bluuebunny/crossref_metadata_2025 huggingface dataset:
Phenylalanine requirement in children with classical PKU determined by indicator amino acid oxidation
Authors: Courtney-Martin Glenda , Bross Rachelle , Raffi Mahroukh , Clarke Joe T. R. , Ball Ronald O. , Pencharz Paul B.
Published: February 2015

Dietary restriction of phenylalanine is the main treatment for phenylketonuria (PKU), and current estimates of requirements are based on plasma phenylalanine concentration and growth. The present study aimed to determine more precisely the phenylalanine requirements in patients with the disease by use of indicator amino acid oxidation, withl-[1-13C]lysine as the indicator. Breath13CO2production (F13co2) was used as the end point. Finger-prick blood samples were also collected for measurement of phenylalanine to relate phenylalanine intake to blood phenylalanine levels. The mean phenylalanine requirement, estimated using a two-phase linear regression crossover analysis, was 14 mg · kg−1· day−1, and the safe population intake (upper 95% confidence interval of the mean) was found to be 19.5 mg · kg−1· day−1. A balance between phenylalanine intake and the difference between fed and fasted blood phenylalanine concentration was observed at an intake of 20 mg · kg−1· day−1. The similarity between these two values (19.5 and 20 mg · kg−1· day−1) suggests that the maximal phenylalanine intake for children with PKU should be no higher than 20 mg · kg−1· day−1.
Effect of prolactin on phosphate transport and incorporation in mouse mammary gland explants
Authors: Rillema James A.
Published: February 2015

Inorganic phosphate is present in milk at a concentration that is severalfold higher than in maternal plasma. In cultured mammary tissues from 12- to 14-day-pregnant mice, the intracellular concentration of 32PO4 was six times higher than in the culture medium after a 4-h treatment with32PO4. Of the principal lactogenic hormones [insulin (I), cortisol (H), and prolactin (PRL)], only I and PRL (in the presence of H and I) stimulated 32PO4uptake into cultured mammary tissues; H, by itself or in the presence of I or PRL, inhibited 32PO4 uptake. All three lactogenic hormones together effected the greatest stimulation of32PO4 uptake. Similar hormone effects were observed with regard to 32PO4 incorporation into lipids and trichloroacetic acid-insoluble molecules. In a time course study, the onset of the PRL stimulation of32PO4 uptake and incorporation occurred 8–12 h after PRL addition; in dose-response studies, the PRL effect was manifested with PRL concentrations of 50 ng/ml and above. From kinetic studies, the apparent maximal velocity of PO4uptake was determined to be ∼7.7 mM · h−1 · l cell water−1; the apparent Michaelis-Menten constant was ∼3–5 mM. The PRL effect on 32PO4 uptake was abolished when sodium was absent from the uptake medium. These studies thus demonstrate a complex interaction of three hormones (I, H, and PRL) in the regulation of 32PO4 uptake and incorporation into macromolecules in cultured mouse mammary tissues.
Soluble epoxide hydrolase inhibition improves coronary endothelial function and prevents the development of cardiac alterations in obese insulin-resistant mice
Authors: Roche Clothilde , Besnier Marie , Cassel Roméo , Harouki Najah , Coquerel David , Guerrot Dominique , Nicol Lionel , Loizon Emmanuelle , Remy-Jouet Isabelle , Morisseau Christophe , Mulder Paul , Ouvrard-Pascaud Antoine , Madec Anne-Marie , Richard Vincent , Bellien Jeremy
Published: February 2015

This study addressed the hypothesis that inhibiting the soluble epoxide hydrolase (sEH)-mediated degradation of epoxy-fatty acids, notably epoxyeicosatrienoic acids, has an additional impact against cardiovascular damage in insulin resistance, beyond its previously demonstrated beneficial effect on glucose homeostasis. The cardiovascular and metabolic effects of the sEH inhibitor trans-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid ( t-AUCB; 10 mg/l in drinking water) were compared with those of the sulfonylurea glibenclamide (80 mg/l), both administered for 8 wk in FVB mice subjected to a high-fat diet (HFD; 60% fat) for 16 wk. Mice on control chow diet (10% fat) and nontreated HFD mice served as controls. Glibenclamide and t-AUCB similarly prevented the increased fasting glycemia in HFD mice, but only t-AUCB improved glucose tolerance and decreased gluconeogenesis, without modifying weight gain. Moreover, t-AUCB reduced adipose tissue inflammation, plasma free fatty acids, and LDL cholesterol and prevented hepatic steatosis. Furthermore, only the sEH inhibitor improved endothelium-dependent relaxations to acetylcholine, assessed by myography in isolated coronary arteries. This improvement was related to a restoration of epoxyeicosatrienoic acid and nitric oxide pathways, as shown by the increased inhibitory effects of the nitric oxide synthase and cytochrome P-450 epoxygenase inhibitors l-NA and MSPPOH on these relaxations. Moreover, t-AUCB decreased cardiac hypertrophy, fibrosis, and inflammation and improved diastolic function, as demonstrated by the increased E/A ratio (echocardiography) and decreased slope of the end-diastolic pressure-volume relation (invasive hemodynamics). These results demonstrate that sEH inhibition improves coronary endothelial function and prevents cardiac remodeling and diastolic dysfunction in obese insulin-resistant mice.
Albumin impairs renal tubular tight junctions via targeting the NLRP3 inflammasome
Authors: Zhuang Yibo , Hu Caiyu , Ding Guixia , Zhang Yue , Huang Songming , Jia Zhanjun , Zhang Aihua
Published: February 2015

