Consistent Value of Two-Stage Pedicle Flaps in the Age of Microsurgical Maxillofacial Reconstruction.

Introduction: Up to the second half of the twentieth century, pedicled flaps marked the gold standard in reconstructive surgery. Followed by the introduction of microsurgical techniques, these flaps were increasingly abandoned. We conducted a retrospective study to determine the value of two-stage pedicle flaps in modern maxillofacial reconstruction. Material & Methods: A chart review from October 2017 to November 2020 was performed to identify patients who were treated by a two-stage pedicle flap in our Department of Oral and Maxillofacial Surgery. Results: A total of 31 patients, 17 female and 14 males received 36 two-stage pedicle flaps. All patients were in noticeably impaired health condition with a majority of ASA-score 3. The defect location mainly contained extraoral resections (58.3%). A variety of flaps were harvested consisting of buccal flaps, Abbe flaps, forehead flaps, deltopectoral flaps, nasolabial flaps, and a tubed flap. Discussion: The study outlines two indications for the use of two-stage pedicle flaps. Firstly, as a back-up strategy in heavily pre-treated wound beds and secondly in an almost contrarily indication as a first-choice reconstructive option of the facial skin in esthetic demanding cases. Conclusion: The timesaving and straight forward surgical approach as well as their low postsurgical complications and strong long-time success rates secure the two-stage pedicle flap a justified niche role in times of microsurgical maxillofacial reconstruction. Supplementary Information: The online version contains supplementary material available at 10.1007/s12663-021-01635-9.

Three-dimensional evaluation of condylar position after mandibular reconstruction with a fibula free flap-comparison of different surgical techniques.

Three-dimensional positional changes of the temporomandibular joint after mandible reconstruction using microvascular fibula flaps were investigated in 58 patients. The results of preoperative virtually planned surgery, intraoperative resection- and cutting-guided surgery, and non-guided surgery were compared. Pre- and postoperative computed tomography data of each patient were processed and superimposed digitally. The condyle deviations and rotations along the axes and planes of the skull, as well as Euclidean distances, were determined. Reliability analyses, descriptive statistics, and non-parametric tests were performed with the alpha level set at P = 0.05. Reliability proved to be excellent for all variables. The median Euclidean distance was 2.07 mm for the left condyle and 2.11 mm for the right condyle. Deviations of ≥ 10 mm occurred in nine (16%) cases. The maximum deviation occurred in the horizontal plane and the least deviation in the sagittal plane. Median rotation was ≤ 1.4° around all axes. The condylar displacements did not differ significantly between the different surgical techniques investigated. The three-dimensional measurement method applied is highly reliable for evaluating the three-dimensional condylar position after mandibular reconstruction.

Performance of different osteosynthesis materials in microvascular fibula free flap reconstruction.

Fibular free flap (FFF) is the main reconstructive choice for large mandibular defects. Recent improvements have been made regarding planning and surgical procedure, but choice of osteosynthesis material (OSM) for segment-fixation remains controversial. A retrospective cohort study obtained clinical and radiological data from FFF-patients. Data were screened for OSM, surgical procedure and complications as OSM fractures, loosening, exposure, or insufficient osseous consolidation. Eighty patients with FFF were included. Planning was CAD/CAM (n=29), Recon Guide (n=26) or without planning (n=25). OSM was 2.0mm-miniplates in standard (n=26), preformed (n=6), CAD/CAM (n=14) or ReconGuide (n=23) variation and 2.3mm-reconstruction-plates in standard (n=5) or CAD/CAM (n=6) variation. Complications were observed in 21 cases, fractures occurred 10 times overall, but with low rates for preformed (n=1), ReconGuide (n=3) and none for CAD/CAM. Analysis detected significant correlations between used OSM and plate exposure (p = 0.000), but none regarding fracture (p = 0.275), loosening (p = 0.714) or insufficient osseous consolidation (p = 0.208). No correlations were observed between complications and OSM (p = 0.609) or diagnosis (p = 0.716). Fixation of FFF segments for reconstruction is possible with various OSM providing good clinical outcome. No significant differences were detected regarding prevention of complications by any osteosynthesis material (miniplate vs. macroplate). Although no differences were detected, miniplate usage is advocated whenever clinically reasonable, due to easier reintervention possibilities and reduced implanted foreign material. Nevertheless, decision for ideal OSM must remain patient-specific and cannot be generalised.

