bluuebunny/crossref_metadata_2025 huggingface dataset:
Curcumin Alleviates Diabetic Retinopathy in Experimental Diabetic Rats
Authors: Yang Fang , Yu Jinqiang , Ke Feng , Lan Mei , Li Dekun  , Tan Ke , Ling Jiaojiao , Wang Ying , Wu Kaili , Li Dai
Published: March 2018

Purpose: To investigate the potential protective effects of curcumin on the retina in diabetic rats. Methods: An experimental diabetic rat model was induced by a low dose of streptozotocin combined with a high-energy diet. Rats which had blood glucose levels ≥11.6 mmol/L were used as diabetic rats. The diabetic rats were randomly divided into 3 groups: diabetic rats with no treatment (DM), diabetic rats treated with 100 mg/kg curcumin (DM + Cur 100 mg/kg), and diabetic rats treated with 200 mg/kg curcumin (DM + Cur 200 mg/kg). Curcumin was orally administered daily for 16 weeks. After 16 weeks of administration, the rats were euthanized, and eyes were dissected. Retinal histology was examined, and the thickness of the retina was measured. Ultrastructural changes of retinal ganglion cells, inner layer cells, retinal capillary, and membranous disks were observed by electron microscopy. Malondialdehyde, superoxide dismutase, and total antioxidant capacity were measured by ELISA. Expression levels of vascular endothelial growth factor (VEGF) in retina tissues were examined by immunohistochemical staining and ELISA. Expression levels of Bax and Bcl-2 in retina tissues were determined by immunohistochemical staining and Western blotting. Results: Curcumin reduced the blood glucose levels of diabetic rats and decreased diabetes-induced body weight loss. Curcumin prevented attenuation of the retina in diabetic rats and ameliorated diabetes-induced ultrastructure changes of the retina, including thinning of the retina, apoptosis of the retinal ganglion cells and inner nuclear layer cells, thickening of retinal capillary basement membrane and disturbance of photoreceptor cell membranous disks. We also found that curcumin has a strong antioxidative ability in the retina of diabetic rats. It was observed that curcumin attenuated the expression of VEGF in the retina of diabetic rats. We also discovered that curcumin had an antiapoptotic effect by upregulating the expression of Bcl-2 and downregulating the expression of Bax in the retina of diabetic rats. Conclusions: Taken together, these results suggest that curcumin may have great therapeutic potential in the treatment of diabetic retinopathy which could be attributed to the hypoglycemic, antioxidant, VEGF-downregulating and neuroprotection properties of curcumin.
Dermocosmetics for Use in Rosacea: Guideline of the Society for Dermopharmacy
Authors: Kresken Joachim , Kindl Ursula , Wigger-Alberti Walter , Clanner-Engelshofen Benjamin M. , Reinholz Markus
Published: March 2018

Rosacea is a widespread inflammatory skin disease that is chronically recurrent and affects predominately the central parts of the face. Affected individuals typically react to numerous cosmetics with redness, burning, and/or worsening of the complexion. Consequently, there is a high demand for dermocosmetics that do not provoke such reactions and are suitable for use in rosacea. The present guideline of the Society for Dermopharmacy describes the requirements that dermocosmetics for use in rosacea should meet. They include, inter alia, methods to prove the efficacy of and tolerance to these cosmetics, as well as the product documentation that the manufacturer or the distributing company should make available to professionals, like dermatologists and pharmacists, counseling patients with rosacea.
Zika virus Pathogenesis in Infant Mice after Natural Transmission by the Bite of Infected Mosquitoes
Authors: Yadav Pragya D. , Kumar Vimal , Kumar Sandeep , Mote Chandrashekhar S. , Majumdar Triparna D. , Gokhale Mangesh , Kore Pravin , Mourya Devendra T.
Published: March 2018

Objectives: The objective of this study was to understand natural disease progression in infant CD1 mice after the bite of Aedes aegypti mosquitoes infected by the Zika virus (ZIKV, MR-766 strain). Methods: A. aegypti mosquitoes were experimentally infected with ZIKV MR-766 strain via the oral feeding route. Infected mosquitoes were allowed to feed on infant CD1 mice. Sick mice were euthanized, and their organs were collected and subjected to real-time RT-PCR, histo­pathology, and immunohistochemistry. Results: Clinical symptoms appeared in mice after 4–5 days of being bitten by mosquitoes, following which they were euthanized. Real-time RT-PCR analysis showed the presence of viral RNA in various organs such as the brain, liver, kidney, spleen, lungs, and intestines of the mice. The brain tissue specimens showed higher viral loads as determined by threshold values (Ct value) in the real-time RT-PCR assay. Histopathological and immunohistochemistry studies also revealed the presence of the virus and associated lesions in the brain, indicating that ZIKV shows tropism for neuronal tissue. Conclusions: This study demonstrates ZIKV pathogenesis in infant CD1 mice and that these mice are highly susceptible to natural infection with this ZIKV strain.
Identification of Cytological Features Distinguishing Mucosa-Associated Lymphoid Tissue Lymphoma from Reactive Lymphoid Proliferation Using Thyroid Liquid-Based Cytology
Authors: Suzuki Ayana , Hirokawa Mitsuyoshi , Ito Aki , Takada Nami , Higuchi Miyoko , Hayashi Toshitetsu , Kuma Seiji , Miyauchi Akira
Published: March 2018