Proteinuria is, not only a hallmark of glomerular disease, but also a contributor to kidney injury. However, its pathogenic mechanism is still elusive. In the present study, the effects of albumin on renal tubular tight junctions and the potential molecular mechanisms of those effects were investigated. In mouse proximal tubular cells (mPTCs), albumin treatment resulted in a significant loss of the cellular tight junction proteins zonula occludens-1 (ZO-1) and claudin-1 in a time- and dose-dependent manner, indicating a severe impairment of the tight junctions. On the basis of our previous study showing that albumin stimulated NLRP3 [neuronal apoptosis inhibitor protein, major histocompatibility complex class 2 transcription activator, incompatibility locus protein from Podospora anserina, and telomerase-associated protein (NACHT); leucine-rich repeat (LRR); and pyrin domain (PYD) domains-containing protein 3] inflammasome activation in mPTCs, we pretreated mPTCs with NLRP3 siRNA (siNLRP3) and found that NLRP3 knockdown significantly blocked the downregulation of ZO-1 and claudin-1 induced by albumin. Similarly, in albumin-overloaded wild-type mice, both ZO-1 and claudin-1 were downregulated at the protein and mRNA levels in parallel with the impaired formation of the tight junctions on transmission electron microscopy and the abnormal renal tubular morphology on periodic acid-Schiff staining, which contrasted with the stimulation of NLRP3 in the renal tubules. In contrast, NLRP3 knockout (NLRP3−/−) mice preserved normal ZO-1 and claudin-1 expression as well as largely normal tight junctions and tubular morphology. More importantly, deletion of the NLRP3 pathway downstream component caspase-1 similarly blocked the albumin overload-induced downregulation of ZO-1 and claudin-1. Taken together, these findings demonstrated an important role of the albumin-NLRP3 inflammasome axis in mediating the impairment of renal tubular tight junctions and integrity.
Role of intraglomerular circuits in shaping temporally structured responses to naturalistic inhalation-driven sensory input to the olfactory bulb
Authors: Carey Ryan M. , Sherwood William Erik , Shipley Michael T. , Borisyuk Alla , Wachowiak Matt
Published: February 2015

Olfaction in mammals is a dynamic process driven by the inhalation of air through the nasal cavity. Inhalation determines the temporal structure of sensory neuron responses and shapes the neural dynamics underlying central olfactory processing. Inhalation-linked bursts of activity among olfactory bulb (OB) output neurons [mitral/tufted cells (MCs)] are temporally transformed relative to those of sensory neurons. We investigated how OB circuits shape inhalation-driven dynamics in MCs using a modeling approach that was highly constrained by experimental results. First, we constructed models of canonical OB circuits that included mono- and disynaptic feedforward excitation, recurrent inhibition and feedforward inhibition of the MC. We then used experimental data to drive inputs to the models and to tune parameters; inputs were derived from sensory neuron responses during natural odorant sampling (sniffing) in awake rats, and model output was compared with recordings of MC responses to odorants sampled with the same sniff waveforms. This approach allowed us to identify OB circuit features underlying the temporal transformation of sensory inputs into inhalation-linked patterns of MC spike output. We found that realistic input-output transformations can be achieved independently by multiple circuits, including feedforward inhibition with slow onset and decay kinetics and parallel feedforward MC excitation mediated by external tufted cells. We also found that recurrent and feedforward inhibition had differential impacts on MC firing rates and on inhalation-linked response dynamics. These results highlight the importance of investigating neural circuits in a naturalistic context and provide a framework for further explorations of signal processing by OB networks.
Distinct neuronal organizations of the caudal cingulate motor area and supplementary motor area in monkeys for ipsilateral and contralateral hand movements
Authors: Nakayama Yoshihisa , Yokoyama Osamu , Hoshi Eiji
Published: February 2015

The caudal cingulate motor area (CMAc) and the supplementary motor area (SMA) play important roles in movement execution. The present study aimed to characterize the functional organization of these regions during movement by investigating laterality representations in the CMAc and SMA of monkeys via an examination of neuronal activity during a button press movement with either the right or left hand. Three types of movement-related neuronal activity were observed: 1) with only the contralateral hand, 2) with only the ipsilateral hand, and 3) with either hand. Neurons in the CMAc represented contralateral and ipsilateral hand movements to the same degree, whereas neuronal representations in the SMA were biased toward contralateral hand movement. Furthermore, recording neuronal activities using a linear-array multicontact electrode with 24 contacts spaced 150 μm apart allowed us to analyze the spatial distribution of neurons exhibiting particular hand preferences at the submillimeter scale. The CMAc and SMA displayed distinct microarchitectural organizations. The contralateral, ipsilateral, and bilateral CMAc neurons were distributed homogeneously, whereas SMA neurons exhibiting identical hand preferences tended to cluster. These findings indicate that the CMAc, which is functionally organized in a less structured manner than the SMA is, controls contralateral and ipsilateral hand movements in a counterbalanced fashion, whereas the SMA, which is more structured, preferentially controls contralateral hand movements.
Unusual Fungal Infections in Renal Transplant Recipients
Authors: Eswarappa Mahesh , Varma P. Vijay , Madhyastha Rakesh , Reddy Sujeeth , Gireesh M. S. , Gurudev K. C. , Mysorekar Vijaya V. , Hemanth Beena
Published: February 2015

Fungal infections are an important cause of morbidity and mortality in renal transplant recipients. The causative agent and the risk factors differ depending on the period after the kidney transplant. Also the incidence varies according to the geographical area. We are reporting three cases of fungal infections in renal transplant recipients. Two of them have etiological agents which are common among immunosuppressed patients, but with an atypical clinical presentation, while one of them is a subcutaneous infection caused by a less frequent dematiaceous fungus,Aureobasidium pullulans. These cases highlight how a high index of clinical suspicion and prompt diagnosis is very much essential for better outcome. The emerging fungal infections and paucity of data regarding their management pose a challenge to the transplant physicians.
Formulation and Evaluation of Galantamine Gel as Drug Reservoir in Transdermal Patch Delivery System
Authors: Fong Yen Woo , Basri Mahiran , Ahmad Mansor , Ismail Maznah
Published: February 2015

Galantamine hydrobromide is formulated in tablets and capsules prescribed through oral delivery for the treatment of Alzheimer’s disease. However, oral delivery of drugs can cause severe side effects such as nausea, vomiting, and gastrointestinal disturbance. Transdermal delivery of galantamine hydrobromide could avoid these unwanted side effects. In this work, galantamine hydrobromide was formulated in gel drug reservoir which was then fabricated in the transdermal patch. The in vitro drug release studies revealed that the drug release from the donor chamber to receptor chamber of Franz diffusion cell was affected by the amount of polymer, amount of neutralizer, amount of drug, types of permeation enhancer, and amount of permeation enhancer. Visual observations of the gels showed that all formulated gels are translucent, homogeneous, smooth, and stable. These gels have pH in the suitable range for skin. The gel also showed high drug content uniformity. Hence, this formulation can be further used in the preparation of transdermal patch drug delivery system.
Unusual Initial Presentation of Herpes Simplex Virus as Inguinal Lymphadenopathy
Authors: Fleming Sarah A. , Strickler John G.
Published: February 2015

Genital herpes simplex virus (HSV) infections are a common cause of inguinal lymphadenopathy. However, surgical excision of enlarged inguinal nodes is almost never performed to initially diagnose genital herpes simplex virus, due to the distinct external presentation of genital herpetic vesicles that usually occur with the first symptoms of infection. Therefore, the histologic and immunophenotypic features of HSV-associated inguinal lymphadenopathy are unfamiliar to most pathologists. The current report describes the lymph node pathology of two immunocompetent patients, whose initial HSV diagnosis was established through surgical excision of enlarged inguinal lymph nodes. Histologic examination showed features consistent with viral lymphadenopathy, including florid follicular hyperplasia, monocytoid B-cell hyperplasia, and paracortical hyperplasia without extensive necrosis. Immunohistochemical stains for HSV antigens, using polyclonal anti-HSV I and II antibodies, demonstrate strong immunoreactivity for HSV in a small number of cells in the subcapsular sinuses, especially in areas with monocytoid B-cell hyperplasia. Rare scattered HSV-positive cells also are identified in paracortical areas and germinal centers. We conclude that an initial diagnosis of genital HSV infection may be established by inguinal lymph node biopsy.
Laparoscopic Treatment of a Spontaneously Ruptured Kidney (Wunderlich Syndrome)
Authors: Bretterbauer Katharina Maria , Markić Dean , Colleselli Daniela , Hruby Stephan , Magdy Ahmed , Janetschek Günter , Mitterberger Michael Josef
Published: February 2015

Spontaneous, nontraumatic retroperitoneal hemorrhage or Wunderlich syndrome (WS) is a rare but potential life-threatening condition. In most patients a bleeding renal neoplasm is the cause of the retroperitoneal hematoma. The management of this condition includes a conservative approach in the hemodynamically stable patients and active treatment in the unstable patients. Active treatment includes angioembolization or surgery. If angioembolization is not available open surgery is in most cases the preferred approach. We present a patient with a spontaneously ruptured kidney due to a central renal angiomyolipoma, which was treated by laparoscopic nephrectomy.
Rapid Fabrication of Periodic Patterns on Poly(styrene-co-acrylonitrile) Surfaces Using Direct Laser Interference Patterning
Authors: Broglia Martin F. , Acevedo Diego F. , Langheinrich Denise , Perez-Hernandez Heidi R. , Barbero Cesar A. , Lasagni Andrés F.
Published: February 2015

Periodic microstructures in styrene-acrylonitrile (SAN) copolymers are fabricated by two-beam direct laser interference patterning using a nanosecond pulsed laser operating at a wavelength of 266 nm. The SAN copolymers are synthesized using different molar ratios (styrene to acrylonitrile) by a free radical polymerization process. The chemical composition of the copolymers and their properties are determined using Fourier transformed infrared spectroscopy (FTIR) and differential scanning calorimetry (DSC). Depending on the composition of the irradiated copolymer films, with weight ratios ranging from 58 to 96.5% of styrene to acrylonitrile, different ablation behaviors are observed. The laser fluence necessary to locally ablate the copolymer is found to be dependent on the copolymer composition. Unlike other dielectric polymers, the laser irradiation produced both direct ablation of the irradiated material and collapse of the surface. It is shown that, by varying the laser fluence and the copolymer composition, the surface structure can be changed from a periodic pattern with a swelled topography to an ablated-like structure. The number of holes does not depend monotonically on the amount of PS or PAN units but shows a more complex behavior which depends on the copolymer composition and the laser fluence.
Survival among HIV-Infected and HIV-Uninfected Individuals with Common Non–AIDS-Defining Cancers
Authors: Marcus Julia L. , Chao Chun , Leyden Wendy A. , Xu Lanfang , Yu Jeanette , Horberg Michael A. , Klein Daniel , Towner William J. , Quesenberry Charles P. , Abrams Donald I. , Silverberg Michael J.
Published: February 2015

Background: Non–AIDS-defining cancers increasingly contribute to mortality among human immunodeficiency virus (HIV)–infected individuals. However, few studies have compared cancer prognosis by HIV status with adjustment for risk factors.

