bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prime-boost vaccination strategy with bacillus Calmette–Guérin (BCG) and liposomized alpha-crystalline protein 1 reinvigorates BCG potency
Authors: Siddiqui K F , Amir M , Khan N , Rama Krishna G , Sheikh J A , Rajagopal K , Agrewala J N 
Published: April 2015

Summary
Bacillus Calmette–Guérin (BCG) remains the only available and most widely administered vaccine against Mycobacterium tuberculosis (Mtb), yet it fails to protect vaccinated individuals either from primary infection or reactivation of latent tuberculosis (TB). Despite BCG's variable efficacy against TB, the fact remains that BCG imparts protection in children against the disease, indicating that BCG possesses a wide protective antigenic repertoire. However, its failure to impart protection in adulthood can be linked to its failure to generate long-lived memory response and elicitation of an inadequate immune response against latency-associated antigens. Therefore, to improve the protective efficacy of BCG, a novel vaccination strategy is required. Consequently, in the present study, we have exploited the vaccination potential of liposomized α-crystalline 1 (Acr1L), a latency-associated antigen to induce enduring protective immunity against Mtb in BCG-primed animals. It is noteworthy that an increase in the multi-functional [interferon (IFN)-γhi/tumour necrosis factor (TNF)-αhi] CD4 and CD8 T cells were observed in BCG-primed and Acr1L-boosted (BCG-Acr1L) animals, compared to BCG alone. Further, substantial expansion of both central memory (CD44hi/CD62Lhi) and effector memory (CD44hi/CD62Llo) populations of CD4 and CD8 T cells was noted. Importantly, BCG-Acr1L exhibited significantly better protection than BCG, as evidenced by a reduction in the bacterial burden and histopathological data of the lungs. In essence, BCG-Acr1L could be a potent future vaccination strategy to reinvigorate BCG potency.
Increased lymphocyte apoptosis in mouse models of colitis upon ABT-737 treatment is dependent upon BIM expression
Authors: Lutz C , Mozaffari M , Tosevski V , Caj M , Cippà P , McRae B L , Graff C L , Rogler G , Fried M , Hausmann M 
Published: April 2015

SummaryExaggerated activation of lymphocytes contributes to the pathogenesis of inflammatory bowel disease (IBD). Medical therapies are linked to the BCL-2 family-mediated apoptosis. Imbalance in BCL-2 family proteins may cause failure in therapeutic responses. We investigated the role of BCL-2 inhibitor ABT-737 for lymphocyte apoptosis in mice under inflammatory conditions. B.6129P2-interleukin (IL)-10tm1Cgn/J (IL-10−/−) weighing 25–30 g with ongoing colitis were used. Fifty mg/kg/day ABT-737 was injected intraperitoneally (i.p.). Haematological analyses were performed with an ADVIA 2120 flow cytometer and mass cytometry with a CyTOF 2. Following i.p. administration, ABT-737 was detected in both spontaneous and acute colitis in peripheral blood (PBL) and colon tissue. Treatment led to lymphopenia. CD4+CD44+CD62L+ central memory and CD8+, CD44+ CD62L− central memory T cells were decreased in PBL upon ABT-737 compared to vehicle-receiving controls. Increased apoptosis upon ABT-737 was determined in blood lymphocytes, splenocytes and Peyer's patches and was accompanied by a decrease in TNF and IL-1B. ABT-737 positively altered the colonic mucosa and ameliorated inflammation, as shown by colonoscopy, histology and colon length. A decreased BIM/BCL-2 ratio or absence of BIM in both Bim−/− and Il10−/− × Bim−/− impeded the protective effect of ABT-737. The BIM/BCL-2 ratio decreased with age and during the course of treatment. Thus, long-term treatment resulted in adapted TNF levels and macroscopic mucosal damage. ABT-737 was efficacious in diminishing lymphocytes and ameliorating colitis in a BIM-dependent manner. Regulation of inappropriate survival of lymphocytes by ABT-737 may provide a therapeutic strategy in IBD.
Immunoglobulin A in serum: an old acquaintance as a new prognostic biomarker in idiopathic pulmonary fibrosis
Authors: ten Klooster L , van Moorsel C H M , Kwakkel-van Erp J M , van Velzen-Blad H , Grutters J C 
Published: April 2015

