Evaluation of symmetry behavior of surgically assisted rapid maxillary expansion with simulation-driven targeted bone weakening.

OBJECTIVES: Surgically assisted rapid maxillary expansion (SARME) is a treatment modality to overcome maxillary constrictions. During the procedure of transverse expansion, unwanted asymmetries can occur. This retrospective study investigates the transverse expansion behavior of the maxilla utilizing a simulation-driven SARME with targeted bone weakening. MATERIALS AND METHODS: Cone beam computer tomographies of 21 patients before (T1) and 4 months after treatment (T2) with simulation-driven SARME combined with a transpalatal distractor (TPD) and targeted bone weakening were superimposed. The movements of the left, right, and frontal segments were evaluated at the modified WALA ridge, mid root level, and at the root tip of all upper teeth. Linear and angular measurements were performed to detect dentoalveolar changes. RESULTS: Dentoalveolar changes were unavoidable, and buccal tipping of the premolars (6.1° ± 5.0°) was significant (p < 0.05). Transverse expansion in premolar region was higher (6.13 ± 4.63mm) than that in the molar region (4.20 ± 4.64mm). Expansion of left and right segments did not differ significantly (p > 0.05). CONCLUSION: Simulation-driven SARME with targeted bone weakening is effective to achieve symmetrical expansion in the transverse plane. CLINICAL RELEVANCE: Simulation-driven targeted bone weakening is a novel method for SARME to achieve symmetric expansion. Dental side effects cannot be prohibited.

Dissecting bipolar disorder complexity through epigenomic approach.

In recent years, numerous studies of gene regulation mechanisms have emerged in neuroscience. Epigenetic modifications, described as heritable but reversible changes, include DNA methylation, DNA hydroxymethylation, histone modifications and noncoding RNAs. The pathogenesis of psychiatric disorders, such as bipolar disorder, may be ascribed to a complex gene-environment interaction (G × E) model, linking the genome, environmental factors and epigenetic marks. Both the high complexity and the high heritability of bipolar disorder make it a compelling candidate for neurobiological analyses beyond DNA sequencing. Questions that are being raised in this review are the precise phenotype of the disorder in question, and also the trait versus state debate and how these concepts are being implemented in a variety of study designs.

Assessment of two e-learning methods teaching undergraduate students cephalometry in orthodontics.

AIM: Cephalometry is important for orthodontic diagnosis and treatment planning and is part of the core curriculum for training dentists. Training involves identifying anatomical landmarks. The aim of this investigation was to assess whether e-learning improves learning efficiency; a programme specifically designed for this purpose was compared to commercially available software. METHODS: Thirty undergraduate students underwent traditional training of cephalometry consisting of lectures and tutorials. Tracing skills were tested immediately afterwards (T0). The students were then randomly allocated to three groups: 10 students served as control (CF); they were asked to improve their skills using the material provided so far. Ten students were given a program specifically designed for this study that was based on a power point presentation (PPT). The last group was given a commercially available program that included teaching elements (SW). The groups were tested at the end the six week training (T1). The test consisted of tracing 30 points on two radiographs and a point score improvement was calculated. The students were interviewed after the second test. RESULTS: Both e-learning groups improved more than the traditional group. Improvement scores were four for CF; 8.6 for PPT and 2.8 for SW. For PPT all participants improved and the student feedback was the best compared to the other groups. For the other groups some candidates worsened. CONCLUSIONS: Blended learning produced better learning outcomes compared to using a traditional teaching method alone. The easy to use Power Point based custom software produced better results than the commercially available software.

[Total Pancreatectomy and Islet Autotransplantation in a Child with Recurrent Pancreatitis]. / Totale Pankreatektomie und Inselautotransplantation bei einem Kind mit chronisch rezidivierender Pankreatitis.

