bluuebunny/crossref_metadata_2025 huggingface dataset:
Fetal Foot Length and Femur/ Foot Length Ratio: Significance in Nepalese Context
Authors: Joshi KS , Marahatta SB , Karki S , Tamrakar S , Shrestha NC
Published: June 2012

Aim: 1. To assess relationship between fetal foot length and gestation age and develop a nomogram. 2. To assess relationship between fetal foot length and femur length. Meterials and Method: Cross sectional study. Fetal foot length was taken from the skin edge overlying calcaneus to the distal end of the longest toe on either plantar or the sagittal view in 860 singleton pregnant women between 15 and 40 weeks’ gestation. Normal case was defined as normal sonographic findings during examination and normal infant examination at birth or both. Final study population constituted 779 healthy fetuses. The relationship between gestational age to foot length was analyzed by simple linear regression. Correlation of fetal foot length with gestational age and femur length were also obtained. Results: A nomogram for fetal foot length was obtained. There is linear relationship between foot length and gestational age [foot length (mm)=2.494xGestational age (weeks)-15.46] with significant correlation (r=0.970 and p=0.000) and between foot length and femur length [foot length(mm)=1.049xfemur length (mm)+0.648] with significant correlation (r=0.980 and P=0.000). Femur length/ Foot Length ratio was 0.9 and 1.0 in most of the cases. Conclusion: Nomogram was obtained for fetal foot length at various gestational ages in our population. There is linear relationship and good correlation between foot length and gestational age and foot length and femur length. Fetal foot length can be used as an alternative fetal parameter to assess gestational age. Femur length/ Foot Length ratio is fairly constant throughout gestation. DOI: http://dx.doi.org/10.3126/njr.v1i1.6317 Nepalese Journal of Radiology Vol.1(1): 15-22
Incidental Pancreatic Lipomas: A Case Series on 64 Slice MDCT done for Different Pathologies
Authors: Dwivedi AD , Srivastava A , Shukla R , Patwari S
Published: June 2012

Pancreatic lipomas are rare benign lesions, with only 50 cases being documented in the current literature to the best of our knowledge. We describe four cases of intrapancreatic lipomas from a single institution, all incidentally found using multi detector computed tomography within a 6-month period. Computed tomography depicted lipomas as homogeneous, nonenhancing, well-marginated lesions with a density coefficient consistent with adipose tissue. DOI: http://dx.doi.org/10.3126/njr.v1i1.6318 Nepalese Journal of Radiology Vol.1(1): 23-26
Thoracic Intradural Extramedullary AV Malformation Presenting as Foix-Alajouanine Syndrome: A Case Report
Authors: Patwari S , Verma A , Srivastava A , Shukla RC
Published: June 2012

Acute or subacute myelopathy with spontaneous thrombosis of the veins in a patient with a spinal arteriovenous malformation (AVM) has been referred to as "Foix-Alajouanine syndrome (FAS)". A previously healthy 35-year-old man developed neurological illness with progressive lower extremity weakness and low back pain. MRI demonstrated diffuse swelling of the thoracic spinal cord, suggesting myelopathy with few intradural extramedullary serpeginous flow voids. We report a case of Foix-Alajouanine syndrome with a review of the literature. DOI: http://dx.doi.org/10.3126/njr.v1i1.6319 Nepalese Journal of Radiology Vol.1(1): 27-29
Pancreatoblastoma Mimicking Liver Abscess: A Case Report
Authors: Syed Z , Chakravarthy S , Singh M , Narayan R
Published: June 2012

Pancreatoblastoma is an extremely rare pancreatic tumour most commonly encountered in infants and young children. This is a case of childhood pancreatoblastoma being reported to emphasize the dilemma of clinical and radiological features in diagnosing this rare tumour. A 3-year-old boy complained of distension of the abdomen with mild jaundice. Initially, physical and radiological investigations were in favour of liver abscess. Histopathological examination of the resected specimen was interpreted as liver mass. Serological investigations and immunohistochemistry for malignancy were helpful in suspecting Pancreatoblastoma. Pancreatoblastoma can mimic a liver mass (caudate lobe) on imaging as is shown in this case report. DOI: http://dx.doi.org/10.3126/njr.v1i1.6321 Nepalese Journal of Radiology Vol.1(1): 33-36
Interruption of Left Pulmonary Artery with Right Sided Aortic Arch with TOF: A Complete Anomaly Combination
Authors: Gangadhar Kiran
Published: June 2012

Interruption of the pulmonary artery is a rare congenital disorder. The clinical symptoms are non-specific and radiological investigations are the key to diagnosis. We present a case of interruption of the left pulmonary artery associated with Tetralogy of Fallot in a young male. The radiological and clinical features of this condition are also reviewed. DOI: http://dx.doi.org/10.3126/njr.v1i1.6322 Nepalese Journal of Radiology Vol.1(1): 37-40
Hidden Foreign Body in the Orbit and Cavernous Sinus Masquerading Strabismus
Authors: Rauniyar RK , Badhu B , Sharma U , Panda A
Published: June 2012

Intraorbital foreign bodies with intracranial extension can produce both visual and life threatening problems. The present report highlights a 9 year old patient who sustained an ocular trauma following a fall from a height, but refused to admit the same and reported to the ophthalmologist late when complicated symptoms such as deviation of eye ball with mild proptosis appeared. The authors described the value of accurate history taking and complete radiological evaluation for these traumatised eyes. Clinical examination and routine radiological study may not be sufficient to detect these foreign bodies. DOI: http://dx.doi.org/10.3126/njr.v1i1.6323 Nepalese Journal of Radiology Vol.1(1): 41-44
Typical MRI Features in Spontaneous Intracranial Hypotension: A Rare Cause of Headache
Authors: Hekha N , Lim CC Tchoyoson
Published: June 2012