Methods: We conducted a cohort study of HIV-infected and HIV-uninfected adults in Kaiser Permanente California during 1996 to 2011, following subjects diagnosed with Hodgkin lymphoma or anal, prostate, colorectal, or lung cancers. We used Kaplan–Meier curves and Cox regression to assess cancer-related mortality within 5 years, comparing HIV-infected with HIV-uninfected subjects. Adjusted models included age, race/ethnicity, sex, cancer stage, cancer treatment, and smoking.

Results: Among HIV-infected and HIV-uninfected subjects, there were 68 and 51 cases of Hodgkin lymphoma, 120 and 28 of anal cancer, 150 and 2,050 of prostate cancer, 53 and 646 of colorectal cancer, and 80 and 507 of lung cancer, respectively. Five-year cancer-related survival was reduced for HIV-infected compared with HIV-uninfected subjects, reaching statistical significance for lung cancer (10% vs. 19%, P = 0.002) but not Hodgkin lymphoma (83% vs. 89%, P = 0.40) or anal (64% vs. 74%, P = 0.38), prostate (86% vs. 92%, P = 0.074), or colorectal cancers (49% vs. 58%, P = 0.55). Adjusted results were similar, with lung cancer [HR, 1.3; 95% confidence interval (CI), 1.0–1.7] and prostate cancer (HR, 2.1; 95% CI, 1.1–4.1) reaching significance.

Conclusions: Cancer-related mortality was higher among HIV-infected compared with HIV-uninfected individuals for prostate and lung cancers, but not Hodgkin lymphoma, anal cancer, or colorectal cancer.

Impact: Our findings emphasize the need for a focus on prevention, early detection, and adequate treatment of cancer among HIV-infected individuals. Cancer Epidemiol Biomarkers Prev; 24(8); 1167–73. ©2015 AACR.

See related commentary by Coghill and Engels, p. 1165
CAR-T Cells Inflict Sequential Killing of Multiple Tumor Target Cells
Authors: Davenport Alexander J. , Jenkins Misty R. , Cross Ryan S. , Yong Carmen S. , Prince H. Miles , Ritchie David S. , Trapani Joseph A. , Kershaw Michael H. , Darcy Phillip K. , Neeson Paul J.
Published: February 2015

Adoptive therapy with chimeric antigen receptor (CAR) T cells shows great promise clinically. However, there are important aspects of CAR-T-cell biology that have not been explored, particularly with respect to the kinetics of activation, immune synapse formation, and tumor cell killing. Moreover, the effects of signaling via the endogenous T-cell receptor (TCR) or CAR on killing kinetics are unclear. To address these issues, we developed a novel transgenic mouse (designated CAR.OT-I), in which CD8+ T cells coexpressed the clonogenic OT-I TCR, recognizing the H-2Kb–presented ovalbumin peptide SIINFEKL, and an scFv specific for human HER2. Primed CAR.OT-I T cells were mixed with SIINFEKL-pulsed or HER2-expressing tumor cells and visualized in real-time using time-lapse microscopy. We found that engagement via CAR or TCR did not affect cell death kinetics, except that the time from degranulation to CAR-T-cell detachment was faster when CAR was engaged. We showed, for the first time, that individual CAR.OT-I cells can kill multiple tumor cells (“serial killing”), irrespective of the mode of recognition. At low effector:target ratios, the tumor cell killing rate was similar via TCR or CAR ligation over the first 20 hours of coincubation. However, from 20 to 50 hours, tumor cell death mediated through CAR became attenuated due to CAR downregulation throughout the time course. Our study provides important insights into CAR-T–tumor cell interactions, with implications for single- or dual receptor–focused T-cell therapy. Cancer Immunol Res; 3(5); 483–94. ©2015 AACR.

See related commentary by June, p. 470
Assessment of Apparent Diffusion Coefficient of Normal Fetal Brain Development from Gestational Age Week 24 Up to Term Age: A Preliminary Study
Authors: Han Rui , Huang Lu , Sun Ziyan , Zhang Dongyou , Chen Xinlin , Yang Xiaohong , Cao Zhongqiang
Published: February 2015

Objectives: This study was designed to investigate the feasibility of apparent diffusion coefficient (ADC) values in evaluating normal fetal brain development from gestational week 24 up to term age. Methods: Diffusion-weighted imaging (DWI) was performed on 40 normal fetuses (with normal results on sonography and normal fetal MRI results), with two b-values of 0 and 600 s/mm2 in the three (x, y, z) orthogonal axes. Ten regions of interest (ROIs) were manually placed symmetrically in the bilateral frontal white matter (FWM), occipital white matter (OWM), thalamus (THAL), basal ganglia (BG), and cerebellar hemispheres (CH). ADC values of the ten ROIs in all subjects were measured by two radiologists independently. One-way ANOVA was used to calculate the differences among the five regions in the fetal brain and linear regression analysis was used to evaluate the correlation between ADC values and gestational age (GA). p < 0.05 was considered significantly different. Results: Mean GA was 31.3 ± 3.9 (range 24-41) weeks. The overall mean ADC values (×10-6 mm2/s) of the fetuses were 1,800 ± 214 (FWM), 1,400 ± 100 (BG), 1,300 ± 126 (THAL), 1,700 ± 133 (OWM) and 1,400 ± 155 (CH), respectively. The ADC value of BG was not significantly different from those of THAL and CH, while the other four ROIs had significant differences with each other. The ADC values of BG, THAL, OWM and CH had strong negative correlations with increasing GA (R were -0.568, -0.716, -0.830 and -0.700, respectively, all p < 0.01), OWM declined fastest with GA, followed by CH and THAL, the slowest being BG. The ADC value of FWM had no significant change with GA (p = 0.366). Conclusions: The measurement of ADC values is feasible to evaluate fetal brain development with high reliability and reproducibility.
Postnatal Outcome in Cases of Prenatally Diagnosed Fetal Ovarian Cysts under Conservative Prenatal Management
Authors: Nakamura Manabu , Ishii Keisuke , Murata Masaharu , Sasahara Jun , Mitsuda Nobuaki
Published: February 2015

Aim: To evaluate the outcome of cases of prenatally diagnosed fetal ovarian cyst under conservative prenatal management. Methods: This retrospective cohort study included patients diagnosed between January 2005 and August 2013. They were managed expectantly during pregnancy and followed up until spontaneous regression of the cyst or postnatal surgery. The outcomes of fetal ovarian cysts were compared combined appearance as being simple or complex at prenatal scan and maximum size of cysts ≥40 or <40 mm. Results: There were 33 study cases. Prenatally 3/33 cases (9%) had spontaneous cyst regression during pregnancy. 14 cysts (42%) were treated surgically, of which torsion was confirmed in 4 (29%). Another 14/33 cases (42%) regressed spontaneously under conservative management after birth. The ovaries could be preserved in 28 patients (85%). The incidence of torsion between complex cysts and simple cysts was not statistically different. The incidence of torsion between patients with cyst size ≥40 and <40 mm was similar. Conclusions: The ovaries could be preserved in approximately 85% of patients under conservative management. The present study could not reveal the significance of prenatal ultrasonographic findings of fetal ovarian cyst for predicting the outcome of patients' ovaries.
Amino acid residues in the laminin G domains of protein S involved in tissue factor pathway inhibitor interaction
Authors: Somajo Sofia , Ahnström Josefin , Fernandez-Recio Juan , Gierula Magdalena , Villoutreix Bruno O. , Dahlbäck Björn
Published: February 2015

Protein S functions as a cofactor for tissue factor pathway inhibitor (TFPI) and activated protein C (APC). The sex hormone binding globulin (SHBG)-like region of protein S, consisting of two laminin G-like domains (LG1 and LG2), contains the binding site for C4b-binding protein (C4BP) and TFPI. Furthermore, the LG-domains are essential for the TFPI-cofactor function and for expression of full APC-cofactor function. The aim of the current study was to localise functionally important interaction sites in the protein S LG-domains using amino acid substitutions. Four protein S variants were created in which clusters of surface-exposed amino acid residues within the LG-domains were substituted. All variants bound normally to C4BP and were fully functional as cofactors for APC in plasma and in pure component assays. Two variants, SHBG2 (E612A, I614A, F265A, V393A, H453A), involving residues from both LG-domains, and SHBG3 (K317A, I330A, V336A, D365A) where residues in LG1 were substituted, showed 50–60 % reduction in enhancement of TFPI in FXa inhibition assays. For SHBG3 the decreased TFPI cofactor function was confirmed in plasma based thrombin generation assays. Both SHBG variants bound to TFPI with decreased affinity in surface plasmon resonance experiments. The TFPI Kunitz 3 domain is known to contain the interaction site for protein S. Using in silico analysis and protein docking exercises, preliminary models of the protein S SHBG/TFPI Kunitz domain 3 complex were created. Based on a combination of experimental and in silico data we propose a binding site for TFPI on protein S, involving both LGdomains.
Synchronous Systolic Subcellular Ca
2+
-Elevations Underlie Ventricular Arrhythmia in Drug-Induced Long QT Type 2
Authors: Kim Jong J. , Němec Jan , Li Qiao , Salama Guy
Published: February 2015

Background—

Repolarization delay is a common clinical problem, which can promote ventricular arrhythmias. In myocytes, abnormal sarcoplasmic reticulum Ca
2+
-release is proposed as the mechanism that causes early afterdepolarizations, the cellular equivalent of ectopic-activity in drug-induced long-QT syndrome. A crucial missing link is how such a stochastic process can overcome the source–sink mismatch to depolarize sufficient ventricular tissue to initiate arrhythmias.

Methods and Results—

Optical maps of action potentials and Ca
2+
-transients from Langendorff rabbit hearts were measured at low (150×150 μm
2
/pixel) and high (1.5×1.5 μm
2
/pixel) resolution before and during arrhythmias. Drug-induced long QT type 2, elicited with dofetilide inhibition of IKr (the rapid component of rectifying K+ current), produced spontaneous Ca
2+
-elevations during diastole and systole, before the onset of arrhythmias. Diastolic Ca
2+-
waves appeared randomly, propagated within individual myocytes, were out-of-phase with adjacent myocytes, and often died-out. Systolic secondary Ca
2+-
elevations were synchronous within individual myocytes, appeared 188±30 ms after the action potential-upstroke, occurred during high cytosolic Ca
2+
(40%–60% of peak-Ca
2+
-transients), appeared first in small islands (0.5×0.5 mm
2
) that enlarged and spread throughout the epicardium. Synchronous systolic Ca
2+-
elevations preceded voltage-depolarizations (9.2±5 ms; n=5) and produced pronounced Spatial Heterogeneities of Ca
2+
-transient-durations and action potential-durations. Early afterdepolarizations originating from sites with the steepest gradients of membrane-potential propagated and initiated arrhythmias. Interestingly, more complex subcellular Ca
2+
-dynamics (multiple chaotic Ca
2+
-waves) occurred during arrhythmias. K201, a ryanodine receptor stabilizer, eliminated Ca
2+
-elevations and arrhythmias.

Conclusions—

The results indicate that systolic and diastolic Ca
2+
-elevations emanate from sarcoplasmic reticulum Ca
2+
-release and systolic Ca
2+
-elevations are synchronous because of high cytosolic and luminal-sarcoplasmic reticulum Ca
2+
, which overcomes source–sink mismatch to trigger arrhythmias in intact hearts.
Activities of Daily Living and Outcomes in Heart Failure
Authors: Dunlay Shannon M. , Manemann Sheila M. , Chamberlain Alanna M. , Cheville Andrea L. , Jiang Ruoxiang , Weston Susan A. , Roger Véronique L.
Published: February 2015

Background—

Chronic disease can contribute to functional disability, which can degrade quality of life. However, the prevalence of functional disability and its association with outcomes among patients with heart failure requires further study.

Methods and Results—

Southeastern Minnesota residents with heart failure were enrolled from September 2003 through January 2012 into a cohort study with follow-up through December 2012. Difficulty with 9 activities of daily living (ADLs) was assessed by a questionnaire. Patients were divided into 3 categories of ADL difficulty (no/minimal, moderate, severe). The associations of ADL difficulty with mortality and hospitalization were assessed using Cox and Andersen-Gill models. Among 1128 patients (mean age, 74.7 years; 49.2% female), a majority (59.4%) reported difficulty with one or more ADLs at enrollment, with 272 (24.1%) and 146 (12.9%) experiencing moderate and severe difficulty, respectively. After a mean (SD) follow-up of 3.2 (2.4) years, 614 patients (54.4%) had died. Mortality increased with increasing ADL difficulty; the hazard ratio (95% confidence interval) for death was 1.49 (1.22–1.82) and 2.26 (1.79–2.86) for those with moderate and severe difficulty, respectively, compared to those with no/minimal difficulty (
P
trend
<0.001). Patients with moderate and severe difficulty were at an increased risk for all-cause and noncardiovascular hospitalization. In a second assessment, 17.7% of survivors reported more difficulty with ADLs and patients with persistently severe or worsening difficulty were at an increased risk for death (hazard ratio, 2.10; 95% confidence interval, 1.71–2.58;
P
<0.001) and hospitalization (hazard ratio, 1.51; 95% confidence interval, 1.31–1.74;
P
<0.001).

Conclusions—

Functional disability is common in patients with heart failure, can progress over time, and is associated with adverse prognosis.
The Mitochondrial Permeability Transition Pore Regulates Endothelial Bioenergetics and Angiogenesis
Authors: Marcu Raluca , Kotha Surya , Zhi Zhongwei , Qin Wan , Neeley Christopher K. , Wang Ruikang K. , Zheng Ying , Hawkins Brian J.
Published: February 2015

Rationale:

The mitochondrial permeability transition pore is a well-known initiator of cell death that is increasingly recognized as a physiological modulator of cellular metabolism.

Objective:

We sought to identify how the genetic deletion of a key regulatory subunit of the mitochondrial permeability transition pore, cyclophilin D (CypD), influenced endothelial metabolism and intracellular signaling.

Methods and Results:

In cultured primary human endothelial cells, genetic targeting of CypD using siRNA or shRNA resulted in a constitutive increase in mitochondrial matrix Ca
2+
and reduced nicotinamide adenine dinucleotide (NADH). Elevated matrix NADH, in turn, diminished the cytosolic NAD
+
/NADH ratio and triggered a subsequent downregulation of the NAD
+
-dependent deacetylase sirtuin 1 (SIRT1). Downstream of SIRT1, CypD-deficient endothelial cells exhibited reduced phosphatase and tensin homolog expression and a constitutive rise in the phosphorylation of angiogenic Akt. Similar changes in SIRT1, phosphatase and tensin homolog, and Akt were also noted in the aorta and lungs of CypD knockout mice. Functionally, CypD-deficient endothelial cells and aortic tissue from CypD knockout mice exhibited a dramatic increase in angiogenesis at baseline and when exposed to vascular endothelial growth factor. The NAD
+
precursor nicotinamide mononucleotide restored the cellular NAD
+
/NADH ratio and normalized the CypD-deficient phenotype. CypD knockout mice also presented accelerated wound healing and increased neovascularization on tissue injury as monitored by optical microangiography.

Conclusions:

Our study reveals the importance of the mitochondrial permeability transition pore in the regulation of endothelial mitochondrial metabolism and vascular function. The mitochondrial regulation of SIRT1 has broad implications in the epigenetic regulation of endothelial phenotype.
Contemporary Trends and Predictors of Postacute Service Use and Routine Discharge Home After Stroke
Authors: Prvu Bettger Janet , McCoy Lisa , Smith Eric E. , Fonarow Gregg C. , Schwamm Lee H. , Peterson Eric D.
Published: February 2015

Background

Returning home after the hospital is a primary aim for healthcare; however, additional postacute care (
PAC
) services are sometimes necessary for returning stroke patients to their pre‐event status. Recent trends in hospital discharge disposition specifying
PAC
use have not been examined across age groups or health insurance types.

