Transport Properties in Multicomponent Systems Containing Cyclodextrins and Nickel Ions.

In this work, we propose a comprehensive experimental study of the diffusion of nickel ions in combination with different cyclodextrins as carrier molecules for enhanced solubility and facilitated transport. For this, ternary mutual diffusion coefficients measured by Taylor dispersion method are reported for aqueous solutions containing nickel salts and different cyclodextrins (that is, α-CD, ß-CD, and γ-CD) at 298.15 K. A combination of Taylor dispersion and other methods, such as UV-vis spectroscopy, will be used to obtain complementary information on these systems. The determination of the physicochemical properties of these salts with CDs in aqueous solution provides information that allows us to understand solute-solvent interactions, and gives a significant contribution to understanding the mechanisms underlying diffusional transport in aqueous solutions, and, consequently, to mitigating the potential toxicity associated with these metal ions. For example, using mutual diffusion data, it is possible to estimate the number of moles of each ion transported per mole of the cyclodextrin driven by its own concentration gradient.

DNA damage independent inhibition of NF-κB transcription by anthracyclines.

Anthracyclines are among the most used and effective anticancer drugs. Their activity has been attributed to DNA double-strand breaks resulting from topoisomerase II poisoning and to eviction of histones from select sites in the genome. Here, we show that the extensively used anthracyclines Doxorubicin, Daunorubicin, and Epirubicin decrease the transcription of nuclear factor kappa B (NF-κB)-dependent gene targets, but not interferon-responsive genes in primary mouse (Mus musculus) macrophages. Using an NMR-based structural approach, we demonstrate that anthracyclines disturb the complexes formed between the NF-κB subunit RelA and its DNA-binding sites. The anthracycline variants Aclarubicin, Doxorubicinone, and the newly developed Dimethyl-doxorubicin, which share anticancer properties with the other anthracyclines but do not induce DNA damage, also suppressed inflammation, thus uncoupling DNA damage from the effects on inflammation. These findings have implications for anticancer therapy and for the development of novel anti-inflammatory drugs with limited side effects for life-threatening conditions such as sepsis.

The burden of coronary heart disease in simultaneous pancreas-kidney transplantation: coronary angiography as a diagnostic method for all? - a retrospective study / O peso da doença arterial coronariana no transplante de pâncreas-rim simultâneo: angiografia coronária como método diagnóstico para todos? - um estudo retrospectivo

Abstract Introduction: Type 1 diabetes mellitus is associated with an increased risk of coronary artery disease, which is frequently asymptomatic. This risk increases significantly in those with nephropathy. In selected patients, simultaneous pancreas-kidney transplantation is the renal and pancreatic replacement therapy of choice, as it increases longevity and stabilizes diabetic complications. Despite essential, universal screening protocols are still controversial for coronary artery disease in this population. Methods: We retrospectively analysed 99 simultaneous pancreas-kidney recipients from our centre from 2011 to 2018 and selected 77 patients who underwent coronary angiography during the pre-transplant evaluation. Our aim was to identify potential risk factors associated with significant lesions on coronary angiography. Results: Almost half of our cohort of 77 candidates submitted to coronary angiography had coronary artery disease. Of these, nearly 30% underwent revascularization, although only one of them reported symptoms of myocardial ischemia. In a univariate analysis, the presence of smoking habits was the only risk factor for coronary artery disease. We also found that 20 or more years of type 1 diabetes mellitus was significantly associated with the presence of coronaropathy. Discussion: Selection of diabetic candidates with acceptable cardiac risk before simultaneous pancreas-kidney transplantation is imperative. Given the impact of a correct diagnosis and a low procedural risk, we defend the routine use of coronary angiography as the initial screening method for coronary artery disease in this population. Particularly care must be taken in evaluating asymptomatic patients with long-term type 1 diabetes mellitus and smokers.

