Impact of a diabetes disease management program on guideline-adherent care, hospitalization risk and health care costs: a propensity score matching study using real-world data.

OBJECTIVE: To evaluate the impact of a DMP for patients with diabetes mellitus in a Swiss primary care setting. METHODS: In a prospective observational study, we compared diabetes patients in a DMP (intervention group; N = 538) with diabetes patients receiving usual care (control group; N = 5050) using propensity score matching with entropy balancing. Using a difference-in-difference (DiD) approach, we compared changes in outcomes from baseline (2017) to 1-year (2017/18) and to 2-year follow-up (2017/19). Outcomes included four measures for guideline-adherent diabetes care, hospitalization risk, and health care costs. RESULTS: We identified a positive impact of the DMP on the share of patients fulfilling all measures for guideline-adherent care [DiD 2017/18: 7.2 percentage-points, p < 0.01; 2017/19: 8.4 percentage-points, p < 0.001]. The hospitalization risk was lower in the intervention group in both years, but only statistically significant in the 1-year follow-up [DiD 2017/18: - 5.7 percentage-points, p < 0.05; 2017/19: - 3.9 percentage points, n.s.]. The increase in health care costs was smaller in the intervention than in the control group [DiD 2017/18: CHF - 852; 2017/19: CHF - 909], but this effect was not statistically significant. CONCLUSION: The DMP under evaluation seems to exert a positive impact on the quality of diabetes care, reflected in the increase in the measures for guideline-adherent care and in a reduction of the hospitalization risk in the intervention group. It also might reduce health care costs, but only a longer follow-up will show whether the observed effect persists over time.

A genetically encoded biosensor for visualising hypoxia responses in vivo.

Cells experience different oxygen concentrations depending on location, organismal developmental stage, and physiological or pathological conditions. Responses to reduced oxygen levels (hypoxia) rely on the conserved hypoxia-inducible factor 1 (HIF-1). Understanding the developmental and tissue-specific responses to changing oxygen levels has been limited by the lack of adequate tools for monitoring HIF-1 in vivo. To visualise and analyse HIF-1 dynamics in Drosophila, we used a hypoxia biosensor consisting of GFP fused to the oxygen-dependent degradation domain (ODD) of the HIF-1 homologue Sima. GFP-ODD responds to changing oxygen levels and to genetic manipulations of the hypoxia pathway, reflecting oxygen-dependent regulation of HIF-1 at the single-cell level. Ratiometric imaging of GFP-ODD and a red-fluorescent reference protein reveals tissue-specific differences in the cellular hypoxic status at ambient normoxia. Strikingly, cells in the larval brain show distinct hypoxic states that correlate with the distribution and relative densities of respiratory tubes. We present a set of genetic and image analysis tools that enable new approaches to map hypoxic microenvironments, to probe effects of perturbations on hypoxic signalling, and to identify new regulators of the hypoxia response.

Cdk4 functions in multiple cell types to control Drosophila intestinal stem cell proliferation and differentiation.

The proliferation of intestinal stem cells (ISCs) and differentiation of enteroblasts to form mature enteroendocrine cells and enterocytes in the Drosophila intestinal epithelium must be tightly regulated to maintain homeostasis. We show that genetic modulation of CyclinD/Cdk4 activity or mTOR-dependent signalling cell-autonomously regulates enterocyte growth, which influences ISC proliferation and enteroblast differentiation. Increased enterocyte growth results in higher numbers of ISCs and defective enterocyte growth reduces ISC abundance and proliferation in the midgut. Adult midguts deficient for Cdk4 show severe disruption of intestinal homeostasis characterised by decreased ISC self-renewal, enteroblast differentiation defects and low enteroendocrine cell and enterocyte numbers. The ISC/enteroblast phenotypes result from a combination of cell autonomous and non-autonomous requirements for Cdk4 function. One non-autonomous consequence of Cdk4-dependent deficient enterocyte growth is high expression of Delta in ISCs and Delta retention in enteroblasts. We postulate that aberrant activation of the Delta-Notch pathway is a possible partial cause of lost ISC stemness. These results support the idea that enterocytes contribute to a putative stem cell niche that maintains intestinal homeostasis in the Drosophila anterior midgut.

Sensitivity improvement in laser ablation inductively coupled plasma mass spectrometry achieved using a methane/argon and methanol/water/argon mixed gas plasma.