A microdosing framework for absolute bioavailability assessment of poorly soluble drugs: A case study on cold-labeled venetoclax, from chemistry to the clinic.

This work presents an end-to-end approach for assessing the absolute bioavailability of highly hydrophobic, poorly water-soluble compounds that exhibit high nonspecific binding using venetoclax as a model drug. The approach utilizes a stable labeled i.v. microdose and requires fewer resources compared with traditional approaches that use radioactive 14 C-labeled compounds. The stable labeled venetoclax and internal standard were synthesized, then an i.v. formulation was developed. In the clinical study, female subjects received a single oral dose of venetoclax 100 mg followed by a 100-µg i.v. dose of cold-labeled 13 C-venetoclax at the oral time of maximum concentration (Tmax ). The i.v. microdose was prepared as an extemporaneous, sterile compounded solution on the dosing day by pharmacists at the clinical site. Several measures were taken to ensure the sterility and safety of the i.v. preparation. A sensitive liquid chromatography-tandem mass spectrometry method was developed to allow the detection of plasma levels from the i.v. microdose. Plasma samples were collected through 72 h, and pharmacokinetic parameters were estimated using noncompartmental methods. Postdosing sample analysis demonstrated the consistency of the preparations and allowed the precise calculation of the pharmacokinetic parameters based on the actual injected dose. The absolute bioavailability of venetoclax was estimated at 5.4% under fasting conditions. Venetoclax extraction ratio was estimated to be 0.06 suggesting that the fraction transferred from the enterocytes into the liver is limiting venetoclax bioavailability. The proposed framework can be applied to other highly hydrophobic, poorly water-soluble compounds that exhibit high nonspecific binding to support the understanding of their absorption and disposition mechanisms and guide formulation development.

Gobbling across landscapes: Eastern wild turkey distribution and occupancy-habitat associations.

Extensive restoration and translocation efforts beginning in the mid-20th century helped to reestablish eastern wild turkeys (Meleagris gallopavo silvestris) throughout their ancestral range. The adaptability of wild turkeys resulted in further population expansion in regions that were considered unfavorable during initial reintroductions across the northern United States. Identification and understanding of species distributions and contemporary habitat associations are important for guiding effective conservation and management strategies across different ecological landscapes. To investigate differences in wild turkey distribution across two contrasting regions, heavily forested northern Wisconsin, USA, and predominately agricultural southeast Wisconsin, we conducted 3050 gobbling call-count surveys from March to May of 2014-2018 and used multiseason correlated-replicate occupancy models to evaluate occupancy-habitat associations and distributions of wild turkeys in each study region. Detection probabilities varied widely and were influenced by sampling period, time of day, and wind speed. Spatial autocorrelation between successive stations was prevalent along survey routes but was stronger in our northern study area. In heavily forested northern Wisconsin, turkeys were more likely to occupy areas characterized by moderate availability of open land cover. Conversely, large agricultural fields decreased the likelihood of turkey occupancy in southeast Wisconsin, but occupancy probability increased as upland hardwood forest cover became more aggregated on the landscape. Turkeys in northern Wisconsin were more likely to occupy landscapes with less snow cover and a higher percentage of row crops planted in corn. However, we were unable to find supporting evidence in either study area that the abandonment of turkeys from survey routes was associated with snow depth or with the percentage of agricultural cover. Spatially, model-predicted estimates of patch-specific occupancy indicated turkey distribution was nonuniform across northern and southeast Wisconsin. Our findings demonstrated that the environmental constraints of turkey occupancy varied across the latitudinal gradient of the state with open cover, snow, and row crops being influential in the north, and agricultural areas and hardwood forest cover important in the southeast. These forces contribute to nonstationarity in wild turkey-environment relationships. Key habitat-occupancy associations identified in our results can be used to prioritize and strategically target management efforts and resources in areas that are more likely to harbor sustainable turkey populations.

Meeting report of the 7th Heidelberg Myeloma Workshop: today and tomorrow.

