreadas para o câncer cervical

OBJETIVO: Analisar a prevalência da infecção genital por papilomavírus humano (HPV) de alto risco por faixa etária e fatores associados. MÉTODOS: Estudo transversal com amostra de 2.300 mulheres (15-65 anos) que buscaram rastreamento para o câncer cervical entre fevereiro de 2002 e março de 2003 em São Paulo e Campinas, estado de São Paulo. Aplicou-se questionário epidemiológico e realizou-se coleta cervical para citologia oncológica e teste de captura híbrida II. As análises estatísticas empregadas foram teste de qui-quadrado de Pearson e análise multivariada pelo método forward likelihood ratio. RESULTADOS: A prevalência total da infecção genital por HPV de alto risco foi de 17,8%, distribuída nas faixas etárias: 27,1% (<25 anos), 21,3% (25-34 anos), 12,1% (35-44 anos), 12,0% (45-54 anos) e de 13,9% (55-65 anos). Participantes com maior número de parceiros sexuais durante a vida apresentaram maior freqüência da infecção. Relacionamento estável, idade de 35 a 44 anos e ex-fumantes foram associados à proteção da infecção. A infecção genital por HPV de alto risco ocorreu em 14,3% das citologias normais, em 77,8% das lesões escamosas de alto grau e nos dois (100%) casos de carcinoma. CONCLUSÕES: A prevalência da infecção genital por HPV de alto risco na amostra estudada foi alta. Houve predomínio de casos abaixo dos 25 anos e tendência a um novo aumento após os 55 anos, com maior freqüência naqueles com maior número de parceiros sexuais durante a vida

Bioassay guided purification of the antimicrobial fraction of a Brazilian propolis from Bahia state

Background: Brazilian propolis type 6 (Atlantic forest, Bahia) is distinct from the other types of propolis especially due to absence of flavonoids and presence of other non-polar, long chain compounds, but presenting good in vitro and in vivo antimicrobial activity. Several authors have suggested that fatty acids found in this propolis might be responsible for its antimicrobial activity; however, so far no evidence concerning this finding has been reported in the literature. The goals of this study were to evaluate the antibacterial activity of the main pure fatty acids in the ethanolic extract and fractions and elucidate the chemical nature of the bioactive compounds isolated from Brazilian propolis type 6. Methods: Brazilian propolis type 6 ethanolic extract (EEP), hexane fraction (H-Fr), major fatty acids, and isolated sub-fractions were analyzed using high performance liquid chromatography (HPLC), high resolution gas chromatography with flame ionization detection (HRGC-FID), and gas chromatography-mass spectrometry (GC-MS). Three sub-fractions of H-Fr were obtained through preparative HPLC. Antimicrobial activity of EEP, H-Fr, sub-fractions, and fatty acids were tested against Staphyloccus aureus ATCC 25923 and Streptococcus mutans Ingbritt 1600 using minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC). Results: EEP and H-Fr inhibited the growth of the microorganisms tested; nevertheless, no antimicrobial activity was found for the major fatty acids. The three sub-fractions (1, 2, and 3) were isolated from H-Fr by preparative HPLC and only sub-fraction 1 showed antimicrobial activity. Conclusion: a) The major fatty acids tested were not responsible for the antimicrobial activity of propolis type 6; b) Sub-fraction 1, belonging to the benzophenone class, was responsible for the antimicrobial activity observed in the present study. The identification of the bioactive compound will improve the development of more efficient uses of this natural product.

Low- and High-Intensity Lasers in the Treatment of Herpes Simplex Virus 1 Infection

Herpes simplex virus (HSV) is one of the most common viral infections of the human being. Although most of the seropositive persons do not manifest symptoms, infected individuals may present recurrent infections, characterized by cold sores. HSV-1 infection can result in potentially harmful complications in some patients, especially in those with compromised immunity. We report a clinical case of a patient with severe oral HSV-1 infection in the lower lip. The treatment of the lesions with the association of high-intensity (erbium-doped yttrium aluminum garnet, 2.94 mu m, 80 mJ/pulse, 2-4 Hz) and low-intensity (indium gallium aluminum phosphide, 660 nm, 3.8 J/cm(2), 10mW) lasers has not been reported in the literature. During treatment, no systemic or topical medication was used. Pain sensitivity was completely gone after the first irradiation with the low-intensity laser. During the healing process, lesions were traumatized twice, on the days 4 and 7. Even though the lesions were completely healed within 10 days.