INTRODUCTION: Hereditary pancreatitis in children is rare. The indications for surgery in these children are complications and severe pain that cannot be managed by conservative treatment. Surgical treatment options are duodenum preserving resections as well as drainage procedures. Recurrences are common following theses surgical procedures, because usually the whole pancreas is affected. The majority of the children with symptomatic hereditary pancreatitis are free of pain after total pancreatectomy. When total pancreatectomy is combined with islet autotransplantation, pancreoprivic diabetes can be attenuated or even prevented. The principle of spleen-preserving total pancreatectomy combined with subsequent islet autotransplantation is shown in a case of a 10-year-old child with chronic recurrent pancreatitis in this video. INDICATION: Symptomatic chronic hereditary pancreatitis in children. PROCEDURE: Spleen-preserving total pancreatectomy, reconstruction with hepatico-jejunostomy and duodeno-jejunostomy, islet autotransplantation via portal vein. CONCLUSION: If the surgeon has appropriate experience, spleen-preserving total pancreatectomy is a safe procedure. In combination with islet autotransplantation, it may attenuate or prevent diabetes mellitus associated with total pancreatectomy. In highly selected pediatric patients, this surgical procedure has a major benefit compared to a purely symptomatic therapy.

Islet transplantation at the Dresden diabetes center: five years' experience.

For the majority of patients with type 1 diabetes intensive insulin therapy is effective and safe for maintaining glycemia and minimizing diabetes-associated complications. However, a rare number of patients show highly labile metabolic control and experience repeated and unpredictable hypoglycemic episodes. Such condition is often caused by defective counterregulatory mechanisms and autonomous neuropathy. Patients are at high risk for severe acute and chronic complications, and quality of life is considerably impaired. For this small subset of patients, restoration of endogenous insulin secretion can substantially improve metabolic control and quality of life. In our experience, this is irrespective of insulin independency. Here, we report on our 5 years' experience with implementing islet transplantation as a potential treatment option for type 1 diabetes. All patients were treated by long-term insulin pump therapy prior to enrolment. The main indication was severely unstable diabetes and repeated hypoglycemia. From 2008 to 2013, 10 patients have been transplanted with single islet infusion; mean follow-up time was 35 months. All patients show persistent graft function, stable glycemic control with a reduction in HbA1c in the absence of hypoglycemia. All patients are kept on minimal exogenous insulin. In conclusion, islet transplantation can be an excellent therapy for selected patients. Key prerequisite for success is a strict indication. The primary goal for islet transplantation should be stabile glycemia and prevention of hypoglycemia rather than insulin independence. In fact, maintaining minimal exogenous insulin may protect the islet graft from metabolic stress and even prolong islet graft function.

Oxygen supply by photosynthesis to an implantable islet cell device.

Transplantation of islet cells is an effective treatment for type 1 diabetes with critically labile metabolic control. However, during islet isolation, blood supply is disrupted, and the transport of nutrients/metabolites to and from the islet cells occurs entirely by diffusion. Adequate oxygen supply is essential for function/survival of islet cells and is the limiting factor for graft integrity. Recently, we developed an immunoisolated chamber system for transplantation of human islets without immunosuppression. This system depended on daily oxygen supply. To provide independence from this external source, we incorporated a novel approach based on photosynthetically-generated oxygen. The chamber system was packed sandwich-like with a slab of immobilized photosynthetically active microorganisms (Synechococcus lividus) on top of a flat light source (LEDs, red light at 660 nm, intensity of 8 µE/m(2)/s). Islet cells immobilized in an alginate slab (500-1,000 islet equivalents/cm(2)) were mounted on the photosynthetic slab separated by a gas permeable silicone rubber-Teflon membrane, and the complete module was sealed with a microporous polytetrafluorethylene (Teflon) membrane (pore size: 0.4 µm) to protect the contents from the host immune cells. Upon illumination, oxygen produced by photosynthesis diffused via the silicone Teflon membrane into the islet compartment. Oxygen production from implanted encapsulated microorganisms was stable for 1 month. After implantation of the device into diabetic rats, normoglycemia was achieved for 1 week. Upon retrieval of the device, blood glucose levels returned to the diabetic state. Our results demonstrate that an implanted photosynthetic bioreactor can supply oxygen to transplanted islets and thus maintain islet viability/functionality.

Increased gene expression of the cardiac endothelin system in obese mice.