PURPOSE: The 7th Heidelberg Myeloma Workshop was held on April 5th and 6th, 2019 at the University Hospital Heidelberg. METHODS AND RESULTS: Main topics of the meeting were (1) diagnostics and prognostic factors, (2) role of immunotherapy in multiple myeloma (MM), (3) current therapy of MM, (4) biology and genomics of MM as well as (5) novel treatment concepts. A debate on the status of minimal residual disease (MRD) driven therapy was held. CONCLUSION: Diagnostics and treatment of newly diagnosed and relapsed MM are continuously evolving. While advances in the field of (single cell) genetic analysis now allow for characterization of the disease at an unprecedented resolution, immunotherapeutic approaches and MRD testing are at the forefront of the current clinical trial landscape.

Validation of a microdose probe drug cocktail for clinical drug interaction assessments for drug transporters and CYP3A.

A microdose cocktail containing midazolam, dabigatran etexilate, pitavastatin, rosuvastatin, and atorvastatin has been established to allow simultaneous assessment of a perpetrator impact on the most common drug metabolizing enzyme, cytochrome P450 (CYP)3A, and the major transporters organic anion-transporting polypeptides (OATP)1B, breast cancer resistance protein (BCRP), and MDR1 P-glycoprotein (P-gp). The clinical utility of these microdose cocktail probe substrates was qualified by conducting clinical drug interaction studies with three inhibitors with different in vitro inhibitory profiles (rifampin, itraconazole, and clarithromycin). Generally, the pharmacokinetic profiles of the probe substrates, in the absence and presence of the inhibitors, were comparable to their reported corresponding pharmacological doses, and/or in agreement with theoretical expectations. The exception was dabigatran, which resulted in an approximately twofold higher magnitude for microdose compared to conventional dosing, and, thus, can be used to flag a worst-case scenario for P-gp. Broader application of the microdose cocktail will facilitate a more comprehensive understanding of the roles of drug transporters in drug disposition and drug interactions.

Search for a reliable model for bisphosphonate-related osteonecrosis of the jaw: establishment of a model in pigs and description of its histomorphometric characteristics.

The pathogenesis of bisphosphonate-related osteonecrosis of the jaw (BRONJ) remains unknown, and the development of a reliable experimental model would help to improve our understanding of it. We used 12 domestic pigs of which 6 made up the experimental group and were treated with zoledronate 4mg intravenously weekly for 5 weeks, while the control group (n=6) were given no drugs. On day 60 the right second maxillary and mandibular third molars were extracted. Thirty days later 3 animals in each group were killed; the rest were killed 90 days later. Histopathological specimens from the extraction sites were analysed for bone density, collagen architecture, density of osteons, and the amount of non-mineralised bone. Bone density, amount of non-mineralised bone, and density of osteons differed significantly between the 2 groups (p<0.001 in each case), but the chromatic pattern dictated by the collagen architecture did not. Our results correspond to the observations that have been made in patients with BRONJ, which means that the histomorphometric conditions seen in patients can be reproduced in this experimental setting.

Quantitation of anacetrapib, stable-isotope labeled-anacetrapib (microdose), and four metabolites in human plasma using liquid chromatography tandem mass spectrometry.