Spontaneous CSF leakage from the spinal canal can give rise to spontaneous intracranial hypotension (SIH). Typically, these patients complain of orthostatic (postural) headache, have very low CSF pressure on lumbar puncture (LP) and usually respond to conservative treatment or by an epidural blood patch. The characteristic MRI features include subdural fluid collections, enhancement of the pachymeninges, engorgement of venous structures, pituitary hyperaemia and sagging of the cerebellar tonsils. Radiologists should recognize the typical clinical and imaging features of SIH and distinguish it from more sinister or malignant differential diagnosis, in order to prevent a delay in diagnosis or unnecessary surgical intervention, especially in resource-constrained situations in developing nations.DOI: http://dx.doi.org/10.3126/njr.v1i1.6324 Nepalese Journal of Radiology Vol.1(1): 45-51
Traumatic Intracranial Frontal Extradural Hematoma Associated with Orbital Subperiosteal Hematoma
Authors: Gupta MK , Dhungel K , Sah PL , Ahmad K , Rauniyar RK
Published: June 2012

Intracranial extradural hematoma (EDH) is a frequent lesion but simultaneous occurrence of EDH with orbital subperiosteal hematoma following head injury is a rare event. We report a 22 year old male who sustained head injury during road traffic accident. Glasgow coma scale was 13/15 on arrival and he had left orbital ecchymosis & subconjunctival hemorrhage. CT revealed left frontal extradural hematoma with associated orbital subperiosteal hematoma. No bone fracture was seen. The patient had good clinical recovery following surgical evacuation of the hematomas.DOI: http://dx.doi.org/10.3126/njr.v1i1.6325 Nepalese Journal of Radiology Vol.1(1): 52-53
MR Imaging of the Adnexal Masses: A Review
Authors: Ahmad I , Kirimani S , Rashid M , Ahmad K
Published: June 2012

MR (magnetic resonance) imaging is a non invasive technique for evaluation of female pelvic masses. Due to its high spatial resolution and excellent tissue contrast, various masses of adnexal origin can be imaged and a confident diagnosis can be made. MRI helps to delineate normal anatomical structures and elucidate the pathological lesions. It has high sensitivity and specificity for differentiating benign adnexal masses from malignant ones. This review article gives a brief account of approach to adnexal masses based on tissue characterization on MR imaging.DOI: http://dx.doi.org/10.3126/njr.v1i1.6326 Nepalese Journal of Radiology Vol.1(1): 54-60
A Variant of Poland’s syndrome - Case Report and Review of Literature
Authors: Rauniyar RK , Baboo S , Sharma U , Garg M
Published: June 2012

Poland’s syndrome is the association of congenital thoracic abnormalities with ipsilateral syndactyly along with various other associated anomalies. A variant of Poland’s syndrome without syndactyly along with review of literature is presented here. Various associated anomalies of the syndrome is summarized. Syndactyly believed to be constant features in Poland’s Syndrome in earlier reports, may not be present.DOI: http://dx.doi.org/10.3126/njr.v1i1.6328 Nepalese Journal of Radiology Vol.1(1): 65-69
Does MR Sialography Have A Greater Diagnostic Accuracy Than Conventional X-Ray And Digital Subtraction Sialography In Detecting Salivary Glands Disease? A Literature Review
Authors: Uddin SM
Published: June 2012

Aim: The main aim was to determine the diagnostic accuracy of MR Sialography as compared to conventional x-ray and digital sialography in detecting salivary gland diseases on the basis of research evidences available in the literature. Description: It is noticed that almost all people develop illness of salivary glands at some stage of their lives. The major effects on salivary glands become evident as stones; infection tumors which may also involve related organs. Imaging methods like Ultrasound, Computed Tomography (CT) and Digital subtraction sialography (DSS) are used for assessment of parotid, sub-mandibular and sub-lingual glands in addition to conventional x-ray sialography which is marked as a gold standard for salivary glands assessment. Due to the non-invasive nature and level of comfort, MR Sialography is now being considered as an advanced technique for the detection of stones and tumor spread in the soft tissues with no risk of radiation exposure. Methods and Results: Different databases which include Science direct, CINAHL, Ebesco Host, PubMed, Swetswise, Wiley Interscience, sage pub, and The Cochrane library were explored to get published literature. Total 10 studies were included and critically appraised under critical appraisal skills programme (CASP) tool. Conclusion: The review proposed that though the use of MRS as the only diagnostic examination is useful but X-ray sialography remains the standard investigation tool due to its higher spatial resolution. MRS can be utilized as an alternative imaging technique by using special MR sequences such as 3D CISS and RARE where x-ray sialography cannot be performed. DOI: http://dx.doi.org/10.3126/njr.v1i1.6329 Nepalese Journal of Radiology Vol.1(1): 70-77
Insights into the Connectivity of the Human Brain Using DTI
Authors: Kollias S
Published: June 2012

