bluuebunny/crossref_metadata_2025 huggingface dataset:
Application of a health‐related quality of life conceptual model in community‐dwelling older Chinese people with diabetes to understand the relationships among clinical and psychological outcomes
Authors: Shiu Ann Tak Ying , Choi Kai Chow , Lee Diana Tze Fan , Yu Doris Sau Fung , Man Ng Wai
Published: February 2014

Aims/Introduction

The present study applied the Wilson–Cleary model of health‐related quality of life (HRQOL) by using the structural equation modeling (SEM) approach to understand the interrelationships among clinical, sociodemographic and psychological characteristics in older people with diabetes.

Materials and Methods

This was a cross‐sectional study with 452 Chinese older people with diabetes recruited from three primary care clinics. A series of assessments were made, including four instruments: the Chinese version of the Short Form 36 Health Survey, Older American Resources and Services Multidimensional Functional Assessment Questionnaire, Rand Mental Health Inventory and Medical Outcomes Study Social Support Survey; and clinical outcomes (diabetes‐related characteristics and physiological data).

Results

In the present study, we identified six patient individual and environmental characteristics, namely, age, sex, physical activity, psychological distress, social support and adequacy of income, that significantly influence HRQOL directly or by way of physical functional status and general health perception.

Conclusions

Improving social and financial support as well as providing interventions to promote physical activity and to cope with psychological distress in this patient population might be effective to eventually enhance their HRQOL. The present findings add to the literature the underlying complex biological and psychological processes of HRQOL, and take the body of knowledge in HRQOL of older people with diabetes to a theoretical level, and provide insights for development of appropriate strategies to optimize their HRQOL.
cDNA cloning and expression characterization of serum transferrin gene from oriental weatherfish Misgurnus anguillicaudatus
Authors: Chen J. H. , Wang C. H. , Li Y. L. , Wang H. M. , Zhang X. J. , Yan B. L.
Published: February 2014

In this study, the cDNA coding serum transferrin (stf) of Misgurnus anguillicaudatus (mastf) was cloned. mastf cDNA is composed of 2326 bp with a 2007 bp open reading frame encoding 668 amino acids. The deduced Mastf protein consists of a signal peptide, two lobes (N and C‐lobes) and signature motifs of transferrin (Tf) family. The results of tissue distribution indicated that mastf mRNA was predominantly expressed in the liver. The results indicate that the mastf expression increased significantly in liver, blood, spleen and head kidney after the challenge with Aeromonas sobria, acting as a positive acute protein, suggesting that mastf is related to the immune response. The cloning and expression analysis of mastf further demonstrates the evolutionary conservation of Stf and immune function in vertebrates.
PNPLA3 in end‐stage liver disease: Alcohol consumption, hepatocellular carcinoma development, and transplantation‐free survival
Authors: Friedrich Kilian , Wannhoff Andreas , Kattner Stefan , Brune Maik , Hov Johannes Roksund , Weiss Karl Heinz , Antoni Christoph , Dollinger Matthias , Neumann‐Haefelin Christoph , Seufferlein Thomas , Schemmer Peter , Schirmacher Peter , Stremmel Wolfgang , Gotthardt Daniel Nils
Published: February 2014

Background and Aims

The rs738409 variant (I148M) of the patatin‐like phospholipase domain‐containing protein 3 (PNPLA3) gene is associated with several liver malfunctions. Its impact on end‐stage liver disease has not been addressed yet.

Methods

The I148M polymorphism was genotyped in a well‐characterized cohort of 421 Caucasian patients and retrospectively analyzed from the time of enrollment at Eurotransplant.

Results

The G allele of the I148M variant was significantly overrepresented in patients with alcoholic liver disease (ALD, P < 0.001) and associated with hepatocellular carcinoma (HCC) development (odds ratio [OR] = 2.399; 95% confidence interval [CI]: 1.292–4.455; P = 0.008) while not affecting the other liver disease entities. Time until hydropic decompensation (P = 0.04) and hepatic encephalopathy (P = 0.043) was significantly impaired for ALD patients carrying either one or two mutated G alleles. Actuarial survival free of liver transplantation was further reduced for ALD carriers of the I148M variant (CC = 30.7 months ± 7.9, 95% CI: 15.1–46.2 vs CG/GG: 17.1 months ± 3.3, 95% CI: 3.3–10.6; P = 0.012) compared with wild‐type patients. Cox multivariate analysis identified the PNPLA3 I148M genotype as an independent predictor actuarial survival free of liver transplantation (OR = 1.77; 95% CI: 1.27–2.47; P = 0.001).

Conclusions

In end‐stage liver disease patients, we identified ALD to be predominantly affected by the PNPLA3 I148M variant resulting in an increased risk of HCC and reduced transplantation free survival. Genetic testing of the I148M genotype in ALD patients awaiting liver transplantation might be beneficial for these patients.
Amyloid‐β concentration and structure influences the transport and immunomodulatory effects ofIVIG
Authors: Wuest Diane M. , Lee Kelvin H.
Published: February 2014

