bluuebunny/crossref_metadata_2025 huggingface dataset:
Potential for combination of dipeptidyl peptidase‐4 inhibitors and sodium‐glucose co‐transporter‐2 inhibitors for the treatment of type 2 diabetes
Authors: Sharma M. D.
Published: February 2015

In individuals with advanced type 2 diabetes (T2DM), combination therapy is often unavoidable to maintain glycaemic control. Currently metformin is considered the first line of defence, but many patients experience gastrointestinal adverse events, necessitating an alternative treatment approach. Established therapeutic classes, such as sulphonylureas and thiazolidinediones, have some properties undesirable in individuals with T2DM, such as hypoglycaemia risk, weight gain and fluid retention, highlighting the need for newer agents with more favourable safety profiles that can be combined and used at all stages of T2DM. New treatment strategies have focused on both dipeptidyl peptidase (DPP)‐4 inhibitors, which improve hyperglycaemia by stimulating insulin secretion in a glucose‐dependent fashion and suppressing glucagon secretion, and sodium‐glucose co‐transporter‐2 (SGLT2) inhibitors, which reduce renal glucose reabsorption and induce urinary glucose excretion, thereby lowering plasma glucose. The potential complimentary mechanism of action and good tolerance profile of these two classes of agents make them attractive treatment options for combination therapy with any of the existing glucose‐lowering agents, including insulin. Together, the DPP‐4 and SGLT2 inhibitors fulfill a need for treatments with mechanisms of action that can be used in combination with a low risk of adverse events, such as hypoglycaemia or weight gain.
Imeglimin increases glucose‐dependent insulin secretion and improves β‐cell function in patients with type 2 diabetes
Authors: Pacini G. , Mari A. , Fouqueray P. , Bolze S. , Roden M.
Published: February 2015

Aims

To assess the glucose‐stimulated insulin secretion effect of imeglimin in patients with type 2 diabetes.

Methods

We conducted a double‐blind, randomized, placebo‐controlled study in 33 patients with type 2 diabetes [glycated haemoglobin 6.8 ± 0.1% (51 mmol/mol)], who were drug‐naïve or withdrawn from their previous metformin monotherapy for 2 weeks and received imeglimin 1500 mg twice daily or placebo for 1 week. Glucose‐stimulated insulin secretion was assessed using a hyperglycaemic clamp. The primary endpoint was insulin secretion as defined by total insulin response [incremental area under the curve (iAUC)0–45 min] and insulin secretion rate (ISR) calculated from C‐peptide deconvolution. β‐cell glucose sensitivity at steady state (second phase: 25–45 min), hepatic insulin extraction and insulin clearance were also calculated.

Results

Imeglimin treatment for 7 days raised the insulin secretory response to glucose by +112% (iAUC0‐45, p = 0.035), first‐phase ISR by +110% (p = 0.034) and second‐phase ISR by +29% (p = 0.031). Imeglimin improved β‐cell glucose sensitivity by +36% (p = 0.034) and tended to decrease hepatic insulin extraction (−13%; p = 0.056). Imeglimin did not affect glucagon secretion.

Conclusions

In patients with type 2 diabetes, imeglimin improves β‐cell function, which may contribute to the glucose‐lowering effect observed with imeglimin in clinical trials.
Utility of labile plasma iron and transferrin saturation in addition to serum ferritin as iron overload markers in different underlying anemias before and after deferasirox treatment
Authors: Porter John B. , El‐Alfy Mohsen , Viprakasit Vip , Giraudier Stephane , Chan Lee Lee , Lai Yongrong , El‐Ali Ali , Han Jackie , Cappellini Maria D.
Published: February 2015

Objectives

Plasma markers in addition to serum ferritin (SF) may be useful for the assessment of iron overload; however, predictive utility may differ depending on underlying, transfusion‐dependent, anemias.

Methods

Data were collected before and after 1 year of deferasirox treatment (end of study; EOS) from the large, 1‐year EPIC (Evaluation of Patients’ Iron Chelation with Exjade®) study. Trends were evaluated between liver iron concentration (LIC), transferrin saturation (TfSat), predose labile plasma iron (LPI) and their relationship to SF categories in 1530 patients: thalassemia major (TM; n = 1114), myelodysplastic syndromes (MDS, n = 336), and sickle‐cell disease (SCD, n = 80).

Results

Baseline and EOS SF values showed a clear and similar relationship to LIC for all disease groups. TfSat also showed a relationship to SF, most clearly in patients with SCD, where TfSat was lowest in the lowest relative SF category. Unlike SF or LIC, TfSat did not decrease at EOS in any disease group. Baseline LPI was raised in TM and MDS, but not in patients with SCD, decreasing at EOS in both patient groups. After 1 year of chelation therapy, there was a significant trend for greater LPI reduction in patients with TM achieving LIC <7 mg Fe/g dw (P = 0.0137).