Resumo Introdução: O diabetes mellitus tipo 1 está associado ao risco aumentado de doença arterial coronariana, que é frequentemente assintomática. Este risco aumenta significativamente em pessoas com nefropatia. Em pacientes selecionados, o transplante de pâncreas- rim simultâneo é a terapia substitutiva, renal e pancreática, de escolha, pois aumenta a longevidade e estabiliza complicações diabéticas. Apesar de essenciais, protocolos de triagem universais ainda são controversos para doença arterial coronariana nesta população. Métodos: Analisamos retrospectivamente 99 receptores de pâncreas-rim simultâneo de nosso centro, de 2011 a 2018, e selecionamos 77 pacientes que realizaram angiografia coronária durante avaliação pré-transplante. Nosso objetivo foi identificar fatores de risco potenciais associados a lesões significativas na angiografia coronária. Resultados: Quase metade de nossa coorte de 77 candidatos submetidos à angiografia coronária apresentou doença arterial coronariana. Destes, quase 30% foram submetidos à revascularização, embora apenas um tenha relatado sintomas de isquemia miocárdica. Em uma análise univariada, a presença do hábito de fumar foi o único fator de risco para doença arterial coronariana. Também descobrimos que 20 ou mais anos de diabetes mellitus tipo 1 estavam significativamente associados à presença de coronariopatia. Discussão: A seleção de candidatos diabéticos com risco cardíaco aceitável antes do transplante de pâncreas-rim simultâneo é imperativa. Dado o impacto de um diagnóstico correto e baixo risco de procedimento, defendemos o uso rotineiro da angiografia coronária como método de triagem inicial para doença arterial coronariana nesta população. Deve-se ter um cuidado especial na avaliação de pacientes assintomáticos com diabetes mellitus tipo 1 de longa duração e fumantes.

The burden of coronary heart disease in simultaneous pancreas-kidney transplantation: coronary angiography as a diagnostic method for all? - a retrospective study.

INTRODUCTION: Type 1 diabetes mellitus is associated with an increased risk of coronary artery disease, which is frequently asymptomatic. This risk increases significantly in those with nephropathy. In selected patients, simultaneous pancreas-kidney transplantation is the renal and pancreatic replacement therapy of choice, as it increases longevity and stabilizes diabetic complications. Despite essential, universal screening protocols are still controversial for coronary artery disease in this population. METHODS: We retrospectively analysed 99 simultaneous pancreas-kidney recipients from our centre from 2011 to 2018 and selected 77 patients who underwent coronary angiography during the pre-transplant evaluation. Our aim was to identify potential risk factors associated with significant lesions on coronary angiography. RESULTS: Almost half of our cohort of 77 candidates submitted to coronary angiography had coronary artery disease. Of these, nearly 30% underwent revascularization, although only one of them reported symptoms of myocardial ischemia. In a univariate analysis, the presence of smoking habits was the only risk factor for coronary artery disease. We also found that 20 or more years of type 1 diabetes mellitus was significantly associated with the presence of coronaropathy. DISCUSSION: Selection of diabetic candidates with acceptable cardiac risk before simultaneous pancreas-kidney transplantation is imperative. Given the impact of a correct diagnosis and a low procedural risk, we defend the routine use of coronary angiography as the initial screening method for coronary artery disease in this population. Particularly care must be taken in evaluating asymptomatic patients with long-term type 1 diabetes mellitus and smokers.

Impact of the COVID-19 pandemic on breast and cervical cancer stage at diagnosis in Brazil.

BACKGROUND: The COVID-19 pandemic has led to the need for health services adjustments, which may have compromised management of other diseases. For cancer patients, delays may significantly impair outcomes in some situations. We aimed to assess the impact of the COVID-19 pandemic in breast and cervical cancer diagnosis and treatment compared to the same period prior to the pandemic. METHODS: Data were collected from patients attending their first visit to a Brazilian cancer centre from 1 September 2020 to 31 January 2021 and from 1 September 2019 to 31 January 2020. The pandemic started in February 2020 in Brazil and is still ongoing. We considered this period (September/20-January/21) to be representative of the pandemic impact on cancer management. The primary endpoint was breast and cervical cancer stages at diagnosis. RESULTS: A total of 268 breast cancer patients and 44 cervical cancer patients had their first consult in our cancer centre from September/20 to January/21; 457 and 60, respectively, occurred from September/19 to January/20. Patients who attended their first visit during the pandemic (September/20-January/21) presented with more advanced-stage breast cancer (p < 0.001) and cervical cancer (p = 0.328) than those in the period prior to the pandemic (September/19-January/20), although the difference was not statistically significant for cervical cancer. The proportion of cervical cancer patients diagnosed with locally advanced disease (stages III-IVA) was 56.8% (N = 25) in September/20-January/21 compared to 43.3% (N = 26) in September/19-January/20. Similarly, 37.3% (N = 100) of breast cancer patients had stage III disease in September/20-January/21 compared to 23.2% (N = 106) in September/19-January/20. Fewer breast cancer patients (13.7%) were diagnosed due to screening tests during the pandemic than before it (25.5%) (p < 0.001). CONCLUSIONS: Breast and cervical cancer patients had more advanced-stage diseases in their first visit to a cancer centre during the COVID-19 pandemic compared to a similar period prior to the pandemic. Efforts should be made not to compromise essential cancer services since this results in long-term negative impacts for oncologic patients.