Intravenous immunoglobulin (IVIG) contains anti‐amyloid‐β antibodies as well as antibodies providing immunomodulatory effects that may modify chronic inflammation in Alzheimer's disease. Answers to important questions about IVIG transport into the central nervous system and assessments of any impact amyloid‐β has on this transport can be provided byin vitromodels of the blood–brain barrier. In this study, amyloid‐β[1‐42]was pre‐aggregated into fibrillar or oligomeric structures, and various concentrations were incubated in the brain side of the blood–brain barrier model, followed by IVIG administration in the blood side at the therapeutically relevant concentrations of 5 and 20 mg/mL. IVIG accumulated in the brain side at physiologically relevant levels, with amyloid‐β pre‐incubation increasing IVIG accumulation. The increased transport effect was dependent on amyloid‐β structural form, amyloid‐β concentration, and IVIG dose. IVIG was found to decrease monocyte chemotactic protein‐1 levels 6.5–18% when low amyloid‐β levels were present and increase levels 4.2–23% when high amyloid‐β levels were present. Therefore, the presence, concentration, and structure of amyloid‐β plays an important role in the effect of IVIG therapy in the brain.

image

The mechanisms of action and transport across the blood–brain barrier (BBB) for an Alzheimer's disease therapeutic, intravenous immunoglobulin (IVIG), remain unknown. We investigated the transport of IVIG across endothelial cell BBB monolayers pre‐incubated with amyloid‐β peptides. We found that the concentration and structure of amyloid‐β plays an important role in the effect of IVIG on BBB tightening and cytokine neutralization. (Note: Figure not drawn to scale.)
Unique method of tooth replacement in durophagous placodont marine reptiles, with new data on the dentition of Chinese taxa
Authors: Neenan James M. , Li Chun , Rieppel Olivier , Bernardini Federico , Tuniz Claudio , Muscio Giuseppe , Scheyer Torsten M.
Published: February 2014

The placodonts of the Triassic period (~252–201 mya) represent one of the earliest and most extreme specialisations to a durophagous diet of any known reptile group. Exceptionally enlarged crushing tooth plates on the maxilla, dentary and palatine cooperated to form functional crushing areas in the buccal cavity. However, the extreme size of these teeth, combined with the unusual way they occluded, constrained how replacement occurred. Using an extensive micro‐computed tomographic dataset of 11 specimens that span all geographic regions and placodont morphotypes, tooth replacement patterns were investigated. In addition, the previously undescribed dental morphologies and formulae of Chinese taxa are described for the first time and incorporated into the analysis. Placodonts have a unique tooth replacement pattern and results follow a phylogenetic trend. The plesiomorphic Placodus species show many replacement teeth at various stages of growth, with little or no discernible pattern. On the other hand, the more derived cyamodontoids tend to have fewer replacement teeth growing at any one time, replacing teeth unilaterally and/or in functional units, thus maintaining at least one functional crushing area at all times. The highly derived placochelyids have fewer teeth and, as a result, only have one or two replacement teeth in the upper jaw. This supports previous suggestions that these taxa had an alternative diet to other placodonts. Importantly, all specimens show at least one replacement tooth growing at the most posterior palatine tooth plates, indicating increased wear at this point and thus the most efficient functional crushing area.
Treatment of Radial Artery Occlusions Using Balloon Angioplasty and Localized Intra‐Arterial Abciximab
Authors: JARADAT ZIAD , BASIR BABAR , REVTYAK GEORGE
Published: February 2014

Objectives

To study an alternative strategy for the treatment of radial artery occlusion (RAO) using balloon angioplasty and intrathrombus administration of abciximab.

Background

RAO is a well‐described complication of transradial procedures. The optimal method to restore the patency of the radial artery following its occlusion remains unclear. Spontaneous recanalization can occur in some patients and systemic anticoagulation can be recommended but is often unsuccessful.

Methods

A retrospective review of all patients in our database from 2009 to 2013 with RAO who underwent treatment with balloon angioplasty and intra‐arterial abciximab administered directly at the site of occlusion.

Results

Four patients with symptomatic RAO following transradial catheterization were treated with balloon angioplasty and a 90‐second intrathrombus infusion of abciximab. All procedures were successful and patency was documented the following day with duplex sonography and again at follow‐up (mean 189 days). The patients also remained free of symptoms at follow‐up. The fifth patient was treated with balloon angioplasty alone. This patient suffered symptomatic reocclusion of the radial artery.

Conclusions

Balloon angioplasty and intrathrombus administration of abciximab via a catheter appears to be a safe, effective, and durable technique for reestablishing the patency of an occluded radial artery following transradial catheterization. Larger studies are needed to confirm our findings and establish the role for this technique in an algorithm for treatment of RAO. (J Interven Cardiol 2014;27:217–222)
The efficacy and safety of levetiracetam in paediatric patients treated with chemotherapeutic agents for haematologic disorders
Authors: Bayram Erhan , Topcu Yasemin , Tufekci Ozlem , Karaoglu Pakize , Yis Uluc , Oren Hale , Kurul Semra Hiz
Published: February 2014

Aim

We aimed to describe the efficacy and safety of levetiracetam in paediatric patients receiving chemotherapy for haematologic disorders.

Methods

Children with haematologic disorders who were receiving chemotherapy agents and developed seizure during treatment and treated with levetiracetam were included in the study. The clinical data of the patients were retrospectively evaluated. Primary haematologic diagnosis, chemotherapeutic agents, age at first seizure, seizure type, interictal electroencephalography findings, magnetic resonance imaging findings, response to the levetiracetam treatment, dose of levetiracetam, levetiracetam side effects and treatment period were recorded.