An ultra-high performance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS) method for the simultaneous determination of (4S,5R)-5-[3,5-bis (trifluoromethyl)phenyl]-3-{[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl] methyl}-4-methyl-1,3-oxazolidin-2-one (anacetrapib, I) and [(13)C5(15)N]-anacetrapib, II in human plasma has been developed to support a clinical study to determine the absolute bioavailability of I. The analytes and the stable-isotope labeled internal standard ([(13)C7(15)N(2)H7]-anacetrapib, III) were extracted from 100µL of human plasma by liquid-liquid extraction using 20/80 isopropyl alcohol/hexane (v/v). The chromatographic separation of the analytes was achieved using Waters BEH Shield RP 18 (50×2.1mm×1.7µm) column and mobile phase gradient of 0.1% formic acid in water (Solvent A) and 0.1% formic acid in acetonitrile (Solvent B) at 0.6mL/min flow rate. The MS/MS detection was performed on AB Sciex 5000 or AB 5500 in positive electrospray ionization mode, operated in selected reaction monitoring mode. The assay was validated in the concentration range 1-2000ng/mL for I; and a lower curve range, 0.025-50ng/mL for II. In addition to the absolute bioavailability determination, it was desired to better elucidate the pharmacokinetic behavior of several hydroxylated metabolites of I. Toward this end, two exploratory assays for the hydroxy metabolites of I were qualified in the concentration range 0.5-500ng/mL. All metabolites were separated on a Supelco Ascentis Express Phenyl-Hexyl (50×2.1mm, 2.7µm) column. Metabolite M4 was analyzed in the negative mode with a mobile phase consisting of a gradient mixture of water (A) and acetonitrile (B). The other three metabolites, M1-M3 were analyzed in the positive mode using a mobile phase gradient of water with 0.1% formic acid (A) and acetonitrile with 0.1% formic acid (B). The assays were utilized to support a clinical study in which a microdosing approach was used to determine the pharmacokinetics of anacetrapib and its metabolites.

Contenido de sodio en minutas del Programa Nacional de Alimentación Escolar, su relación con el estado nutricional y presión arterial de escolares de primero básico de Quillota, Chile / Sodium content of meals provided by the National Public Schools Feeding Program and its realtionship with nutritional status and blood pressure in children from first grade, Quillota, Chile

Chilean children attending basic schools exhibit a high prevalence of overweight and obesity, and may present hypertension associated with an excessive sodium intake. The aim of the study was to measure the sodium content of the servings provided by the National Schools Feeding Program to first grade children attending public schools in Quillota during the year 2011, compare the results with the sodium intake recommendation established by WHO, and evaluate the nutritional status and blood pressure (BP). Sodium content of servings (ICP), nutritional status (BMI) and BP (sphingomanometer) of 333 children were measured. Meals contained 3.53+1.42 g sodium per serving. 19.2% of the children were overweight and 21.3% were obese, 7 exhibited prehypertension and I presented hypertension. The study provides background data related to early sodium exposure that is useful for designing strategies towards the reduction of sodium intake in Chile in order to reduce cardiovascular risk.

Los escolares chilenos presentan alta prevalencia de sobrepeso y obesidad, y podrían presentar hipertensión arterial asociada al consumo excesivo de sodio. El objetivo del estudio fue medir el sodio de las minutas del Programa de Alimentación Escolar entregadas a primero básico en las escuelas municipalizadas de Quillota en el año 2011, comparar los resultados con la recomendación de ingesta de la OMS, evaluar el estado nutricional y la presión arterial (PA) de escolares. Se midió el contenido de sodio de las minutas (ICP), se evaluó el estado nutricional (IMC) y se midió la PA (esfigmomanómetro) de 333 escolares. Las minutas contenían 3,53+1,42 g de sodio por ración 19,2% de escolares presentaban sobrepeso y 21,3% eran obesos, 7 escolares eran pre-hipertensos y 1 hipertenso. El estudio aporta antecedentes de exposición temprana al sodio, útiles para diseñar estrategias dirigidas a disminuir el consumo de sodio en Chile como medida de reducción del riesgo cardiovascular.

Visualizing the spatiotemporal dynamics of DNA damage in budding yeast.

Fluorescence microscopy has enabled the analysis of both the spatial distribution of DNA damage and its dynamics during the DNA damage response (DDR). Three microscopic techniques can be used to study the spatiotemporal dynamics of DNA damage. In the first part we describe how we determine the position of DNA double-strand breaks (DSBs) relative to the nuclear envelope. The second part describes how to quantify the co-localization of DNA DSBs with nuclear pore clusters, or other nuclear subcompartments. The final protocols describe methods for the quantification of locus mobility over time.

Injectable formulations for an intravitreal sustained-release application of a novel single-chain VEGF antibody fragment.