Objective: To identify cytological differences between mucosa-associated lymphoid tissue lymphoma (MALT-L) and nonneoplastic lymphocytes using thyroid liquid-based cytology (LBC). Study Design: We observed LBC and conventional specimens from 35 MALT-L cases, 3 diffuse large B-cell cell lymphoma (DLBCL) cases, and 44 prominent nonneoplastic lymphocytic infiltration cases. Results: In MALT-L cases, the incidence of lymphoglandular bodies in the LBC specimens was lower than that in the conventional specimens (p < 0.001). Moreover, the nuclear sizes in LBC specimens were larger than those in conventional specimens. In 62.9% of the MALT-L and all DLBCL specimens, large nuclei were present in > 10% of the lymphoid cells in LBC specimens. Two cases with prominent nonneoplastic lymphocytic infiltration also exhibited these findings. In LBC specimens, swollen naked nuclei with less punctate chromatin patterns and thin nuclear margins were observed in 92.1% of lymphoma and 20.5% of prominent nonneoplastic lymphocytic infiltration. Elongated nuclei were significantly more apparent in thyroid lymphoma than in prominent nonneoplastic lymphocytic infiltration (p < 0.001), with a significantly higher incidence in LBC specimens than in conventional specimens (p < 0.001). Conclusions: Lymphoglandular bodies are not reliable markers for lymphoma diagnosis using LBC specimens. Large, swollen naked, and elongated nuclei are useful in distinguishing thyroid lymphoma from nonneoplastic lymphocytes in LBC specimens.
Multidisciplinary Taiwan Consensus Recommendations for the Use of DEBDOX-TACE in Hepatocellular Carcinoma Treatment
Authors: Chang Pi-Yi , Huang Chun-Chieh , Hung Chao-Hung , Yu Chih-Yung , Wu Ding-Kwo , Hwang Jen-I , Liang Po-Chin , Wu Reng-Hong , Tsai Wei-Lun , Lin Yih-Jyh , Liu Yi-Sheng , Liang Huei-Lung , Lee Rheun-Chuan , Chen Chien-Hung
Published: March 2018

Transarterial chemoembolization (TACE) is the first-line treatment in patients with unresectable hepatocellular carcinoma (HCC). In recent years, there has been increasing clinical evidence that drug-eluting beads provide a combined ischemic and cytotoxic effect that may be superior to conventional TACE, with low systemic toxicity. The therapeutic value of TACE performed using the embolic microsphere DC Bead loaded with doxorubicin (drug-eluting bead doxorubicin [DEBDOX]) has been shown by several randomized controlled trials. Since Lencioni et al. [Cardiovasc Intervent Radiol 2012; 35: 980–985] published the first widely accepted technical recommendations on HCC embolization with DEBDOX-TACE in 2012, new studies have contributed to a better understanding of when and how to apply this new therapeutic modality, and they have yet to be incorporated into an updated guideline. Additionally, differences in the underlying liver pathology and practice of transcatheter embolization between Asian and Western populations have not been adequately addressed, and there remain significant variations in the TACE protocols adopted in different parts of the world. These mainly revolve around the number and type of chemotherapeutic agents used, type of embolic material, reliance on Lipiodol, and selectivity of catheter positioning. As a result of these issues, it has been difficult to interpret and compare results obtained from different centers in a systematic fashion. To address these concerns, we convened a panel of experts specializing in different aspects of HCC treatment to craft an updated set of recommendations that better reflect recent clinical experiences and are tailored to the use of DEBDOX-TACE in Taiwan. The conclusions of this expert panel are described in the following article.
Associations between Pre-Admission Risk Scores and Two-Year Clinical Outcomes in Ischemic Stroke or Transient Ischemic Attack Patients with Non-Valvular Atrial Fibrillation
Authors: Tokunaga Keisuke , Yamagami Hiroshi , Koga Masatoshi , Todo Kenichi , Kimura Kazumi , Itabashi Ryo , Terasaki Tadashi , Shiokawa Yoshiaki , Kamiyama Kenji , Takizawa Shunya , Okuda Satoshi , Okada Yasushi , Kameda Tomoaki , Nagakane Yoshinari , Hasegawa Yasuhiro , Shibuya Satoshi , Ito Yasuhiro , Matsuoka Hideki , Takamatsu Kazuhiro , Nishiyama Kazutoshi , Kario Kazuomi , Yagita Yoshiki , Kitazono Takanari , Kinoshita Naoto , Takasugi Junji , Okata Takuya , Yoshimura Sohei , Sato Shoichiro , Arihiro Shoji , Toyoda Kazunori ,   SAMURAI Study Investigators
Published: March 2018

Background: We aimed to clarify associations between pre-admission risk scores (CHADS2, CHA2DS2-VASc, and HAS-BLED) and 2-year clinical outcomes in ischemic stroke or transient ischemic attack (TIA) patients with non-valvular atrial fibrillation (NVAF) using a prospective, multicenter, observational registry. Methods: From 18 Japanese stroke centers, ischemic stroke or TIA patients with NVAF hospitalized within 7 days after onset were enrolled. Outcome measures were defined as death/disability (modified Rankin Scale score ≥3) at 2 years, 2-year mortality, and ischemic or hemorrhagic events within 2 years. Results: A total of 1,192 patients with NVAF (527 women; mean age, 78 ± 10 years), including 1,141 ischemic stroke and 51 TIA, were analyzed. Rates of death/disability, mortality, and ischemic or hemorrhagic events increased significantly with increasing pre-admission CHADS2 (p for trend <0.001 for death/disability and mortality, p for trend = 0.024 for events), CHA2DS2-VASc (p for trend <0.001 for all), and HAS-BLED (p for trend = 0.004 for death/disability, p for trend <0.001 for mortality, p for trend = 0.024 for events) scores. Pre-admission CHADS2 (OR per 1 point, 1.52; 95% CI 1.35–1.71; p <0.001 for death/disability; hazard ratio (HR) per 1 point, 1.23; 95% CI 1.12–1.35; p <0.001 for mortality; HR per 1 point, 1.14; 95% CI 1.02–1.26; p = 0.016 for events), CHA2DS2-VASc (1.55, 1.41–1.72, p < 0.001; 1.21, 1.12–1.30, p < 0.001; 1.17, 1.07–1.27, p < 0.001; respectively), and HAS-BLED (1.33, 1.17–1.52, p < 0.001; 1.23, 1.10–1.38, p < 0.001; 1.18, 1.05–1.34, p = 0.008; respectively) scores were independently associated with all outcome measures. Conclusions: In ischemic stroke or TIA patients with NVAF, all pre-admission risk scores were independently associated with death/disability at 2 years and 2-year mortality, as well as ischemic or hemorrhagic events within 2 years.
Transcatheter Closure of Patent Foramen Ovale versus Medical Therapy after Cryptogenic Stroke: A Meta-Analysis of Randomized Controlled Trials
Authors: Darmoch Fahed , Al-Khadra Yasser , Soud Mohamad , Fanari Zaher , Alraies M. Chadi
Published: March 2018