Methods and Results

We examined trends in discharge to inpatient rehabilitation facilities (
IRFs
), skilled nursing facilities (
SNFs
), home with home health (
HH
), and home without services for 849 780 patients ≥18 years of age with ischemic or hemorrhagic stroke at 1687 hospitals participating in Get With The Guidelines—Stroke. Multivariable analysis was used to identify factors associated with discharge to any
PAC
(
IRF
,
SNF
, or
HH
) versus discharge home without services. From 2003 to 2011, there was a 2.1% increase (unadjusted
P
=0.001) in
PAC
use after a stroke hospitalization. Change was greatest in
SNF
use, an 8.3% decrease over the period.
IRF
and
HH
increased 6.9% and 3.6%, respectively. The 2 strongest clinical predictors of
PAC
use after acute care were patients not ambulating on the second day of their hospital stay (ambulation odds ratio [
OR
], 3.03; 95% confidence interval [
CI
], 2.86 to 3.23) and those who failed a dysphagia screen or had an order restricting oral intake (
OR
, 2.48; 95%
CI
, 2.37 to 2.59).

Conclusions

Four in 10 stroke patients are discharged home without services. Although little has changed overall in
PAC
use since 2003, further research is needed to explain the shift in service use by type and its effect on outcomes.
Natural History and Management of Basilar Trunk Artery Aneurysms
Authors: Saliou Guillaume , Sacho Raphael H. , Power Sarah , Kostynskyy Alex , Willinsky Robert A. , Tymianski Michael , terBrugge Karel G. , Rawal Sapna , Krings Timo
Published: February 2015

Background and Purpose—

Basilar trunk aneurysms (BTAs), defined as aneurysms distal to the basilar origin and proximal to the origin of the superior cerebellar artery, are rare and challenging to manage. We describe the natural history and management in a consecutive series of BTAs.

Methods—

Between 2000 and 2013, 2522 patients with 3238 aneurysms were referred to our institution for aneurysm management. A retrospective review of this database was conducted to identify all patients with BTAs.

Results—

In total, 52 patients had a BTA. Mean age was 56 (SD±18) years. Median clinical follow-up was 33 (interquartile range, 8–86) months, and imaging follow-up was 26 (interquartile range, 2–80.5) months. BTAs were classified into 4 causal subtypes: acute dissecting aneurysms, segmental fusiform ectasia, mural bleeding ectasia, and saccular aneurysms. Multiple aneurysms were more frequently noticed among the 13 saccular aneurysms when compared with overall population (
P
=0.021). There was preponderance of segmental ectasia or mural bleeding ectasia (
P
=0.045) in patients presenting with transit ischemic attack/stroke or mass effect. Six patients with segmental and 4 with mural bleeding ectasia demonstrated increasing size of their aneurysm, with 2 having subarachnoid hemorrhage caused by aneurysm rupture. None of the fusiform aneurysms that remained stable bled.

Conclusions—

BTAs natural histories may differ depending on subtype of aneurysm. Saccular aneurysms likely represent an underlying predisposition to aneurysm development because more than half of these cases were associated with multiple intracranial aneurysms. Intervention should be considered in segmental ectasia and chronic dissecting aneurysms, which demonstrate increase in size over time as there is an increased risk of subarachnoid hemorrhage.
“As You Are Brothers of Mine”: Thoreau and the Irish
Authors: Walls Laura Dassow
Published: February 2015

Did Thoreau really hate the Irish? No, but he did hate seeing his Irish neighbors buying into Yankee consumerism. While Irish wage-slavery becomes the crisis of Walden, elsewhere Thoreau admires and envies the Irish, figures for redemption: his quarrel with them becomes a quarrel with himself, then a quarrel with America.
Foundations of the Consensus against Surrogacy Arrangements in Islamic Law
Authors: Shabana Ayman
Published: February 2015

This essay traces the emergence and development of the consensus against surrogacy arrangements, mostly in the Sunni world, on the basis of a number of institutional fatwas, recommendations, and decisions. Despite this consensus against surrogacy, jurists discuss in detail its potential effects if it is performed. This juristic attitude reflects an understanding of sharīʿah as a legal system that not only institutes rules for cases that match its moral vision but also regulates the consequences of cases that do not match that vision. In the absence of clear and binding legislation on surrogacy in most Muslim-majority countries, this body of religious and ethical deliberations represents the main resource for moral decision-making on surrogacy and its impact on the genealogical connections within the nuclear family.
The Linguistic Reflexes of Ontological Dependence
Authors: Szekely Rachel
Published: February 2015

Nouns used to pick out ontologically dependent entities such as holes and flaws, unlike those picking out “ordinary” entities, such as coats and tables, cannot felicitously stand as indefinite subjects of a locative copular sentence (#A hole is in the bucket), but appear freely in there-sentences (There is a hole in the bucket). This contrast is further evidence in favour of the idea that the two sentence types have different underlying predication structures (cf. Barwise and Cooper, 1981; Francez, 2007; Hazout, 2004; McNally 1998a; Williams, 1984, 1994), but also that the preposition in, occurring in both constructions, is ambiguous between a locative and relational meaning. That locative in is distinct from the in that relates a dependent entity to its host is confirmed by inferences between and among sentences containing these two forms. Locative in, whose meaning is roughly that of enclosure or containment, is licensed as a predicate in a locative copular sentence; this sentence type is used to state the location of an entity. However, because a dependent entity’s location is entirely contingent on its host, it cannot be felicitously introduced in this way. By contrast, it is possible to introduce a dependent entity by stating that its host has the dependent entity in it, which is what a there-sentence does. Following Hornstein, Uriagereka and Rosen (1994), the underlying representation of a there-sentence which realizes this relation does not contain a preposition; rather, relational in is derived via incorporation into the copula, like have (Kayne, 1993).
Marked Subjects in Old Finnish
Authors: de Smit Merlijn
Published: February 2015