SummaryImmunoglobulin (Ig)A is an important immunoglobulin in mucosal immunity and protects the lungs against invading pathogens. The production of IgA is regulated by transforming growth factor (TGF)-β, a versatile cytokine and key player in the pathogenesis of pulmonary fibrosis. TGF-β is up-regulated in patients with idiopathic pulmonary fibrosis (IPF), but difficult to use as a biomarker. The aim of this study was to evaluate the prognostic value of IgA in serum in patients with IPF. We examined IgA levels at time of diagnosis in 86 patients diagnosed with IPF. Mean serum IgA level in IPF is 3·22 g/l and regression analyses showed a significant association with mortality (hazard ratio = 1·445, P = 0·002). A significantly worse survival was found in patients with IgA serum levels &gt; 2·85 g/l compared to patients with lower IgA serum levels (P = 0·003). These findings were confirmed in a duplication cohort. In conclusion, the level of IgA in blood is a promising prognostic marker in IPF and can be implemented easily in the hospital setting. Future studies are warranted to investigate if repeated measurements of serum IgA can further improve the performance of serum IgA as a prognostic marker.
10-valent pneumococcal non-typeable Haemophilus influenzae protein-D conjugate vaccine (PHiD-CV) induces memory B cell responses in healthy Kenyan toddlers
Authors: Muema D M , Nduati E W , Uyoga M , Bashraheil M , Scott J A G , Hammitt L L , Urban B C 
Published: April 2015

Summary
Memory B cells are long-lived and could contribute to persistence of humoral immunity by maintaining the plasma-cell pool or making recall responses upon re-exposure to an antigen. We determined the ability of a pneumococcal conjugate vaccine to induce anti-pneumococcal memory B cells. Frequencies of memory B cells against pneumococcal capsular polysaccharides from serotypes 1, 6B, 14, 19F and 23F were determined by cultured B cell enzyme-linked immunospot (ELISPOT) in 35 children aged 12–23 months who received pneumococcal non-typeable Haemophilus influenzae protein-D conjugate vaccine (PHiD-CV). The relationships between plasma antibodies and memory B cell frequencies were also assessed. After two doses of PHiD-CV, the proportion of subjects with detectable memory B cells against pneumococcal capsular polysaccharides increased significantly for serotypes 1 (3–45%; P &lt; 0·01), 19F (21–66%; P &lt; 0·01) and 23F (13–36%; P = 0·02), but not serotypes 6B (24–42%; P = 0·24) and 14 (21–40%; P = 0·06). Correlations between antibodies and memory B cells were weak. Carriage of serotype 19F at enrolment was associated with poor memory B cell responses against this serotype at subsequent time-points (day 30: non-carriers, 82% versus carriers, 0%, P &lt; 0·01; day 210: non-carriers, 72% versus carriers, 33%, P = 0·07). PHiD-CV is capable of inducing memory B cells against some of the component pneumococcal capsular polysaccharides.
Endoplasmic reticulum stress causes autophagy and apoptosis leading to cellular redistribution of the autoantigens Ro/Sjögren's syndrome-related antigen A (SSA) and La/SSB in salivary gland epithelial cells
Authors: Katsiougiannis S , Tenta R , Skopouli F N 
Published: April 2015