Background: Patent foramen ovale (PFO) with atrial septal aneurysm is suggested as an important potential source for cryptogenic strokes. Percutaneous PFO closure to reduce the recurrence of stroke compared to medical therapy has been intensely debated. The aim of this study is to assess whether PFO closure in patients with cryptogenic stroke is safe and effective compared with medical therapy. Method: A search of PubMed, Medline, and Cochrane Central Register from January 2000 through September 2017 for randomized controlled trails (RCT), which compared PFO closure to medical therapy in patients with cryptogenic stroke was conducted. We used the items “PFO or patent foramen ovale”, “paradoxical embolism”, “PFO closure” and “stroke”. Data were pooled for the primary outcome measure using the random-effects model as pooled rate ratio (RR). The primary outcome was reduction in recurrent strokes. Result: Among 282 studies, 5 were selected. Our analysis included 3,440 patients (mean age 45 years, 55% men, mean follow-up 2.9 years), 1,829 in the PFO closure group and 1,611 in the medical therapy group. The I2 heterogeneity test was found to be 48%. A random effects model combining the results of the included studies demonstrated a statistically significant risk reduction in risk of recurrent stroke in the PFO closure group when compared with medical therapy (RR 0.42; 95% CI 0.20–0.91, p = 0.03). Conclusion: Pooled data from 5 large RCTs showed that PFO closure in patients with cryptogenic stroke is safe and effective intervention for prevention of stroke recurrence compared with medical therapy.
Acute Treatment with T-Type Calcium Channel Enhancer SAK3 Reduces Cognitive Impairments Caused by Methimazole-Induced Hypothyroidism Via Activation of Cholinergic Signaling
Authors: Husain Noreen , Yabuki Yasushi , Shinoda Yasuharu , Fukunaga Kohji
Published: March 2018

Hypothyroidism is a common disorder that is associated with psychological disturbances such as dementia, depression, and psychomotor disorders. We recently found that chronic treatment with the T-type calcium channel enhancer SAK3 prevents the cholinergic neurodegeneration induced by a single intraperitoneal (i.p.) injection of methimazole (MMI; 75 mg/kg), thereby improving cognition. Here, we evaluated the acute effect of SAK3 on cognitive impairments and its mechanism of action following the induction of hypothyroidism. Hypothyroidism was induced by 2 injections of MMI (75 mg/kg, i.p.) administered once per week. Four weeks after the final MMI treatment, MMI-treated mice showed reduced serum thyroxine (T4) levels and cognitive impairments without depression-like behaviors. Although acute SAK3 (1.0 mg/kg, p.o.) administration failed to ameliorate the decreased T4 levels and histochemical destruction of the glomerular structure, acute SAK3 (1.0 mg/kg, p.o.) administration significantly reduced cognitive impairments in MMI-treated mice. Importantly, the α7 nicotinic acetylcholine receptor (nAChR)-selective inhibitor methyllycaconitine (MLA; 12 mg/kg, i.p.) and T-type calcium channel-specific blocker NNC 55–0396 (25 mg/kg, i.p.) antagonized the acute effect of SAK3 on memory deficits in MMI-treated mice. We also confirmed that acute SAK3 administration does not rescue reduced olfactory marker protein or choline acetyltransferase immunoreactivity levels in the olfactory bulb or medial septum. Taken together, these results suggest that SAK3 has the ability to improve the cognitive decline caused by hypothyroidism directly through activation of nAChR signaling and T-type calcium channels.
Levels of Endocan, Angiopoietin-2, and Hypoxia-Inducible Factor-1a in Patients with Autosomal Dominant Polycystic Kidney Disease and Different Levels of Renal Function
Authors: Raptis Vassilios , Bakogiannis Constantinos , Loutradis Charalampos , Boutou Afroditi K. , Lampropoulou Ioanna , Intzevidou Elena , Sioulis Athanasios , Balaskas Elias , Sarafidis Pantelis A.
Published: March 2018

Background: Endothelial dysfunction leading to unbalanced vasoconstriction and ischemia of renal parenchyma is increasingly proposed as an alternative pathway of renal damage in autosomal dominant polycystic kidney disease (ADPKD). However, human studies investigating the evolution of such phenomena are limited. This study investigated the levels of emerging biomarkers of endothelial function, angiogenesis and hypoxia, in ADPKD patients with different renal function. Methods: The study population consisted of three groups: 26 ADPKD patients with impaired renal function (Group A; estimated glomerular filtration rate [eGFR] 45–70 mL/min/1.73 m2), 26 ADPKD patients with preserved renal function (Group B; eGFR >70 mL/min/1.73 m2), and 26 age- and sex-matched controls with no history of renal disease. Circulating levels of endocan (endothelial cell-specific molecule-1) angiopoietin-2, and hypoxia-inducible factor-1a (HIF-1a) were determined by enzyme-linked immunosorbent assay techniques. Results: Patients in Group A had significantly higher levels of endocan (7.17 ± 0.43 ng/mL), angiopoietin-2 (5,595.43 ± 3,390), and HIF-1a (163.68 ± 37.84 pg/mL) compared to patients in Group B (6.86 ± 0.59 ng/mL, p = 0.017, 3,854.41 ± 3,014.30, p = 0.018, 136.84 ± 42.10 pg/mL, p = 0.019 respectively) or controls (4.83 ± 0.69 ng/mL, 1,069 ± 427.88 pg/mL, 70.20 ± 17.49 pg/mL, p < 0.001 for all comparisons). Of note, patients in Group B had also higher levels of all markers compared to controls (p < 0.001) despite having similar renal function. In correlation analyses within ADPKD patients, we noted strong correlations of all studied markers with asymmetric dimethylarginine (ADMA; endocan r = 0.908, p < 0.001, angiopoietin-2 r = 0.983, p < 0.001 and HIF-1a r = 0.998, p < 0.001), and only weak or modest correlations with eGFR. Conclusions: This study suggests that endothelial dysfunction causing microcirculatory changes, linked to angiogenesis and hypoxia, may come early in the course of ADPKD and could be a key regulator of renal injury progression.
Feasibility of “Watch-and-Wait” Management before Repeat Hepatectomy for Colorectal Liver Metastases
Authors: Kishi Yoji , Nara Satoshi , Esaki Minoru , Shimada Kazuaki
Published: March 2018

Background: Whether repeat hepatectomy for colorectal liver metastases should be performed after chemotherapy or observation is unclear. Methods: We selected patients with resectable hepatic recurrence after their first hepatectomies performed between 2000 and 2015. They were classified according to the further treatment: Group A, prompt repeat hepatectomy; Group B, observation; and Group C, ≤6 months of chemotherapy. In Group B/C, patients who later underwent hepatectomy and those who did not due to disease progression were classified as B1/C1 and B2/C2, respectively. Predictors of B2/C2 were evaluated. Results: Groups A, B, and C consisted of 81, 36, and 17 patients, respectively. Recurrence-free interval was longer in Group A (median months; Group A, 10.3; Group B, 5.7; Group C, 3.5; p < 0.01). Group B1/C1 and B2/C2 included 34 and 19 patients, respectively. Five-year survival after recurrence of Group B1/C1 was 56%, which was comparable with Group A (56%, p = 0.77) and better than Group B2/C2 (0%, p < 0.01). Multivariate analysis showed synchronous colorectal liver metastases (OR 7.23) and recurrent hepatic tumor number (OR 4.04) were predictors of tumor progression. Conclusion: Selecting patients optimally either for prompt or delayed repeat hepatectomy following chemotherapy or observation is a feasible strategy.
Isolated Renal Hydatid Cyst Misdiagnosed and Operated as a Cystic Renal Tumor
Authors: Gadelkareem Rabea A. , Elqady Ayman A. , Abd-Elshafy Sayed K. , Imam Hisham , Abolella Hassan A.
Published: March 2018

Objective: The aim of this work is the presentation of a case of isolated renal hydatid cyst with novel findings and an unusual surgical scenario. Clinical Presentation and Intervention: A 54-year-old female patient presented with left loin pain and a palpable left renal mass. Imaging described a well-demarcated left renal cystic lesion with a double-layer wall. Radical nephrectomy was performed due to the possibility of malignancy. On retrograde revision, the double-layer wall represented the detached germinative membrane of a hydatid cyst that was confirmed by histopathology. Conclusion: Isolated renal hydatid cyst could be misinterpreted as a renal tumor. It should be considered in the differential diagnosis of renal cystic lesions.
Telomerase Mediates Lymphocyte Proliferation but Not the Atherosclerosis-Suppressive Potential of Regulatory T-Cells
Authors: Richardson Gavin David , Sage Andrew , Bennaceur Karim , Al Zhrany Nayef , Coelho-Lima Jose , Dookun Emily , Draganova Lilia , Saretzki Gabriele , Breault David T. , Mallat Ziad , Spyridopoulos Ioakim
Published: March 2018

Objective—

Atherosclerosis is an age-related disease characterized by systemic oxidative stress and low-grade inflammation. The role of telomerase and telomere length in atherogenesis remains contentious. Short telomeres of peripheral leukocytes are predictive for coronary artery disease. Conversely, attenuated telomerase has been demonstrated to be protective for atherosclerosis. Hence, a potential causative role of telomerase in atherogenesis is critically debated.

Approach and Results—

In this study, we used multiple mouse models to investigate the regulation of telomerase under oxidative stress as well as its impact on atherogenesis in vitro and in vivo. Using primary lymphocytes and myeloid cell cultures, we demonstrate that cultivation under hyperoxic conditions induced oxidative stress resulting in chronic activation of CD4
+
cells and significantly reduced CD4
+
T-cell proliferation. The latter was telomerase dependent because oxidative stress had no effect on the proliferation of primary lymphocytes isolated from telomerase knockout mice. In contrast, myeloid cell proliferation was unaffected by oxidative stress nor reliant on telomerase. Telomerase reverse transcriptase deficiency had no effect on regulatory T-cell (T
reg
) numbers in vivo or suppressive function ex vivo. Adoptive transfer of telomerase reverse transcriptase
–
/–
T
regs
into Rag2
–/–
ApoE
–/–
(recombination activating gene 2/apolipoprotein E) double knockout mice demonstrated that telomerase function was not required for the ability of T
regs
to protect against atherosclerosis. However, telomere length was critical for T
reg
function.

Conclusions—

Telomerase contributes to lymphocyte proliferation but plays no major role in T
reg
function, provided that telomere length is not critically short. We suggest that oxidative stress may contribute to atherosclerosis via suppression of telomerase and acceleration of telomere attrition in T
regs
.
Extracellular and Intracellular Cyclophilin A, Native and Post-Translationally Modified, Show Diverse and Specific Pathological Roles in Diseases
Authors: Xue Chao , Sowden Mark P. , Berk Bradford C.
Published: March 2018

CypA (cyclophilin A) is a ubiquitous and highly conserved protein with peptidyl prolyl isomerase activity. Because of its highly abundant level in the cytoplasm, most studies have focused on the roles of CypA as an intracellular protein. However, emerging evidence suggests an important role for extracellular CypA in the pathogenesis of several diseases through receptor (CD147 or other)-mediated autocrine and paracrine signaling pathways. In this review, we will discuss the shared and unique pathological roles of extracellular and intracellular CypA in human cardiovascular diseases. In addition, the evolving role of post-translational modifications of CypA in the pathogenesis of disease is discussed. Finally, recent studies with drugs specific for extracellular CypA show its importance in disease pathogenesis in several animal models and make extracellular CypA a new therapeutic target.
CaMKII (Ca
2+
/Calmodulin-Dependent Kinase II) in Mitochondria of Smooth Muscle Cells Controls Mitochondrial Mobility, Migration, and Neointima Formation
Authors: Nguyen Emily K. , Koval Olha M. , Noble Paige , Broadhurst Kim , Allamargot Chantal , Wu Meng , Strack Stefan , Thiel William H. , Grumbach Isabella M.
Published: March 2018

Objective—

The main objective of this study is to define the mechanisms by which mitochondria control vascular smooth muscle cell (VSMC) migration and impact neointimal hyperplasia.

Approach and Results—

The multifunctional CaMKII (Ca
2+
/calmodulin-dependent kinase II) in the mitochondrial matrix of VSMC drove a feed-forward circuit with the mitochondrial Ca
2+
uniporter (MCU) to promote matrix Ca
2+
influx. MCU was necessary for the activation of mitochondrial CaMKII (mtCaMKII), whereas mtCaMKII phosphorylated MCU at the regulatory site S92 that promotes Ca
2+
entry. mtCaMKII was necessary and sufficient for platelet-derived growth factor–induced mitochondrial Ca
2+
uptake. This effect was dependent on MCU. mtCaMKII and MCU inhibition abrogated VSMC migration and mitochondrial translocation to the leading edge. Overexpression of wild-type MCU, but not MCU S92A, mutant in MCU
−
/−
VSMC rescued migration and mitochondrial mobility. Inhibition of microtubule, but not of actin assembly, blocked mitochondrial mobility. The outer mitochondrial membrane GTPase Miro-1 promotes mitochondrial mobility via microtubule transport but arrests it in subcellular domains of high Ca
2+
concentrations. In Miro-1
−/−
VSMC, mitochondrial mobility and VSMC migration were abolished, and overexpression of mtCaMKII or a CaMKII inhibitory peptide in mitochondria (mtCaMKIIN) had no effect. Consistently, inhibition of mtCaMKII increased and prolonged cytosolic Ca
2+
transients. mtCaMKII inhibition diminished phosphorylation of focal adhesion kinase and myosin light chain, leading to reduced focal adhesion turnover and cytoskeletal remodeling. In a transgenic model of selective mitochondrial CaMKII inhibition in VSMC, neointimal hyperplasia was significantly reduced after vascular injury.

Conclusions—

These findings identify mitochondrial CaMKII as a key regulator of mitochondrial Ca
2+
uptake via MCU, thereby controlling mitochondrial translocation and VSMC migration after vascular injury.
Standards and Methodological Rigor in Pulmonary Arterial Hypertension Preclinical and Translational Research
Authors: Provencher Steeve , Archer Stephen L. , Ramirez F. Daniel , Hibbert Benjamin , Paulin Roxane , Boucherat Olivier , Lacasse Yves , Bonnet Sébastien
Published: March 2018

Despite advances in our understanding of the pathophysiology and the management of pulmonary arterial hypertension (PAH), significant therapeutic gaps remain for this devastating disease. Yet, few innovative therapies beyond the traditional pathways of endothelial dysfunction have reached clinical trial phases in PAH. Although there are inherent limitations of the currently available models of PAH, the leaky pipeline of innovative therapies relates, in part, to flawed preclinical research methodology, including lack of rigour in trial design, incomplete invasive hemodynamic assessment, and lack of careful translational studies that replicate randomized controlled trials in humans with attention to adverse effects and benefits. Rigorous methodology should include the use of prespecified eligibility criteria, sample sizes that permit valid statistical analysis, randomization, blinded assessment of standardized outcomes, and transparent reporting of results. Better design and implementation of preclinical studies can minimize inherent flaws in the models of PAH, reduce the risk of bias, and enhance external validity and our ability to distinguish truly promising therapies form many false-positive or overstated leads. Ideally, preclinical studies should use advanced imaging, study several preclinical pulmonary hypertension models, or correlate rodent and human findings and consider the fate of the right ventricle, which is the major determinant of prognosis in human PAH. Although these principles are widely endorsed, empirical evidence suggests that such rigor is often lacking in pulmonary hypertension preclinical research. The present article discusses the pitfalls in the design of preclinical pulmonary hypertension trials and discusses opportunities to create preclinical trials with improved predictive value in guiding early-phase drug development in patients with PAH, which will need support not only from researchers, peer reviewers, and editors but also from academic institutions, funding agencies, and animal ethics authorities.
Experimental Right Ventricular Hypertension Induces Regional β1‐Integrin–Mediated Transduction of Hypertrophic and Profibrotic Right and Left Ventricular Signaling
Authors: Sun Mei , Ishii Ryo , Okumura Kenichi , Krauszman Adrienn , Breitling Siegfried , Gomez Olga , Hinek Aleksander , Boo Stellar , Hinz Boris , Connelly Kim A. , Kuebler Wolfgang M. , Friedberg Mark K.
Published: March 2018

Background

Development of right ventricular (
RV
) hypertension eventually contributes to
RV
and left ventricular (
LV
) myocardial fibrosis and dysfunction. The molecular mechanisms are not fully elucidated.

Methods and Results

Pulmonary artery banding was used to induce
RV
hypertension in rats in vivo. Then, we evaluated cardiac function and regional remodeling 6 weeks after pulmonary artery banding. To further elucidate mechanisms responsible for regional cardiac remodeling, we also mimicked
RV
hypertensive stress by cyclic mechanical stretching applied to confluent cultures of cardiac fibroblasts, isolated from the
RV
free wall, septal hinge points, and
LV
free wall. Echocardiography and catheter evaluation demonstrated that rats in the pulmonary artery banding group developed
RV
hypertension with leftward septal displacement,
LV
compression, and increased
LV
end‐diastolic pressures. Picrosirius red staining indicated that pulmonary artery banding induced marked
RV
fibrosis and dysfunction, with prominent fibrosis and elastin deposition at the septal hinge points but less
LV
fibrosis. These changes were associated with proportionally increased expressions of integrin‐β1 and profibrotic signaling proteins, including phosphorylated Smad2/3 and transforming growth factor‐β1. Moreover, mechanically stretched fibroblasts also expressed significantly increased levels of α‐smooth muscle actin, integrin‐β1, transforming growth factor‐β1, collagen I deposition, and wrinkle formation on gel assays, consistent with myofibroblast transformation. These changes were not observed in parallel cultures of mechanically stretched fibroblasts, preincubated with the integrin inhibitor (
BTT
‐3033).

Conclusions

Experimentally induced
RV
hypertension triggers regional
RV
, hinge‐point, and
LV
integrin β1‐dependent mechanotransduction signaling pathways that eventually trigger myocardial fibrosis via transforming growth factor‐β1 signaling. Reduced
LV
fibrosis and preserved global function, despite geometrical and pressure aberrations, suggest a possible elastin‐mediated protective mechanism at the septal hinge points.
Introduction: Perspectives on Women’s Religious Activities in Early Modern Europe and the Americas
Authors: Lehtsalu Liise , Moran Sarah , Evangelisti Silvia
Published: March 2018

Proposing activity as a useful category of analysis, this special issue considers Catholic and Protestant women in Europe and the Americas in the sixteenth to the eighteenth centuries. We examine women in religious communities, which include both monastic communities as well as confessional communities. A close analysis of the social, economic, and cultural actions of these women religious challenges historiographical assumptions about monastic cloister and domestic space in the early modern period. In fact, we revisit monastic and domestic spaces to reveal them as stages for previously unexamined activity. This cross-denominational and transnational special issue highlights new spheres of women’s religious activity and raises new questions for the study of early modern women’s lives and their capacity to act in early modern society, economy, and culture.
The Horizontal Effect of International Human Rights Law in Practice
Authors: Lane Lottie
Published: March 2018

This article critically examines whether, and how, five United Nations human rights treaty monitoring bodies deal with situations in which human rights have been interfered with by non-State actors. The article uses the concepts of ‘direct’ and ‘indirect’ horizontal effect of international human rights law. An in-depth comparative analysis reviews the monitoring bodies’ general comments and views on individual communications from the bodies’ establishment until August 2017. The analysis identifies very limited evidence of ‘direct’, and two main kinds of ‘indirect’ horizontal effect of human rights applied by the bodies. First, it finds that while the bodies do engage with the ways in which non-State actors can interfere with human rights, they predominantly focus on the positive and procedural obligations of States. Second, it finds that where non-State actors are sufficiently ‘State-like’ in their nature and actions, they may be re-categorised as public actors for the purposes of human rights.
Taxonomic and ecological characterization of two Ulnaria species (Bacillariophyta) from streams in Cyprus
Authors: CANTONATI MARCO , LANGE-BERTALOT HORST , KELLY MARTYN G. , ANGELI NICOLA
Published: March 2018

During a study of the diatoms of streams in Cyprus, two Ulnaria species were difficult to identify using current taxonomic concepts, which created difficulties when trying to understand their ecological preferences. As a result, both taxa were investigated in detail using light (LM) and scanning electron (SEM) microscopy. Literature searches showed that one of these corresponds to Synedra Monodi Guermeur, a “forgotten” species often misidentified as Fragilaria biceps. This species was shown to belong to the genus Ulnaria, and a new combination is provided together with LM and SEM illustrations and an expanded description. U. monodii appears to be widely distributed and was sometimes abundant. It is an important species in diatom assemblages in streams with relatively warm waters (Mediterranean or tropical / subtropical climate). The second species, one of several forms to which the name Ulnaria acus has often been inappropriately applied, is described as a species new to science (Ulnaria acuscypriacus sp. nov.). The new species differs from all similar taxa by a combination of characters including width, outline, central area shape, and the possession of biseriate areolae. A comprehensive environmental dataset allowed the ecological preferences of Ulnaria monodii comb. nov. to be established. This species was generally associated with low concentrations of total nitrogen and total phosphorus, corresponding to slightly nutrient enriched situations. By contrast, the low number of occurrences of U. acuscypriacus sp. nov. did not allow us to identify clear nutrient preferences. U. acuscypriacus sp. nov. was observed across a large conductivity range, suggesting that it may be more tolerant of brackish conditions than Ulnaria monodii comb. nov.
Nomenclatural notes in Anathallis microphyta (Pleurothallidinae, Orchidaceae)
Authors: SANTOS MILENA C. , TOSCANO DE BRITO A. L. V. , AMANO ERIKA , SMIDT ERIC C.
Published: March 2018

In the course of preparing a generic treatment of the genus Anathallis for Flora do Paraná, southern Brazil, historical material and literature of several taxa related to Anathallis microphyta have been studied and their morphologies and nomenclature elucidated. Three species and one variety are proposed as synonyms: Anathallis longiglossa, A. microgemma, A. paranaensis and A. microphyta var. missionum. Illustrations, an updated synonym list, and taxonomic discussions are also provided.
Morphology and phylogeny of Tamhinispora srinivasanii sp. nov. (Tubeufiaceae) from northern Western Ghats, India
Authors: RAJESHKUMAR KUNHIRAMAN C. , BHAT D. JAYARAMA , LAD SNEHA S. , WIJAYAWARDENE NALIN W. , SINGH SANJAY K. , PANDKAR MADHURA R. , MAURYA DEEPAK K. , ASHTEKAR NIKHIL D. , HYDE KEVIN D.
Published: March 2018

In this paper we introduce a new species of Tamhinispora collected from Western Ghats of Maharashtra, India. This monotypic genus, belonging to Tubeufiaceae, was established based on the type species T. indica, collected from Tamhini Ghats of western India. The new species differs from the type species based on key characteristics, such as branched or Y-shaped conidial body and presence of arm-like conidial appendages. Single conidial cultures were developed and sporulation was established on MEA media following a long period of incubation. Phylogenetic analyses using ITS and LSU sequence data confirmed the position of T. srinivasanii along with T. indica in the Tamhinispora clade in Tubeufiaceae.
New species and records of Clavigeritae (Coleoptera: Staphylinidae: Pselaphinae) from Africa and Asia
Authors: NAKLÁDAL OTO , HLAVÁČ PETER
Published: March 2018

New species of Clavigeritae, Monodiger ivoricus sp. n. from Ivory Coast and Disarthricerus bruneicus sp. n. from Brunei are described. New records are given for the following species: Zuluclavodes Hlaváč, 2007 new genus for Zambia, Fustigerinus formicarius Bryant, 1943 (new combination), new genus and species for Ivory Coast and Hoplitoxenus joannae Jeannel, 1960, new genus and species for Cameroon. A new locality in South Africa is recorded for Ischyroceros mirus Reichensperger, 1915.
Who Do They Think They Are? Identity as an Antecedent of Social Activism by Institutional Shareholders
Authors: Sikavica Katarina , Perrault Elise , Rehbein Kathleen
Published: March 2018

Shareholder activists increasingly pressure corporations on social policy issues; yet, extant research provides little understanding of who these activists are and how they choose their corporate targets. In this article, we adopt an activist-centered approach and rely on hybrid organizational identity theory to determine, in a two-phase analysis, how shareholder activists define their economic and social identities and whether these identities are associated with specific target characteristics and tactical strategies. Our findings form the premise of a typology of institutional shareholder activists that is empirically derived and takes into account the wide range of hybrid organizational identities that shareholders exhibit. With a sample of 735 social policy shareholder proposals filed by 104 institutional shareholders in the 2009-2010 period, our study presents one of the first empirical tests examining the heterogeneity of identities within the broad stakeholder category of “social shareholder activists.” Our empirical evidence demonstrates that these shareholders’ mix of economic and social identities is systematically related to their targets’ characteristics and tactical strategies. The implications of our new typology for research on shareholder activism and the value of our findings for managers conclude this article.
Identification of an effective nondestructive technique for bond defect determination in laminate composites—A technical review
Authors: Asif Muhammad , Khan Muhammad A , Khan Sohaib Z , Choudhry Rizwan S , Khan Kamran A
Published: March 2018

Laminate composites are commonly used for the production of critical mechanical structures and components such as wind turbine blades, helicopter rotors, unmanned aerial vehicle wings and honeycomb structures for aircraft wings. During the manufacturing process of these composite structures, zones or areas with weak bond strength are always issues, which may affect the strength and performance of components. The identification and quantification of these zones are always challenging and necessary for the mass production. Non-destructive testing methods available, including ultrasonic A, B, and C-Scan, laser shearography, X-ray tomography, and thermography can be useful for the mentioned purposes. A comparison of these techniques concerning their capacity of identification and quantification of bond defects; however, still needs a comprehensive review. In this paper, a detailed comparison of several non-destructive testing techniques is provided. Emphasis is placed to institute a guideline to select the most suitable technique for the identification of zones with bond defects in laminated composites. Experimental tests on different composite based machined components are also discussed in detail. The discussion provides practical evidence about the effectiveness of different non-destructive testing techniques.
Seroepidemiology and phylogenetic analysis of human herpesvirus type 8 in injection drug users and men who have sex with men in northern Taiwan
Authors: Lee Yuan-Ming , Hung Pei-Shih , Lin Cheng-Wen
Published: March 2018

Objectives

Human herpesvirus 8 (HHV-8) is transmissible and causes Kaposi’s sarcoma and other malignancies. This study analyzed the seroepidemiology and phylogeny of HHV-8 among 515 injection drug users (IDUs) and 229 men who have sex with men (MSM) in Taiwan.

Methods

Blood and peripheral mononuclear cells were analyzed for HHV-8 seroprevalence using enzyme-linked immunosorbent and immunofluorescence assays. Viral loads were measured using a real-time PCR assay. Phylogenetic analysis of the K1 gene was performed using nested PCR and DNA sequencing.

Results

HHV-8 infection rate was higher in MSM (24.9%) than in IDUs (3.8%). The rate of HHV-8 infection was higher in HIV-1-positive patients (32.8%, MSM; 5.5%, IDUs) than in HIV-1 negative patients. HHV-8 load was not significantly different between HHV-8 seropositive and seronegative patients. HHV-8 genotypes C and A variants were detected at frequencies of 80% and 20%, respectively, among IDUs; and genotypes C, D, E, and A were detected at frequencies of 55.6%, 11.1%, 11.1%, and 5.6%, respectively, among MSM. Variants of K1 amino acid residues 54–84 were detected in most IDUs and MSM.

Conclusions

HHV-8 prevalence was significantly higher among MSM than among IDUs. Evolution of the K1 gene occurred in HHV-8 variants of IDUs and MSM.
Factors Predictive of Healing in Large Rotator Cuff Tears: Is It Possible to Predict Retear Preoperatively?
Authors: Jeong Ho Yeon , Kim Hwan Jin , Jeon Yoon Sang , Rhee Yong Girl
Published: March 2018

Background:

Many studies have identified risk factors that cause retear after rotator cuff repair. However, it is still questionable whether retears can be predicted preoperatively.

Purpose:

To determine the risk factors related to retear after arthroscopic rotator cuff repair and to evaluate whether it is possible to predict the occurrence of retear preoperatively.

Study Design:

Case-control study; Level of evidence, 3.

Methods:

This study enrolled 112 patients who underwent arthroscopic rotator cuff repair with single-row technique for a large-sized tear, defined as a tear with a mediolateral length of 3 to 5 cm. All patients underwent routine magnetic resonance imaging (MRI) at 9 months postoperatively to assess tendon integrity. The sample included 61 patients (54.5%) in the healed group and 51 (45.5%) in the retear group.

Results:

In multivariate analysis, the independent predictors of retears were supraspinatus muscle atrophy ( P < .001) and fatty infiltration of the infraspinatus ( P = .027), which could be preoperatively measured by MRI. A significant difference was found between the two groups in sex, the acromiohumeral interval, tendon tension, and preoperative or intraoperative mediolateral tear length and musculotendinous junction position in univariate analysis. However, these variables were not independent predictors in multivariate analysis. The cutoff values of occupation ratio of supraspinatus and fatty infiltration of the infraspinatus were 43% and grade 2, respectively. The occupation ratio of supraspinatus <43% and grade ≥2 fatty infiltration of the infraspinatus were the strongest predictors of retear, with an area under the curve of 0.908, sensitivity of 98.0%, and specificity of 83.6% (accuracy = 90.2%).

Conclusion:

In patients with large rotator cuff tears, it was possible to predict the retear before rotator cuff repair regardless of intraoperative factors. The retear could be predicted most effectively when the occupation ratio of supraspinatus was <43% or the fatty infiltration of infraspinatus was grade ≥2. Predicting retear preoperatively may help surgeons determine proper treatment and predict the postoperative prognosis.
Fluidized bed combustion bottom ash: A better and alternative geo-material resource for construction
Authors: Mandal AK , Paramkusam Bala Ramudu , Sinha OP
Published: March 2018

Though the majority of research on fly ash has proved its worth as a construction material, the utility of bottom ash is yet questionable due to its generation during the pulverized combustion process. The bottom ash produced during the fluidized bed combustion (FBC) process is attracting more attention due to the novelty of coal combustion technology. But, to establish its suitability as construction material, it is necessary to characterize it thoroughly with respect to the geotechnical as well as mineralogical points of view. For fulfilling these objectives, the present study mainly aims at characterizing the FBC bottom ash and its comparison with pulverized coal combustion (PCC) bottom ash, collected from the same origin of coal. Suitability of FBC bottom ash as a dike filter material in contrast to PCC bottom ash in replacing traditional filter material such as sand was also studied. The suitability criteria for utilization of both bottom ash and river sand as filter material on pond ash as a base material were evaluated, and both river sand and FBC bottom ash were found to be satisfactory. The study shows that FBC bottom ash is a better geo-material than PCC bottom ash, and it could be highly recommended as an alternative suitable filter material for constructing ash dikes in place of conventional sand.
Increasing Proactive Coping in Organizational Newcomers: Improving Job Adaptation or Rocking the Boat?
Authors: Ślebarska Katarzyna , Soucek Roman , Moser Klaus
Published: March 2018

Proactivity has positive effects for the adaptation to the workplace. This study introduces an intervention that aims to enhance one important resource of newcomer adaptation, proactive coping, by a resource accumulation and controllability intervention for organizational newcomers. The effectiveness of the intervention (a structured booklet) was assessed in a sample of organizational newcomers ( N = 172) within a longitudinal evaluation design (one-pretest double-posttest design with a treatment and a control group). The intervention improved proactive coping and enhanced an important proximal adaptation outcome, role clarity (mediated by proactive coping). However, the intervention also increased intention to quit especially among those newcomers who had previous job experience (i.e., job changers). Overall, the study demonstrates that increasing proactive coping improves the adaptation of organizational newcomers with respect to role clarity and therefore provides a promising starting point for additional intervention programs but also demonstrates limits of such an intervention.