The influence of the addition of carbon using methane or methanol/water to an inductively coupled plasma (ICP) via the carrier gas flow on the sensitivity in laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) was studied. During the ablation of SRM NIST 610 with simultaneous addition of CH(4) (0.6-1.4 ml min(-1)), a sensitivity enhancement of more than one order of magnitude for selected analytes (e.g. (75)As(+)) was observed. In addition to the sensitivity enhancement for As, Te, I and Se, also all other measured elements showed a significantly enhanced sensitivity (minimum by a factor of 2). Potential mechanisms for the observed intensity enhancement include charge transfer reactions, a change in the ICP shape and a temperature increase in the plasma. Furthermore, the aspiration of a methanol-water mixture into a cooled spray chamber and the simultaneous addition to the laser ablated aerosol was investigated. This type of mixing leads to a sensitivity enhancement up to a factor of 20. To prevent clogging of the sampler cone and skimmer cone by carbon deposition, a fast cleaning procedure for the interface is tested during running ICP, which allows the application of such a set-up for specific applications.

Mitochondria in response to nutrients and nutrient-sensitive pathways.

Mitochondria are abundant cellular organelles, and are required for the generation of energy through oxidative catabolism. Equally important, mitochondria also provide substrates for de novo synthesis of fatty acids and multiple amino acids. Mitochondrial functions must therefore be tightly linked to cellular nutrient availability. This review focuses on the current knowledge of how nutrients affect mitochondria. In particular, we describe how the transcriptional profile of the nucleus is altered to mediate this control, and the transcription factors that are involved. In addition, we summarize recent progress in our understanding of how transcription-independent mechanisms, most notably through the cellular energy sensor mTOR, are used to adapt mitochondrial functions in respect to cellular metabolic needs.

The Drosophila PGC-1 homologue Spargel coordinates mitochondrial activity to insulin signalling.

Mitochondrial mass and activity must be adapted to tissue function, cellular growth and nutrient availability. In mammals, the related transcriptional coactivators PGC-1alpha, PGC-1beta and PRC regulate multiple metabolic functions, including mitochondrial biogenesis. However, we know relatively little about their respective roles in vivo. Here we show that the Drosophila PGC-1 family homologue, Spargel, is required for the expression of multiple genes encoding mitochondrial proteins. Accordingly, spargel mutants showed mitochondrial respiration defects when complex II of the electron transport chain was stimulated. Spargel, however, was not limiting for mitochondrial mass, but functioned in this respect redundantly with Delg, the fly NRF-2alpha/GABPalpha homologue. More importantly, in the larval fat body, Spargel mediated mitochondrial activity, cell growth and transcription of target genes in response to insulin signalling. In this process, Spargel functioned in parallel to the insulin-responsive transcription factor, dFoxo, and provided a negative feedback loop to fine-tune insulin signalling. Taken together, our data place Spargel at a nodal point for the integration of mitochondrial activity to tissue and organismal metabolism and growth.

Nutrition controls mitochondrial biogenesis in the Drosophila adipose tissue through Delg and cyclin D/Cdk4.

MITOCHONDRIA ARE CELLULAR ORGANELLES THAT PERFORM CRITICAL METABOLIC FUNCTIONS: they generate energy from nutrients but also provide metabolites for de novo synthesis of fatty acids and several amino acids. Thus mitochondrial mass and activity must be coordinated with nutrient availability, yet this remains poorly understood. Here, we demonstrate that Drosophila larvae grown in low yeast food have strong defects in mitochondrial abundance and respiration activity in the larval fat body. This correlates with reduced expression of genes encoding mitochondrial proteins, particularly genes involved in oxidative phosphorylation. Second, genes involved in glutamine metabolism are also expressed in a nutrient-dependent manner, suggesting a coordination of amino acid synthesis with mitochondrial abundance and activity. Moreover, we show that Delg (CG6338), the Drosophila homologue to the alpha subunit of mammalian transcription factor NRF-2/GABP, is required for proper expression of most genes encoding mitochondrial proteins. Our data demonstrate that Delg is critical to adjust mitochondrial abundance in respect to Cyclin D/Cdk4, a growth-promoting complex and glutamine metabolism according to nutrient availability. However, in contrast to nutrients, Delg is not involved in the regulation of mitochondrial activity in the fat body. These findings are the first genetic evidence that the regulation of mitochondrial mass can be uncoupled from mitochondrial activity.

Single postoperative instillation of gemcitabine in patients with non-muscle-invasive transitional cell carcinoma of the bladder: a randomised, double-blind, placebo-controlled phase III multicentre study.