Clinical and radiographic performance of self-locking conical connection implants in the posterior mandible: Five-year results of a two-centre prospective study.

OBJECTIVE: This prospective study aims to assess the 5-year clinical performance of implants with internal conical connection and platform-switched abutments in the posterior mandible. MATERIAL AND METHODS: Healthy adults missing at least two teeth in the posterior mandible and with a natural tooth mesial to the implant site received two or three adjacent implants. After a transmucosal healing period single crown restorations were cemented on platform-switched abutments. Changes in marginal bone levels were investigated in standardized periapical radiographs from surgery and loading (baseline) to 60-months post-loading. RESULTS: Twenty-four patients received 52 implants. Bone remodelling took place between surgery and loading (mean:-0.5, SD:±0.4 mm). From loading to 60 months, there was a mean bone change of 0.27 (SD:±0.47 mm) which stabilized 24 months after prosthesis delivery (mean:0.2, SD:±0.46 mm). 71.7% of all implants presented bone preservation at 60 months irrespective of the initial insertion depth. Two implants were lost after 5 years and the success rate was 95.1%. Patient enquiry revealed high satisfaction. CONCLUSION: Internal conical connection implants with platform-switched abutments presented a high success rate and preservation of marginal bone levels at the implant shoulder after 5 years of loading.

Structural Insight into IAPP-Derived Amyloid Inhibitors and Their Mechanism of Action.

Designed peptides derived from the islet amyloid polypeptide (IAPP) cross-amyloid interaction surface with Aß (termed interaction surface mimics or ISMs) have been shown to be highly potent inhibitors of Aß amyloid self-assembly. However, the molecular mechanism of their function is not well understood. Using solution-state and solid-state NMR spectroscopy in combination with ensemble-averaged dynamics simulations and other biophysical methods including TEM, fluorescence spectroscopy and microscopy, and DLS, we characterize ISM structural preferences and interactions. We find that the ISM peptide R3-GI is highly dynamic, can adopt a ß-like structure, and oligomerizes into colloid-like assemblies in a process that is reminiscent of liquid-liquid phase separation (LLPS). Our results suggest that such assemblies yield multivalent surfaces for interactions with Aß40. Sequestration of substrates into these colloid-like structures provides a mechanistic basis for ISM function and the design of novel potent anti-amyloid molecules.

Confiança seletiva em crianças pré-escolares: uma revisão sistemática / La confiança selectiva: una revisión sistemática / Selective trust in preschoolers: a systematic review

RESUMO. Embora o campo de estudos sobre confiança seletiva tenha ganhado destaque nos últimos anos, essa linha de pesquisa não é ainda suficientemente divulgada no Brasil. A presente revisão sistemática teve como objetivo avaliar a produção científica sobre confiança seletiva em crianças pré-escolares, bem como sobre possíveis variáveis que influenciam os julgamentos de confiança. A busca foi realizada nas bases de dados PSYCINFO, Scielo Brasil, PEPSIC e LILACS, utilizando-se as palavras-chave selective trust, epistemic trust e seus correspondentes em português 'confiança seletiva' e 'confiança epistêmica'. De um total de 103 trabalhos, foram analisados 45 artigos empíricos, publicados entre 2008 e 2018, seguindo o protocolo PRISMA. Contrariando uma crença predominante em muitas culturas de que as crianças acreditam em tudo o que ouvem, elas não são consumidoras ingênuas de informação. Discutem-se os efeitos de variáveis individuais e contextuais sobre os julgamentos de confiança seletiva que apontam para direções futuras promissoras de pesquisa.

