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1.  Characterization of ocular gland morphology and tear composition of pinnipeds 
Veterinary ophthalmology  2012;16(4):269-275.
The importance of tear film integrity to ocular health in terrestrial mammals is well established, however, in marine mammals, the role of the tear film in protection of the ocular surface is not known. In an effort to better understand the function of tears in maintaining health of the marine mammal eye surface, we examined ocular glands of the California sea lion, and began to characterize the biochemical nature of the tear film of pinnipeds.
Glands dissected from California sea lion eyelids and adnexa were examined for gross morphology, sectioned for microscopic analysis, and stained with haematoxylin and eosin. The tear film was examined using interferometry. Tears were collected from humans and pinnipeds for analysis of protein and carbohydrate content.
The sea lion has sebaceous glands in the lid, but these glands are different in size and orientation compared to typical meibomian glands of terrestrial mammals. Two other accessory ocular glands located dorsotemporally and medially appeared to be identical in morphology, with tubulo-acinar morphology. An outer lipid layer on the ocular surface of the sea lion was not detected using interferometry, consistent with the absence of typical meibomian glands. Similar to human tears, the tears of pinnipeds contain several proteins but the ratio of carbohydrate to protein was greater than that in human tears.
Our findings indicate that the ocular gland architecture and biochemical nature of the tear film of pinnipeds have evolved to adapt to the challenges of an aquatic environment.
PMCID: PMC3594129  PMID: 23067374
ocular surface; tear film; pinnipeds; meibomian glands
2.  Transcription, Translation, and Function of Lubricin, a Boundary Lubricant, at the Ocular Surface 
JAMA ophthalmology  2013;131(6):10.1001/jamaophthalmol.2013.2385.
Lubricin may be an important barrier to the development of corneal and conjunctival epitheliopathies that may occur in dry eye disease and contact lens wear.
To test the hypotheses that lubricin (ie, proteoglycan 4 [PRG4]), a boundary lubricant, is produced by ocular surface epithelia and acts to protect the cornea and conjunctiva against significant shear forces generated during an eyelid blink and that lubricin deficiency increases shear stress on the ocular surface and promotes corneal damage.
Design, Setting, and Participants
Human, porcine, and mouse tissues and cells were processed for molecular biological, immunohistochemical, and tribological studies, and wild-type and PRG4 knockout mice were evaluated for corneal damage.
Our findings demonstrate that lubricin is transcribed and translated by corneal and conjunctival epithelial cells. Lubricin messenger RNA is also present in lacrimal and meibomian glands, as well as in a number of other tissues. Absence of lubricin in PRG4 knockout mice is associated with a significant increase in corneal fluorescein staining. Our studies also show that lubricin functions as an effective friction-lowering boundary lubricant at the human cornea-eyelid interface. This effect is specific and cannot be duplicated by the use of hyaluronate or bovine serum albumin solutions.
Conclusions and Relevance
Our results show that lubricin is transcribed, translated, and expressed by ocular surface epithelia. Moreover, our findings demonstrate that lubricin presence significantly reduces friction between the cornea and conjunctiva and that lubricin deficiency may play a role in promoting corneal damage.
PMCID: PMC3887468  PMID: 23599181
4.  Targeted sequencing using a 47 gene multiple myeloma mutation panel (M3P) in -17p high risk disease 
British journal of haematology  2014;168(4):507-510.
We constructed a multiple myeloma (MM)-specific gene panel for targeted sequencing and investigated 72 untreated high-risk (del17p) MM patients. Mutations were identified in 78% of the patients. While the majority of studied genes were mutated at similar frequency to published literature, the prevalence of TP53 mutation was increased (28%) and no mutations were found in FAM46C. This study provides a comprehensive insight into the mutational landscape of del17p high-risk MM. Additionally, our work demonstrates the practical use of a customized sequencing panel, as an easy, cheap and fast approach to characterize the mutational profile of MM.
PMCID: PMC4314325  PMID: 25302557
myeloma; cancer genetics; DNA mutation; DRUG resistance; genetic analysis
5.  Predictive Value of Assessing Diastolic Strain Rate on Survival in Cardiac Amyloidosis Patients with Preserved Ejection Fraction 
PLoS ONE  2014;9(12):e115910.
Since diastolic abnormalities are typical findings of cardiac amyloidosis (CA), we hypothesized that speckle-tracking-imaging (STI) derived longitudinal early diastolic strain rate (LSRdias) could predict outcome in CA patients with preserved left ventricular ejection fraction (LVEF >50%).
Diastolic abnormalities including altered early filling are typical findings and are related to outcome in CA patients. Reduced longitudinal systolic strain (LSsys) assessed by STI predicts increased mortality in CA patients. It remains unknown if LSRdias also related to outcome in these patients.
Conventional echocardiography and STI were performed in 41 CA patients with preserved LVEF (25 male; mean age 65±9 years). Global and segmental LSsys and LSRdias were obtained in six LV segments from apical 4-chamber views.
Nineteen (46%) out of 41 CA patients died during a median of 16 months (quartiles 5–35 months) follow-up. Baseline mitral annular plane systolic excursion (MAPSE, 6±2 vs. 8±3 mm), global LSRdias and basal-septal LSRdias were significantly lower in non-survivors than in survivors (all p<0.05). NYHA class, number of non-cardiac organs involved, MAPSE, mid-septal LSsys, global LSRdias, basal-septal LSRdias and E/LSRdias were the univariable predictors of all-cause death. Multivariable analysis showed that number of non-cardiac organs involved (hazard ratio [HR]  = 1.96, 95% confidence interval [CI] 1.17–3.26, P = 0.010), global LSRdias (HR = 7.30, 95% CI 2.08–25.65, P = 0.002), and E/LSRdias (HR = 2.98, 95% CI 1.54–5.79, P = 0.001) remained independently predictive of increased mortality risk. The prognostic performance of global LSRdias was optimal at a cutoff value of 0.85 S−1 (sensitivity 68%, specificity 67%). Global LSRdias <0.85 S−1 predicted a 4-fold increased mortality in CA patients with preserved LVEF.
STI-derived early diastolic strain rate is a powerful independent predictor of survival in CA patients with preserved LVEF.
PMCID: PMC4277448  PMID: 25542015
6.  Effects of lixisenatide on elevated liver transaminases: systematic review with individual patient data meta-analysis of randomised controlled trials on patients with type 2 diabetes 
BMJ Open  2014;4(12):e005325.
To evaluate the effects of the glucagon-like peptide-1 receptor agonist lixisenatide on elevated liver blood tests in patients with type 2 diabetes.
Systematic review.
Data sources
Electronic and manual searches were combined.
Study selection
Randomised controlled trials (RCTs) on lixisenatide versus placebo or active comparators for type 2 diabetes were included.
Individual patient data were retrieved to calculate outcomes for patients with elevated liver blood tests.
Main outcome measures
Normalisation of alanine aminotransferase (ALT) and aspartate aminotransferase (AST).
Data synthesis
The results of included trials were combined in meta-analyses. Sequential, subgroup and regression analyses were performed to evaluate heterogeneity and bias.
We included 12 RCTs on lixisenatide versus placebo and 3 RCTs with the active comparators liraglutide, exenatide or sitagliptin. The mean treatment duration was 29 weeks. Lixisenatide increased the proportion of patients with normalisation of ALT (risk difference: 0.07; 95% CI 0.01 to 0.14; number needed to treat: 14 patients, p=0.042). The effect was not confirmed in sequential analysis. No effects of lixisenatide were identified on AST, alkaline phosphatase or bilirubin. No evidence of bias was identified. Mixed effect multilevel meta-regression analyses suggest that the benefit of lixisenatide on ALT was limited to patients who were overweight or obese.
This review suggests that lixisenatide increases the proportion of obese or overweight patients with type 2 diabetes who achieve normalisation of ALT. Additional research is needed to determine if the findings translate to clinical outcome measures.
Trial registration number
PROSPERO; CRD42013005779.
PMCID: PMC4275683  PMID: 25526792
7.  PCR Duplication: A One-Step Cloning-Free Method to Generate Duplicated Chromosomal Loci and Interference-Free Expression Reporters in Yeast 
PLoS ONE  2014;9(12):e114590.
Here, we report on a novel PCR targeting-based strategy called ‘PCR duplication’ that enables targeted duplications of genomic regions in the yeast genome using a simple PCR-based approach. To demonstrate its application we first duplicated the promoter of the FAR1 gene in yeast and simultaneously inserted a GFP downstream of it. This created a reporter for promoter activity while leaving the FAR1 gene fully intact. In another experiment, we used PCR duplication to increase the dosage of a gene in a discrete manner, from 1× to 2x. Using TUB4, the gene encoding for the yeast γ-tubulin, we validated that this led to corresponding increases in the levels of mRNA and protein. PCR duplication is an easy one-step procedure that can be adapted in different ways to permit rapid, disturbance-free investigation of various genomic regulatory elements without the need for ex vivo cloning.
PMCID: PMC4262419  PMID: 25493941
8.  The PREDICTS database: a global database of how local terrestrial biodiversity responds to human impacts 
Hudson, Lawrence N | Newbold, Tim | Contu, Sara | Hill, Samantha L L | Lysenko, Igor | De Palma, Adriana | Phillips, Helen R P | Senior, Rebecca A | Bennett, Dominic J | Booth, Hollie | Choimes, Argyrios | Correia, David L P | Day, Julie | Echeverría-Londoño, Susy | Garon, Morgan | Harrison, Michelle L K | Ingram, Daniel J | Jung, Martin | Kemp, Victoria | Kirkpatrick, Lucinda | Martin, Callum D | Pan, Yuan | White, Hannah J | Aben, Job | Abrahamczyk, Stefan | Adum, Gilbert B | Aguilar-Barquero, Virginia | Aizen, Marcelo A | Ancrenaz, Marc | Arbeláez-Cortés, Enrique | Armbrecht, Inge | Azhar, Badrul | Azpiroz, Adrián B | Baeten, Lander | Báldi, András | Banks, John E | Barlow, Jos | Batáry, Péter | Bates, Adam J | Bayne, Erin M | Beja, Pedro | Berg, Åke | Berry, Nicholas J | Bicknell, Jake E | Bihn, Jochen H | Böhning-Gaese, Katrin | Boekhout, Teun | Boutin, Céline | Bouyer, Jérémy | Brearley, Francis Q | Brito, Isabel | Brunet, Jörg | Buczkowski, Grzegorz | Buscardo, Erika | Cabra-García, Jimmy | Calviño-Cancela, María | Cameron, Sydney A | Cancello, Eliana M | Carrijo, Tiago F | Carvalho, Anelena L | Castro, Helena | Castro-Luna, Alejandro A | Cerda, Rolando | Cerezo, Alexis | Chauvat, Matthieu | Clarke, Frank M | Cleary, Daniel F R | Connop, Stuart P | D'Aniello, Biagio | da Silva, Pedro Giovâni | Darvill, Ben | Dauber, Jens | Dejean, Alain | Diekötter, Tim | Dominguez-Haydar, Yamileth | Dormann, Carsten F | Dumont, Bertrand | Dures, Simon G | Dynesius, Mats | Edenius, Lars | Elek, Zoltán | Entling, Martin H | Farwig, Nina | Fayle, Tom M | Felicioli, Antonio | Felton, Annika M | Ficetola, Gentile F | Filgueiras, Bruno K C | Fonte, Steven J | Fraser, Lauchlan H | Fukuda, Daisuke | Furlani, Dario | Ganzhorn, Jörg U | Garden, Jenni G | Gheler-Costa, Carla | Giordani, Paolo | Giordano, Simonetta | Gottschalk, Marco S | Goulson, Dave | Gove, Aaron D | Grogan, James | Hanley, Mick E | Hanson, Thor | Hashim, Nor R | Hawes, Joseph E | Hébert, Christian | Helden, Alvin J | Henden, John-André | Hernández, Lionel | Herzog, Felix | Higuera-Diaz, Diego | Hilje, Branko | Horgan, Finbarr G | Horváth, Roland | Hylander, Kristoffer | Isaacs-Cubides, Paola | Ishitani, Masahiro | Jacobs, Carmen T | Jaramillo, Víctor J | Jauker, Birgit | Jonsell, Mats | Jung, Thomas S | Kapoor, Vena | Kati, Vassiliki | Katovai, Eric | Kessler, Michael | Knop, Eva | Kolb, Annette | Kőrösi, Ádám | Lachat, Thibault | Lantschner, Victoria | Le Féon, Violette | LeBuhn, Gretchen | Légaré, Jean-Philippe | Letcher, Susan G | Littlewood, Nick A | López-Quintero, Carlos A | Louhaichi, Mounir | Lövei, Gabor L | Lucas-Borja, Manuel Esteban | Luja, Victor H | Maeto, Kaoru | Magura, Tibor | Mallari, Neil Aldrin | Marin-Spiotta, Erika | Marshall, E J P | Martínez, Eliana | Mayfield, Margaret M | Mikusinski, Grzegorz | Milder, Jeffrey C | Miller, James R | Morales, Carolina L | Muchane, Mary N | Muchane, Muchai | Naidoo, Robin | Nakamura, Akihiro | Naoe, Shoji | Nates-Parra, Guiomar | Navarrete Gutierrez, Dario A | Neuschulz, Eike L | Noreika, Norbertas | Norfolk, Olivia | Noriega, Jorge Ari | Nöske, Nicole M | O'Dea, Niall | Oduro, William | Ofori-Boateng, Caleb | Oke, Chris O | Osgathorpe, Lynne M | Paritsis, Juan | Parra-H, Alejandro | Pelegrin, Nicolás | Peres, Carlos A | Persson, Anna S | Petanidou, Theodora | Phalan, Ben | Philips, T Keith | Poveda, Katja | Power, Eileen F | Presley, Steven J | Proença, Vânia | Quaranta, Marino | Quintero, Carolina | Redpath-Downing, Nicola A | Reid, J Leighton | Reis, Yana T | Ribeiro, Danilo B | Richardson, Barbara A | Richardson, Michael J | Robles, Carolina A | Römbke, Jörg | Romero-Duque, Luz Piedad | Rosselli, Loreta | Rossiter, Stephen J | Roulston, T'ai H | Rousseau, Laurent | Sadler, Jonathan P | Sáfián, Szabolcs | Saldaña-Vázquez, Romeo A | Samnegård, Ulrika | Schüepp, Christof | Schweiger, Oliver | Sedlock, Jodi L | Shahabuddin, Ghazala | Sheil, Douglas | Silva, Fernando A B | Slade, Eleanor M | Smith-Pardo, Allan H | Sodhi, Navjot S | Somarriba, Eduardo J | Sosa, Ramón A | Stout, Jane C | Struebig, Matthew J | Sung, Yik-Hei | Threlfall, Caragh G | Tonietto, Rebecca | Tóthmérész, Béla | Tscharntke, Teja | Turner, Edgar C | Tylianakis, Jason M | Vanbergen, Adam J | Vassilev, Kiril | Verboven, Hans A F | Vergara, Carlos H | Vergara, Pablo M | Verhulst, Jort | Walker, Tony R | Wang, Yanping | Watling, James I | Wells, Konstans | Williams, Christopher D | Willig, Michael R | Woinarski, John C Z | Wolf, Jan H D | Woodcock, Ben A | Yu, Douglas W | Zaitsev, Andrey S | Collen, Ben | Ewers, Rob M | Mace, Georgina M | Purves, Drew W | Scharlemann, Jörn P W | Purvis, Andy
Ecology and Evolution  2014;4(24):4701-4735.
Biodiversity continues to decline in the face of increasing anthropogenic pressures such as habitat destruction, exploitation, pollution and introduction of alien species. Existing global databases of species’ threat status or population time series are dominated by charismatic species. The collation of datasets with broad taxonomic and biogeographic extents, and that support computation of a range of biodiversity indicators, is necessary to enable better understanding of historical declines and to project – and avert – future declines. We describe and assess a new database of more than 1.6 million samples from 78 countries representing over 28,000 species, collated from existing spatial comparisons of local-scale biodiversity exposed to different intensities and types of anthropogenic pressures, from terrestrial sites around the world. The database contains measurements taken in 208 (of 814) ecoregions, 13 (of 14) biomes, 25 (of 35) biodiversity hotspots and 16 (of 17) megadiverse countries. The database contains more than 1% of the total number of all species described, and more than 1% of the described species within many taxonomic groups – including flowering plants, gymnosperms, birds, mammals, reptiles, amphibians, beetles, lepidopterans and hymenopterans. The dataset, which is still being added to, is therefore already considerably larger and more representative than those used by previous quantitative models of biodiversity trends and responses. The database is being assembled as part of the PREDICTS project (Projecting Responses of Ecological Diversity In Changing Terrestrial Systems – We make site-level summary data available alongside this article. The full database will be publicly available in 2015.
PMCID: PMC4278822  PMID: 25558364
Data sharing; global change; habitat destruction; land use
9.  Quantification of cytosolic interactions identifies Ede1 oligomers as key organizers of endocytosis 
Molecular Systems Biology  2014;10(11):756.
Clathrin-mediated endocytosis is a highly conserved intracellular trafficking pathway that depends on dynamic protein–protein interactions between up to 60 different proteins. However, little is known about the spatio-temporal regulation of these interactions. Using fluorescence (cross)-correlation spectroscopy in yeast, we tested 41 previously reported interactions in vivo and found 16 to exist in the cytoplasm. These detected cytoplasmic interactions included the self-interaction of Ede1, homolog of mammalian Eps15. Ede1 is the crucial scaffold for the organization of the early stages of endocytosis. We show that oligomerization of Ede1 through its central coiled coil domain is necessary for its localization to the endocytic site and we link the oligomerization of Ede1 to its function in locally concentrating endocytic adaptors and organizing the endocytic machinery. Our study sheds light on the importance of the regulation of protein–protein interactions in the cytoplasm for the assembly of the endocytic machinery in vivo.
PMCID: PMC4299599  PMID: 25366307
Ede1; endocytosis; fluorescence (cross-)correlation spectroscopy
10.  On the role of gallbladder emptying and incretin hormones for nutrient-mediated TSH suppression in patients with type 2 diabetes 
Endocrine Connections  2014;3(4):193-199.
Bile acids are possible candidate agents in newly identified pathways through which energy expenditure may be regulated. Preclinical studies suggest that bile acids activate the enzyme type 2 iodothyronine deiodinase, which deiodinates thyroxine (T4) to the biologically active triiodothyronine (T3). We aimed to evaluate the influence of bile acid exposure and incretin hormones on thyroid function parameters in patients with type 2 diabetes. Thyroid-stimulating hormone (TSH) and thyroid hormones (total T3 and free T4) were measured in plasma from two human studies: i) 75 g-oral glucose tolerance test (OGTT) and three isocaloric (500 kcal) and isovolaemic (350 ml) liquid meals with increasing fat content with concomitant ultrasonographic evaluation of gallbladder emptying in 15 patients with type 2 diabetes and 15 healthy age, gender and BMI-matched controls (meal-study) and ii) 50 g-OGTT and isoglycaemic intravenous glucose infusions (IIGI) alone or in combination with glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide 1 (GLP1) and/or GLP2, in ten patients with type 2 diabetes (IIGI-study). In both studies, TSH levels declined (P<0.01) similarly following all meal and infusion stimuli. T3 and T4 concentrations did not change in response to any of the applied stimuli. TSH levels declined independently of the degree of gallbladder emptying (meal-study), route of nutrient administration and infusion of gut hormones. In conclusion, intestinal bile flow and i.v. infusions of the gut hormones, GIP, GLP1 and/or GLP2, do not seem to affect thyroid function parameters. Thus, the presence of a ‘gut–thyroid–pituitary’ axis seems questionable.
PMCID: PMC4201783  PMID: 25277744
bile acids; gallbladder; glucagon-like peptide 1; GLP1; thyroid; thyroid-stimulating hormone; TSH; TGR5; type 2 diabetes
11.  Secretion of Glucose-Dependent Insulinotropic Polypeptide in Patients With Type 2 Diabetes 
Diabetes Care  2013;36(10):3346-3352.
To investigate glucose-dependent insulinotropic polypeptide (GIP) secretion in patients with type 2 diabetes and nondiabetic control subjects during oral glucose or meal tests.
Eligible trials were identified by The Cochrane Library, MEDLINE, Embase, and Web of Science. Data were retrieved and random-effects models for the primary meta-analysis, random-effects meta-regression, and subgroup and regression analyses were applied.
Random-effects meta-analysis of GIP responses in 23 trials during 28 different stimulation tests showed that patients with type 2 diabetes (n = 363) exhibited no significant differences (P = not significant) in peak plasma GIP, total area under the curve (tAUC), time-corrected tAUC (tAUC × min−1), and time-corrected incremental area under the curve (iAUC × min−1) in comparison with nondiabetic control subjects (n = 325) but had lower GIP responses as evaluated from iAUC (weighted mean difference, −648 pmol/L × min; 95% CI, −1,276 to −21). Fixed-effects models meta-analyses confirmed most of the results of the primary meta-analysis but showed iAUC × min−1 to be reduced and showed tAUC and tAUC × min−1 to be higher in diabetic patients. Random-effects meta-regression of the primary meta-analysis showed that age (peak GIP, tAUC, iAUC, and iAUC × min−1), BMI (tAUC, iAUC, and iAUC × min−1), and HbA1c (iAUC and iAUC × min−1) predicted some of the GIP outcomes. Post hoc subgroup analysis showed a negative influence of age and of HbA1c on GIP responses and showed a positive influence of BMI on GIP responses.
Our results suggest that patients with type 2 diabetes are characterized by preserved GIP secretion in response to oral glucose and meal tests. They also suggest that high BMI is associated with increased GIP responses but increasing age and HbA1c are associated with reduced GIP secretion.
PMCID: PMC3781498  PMID: 24065842
12.  18FDG-PET/CT for prognostic stratification of patients with multiple myeloma relapse after stem cell transplantation 
Oncotarget  2014;5(17):7381-7391.
The aim of this study was to investigate the prognostic value of 18F-fluorodeoxyglucose positron emission tomography–computed tomography (18F-FDG-PET/CT) in 37 patients with a history of multiple myeloma (MM) and suspected or confirmed recurrence after stem cell transplantation (SCT). All patients had been heavily pretreated. Time to progression (TTP) and overall survival (OS) were correlated to a number of different PET-derived as well as clinical parameters. Impact on patient management was assessed.
Absence of FDG-avid MM foci was a positive prognostic factor for both TTP and OS (p<0.01). Presence of >10 focal lesions correlated with both TTP (p<0.01) and OS (p<0.05). Interestingly, presence of >10 lesions in the appendicular skeleton proved to have the strongest association with disease progression. Intensity of glucose uptake and presence of extramedullary disease were associated with shorter TTP (p=0.037 and p=0.049, respectively). Manifestations in soft tissue structures turned out to be a strong negative predictor for both, TTP and OS (p<0.01, respectively). PET resulted in a change of management in 30% of patients.
Our data underline the prognostic value of 18F-FDG-PET/CT in MM patients also in the setting of post-SCT relapse. PET/CT has a significant impact on patient management.
PMCID: PMC4202130  PMID: 25277179
Multiple myeloma; molecular imaging; FDG-PET/CT
13.  The effects of sodium-glucose co-transporter 2 inhibitors in patients with type 2 diabetes: protocol for a systematic review with meta-analysis of randomised trials 
BMJ Open  2014;4(8):e005378.
Sodium-glucose co-transporter 2 inhibitors (SGLT-2i) increase urinary glucose excretion through a reduced renal glucose reabsorption. We plan to perform a systematic review of SGLT-2i for treatment of type 2 diabetes.
Methods and analysis
A systematic review with meta-analyses of randomised clinical trials on SGLT-2i versus placebo, other oral glucose lowering drugs or insulin for patients with type 2 diabetes will be performed. The primary end point will be the glycated haemoglobin. Secondary end points will include changes in body weight, body mass index, fasting plasma glucose, plasma cholesterol, kidney and liver blood tests, blood pressure and adverse events. Electronic (the Cochrane Library, MEDLINE, EMBASE and the Science Citation Index) and manual searches will be performed. Meta-analyses will be performed and the results presented as mean differences for continuous outcomes and risk differences for dichotomous outcomes, both with 95% CIs. Subgroup, sensitivity, regression and sequential analyses will be performed to evaluate intertrial heterogeneity, bias and the robustness of results due to cumulative testing.
Ethics and dissemination
The study will contribute to the knowledge regarding the beneficial and harmful effects of SGLT-2i in patients with type 2 diabetes. We plan to publish the study irrespective of the results.
The study will be disseminated by peer-review publication and conference presentation.
Trial registration number
PROSPERO CRD42014008960
PMCID: PMC4139650  PMID: 25232561
Type 2 diabetes; meta-analysis; sodium-glucose co-transporter 2 inhibitor; ORAL MEDICINE
14.  Mechanism of Metabolic Advantages After Bariatric Surgery 
Diabetes Care  2013;36(Suppl 2):S287-S291.