BACKGROUND: Recurrence prophylaxis with intravesical gemcitabine (GEM) was effective and safe in patients with non-muscle-invasive bladder cancer (NMIBC); efficacy as single-shot instillation remains to be proved. OBJECTIVE: To compare the efficacy of a single GEM instillation versus placebo (PBO) immediately after transurethral resection (TUR) of tumour in patients with histologically confirmed NMIBC (pTa/pT1,G1-3). DESIGN, SETTING, AND PARTICIPANTS: This was a double-blind, randomised, PBO-controlled study in patients with clinical evidence of primary or recurrent NMIBC (Ta/T1,G1-3). Of 355 patients randomised at 24 urologic centres, 328 underwent TUR and received instillation (92.4%; GEM/PBO: 166/162). In case of nonmalignancy, carcinoma in situ (CIS), > or = pT2 disease, or intraoperative complications, patients were discontinued. INTERVENTION: We used a single, postoperative 30-40-min instillation of GEM (2000 mg/100 ml of saline) or PBO (100 ml of saline) followed by continuous bladder irrigation for > or = 20 h. A second TUR (no instillation) and adjuvant bacillus Calmette-Guérin (BCG) instillations were allowed. MEASUREMENTS: Primary outcome was recurrence-free survival (RFS). Secondary outcomes included type of recurrence and adverse events. To detect a difference in RFS, 191 recurrences were required (80% power, log-rank-test, alpha = 0.050). RESULTS AND LIMITATIONS: Two hundred forty-eight patients (69.9%, GEM, PBO: 124, 124) had histologically confirmed pTa/pT1 G1-3 Gx tumour and were eligible for efficacy (GEM: 76.6% male; median age: 65 yr; PBO: 83.1% male; median age: 67 yr). Treatment groups were balanced (pTa: 75.0%, 71.0%; G1-G2: 85.5%, 87.9%; recurrent tumour: 24.2%, 21.0%; BCG: 10.5%, 16.9%). After a median follow-up of 24 mo, there were only 94 recurrences and 11 deaths. The study was terminated early based on predefined decision criteria. RFS was high in both groups (12-mo RFS [95% confidence interval (CI)]: GEM: 77.7% [68.8-84.3]; PBO: 75.3% [66.3-82.3]). There was no significant group difference (hazard ratio [HR]: 0.946 [0.64-1.39], log-rank test, p=0.777). CONCLUSIONS: In this study of NMIBC, the immediate single instillation of GEM 2000 mg/100 ml of saline after TUR was not superior to PBO in terms of RFS. Rigid continuous irrigation and improved TUR/cystoscopy techniques may have contributed to the high RFS in both groups.

Implants in the esthetic zone.

Over the last 15 years implant dentistry has made great progress. Especially in the anterior region, esthetics plays a vital role in treatment. Patients expect not only a fully functional restoration, but also an esthetically pleasing and long-lasting solution. A predictable and esthetic result can only be achieved by adhering to a proven clinical protocol, which is based on experience, precise diagnostic procedures, and meticulous treatment planning. This article presents a practical protocol used in the authors' practice for esthetic reconstructions with dental implants in the anterior region with four patient cases.

Mammalian cyclin D1/Cdk4 complexes induce cell growth in Drosophila.

The Drosophila melanogaster cyclin dependent protein kinase complex CycD/Cdk4 has been shown to regulate cellular growth (accumulation of mass) as well as proliferation (cell cycle progression). In contrast, the orthologous mammalian complex has been shown to regulate cell cycle progression, but possible functions in growth control have not been addressed directly. To test whether mammalian Cyclin D1/Cdk4 complexes are capable of driving cell growth, we expressed such a complex in Drosophila. Using assays that distinguish between mass increase and cell cycle progression, we found that this complex stimulated cell growth, like its Drosophila counterpart. Furthermore, Hif-1 prolyl hydroxylase (Hph) is required for both complexes to drive growth. Our data suggest that the growth-specific function of CycD/Cdk4 is conserved from arthropods to mammals.

[Periotest-analysis in penradicular surgery: preliminary results of a clinical-prospective study]. / Der Periotest in der periradikulären Chirurgie: vorläufige Resultate einer klinisch-prospektiven Studie.

The two objectives of the present study were: to assess the healing after periradicular surgery using the Periotest device, and to compare the recorded Periotest values with the healing category determined after a one-year follow-up using radiographic and clinical criteria. In 43 patients with periradicular surgery, Periotest values could be recorded pre- and postoperatively, as well as after six and twelve months. Cases with a successful healing, as determined at the one-year follow-up, demonstrated a continuous decrease of the Periotest values over time, whereas one-year failures showed increasing Periotest values over the study period. In control teeth, the Periotest values remained unchanged for the whole study period. It appears that the Periotest measurements correlate with the postoperative healing mode following periradicular surgery, and therefore, allow an additional assessment of the healing outcome.