RESUMEN. Aunque el campo de estudios sobre confianza selectiva ha ganado destaque en los últimos años, esta línea de investigación aún no ha sido suficientemente divulgada en Brasil. En la presente revisión sistemática se tuvo como objetivo evaluar la producción científica sobre confianza selectiva en niños preescolares, así como sobre posibles variables que influencian los juicios de confianza. La búsqueda fue realizada en las bases de datos PSYINFO, Scielo Brasil, PEPSIC y LILACS, utilizando las palabras clave selective trust, epistemic trust y sus correspondientes en portugués 'confiança seletiva' y 'confiança epistémica'. De un total de 103 estudios, se analizaron 45 artículos empíricos, publicados entre 2008 y 2018, siguiendo el protocolo PRISMA. Contrariando una creencia predominante en muchas culturas de que los niños creen en todo lo que oyen, ellos no son consumidores ingenuos de información. Se discuten los efectos de variables individuales y contextuales sobre los juicios de confianza selectiva que apuntan a futuras direcciones prometedoras de investigación.

ABSTRACT. Although the field of studies on selective trust has gained much attention in recent years, this line of research is not yet sufficiently publicized in Brazil. The present systematic review aimed to assess scientific evidence on selective trust in preschool children, as well as on possible variables influencing trust judgements. The search was performed in PSYCINFO, ScieloBrasil, PEPSIC and LILACS, using the keywords 'selective trust', 'epistemic trust' and their correspondents in Portuguese confiança seletiva and confiança epistêmica. From a total of 103 studies found, 45 empirical articles, published between 2008 and 2018, were analyzed using the PRISMA protocol. In contrast to a predominant view in many cultures that children believe everything they hear, they are not naïve consumers of information. Effects of individual and contextual variables on selective trust judgments are discussed, which point to promising future research directions.

Immediate versus early loading protocols of titanium-zirconium narrow-diameter implants for mandibular overdentures in edentulous patients: 1-year results from a randomized controlled trial.

OBJECTIVES: The purpose of this randomized clinical trial was to compare immediate and early loading protocols for mandibular overdentures with two-splinted narrow-diameter implants in thin, non-augmented residual ridge situations. MATERIAL AND METHODS: Each edentulous patient received two implants in the interforaminal region. If primary stability after implant placement was achieved, patients were randomized either to the immediate (48 hr post-surgery) or the early (2 weeks after surgery) loading group. In prosthetic rehabilitation, a bar prosthetic system with a titanium bar was used. Implant survival, success rates, and radiographic changes at the crestal bone level were evaluated after 1 year, and patient satisfaction was recorded at 1 and 6 months post-surgery. RESULTS: Twenty-four patients with a mean age of 67 ± 9 years were included. One patient passed away after 11 months due to treatment-independent reasons. In the 24 implants of the immediate loading group, the mean bone level change from surgery/loading to the first-year evaluation was 0.32 ± 0.80 mm (p = .066). Regarding the early group (22 implants), the mean bone level change from loading to 1 year was 0.34 ± 0.69 mm (p = .048). After 1 year, no differences could be detected between groups (p = .91) with a mean difference of 0.02 mm (95% CI: [-0.42, 0.47]). The mean implant survival and success rates were 100% for both groups. Patient satisfaction was high; however, at 6 months, there was a difference between groups regarding the ability to chew. CONCLUSIONS: Both loading protocols for mandibular overdentures supported by two-splinted narrow-diameter implants were successful at the 1-year follow-up.

Peri-implant marginal bone loss reduction with platform-switching components: 5-Year post-loading results of an equivalence randomized clinical trial.

AIM: To compare the clinical performance and marginal bone levels of implants restored with platform-switching (PS) or platform-matching (PM) abutments. MATERIALS AND METHODS: Adult patients missing two or more adjacent teeth in the posterior mandible received 2-4 CAMLOG SCREW-LINE implants and were randomly allocated to the PM or PS group, receiving the corresponding prosthetic components from surgery onwards. Implants were conventionally loaded with single cemented crowns. Patients were followed annually for 5 years. Outcome measures were marginal bone level changes, implant survival, performance of the prosthetic components and clinical parameters plaque index, sulcus bleeding index and pocket probing depth. RESULTS: Thirty-three patients received 72 implants in the PM group, and thirty-five patients received 74 implants in the PS group. Sixty patients attended the final appointment, 31 had received PS components and 29 had received PM components with 65 and 63 implants, respectively. Global survival rate was 96.6% with no differences between groups (p = 0.647). After 5 years of functional loading, PS restored implants presented 0.23mm (95% CI: [0.03, 0.43], p = 0.025) lower marginal bone level changes. The two groups were declared non-equivalent. CONCLUSION: Patients requiring implant supported restorations in healed bounded or free end edentulous gaps of the mandible benefit from the use of PS components in terms of peri-implant marginal bone level maintenance, though it may not be clinically noticeable.