Stromal cells play a role in cervical cancer progression mediated by MMP-2 protein

Metalloproteinases, especially metal loprotemase-2 (MMP-2), are known for their role in the degradation of the extracellular matrix. Nevertheless, a thorough understanding of MMP-2 expression in neoplastic lesions of the uterine cervix has yet to be accomplished. This study aimed to analyze the MMP-2 expression in cervical intraepithelial neoplasia III (CIN3) and in cervical squamous cell carcinoma, in tumor cells and adjacent stromal cells. MMP-2 expression was assessed by an immunohistochernical technique. MMP-2 expression was greater in the stromal cells of invasive carcinomas than in CIN3 (p < 0.0001). MMP-2 expression in stromal cells correlates with the clinical stage, gradually increasing as the tumor progresses (p = 0.04). This study corroborates that stromal cells play an important role in tumor invasion and progression, mediated by the progressive enhancement of MMP-2 expression from CIN3 to advanced invasive tumor. The intense MMP-2 expression most probably is associated with poor tumor prognosis.

Predictors of genital warts among women attending two family planning clinics

Objectives: To establish the prevalence and predictors of genital warts among healthy women presenting for contraceptive advice at two family planning clinics, one in a major Australian city and one in a country town in the same state. Methods: Consecutive consenting attendees (n = 1218)at two family planning clinics in Queensland completed a questionnaire and were examined for genital warts. Results: The point prevalence of visible genital warts was 3.3 per cent in the city clinic and 14.4 per cent in the country town. For half of these clients a finding of warts was unexpected, in that the client was unaware of their presence and presentation to the family planning clinic was not specifically for advice about sexually transmitted infections. The major predictor of a finding of warts was client age, with the highest prevalence in 20- to 25-year-olds. Warts were also commoner amongst smokers in the country town but not in Brisbane. However, no analysed sociodemographic variable predicted a finding of warts of which the client was not aware. Conclusions: Genital warts are common among young women presenting for contraceptive advice. Such women are often unaware that they have warts. Examination for genital warts should be a part of any routine examination of sexually active women, and medical practitioners should be aware of appropriate advice for patients who are found to have genital warts on routine examination.

Screening Anal Dysplasia in HIV-Infected Patients: Is There an Agreement Between Anal Pap Smear and High-Resolution Anoscopy-Guided Biopsy?

PURPOSE: The purpose of this study was to analyze the agreement between anal Pap smear and high-resolution anoscopy-guided biopsy in diagnosing anal dysplasia in HIV-infected patients. METHODS: We conducted cross-sectional analysis of HIV-infected patients receiving anal dysplasia screening as part of routine care. Agreement between measures was estimated by weighted kappa statistics, using a three-tiered cytologic and histologic grading system (normal, low-grade dysplasia, and high-grade dysplasia). Estimates of sensitivity, specificity, and predictive values were calculated using a two-tiered cytologic and histologic grading system (""without dysplasia"" and ""with dysplasia of any grade""). Estimates were also calculated for the detection of high-grade dysplasia. RESULTS: During a one-year period, 222 patients underwent 330 anal Pap smears followed by high-resolution anoscopy-guided biopsies. There were 311 satisfactory Pap smears with concurrent biopsies. Considering histology the standard, the frequency of anal dysplasia was 46%. Kappa agreement between anal Pap smear and biopsy was 0.20. For detection of anal dysplasia of any grade, anal Pap smear showed sensitivity of 61%, specificity of 60%, positive predictive value of 56%, and negative predictive value of 64%. For high-grade dysplasia, anal Pap smear showed sensitivity of 16% and specificity of 97%. CONCLUSION: Anal Pap smears alone were not sensitive enough to rule out anal dysplasia. We recommend that high-resolution anoscopy-guided biopsy be incorporated as a complementary screening test for anal dysplasia in high-risk patients. Following baseline high-resolution anoscopy, these individuals could be followed with serial anal cytology to dictate the need for future high-resolution anoscopy-guided biopsies.