Sustained-release formulations of a single-chain anti-VEGF-A antibody fragment were investigated in vitro toward their potential use for intravitreal applications. The hydrophobic polyester hexylsubstituted poly(lactic acid) (hexPLA) was selected as the sustained-release excipient for its biodegradability and semi-solid aggregate state, allowing an easy and mild formulation procedure. The lyophilized antibody fragment ESBA903 was micronized and incorporated into the liquid polymer matrix by cryo-milling, forming homogeneous and injectable suspensions. The protein showed excellent compatibility with the hexPLA polymer and storage stability at 4°C for 10 weeks. Additionally, hexPLA shielded the incorporated active substance from the surrounding medium, resulting in a better stability of ESBA903 inside the polymer than after its release in the buffer solution. Formulations of ESBA903 with hexPLA having drug loadings between 1.25% and 5.0% and polymer molecular weights of 1500 g/mol, 2500 g/mol, 3500 g/mol and 5000 g/mol were investigated regarding their in vitro release. All formulations except with the highest molecular weight formed spherical depots in aqueous buffer solutions and released the antibody fragment for at least 6-14 weeks. The polymer viscosity derived from the molecular weight strongly influenced the release rate, while the drug loading had minor influence, allowing customization of the release profile and the daily drug release. Size exclusion chromatography and SDS-PAGE revealed that the antibody fragment structure was kept intact during incorporation and release from the liquid matrix. Furthermore, the released protein monomer maintained its high affinity to human VEGF-A, as measured by surface plasmon resonance analysis. Formulations of ESBA903 in hexPLA meet the basic needs to be used for intravitreal sustained-release applications in age-related macular degeneration treatment.

Chromosome conformation maps in fission yeast reveal cell cycle dependent sub nuclear structure.

Successful progression through the cell cycle requires spatial and temporal regulation of gene transcript levels and the number, positions and condensation levels of chromosomes. Here we present a high resolution survey of genome interactions in Schizosaccharomyces pombe using synchronized cells to investigate cell cycle dependent changes in genome organization and transcription. Cell cycle dependent interactions were captured between and within S. pombe chromosomes. Known features of genome organization (e.g. the clustering of telomeres and retrotransposon long terminal repeats (LTRs)) were observed throughout the cell cycle. There were clear correlations between transcript levels and chromosomal interactions between genes, consistent with a role for interactions in transcriptional regulation at specific stages of the cell cycle. In silico reconstructions of the chromosome organization within the S. pombe nuclei were made by polymer modeling. These models suggest that groups of genes with high and low, or differentially regulated transcript levels have preferred positions within the S. pombe nucleus. We conclude that the S. pombe nucleus is spatially divided into functional sub-nuclear domains that correlate with gene activity. The observation that chromosomal interactions are maintained even when chromosomes are fully condensed in M phase implicates genome organization in epigenetic inheritance and bookmarking.

A metapopulation approach to African lion (Panthera leo) conservation.

Due to anthropogenic pressures, African lion (Panthera leo) populations in Kenya and Tanzania are increasingly limited to fragmented populations. Lions living on isolated habitat patches exist in a matrix of less-preferred habitat. A framework of habitat patches within a less-suitable matrix describes a metapopulation. Metapopulation analysis can provide insight into the dynamics of each population patch in reference to the system as a whole, and these analyses often guide conservation planning. We present the first metapopulation analysis of African lions. We use a spatially-realistic model to investigate how sex-biased dispersal abilities of lions affect patch occupancy and also examine whether human densities surrounding the remaining lion populations affect the metapopulation as a whole. Our results indicate that male lion dispersal ability strongly contributes to population connectivity while the lesser dispersal ability of females could be a limiting factor. When populations go extinct, recolonization will not occur if distances between patches exceed female dispersal ability or if females are not able to survive moving across the matrix. This has profound implications for the overall metapopulation; the female models showed an intrinsic extinction rate from five-fold to a hundred-fold higher than the male models. Patch isolation is a consideration for even the largest lion populations. As lion populations continue to decline and with local extinctions occurring, female dispersal ability and the proximity to the nearest lion population are serious considerations for the recolonization of individual populations and for broader conservation efforts.