Mutations in PPCS, Encoding Phosphopantothenoylcysteine Synthetase, Cause Autosomal-Recessive Dilated Cardiomyopathy.

Coenzyme A (CoA) is an essential metabolic cofactor used by around 4% of cellular enzymes. Its role is to carry and transfer acetyl and acyl groups to other molecules. Cells can synthesize CoA de novo from vitamin B5 (pantothenate) through five consecutive enzymatic steps. Phosphopantothenoylcysteine synthetase (PPCS) catalyzes the second step of the pathway during which phosphopantothenate reacts with ATP and cysteine to form phosphopantothenoylcysteine. Inborn errors of CoA biosynthesis have been implicated in neurodegeneration with brain iron accumulation (NBIA), a group of rare neurological disorders characterized by accumulation of iron in the basal ganglia and progressive neurodegeneration. Exome sequencing in five individuals from two unrelated families presenting with dilated cardiomyopathy revealed biallelic mutations in PPCS, linking CoA synthesis with a cardiac phenotype. Studies in yeast and fruit flies confirmed the pathogenicity of identified mutations. Biochemical analysis revealed a decrease in CoA levels in fibroblasts of all affected individuals. CoA biosynthesis can occur with pantethine as a source independent from PPCS, suggesting pantethine as targeted treatment for the affected individuals still alive.

MPO-ANCA-associated necrotizing glomerulonephritis in rheumatoid arthritis; a case report and review of literature.

BACKGROUND: Renal involvement in rheumatoid arthritis (RA) is common and has a negative impact on patient survival. Only few cases have been reported of necrotizing glomerulonephritis (GN) associated with myeloperoxidase anti-neutrophil cytoplasmic antibody (MPO-ANCA) in patients with RA. CASE PRESENTATION: We report a patient with RA who developed a necrotizing GN associated with ANCA-MPO, treated with rituximab (RTX). A 55-year-old man with a 27-year history of RA under secukinumab was referred to our nephrology clinic with worsening renal function associated with microhematuria and proteinuria. Our laboratory evaluation showed hypocomplementemia and positive titers for MPO-ANCA (615 U/mL). A renal biopsy demonstrated pauci-immune necrotizing GN. The patient was treated with 3 consecutive pulses of methylprednisolone followed by oral prednisolone (1 mg/Kg) and rituximab (1000 mg, repeated 14 days later). After a 10-month follow-up, the arthritis remains well-controlled, renal function stabilized, proteinuria improved and MPO-ANCA titer normalized (6.3 U/mL). CONCLUSIONS: Necrotizing GN is a rare but a serious condition and an early diagnosis is essential to treatment. This is the first case of necrotizing GN (without extra-renal manifestations of vasculitis) in a patient with active RA, successfully treated with RTX.

Effect of Nebivolol on MIBG Parameters and Exercise in Heart Failure with Normal Ejection Fraction / Efeito do Nebivolol sobre Parâmetros do MIBG e Exercício na Insuficiência Cardíaca com Fração de Ejeção Normal

Abstract Background: More than 50% of the patients with heart failure have normal ejection fraction (HFNEF). Iodine-123 metaiodobenzylguanidine (123I-MIBG) scintigraphy and cardiopulmonary exercise test (CPET) are prognostic markers in HFNEF. Nebivolol is a beta-blocker with vasodilating properties. Objectives: To evaluate the impact of nebivolol therapy on CPET and123I-MIBG scintigraphic parameters in patients with HFNEF. Methods: Twenty-five patients underwent 123I-MIBG scintigraphy to determine the washout rate and early and late heart-to-mediastinum ratios. During the CPET, we analyzed the systolic blood pressure (SBP) response, heart rate (HR) during effort and recovery (HRR), and oxygen uptake (VO2). After the initial evaluation, we divided our cohort into control and intervention groups. We then started nebivolol and repeated the tests after 3 months. Results: After treatment, the intervention group showed improvement in rest SBP (149 mmHg [143.5-171 mmHg] versus 135 mmHg [125-151 mmHg, p = 0.016]), rest HR (78 bpm [65.5-84 bpm] versus 64.5 bpm [57.5-75.5 bpm, p = 0.028]), peak SBP (235 mmHg [216.5-249 mmHg] versus 198 mmHg [191-220.5 mmHg], p = 0.001), peak HR (124.5 bpm [115-142 bpm] versus 115 bpm [103.7-124 bpm], p= 0.043), HRR on the 1st minute (6.5 bpm [4.75-12.75 bpm] versus 14.5 bpm [6.7-22 bpm], p = 0.025) and HRR on the 2nd minute (15.5 bpm [13-21.75 bpm] versus 23.5 bpm [16-31.7 bpm], p = 0.005), but no change in peak VO2 and 123I-MIBG scintigraphic parameters. Conclusion: Despite a better control in SBP, HR during rest and exercise, and improvement in HRR, nebivolol failed to show a positive effect on peak VO2 and 123I-MIBG scintigraphic parameters. The lack of effect on adrenergic activity may be the cause of the lack of effect on functional capacity.