Conclusions

Despite limitations, SF showed the clearest relationship, of the plasma markers evaluated, to LIC before and after 1 year of deferasirox in patients with TM, MDS, and SCD. In patients with TM, changes in LPI with chelation show a significant relationship to EOS LIC and may provide an additional indicator of chelation response (clinicaltrials.gov identifier: NCT00171821).
Preservation of resin–dentin interfaces treated with benzalkonium chloride adhesive blends
Authors: Sabatini Camila , Ortiz Pilar A. , Pashley David H.
Published: February 2015

Reducing collagen degradation within hybrid layers may contribute to the preservation of adhesive interfaces. This study evaluated the stability of resin–dentin interfaces treated with benzalkonium chloride (BAC)‐modified adhesive blends and assessed collagen degradation in dentin matrices treated with BAC. The etch‐and‐rinse adhesive, Adper Single Bond Plus, modified with 0.5% and 1.0% BAC, was evaluated for microtensile bond strength (μTBS) and nanoleakage (NL) after 24 h and 1 yr. Thirty completely demineralized dentin beams from human molars were dipped for 60 s in deionized water (DW; control), or in 0.5% or 1.0% BAC, and then incubated in simulated body fluid (SBF). Collagen degradation was assessed by quantification of the dry mass loss and the amount of hydroxyproline (HYP) released from hydrolyzed specimens after 1 or 4 wk. Although all groups demonstrated a significant increase in NL after 1 yr, adhesive modified with 0.5% BAC showed stable bond strength after 1 yr (9% decrease) relative to the control (44% decrease). Significantly less HYP release and dry mass loss were observed for both 0.5% and 1.0% BAC relative to the control. This in vitro study demonstrates that BAC contributes to the preservation of resin–dentin bonds for up to 1 yr by reducing collagen degradation.
Paracrine crosstalk between human hair follicle dermal papilla cells and microvascular endothelial cells
Authors: Bassino Eleonora , Gasparri Franco , Giannini Valentina , Munaron Luca
Published: February 2015

Human follicle dermal papilla cells (FDPC) are a specialized population of mesenchymal cells located in the skin. They regulate hair follicle (HF) development and growth, and represent a reservoir of multipotent stem cells. Growing evidence supports the hypothesis that HF cycling is associated with vascular remodeling. Follicular keratinocytes release vascular endothelial growth factor (VEGF) that sustains perifollicular angiogenesis leading to an increase of follicle and hair size. Furthermore, several human diseases characterized by hair loss, including Androgenetic Alopecia, exhibit alterations of skin vasculature. However, the molecular mechanisms underlying HF vascularization remain largely unknown. In vitro coculture approaches can be successfully employed to greatly improve our knowledge and shed more light on this issue. Here we used Transwell‐based co‐cultures to show that FDPC promote survival, proliferation and tubulogenesis of human microvascular endothelial cells (HMVEC) more efficiently than fibroblasts. Accordingly, FDPC enhance the endothelial release of VEGF and IGF‐1, two well‐known proangiogenic growth factors. Collectively, our data suggest a key role of papilla cells in vascular remodeling of the hair follicle.
Vitiligo patient‐derived keratinocytes exhibit characteristics of normal wound healing via epithelial to mesenchymal transition
Authors: Banerjee Poulomi , Venkatachalam Sandhyaa , Mamidi Murali Krishna , Bhonde Ramesh , Shankar Krupa , Pal Rajarshi
Published: February 2015

Vitiligo is an autoimmune disorder that leads to depigmentation of skin via melanocyte dysfunction. Keratinocyte‐induced toxicity is one among the several etiological factors implicated for vitiligo, and hence, autologous keratinocyte grafting is projected as one of the primary mode of treatment for vitiligo. However, reports indicate that perilesional keratinocytes not only display signatures of apoptosis but also could secrete cytokines and mediators which have antagonistic effect on proliferation or survival. Therefore, we investigated how vitiligo patients' derived keratinocytes respond to surplus amounts of inflammatory cytokines and whether they recapitulate events that take place during conventional wound healing. The primary objective of our study was to determine whether keratinocytes isolated from a vitiligo patient would undergo epithelial–mesenchymal transition similar to their normal counterparts upon induction with inflammatory cytokines such as TGF‐b1 and EGF. We found that these keratinocytes undergo EMT during wound repair accompanied with increase in the levels of mesenchymal markers and ECM proteins; decrease in the levels of epithelial markers and enhanced migratory ability. Besides, we also demonstrated that EMT induction leads to activation of SMAD and MAPK pathways via Ras, Raf, PAI 1, Snail, Slug and ZO1. To our knowledge, this is the first report on the characterization of primary keratinocytes isolated from vitiligo patients with respect to their wound healing capacity.
Ionizing radiation‐inducible miR‐30e promotes glioma cell invasion through EGFR stabilization by directly targeting CBL‐B
Authors: Kwak Seo‐Young , Kim Bu‐Yeon , Ahn Hyun‐Joo , Yoo Je‐Ok , Kim Joon , Bae In Hwa , Han Young‐Hoon
Published: February 2015

MicroRNAs (miRNAs) are small non‐coding RNA molecules that regulate gene expression at the transcriptional and post‐transcriptional levels. Here we show that miR‐30e, which was previously identified as an ionizing radiation‐inducible miRNA, enhances cellular invasion by promoting secretion of the matrix metalloproteinase MMP‐2. The enhancement of cellular invasion by miR‐30e involved up‐regulation of the epidermal growth factor receptor (EGFR) and subsequent activation of its downstream signaling mediators, AKT and extracellular signal‐regulated kinase. EGFR up‐regulation by miR‐30e occurred due to stabilization of the EGFR protein. The E3 ubiquitin ligase casitas B‐lineage lymphoma B (CBL‐B) was down‐regulated by miR‐30e, and this led to increased EGFR abundance. A 3′ UTR reporter assay confirmed that CBL‐B is a direct target of miR‐30e. Knocking down CBL‐B expression phenocopied the effects of miR‐30e, whereas ectopic expression of CBL‐B suppressed miR‐30e‐induced EGFR up‐regulation and invasion. Collectively, our results suggest that targeting miR‐30e may limit the invasiveness induced during glioma radiotherapy.
Bending fatigue life characterisation of direct metal laser sintering nickel alloy 718
Authors: Scott‐Emuakpor O. , Schwartz J. , George T. , Holycross C. , Cross C. , Slater J.
Published: February 2015

Bending fatigue behaviour of direct metal laser sintering (DMLS), Nickel (Ni) Alloy 718 has been assessed as preliminary qualification to additively manufacture advanced gas turbine engine components. Motivation for this work comes from the possibility of using DMLS to improve functionality of hot‐section components. By using DMLS, turbine blades and heat exchangers cooling passages can be enhanced, leading to improved engine performance. This study focuses on vibratory high cycle fatigue (HCF) assessment of DMLS Ni Alloy 718 from two suppliers. Specimens were fatigued via vibration‐based bending and compared with published rotating bending cold‐rolled Ni Alloy 718. Tensile analysis and microscopy were also conducted to understand fatigue and fracture trends. HCF, tensile properties and microscopy comparisons show that fatigue and strength of DMLS Ni may be sensitive to post‐fusion treatments. Nonetheless, fatigue performance of DMLS Ni compares well with rotating bending fatigue of cold‐rolled Ni.
Fracture toughness and fatigue crack growth in Ti‐6Al‐4V friction stir welds
Authors: Edwards P. , Ramulu M.
Published: February 2015

Friction stir welding of titanium holds the promise for producing joints with microstructures and mechanical properties that are more comparable to wrought material than traditional fusion welding processes. Extensive data exist on the microstructure and static mechanical properties of titanium friction stir welds, but very little are available on the durability (fatigue) and even less on the damage tolerance (fracture toughness and fatigue crack growth). This paper presents the results of an investigation into the damage tolerance of friction stir welds made in 6 mm thick Ti‐6Al‐4V after a post‐weld heat treatment. It was found that the apparent fracture toughness was lower than the wrought base material, 7–25% depending on the crack orientation relative to the weld, but the crack growth performance (ΔK vs. da/dN) of the weld in the absence of weld‐induced residual stresses was identical to the base material.
End‐stage renal disease from hemolytic uremic syndrome in the United States, 1995–2010
Authors: Sexton Donal J. , Reule Scott , Solid Craig A. , Chen Shu‐Cheng , Collins Allan J. , Foley Robert N.
Published: February 2015

Management of hemolytic uremic syndrome (HUS) has evolved rapidly, and optimal treatment strategies are controversial. However, it is unknown whether the burden of end‐stage renal disease (ESRD) from HUS has changed, and outcomes on dialysis in the United States are not well described. We retrospectively examined data for patients initiating maintenance renal replacement therapy (RRT) (n = 1,557,117), 1995–2010, to define standardized incidence ratios (SIRs) and outcomes of ESRD from HUS) (n = 2241). Overall ESRD rates from HUS in 2001–2002 were 0.5 cases/million per year and were higher for patients characterized by age 40–64 years (0.6), ≥65 years (0.7), female sex (0.6), and non‐Hispanic African American race (0.7). Standardized incidence ratios remained unchanged (P ≥ 0.05) between 2001–2002 and 2009–2010 in the overall population. Compared with patients with ESRD from other causes, patients with HUS were more likely to be younger, female, white, and non‐Hispanic. Over 5.4 years of follow‐up, HUS patients differed from matched controls with ESRD from other causes by lower rates of death (8.3 per 100 person‐years in cases vs. 10.4 in controls, P < 0.001), listing for renal transplant (7.6 vs. 8.6 per 100 person‐years, P = 0.04), and undergoing transplant (6.9 vs. 9 per 100 person‐years, P < 0.001). The incidence of ESRD from HUS appears not to have risen substantially in the last decade. However, given that HUS subtypes could not be determined in this study, these findings should be interpreted with caution.
Altered intrahepatic microcirculation of idiopathic portal hypertension in relation to glutamine synthetase expression
Authors: Sato Yasunori , Harada Kenichi , Sasaki Motoko , Nakanuma Yasuni
Published: February 2015

Aim

Alteration in intrahepatic microcirculation of idiopathic portal hypertension (IPH) has been poorly understood. This study aimed to characterize altered intrahepatic microcirculation of IPH focusing on the expression pattern of glutamine synthetase (GS).

Methods

Immunohistochemical staining of GS was performed using liver sections of IPH (n = 28). Serial section analysis was performed to determine microcirculatory disturbances of IPH.

Results

Paraportal shunt vessels were observed in 20 cases of IPH, and they were divided into two types according to the GS staining pattern; hepatocytes surrounding the vessels were negative for GS (type 1) and positive for GS (type 2). All 20 cases had one or more type 1 vessels within a section, and 10 cases were further associated with type 2 vessels. The cases with type 2 vessels showed infrequent symptoms of esophageal varices. Regarding the GS staining as an indicator of hepatic veins, some type 2 vessels were supposed to represent portovenous shunts. Isolated arteries in hepatic parenchyma were present in 21 cases, and they were located around terminal hepatic venules in six cases, corresponding to centrizonal arteries. Broad hepatocellular GS staining in hyperplastic lesions was noted in five cases, whereas nodular regenerative hyperplasia lacked GS expression.