PMCID: PMC3920787  PMID: 23882061
15.  Unprecedented high insulin secretion in a healthy human subject after intravenous glucagon-like peptide-1: a case report 
BMC Research Notes  2014;7:326.
The gut-derived incretin hormones, glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1, are released in response to ingestion of nutrients. Both hormones are highly insulinotropic in strictly glucose-dependent fashions and glucagon-like peptide-1 is often referred to as one of the most insulinotropic substances known.
Case presentation
Plasma insulin and C-peptide concentrations were measured in a healthy Caucasian male (age: 53 years; body mass index: 28.6 kg/m2; fasting plasma glucose: 5.7 mM; 2 h plasma glucose value following 75 g-oral glucose tolerance test: 3.5 mM; glycated haemoglobin A1c: 5.5%) during glucagon (1 mg) and meal (2,370 kJ) tests, and during two 2 h 15 mM-hyperglycaemic clamps with continuous intravenous infusion of glucagon-like peptide-1 (1 pmol/kg/min) and glucose-dependent insulinotropic polypeptide (4 pmol/kg/min), respectively. Normal insulin and C-peptide responses were observed during meal test (peak concentrations: 300 and 3,278 pM) and glucagon test (peak concentrations: 250 and 2,483 pM). During the hyperglycaemic clamp with continuous intravenous infusion of GLP-1 the subject exhibited plasma insulin and C-peptide concentrations of 13,770 and 22,380 pM, respectively.
To our knowledge insulin and C-peptide concentrations of these magnitudes have never been reported. Thus, the present data support the view that glucagon-like peptide-1 is one of the most insulinotropic substances known.
PMCID: PMC4053292  PMID: 24885055
Incretin hormones; Glucagon-like peptide-1 (GLP-1); Glucose-dependent insulinotropic polypeptide (GIP); Insulin
16.  Forty-Five-Year Mortality Rate as a Function of the Number and Type of Psychiatric Diagnoses Found in a Large Danish Birth Cohort 
Psychiatric comorbidities are common among psychiatric patients and typically associated with poorer clinical prognoses. Subjects of a large Danish birth cohort were used to study the relation between mortality and co-occurring psychiatric diagnoses.
We searched the Danish Central Psychiatric Research Registry for 8109 birth cohort members aged 45 years. Lifetime psychiatric diagnoses (International Classification of Diseases, Revision 10, group F codes, Mental and Behavioural Disorders, and one Z code) for identified subjects were organized into 14 mutually exclusive diagnostic categories. Mortality rates were examined as a function of number and type of co-occurring diagnoses.
Psychiatric outcomes for 1247 subjects were associated with 157 deaths. Early mortality risk in psychiatric patients correlated with the number of diagnostic categories (Wald χ2 = 25.0, df = 1, P < 0.001). This global relation was true for anxiety and personality disorders, but not for schizophrenia and substance abuse, which had intrinsically high mortality rates with no comorbidities.
Risk of early mortality among psychiatric patients appears to be a function of both the number and the type of psychiatric diagnoses.
PMCID: PMC4011187  PMID: 22854033
mortality; mental illness; psychiatric illness; comorbidity
17.  When yeast cells meet, karyogamy! 
Nucleus  2013;4(3):182-188.
Cytoskeleton-mediated transport processes are central to the subcellular organization of cells. The nucleus constitutes the largest organelle of a cell, and studying how it is positioned and moved around during various types of cell morphogenetic processes has puzzled researchers for a long time. Now, the molecular architectures of the underlying dynamic processes start to reveal their secrets.
In yeast, karyogamy denotes the migration of two nuclei toward each other—termed nuclear congression—upon partner cell mating and the subsequent fusion of these nuclei to form a diploid nucleus. It constitutes a well-studied case. Recent insights completed the picture about the molecular processes involved and provided us with a comprehensive model amenable to quantitative computational simulation of the process. This review discusses our understanding of yeast nuclear congression and karyogamy and seeks to explain how a detailed, quantitative and systemic understanding has emerged from this knowledge.
PMCID: PMC3720748  PMID: 23715006
yeast mating; spindle pole body; karyogamy; nuclear migration; microtubule dynamics; kinesin-14; Kar3; yeast cell morphogenesis; microtubule motor protein; nuclear fusion
18.  Tracking protein turnover and degradation by microscopy: photo-switchable versus time-encoded fluorescent proteins 
Open Biology  2014;4(4):140002.
Expanded fluorescent protein techniques employing photo-switchable and fluorescent timer proteins have become important tools in biological research. These tools allow researchers to address a major challenge in cell and developmental biology, namely obtaining kinetic information about the processes that determine the distribution and abundance of proteins in cells and tissues. This knowledge is often essential for the comprehensive understanding of a biological process, and/or required to determine the precise point of interference following an experimental perturbation.
PMCID: PMC4043113  PMID: 24740984
protein dynamics; fluorescent timer proteins; live cell microscopy; photo-switchable fluorescent proteins
19.  Nicotine effect on bone remodeling during orthodontic tooth movement: Histological study in rats 
Nicotine is harmful to angiogenesis, osteogenesis and synthesis of collagen.