Resumo Fundamento: Mais de 50% dos pacientes com insuficiência cardíaca têm fração de ejeção preservada (ICFEN). A cintilografia marcada com iodo 123 com metaiodobenzilguanidina (123I-MIBG) e o teste cardiopulmonar do exercício (TCPE) são marcadores de prognóstico da ICFEN. O nebivolol é um betabloqueador com propriedade vasodilatadora. Objetivos: Avaliar o impacto da terapia com nebivolol sobre as variáveis da cintilografia com 123I-MIBG e do TCPE em pacientes com ICFEN. Métodos: Vinte e cinco pacientes realizaram cintilografia com 123I-MIBG para avaliar a taxa de washout e a relação coração/mediastino precoce e tardia. Durante o TCPE, foi analisado o comportamento da pressão arterial sistólica (PAS), frequência cardíaca (FC) durante o esforço e a recuperação (FCR) e o consumo de oxigênio (VO2). Após avaliação inicial, separamos nossa amostra em grupos controle versus intervenção, iniciamos o nebivolol e repetimos os exames após 3 meses. Resultados: Após o tratamento, o grupo intervenção apresentou melhora na PAS (149 mmHg [143,5-171 mmHg] versus 135 mmHg [125-151 mmHg, p = 0,016]), FC em repouso (78 bpm [65,5-84 bpm] versus 64,5 bpm [57,5-75,5 bpm, p = 0,028]), PAS no pico do esforço (235 mmHg [216,5-249 mmHg] versus 198 mmHg [191-220,5 mmHg], p = 0,001), FC no pico do esforço (124,5 bpm [115-142 bpm] versus 115 bpm [103,7-124 bpm], p = 0,043) e FCR no 1º minuto (6,5 bpm [4,75-12,75 bpm] versus 14,5 bpm [6,7-22 bpm], p = 0,025) e no 2º minuto (15,5 bpm [13-21,75 bpm] versus 23,5 bpm [16-31,7 bpm], p = 0,005), porém não apresentou mudança no VO2 de pico e nos parâmetros da cintilografia com 123I-MIBG. Conclusão: Apesar de um melhor controle da PAS e na FC em repouso e durante o esforço e uma melhora na FCR, o nebivolol não ocasionou efeito positivo sobre o VO2 de pico e nos parâmetros da cintilografia com 123I-MIBG. A ausência de efeito sobre a atividade adrenérgica pode ser a causa da falta de efeito sobre a capacidade funcional.

Novel small molecules targeting ciliary transport of Smoothened and oncogenic Hedgehog pathway activation.

Trafficking of the G protein-coupled receptor (GPCR) Smoothened (Smo) to the primary cilium (PC) is a potential target to inhibit oncogenic Hh pathway activation in a large number of tumors. One drawback is the appearance of Smo mutations that resist drug treatment, which is a common reason for cancer treatment failure. Here, we undertook a high content screen with compounds in preclinical or clinical development and identified ten small molecules that prevent constitutive active mutant SmoM2 transport into PC for subsequent Hh pathway activation. Eight of the ten small molecules act through direct interference with the G protein-coupled receptor associated sorting protein 2 (Gprasp2)-SmoM2 ciliary targeting complex, whereas one antagonist of ionotropic receptors prevents intracellular trafficking of Smo to the PC. Together, these findings identify several compounds with the potential to treat drug-resistant SmoM2-driven cancer forms, but also reveal off-target effects of established drugs in the clinics.

Effect of platform switching on crestal bone levels around implants in the posterior mandible: 3 years results from a multicentre randomized clinical trial.

OBJECTIVE: Evaluation of differences in the clinical performance and crestal bone levels between implants restored with single crowns with platform-matched or platform-switched abutments after 3 years. MATERIAL AND METHODS: The study enrolled adult patients missing two or more adjacent teeth in the posterior mandible with natural teeth mesial to the implant site. Randomization followed open-flap implant insertion and the corresponding matching or switching healing abutments placed at surgery. Conventional loading was made with cemented crowns. Clinical follow-up took place annually after loading up to 3 years. Bone level changes were measured in standardized radiographs as the variation in crestal bone from one evaluation to the next. RESULTS: Sixty-three patients with a total of 135 implants (66 platform matching, 69 platform switching) were analysed. From surgery to 36 months, mean bone loss was 0.28 ± 0.56 mm for the platform-switching group and 0.68 ± 0.64 mm for the platform-matching group. A statistically significant difference was found between groups (p = 0.002) with an estimate of 0.39 mm (0.15-0.64, 95% CI) in favour of platform switching. CONCLUSIONS: After 3 years, platform-switching restorations showed a significant effect in the preservation of marginal bone levels compared to platform-matching restorations.

Inhibition of Canonical NF-κB Signaling by a Small Molecule Targeting NEMO-Ubiquitin Interaction.

The IκB kinase (IKK) complex acts as the gatekeeper of canonical NF-κB signaling, thereby regulating immunity, inflammation and cancer. It consists of the catalytic subunits IKKα and IKKß and the regulatory subunit NEMO/IKKγ. Here, we show that the ubiquitin binding domain (UBAN) in NEMO is essential for IKK/NF-κB activation in response to TNFα, but not IL-1ß stimulation. By screening a natural compound library we identified an anthraquinone derivative that acts as an inhibitor of NEMO-ubiquitin binding (iNUB). Using biochemical and NMR experiments we demonstrate that iNUB binds to NEMOUBAN and competes for interaction with methionine-1-linked linear ubiquitin chains. iNUB inhibited NF-κB activation upon UBAN-dependent TNFα and TCR/CD28, but not UBAN-independent IL-1ß stimulation. Moreover, iNUB was selectively killing lymphoma cells that are addicted to chronic B-cell receptor triggered IKK/NF-κB activation. Thus, iNUB disrupts the NEMO-ubiquitin protein-protein interaction interface and thereby inhibits physiological and pathological NF-κB signaling.

Radiographic evaluation of conical tapered platform-switched implants in the posterior mandible: 1-year results of a two-center prospective study.

OBJECTIVE: Long-term success of dental implants depends on healthy peri-implant soft tissues and adequate bone levels. This prospective study aims to assess bone level changes around implants with internal conical connection and platform-switching abutments in the posterior mandible. MATERIAL AND METHODS: Adult patients missing at least two teeth in the posterior mandible and with a natural tooth mesial to the implant site received two or three adjacent internal conical connection implants. After a minimum transmucosal healing period of 8 weeks, single crown restorations were cemented over platform-switching abutments. Changes in marginal bone levels were measured in standardized periapical radiographs from surgery and loading (baseline) to 12 months post-loading. RESULTS: Twenty-four patients received 52 implants. Bone remodeling took place between surgery and loading (-0.53 ± 0.40 mm). From loading to 12 months, there was a mean bone gain of 0.12 ± 0.42 mm which occurred mainly in the first 6 months after prosthesis delivery (0.11 ± 0.36 mm) and stabilized afterward. A total of 71.7% of all implants presented bone preservation or gain. No implant was lost at 1 year and the success rate was 100%. Patient inquiry revealed high satisfaction. CONCLUSION: Internal conical connection implants with platform-switching abutments presented high success rate and enhancement or preservation of marginal bone levels after 1 year of loading.

Horizontal Resorption of Fresh-Frozen Corticocancellous Bone Blocks in the Reconstruction of the Atrophic Maxilla at 5 Months.