Desafíos en investigación, desarrollo e innovación en alimentos y nutrición / Challenges in research, development and innovation in foods and nutrition

Research, development and innovation (R+D+i) in food and nutrition sciences have exhibited different goals through the years. The current challenges in these areas are represented basically by significant modifications in dietary habits associated to the epidemiological changes observed in the last decades, characterized by a high prevalence of non-communicable diseases. Consumers have understood that foods are determinant factors in their welfare and are willing to choose those products that are associated to health and the reduction of risk factors of the diseases related to ageing and longevity. Current R+D+i in nutrition sciences have to gather the consumers' doubts caring for their welfare. These activities are closely related to the biomedical sciences and require to be complemented with various professionals with diverse backgrounds to reach an integrative, systemic view of the individual as such and as a member of society. Innovation in food and nutrition sciences for health represents a major challenge to develop multidisciplinary, associative, complimentary research, requiring professionals that have the necessary aptitudes for fulfill this goal.

Las actividades de investigación, desarrollo e innovación (I+D+i) en las ciencias de los alimentos y de la nutrición han tenido diferentes enfoques a través de los años. Se presentan algunos desafíos actuales en estas materias, representados fundamentalmente por modificaciones significativas en los patrones de consumo asociadas a los cambios epidemiológicos observados en las últimas décadas, donde destaca la alta prevalencia de enfermedades crónicas no transmisibles. Las personas han comprendido que los alimentos son determinantes de su bienestar, y están dispuestas a elegir productos que se asocian a una mantención u optimización de la salud y a la reducción de factores de riesgo de las enfermedades asociadas al aumento de la longevidad. La I+D+i actual debe hacerse cargo de las dudas del consumidor preocupado por su bienestar, está estrechamente ligada al área biomédica y requiere de la complementación entre investigadores de formación diversa capacitados para, en conjunto, lograr una visión integral y sistémica del individuo como sujeto en sí y como miembro de la sociedad. Innovar en alimentos y nutrición para la salud representa un gran desafío para realizar una investigación multidisciplinaria, asociativa, complementaria, la que requiere de profesionales que posean las competencias necesarias para lograr esta meta.

Reactivating head regrowth in a regeneration-deficient planarian species.

Species capable of regenerating lost body parts occur throughout the animal kingdom, yet close relatives are often regeneration incompetent. Why in the face of 'survival of the fittest' some animals regenerate but others do not remains a fascinating question. Planarian flatworms are well known and studied for their ability to regenerate from minute tissue pieces, yet species with limited regeneration abilities have been described even amongst planarians. Here we report the characterization of the regeneration defect in the planarian Dendrocoelum lacteum and its successful rescue. Tissue fragments cut from the posterior half of the body of this species are unable to regenerate a head and ultimately die. We find that this defect originates during the early stages of head specification, which require inhibition of canonical Wnt signalling in other planarian species. Notably, RNA interference (RNAi)-mediated knockdown of Dlac-ß-catenin-1, the Wnt signal transducer, restored the regeneration of fully functional heads on tail pieces, rescuing D. lacteum's regeneration defect. Our results demonstrate the utility of comparative studies towards the reactivation of regenerative abilities in regeneration-deficient animals. Furthermore, the availability of D. lacteum as a regeneration-impaired planarian model species provides a first step towards elucidating the evolutionary mechanisms that ultimately determine why some animals regenerate and others do not.

Osseointegration of SLActive implants in diabetic pigs.

OBJECTIVES: Diabetes mellitus is currently classified as a relative contraindication for implant treatment because of microangiopathies with the consequence of impaired bone regeneration and higher rates of implant failure. The study aim was to investigate peri-implant bone formation in a diabetic animal model in comparison to healthy animals and to evaluate the differences between conventional (SLA(®) ) and modified (SLActive(®) ) titanium implant surfaces on osseointegration. MATERIAL AND METHODS: Each six implants were placed in the calvaria of 11 diabetic and 4 healthy domestic pigs. At 30 and 90 days after implant placement, the bone-to-implant contact (BIC) and bone density (BD) were appraised. Additionally, the expression of the bone-matrix proteins collagen type I and osteocalcin was evaluated at both points in time by using immunohistochemical staining methods. RESULTS: Overall, BIC was reduced in the diabetic group at 30 and 90 days. After 90 days, the SLActive(®) implants showed significantly higher BICs compared with the SLA(®) implants in diabetic animals. Peri-implant BD was higher in the SLActive(®) group at 30 and 90 days in healthy and diabetic animals. Collagen type I protein expression was higher using SLA(®) implants in diabetic pigs at 30 days. Values for osteocalcin expression were not consistent. CONCLUSIONS: The results indicate the negative effect of untreated diabetes mellitus on early osseointegration of dental implants. The modified SLA(®) surface (SLActive(®) ) elicited an accelerated osseointegration of dental implants, suggesting that a better prognosis for implant treatment of diabetic patients is possible.