SummaryThe aim of this study was to examine the levels of endoplasmic reticulum (ER) stress in minor salivary glands, to investigate the interplay between ER stress-induced autophagy and apoptosis in human salivary gland (HSG) cells and to test the effect of ER stress-induced apoptosis on the cellular redistribution of the two major Sjögren's syndrome (SS) autoantigens Ro/Sjögren's syndrome-related antigen A (SSA) and La/Sjögren's syndrome-related antigen B (SSB). Minor salivary gland biopsies from SS patients and sicca controls were examined by immunohistochemistry for the expression of 78 kDa glucose-regulated protein/binding immunoglobulin protein (GRP78/BiP) as an indicator of unfolded protein response (UPR). HSG cells were treated with thapsigargin (TG) and cell viability, autophagy and apoptosis were assessed. Immunoblot was applied to detect the conversion of LC3I to LC3II and the protein levels of GRP78/BiP and X-box binding protein-1 (XBP-1). Apoptosis was evaluated by a single-stranded DNA enzyme-linked immunosorbent assay (ELISA). Ro/SSA and La/SSB localization was visualized using immunofluorescence. GRP78/BiP was expressed by acinar and ductal epithelial cells in salivary glands of patients and sicca controls. TG treatment induced autophagy, as indicated by enhanced protein expression of LC3II. The protein levels of UPR marker XBP-1 were increased after TG treatment, while GRP78/BiP levels were decreased. TG treatment resulted in induction of HSG apoptosis. Ro/SSA and La/SSB autoantigens were localized predominantly to the cytoplasm in resting cells, while they were redistributed to cell membrane and blebs in the apoptotic cells. In conclusion, ER stress is activated in minor salivary gland epithelial cells from SS patients and controls. ER stress-induced apoptosis in HSG cells leads to cell surface and apoptotic blebs relocalization of Ro/SSA and La/SSB autoantigens.
Remission of systemic lupus erythematosus disease activity with regulatory cytokine interleukin (IL)-35 in Murphy Roths Large (MRL)/lpr mice
Authors: Cai Z , Wong C K , Dong J , Chu M , Jiao D , Kam N W , Lam C W K , Tam L S 
Published: April 2015

Summary
The immunological mechanisms mediated by regulatory cytokine interleukin (IL)-35 are unclear in systemic lupus erythematosus (SLE). We investigated the frequency of CD4+CD25+forkhead box protein 3 (FoxP3)+ regulatory T (Treg) and IL-10+ regulatory B (Breg) cells and related immunoregulatory mechanisms in a female Murphy Roths Large (MRL)/lpr mouse model of spontaneous lupus-like disease, with or without IL-35 treatment. A remission of histopathology characteristics of lupus flare and nephritis was observed in the MRL/lpr mice upon IL-35 treatment. Accordingly, IL-35 and IL-35 receptor subunits (gp130 and IL-12Rβ2) and cytokines of MRL/lpr and BALB/c mice (normal controls) were measured. The increased anti-inflammatory cytokines and decreased proinflammatory cytokines were possibly associated with the restoration of Treg and Breg frequency in MRL/lpr mice with IL-35 treatment, compared to phosphate-buffered saline (PBS) treatment. mRNA expressions of Treg-related FoxP3, IL-35 subunit (p35 and EBI3) and soluble IL-35 receptor subunit (gp130 and IL12Rβ2) in splenic cells were up-regulated significantly in IL-35-treated mice. Compared with the PBS treatment group, IL-35-treated MRL/lpr mice showed an up-regulation of Treg-related genes and the activation of IL-35-related intracellular Janus kinase/signal transducer and activator of transcription signal pathways, thereby indicating the immunoregulatory role of IL-35 in SLE. These in vivo findings may provide a biochemical basis for further investigation of the regulatory mechanisms of IL-35 for the treatment of autoimmune-mediated inflammation.
Oral administration of non-absorbable delayed release 6-mercaptopurine is locally active in the gut, exerts a systemic immune effect and alleviates Crohn's disease with low rate of side effects: results of double blind Phase II clinical trial
Authors: Israeli E , Goldin E , Fishman S , Konikoff F , Lavy A , Chowers Y , Melzer E , Lahat A , Mahamid M , Shirin H , Nussinson E , Segol O , Ben Ya'acov A , Shabbat Y , Ilan Y 
Published: April 2015