The Drosophila mitochondrial ribosomal protein mRpL12 is required for Cyclin D/Cdk4-driven growth.

The Drosophila melanogaster cyclin-dependent protein kinase complex CycD/Cdk4 stimulates both cell cycle progression and cell growth (accumulation of mass). CycD/Cdk4 promotes cell cycle progression via the well-characterized RBF/E2F pathway, but our understanding of how growth is stimulated is still limited. To identify growth regulatory targets of CycD/Cdk4, we performed a loss-of-function screen for modifiers of CycD/Cdk4-induced overgrowth of the Drosophila eye. One mutation that suppressed CycD/Cdk4 was in a gene encoding the mitochondrial ribosomal protein, mRpL12. We show here that mRpL12 is required for CycD/Cdk4-induced cell growth. Cells homozygous mutant for mRpL12 have reduced mitochondrial activity, and exhibit growth defects that are very similar to those of cdk4 null cells. CycD/Cdk4 stimulates mitochondrial activity, and this is mRpL12 dependent. Hif-1 prolyl hydroxylase (Hph), another effector of CycD/Cdk4, regulates growth and is required for inhibition of the hypoxia-inducible transcription factor 1 (Hif-1). Both functions depend on mRpL12 dosage, suggesting that CycD/Cdk4, mRpL12 and Hph function together in a common pathway that controls cell growth via affecting mitochondrial activity.

Assessment of the suitability of a new brushite calcium phosphate cement for cranioplasty - an experimental study in sheep.

INTRODUCTION: Aim of this experimental study was to assess the suitability of a new brushite calcium phosphate cement (chronOS Inject) for cranioplasty and to compare the results with a commercially available apatite calcium phosphate bone cement (Biobon). MATERIAL AND METHODS: A bilateral full-size craniotomy defect (23 mm in diameter) was created in the parietal bones of 18 adult Swiss Alpine sheep and filled with either chronOS Inject or Biobon. The observation intervals were 2, 4 and 6 months. Macroscopical, radiological, histological and histomorphometrical evaluations were performed. RESULTS: New bone formation was moderate and did not differ significantly between the biomaterials. Cement resorption occurred centripetally in the chronOS Inject group and proceeded significantly faster than the degradation process of Biobon. However, implantation of chronOS Inject was associated with a significantly higher rate of fibrous tissue formation. Cement resorption was mediated by macrophages in the chronOS Inject group, while osteoclasts were the predominant cell type involved in degradation of Biobon. Osteoblasts were found adjacent to residual cement in both groups. CONCLUSION: chronOS Inject demonstrated osteoconductive properties, good biocompatibility and superior bioresorbability but none of the cements proved suitable for filling large cranial bony defects due to the high rate of fibrous tissue formation and insufficient bony regeneration.

Biocompatibility and resorption of a brushite calcium phosphate cement.

A hydraulic calcium phosphate cement with beta-tricalcium phosphate (TCP) granules embedded in a matrix of dicalcium phosphate dihydrate (DCPD) was implanted in experimentally created defects in sheep. One type of defect consisted of a drill hole in the medial femoral condyle. The other, partial metaphyseal defect was located in the proximal aspect of the tibia plateau and was stabilized using a 3.5 mm T-plate. The bone samples of 2 animals each per group were harvested after 2, 4, 6 and 8 weeks. Samples were evaluated for cement resorption and signs of immediate reaction, such as inflammation, caused by the cement setting in situ. Differences regarding these aspects were assessed for both types of defects using macroscopical, radiological, histological and histomorphometrical evaluations. In both defects the brushite matrix was resorbed faster than the beta-TCP granules. The resorption front was followed directly by a front of new bone formation, in which residual beta-TCP granules were embedded. Cement resorption occurred through (i) extracellular liquid dissolution with cement disintegration and particle formation, and (ii) phagocytosis of the cement particles through macrophages. Signs of inflammation or immunologic response leading to delayed new bone formation were not noticed at any time. Cement degradation and new bone formation occurred slightly faster in the femur defects.

Study on the necessity for cross-section imaging of the posterior mandible for treatment planning of standard cases in implant dentistry.