Conclusion

GS immunostaining revealed microcirculatory disturbances of IPH that were associated with abnormalities in both venous and arterial vessels.
Enhanced survival of mice infused with bone marrow‐derived as compared with adipose‐derived mesenchymal stem cells
Authors: Shiratsuki Shogo , Terai Shuji , Murata Yasuhiko , Takami Taro , Yamamoto Naoki , Fujisawa Koichi , Burganova Guzel , Quintanilha Luiz Fernando , Sakaida Isao
Published: February 2015

Aim

Less invasive therapies using mesenchymal stem cells (MSC) are being developed to treat patients with severe liver cirrhosis. MSC constitute a promising cell source for regenerative therapy and are frequently isolated from bone marrow (BMSC) or adipose tissue (ASC). Therefore, this study assessed the characteristics of these two cell types and their safety for cell infusion.

Methods

In vitro, exhaustive genetic analysis was performed using human (h)BMSC and hASC. Subsequently, the expression of mRNA and protein was evaluated. In vivo, mouse (m)BMSC or mASC was infused into serial mice via the peripheral vein, and 24‐h survival rate, prothrombin time and cause of death were analyzed.

Results

On polymerase chain reaction, western blotting, enzyme‐linked immunoassay and fluorescence‐activated cell sorting, tissue factor was found to be expressed at higher levels in hASC than in hBMSC. Prothrombin time in mice infused with mASC (>120 s) was markedly longer than that of untreated mice (6.5 ± 1.7 s) and that of mice infused with BMSC (6.7 ± 0.8 s) (P < 0.001), indicating that pro‐coagulation activity was potently enhanced after ASC infusion. The 24‐h survival rates in the mASC‐ and mBMSC‐infused groups were 46.4% (13/28) and 95.5% (21/22), respectively; in the former, the rate decreased with increasing number of infused mASC. This cell number‐dependent effect was not observed with mBMSC. A histopathological analysis of mice that died immediately following mASC infusion revealed multiple thrombi in the blood vessels of the lungs.

Conclusion

These results indicate that BMSC are a superior and safer cell source for regenerative therapy.
Developing a rehabilitation programme for male urinary incontinence: detailed schemes and results on 122 patients
Authors: Terzoni Stefano , Montanari Emanuele , Mora Cristina , Ricci Cristian , Destrebecq Anne
Published: February 2015

Urinary incontinence (UI) is a common complication of prostatectomy. International guidelines suggest using pelvic floor muscle training (PFMT) as a first‐line intervention (grade A) to help patients reduce the involuntary urine leakages. In the literature it is hard to find a complete exercise scheme, with full details (e.g. body position during PFMT, how to avoid antagonist synergies), information on how to make exercises progressively more difficult, and data showing the efficacy of the whole programme. This study presents a complete PFMT programme, with full details and outcomes. A scheme of five progressive exercises was built, each with precise characteristics and times. Totally 131 patients with stress UI after radical retropubic prostatectomy were enrolled and followed a written scheme of PFMT with the five exercises. Leakages were quantified using the 24‐h pad test. Rehabilitation ended when patients had leakages less than 10 g/d. Nine patients could not achieve results and decided to exit the programme after a median of five sessions (InterQuartile Range, IQR = [4;7]). Out of the 122 patients, 90 patients who followed the full programme achieved the rehabilitation (70.3%); they had median leakages of 150 g, IQR = [90;300]. Those who did not reach the result had higher leakages [540 g/d, IQR = (300;840)] but obtained clinically significant reduction and reached a median of 90 g/d, IQR = [90;157] after comparable rehabilitation times (median of 6 or 7 sessions, corresponding to 8 or 10 weeks, for rehabilitated and non‐rehabilitated patients, respectively). Future studies will investigate the long‐term results of this programme.
On Invariant Post‐randomization for Statistical Disclosure Control
Authors: Nayak Tapan K. , Adeshiyan Samson A.
Published: February 2015

In this paper, we investigate certain operational and inferential aspects of invariant Post‐randomization Method (PRAM) as a tool for disclosure limitation of categorical data. Invariant PRAM preserves unbiasedness of certain estimators, but inflates their variances and distorts other attributes. We introduce the concept of strongly invariant PRAM, which does not affect data utility or the properties of any statistical method. However, the procedure seems feasible in limited situations. We review methods for constructing invariant PRAM matrices and prove that a conditional approach, which can preserve the original data on any subset of variables, yields invariant PRAM. For multinomial sampling, we derive expressions for variance inflation inflicted by invariant PRAM and variances of certain estimators of the cell probabilities and also their tight upper bounds. We discuss estimation of these quantities and thereby assessing statistical efficiency loss from applying invariant PRAM. We find a connection between invariant PRAM and creating partially synthetic data using a non‐parametric approach, and compare estimation variance under the two approaches. Finally, we discuss some aspects of invariant PRAM in a general survey context.
Glucose control and fatigue in type 2 diabetes: the mediating roles of diabetes symptoms and distress
Authors: Park Hanjong , Park Chang , Quinn Laurie , Fritschi Cynthia
Published: February 2015

Aim

The purpose of this study was to examine the mediating influence of diabetes health characteristics (diabetes distress, depression symptoms and diabetes symptoms) on the relationship between glucose control and fatigue in adults with type 2 diabetes.

Background

In patients with type 2 diabetes, fatigue is common and can affect diabetes self‐management behaviours. Although long thought to result from hyperglycaemia, little evidence supports a relationship between fatigue and glucose control.

Design

A cross‐sectional, descriptive study design was used.

Method

Data were combined from two studies conducted at a large urban university in the Midwestern United States, resulting in a total sample of 155 urban‐dwelling adults with type 2 diabetes. Data were collected over the course of 6 days from 2013–March 2014. Fatigue and related biological and psychological phenomena were measured to perform path analyses using structural equation modelling methods. The STATA software was used to analyse the data.