The aim of this study was to investigate the effect of nicotine on bone remodeling during orthodontic movement in rats.
Eighty male Wistar rats were randomly divided into three groups: Group C (control), group CM (with orthodontic movement) and group NM (nicotine with orthodontic movement) groups. The animals comprising groups C and CM received 0.9% saline solution while group NM received nicotine solution (2 mg/kg). A nickel-titanium closed-coil spring was used to induce tooth movement. The animals were euthanized and tissue specimens were processed histologically. We quantified blood vessels, Howship's lacunae and osteoclast-like cells present in the tension and compression areas of periodontal ligaments. The extent of bone formation was evaluated under polarized light to determine the percentage of immature/mature collagen.
We observed lower blood vessel densities in the NM group in comparison to the CM group, three (p < 0.001) and seven (p < 0.05) days after force application. Osteoclast-like cells and Howship's lacunae in the NM group presented lower levels of expression in comparison to the CM group, with significant differences on day 7 (p < 0.05 for both variables) and day 14 (p < 0.05 for osteoclast-like cells and p < 0.01 for Howship's lacunae). The percentage of immature collagen increased in the NM group in comparison to the CM group with a statistically significant difference on day 3 (p < 0.05), day 7 (p < 0.001), day 14 (p < 0.001) and day 21 (p < 0.001).
Nicotine affects bone remodeling during orthodontic movement, reducing angiogenesis, osteoclast-like cells and Howship's lacunae, thereby delaying the collagen maturation process in developed bone matrix.
PMCID: PMC4296601  PMID: 24945520
Tooth movement; Bone resorption; Bone formation; Blood vessels; Nicotine
20.  Cardiac Chaos 
PMCID: PMC3943776  PMID: 24649427
21.  Experimental Analysis of Tablet Properties for Discrete Element Modeling of an Active Coating Process 
AAPS PharmSciTech  2013;14(1):402-411.
Coating of solid dosage forms is an important unit operation in the pharmaceutical industry. In recent years, numerical simulations of drug manufacturing processes have been gaining interest as process analytical technology tools. The discrete element method (DEM) in particular is suitable to model tablet-coating processes. For the development of accurate simulations, information on the material properties of the tablets is required. In this study, the mechanical parameters Young’s modulus, coefficient of restitution (CoR), and coefficients of friction (CoF) of gastrointestinal therapeutic systems (GITS) and of active-coated GITS were measured experimentally. The dynamic angle of repose of these tablets in a drum coater was investigated to revise the CoF. The resulting values were used as input data in DEM simulations to compare simulation and experiment. A mean value of Young’s modulus of 31.9 MPa was determined by the uniaxial compression test. The CoR was found to be 0.78. For both tablet–steel and tablet–tablet friction, active-coated GITS showed a higher CoF compared with GITS. According to the values of the dynamic angle of repose, the CoF was adjusted to obtain consistent tablet motion in the simulation and in the experiment. On the basis of this experimental characterization, mechanical parameters are integrated into DEM simulation programs to perform numerical analysis of coating processes.
PMCID: PMC3581635  PMID: 23354469
active film coating; DEM simulation; dynamic angle of repose; tablet coating; tablet mechanical properties
22.  Treatment of antipsychotic-associated obesity with a GLP-1 receptor agonist—protocol for an investigator-initiated prospective, randomised, placebo-controlled, double-blinded intervention study: the TAO study protocol 
BMJ Open  2014;4(1):e004158.
Antipsychotic medication is widely associated with dysmetabolism including obesity and type 2 diabetes, cardiovascular-related diseases and early death. Obesity is considered the single most important risk factor for cardiovascular morbidity and mortality. Interventions against antipsychotic-associated obesity are limited and insufficient. Glucagon-like peptide-1 (GLP-1) receptor agonists are approved for the treatment of type 2 diabetes, but their bodyweight-lowering effects have also been recognised in patients with non-diabetes. The primary endpoint of this trial is weight loss after 3 months of treatment with a GLP-1 receptor agonist (exenatide once weekly) in patients with non-diabetic schizophrenia with antipsychotic-associated obesity. Secondary endpoints include physiological and metabolic measurements, various psychopathological and cognitive measures, and structural and functional brain MRI.
Methods and analysis
40 obese patients with schizophrenia or schizoaffective disorder treated with antipsychotic drugs will be randomised to subcutaneous injection of exenatide once weekly (2 mg) or placebo for 3 months, adjunctive to their antipsychotic treatment.
Ethics and dissemination
The trial has been approved by the Danish Health and Medicines Authority, the National Committee on Health Research Ethics and the Danish Data Protection Agency. Trial participation presupposes theoral and written patient informed consent. An external, independent monitoring committee (Good Clinical Practice Unit at Copenhagen University Hospital) will monitor the study according to the GCP Guidelines. Trial data, including positive, negative and inconclusive results, will be presented at national and international scientific meetings and conferences. Papers will be submitted to peer-reviewed journals.
Trial registration identifier: NCT01794429; National Committee on Health Research Ethics project number: 36378; EudraCT nr: 2012-005404-17; The Danish Data Protection Agency project number: RHP-2012-027.