OBJECTIVE: To investigate whether cross-section imaging influences the planning and therapy of standard implant cases in the posterior mandible. MATERIAL AND METHODS: In a prospective study conducted over 16 months, the planned treatment (standard implant therapy without bone augmentation procedures in the premolar and molar regions of the mandible) was compared with the postoperative result in 50 randomly selected patients. Clinical examinations and panoramic radiographs were performed pre- and postoperatively, whereas cross-sectional tomography was performed only preoperatively. RESULTS: The vertical magnification factor in the panoramic radiographs was very constant pre- and postoperatively with 1 : 1.27 and in the spiral tomograms with 1 : 1.52. In 11 of 77 implant sites, the mandibular canal could not be evaluated in the spiral tomograms. The additional information from cross-sectional spiral tomography did not influence the original planning in 74 of 77 (96.1%) implant sites. Based on the postoperative panoramic radiograph, the average distance from the tip of the implants to the mandibular canal was 3.04+/-2.06 mm. In two cases (2.6%), transient postoperative altered tactile sensation of the mental nerve was found. CONCLUSION: The information from preoperative cross-sectional spiral tomography has minor impact on treatment planning in standard implant cases in mandibular premolar and molar regions. The clinical examination provides sufficient information for selecting implant diameter and the panoramic radiograph provides sufficient information for implant length selection.

Osteosarcoma of the maxilla and the maxillary sinus: a case report.

Osteosarcoma of the jawbones is a rare malignant mesenchymal neoplasm with the tendency for new bone being directly formed by the tumor cells. Clinically, the tumor may be central or peripheral--periosteal--and histologically can be divided into three subtypes: osteoblastic, fibroblastic, and chondroblastic. This report presents a case of a central osteoblastic osteosarcoma of the left maxillary tuberosity and maxillary sinus. Problems related to definitive diagnosis and therapy are described and discussed.

Cyclin D/Cdk4: new insights from Drosophila.

The Drosophila cyclin-dependent protein kinase complex CycD/Cdk4 has been known to drive cellular growth (accumulation of mass) as well as proliferation (cell cycle progression). Recent data demonstrate that Hif prolyl hydroxylase (Hph) is required for the induction of growth, but not for the induction of proliferation. Normal levels of Hph are required for cellular growth, demonstrating that Hph, in addition to its known function in the cellular response low oxygen levels, regulates growth. Since Hph's hydroxylation activity depends on oxygen and possibly the mitochondrial activity, these data provide a link between CycD/Cdk4 and oxygen/energy homeostasis.

Drosophila cyclin D/Cdk4 requires Hif-1 prolyl hydroxylase to drive cell growth.

The Drosophila cyclin-dependent protein kinase complex Cyclin D/Cdk4 induces cell growth (accumulation of mass) as well as proliferation (cell cycle progression). To understand how CycD/Cdk4 promotes growth, we performed a screen for modifiers of CycD/Cdk4-driven overgrowth in the eye. Loss-of-function mutations in Hif-1 prolyl hydroxylase (Hph), an enzyme involved in the cellular response to hypoxic stress, dominantly suppress the growth but not the proliferation function of CycD/Cdk4. hph mutant cells are defective for growth, and, remarkably, ectopic expression of Hph is sufficient to increase cellular growth. Epistasis analysis places Hph downstream of CycD/Cdk4. Overexpressed CycD/Cdk4 causes an increase in Hph protein in tissues where Hph induces growth, suggesting a mechanism whereby Hph levels are regulated posttranscriptionally in response to CycD/Cdk4. Our data suggest that Hph, in addition to its function in hypoxic response, is a regulator of cellular growth and that it is a key mediator for CycD/Cdk4.

[Periradicular surgery with and without endoscopy: a prospective clinical comparative study]. / Periradikuläre Chirurgie mit und ohne Endoskopie: eine klinisch-prospektive Vergleichsstudie.

A total of 129 teeth with periradicular surgeries (apicoectomies) were analyzed in a prospective clinical study. In the test group including 62 teeth, an endoscope (Tele-Otoscope with a 70 degrees viewing angle) was used as an intraoperative visualization aid to monitor the following surgical steps: root-end resection, root-end cavity preparation and retrograde root-canal obturation. In the control group including 67 teeth, intraoperative diagnostics were carried out using micromirrors. Fifty-four and 61 teeth could be re-examined after one year. Based on the clinical and radiographic findings they were categorized as success, uncertain healing or failure. In the test group with endoscopy, the success rate was 88.9%, whereas in the control group it was only 75.4%. However, statistically no significant difference was found between the two groups. Additional experimental and clinical studies will show if endoscopy will improve the success rates in periradicular surgery any further.