Findings

In patients with A1C less than or equal to 7%, fatigue was related to diabetes distress and diabetes symptoms, but not to A1C directly or indirectly. In the group with A1C greater than 7%, fatigue was indirectly related to A1C; this relationship was mediated through diabetes symptoms, depression and diabetes distress.

Conclusion

Our findings suggest that fatigue is indirectly related to glucose control, but only in patients who have elevated A1C levels. In those with adequate glucose control, fatigue is mainly influenced by the presence of diabetes symptoms and distress. In both groups, the number and severity of diabetes symptoms were the strongest predictors of fatigue, regardless of blood glucose control.
The Mass and Energy Exchange of a Tibetan Glacier: Distributed Modeling and Climate Sensitivity
Authors: Li Binquan , Acharya Kumud , Yu Zhongbo , Liang Zhongmin , Su Fengge
Published: February 2015

Most glaciers in the Tibetan Plateau (TP) are not closely monitored for mass balance (MB) due to their inaccessibility, which makes it difficult to better understand the dynamics of glacial advancement or retreat. Surface energy budget, MB, and the resulting melt runoff were calculated for Zhadang glacier (5,710 m above sea level) of the central TP. Energy balance was calculated on 30‐m square grids for the summers of 2007 and 2008. On average, net radiation dominated the total energy source (66%) while the residual was supplied by sensible heat flux. More than 67% of the energy sink was available for melting on the glacier. Thus, less than 33% of the total energy was consumed by latent heat flux. A large and a slightly negative summer MB were calculated for the 2007 and 2008 summers, respectively. The high sensitivity of the glacier to air temperature may indicate that the lower than average seasonal temperature was more important than the increased precipitation for the slightly negative MB in the summer of 2008. Comparisons of glacial melt runoff indicated that rainfall and snowmelt were the dominant contribution to total runoff in the glacierized basin and the ice melting is also very important. Glacial melt calculation provides a basis for quantifying glacial melt‐runoff contribution to the river streamflow in the TP.
Using species richness and functional traits predictions to constrain assemblage predictions from stacked species distribution models
Authors: D'Amen Manuela , Dubuis Anne , Fernandes Rui F. , Pottier Julien , Pellissier Loïc , Guisan Antoine
Published: February 2015

Aim

Modelling species distributions at the community level is required to make effective forecasts of global change impacts on diversity and ecosystem functioning. Community predictions may be achieved using macroecological properties of communities (macroecological models, MEM), or by stacking of individual species distribution models (stacked species distribution models, S‐SDMs). To obtain more realistic predictions of species assemblages, the SESAM (spatially explicit species assemblage modelling) framework suggests applying successive filters to the initial species source pool, by combining different modelling approaches and rules. Here we provide a first test of this framework in mountain grassland communities.

Location

The western Swiss Alps.

Methods

Two implementations of the SESAM framework were tested: a ‘probability ranking’ rule based on species richness predictions and rough probabilities from SDMs, and a ‘trait range’ rule that uses the predicted upper and lower bound of community‐level distribution of three different functional traits (vegetative height, specific leaf area, and seed mass) to constrain a pool of species from binary SDMs predictions.

Results

We showed that all independent constraints contributed to reduce species richness overprediction. Only the ‘probability ranking’ rule allowed slight but significant improvements in the predictions of community composition.

Main conclusions

We tested various implementations of the SESAM framework by integrating macroecological constraints into S‐SDM predictions, and report one that is able to improve compositional predictions. We discuss possible improvements, such as further understanding the causality and precision of environmental predictors, using other assembly rules and testing other types of ecological or functional constraints.
Spontaneous calcification process in primary renal cells from a medullary sponge kidney patient harbouring a GDNF mutation
Authors: Mezzabotta Federica , Cristofaro Rosalba , Ceol Monica , Del Prete Dorella , Priante Giovanna , Familiari Alessandra , Fabris Antonia , D'Angelo Angela , Gambaro Giovanni , Anglani Franca
Published: February 2015

Medullary nephrocalcinosis is a hallmark of medullary sponge kidney (MSK). We had the opportunity to study a spontaneous calcification process in vitro by utilizing the renal cells of a patient with MSK who was heterozygous for the c.‐27 + 18G>A variant in the GDNF gene encoding glial cell‐derived neurotrophic factor. The cells were obtained by collagenase digestion of papillary tissues from the MSK patient and from two patients who had no MSK or nephrocalcinosis. These cells were typed by immunocytochemistry, and the presence of mineral deposits was studied using von Kossa staining, scanning electron microscopy analysis and an ALP assay. Osteoblastic lineage markers were studied using immunocytochemistry and RT‐PCR. Staminality markers were also analysed using flow cytometry, magnetic cell separation technology, immunocytochemistry and RT‐PCR. Starting from p2, MSK and control cells formed nodules with a behaviour similar to that of calcifying pericytes; however, Ca2PO4 was only found in the MSK cultures. The MSK cells had morphologies and immunophenotypes resembling those of pericytes or stromal stem cells and were positive for vimentin, ZO1, αSMA and CD146. In addition, the MSK cells expressed osteocalcin and osteonectin, indicating an osteoblast‐like phenotype. In contrast to the control cells, GDNF was down‐regulated in the MSK cells. Stable GDNF knockdown was established in the HK2 cell line and was found to promote Ca2PO4 deposition when the cells were incubated with calcifying medium by regulating the osteonectin/osteopontin ratio in favour of osteonectin. Our data indicate that the human papilla may be a perivascular niche in which pericyte/stromal‐like cells can undergo osteogenic differentiation under particular conditions and suggest that GDNF down‐regulation may have influenced the observed phenomenon.
Mitochondria of a human multidrug‐resistant hepatocellular carcinoma cell line constitutively express inducible nitric oxide synthase in the inner membrane
Authors: Fantappiè Ornella , Sassoli Chiara , Tani Alessia , Nosi Daniele , Marchetti Serena , Formigli Lucia , Mazzanti Roberto
Published: February 2015