Obesity is a well-known risk factor of atherosclerosis and heart failure. In the human heart, a local endothelin system containing prepro-endothelin-1, endothelin-converting enzyme-1, and endothelin receptors A and B has been described. The endothelin system is activated in heart failure; however, the impact of obesity on the cardiac endothelin system is unknown. In this study, 18-week-old male C57BL/6 mice fed either a control diet or a high-fat diet for 10 weeks were analyzed. High-fat diet significantly increased the body weight of the animals and augmented low-density lipoprotein, high-density lipoprotein, and cholesterol plasma levels, compared to control. The animal groups showed no significant differences in left ventricular size or function (heart rate, ejection fraction, fractional shortening, left ventricular posterior wall thickness, cardiac output) after control or high-fat diet. We did not observe signs of cardiac hypertrophy or changes in markers of cardiac fibrosis in these heart samples. The cardiac expression of prepro-endothelin-1 mRNA, endothelin-converting enzyme-1 mRNA, and protein and endothelin receptors A and B mRNA was increased in 18-week-old obese C57BL/6 mice compared to animals with normal weight (p<0.05 vs. control). Furthermore, endothelin-1 plasma levels showed an increasing trend. In conclusion, an increased expression of genes of the endothelin system was observed in the hearts of 18-week-old mice after high-fat diet, possibly contributing to later cardiovascular complications of obesity.

Xenotransplantation of porcine islet cells as a potential option for the treatment of type 1 diabetes in the future.

Solid organ and cell transplantation, including pancreatic islets constitute the treatment of choice for chronic terminal diseases. However, the clinical use of allogeneic transplantation is limited by the growing shortage of human organs. This has prompted us to initiate a unique multi-center and multi-team effort to promote translational research in xenotransplantation to bring xenotransplantation to the clinical setting. Supported by the German Research Foundation, an interdisciplinary group of surgeons, internal medicine doctors, diabetologists, material sciences experts, immunologists, cell biologists, virologists, veterinarians, and geneticists have established a collaborative research center (CRC) focusing on the biology of xenogeneic cell, tissue, and organ transplantation. A major strength of this consortium is the inclusion of members of the regulatory bodies, including the Paul-Ehrlich Institute (PEI), infection specialists from the Robert Koch Institute and PEI, veterinarians from the German Primate Center, and representatives of influential ethical and religious institutions. A major goal of this consortium is to promote islet xenotransplantation, based on the extensive expertise and experience of the existing clinical islet transplantation program. Besides comprehensive approaches to understand and prevent inflammation-mediated islet xenotransplant dysfunction [immediate blood-mediated inflammatory reaction (IBMIR)], we also take advantage of the availability of and experience with islet macroencapsulation, with the goal to improve graft survival and function. This consortium harbors a unique group of scientists with complementary expertise under a cohesive program aiming at developing new therapeutic approaches for islet replacement and solid organ xenotransplantation.

Patient-specific pre-operative simulation of the surgically assisted rapid maxillary expansion using finite element method and Latin hypercube sampling: workflow and first clinical results.

Asymmetric distraction with different expansions of left and right maxillary parts is a serious complication of surgically assisted rapid maxillary expansion. An individual, highly standardized surgical intervention based on three-dimensional finite element analysis (FEA) is a new method to improve the quality of therapy. We describe a fundamental simulation-based workflow for preoperative evaluation of the osteotomies in a pilot study to achieve symmetry. A CT scan of the skull was used for analysis. Many feasible osteotomy configurations were generated and optimized using Latin hypercube sampling method and FEA choosing an individual osteotomy and maxillary movement. We successfully applied this workflow to 14 patients with symmetrical distraction.

An observed population of intermediate-mass helium stars that have been stripped in binaries.

The hydrogen-rich outer layers of massive stars can be removed by interactions with a binary companion. Theoretical models predict that this stripping produces a population of hot helium stars of ~2 to 8 solar masses (M☉), however, only one such system has been identified thus far. We used ultraviolet photometry to identify potential stripped helium stars then investigated 25 of them using optical spectroscopy. We identified stars with high temperatures (~60,000 to 100,000 kelvin), high surface gravities, and hydrogen-depleted surfaces; 16 stars also showed binary motion. These properties match expectations for stars with initial masses of 8 to 25 M☉ that were stripped by binary interaction. Their masses fall in the gap between subdwarf helium stars and Wolf-Rayet stars. We propose that these stars could be progenitors of stripped-envelope supernovae.

An update on preventive and regenerative therapies in diabetes mellitus.