Summary
Therapy for Crohn's disease (CD) with thiopurines is limited by systemic side effects. A novel formulation of fixed-dose, delayed-release 6-mercaptopurine (DR-6MP) was developed, with local effect on the gut immune system and minimal absorption. The aim of this study was to evaluate the safety and efficacy of DR-6MP in patients with moderately severe CD compared to systemically delivered 6-mercaptopurine (Purinethol). Seventy CD patients were enrolled into a 12-week, double-blind controlled trial. The primary end-point was the percentage of subjects with clinical remission [Crohn's Disease Activity Index (CDAI) &lt; 150] or clinical response (100-point CDAI reduction). Twenty-six (56·5%) and 13 (54·2%) subjects from the DR-6MP and Purinethol cohorts, respectively, completed the study. DR-6MP had similar efficacy to Purinethol following 12 weeks of treatment. However, the time to maximal clinical response was 8 weeks for DR-6MP versus 12 weeks for Purinethol. A higher proportion of patients on DR-6MP showed clinical remission at week 8. A greater improvement in Inflammatory Bowel Disease Questionnaire (IBDQ) score was noted in the DR-6MP group. DR-6MP led to a decrease of CD62+ expression on T cells, implying a reduction of lymphocyte adhesion to site of inflammation. DR-6MP was safer than Purinethol, with significantly fewer adverse events (AEs). There was no evidence of drug-induced leucopenia in the DR-6MP group; the proportion of subjects who developed hepatotoxicity was lower for the DR-6MP. Non-absorbable DR-6MP is safe and biologically active in the gut. It is clinically effective, exerting a systemic immune response with low systemic bioavailability and a low incidence of side effects.
Relationship between pituitary stalk (PS) visibility and the severity of hormone deficiencies: PS interruption syndrome revisited
Authors: Wang Weiqing , Wang Shuwei , Jiang Yiran , Yan Fuhua , Su Tingwei , Zhou Weiwei , Jiang Lei , Zhang Yifei , Ning Guang 
Published: April 2015

SummaryContextPituitary stalk interruption syndrome (PSIS) is a rare cause of combined pituitary hormone deficiency characterized by a triad shown in pituitary imaging, yet it has never been evaluated due to the visibility of pituitary stalk (PS) in imaging findings.ObjectiveThe major objective of the study was to systematically describe the disease including clinical presentations, imaging findings and to estimate the severity of anterior pituitary hormone deficiency based on the visibility of the PS.MethodsThis was a retrospective study including 74 adult patients with PSIS in Shanghai Clinical Center for Endocrine and Metabolic Diseases between January 2010 and June 2014. Sixty had invisible PS according to the findings on MRI, while the rest had a thin or intersected PS. Basic characteristics and hormonal status were compared.ResultsOf the 74 patients with PSIS, age at diagnosis was 25 (22–28) years. Absent pubertal development (97·3%) was the most common presenting symptom, followed by short stature. Insulin tolerance test (ITT) and gonadotrophin‐releasing hormone (GnRH) stimulation test were used to evaluate the function of anterior pituitary. The prevalence of isolated deficiency in growth hormone (GH), gonadotrophins, corticotrophin and thyrotrophin were 100%, 97·2%, 88·2% and 70·3%, respectively. Although the ratio of each deficiency did not vary between patients with invisible PS and with visible PS, panhypopituitarism occurred significantly more frequent in patients with invisible PS. Patients with invisible PS had significantly lower levels of luteinizing hormone (LH), follicle stimulation hormone (FSH) and hormones from targeted glands including morning cortisol, 24‐h urine free cortisol, free triiodothyronine (FT3), free thyroxine (FT4) and testosterone (T) in male than patients with visible PS. