Bone morphogenetic proteins and their antagonists: current and emerging clinical uses

Bone morphogenetic proteins (BMPs) are members of the TGFβ superfamily of secreted cysteine knot proteins that includes TGFβ₁, nodal, activins and inhibins. BMPs were first discovered by Urist in the 1960s when he showed that implantation of demineralized bone into intramuscular tissue of rabbits induced bone and cartilage formation. Since this seminal discovery, BMPs have also been shown to play key roles in several other biological processes, including limb, kidney, skin, hair and neuronal development, as well as maintaining vascular homeostasis. The multifunctional effects of BMPs make them attractive targets for the treatment of several pathologies, including bone disorders, kidney and lung fibrosis, and cancer. This review will summarize current knowledge on the BMP signalling pathway and critically evaluate the potential of recombinant BMPs as pharmacological agents for the treatment of bone repair and tissue fibrosis in patients.

Prediction of integral type failures in semiconductor manufacturing through classification methods

Smart management of maintenances has become fundamental in manufacturing environments in order to decrease downtime and costs associated with failures. Predictive Maintenance (PdM) systems based on Machine Learning (ML) techniques have the possibility with low added costs of drastically decrease failures-related expenses; given the increase of availability of data and capabilities of ML tools, PdM systems are becoming really popular, especially in semiconductor manufacturing. A PdM module based on Classification methods is presented here for the prediction of integral type faults that are related to machine usage and stress of equipment parts. The module has been applied to an important class of semiconductor processes, ion-implantation, for the prediction of ion-source tungsten filament breaks. The PdM has been tested on a real production dataset. © 2013 IEEE.

Conventional in vivo irradiation procedures are insufficient to accurately determine tumor responses to non-uniform radiation fields

Purpose: To determine differences in overall tumor responses measured by volumetric assessment and bioluminescence imaging (BLI) following exposure to uniform and non-uniform radiation fields in an ectopic prostate tumor model.

Materials and methods: Bioluminescent human prostate tumor xenografts were established by subcutaneous implantation into male mice. Tumors were irradiated with uniform or non-uniform field configurations using conventional in vivo irradiation procedures performed using a 225 kVp generator with custom lead shielding. Tumor responses were measured using Vernier calipers and by BLI using an in vivo imaging system. Survival was defined as the time to quadroupling of pre-treatment tumor volume. 

Results: The correlation between BLI and tumor volume measurements was found to be different for un-irradiated (R = 0.61), uniformly irradiated (R = 0.34) and partially irradiated (R = 0.30) tumors. Uniformly irradiated tumors resulted in an average tumor growth delay of 60 days with median survival of 75 days, compared to partially irradiated tumors which showed an average growth delay of 24 days and median survival of 38 days. 

Conclusions: Correlation between BLI and tumor volume measurements is lower for partially irradiated tumors than those exposed to uniform dose distributions. The response of partially irradiated tumors suggests non-uniformity in response beyond physical dose distribution within the target volume. Dosimetric uncertainty associated with conventional in vivo irradiation procedures prohibits their ability to accurately determine tumor response to non-uniform radiation fields and stresses the need for image guided small animal radiation research platforms.

Urethral atrophy after artificial urinary sphincter placement:Is cuff downsizing effective?

Purpose: We reviewed the outcome of cuff downsizing with an artificial urinary sphincter for treating recurrent incontinence due to urethral atrophy.

Materials and Methods: We analyzed the records of 17 patients in a 7-year period in whom clinical, radiological and urodynamic evidence of urethral atrophy was treated with cuff downsizing. Cuff downsizing was accomplished by removing the existing cuff and replacing it with a 4 cm. cuff within the established false capsule. Incontinence and satisfaction parameters before and after the procedure were assessed by a validated questionnaire.

Results: Mean patient age was 70 years (range 62 to 79). Average time to urethral atrophy was 31 months (range 5 to 96) after primary sphincter implantation. Mean followup after downsizing was 22 months (range 1 to 64). Cuff downsizing caused a mean decrease of 3.9 to 0.5 pads daily. The number of severe leakage episodes decreased from a mean of 5.4 to 2.1 The mean SEAPI (stress leakage, emptying, anatomy, protection, inhibition) score decreased from 8.2 to 2.4. Patient satisfaction increased from 15% to 80% after cuff downsizing. In 1 patient an infected cuff required complete removal of the device.

Conclusions: Patient satisfaction and continence parameters improved after cuff downsizing. We believe that this technique is a simple and effective method of restoring continence after urethral atrophy.

THE ARTIFICIAL URINARY SPHINCTER - A NEW SOLUTION FOR INCONTINENT PATIENTS

Treatment of urinary incontinence with the artificial urinary sphincter has been available in centres such as London and Liverpool for a number of years. This service is now available in the department of urology of the Belfast City Hospital. Twelve patients have had successful implantation of an artificial urinary sphincter for urinary incontinence, and ten are now fully continent. One patient with Wegener's granulomatosis developed active disease in his urethra which has precluded activation of the device. One patient has had the device removed because of erosion into the urethra.

Accelerated rehabilitation of an edentulous patient with an implant retained dental prosthesis: a case report

This case report details the successful rehabilitation of an edentulous patient using a complete upper prosthesis and a lower implant retained overdenture. The provision of care was split between a specialist centre and a primary care setting. This approach reduced inconvenience to the patient. Modern surgical and prosthodontic techniques also reduced the total delivery time. After initial consultation a new set of complete dentures was prescribed with changes in design to the originals. The patient was also planned for placement of two mandibular implants to stabilise and retain the mandibular denture. The first line of treatment involved provision of a new set of dentures constructed by the patient's general dental practitioner. Dental implants were then placed in a specialist centre and the patient returned to the dental practice for attachment of the lower denture to the dental implants. The benefits and success of mandibular implant retained dentures are well documented. With delivery of the overdenture, the patient reported increased satisfaction with his prostheses which allowed him to eat a greater range of foods and enabled him to feel confident when speaking and socialising.

Prostaglandin E2 as a regulator of germ cells during ovarian development

CONTEXT: The formation of primordial follicles occurs during fetal life yet is critical to the determination of adult female fertility. Prior to this stage, germ cells proliferate, enter meiosis, and associate with somatic cells. Growth and survival factors implicated in these processes include activin A (INHBA), the neurotrophins BDNF and NT4 (NTF5), and MCL1. The prostaglandins have pleiotrophic roles in reproduction, notably in ovulation and implantation, but there are no data regarding roles for prostaglandins in human fetal ovarian development.

OBJECTIVE: The aim of the study was to investigate a possible role for prostaglandin (PG) E(2) in human fetal ovary development.

DESIGN: In vitro analysis of ovarian development between 8 and 20 wk gestation was performed.

MAIN OUTCOME MEASURE(S): The expression patterns of PG synthesis enzymes and the PGE(2) receptors EP2 and EP4 in the ovary were assessed, and downstream effects of PGE(2) on gene expression were analyzed.

RESULTS: Ovarian germ cells express the PG synthetic enzymes COX2 and PTGES as well as the EP2 and EP4 receptors, whereas COX1 is expressed by ovarian somatic cells. Treatment in vitro with PGE(2) increased the expression of BDNF mRNA 1.7 +/- 0.16-fold (P = 0.004); INHBA mRNA, 2.1 +/- 0.51-fold (P = 0.04); and MCL1 mRNA, 1.15 +/- 0.06-fold (P = 0.04), but not that of OCT4, DAZL, VASA, NTF5, or SMAD3.

CONCLUSIONS: These data indicate novel roles for PGE(2) in the regulation of germ cell development in the human ovary and show that these effects may be mediated by the regulation of factors including BDNF, activin A, and MCL1.

c-Kit+ progenitors generate vascular cells for tissue-engineered grafts through modulation of the Wnt/Klf4 pathway

The development of decellularised scaffolds for small diameter vascular grafts is hampered by their limited patency, due to the lack of luminal cell coverage by endothelial cells (EC) and to the low tone of the vessel due to absence of a contractile smooth muscle cells (SMC). In this study, we identify a population of vascular progenitor c-Kit+/Sca-1- cells available in large numbers and derived from immuno-privileged embryonic stem cells (ESCs). We also define an efficient and controlled differentiation protocol yielding fully to differentiated ECs and SMCs in sufficient numbers to allow the repopulation of a tissue engineered vascular graft. When seeded ex vivo on a decellularised vessel, c-Kit+/Sca-1-derived cells recapitulated the native vessel structure and upon in vivo implantation in the mouse, markedly reduced neointima formation and mortality, restoring functional vascularisation. We showed that Krüppel-like transcription factor 4 (Klf4) regulates the choice of differentiation pathway of these cells through β-catenin activation and was itself regulated by the canonical Wnt pathway activator lithium chloride. Our data show that ESC-derived c-Kit+/Sca-1-cells can be differentiated through a Klf4/β-catenin dependent pathway and are a suitable source of vascular progenitors for the creation of superior tissue-engineered vessels from decellularised scaffolds.

Effect of position of near addition in an asymmetric refractive multifocal intraocular lens on quality of vision

Purpose
To evaluate the impact of the position of an asymmetric multifocal near segment on visual quality.

Setting
Cathedral Eye Clinic, Belfast, United Kingdom.

Design
Retrospective comparative case series.

Methods
Data from consecutive patients who had bilateral implantation of the Lentis Mplus LS-312 multifocal intraocular lens were divided into 2 groups. One group received inferonasal near-segment placement and the other, superotemporal near-segment placement. A +3.00 diopter (D) reading addition (add) was used in all eyes. The main outcome measures included uncorrected distance visual acuity (UDVA), uncorrected near visual acuity (UNVA), contrast sensitivity, and quality of vision. Follow-up was 3 months.

Results
Patients ranged in age from 43 to 76 years. The inferonasal group comprised 80 eyes (40 patients) and the superotemporal group, 76 eyes (38 patients). The mean 3-month spherical equivalent was −0.11 D ± 0.49 (SD) in the inferonasal group and −0.18 ± 0.46 D in the superotemporal group. The mean postoperative UDVA was 0.14 ± 0.10 logMAR and 0.18 ± 0.15 logMAR, respectively. The mean monocular UNVA was 0.21 ± 0.14 logRAD and 0.24 ± 0.13 logRAD, respectively. No significant differences were observed in the higher-order aberrations, total Strehl ratio (point-spread function), or modulation transfer function between the groups. Dysphotopic symptoms measured with a validated quality-of-vision questionnaire were not significantly different between groups.

Conclusion
Positioning of the near add did not significantly affect objective or subjective visual function parameters.

Phacoemulsification combined with posterior capsulorhexis and anterior vitrectomy in the management of malignant glaucoma in phakic eyes

Purpose: To describe sequential phacoemulsification-intraocular lens (IOL) implantation-posterior capsulorhexis-anterior vitrectomy in the management of phakic malignant glaucoma. Methods: Twenty consecutive patients (25 eyes) with phakic malignant glaucoma were enrolled at the Zhongshan Ophthalmic Center, Sun Yat-sen University. All patients underwent phacoemulsification, IOL implantation and posterior capsulorhexis together with anterior vitrectomy via a clear corneal paracentesis. Visual acuity, intraocular pressure (IOP), anterior chamber depth (ACD), surgical complications and medications required after the surgery were recorded. Results: After surgery, the mean LogMAR visual acuity and ACD increased significantly (visual acuity from -1.56 ± 1.17 to -0.54 ± 0.81, p < 0.001; ACD from 0.367 ± 0.397 mm to 2.390 ± 0.575 mm, p < 0.001), and mean IOP decreased significantly (from 39.6 ± 10.6 mm Hg to 14.5 ± 4.1 mmHg, p < 0.001). No serious perioperative complications occurred, and only five eyes required topical glaucoma medications after surgery. Conclusion: Combined phacoemulsification-IOL implantation-posterior capsulorhexis-anterior vitrectomy surgery is a safe and effective method for treating patients with phakic malignant glaucoma. © 2012 The Authors. Acta Ophthalmologica © 2012 Acta Ophthalmologica Scandinavica Foundation.

In-the-Bag Intraocular Lens Placement via Secondary Capsulorhexis with Radiofrequency Diathermy in Pediatric Aphakic Eyes

Pediatric ophthalmologists increasingly recognize that the ideal site for intraocular lens (IOL) implantation is in the bag for aphakic eyes, but it is always very difficult via conventional technique. We conducted a prospective case series study to investigate the success rate and clinical outcomes of capsular bag reestablishment and in-the-bag IOL implantation via secondary capsulorhexis with radiofrequency diathermy (RFD) in pediatric aphakic eyes, in which twenty-two consecutive aphakic pediatric patients (43 aphakic eyes) enrolled in the Childhood Cataract Program of the Chinese Ministry of Health were included. The included children underwent either our novel technique for secondary IOL implantation (with RFD) or the conventional technique (with a bent needle or forceps), depending on the type of preoperative proliferative capsular bag present. In total, secondary capsulorhexis with RFD was successfully applied in 32 eyes (32/43, 74.4%, age 5.6±2.3 years), of which capsular bag reestablishment and in-the-bag IOL implantation were both achieved in 30 eyes (30/43, 70.0%), but in the remaining 2 eyes (2/32, 6.2%) the IOLs were implanted in the sulcus with a capsular bag that was too small. Secondary capsulorhexis with conventional technique was applied in the other 11 eyes (11/43, 25.6%, age 6.9±2.3 years), of which capsular bag reestablishment and in-the-bag IOL implantation were both achieved only in 3 eyes(3/43, 7.0%), and the IOLs were implanted in the sulcus in the remaining 8 eyes. A doughnut-like proliferative capsular bag with an extensive Soemmering ring (32/43, 74.4%) was the main success factor for secondary capsulorhexis with RFD, and a sufficient capsular bag size (33/43, 76.7%) was an additional factor in successful in-the-bag IOL implantation. In conclusion, RFD secondary capsulorhexis technique has 70% success rate in the capsular bag reestablishment and in-the-bag IOL implantation in pediatric aphakic eyes, particularly effective in cases with a doughnut-like, extensively proliferative Soemmering ring. © 2013 Luo et al.

Five-year incidence and postoperative visual outcome of cataract surgery in urban southern China:The liwan eye study

Purpose. To determine the 5-year incidence and visual outcome of cataract surgery in an adult urban Chinese population. Methods. A comprehensive eye examination was performed at baseline and 5 years later on subjects participating in a population-based study. Incident cataract surgery was defined as having undergone surgery in either eye during the 5-year period. Postoperative visual impairment (PVI) was defined as visual acuity (VA) <6/18 based on both presenting VA (PVA) and best corrected VA (BCVA) in the operated eye. Results. Among the 1405 baseline participants, 75% (924) of survivors were seen at the 5-year follow-up visit. Forty-four returning participants (62 eyes) had undergone incident cataract surgery, an incidence of 4.84% (95% confidence interval [CI] - [3.53, 6.44]). Detailed medical and surgical records were available for 54/62 (87.1%) eyes, and of these, 5/ 54 (24.1%) had an immediate preoperative visual acuity <6/ 120. All recorded surgeries were performed at tertiary-level hospitals with phacoemulsification and foldable intraocular lens implantation. Those undergoing cataract surgery were more educated (P < 0.05) and had poorer baseline PVA in the worse-seeing eye (P < 0.001) than 54 persons with baseline PVA <6/18 due to cataract who had not had surgery. Among the 62 operated eyes, 22.6% (14/62) had PVI based on PVA and 9.6% (6/62) based on BCVA. Conclusions. Despite somewhat lower incidence, outcomes of cataract surgery in urban southern China are comparable with developed countries and better than for rural China. In urban China, emphasis should be on improving access to surgery. (Invest Ophthalmol Vis Sci. 2012;53:7936-7942) © 2012 The Association for Research in Vision and Ophthalmology, Inc.

Caracterização e modificação de heteroestruturas de nitretos do grupo III

Os nitretos binários semicondutores do grupo III, e respetivos compostos, são vastamente estudados devido à sua possível aplicabilidade em dispositivos optoeletrónicos, tais como díodos emissores de luz (LEDs) e LASERs, assim como dispositivos para a eletrónica de elevadas temperatura, potência e frequência. Enquanto se concretizou a comercialização na última década de LEDs e LASERs recorrendo ao ternário In1-yGayN, estudos das propriedades fundamentais estruturais e óticas, assim como de técnicas de processamento no desenvolvimento de novas aplicações de outros ternários do grupo III-N encontram-se na sua fase inicial. Esta tese apresenta a investigação experimental de filmes finos epitaxiais de Al1-xInxN crescidos sobre camadas tampão de GaN e de Al1-yGayN e o estudo do recozimento e implantação de super-redes (SL) compostas por pontos quânticos de GaN (QD) envolvidos por camadas de AlN. Apesar do hiato energético do Al1-xInxN poder variar entre os 0,7 eV e os 6,2 eV e, por isso, numa gama, consideravelmente superior à dos ternários Al1-yGayN e InyGa1-yN, o primeiro é o menos estudado devido a dificuldades no crescimento de filmes com elevada qualidade cristalina. É efetuada, nesta tese, uma caracterização estrutural e composicional de filmes finos de Al1-xInxN crescidos sobre camadas tampão de GaN e de Al1-yGayN usando técnicas de raios-X, feixe de iões e de microscopia. Mostra-se que o Al1-xInxN pode ser crescido com elevada qualidade cristalina quando a epitaxia do crescimento se aproxima da condição de rede combinada do Al1-xInxN e da camada tampão (GaN ou Al1-yGayN), isto é, com conteúdo de InN de ~18%, quando crescido sobre uma camada de GaN. Quando o conteúdo de InN é inferior/superior à condição de rede combinada, fenómenos de relaxação de tensão e deterioração do cristal tais como o aumento da rugosidade de superfície prejudicam a qualidade cristalina do filme de Al1-xInxN. Observou-se que a qualidade dos filmes de Al1-xInxN depende fortemente da qualidade cristalina da camada tampão e, em particular, da sua morfologia e densidade de deslocações. Verificou-se que, dentro da exatidão experimental, os parâmetros de rede do ternário seguem a lei empírica de Vegard, ou seja, variam linearmente com o conteúdo de InN. Contudo, em algumas amostras, a composição determinada via espetrometria de retrodispersão de Rutherford e difração e raios-X mostra valores discrepantes. Esta discrepância pode ser atribuída a defeitos ou impurezas capazes de alterar os parâmetros de rede do ternário. No que diz respeito às SL dos QD e camadas de AlN, estudos de recozimento mostraram elevada estabilidade térmica dos QD de GaN quando estes se encontram inseridos numa matriz de AlN. Por implantação iónica, incorporou-se európio nestas estruturas e, promoveu-se a ativação ótica dos iões de Eu3+ através de tratamentos térmicos. Foram investigados os efeitos da intermistura e da relaxação da tensão ocorridos durante o recozimento e implantação nas propriedades estruturais e óticas. Verificou-se que para fluências elevadas os defeitos gerados por implantação são de difícil remoção. Contudo, a implantação com baixa fluência de Eu, seguida de tratamento térmico, promove uma elevada eficiência e estabilidade térmica da emissão vermelha do ião lantanídeo incorporado nos QD de GaN. Estes resultados são, particularmente relevantes, pois, na região espetral indicada, a eficiência quântica dos LEDs convencionais de InGaN é baixa.