PMCID: PMC3902332  PMID: 24401727
Antipsychotic-associated obesity; The metabolic syndrome; Cardiovascular disease; Glucagon-like peptide-1 (GLP-1) receptor agonist
23.  Targeting Paraprotein Biosynthesis for Non-Invasive Characterization of Myeloma Biology 
PLoS ONE  2013;8(12):e84840.
Multiple myeloma is a hematologic malignancy originating from clonal plasma cells. Despite effective therapies, outcomes are highly variable suggesting marked disease heterogeneity. The role of functional imaging for therapeutic management of myeloma, such as positron emission tomography with 2-deoxy-2-[18F]fluoro-D-glucose (18F-FDG-PET), remains to be determined. Although some studies already suggested a prognostic value of 18F-FDG-PET, more specific tracers addressing hallmarks of myeloma biology, e.g. paraprotein biosynthesis, are needed. This study evaluated the amino acid tracers L-methyl-[11C]-methionine (11C-MET) and [18F]-fluoroethyl-L-tyrosine (18F-Fet) for their potential to image myeloma and to characterize tumor heterogeneity.
Experimental Design
To study the utility of 11C-MET, 18F-Fet and 18F-FDG for myeloma imaging, time activity curves were compared in various human myeloma cell lines (INA-6, MM1.S, OPM-2) and correlated to cell-biological characteristics, such as marker gene expression and immunoglobulin levels. Likewise, patient-derived CD138+ plasma cells were characterized regarding uptake and biomedical features.
Using myeloma cell lines and patient-derived CD138+ plasma cells, we found that the relative uptake of 11C-MET exceeds that of 18F-FDG 1.5- to 5-fold and that of 18F-Fet 7- to 20-fold. Importantly, 11C-MET uptake significantly differed between cell types associated with worse prognosis (e.g. t(4;14) in OPM-2 cells) and indolent ones and correlated with intracellular immunoglobulin light chain and cell surface CD138 and CXCR4 levels. Direct comparison of radiotracer uptake in primary samples further validated the superiority of 11C-MET.
These data suggest that 11C-MET might be a versatile biomarker for myeloma superior to routine functional imaging with 18F-FDG regarding diagnosis, risk stratification, prognosis and discrimination of tumor subtypes.
PMCID: PMC3871597  PMID: 24376850
24.  Jack-of-all-trades: phenotypic plasticity facilitates the invasion of an alien slug species 
Invasive alien species might benefit from phenotypic plasticity by being able to (i) maintain fitness in stressful environments (‘robust’), (ii) increase fitness in favourable environments (‘opportunistic’), or (iii) combine both abilities (‘robust and opportunistic’). Here, we applied this framework, for the first time, to an animal, the invasive slug, Arion lusitanicus, and tested (i) whether it has a more adaptive phenotypic plasticity compared with a congeneric native slug, Arion fuscus, and (ii) whether it is robust, opportunistic or both. During one year, we exposed specimens of both species to a range of temperatures along an altitudinal gradient (700–2400 m a.s.l.) and to high and low food levels, and we compared the responsiveness of two fitness traits: survival and egg production. During summer, the invasive species had a more adaptive phenotypic plasticity, and at high temperatures and low food levels, it survived better and produced more eggs than A. fuscus, representing the robust phenotype. During winter, A. lusitanicus displayed a less adaptive phenotype than A. fuscus. We show that the framework developed for plants is also very useful for a better mechanistic understanding of animal invasions. Warmer summers and milder winters might lead to an expansion of this invasive species to higher altitudes and enhance its spread in the lowlands, supporting the concern that global climate change will increase biological invasions.
PMCID: PMC3479723  PMID: 23015630
phenotypic plasticity; Jack-of-all-trades; molluscs; global warming; invasion; altitudinal gradient
25.  Human Treg responses allow sustained recombinant adeno-associated virus–mediated transgene expression 
The Journal of Clinical Investigation  2013;123(12):5310-5318.
Recombinant adeno-associated virus (rAAV) vectors have shown promise for the treatment of several diseases; however, immune-mediated elimination of transduced cells has been suggested to limit and account for a loss of efficacy. To determine whether rAAV vector expression can persist long term, we administered rAAV vectors expressing normal, M-type α-1 antitrypsin (M-AAT) to AAT-deficient subjects at various doses by multiple i.m. injections. M-specific AAT expression was observed in all subjects in a dose-dependent manner and was sustained for more than 1 year in the absence of immune suppression. Muscle biopsies at 1 year had sustained AAT expression and a reduction of inflammatory cells compared with 3 month biopsies. Deep sequencing of the TCR Vβ region from muscle biopsies demonstrated a limited number of T cell clones that emerged at 3 months after vector administration and persisted for 1 year. In situ immunophenotyping revealed a substantial Treg population in muscle biopsy samples containing AAT-expressing myofibers. Approximately 10% of all T cells in muscle were natural Tregs, which were activated in response to AAV capsid. These results suggest that i.m. delivery of rAAV type 1–AAT (rAAV1-AAT) induces a T regulatory response that allows ongoing transgene expression and indicates that immunomodulatory treatments may not be necessary for rAAV-mediated gene therapy.
PMCID: PMC3859421  PMID: 24231351

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