Diffusion tensor imaging (DTI) is a neuroimaging MR technique, which allows in vivo and non-destructive visualization of myeloarchitectonics in the neural tissue and provides quantitative estimates of WM integrity by measuring molecular diffusion. It is based on the phenomenon of diffusion anisotropy in the nerve tissue, in that water molecules diffuse faster along the neural fibre direction and slower in the fibre-transverse direction. On the basis of their topographic location, trajectory, and areas that interconnect the various fibre systems of the mammalian brain are divided into commissural, projectional and association fibre systems. DTI has opened an entirely new window on the white matter anatomy with both clinical and scientific applications. Its utility is found in both the localization and the quantitative assessment of specific neuronal pathways. The potential of this technique to address connectivity in the human brain is not without a few methodological limitations. A wide spectrum of diffusion imaging paradigms and computational tractography algorithms has been explored in recent years, which established DTI as promising new avenue, for the non-invasive in vivo mapping of structural connectivity at the macroscale level. Further improvements in the spatial resolution of DTI may allow this technique to be applied in the near future for mapping connectivity also at the mesoscale level. DOI: http://dx.doi.org/10.3126/njr.v1i1.6330 Nepalese Journal of Radiology Vol.1(1): 78-91
Current Status of Endovascular Repair of Aortic Dissections
Authors: Sharma S
Published: June 2012

Aortic dissection is a medical emergency and can quickly lead to death, even with optimal treatment. The Stanford classification is widely used and is in close relationship to clinical practice, as type A dissections require primary surgical repair whereas type B dissections are treated medically as initial treatment with surgery or endovascular repair reserved for any complications. Multi-slice CT is fast emerging as the investigation of choice to establish the diagnosis and plan treatment strategies in aortic dissection. The therapeutic strategies differ for treatment of an acute dissection compared to a chronic dissection. Most institutions favor a ‘complication specific’ approach for type B dissections with medical anti-hypertensive treatment and the use of beta-blockers as the primary therapy. Surgery or endovascular repair is reserved for patients with recurrent pain, life-threatening complications or rapid aortic expansion. Procedural success during endovascular repair for type B aortic dissection is reported in 99.2+ 0.1% of patients. Overall survival rates of 96.9% at 30 days, 96.7% at 6 months, 96.4% at 1 year, 95.6% at 2 years, and 95.2% at 5 years are reported after endovascular repair in Type B aortic dissections. There is evidence that endovascular repair may be non-inferior to surgery in this group of patients. Device designs and management algorithms are still evolving. More validated clinical data is necessary to define the role of endovascular repair in the management of type B aortic dissections. DOI: http://dx.doi.org/10.3126/njr.v1i1.6331 Nepalese Journal of Radiology Vol.1(1): 92-98
Effects of Delta-Aminolevulinic Acid Dehydratase Polymorphisms on Susceptibility to Lead in Han Subjects from Southwestern China
Authors: Yang Yuelin , Wu Jin , Sun Pin
Published: July 2012

This study is to determine the distribution of the delta-aminolevulinic acid dehydratase (ALAD) polymorphism among Han subjects of the Chinese population and to study whether the polymorphism in the ALAD gene modifies the toxicity of lead in lead-exposed workers. For this purpose we conducted a cross-sectional study on 156 Chinese workers who were exposed to lead in lead-acid battery and electric-flex manufacturing plants. The authors found that the allele frequencies of ALAD1 and ALAD2 were 0.9679 and 0.0321, respectively. Workers with the ALAD 1-1 genotype were associated with higher blood lead levels than those with the ALAD 1-2 genotype. Blood and urine lead levels were much higher in storage battery workers than in cable workers. The self-conscious symptom survey showed that the incidences of debilitation, amnesia and dreaminess were much higher in those had more than five years of tenure or contact with lead on the job within the ALAD 1-1 genotype subgroup. Laboratory examinations showed that serum iron and zinc levels in workers’ with the ALAD 1-2 genotype were higher than those with the ALAD 1-1 genotype, especially in storage-battery workers. Correlation analysis indicated that the blood lead level negatively correlated with serum calcium, iron and zinc level. The data of this study suggest that the ALAD gene polymorphism and serum ion levels may modify the kinetics of lead in blood. Therefore, the authors recommend that an adequate intake of dietary calcium, iron, and zinc or the calcium, iron, and zinc supplementation should be prescribed to Chinese lead exposed workers.
Genetic Variation and Population Differentiation in a Medical Herb Houttuynia cordata in China Revealed by Inter-Simple Sequence Repeats (ISSRs)
Authors: Wei Lin , Wu Xian-Jin
Published: July 2012

Houttuynia cordata is an important traditional Chinese herb with unresolved genetics and taxonomy, which lead to potential problems in the conservation and utilization of the resource. Inter-simple sequence repeat (ISSR) markers were used to assess the level and distribution of genetic diversity in 226 individuals from 15 populations of H. cordata in China. ISSR analysis revealed low genetic variations within populations but high genetic differentiations among populations. This genetic structure probably mainly reflects the historical association among populations. Genetic cluster analysis showed that the basal clade is composed of populations from Southwest China, and the other populations have continuous and eastward distributions. The structure of genetic diversity in H. cordata demonstrated that this species might have survived in Southwest China during the glacial age, and subsequently experienced an eastern postglacial expansion. Based on the results of genetic analysis, it was proposed that as many as possible targeted populations for conservation be included.
Spatial distribution and packing of xylem conduits
Authors: Martínez‐Vilalta Jordi , Mencuccini Maurizio , Álvarez Xavier , Camacho Juan , Loepfe Lasse , Piñol Josep
Published: June 2012

• Premise of the study: The hydraulic properties of the xylem determine the ability of plants to transport water from the soil to the leaves and to cope with important stress factors such as frost and drought. Hydraulic properties have usually been studied as a function of the anatomy of xylem conduits and their pits, but recent studies have proposed that system‐level properties, related to the topology of the xylem network, may also play a role. Here we study how the spatial arrangement of conduits in xylem cross sections affects the relationship between mean conduit lumen area and conduit density (packing function) across species.

• Methods: Point pattern analysis was used to describe the spatial distribution of xylem conduits in 97 woody species. The effect of conduit aggregation on the packing function was tested using phylogenetic generalized least squares. A hydraulic model with an explicit description of the topology of the xylem network was used to interpret the functional significance of our findings.

• Key results: The spatial arrangement of conduits affected the packing function across species, so that species with aggregated distributions tended to have lower conduit densities for a given conduit size and lower conduit lumen fractions. According to our modeling results, the higher conduit‐to‐conduit connectivity of species with aggregated distributions allows them to achieve higher hydraulic conductivity. Species with aggregated conduits, however, pay a cost in terms of increased vulnerability to embolism.

• Conclusions: The spatial arrangement of conduits affects the fundamental structural and functional attributes of the xylem.
Development of indel markers from Citrus clementina (Rutaceae) BAC‐end sequences and interspecific transferability in Citrus
Authors: Ollitrault Frédérique , Terol Javier , Martin Alena Alonso , Pina Jose Antonio , Navarro Luis , Talon Manuel , Ollitrault Patrick
Published: June 2012

• Premise of the study: Indel markers were developed from BAC‐end sequences of Citrus clementina cv. Nules. Transferability and polymorphism were tested in the Citrus genus to estimate the potential of indel markers mined from a single genotype for use in genetic studies.

• Methods and Results: Using polyacrylamide gel electrophoresis and DNA silver staining, 89 indel markers were tested for their transferability and polymorphism. Thirty‐eight markers were selected. Heterozygosity in C . clementina cv. Nules was confirmed for 33 of these indel pairs. A preliminary diversity study using a capillary electrophoresis fragment analyzer was conducted with 21 indels using 45 accessions representing Citrus genus diversity. Intraspecific and interspecific polymorphisms were observed.

• Conclusions: These results indicate the utility of indel markers developed from sequence data of a single genotype of interspecific origin. In Citrus, these markers will be useful for genetic mapping, germplasm characterization, and phylogenetic assignment of DNA fragments.
Development and characterization of nine highly polymorphic microsatellite primers for Platycladus orientalis (Cupressaceae)
Authors: Zhu Lin , Lou Anru
Published: June 2012

• Premise of the study: Microsatellite primers were developed and characterized for the long‐lived tree species Platycladus orientalis for further investigation of its population characteristics.

• Methods and Results: Nine polymorphic microsatellites were identified for P. orientalis. The number of alleles per locus ranged from four to 22 (average = 11) for 94 individual specimens examined from four populations. The observed and expected heterozygosities ranged from 0.208 to 1.000 and 0.555 to 0.931, respectively.

• Conclusions: These nine markers can be used in future studies examining population genetics and the reproductive biology of P. orientalis, thereby revealing the importance of old‐growth populations for the retention of genetic diversity, and providing useful insights into the maintenance of the potential genetic resource of this species.
Development of microsatellite markers in a riparian shrub, Spiraea thunbergii (Rosaceae)
Authors: Ashizawa Kazuya , Kimura Megumi K. , Takahashi Akiko , Lian Chunlan , Kuramoto Noboru
Published: June 2012

• Premise of the study: Microsatellite primers in the deciduous shrub Spiraea thunbergii were developed to investigate genetic diversity and population genetic structure. Cross‐species transferability was assayed in four congeneric species.

• Methods and Results: Using a compound simple sequence repeat (SSR) marker method, 10 primer sets were identified in Japanese populations of S. thunbergii. The primers amplified compound SSRs with two to five alleles per locus. More than half of the primers were also amplified in S. prunifolia, S. nipponica var. nipponica, and S. japonica.

• Conclusions: These markers might be useful for future studies of population genetics of S. thunbergii and congeneric species.
Microsatellite markers for Vellozia gigantea (Velloziaceae), a narrowly endemic species to the Brazilian campos rupestres
Authors: Martins Ana Paula V. , Proite Karina , Kalapothakis Evanguedes , Santos Fabrício R. , Chaves Anderson V. , Borba Eduardo L.
Published: June 2012

• Premise of the study: Microsatellite primers were developed for the first time in Velloziaceae, in the endangered species Vellozia gigantea.

• Methods and Results: Using two different protocols, seven primer sets were characterized in three populations of V. gigantea. The primers amplified di‐ and trinucleotide repeats with six to 12 alleles per locus. These revealed high levels of genetic variation, presenting an average observed heterozygosity of 0.508 in V. gigantea. The seven primers were tested for cross‐amplification in three Vellozia species. All primers successfully amplified in V. auriculata. Six primers amplified in V. compacta and three in V. hirsuta.

• Conclusions: The new marker set described here will be useful for studies of population genetics of V. gigantea. The cross‐amplification results indicate the utility of primers for studies in other Vellozia species.
Performance of Fukuda Stepping Test as a Function of the Severity of Caloric Weakness in Chronic Dizzy Patients
Authors: Honaker Julie A. , Shepard Neil T.
Published: June 2012