Results

Ten patients with a mean age 12.4 ± 2.96 years were included in the study. Possible triggering factors for seizures were chemotherapeutic agents in 60% (n = 6), posterior reversible encephalopathy syndrome in 20% (n = 2) and central nervous system involvement of the primary disease in 20% (n = 2). Nine patients received levetiracetam monotherapy, and one patient received levetiracetam that was added on oxcarbazepine due to the intractable seizures. The mean duration of antiepileptic treatment that overlapped with chemotherapy was 7.3 ± 3.5 months. Nine patients (90%) were seizure free after levetiracetam monotherapy, and one patient (10%) had ≥50% seizure reduction after levetiracetam who was previously treated with oxcarbazepine. No side effects were observed for levetiracetam during treatment.

Conclusion

Levetiracetam treatment is safe and effective to prevent seizures in children receiving chemotherapy for haematologic disorders.
Pigment epithelium-derived factor as a natural matrix metalloproteinase inhibitor: a comparison with classical matrix metalloproteinase inhibitors used for cancer treatment
Authors: Alcantara Marice B , Dass Crispin R
Published: February 2014

Objectives

In the 1990s, the discovery of the important role of matrix metalloproteinases (MMPs) in cancer angiogenesis, growth and metastasis galvanised research efforts to search for ways to inhibit these MMPs. To date, this has resulted in the investigation of approximately 50 MMPIs which have undergone various phases of clinical trials. However, despite a large body of research being devoted to discovery and development of MMPIs, results have largely not been supportive of this approach to anticancer treatment.

Key findings

The reasons for the general failure of these drugs in clinical trials include various unwanted side-effects, the use of healthy volunteers to provide drug dosages which did not correctly reflect dosages for cancer patients, and the exclusion of patients with early stage cancer in clinical trials despite MMPs being determined to be critical for the angiogenic switch, a process associated with early tumour growth. In contrast, a naturally-occurring endogenous protein and a non-functional serine protease inhibitor (serpin), pigment epithelium-derived factor (PEDF), has been proposed for cancer therapy partly due to its ability to regulate specific MMPs central to cancer progression.

PEDF has been found to specifically downregulate membrane-type I matrix metalloproteinase (MT1-MMP) and furthermore, potentially matrix metalloproteinase-2 (MMP-2), two of the most commonly implicated MMPs in neoplasia.
Preparation, characteristic and pharmacological study on inclusion complex of sulfobutylether-β-cyclodextrin with glaucocalyxin A
Authors: Ren Lili , Jing Jianghui , Chen Guoguang , Miao Yanfei , Wei Ping
Published: February 2014

Objectives

The objective of this study was to improve the water solubility and solubility of glaucocalyxin A (GLA) by producing its inclusion complex with sulfobutylether-β-cyclodextrin (SBE-β-CD).

Methods

The formation of its 1 : 1 complex with SBE-β-CD in solution was confirmed by phase-solution and spectral-shift studies. The interaction of GLA and SBE-β-CD was examined by differential scanning calorimetry, powder X-ray diffraction, Fourier transform infrared spectroscopy, proton nuclear magnetic resonance spectroscopy and ultraviolet-visible spectroscopy to determine the formation of the GLA–SBE-β-CD inclusion complex.

Key findings

The solubilities of GLA and its complexes were 2.38 × 102 and 1.82 × 104 μg/ml, respectively, and the values of the inclusion complexes were significantly improved by 76-fold compared with the solubility of free GLA. Moreover, a higher area under the curve0–∞ after inclusion technique was observed in the pharmacokinetics study.

Conclusions

The aforementioned results indicate that GLA–SBE-β-CD could be useful with a better solubility and sustained function in drug delivery.
Effects of topical indomethacin, bromfenac and nepafenac on lipopolysaccharide-induced ocular inflammation
Authors: Bucolo Claudio , Marrazzo Giuseppina , Platania Chiara Bianca Maria , Romano Giovanni Luca , Drago Filippo , Salomone Salvatore
Published: February 2014

Objectives

To evaluate the effects of topical non-steroidal anti-inflammatory drugs (NSAIDs) on retinal vascular leakage, and inflammatory markers in endotoxin-induced uveitis (EIU) in rats.

Methods

EIU was induced in rats by lipopolysaccharide (LPS). Topical 0.5% indomethacin, 0.09% bromfenac and 0.1% nepafenac were given before and after LPS. Twenty-four hours after LPS, the animals were euthanized and plasma along with retina were collected to assess prostaglandin-E2 (PGE2) and C-reactive protein (CRP) levels using enzyme-linked immunosorbent assay. Retinal vascular leakage was assessed by Evans blue. Molecular modelling was used to evaluate interaction of compounds with cyclooxygenase-2 (COX-2).

Key findings

All NSAIDs tested significantly prevented PGE2 production with higher effect of indomethacin and bromfenac in comparison with nepafenac. The three drugs did not affect plasma CRP levels. The analysis of retinal vascular leakage revealed a significant (P < 0.01) decrease after treatment with indomethacin, but no significant changes were observed after treatment with bromfenac and nepafenac. Indomethacin had a different interaction with COX-2 in comparison with bromfenac and amfenac (active metabolite of nepafenac).

Conclusions

Topical treatment with indomethacin, bromfenac and nepafenac has significant anti-inflammatory effects. However, only indomethacin was able to prevent retinal vascular leakage in LPS-injected rats, likely due to the distinctive molecular mechanism.
Sexual Health Discussions with Older Adult Patients During Periodic Health Exams
Authors: Ports Katie A. , Barnack-Tavlaris Jessica L. , Syme Maggie L. , Perera Robert A. , Lafata Jennifer Elston
Published: February 2014

Introduction

Sexual health is an integral part of overall health across the lifespan. In order to address sexual health issues, such as sexually transmitted infections (STIs) and sexual functioning, the sexual history of adult patients should be incorporated as a routine part of the medical history throughout life. Physicians and health-care professionals cite many barriers to attending to and assessing the sexual health needs of older adult patients, underscoring the importance of additional research to improve sexual history taking among older patients.

Aim

The purpose of this article is to explore the content and context of physician–patient sexual health discussions during periodic health exams (PHEs) with adults aged 50–80 years.

Methods

Patients completed a pre-visit telephone survey and attended a scheduled PHE with their permission to audio-record the exam. Transcribed audio recordings of 483 PHEs were analyzed according to the principles of qualitative content analysis.

Main Outcome Measures

Frequency of sexual history taking components as observed in transcripts of PHEs. Physician characteristics were obtained from health system records and patient characteristics were obtained from the pre-visit survey.

Results

Analyses revealed that approximately one-half of the PHEs included some discussion about sexual health, with the majority of those conversations initiated by physicians. A two-level logistic regression model revealed that patient–physician gender concordance, race discordance, and increasing physician age were significantly associated with sexual health discussions.

Conclusion

Interventions should focus on increasing physician self-efficacy for assessing sexual health in gender discordant and race/ethnicity concordant patient interactions. Interventions for older adults should increase education about sexual health and sexual risk behaviors, as well as empower individuals to seek information from their health-care providers.
Powerful Relaxation of Phosphodiesterase Type 4 Inhibitor Rolipram in the Pig and Human Bladder Neck
Authors: Ribeiro Ana S.F. , Fernandes Vítor S. , Martínez-Sáenz Ana , Martínez Pilar , Barahona María Victoria , Orensanz Luis M. , Blaha Igor , Serrano-Margüello Daniel , Bustamante Salvador , Carballido Joaquín , García-Sacristán Albino , Prieto Dolores , Hernández Medardo
Published: February 2014

Introduction

Phosphodiesterase type 5 (PDE5) inhibitors act as effective drugs for the treatment of lower urinary tract symptom (LUTS). There is a poor information, however, about the role of the PDE4 inhibitors on the bladder outflow region contractility.

Aim

To investigate PDE4 expression and the relaxation induced by the PDE4 inhibitor rolipram versus that induced by the PDE5 blockers sildenafil and vardenafil, in the pig and human bladder neck.

Methods

Immunohistochemistry for PDE4 expression, myographs for isometric force recordings and fura-2 fluorescence for simultaneous measurements of intracellular Ca2+ concentration ([Ca2+]i) and tension for rolipram in bladder neck samples were used.

Main Outcome Measures

PDE4 expression and relaxations to PDE4 and PDE5 inhibitors and simultaneous measurements of [Ca2+]i and tension.

Results

PDE4 expression was observed widely distributed in the smooth muscle layer of the pig and human bladder neck. On urothelium-denuded phenylephrine (PhE)-precontracted strips of pig and human, rolipram, sildenafil and vardenafil produced concentration-dependent relaxations with the following order of potency: rolipram> > sildenafil>vardenafil. In pig, the adenylyl cyclase activator forskolin potentiated rolipram-elicited relaxation, whereas protein kinase A (PKA) blockade reduced such effect. On potassium-enriched physiological saline solution (KPSS)-precontracted strips, rolipram evoked a lower relaxation than that obtained on PhE-stimulated preparations. Inhibition of large (BKCa) and intermediate (IKCa) conductance Ca2+-activated K+ channels, neuronal voltage-gated Ca2+ channels, nitric oxide (NO) and hydrogen sulfide (H2S) synthases reduced rolipram responses. Rolipram inhibited the contractions induced by PhE without reducing the PhE-evoked [Ca2+]i increase.

Conclusions

PDE4 is present in the pig and human bladder neck smooth muscle, where rolipram exerts a much more potent relaxation than that elicited by PDE5 inhibitors. In pig, rolipram-induced response is produced through the PKA pathway involving BKCa and IKCa channel activation and [Ca2+]idesensitization-dependent mechanisms, this relaxation also being due to neuronal NO and H2S release.
Detection of Clinically Relevant Pain Relief in Cats with Degenerative Joint Disease Associated Pain
Authors: Gruen M.E. , Griffith E. , Thomson A. , Simpson W. , Lascelles B.D.X.
Published: February 2014

Background

Detection of clinically relevant pain relief in cats with degenerative joint disease (DJD) is complicated by a lack of validated outcome measures and a placebo effect.

Hypothesis/Objectives

To evaluate a novel approach for detection of pain relief in cats with DJD.

Animals

Fifty‐eight client‐owned cats.

Methods

Prospective, double‐masked, placebo‐controlled, stratified, randomized, clinical study. Enrolled cats were 6–21 years of age, with owner‐observed mobility impairment, evidence of pain in at least 2 joints during orthopedic examination, and overlapping radiographic evidence of DJD, and underwent a 2‐week baseline period, 3‐week treatment period with placebo or meloxicam, and 3‐week masked washout period. Outcome measures were evaluated at days 0, 15, 36, and 57.

Results

Both groups significantly improved after the treatment period (day 36) on client‐specific outcome measures (CSOM) and feline musculoskeletal pain index (FMPI) (P < .0001 for both); there was no difference between the groups on CSOM or FMPI score improvement. After the masked washout period, more cats that received meloxicam during the treatment period had a clinically relevant decrease in CSOM score (P = .048) and FMPI score (P = .021) than cats that received placebo.

Conclusions and Clinical Importance

Using both a client‐specific and a general clinical metrology instrument, owners of cats with DJD were able to detect evident recurrence of clinical signs after withdrawal of active medication than after withdrawal of placebo, and that this study design might be a novel and useful way to circumvent the placebo effect and detect the efficacy of pain‐relieving medications.
Comparison of Carboplatin and Doxorubicin‐Based Chemotherapy Protocols in 470 Dogs after Amputation for Treatment of Appendicular Osteosarcoma
Authors: Selmic L.E. , Burton J.H. , Thamm D.H. , Withrow S.J. , Lana S.E.
Published: February 2014

Background

Many chemotherapy protocols have been reported for treatment of canine appendicular osteosarcoma (OSA), but outcome comparisons in a single population are lacking.

Objective

To evaluate the effects of protocol and dose intensity (DI) on treatment outcomes for carboplatin and doxorubicin‐based chemotherapy protocols.

Animals

Four hundred and seventy dogs with appendicularOSA.

Methods

A retrospective cohort study was performed comprising consecutive dogs treated (1997–2012) with amputation followed by 1 of 5 chemotherapy protocols: carboplatin 300 mg/m2IVq21d for 4 or 6 cycles (CARBO6), doxorubicin 30 mg/m2IVq14d or q21d for 5 cycles, and alternating carboplatin 300 mg/m2IVand doxorubicin 30 mg/m2IVq21d for 3 cycles. Adverse events (AE) andDIwere evaluated. Kaplan–Meier survival curves and Cox proportional hazards regression were used to compare disease‐free interval (DFI) and survival time (ST) among protocols.

Results

The overall medianDFIandSTwere 291 days and 284 days, respectively. A lower proportion of dogs prescribedCARBO6 experiencedAEs compared to other protocols (48.4% versus 60.8–75.8%;P = .001).DIwas not associated with development of metastases or death. After adjustment for baseline characteristics and prognostic factors, none of the protocols provided a significant reduction in risk of development of metastases or death.

Conclusions and Clinical Importance

Although choice of protocol did not result in significant differences inDFIorST, theCARBO6 protocol resulted in a lower proportion of dogs experiencingAEs, which could be advantageous in maintaining high quality of life during treatment.DIwas not a prognostic indicator in this study.
Gene variants encoding proteins involved in antioxidant defense system and the clinical expression of Wilson disease
Authors: Gromadzka Grażyna , Kruszyńska Monika , Wierzbicka Diana , Litwin Tomasz , Dzieżyc Karolina , Wierzchowska‐Ciok Agata , Chabik Grzegorz , Członkowska Anna
Published: February 2014

Background & Aims

Wilson disease (WD) is an autosomal recessive disorder of copper metabolism resulting from pathogenic mutations of the ATP7B gene. The basis of phenotypic variability of the disease is not understood. The main mechanism of copper toxicity is probably related to generation of intracellular oxidative stress. To evaluate whether interindividual variability within genes encoding proteins involved in antioxidant defense system may modulate phenotypic expressions of WD.

Methods

Variability within genes encoding the cytosolic enzymes: glutathione peroxidase (GPX1 rs1050450) and manganese superoxide dismutase (SOD2 rs4880), and peroxisomal enzyme: catalase (CAT rs1001179) were analysed in 435 patients. Individual genotypes were tested for their relationship with phenotypic features of WD.

Results

GPX1 genotypes were not related to phenotypic manifestations of WD. Among males homozygocity for the SOD2 rs4880 T allele was related to earlier onset of WD. Patients homozygous for the CAT rs1001179 T allele characterized with later onset of WD [median (interquartile range) age: 29.0 (14.0) years vs. 22.0 (12.0) years, respectively, P < 0.004], later manifestation of hepatic symptoms [34.5 (14.0) years vs. 22.0 (12.0) years, P < 0.0009], and later presentation of neurological symptoms [37.0 (16.0) years vs. 28.0 (13.0) years, P < 0.03] than those having one or two C alleles.

Conclusion

Variability within the CAT gene may be an important modifier of the clinical course of WD. SOD2 genotype may influence WD phenotype among males. These observations indirectly confirm a role of oxidative stress in the pathogenesis of WD, as well as indirectly suggest that peroxisomes impairment may be involved in WD pathophysiology.
Lack of efficacy of mTOR inhibitors and ACE pathway inhibitors as antifibrotic agents in evolving and established fibrosis in Mdr2−/− mice
Authors: Bridle Kim R. , Sobbe Amy L. , de Guzman C. Erika , Santrampurwala Nishreen , Jaskowski Lesley A. , Clouston Andrew D. , Campbell Catherine M. , Nathan Subramaniam V. , Crawford Darrell HG
Published: February 2014

Background & Aims

Mammalian target of rapamycin and angiotensin‐converting enzyme inhibition has been shown to have antifibrotic activity in models of liver fibrosis. The aim of our study was to determine the efficacy of rapamycin, everolimus, irbesartan and captopril, alone and in combination, as antifibrotic agents in the Mdr2−/− model of cholestasis both in early injury and established disease.

Methods

Mdr2−/− mice were treated for 4 weeks with vehicle, rapamycin (1 mg/kg) or everolimus (5 mg/kg) every second day or with captopril (30 mg/kg/day), irbesartan (10 mg/kg/day) or vehicle. Further groups of 3‐week‐old Mdr2−/− mice were treated with rapamycin and irbesartan in combination (1 mg/kg/day and 10 mg/kg/day) or with rapamycin (2 mg/kg/day) for 4 weeks. Liver injury and fibrosis were compared between treated and untreated animals.

Results

There were no significant improvements in liver injury, histology, hepatic hydroxyproline or profibrogenic gene expression following treatment with rapamycin, everolimus, captopril or irbesartan at any time point studied. Likewise, there were no improvements in liver histology or profibrogenic gene expression following combination therapy or high‐dose rapamycin treatment.

Conclusions

The antifibrotic effects of rapamycin, everolimus, captopril and irbesartan seen in other models of fibrosis were not replicated in the Mdr2−/− model in this study. This highlights the clear need to test specific antifibrotic agents in a number of different animal models. We believe this animal model is ideal to study usefulness of antifibrotic agents in cholestatic liver disease because of the similarity in genetics and hepatic histopathology to human cholestatic liver disease.
Results of salvage liver transplantation
Authors: Guerrini Gian Piero , Gerunda Giorgio E. , Montalti Roberto , Ballarin Roberto , Cautero Nicola , De Ruvo Nicola , Spaggiari Mario , Di Benedetto Fabrizio
Published: February 2014

Background & Aims

Salvage liver transplantation (SLT) is an attractive sequential strategy which combines liver resection (LR) for hepatocellular carcinoma (HCC), followed by liver transplant (LT) in the event of HCC recurrence or progressive liver deterioration. To compare the long‐term results of SLT with primary liver transplant (PLT).

Methods

Between 2000 and 2011, 125 patients (72 transplantable) underwent LR and 226 underwent LT in our unit. The outcome of SLT was analysed in a two‐step fashion: firstly, SLT (n = 28) was compared with PLT (n = 198), secondly an intention‐to‐treat analysis was performed on all transplantable HCC patients who underwent LR (LRT group = 72) compared to PLT (n = 198).

Results

The five‐year overall survival (OS) was 65.4% vs. 49.2% (P = 0.63), and disease‐free survival (DFS) was 89.7% vs. 80.6% (P = 0.31) for PLT and SLT respectively.

Predictive factors for DFS after LT included HCC total diameter [hazard ratio (HR) 1.29 P = 0.003], alpha‐foetoprotein (HR 1.002 P < 0.001) and number of HCC nodules (HR 1.317 P = 0.035), whereas viral hepatitis C positivity (HR 1.911 P = 0.03) and outside Up‐to‐seven criteria (HR 2.652 P < 0.001) were negative independent prediction factors of OS. Intention‐to‐treat analysis showed that OS at 5 years was improved in PLT vs. LRT (LRT n = 72 including SLT plus LR group) and was 69.4% vs. 42.2% (P < 0.004), with an additional increase in DFS (89.2% vs. 54.5% respectively P < 0.001).

Conclusion

Salvage liver transplantation is a safe treatment strategy, as it does not impair long‐term survival. At intention‐to‐treat analysis, PLT showed improved survival compared with LRT.
Low‐dose anti‐CD3 antibody induces remission of active autoimmune hepatitis in xenoimmunized mice
Authors: Marceau Gabriel , Yang Roland , Lapierre Pascal , Béland Kathie , Alvarez Fernando
Published: February 2014

Background

Some patients with autoimmune hepatitis (AIH), despite appropriate treatment, progress towards cirrhosis and liver failure, requiring transplantation. New biological agents targeting immune cell subtypes have been developed, with better specificity and longer‐lasting effects than conventional wide‐spectrum immunosuppressive drugs.

Aims

The goal of this study was to evaluate the effectiveness of low dose of αCD3 targeting therapy in a model of type 2 AIH.

Methods

This experimental model is based on xenoimmunization of C57BL/6 mice with DNA coding for human liver autoantigens. Mice with AIH were treated with five daily injections of low dose of αCD3 monoclonal antibody, before disease onset (5.5 months post‐xenoimmunization) or during AIH (7 months post‐xenoimmunization). Along with serum aminotransferases, autoantibody levels and end‐point liver histology, spleen and liver‐infiltrating lymphocytes were phenotyped by flow cytometry and immune response measured by lymphoproliferative assays.

Results

Before onset of AIH, treatment prevented the development of liver inflammation and tissue injury. During active AIH, low dose of αCD3 antibody therapy resulted in a resorption of liver inflammatory infiltrates, normalization of serum aminotransferas levels, reduced autoantibody titres, increased regulatory T cells and lowered proliferation of autoreactive liver lymphocytes.

Conclusions

We report that low dose αCD3 antibody administration is an effective treatment for AIH in an experimental model of type 2 AIH. These data suggest that αCD3 antibody therapy could be tested in clinical trials as a rescue therapy for patients with uncontrolled AIH.
Rorschach Tests, Pluralism, and Hopes for the Future: A Response to the Responses
Authors: Calavita Kitty
Published: February 2014

In this essay, I address some of the concerns raised by contributors to the Symposium onInvitation to Law & Society: An Introduction to the Study of Real Law. I argue that law and society scholarship focusing on race increasingly offers some of our field's best empirical analyses of the interpenetration of law and society; I emphasize the importance of the methodological and theoretical diversity that characterizes our fragmented field, arguing that our pluralism is one of our greatest strengths; I clarify my intended meaning of the term “real law” as I use it in the book's subtitle, as a way to underscore the socially constituted quality of all law; I attempt to rescue the reputation of dialectics from charges of “relativism”; and I reiterate my appreciation for our field's engagement with questions of social justice that has characterized it since its inception. In the second half of the essay, I briefly describe my current prison research and offer some thoughts for the future of our field.
N‐cadherin, A Vascular Smooth Muscle Cell–Cell Adhesion Molecule: Function and Signaling for Vasomotor Control
Authors: Sun Zhe , Parrish Alan R. , Hill Michael A. , Meininger Gerald A.
Published: February 2014