Mitochondria play a crucial role in pathways of stress conditions. They can be transported from one cell to another, bringing their features to the cell where they are transported. It has been shown in cancer cells overexpressing multidrug resistance (MDR) that mitochondria express proteins involved in drug resistance such as P‐glycoprotein (P‐gp), breast cancer resistant protein and multiple resistance protein‐1. The MDR phenotype is associated with the constitutive expression of COX‐2 and iNOS, whereas celecoxib, a specific inhibitor of COX‐2 activity, reverses drug resistance of MDR cells by releasing cytochrome c from mitochondria. It is possible that COX‐2 and iNOS are also expressed in mitochondria of cancer cells overexpressing the MDR phenotype. This study involved experiments using the human HCC PLC/PRF/5 cell line with and without MDR phenotype and melanoma A375 cells that do not express the MDR1 phenotype but they do iNOS. Western blot analysis, confocal immunofluorescence and immune electron microscopy showed that iNOS is localized in mitochondria of MDR1‐positive cells, whereas COX‐2 is not. Low and moderate concentrations of celecoxib modulate the expression of iNOS and P‐gp in mitochondria of MDR cancer cells independently from inhibition of COX‐2 activity. However, A375 cells that express iNOS also in mitochondria, were not MDR1 positive. In conclusion, iNOS can be localized in mitochondria of HCC cells overexpressing MDR1 phenotype, however this phenomenon appears independent from the MDR1 phenotype occurrence. The presence of iNOS in mitochondria of human HCC cells phenotype probably concurs to a more aggressive behaviour of cancer cells.
Influence of bone marrow‐derived mesenchymal stem cells pre‐implantation differentiation approach on periodontal regeneration in vivo
Authors: Cai Xinjie , Yang Fang , Yan Xiangzhen , Yang Wanxun , Yu Na , Oortgiesen Daniel A. W. , Wang Yining , Jansen John A. , Walboomers X. Frank
Published: February 2015

Aim

The implantation of bone marrow‐derived mesenchymal stem cells (MSCs) has previously been shown successful to achieve periodontal regeneration. However, the preferred pre‐implantation differentiation strategy (e.g. maintenance of stemness, osteogenic or chondrogenic induction) to obtain optimal periodontal regeneration is still unknown. This in vivo study explored which differentiation approach is most suitable for periodontal regeneration.

Materials and Methods

Mesenchymal stem cells were obtained from Fischer rats and seeded onto poly(lactic‐co‐glycolic acid)/poly(ɛ‐caprolactone) electrospun scaffolds, and then pre‐cultured under different in vitro conditions: (i) retention of multilineage differentiation potential; (ii) osteogenic differentiation approach; and (iii) chondrogenic differentiation approach. Subsequently, the cell‐scaffold constructs were implanted into experimental periodontal defects of Fischer rats, with empty scaffolds as controls. After 6 weeks of implantation, histomorphometrical analyses were applied to evaluate the regenerated periodontal tissues.

Results

The chondrogenic differentiation approach showed regeneration of alveolar bone and ligament tissues. The retention of multilineage differentiation potential supported only ligament regeneration, while the osteogenic differentiation approach boosted alveolar bone regeneration.

Conclusion

Chondrogenic differentiation of MSCs before implantation is a useful strategy for regeneration of alveolar bone and periodontal ligament, in the currently used rat model.
Soft‐tissue re‐growth following fibre retention osseous resective surgery or osseous resective surgery: a multilevel analysis
Authors: Cairo Francesco , Carnevale Gianfranco , Buti Jacopo , Nieri Michele , Mervelt Jana , Tonelli Paolo , Pagavino Gabriella , Tonetti Maurizio
Published: February 2015

Background

The aim of this study was to assess soft‐tissue re‐growth following Fibre Retention Osseous Resective Surgery (FibReORS) or Osseous Resective Surgery (ORS) over a 12‐month healing period.

Material and Methods

Thirty patients with chronic periodontitis showing persistent periodontal pockets at posterior natural teeth after cause‐related therapy were enroled. Periodontal pockets were associated with infrabony defect ≤3 mm; 15 patients were randomly assigned to FibReORS (test group) and 15 to ORS (control group). Measurements were performed by a blind and calibrated examiner. Soft‐tissue rebound after flap suture was monitored by changes in gingival recession at 1‐, 3‐, 6‐, and 12‐ month follow‐up. Multilevel analysis considering patient, site, and time levels was performed.

Results

Greater osseous resection during surgery and higher post surgical gingival recession was observed in the ORS group. The mean amount of soft‐tissue rebound following surgery was 2.5 mm for ORS‐treated sites and 2.2 mm for FibReORS‐treated sites. Approximately 90% of the coronal re‐growth was detectable after 6 months for both procedures. The interaction between ORS and time of observation showed a higher soft‐tissue rebound after 12 months (p = 0.0233) for ORS‐treated sites.