In the following article, I argue that syntactic borrowing is not an independent mechanism of change, but based on bilingual reanalysis and extension. As a case sample, I examine a frequent modal construction in Old Finnish, namely that involving the auxiliary pitää ‘must’. Where in Modern Finnish this auxiliary takes a genitive or nominative argument depending on such factors as agentivity and clause transitivity, the argument is object-like in a number of Old Finnish texts. I purport to show that this phenomenon rests on the influence of the Latin model pattern of oportet ‘must’ and its accusative and infinitive construction. At the same time, model patterns internal to Old Finnish, specifically those of participial complements to verbs of perception and communication, where the agent of the participle is syntactically the object of the matrix clause, may also have contributed to this development. I argue that in terms of mechanism, the influence of foreign model patterns (oportet) and internal model patterns (the participial constructions) cannot be distinguished: both proceed by reanalysis and (analogical) extension.
Who “laid him in a manger”?
Authors: Graham Jean E.
Published: February 2015

Although female figures from the Bible are largely absent from the poetry of George Herbert, Henry Vaughan, and Thomas Traherne, a few poems treat female biblical characters in a substantive way. Yet even in these poems, biblical women are more passive and more silent than in the Bible, and each of these poems must be considered in the context of a poetic corpus which reinforces female passivity and silence. Overall, in drawing from the biblical narrative the poets follow two patterns: the omission of biblical women, leaving the corresponding male figures; and a treatment of the remaining female figures in which they are usually rendered passive, sometimes objectified, and always silenced.
Beliefs and knowledge about the human papillomavirus vaccine among undergraduate men
Authors: Hunter Theresa , Weinstein Melissa
Published: February 2015

Objective:

The objective of this study was to assess male undergraduate students’ human papillomavirus (HPV) knowledge and intentions to receive the HPV vaccination.

Design:

Cross-sectional survey.

Method:

A sample of 116 male undergraduate students from a university in the Midwestern USA completed a survey questionnaire assessing various aspects related to their attitudes towards the HPV vaccine.

Results:

Results show that awareness and levels of knowledge about HPV and the HPV vaccine were low among male undergraduate students. The study also found that intentions to receive the HPV vaccine were very low among this population.

Conclusion:

The results of this study should encourage the developmental and implementation of campus-wide health education programmes which discuss the HPV vaccine and benefits for men.
Experiences Among Undocumented Migrants Accessing Primary Care in the United Kingdom
Authors: Poduval Shoba , Howard Natasha , Jones Lucy , Murwill Phil , McKee Martin , Legido-Quigley Helena
Published: February 2015

Immigration is a key political issue in the United Kingdom. The 2014 Immigration Act includes a number of measures intended to reduce net immigration, including removing the right of non-European Economic Area migrants to access free health care. This change risks widening existing health and social inequalities. This study explored the experiences of undocumented migrants trying to access primary care in the United Kingdom, their perspectives on proposed access restrictions, and suggestions for policymakers. Semi-structured interviews were conducted with 16 undocumented migrants and four volunteer staff at a charity clinic in London. Inductive thematic analysis drew out major themes. Many undocumented migrants already faced challenges accessing primary care. None of the migrants interviewed said that they would be able to afford charges to access primary care and most said they would have to wait until they were much more unwell and access care through Accident & Emergency (A&E) services. The consequences of limiting access to primary care, including threats to individual and public health consequences and the additional burden on the National Health Service, need to be fully considered by policymakers. The authors argue that an evidence-based approach would avoid legislation that targets vulnerable groups and provides no obvious economic or societal benefit.
ED Law
Authors: Darden Edwin C.
Published: February 2015

Student vaccinations, immunizations, and inoculations are a fact of life. The mandatory injections are a state’s way of protecting the health and safety of all public students, employees, and visitors. All 50 states have laws requiring school vaccinations. State laws unflinchingly require parents to prove that their child’s vaccinations are up-to-date before the youngster can enroll in public school or even remain in class. Massachusetts passed the first law requiring vaccines for schoolchildren in 1855. For some parents, such requirements are a government overreach. Those parents routinely turn to the courts for relief — they also routinely lose. From the early 1900s, antivaccination lawsuits (including those against school districts) have been spectacularly unsuccessful. Parents base their objections on moral, religious, medical, economic, and other grounds. But unless state law has carved out a specific exemption, courts are largely unsympathetic.
Living with Ghosts
Authors: Garrard-Burnett Virginia
Published: February 2015

Although more than three decades have passed since Guatemala’s 36-year-long civil war, bereavement and posttraumatic stress continue to affect many survivors of that dark era, especially since it is only now that a few of the most infamous perpetrators of the violence have recently, if briefly, been brought to justice. The Maya were especially severely affected by the massacres and disappearances of the armed conflict. Because the ongoing relationship between the dead and the living that Maya value requires that the deceased receive proper burial, the exhumation and reburial of war dead have had cathartic effects for the survivors and have actively contributed to the construction of historical memory.

Aunque han pasado más de tres décadas desde la guerra civil de 36 años en Guatemala, la aflicción por la pérdida de seres queridos y el estrés post traumático continúan afectando a muchos sobrevivientes de esa era oscura, especialmente porque es sólo hasta hace poco que algunos de los más infames autores de la violencia han sido llevados ante los trbunales aunque sólo brevemente. Los mayas especialmente fueron gravemente afectados por las masacres y las desapariciones del conflicto armado. Ya que la relación existente entre los muertos y los vivos que los mayas valoran requiere que los muertos reciban una digna sepultura, la exhumación y el nuevo entierro de los muertos en la guerra han tenido efectos catárticos en los sobrevivientes y han contribuido activamente a construir la memoria histórica.