Cell–cell adhesion complexes are increasingly recognized as an important cell‐signaling site, similar to integrin‐extracellular matrix FA. Furthermore, cell–cell adhesions are involved in the regulation of multi‐cellular/tissue organization and organ, tissue, and cellular level functional behavior. Although N‐cadherin is the major cell–cell adhesion molecule in VSM, only limited studies have been undertaken to understand its function in VSM. In contrast, N‐cadherin signaling and functions have been extensively studied in neurons, fibroblasts, and myocytes, as well as in the context of epithelial‐mesenchymal‐transitions. Increasing evidence has indicated that N‐cadherin‐mediated cell–cell adhesions are important for tissue integrity and cell proliferation. Relevant to VSM, N‐cadherin's role in actin cytoskeleton organization and contraction, as well as its role in regulation of Rho family GTPases are of particular interest. This article briefly reviews the fundamentals of N‐cadherin biology that help shape our current understanding of its function and signaling mechanisms. In particular, attention is given to applications of this knowledge to VSM. The review points to the need for more research effort that is directed at understanding the role of N‐cadherins in the regulation of vascular function.
Neuropilin Regulation of Angiogenesis, Arteriogenesis, and Vascular Permeability
Authors: Plein Alice , Fantin Alessandro , Ruhrberg Christiana
Published: February 2014

The formation of the cardiovasculature, consisting of both the heart and blood vessels, is a critical step in embryonic development and relies on three processes termed vasculogenesis, angiogenesis, and vascular remodeling. The transmembrane protein NRP1 is an essential modulator of embryonic angiogenesis with additional roles in vessel remodeling and arteriogenesis. NRP1 also enhances arteriogenesis in adults to alleviate pathological tissue ischemia. However, in certain circumstances, vascular NRP1 signaling can be detrimental, as it may promote cancer by enhancing tumor angiogenesis or contribute to tissue edema by increasing vascular permeability. Understanding the mechanisms of NRP1 signaling is, therefore, of profound importance for the design of therapies aiming to control vascular functions. Previous work has shown that vascular NRP1 can variably serve as a receptor for two secreted glycoproteins, the VEGF‐A and SEMA3A, but it also has a poorly understood role as an adhesion receptor. Here, we review current knowledge of NRP1 function during blood vessel growth and homeostasis, with special emphasis on the vascular roles of its multiple ligands and signaling partners.
A Sparsity‐Inducing Optimization‐Based Algorithm for Planar Patches Extraction from Noisy Point‐Cloud Data
Authors: Zhang Guangcong , Vela Patricio A. , Karasev Peter , Brilakis Ioannis
Published: February 2014

Currently, much of the manual labor needed to generate as‐built building information models (BIMs) of existing facilities is spent converting raw point cloud data sets (PCDs) to BIM descriptions. Automating the PCD conversion process can drastically reduce the cost of generating as‐built BIMs. Due to the widespread existence of planar structures in civil infrastructures, detecting and extracting planar patches from raw PCDs is a fundamental step in the conversion pipeline from PCDs to BIMs. However, existing methods cannot effectively address both automatically detecting and extracting planar patches from infrastructure PCDs. The existing methods cannot resolve the problem due to the large scale and model complexity of civil infrastructure, or due to the requirements of extra constraints or known information. To address the problem, this article presents a novel framework for automatically detecting and extracting planar patches from large‐scale and noisy raw PCDs. The proposed method automatically detects planar structures, estimates the parametric plane models, and determines the boundaries of the planar patches. The first step recovers existing linear dependence relationships amongst points in the PCD by solving a group‐sparsity inducing optimization problem. Next, a spectral clustering procedure based on the recovered linear dependence relationships segments the PCD. Then, for each segmented group, model parameters of the extracted planes are estimated via singular value decomposition (SVD) and maximum likelihood estimation sample consensus (MLESAC). Finally, the α‐shape algorithm detects the boundaries of planar structures based on a projection of the data to the planar model. The proposed approach is evaluated comprehensively by experiments on two types of PCDs from real‐world infrastructures, one captured directly by laser scanners and the other reconstructed from video using structure‐from‐motion techniques. To evaluate the performance comprehensively, five evaluation metrics are proposed which measure different aspects of performance. Experimental results reveal that the proposed method outperforms the existing methods, in the sense that the method automatically and accurately extracts planar patches from large‐scaled raw PCDs without any extra constraints nor user assistance.
Activation of phenotypic subpopulations in response to ciprofloxacin treatment in Acinetobacter baumannii
Authors: MacGuire Ashley E. , Ching Meining Carly , Diamond Brett H. , Kazakov Alexey , Novichkov Pavel , Godoy Veronica G.
Published: February 2014