In vivo biocompatibility, sustained-release and stability of triptorelin formulations based on a liquid, degradable polymer.

Hexylsubstituted poly(lactic acid) (hexPLA) is a viscous polymer, which degrades in the presence of water similar to the structure related poly(lactic acid). With hydrophilic active compounds, like Triptorelin acetate, the lipophilic polymer was formulated in form of parenterally injectable suspensions. This first in vivo study toward the biocompatibility of hexPLA implants in rats over 3 months in comparison to in situ forming poly(lactic-co-glycolic acid) (PLGA) formulations is presented here. The hexPLA implants showed only a mild acute inflammation at the injection site after application, which continuously regressed. In contrast to the PLGA formulations, hexPLA did not provoke an encapsulation of the implant with extracellular matrix. Prior to the formulation application, the stability of Triptorelin inside the hexPLA matrix was assessed under different storage conditions and in the presence of buffer to simulate a peptide degrading environment. At 5°C Triptorelin showed a stability of 98% inside the polymer for at least 6 months. The stability was still 78% at an elevated temperature of 40°C. HexPLA protected the incorporated peptide from the surrounding aqueous environment, which resulted in 20% less degradation inside the polymer compared to the solution. This protection effect supports the use of Triptorelin-hexPLA formulations for parenteral sustained-release formulations. In a second in vivo evaluation in Wistar Hannover rats, formulations containing 5% and 10% Triptorelin in the polymeric matrix released the active compound continuously for 6 months. The formulations showed a higher release during the initial 7 days, which is necessary for the clinical use to down-regulate all GnRH-receptors. Afterwards, a zero order drug release was observed over the first 3 months. After 3 months, the plasma levels decreased slowly but remained at effective concentrations for the total of 6 months. Furthermore, a qualitative in vitro-in vivo correlation was observed, possibly facilitating future optimization of the Triptorelin-hexPLA sustained-release formulations.

Biofunctionalization of the implant surface with different concentrations of a synthetic peptide (P-15).

OBJECTIVE: This study aimed at identifying the ideal concentration of a biofunctional surface coating of dental implants with a synthetic peptide (P-15). In a previous study, P-15 was shown to enhance osseointegration parameters. MATERIAL AND METHODS: Implants (modified ANKYLOS(®) A8; FRIADENT Plus(®) surface) with five different concentrations (0-400 µg/ml) of a P-15 coating as well as uncoated controls were inserted in the frontal bone of 45 adult domestic pigs. The histomorphometric and microradiographic findings for the coated implants were compared to those for the uncoated ones after 7, 14, and 30 days. RESULTS: No significant differences were observed comparing the peri-implant bone density between the coated and uncoated implants The bone-to-implant contact, as the primary histological parameter for osseointegration, showed high rates for all surfaces investigated (between 73.3 ± 17.9% for the control and 81.9 ± 15.2% for P15 20 µg/ml after 30 days). CONCLUSIONS: No significant benefit on osseointegration of a biofunctional P-15 coating of dental implants could be displayed in the present study.

Chromosome positioning and the clustering of functionally related loci in yeast is driven by chromosomal interactions.

In recent years there has been considerable and growing interest in the 3-dimensional organization of genomes. In this manuscript we present an integrated computational-molecular study that produces an ensemble of high-resolution 3-dimensional conformations of the budding yeast genome. The compaction, folding and spatial organization of the chromosomes was based on empirical data determined using proximity-based ligation. Our models incorporate external constraints that allow the separation of gross organizational effects from those due to local interactions. Our models show that yeast chromosomes have preferred yet non-exclusive positions. They also identify interaction dependent clustering of tRNAs, early firing origins of replication, and Gal4 protein binding sites, yet the cluster composition is dynamic. Our results support a link between structure and transcription that occurs within the context of a flexible genome organization.