Conclusions

Both procedures showed a similar coronal soft‐tissue re‐growth with a significant higher recession reduction for ORS‐treated sites. Significant clinical stability of the gingival margin is obtained 6 months after surgery for both procedures.
Detection of CAPN10 copy number variation in Thai patients with type 2 diabetes by denaturing high performance liquid chromatography and real‐time quantitative polymerase chain reaction
Authors: Plengvidhya Nattachet , Chanprasert Kanjana , Tangjittipokin Watip , Thongnoppakhun Wanna , Yenchitsomanus Pa‐thai
Published: February 2015

Aims/Introduction

A combination of multiple genetic and environmental factors contribute to the pathogenesis of type 2 diabetes. Copy number variations (CNVs) are associated with complex human diseases. However, CNVs can cause genotype deviation from the Hardy–Weinberg equilibrium (HWE). A genetic case–control association study in 216 Thai diabetic patients and 192 non‐diabetic controls found that, after excluding genotyping errors, genotype distribution of calpain 10 (CAPN10) SNP44 (rs2975760) deviated from HWE. Here, we aimed to detect CNV within the CAPN10 SNP44 region.

Materials and Methods

CNV within the CAPN10 SNP44 region was detected using denaturing high‐performance liquid chromatography, and the results confirmed by real‐time quantitative polymerase chain reaction with SYBR Green I.

Results

Both methods successfully identified CNV in the CAPN10 SNP44 region, obtaining concordant results. Correction of genotype calling based on the status of identified CNVs showed that the CAPN10 SNP44 genotype is in good agreement with HWE (P > 0.05). However, no association between CNV genotypes and risk of type 2 diabetes was observed.

Conclusions

Identified CNVs for CAPN10 SNP44 genotypes lead to deviation from HWE. Furthermore, both denaturing high‐performance liquid chromatography and real‐time quantitative polymerase chain reaction are useful for detecting CNVs.
Klebsiella pneumoniae thyroid abscess complicated with esophagitis in a woman with newly diagnosed diabetes mellitus: A case report
Authors: Liu Yanxi , Yu Siyao , Ren Xing , Qiao Yue , Sun Guang
Published: February 2015

The thyroid is resistant to infection because of the anatomical and physiological characteristics of the gland, and even though diabetes can induce a compromised immune system, thyroid infection disease is scarcely encountered in diabetic patients. Thyroid abscess formation in an asymptomatic diabetic patient is an even rarer entity. We present a case of a previously asymptomatic diabetic patient showing clinical symptoms of painful swelling in the anterior neck followed by progressing dysphagia, who was later diagnosed with thyroid abscess as a result of Klebsiella pneumoniae, complicated with esophagitis caused by the same microorganism. To our knowledge, this is the first reported case of asymptomatic diabetes being clinically diagnosed with thyroid abscess as the first sign.
Pain and Suffering Damages in Wrongful Death Cases: An Empirical Study
Authors: Chang Yun‐chien , Eisenberg Theodore , Ho Han‐Wei , Wells Martin T.
Published: February 2015

Most jurisdictions in the United States award pain and suffering damages to spouses of victims in wrongful death cases. In several East Asian countries, spouses, parents, and children of the victim can all demand pain and suffering damages. Despite the prevalence of this type of damages, and the oft‐enormous amount of compensation, there has been no large‐scale empirical study on how judges achieve the difficult task of assessing pain and suffering damages. Using a unique data set containing hundreds of car accident cases rendered by the court of first instance in Taiwan, with single‐equation and structural‐equation models, we find the plaintiffs' ad damnum has a statistically significant influence on the court‐adjudicated pain and suffering damages. That could be evidence for the anchoring effect. Nevertheless, courts are very sensitive to the possibility of pushing defendants into financial hardship. When defendants' out‐of‐pocket payments of pecuniary damages, divided by defendants' income, are positive, this amount has a negative effect on the amount of pain and suffering damages, whereas when they are negative (this could happen because the amount of compulsory insurance payment had to be deducted), the amount in absolute value has a positive effect. Not all next‐of‐kin received the same amount. Spouses of the victim received more than other next‐of‐kin, and adult children received the least among eligible relatives. Parents, however, tended to be awarded a high amount of pain and suffering damages when they were the only familial group suing the defendant.
Addressing the Zeros Problem: Regression Models for Outcomes with a Large Proportion of Zeros, with an Application to Trial Outcomes
Authors: Eisenberg Theodore , Eisenberg Thomas , Wells Martin T. , Zhang Min
Published: February 2015

In law‐related and other social science contexts, researchers need to account for data with an excess number of zeros. In addition, dollar damages in legal cases also often are skewed. This article reviews various strategies for dealing with this data type. Tobit models are often applied to deal with the excess number of zeros, but these are more appropriate in cases of true censoring (e.g., when all negative values are recorded as zeros) and less appropriate when zeros are in fact often observed as the amount awarded. Heckman selection models are another methodology that is applied in this setting, yet they were developed for potential outcomes rather than actual ones. Two‐part models account for actual outcomes and avoid the collinearity problems that often attend selection models. A two‐part hierarchical model is developed here that accounts for both the skewed, zero‐inflated nature of damages data and the fact that punitive damage awards may be correlated within case type, jurisdiction, or time. Inference is conducted using a Markov chain Monte Carlo sampling scheme. Tobit models, selection models, and two‐part models are fit to two punitive damage awards data sets and the results are compared. We illustrate that the nonsignificance of coefficients in a selection model can be a consequence of collinearity, whereas that does not occur with two‐part models.
Applying Fuzzy and Probabilistic Uncertainty Concepts to the Material Flow Analysis of Palladium in Austria
Authors: Laner David , Rechberger Helmut , Astrup Thomas
Published: February 2015