Compósitos CNTs/biocerâmico para a estimulação elétrica óssea in situ

The present thesis aims to develop a biocompatible and electroconductor bone graft containing carbon nanotubes (CNTs) that allows the in situ regeneration of bone cells by applying pulsed external electrical stimuli. The CNTs were produced by chemical vapor deposition (CVD) by a semi-continuous method with a yield of ~500 mg/day. The deposition parameters were optimised to obtain high pure CNTs ~99.96% with controlled morphologies, fundamental requisites for the biomedical application under study. The chemical functionalisation of CNTs was also optimised to maximise their processability and biocompatibility. The CNTs were functionalised by the Diels-Alder cycloaddition of 1,3-butadiene. The biological behaviour of the functionalised CNTs was evaluated in vitro with the osteoblastic cells line MG63 and in vivo, by subcutaneous implantation in rats. The materials did not induce an expressed inflammatory response, but the functionalised CNTs showed a superior in vitro and in vivo biocompatibility than the non-functionalised ones. Composites of ceramic matrix, of bioglass (Glass) and hydroxyapatite (HA), reinforced with carbon nanotubes (CNT/Glass/HA) were processed by a wet approach. The incorporation of just 4.4 vol% of CNTs allowed the increase of 10 orders of magnitude of the electrical conductivity of the matrix. In vitro studies with MG63 cells show that the CNT/Glass/HA composites guarantee the adhesion and proliferation of bone cells, and stimulate their phenotype expression, namely the alkaline phosphate (ALP). The interactions between the composite materials and the culture medium (α-MEM), under an applied electrical external field, were studied by scanning vibrating electrode technique. An increase of the culture medium electrical conductivity and the electrical field confinement in the presence of the conductive samples submerged in the medium was demonstrated. The in vitro electrical stimulation of MG63 cells on the conductive composites promotes the increase of the cell metabolic activity and DNA content by 130% and 60%, relatively to the non-stimulated condition, after only 3 days of daily stimulation of 15 μA for 15 min. Moreover, the osteoblastic gene expression for Runx2, osteocalcin (OC) and ALP was enhanced by 80%, 50% and 25%, after 5 days of stimulation. Instead, for dielectric materials, the stimulus delivering was less efficient, giving an equal or lower cellular response than the non-stimulated condition. The proposed electroconductive bone grafts offer exciting possibilities in bone regeneration strategies by delivering in situ electrical stimulus to cells and consequent control of the new bone tissue formation rate. It is expected that conductive smart biomaterials might turn the selective bone electrotherapy of clinical relevance by decreasing the postoperative healing times.

Étude des compétences informatiques et des attitudes du corps professoral face à l'utilisation des technologies de l'information et de la communication (TIC) à l'Institut de Technologie du Cambodge (ITC)

L'utilisation des nouvelles technologies de l'information et de la communication (NTIC) fait l'objet de discussions dans le domaine de l'éducation. La présente recherche a pour objectif principal d'identifier le profil des compétences informatiques et des attitudes du corps professoral d'une haute école de formation technologique du Cambodge au regard de l'utilisation des environnements informatiques dans sa pratique d'enseignement. Cette étude descriptive exploratoire aura comme principale retombée de contribuer au développement de l'intégration des NTIC en pédagogie universitaire au Cambodge. Nous tenterons éventuellement de mettre en lumière les besoins que cette intégration suscite. L'élaboration d'une stratégie de systématisation de l'implantation des NTIC en pédagogie universitaire pourrait être traitée dans une future étude. Le recueil de données a été réalisé à l'aide d'un questionnaire d'enquête ainsi que d'une série d'entrevues réalisées auprès du personnel enseignant de l'Institut de Technologie du Cambodge durant la session d'hiver 2001.