Background:The purpose of the Fukuda Stepping Test (FST) is to measure asymmetrical vestibulospinal reflex tone resulting from labyrinthine dysfunction. The FST is a low cost evaluation for dizzy patients; however, when compared with gold standard caloric irrigation unilateral
weakness (UW) value ≥25%, the FST has not been shown to be a sensitive tool for identifying unilateral vestibular hypofunction.Purpose:The purpose of this technical report is to further evaluate the clinical utility of FST with and without headshake as a function of increased caloric
asymmetry for individuals with unilateral peripheral vestibular pathology.Research Design:Retrospective review of FST results with and without head shaking component as compared to gold standard, caloric irrigation UW outcome values at four severity levels: 0‐24% UW (normal caloric
value); 25‐50% UW (mild caloric UW); 51‐75% UW (moderate caloric UW); 76‐100% UW (severe caloric UW).Study Sample:736 chronic (≥8 wk symptom complaints) dizzy patients.Results:Standard FST and FST following a head shake task are insensitive to detecting
mild to moderate peripheral vestibular paresis. Increased test performance was observed for patients with severe canal paresis (>76% UW); however, continued inconsistencies were found in turn direction toward the severe unilateral vestibular dysfunction.Conclusions:Overall, the FST
provides little benefit to clinicians when used in the vestibular bedside examination.
Fostering Discovery through Web Interface Design
Authors: Kerico Juliet , Anthony Paul , Bulock Chris , Fields Lynn
Published: July 2012

In 2009, the Library & Information Services (LIS) Web Task Force of Southern Illinois University Edwardsville (SIUE) was charged with improving its website in light of the increasing challenges presented by organizing, maintaining, and promoting its rapidly expanding selection of electronic resources. Due to budgetary constraints, a commercial tool for improving resource discovery was not an option. The Task Force chose to consider improved Web design as a solution to the problem. The resulting process of ongoing library Web site redesign, fueled by extensive user feedback at multiple stages, is discussed. In addition, the progression from a paper-based survey to an observation study of users is outlined and analyzed. Such activities inform the user experience and provide an opportunity to use improved design to reinforce principles of library instruction.
Emotion Recognition Model Based on Facial Expressions, Ethnicity and Gender Using Backpropagation Neural Network
Authors: Hewahi Nabil M. , Baraka AbdulRahman M.
Published: July 2012

Many emotion recognition approaches are built using facial expressions, but few of them use both the ethnicity and gender as attributes. The authors have developed an approach based on Artificial Neural Networks (ANN) using backpropagation algorithm to recognize the human emotion through facial expressions, ethnicity and gender. Their approach has been tested by using MSDEF dataset, and found that there is a positive effect on the accuracy of the recognition of emotion if they use both the ethnic group and gender as inputs to the system. Although this effect is not significant, but considerable (Improvement rate reached 8%). The authors also found that females have more accurate emotion expression recognition than males and found that the gender increases the accuracy of emotion recognition. Regardless of the used dataset, the authors’ approach obtained better results than some research on emotion recognition. This could be due to various reasons such as the type of the selected features and consideration of race and gender.
Substrate Rigidity Regulates Human T Cell Activation and Proliferation
Authors: O’Connor Roddy S. , Hao Xueli , Shen Keyue , Bashour Keenan , Akimova Tatiana , Hancock Wayne W. , Kam Lance C. , Milone Michael C.
Published: June 2012

Adoptive immunotherapy using cultured T cells holds promise for the treatment of cancer and infectious disease. Ligands immobilized on surfaces fabricated from hard materials such as polystyrene plastic are commonly employed for T cell culture. The mechanical properties of a culture surface can influence the adhesion, proliferation, and differentiation of stem cells and fibroblasts. We therefore explored the impact of culture substrate stiffness on the ex vivo activation and expansion of human T cells. We describe a simple system for the stimulation of the TCR/CD3 complex and the CD28 receptor using substrates with variable rigidity manufactured from poly(dimethylsiloxane), a biocompatible silicone elastomer. We show that softer (Young’s Modulus [E] < 100 kPa) substrates stimulate an average 4-fold greater IL-2 production and ex vivo proliferation of human CD4+ and CD8+ T cells compared with stiffer substrates (E > 2 MPa). Mixed peripheral blood T cells cultured on the stiffer substrates also demonstrate a trend (nonsignificant) toward a greater proportion of CD62Lneg, effector-differentiated CD4+ and CD8+ T cells. Naive CD4+ T cells expanded on softer substrates yield an average 3-fold greater proportion of IFN-γ–producing Th1-like cells. These results reveal that the rigidity of the substrate used to immobilize T cell stimulatory ligands is an important and previously unrecognized parameter influencing T cell activation, proliferation, and Th differentiation. Substrate rigidity should therefore be a consideration in the development of T cell culture systems as well as when interpreting results of T cell activation based upon solid-phase immobilization of TCR/CD3 and CD28 ligands.
Subcongenic Analyses Reveal Complex Interactions between Distal Chromosome 4 Genes Controlling Diabetogenic B Cells and CD4 T Cells in Nonobese Diabetic Mice
Authors: Stolp Jessica , Chen Yi-Guang , Cox Selwyn L. , Henck Vivien , Zhang Wenyu , Tsaih Shirng-Wern , Chapman Harold , Stearns Timothy , Serreze David V. , Silveira Pablo A.
Published: June 2012

Autoimmune type 1 diabetes (T1D) in humans and NOD mice results from interactions between multiple susceptibility genes (termed Idd) located within and outside the MHC. Despite sharing ∼88% of their genome with NOD mice, including the H2g7 MHC haplotype and other important Idd genes, the closely related nonobese resistant (NOR) strain fails to develop T1D because of resistance alleles in residual genomic regions derived from C57BLKS mice mapping to chromosomes (Chr.) 1, 2, and 4. We previously produced a NOD background strain with a greatly decreased incidence of T1D as the result of a NOR-derived 44.31-Mb congenic region on distal Chr. 4 containing disease-resistance alleles that decrease the pathogenic activity of autoreactive B and CD4 T cells. In this study, a series of subcongenic strains for the NOR-derived Chr. 4 region was used to significantly refine genetic loci regulating diabetogenic B and CD4 T cell activity. Analyses of these subcongenic strains revealed the presence of at least two NOR-origin T1D resistance genes within this region. A 6.22-Mb region between rs13477999 and D4Mit32, not previously known to contain a locus affecting T1D susceptibility and now designated Idd25, was found to contain the main NOR gene(s) dampening diabetogenic B cell activity, with Ephb2 and/or Padi2 being strong candidates as the causal variants. Penetrance of this Idd25 effect was influenced by genes in surrounding regions controlling B cell responsiveness and anergy induction. Conversely, the gene(s) controlling pathogenic CD4 T cell activity was mapped to a more proximal 24.26-Mb region between the rs3674285 and D4Mit203 markers.
Interchangeability of Themis1 and Themis2 in Thymocyte Development Reveals Two Related Proteins with Conserved Molecular Function
Authors: Lesourne Renaud , Zvezdova Ekaterina , Song Ki-Duk , El-Khoury Dalal , Uehara Shoji , Barr Valarie A. , Samelson Lawrence E. , Love Paul E.
Published: June 2012

Themis1, a recently identified T cell protein, has a critical function in the generation of mature CD4+CD8− and CD4−CD8+ (CD4 and CD8 single-positive [SP]) thymocytes and T cells. Although Themis1 has been shown to bind to the adaptor proteins LAT and Grb2, previous studies have yielded conflicting results regarding whether thymocytes from Themis1−/− mice exhibit TCR-mediated signaling defects. In this study, we demonstrate that, in the absence of Themis1, TCR-mediated signaling is selectively impaired in CD4 SP and CD8 SP thymocytes but is not affected in CD4+CD8+ double-positive thymocytes despite high expression of Themis1 in double-positive thymocytes. Like Themis1, Themis2, a related member of the Themis family, which is expressed in B cells and macrophages, contains two conserved cysteine-based domains, a proline-rich region, and a nuclear localization signal. To determine whether Themis1 and Themis2 can perform similar functions in vivo, we analyzed T cell development and TCR-mediated signaling in Themis1−/− mice reconstituted with either Themis1 or Themis2 transgenes. Notably, Themis1 and Themis2 exhibited the same potential to restore T cell development and TCR-mediated signaling in Themis1−/− mice. Both proteins were tyrosine phosphorylated and were recruited within Grb2 signaling complexes to LAT following TCR engagement. These results suggest that conserved molecular features of the Themis1 and Themis2 proteins are important for their biological activity and predict that Themis1 and Themis2 may perform similar functions in T and B cells, respectively.
μ-Chain–Deficient Mice Possess B-1 Cells and Produce IgG and IgE, but Not IgA, following Systemic Sensitization and Inhalational Challenge in a Fungal Asthma Model
Authors: Ghosh Sumit , Hoselton Scott A. , Schuh Jane M.
Published: June 2012

Allergic bronchopulmonary aspergillosis is often difficult to treat and results in morbidity associated with chronic airway changes. This study assessed the requirement for B cells and their products in the allergic pulmonary phenotype in a murine model of fungal allergic asthma that mimics allergic bronchopulmonary aspergillosis. C57BL/6 and μMT mice (assumed to lack peripheral B cells) were sensitized with Aspergillus fumigatus extract and challenged with two inhalation exposures of live conidia to induce airway disease. Airway hyperresponsiveness after methacholine challenge, peribronchovascular inflammation, goblet cell metaplasia, and fibrotic remodeling of the airways was similar between μMT mice and their wild-type counterparts (C57BL/6). Surprisingly, even in the absence of the μ-chain, these μMT mice produced IgE and IgG Abs, although the Abs induced did not have specificity for A. fumigatus Ags. In contrast, IgA was not detected in either the lavage fluid or serum of μMT mice that had been exposed to A. fumigatus. Our findings also reveal the existence of CD19+CD9+IgD+ B-1 cells in the lungs of the μMT animals. These data show the μMT mice to have a developmental pathway independent of the canonical μ-chain route that allows for their survival upon antigenic challenge with A. fumigatus conidia, although this pathway does not seem to allow for the normal development of Ag-specific repertoires. Additionally, this study shows that IgA is not required for either clearance or containment of A. fumigatus in the murine lung, as fungal outgrowth was not observed in the μMT animals after multiple inhalation exposures to live conidia.
B7–CD28 Costimulatory Signals Control the Survival and Proliferation of Murine and Human γδ T Cells via IL-2 Production
Authors: Ribot Julie C. , deBarros Ana , Mancio-Silva Liliana , Pamplona Ana , Silva-Santos Bruno
Published: June 2012

γδ T cells play key nonredundant roles in immunity to infections and tumors. Thus, it is critical to understand the molecular mechanisms responsible for γδ T cell activation and expansion in vivo. In striking contrast to their αβ counterparts, the costimulation requirements of γδ T cells remain poorly understood. Having previously described a role for the TNFR superfamily member CD27, we since screened for other nonredundant costimulatory receptors in γδ T cell activation. We report in this article that the Ig superfamily receptor CD28 (but not its related protein ICOS) is expressed on freshly isolated lymphoid γδ T cells and synergizes with the TCR to induce autocrine IL-2 production that promotes γδ cell survival and proliferation in both mice and humans. Specific gain-of-function and loss-of-function experiments demonstrated a nonredundant function for CD28 interactions with its B7 ligands, B7.1 (CD80) and B7.2 (CD86), both in vitro and in vivo. Thus, γδ cell proliferation was significantly enhanced by CD28 receptor agonists but abrogated by B7 Ab-mediated blockade. Furthermore, γδ cell expansion following Plasmodium infection was severely impaired in mice genetically deficient for CD28. This resulted in the failure to mount both IFN-γ–mediated and IL-17–mediated γδ cell responses, which contrasted with the selective effect of CD27 on IFN-γ–producing γδ cells. Our data collectively show that CD28 signals are required for IL-2–mediated survival and proliferation of both CD27+ and CD27− γδ T cell subsets, thus providing new mechanistic insight for their modulation in disease models.
Helminth Infection Impairs Autophagy-Mediated Killing of Bacterial Enteropathogens by Macrophages
Authors: Su Chien-wen , Cao Yue , Zhang Mei , Kaplan Jess , Su Libo , Fu Ying , Walker W. Allan , Xavier Ramnik , Cherayil Bobby J. , Shi Hai Ning
Published: June 2012

Autophagy is an important mechanism used by macrophages to kill intracellular pathogens. The results reported in this study demonstrate that autophagy is also involved in the macrophage killing of the extracellular enteropathogen Citrobacter rodentium after phagocytosis. The process was significantly impaired in macrophages isolated from mice chronically infected with the helminth parasite Heligmosomoides polygyrus. The H. polygyrus-mediated inhibition of autophagy was Th2 dependent because it was not observed in macrophages isolated from helminth-infected STAT6-deficient mice. Moreover, autophagy of Citrobacter was inhibited by treating macrophages with IL-4 and IL-13. The effect of H. polygyrus on autophagy was associated with decreased expression and processing of L chain protein 3 (LC3), a key component of the autophagic machinery. The helminth-induced inhibition of LC3 expression and processing was STAT6 dependent and could be recapitulated by treatment of macrophages with IL-4 and IL-13. Knockdown of LC3 significantly inhibited autophagic killing of Citrobacter, attesting to the functional importance of the H. polygyrus-mediated downregulation of this process. These observations reveal a new aspect of the immunosuppressive effects of helminth infection and provide mechanistic insights into our earlier finding that H. polygyrus significantly worsens the in vivo course of Citrobacter infection.
Programming of Regulatory T Cells from Pluripotent Stem Cells and Prevention of Autoimmunity
Authors: Haque Rizwanul , Lei Fengyang , Xiong Xiaofang , Bian Yanqing , Zhao Baohua , Wu Yuzhang , Song Jianxun
Published: June 2012

Regulatory T (Treg) cells are being used to treat autoimmunity and prevent organ rejection; however, Treg cell-based therapies have been hampered by the technical limitation in obtaining a high number of functional Treg cells. In this study, we show how to generate functional Treg cells from induced pluripotent stem (iPS) cells and to determine the potential role of such cells for Treg cell-based immunotherapy against autoimmunity in a therapeutic setting. Ligation of a Notch ligand and transduction of the gene Foxp3 induce iPS cells to differentiate into Treg cells. Expression of Foxp3 and coculture on Notch ligand-expressing stromal cells augment expression of CD3, TCR, CD4, CD25, and CTLA-4 on iPS cell-differentiated Treg cells, which are able to secrete TGF-β and IL-10 both in vivo and in vitro. Importantly, adoptive transfer of iPS cell-derived Treg cells expressing large amounts of Foxp3 and Bcl-xL significantly suppresses host immune responses and reduces arthritis development within murine models. These data suggest that Notch signaling and Foxp3 regulate the development and function of Treg cells derived from iPS cells. Our results provide a novel approach for generating potentially therapeutic Treg cells for the treatment of autoimmune diseases.
Critical Role for CCAAT/Enhancer-Binding Protein β in Immune Complex-Induced Acute Lung Injury
Authors: Yan Chunguang , Wu Min , Cao Jay , Tang Huifang , Zhu Mei , Johnson Peter F. , Gao Hongwei
Published: June 2012

C/EBPs, particularly C/EBPβ and C/EBPδ, are known to participate in the regulation of many genes associated with inflammation. However, very little is known regarding the activation and functions of C/EBPβ and C/EBPδ in acute lung inflammation and injury. In this study, we show that both C/EBPβ and C/EBPδ activation are triggered in lungs and in alveolar macrophages following intrapulmonary deposition of IgG immune complexes. We further show that mice carrying a targeted deletion of the C/EBPβ gene displayed significant attenuation of the permeability index (lung vascular leak of albumin), lung neutrophil accumulation (myeloperoxidase activity), total number of WBCs, and neutrophils in bronchoalveolar lavage fluids compared with wild-type mice. Moreover, the mutant mice expressed considerably less TNF-α, IL-6, and CXC/CC chemokine and soluble ICAM-1 proteins in bronchoalveolar lavage fluids, and corresponding mRNAs in the IgG immune complex-injured lung, compared with wild-type mice. These phenotypes were associated with a significant reduction in morphological lung injury. In contrast, C/EBPδ deficiency had no effect on IgG immune complex-induced lung injury. IgG immune complex-stimulated C/EBPβ-deficient alveolar macrophages released significantly less TNF-α, IL-6, MIP-2, keratinocyte cell-derived chemokine, and MIP-1α compared with wild-type cells. Similar decreases in IgG immune complex-induced inflammatory mediator production were observed following small interfering RNA ablation of C/EBPβ in a murine alveolar macrophage cell line. These findings implicate C/EBPβ as a critical regulator of IgG immune complex-induced inflammatory responses and injury in the lung.
Species Selectivity in Poxviral Complement Regulators Is Dictated by the Charge Reversal in the Central Complement Control Protein Modules
Authors: Yadav Viveka Nand , Pyaram Kalyani , Ahmad Muzammil , Sahu Arvind
Published: June 2012