Material flow analysis (MFA) is a widely applied tool to investigate resource and recycling systems of metals and minerals. Owing to data limitations and restricted system understanding, MFA results are inherently uncertain. To demonstrate the systematic implementation of uncertainty analysis in MFA, two mathematical concepts for the quantification of uncertainties were applied to Austrian palladium (Pd) resource flows and evaluated: (1) uncertainty ranges expressed by fuzzy sets and (2) uncertainty ranges defined by normal distributions given as mean values and standard deviations. Whereas normal distributions represent the traditional approach for quantifying uncertainties in MFA, fuzzy sets may offer additional benefits in relation to uncertainty quantification in cases of scarce information. With respect to the Pd case study, the fuzzy representation of uncertain quantities is more consistent with the actual data availability in cases of incomplete databases, and fuzzy sets serve to highlight the effect of uncertainty on resource efficiency indicators derived from the MFA results. For both approaches, data reconciliation procedures offer the potential to reduce uncertainty and evaluate the plausibility of the model results. With respect to Pd resource management, improved formal collection of end‐of‐life (EOL) consumer products is identified as a key factor in increasing the recycling efficiency. In particular, the partial export of EOL vehicles represents a substantial loss of Pd from the Austrian resource system, whereas approximately 70% of the Pd in the EOL consumer products is recovered in waste management. In conclusion, systematic uncertainty analysis is an integral part of MFA required to provide robust decision support in resource management.
Clinician adherence to childhood overweight and obesity recommendations by race/ethnicity of the child
Authors: Gance‐Cleveland Bonnie , Aldrich Heather , Schmiege Sarah , Coursen Cristi , Dandreaux Danielle , Gilbert Lynn
Published: February 2015

Purpose

This study describes school‐based health center (SBHC) providers’ adherence to obesity guidelines.

Design and Methods

Providers (n = 28) were from SBHCs in six states serving children 5–12 years of age. A random sample of well‐child charts (n = 850) were audited for body mass index percentage, blood pressure percentage, overweight/obesity diagnosis, and laboratory assessment.

Results

Body mass index percentage was documented on 73% of charts and blood pressure percentage on 30.5%. Providers accurately diagnosed 40% overweight and 49.3% obese children. Laboratory guidelines were followed in 80.4% of cases. Assessments differed by child's race/ethnicity (p < .05), with most criteria having higher adherence in minority youth.

Practice Implications

There is a need for increased accuracy in how SBHC providers screen overweight/obese children.
Nebulised liposomal amphotericin B for Aspergillus lung diseases: case series and literature review
Authors: Godet Cendrine , Goudet Véronique , Laurent François , Moal Gwenaël Le , Gounant Valérie , Frat Jean‐Pierre , cateau Estelle , Roblot France , Cadranel Jacques
Published: February 2015

Over the past 10 years the incidence of Aspergillus spp. has significantly increased, and it is now the most widespread air transmission fungal pathogen in developed countries. Whatever the clinical expression of the pulmonary disease and despite recent progress in antifungal drug therapy, morbidity and mortality related to aspergillosis lung disease still constitute a serious threat for immunosuppressed or mildly immunocompromised patients. Moreover, the treatments currently used have many limitations due to adverse effects and drug interactions. Finally, subjects exposed to azoles present an increased risk of Aspergillus‐resistant strain emergence. We have reported five cases with aspergillosis lung diseases that were either difficult to control or in which patients had a contra‐indication to triazole therapy, but which showed durable improvement following the administration of nebulised liposomal amphotericin B. Our alternative strategy could be of interest for patients with aspergillosis lung disease who otherwise cannot be conventionally treated by triazoles.
Resting Heart Rate and Incident Atrial Fibrillation in the Elderly
Authors: O'NEAL WESLEY T. , ALMAHMOUD MOHAMED F. , SOLIMAN ELSAYED Z.
Published: February 2015

Background

Alterations in autonomic tone and/or sinus node dysfunction are common with aging. We hypothesized that older persons with low or high heart rates represent a population with subclinical abnormalities who are more likely to develop atrial fibrillation (AF).

Methods

A total of 5,226 participants aged 65 years or more (85% white; 42% male) with complete data from the Cardiovascular Health Study were used in this analysis. AF cases were identified during the yearly study electrocardiograms, participant history of a physician diagnosis, or by hospitalization data. Cox regression was used to compute hazard ratios (HR) and 95% confidence intervals (CI) for the association between resting heart rate and incident AF using clinically relevant categories (heart rate ≤60 beats/min, 60< heart rate beats/min ≤90 beats/min (reference), heart rate >90 beats/min) and as a continuous variable per 5 beats/min decrease.

Results

Over a median follow‐up of 12.7 years, a total of 532 (10.2%) participants developed AF. In a multivariable Cox regression analysis, heart rates ≤60 beats/min (HR = 1.3, 95% CI = 1.1, 1.5), but not >90 beats/min (HR = 1.1, 95% CI = 0.52, 2.3), were associated with an increased risk of AF. Additionally, heart rate per 5 beats/min decrease was associated with an increased risk of AF (HR = 1.06, 95% CI = 1.01, 1.1). The results were consistent in subgroup analyses stratified by age, sex, race, and baseline cardiovascular disease.

Conclusion

In the elderly, low heart rates are associated with an increased risk of AF. Potentially, underlying alterations in autonomic tone and/or subclinical sinus node dysfunction manifested as slow heart rate predispose to AF.