The multidrug‐resistant, opportunistic pathogen, Acinetobacter baumannii, has spread swiftly through hospitals worldwide. Previously, we demonstrated that A. baumannii regulates the expression of various genes in response to DNA damage. Some of these regulated genes, especially those encoding the multiple error‐prone DNA polymerases, can be implicated in induced mutagenesis, leading to antibiotic resistance. Here, we further explore the DNA damage‐inducible system at the single cell level using chromosomal transcriptional reporters for selected DNA damage response genes. We found the genes examined respond in a bimodal fashion to ciprofloxacin treatment, forming two phenotypic subpopulations: induced and uninduced. This bimodal response to ciprofloxacin treatment in A. baumannii is unique and quite different than the Escherichia coli paradigm. The subpopulations are not genetically different, with each subpopulation returning to a starting state and differentiating with repeated treatment. We then identified a palindromic motif upstream of certain DNA damage response genes, and have shown alterations to this sequence to diminish the bimodal induction in response to DNA damaging treatment. Lastly, we are able to show a biological advantage for a bimodal response, finding that one subpopulation survives ciprofloxacin treatment better than the other.
Assessing the essentiality of the decaprenyl‐phospho‐d‐arabinofuranose pathway in Mycobacterium tuberculosis using conditional mutants
Authors: Kolly Gaëlle S. , Boldrin Francesca , Sala Claudia , Dhar Neeraj , Hartkoorn Ruben C. , Ventura Marcello , Serafini Agnese , McKinney John D. , Manganelli Riccardo , Cole Stewart T.
Published: February 2014

In Mycobacterium tuberculosis the decaprenyl‐phospho‐d‐arabinofuranose (DPA) pathway is a validated target for the drugs ethambutol and benzothiazinones. To identify other potential drug targets in the pathway, we generated conditional knock‐down mutants of each gene involved using the TET‐PIP OFF system. dprE1, dprE2, ubiA, prsA, rv2361c, tkt and rpiB were confirmed to be essential under non‐permissive conditions, whereas rv3807c was not required for survival. In the most vulnerable group, DprE1‐depleted cells died faster in vitro and intracellularly than those lacking UbiA and PrsA. Downregulation of DprE1 and UbiA resulted in similar phenotypes, namely swelling of the bacteria, cell wall damage and lysis as observed at the single cell level, by real time microscopy and electron microscopy. By contrast, depletion of PrsA led to cell elongation and implosion, which was suggestive of a more pleiotropic effect. Drug sensitivity assays with known DPA‐inhibitors supported the use of conditional knock‐down strains for target‐based whole‐cell screens. Together, our work provides strong evidence for the vulnerability of all but one of the enzymes in the DPA pathway and generates valuable tools for the identification of lead compounds targeting the different biosynthetic steps. PrsA, phosphoribosyl‐pyrophosphate synthetase, appears to be a particularly attractive new target for drug discovery.
Economic and physical determinants of the global distributions of crop pests and pathogens
Authors: Bebber Daniel P. , Holmes Timothy , Smith David , Gurr Sarah J.
Published: February 2014

Crop pests and pathogens pose a significant and growing threat to food security, but their geographical distributions are poorly understood. We present a global analysis of pest and pathogen distributions, to determine the roles of socioeconomic and biophysical factors in determining pest diversity, controlling for variation in observational capacity among countries.

Known distributions of 1901 pests and pathogens were obtained from CABI. Linear models were used to partition the variation in pest species per country amongst predictors.

Reported pest numbers increased with per capita gross domestic product (GDP), research expenditure and research capacity, and the influence of economics was greater in micro‐organisms than in arthropods. Total crop production and crop diversity were the strongest physical predictors of pest numbers per country, but trade and tourism were insignificant once other factors were controlled. Islands reported more pests than mainland countries, but no latitudinal gradient in species richness was evident.

Country wealth is likely to be a strong indicator of observational capacity, not just trade flow, as has been interpreted in invasive species studies. If every country had US levels of per capita GDP, then 205 ± 9 additional pests per country would be reported, suggesting that enhanced investment in pest observations will reveal the hidden threat of crop pests and pathogens.
Phenotype–genotype correlations in patients with Wilson's disease
Authors: Ferenci Peter
Published: February 2014

There is considerable phenotypic variation in Wilson's disease (WD). Some patients present with hepatic disease during the first decade of life and some with neurological degeneration in adolescence or adult life, with or without overt liver disease. Although the absence of neurologic disease in patients with liver disease in childhood or adolescence can be explained by the limited time exposure of the central nervous system to copper toxicity, it is surprising that late‐onset neurologic WD can occur without any evidence of liver involvement. This huge variability in the clinical presentation of WD in general reflects our limited knowledge on the natural history of WD. Genetic association studies require the phenotype to be defined as accurately as possible.
Legislative frameworks for corn flour and maize meal fortification
Authors: Makhumula Phillip , Dary Omar , Guamuch Monica , Tom Carol , Afidra Ronald , Rambeloson Zo
Published: February 2014

Corn flour and maize meal fortification can benefit the consumer when the added nutrient contents are in amounts appropriate to address nutrient gaps. Legislative instruments (standards and regulations) are needed to provide guidance to the producers and food control authorities. We reviewed a number of national standards and regulations of fortified corn flour and maize meal and identified constraints; contrary to current belief, the practice of using minimum contents or ranges of nutrients has caused confusion, misinterpretation, and conflict, and should therefore be abandoned. On the basis of the findings, a model of fortification legislation is proposed, in which the additional content and the expected average nutrient content in a final product are recommended as the main parameters for quality control and enforcement. For labeling, the average content, or one adjusted to the expected content of the product at the market, can be applied. Variation in micronutrient contents should still be checked to ensure homogeneity but with adherence to clear procedures of sampling and testing, which should be part of the standards and regulations.