Variola and vaccinia viruses, the two most important members of the family Poxviridae, are known to encode homologs of the human complement regulators named smallpox inhibitor of complement enzymes (SPICE) and vaccinia virus complement control protein (VCP), respectively, to subvert the host complement system. Intriguingly, consistent with the host tropism of these viruses, SPICE has been shown to be more human complement-specific than VCP, and in this study we show that VCP is more bovine complement-specific than SPICE. Based on mutagenesis and mechanistic studies, we suggest that the major determinant for the switch in species selectivity of SPICE and VCP is the presence of oppositely charged residues in the central complement control modules, which help enhance their interaction with factor I and C3b, the proteolytically cleaved form of C3. Thus, our results provide a molecular basis for the species selectivity in poxviral complement regulators.
Cutting Edge: Clec9A+ Dendritic Cells Mediate the Development of Experimental Cerebral Malaria
Authors: Piva Lucia , Tetlak Piotr , Claser Carla , Karjalainen Klaus , Renia Laurent , Ruedl Christiane
Published: June 2012

Plasmodium infections trigger strong innate and acquired immune responses, which can lead to severe complications, including the most feared and often fatal cerebral malaria (CM). To begin to dissect the roles of different dendritic cell (DC) subsets in Plasmodium-induced pathology, we have generated a transgenic strain, Clec9A-diphtheria toxin receptor that allows us to ablate in vivo Clec9A+ DCs. Specifically, we have analyzed the in vivo contribution of this DC subset in an experimental CM model using Plasmodium berghei, and we provide strong evidence that the absence of this DC subset resulted in complete resistance to experimental CM. This was accompanied with dramatic reduction of brain CD8+ T cells, and those few cerebral CD8+ T cells present had a less activated phenotype, unlike their wildtype counterparts that expressed IFN-γ and especially granzyme B. This almost complete absence of local cellular responses was also associated with reduced parasite load in the brain.
Elastohydrodynamic Lubrication Analysis of Conjugate Meshing Face Gear Pairs
Authors: Saribay Zihni B. , Bill Robert C. , Smith Edward C. , Rao Suren B.
Published: June 2012

This paper investigates the nominal elastohydrodynamic lubrication (EHL) characteristics of the conjugate meshing face gears and predicts the mesh efficiency of the pericyclic transmission system. The meshing face-gear tooth geometries and meshing kinematics are modeled. Hertzian contact
and the isothermal non-Newtonian lubricant film characteristics of the meshing face-gear pair are investigated. The friction coefficient is calculated with the effects of lubricant behavior and mesh kinematics. Finally, the pericyclic transmission efficiency is calculated as a function of
friction coefficient, mesh loads, and mesh kinematics. The Hertzian contact behavior, film thickness, and friction coefficient values are simulated for an example fixed axis face-gear pair rotating at 1000 rpm with 3.4 kN-m torque. The EHL film thickness ranges from 0.1 to 0.25 μm
in this example. The average friction coefficient is predicted as 0.05. The efficiencies of three different 24:1 reduction ratio 760 HP pericyclic transmission designs are investigated. The minimum and maximum efficiency in the given design space are 97% and 98.7%, respectively.
A Serum Cytokine Network in Immunoglobulin a Nephropathy
Authors: Woo Sang Hoon , Bhattacharya Sanchita , Derby Geraldine , Taylor Isabella , Myers Bryan D. , Lafayette Richard A.
Published: June 2012

Individual cytokines have been reported to be associated with the pathogenesis and prognosis of immunoglobulin A (IgA) nephropathy (IgAN). We attempted to characterize a broad cytokine matrix in the serum of patients, and investigate its association with renal function. Thirty-two cytokines were simultaneous-ly measured from the serum of IgAN patients (n=22) and healthy controls (n=12). Clinical variables including annual inulin based GFR and 24-h proteinuria were collected on the IgAN patients over a 5-year period. There was a significant difference between serum cytokine signature of IgAN and control values. There was a significant increase in 9 serum cytokines in IgAN patients compared with healthy controls, and these consisted of inflammatory cytokines, growth factors and chemokines. These 9 cytokines demonstrated significant inter-correlation and formed a distinct pattern compared to controls. IgAN appears to be associated with the elevation of multiple serum cytokines in a highly coordi-nated fashion. The pattern of cytokine changes could serve as a disease biomarker and may provide insights into disease pathogenesis.
Characterization of Antibodies that Detect Human GFAP after Traumatic Brain Injury
Authors: Zoltewicz J. Susie , Scharf Dancia , Yang Boxuan , Chawla Aarti , Newsom Kimberly J. , Fang Lijuan
Published: June 2012

After traumatic brain injury (TBI), glial fibrillary acidic protein (GFAP) and other brain-derived proteins and their breakdown products are released into biofluids such as CSF and blood. Recently, a sandwich ELISA was constructed that measured GFAP concentrations in CSF or serum from human mild-moderate TBI patients. The goals of the present study were to characterize the same two antibodies used in this ELISA, and to determine which GFAP bands are detected by this antibody combination. Here, both antibodies recognized GFAP specifically in human brain and post-TBI CSF in a cluster of bands ranging from 50–38 kDa, that resembled bands from calpain-cleaved GFAP. By immunoprecipitation, the anti-GFAP Capture antibody recovered full length GFAP and its breakdown products from human brain lysate and post-TBI CSF. These findings demonstrate that the anti-GFAP ELISA antibodies non-preferentially detect intact GFAP and GFAP breakdown products, underscoring their utility for detecting brain injury in human patients.