Type 1A (immune-mediated) and type 2 diabetes mellitus are two of the most common severe chronic illnesses, affecting over 230 million people worldwide with an estimated global prevalence of 5.1%. Although type 1 and type 2 diabetes differ greatly in modes of pathogenesis, these illnesses share a common pathology and consequences characterized by loss of functional beta-cell mass and subsequent dysregulation of carbohydrate and lipid metabolism. Since therapy for diabetes and the associated complications poses enormous public health and economic burdens, novel preventive and regenerative therapies have emerged in the past decade with the aim to preserve beta-cell mass and delay the onset of diabetes. The goal of this review is to provide a comprehensive overview of current efforts in the fight against diabetes, and attempts to document all strategies that have emerged in clinical studies within the past 25 years. First, strategies to identify individuals at risk, ranging from whole-genome scans to autoantibody screening, will be discussed. Second, novel approaches to prevent or delay the onset of disease will be covered. Particular focus is given on emerging strategies for individuals at risk for type 1 diabetes that target T-cell regulation and induction of tolerance, while new pharmaceutical concepts in combination with lifestyle interventions are discussed within the scope of type 2 diabetes prevention. Lastly, important efforts to halt disease progression with emphasis on beta-cell regeneration are presented.

A novel device for islet transplantation providing immune protection and oxygen supply.

Islet transplantation as a biological ß-cell replacement therapy has emerged as a promising option for achieving restoration of metabolic control in type 1 diabetes patients. However, partial or complete loss of islet graft function occurs in relatively short time (months to few years) after implantation. The high rate of early transplant dysfunction has been attributed to poorly viable and/or functional islets and is mediated by innate inflammatory response at the intravascular (hepatic) transplant site and critical lack of initial nutrient/oxygen supply prior to islet engraftment. In addition, the diabetogenic effect of mandatory immunosuppressive agents, limited control of alloimmunity, and the recurrence of autoimmunity limit the long-term success of islet transplantation. In order to abrogate instant blood-mediated inflammatory reaction and to provide oxygen supply for the islet graft, we have developed an extravascular (subcutaneous) transplant macrochamber (the 'ßAir' device). This device contains islets immobilized in alginate, protected from the immune system by a thin hydrophilized teflon membrane impregnated with alginate and supplied with oxygen by daily refueling with oxygen-CO (2) mixture. We have demonstrated successful utilization of the oxygen-refueling macrochamber for sustained islet viability and function as well as immunoprotection after allogeneic subcutaneous transplantation in healthy minipigs. Considering the current limitations of intraportal islet engraftment and the restricted indication for islet transplantation mainly due to necessary immunosuppressive therapy, this work could very likely lead to remarkable improvements in the procedure and moreover opens up further strategies for porcine islet cell xenotransplantation.

Molecular genetics of the genus Paracoccus: metabolically versatile bacteria with bioenergetic flexibility.

Paracoccus denitrificans and its near relative Paracoccus versutus (formerly known as Thiobacilllus versutus) have been attracting increasing attention because the aerobic respiratory system of P. denitrificans has long been regarded as a model for that of the mitochondrion, with which there are many components (e.g., cytochrome aa3 oxidase) in common. Members of the genus exhibit a great range of metabolic flexibility, particularly with respect to processes involving respiration. Prominent examples of flexibility are the use in denitrification of nitrate, nitrite, nitrous oxide, and nitric oxide as alternative electron acceptors to oxygen and the ability to use C1 compounds (e.g., methanol and methylamine) as electron donors to the respiratory chains. The proteins required for these respiratory processes are not constitutive, and the underlying complex regulatory systems that regulate their expression are beginning to be unraveled. There has been uncertainty about whether transcription in a member of the alpha-3 Proteobacteria such as P. denitrificans involves a conventional sigma70-type RNA polymerase, especially since canonical -35 and -10 DNA binding sites have not been readily identified. In this review, we argue that many genes, in particular those encoding constitutive proteins, may be under the control of a sigma70 RNA polymerase very closely related to that of Rhodobacter capsulatus. While the main focus is on the structure and regulation of genes coding for products involved in respiratory processes in Paracoccus, the current state of knowledge of the components of such respiratory pathways, and their biogenesis, is also reviewed.

Cytochrome c oxidase--structure, function, and physiology of a redox-driven molecular machine.