BACKGROUND: Reliable implant-supported rehabilitation of an alveolar ridge needs sufficient volume of bone. In order to achieve a prosthetic-driven positioning, bone graft techniques may be required. PURPOSE: This prospective cohort study aims to clinically evaluate the amount of resorption of corticocancellous fresh-frozen allografts bone blocks used in the reconstruction of the severe atrophic maxilla. MATERIALS AND METHODS: Twenty-two partial and totally edentulous patients underwent bone augmentation procedures with fresh-frozen allogenous blocks from the iliac crest under local anesthesia. Implants were inserted into the grafted sites after a healing period of 5 months. Final fixed prosthesis was delivered ± 4 months later. Ridge width analysis and measurements were performed with a caliper before and after grafting and at implant insertion. Bone biopsies were performed in 16 patients. RESULTS: A total of 98 onlay block allografts were used in 22 patients with an initial mean alveolar ridge width of 3.41 ± 1.36 mm. Early exposure of blocks was observed in four situations and one of these completely resorbed. Mean horizontal bone gain was 3.63 ± 1.28 mm (p < .01). Mean buccal bone resorption between allograph placement and the reopening stage was 0.49 ± 0.54 mm, meaning approximately 7.1% (95% confidence interval: [5.6%, 8.6%]) of total ridge width loss during the integration period. One hundred thirty dental implants were placed with good primary stability (≥ 30 Ncm). Four implants presented early failure before the prosthetic delivery (96.7% implant survival). All patients were successfully rehabilitated. Histomorphometric analysis revealed 20.9 ± 5.8% of vital bone in close contact to the remaining grafted bone. A positive strong correlation (adjusted R(2) = 0.44, p = .003) was found between healing time and vital bone percentage. CONCLUSIONS: Augmentation procedures performed using fresh-frozen allografts from the iliac crest are a suitable alternative in the reconstruction of the atrophic maxilla with low resorption rate at 5 months, allowing proper stability of dental implants followed by fixed prosthetic rehabilitation.

Aplicação de metodologias de segmentação de imagem para medição automatizada dos níveis ósseos de implantes em radiografias periapicais padronizadas / Application of image segmentation methods for automated implant bone level measurements in periapical standardized radiographs

Objetivo: validar um método automatizado para a determinação de níveis ósseos de implantes. Material e métodos: dois examinadores analisaram 60 radiografias de implantes (Camlog Screw-Line) através de uma interface gráfica desenvolvida para a aplicação do método de segmentação de imagem. O processo baseou-se na aplicação de uma série de passos automatizados para isolar a crista óssea e os implantes, a fim de computar a intersecção entre o osso e o implante. Os níveis ósseos foram posteriormente computados através da determinação da distância entre o primeiro contato osso-implante e o ombro do implante. A concordância e a exatidão do método foram determinadas por comparação dos níveis ósseos obtidos pelo método com os correspondentes obtidos manualmente. Resultados: não foram determinadas diferenças entre os resultados das medições manuais e as obtidas através do método de segmentação (teste Anova para medidas repetidas, p=0,852). A análise de concordância revelou um coeficiente de correlação intraclasse de 0,839 ([0,783-0,884, 95% IC], p < 0,01). Mais de 60% das medições foram consideradas exatas. Conclusões: o método proposto provou ser uma ferramenta precisa e fidedigna para a medição de níveis ósseos, contribuindo para a diminuição da variabilidade entre observadores.

A method for segmentation of dental implants and crestal bone.

PURPOSE: Medical imaging and in particular digital radiographic images offer a great deal of information to dentists in the clinical diagnosis and treatment processes on a daily basis. This paper presents a new method aimed to produce an accurate segmentation of dental implants and the crestal bone line in radiographic images. With this, it is possible computing several measures to biomechanical and clinical evaluation of dental implants positioning and evolution. METHODS: The proposed segmentation method includes two major steps: (1) the preprocessing that combine denoising filters, morphological operations and histogram threshold techniques and (2) the final segmentation involving made-to-measure adjusted and trained active shape models for detecting the precise location of the intended structures. RESULTS: Resulting measurements were compared to manual measurements made by experts on representative radiographs from patients. The calculated intraclass correlation coefficient was 0.75 and showed good reliability of the method, and the Bland-Altman analysis showed 95% of the values within the limits of agreement. The mean of the differences between the manual and method-driven measurements was 0.049 mm ([Formula: see text]) 95% CI, inferior to the established limit (0.15mm). CONCLUSIONS: It was demonstrated that the method achieved a precise segmentation of the intended structures. The validation process on standardized periapical radiographs showed good agreement between the manual measurements and the ones produced by the new method. Future work will be focused on making the method more robust to densitometry changes and to validate the method on non-standardized radiographs.