Cytochome c oxidase is the terminal member of the electron transport chains of mitochondria and many bacteria. Providing an efficient mechanism for dioxygen reduction on the one hand, it also acts as a redox-linked proton pump, coupling the free energy of water formation to the generation of a transmembrane electrochemical gradient to eventually drive ATP synthesis. The overall complexity of the mitochondrial enzyme is also reflected by its subunit structure and assembly pathway, whereas the diversity of the bacterial enzymes has fostered the notion of a large family of heme-copper terminal oxidases. Moreover, the successful elucidation of 3-D structures for both the mitochondrial and several bacterial oxidases has greatly helped in designing mutagenesis approaches to study functional aspects in these enzymes.

Genetics of Paracoccus denitrificans.

In bioenergetic research Paracoccus denitrificans has been used as an interesting model to elucidate the mechanisms of bacterial energy transduction. Genes for protein complexes of the respiratory chain and for proteins which are involved in periplasmic electron transport have been cloned and sequenced. Conjugational gene transfer has allowed the construction of site-specific mutant strains. Complementation experiments did not only open the field for site-directed mutagenesis and investigation of the structure/function relationship of the various electron-transport proteins, but also allowed first insights into processes like oxygen-dependent gene regulation or the assembly of electron-transport complexes. Also data will be presented that characterize two restriction-/modification systems, the codon usage and the promoter sequences of Paracoccus. Details will be given about the extrachromosomal localization of a duplicated cytochrome oxidase subunit I gene on one of the Paracoccus megaplasmids.

Induction of photochemical auto-reduction of cytochrome-c oxidase by an organic peroxide.

Cytochrome-c oxidase aa3 (CcO) from Paracoccus denitrificans interacts with tertiary butyl hydroperoxide (t-Bu-O-O-H, TBHP) by forming an adduct as indicated by an absorption shift at 408/432 nm and the induction of photochemical autoreduction. The adduct was stable at room temperature for several days even under aerobic conditions. Upon irradiation (413 nm) of the adduct, a photoproduct, similar to the oxygenated mixed valence species (607 nm form), was formed, as indicated by the 418/442 and 607 nm signals in the absorption-difference spectrum. It is concluded that the adduct formation changes the photochemical properties of heme a3. A molecular model for the binding mechanism of TBHP to CcO and for the photochemistry of heme a3-TBHP adduct is proposed.

Site-directed mutagenesis of cytochrome c oxidase reveals two acidic residues involved in the binding of cytochrome c.

Site-directed mutagenesis in subunit II of the cytochrome c oxidase (haem aa3) from Paracoccus denitrificans reveals that two carboxylic residues, Glu-246 and Asp-206 (corresponding to 198 and 158 in the bovine subunit II), are involved in the binding of cytochrome c. Spectrophotometric and polarographic measurements with the isolated enzymes of both mutant strains show a strongly reduced activity compared to wild-type oxidase, with the overall catalytic capacity (kcat/KM) of both mutants decreased about 8-fold. EPR spectra reveal no significant differences between the wild-type and the mutant enzymes, indicating that neither residue contributes significantly to the structure of the CuA centre. We conclude that Glu-246 and Asp-206 constitute an essential part of the binding site for cytochrome c.

Copper and manganese electron spin resonance studies of cytochrome c oxidase from Paracoccus denitrificans.

The two-subunit cytochrome c oxidase from Paracoccus denitrificans contains two heme a groups and two copper atoms. However, when the enzyme is isolated from cells grown on a commonly employed medium, its electron paramagnetic resonance (EPR) spectrum reveals not only a Cu(II) powder pattern, but also a hyperfine pattern from tightly bound Mn(II). The pure Mn(II) spectrum is observed at -40 degrees C; the pure Cu(II) spectrum can be seen with cytochrome c oxidase from P. denitrificans cells that had been grown in a Mn(II)-depleted medium. This Cu(II) spectrum is very similar to that of cytochrome c oxidase from yeast or bovine heart. Manganese is apparently not an essential component of P. denitrificans cytochrome c oxidase since it is present in substoichometric amounts relative to copper or heme a and since the manganese-free enzyme retains essentially full activity in oxidizing ferrocytochrome c. However, the manganese is not removed by EDTA and its EPR spectrum responds to the oxidation state of the oxidase. In contrast, manganese added to the yeast oxidase or to the manganese-free P. denitrificans enzyme can be removed by EDTA and does not respond to the oxidation state of the enzyme. This suggests that the manganese normally associated with P. denitrificans cytochrome c oxidase is incorporated into one or more internal sites during the biogenesis of the enzyme.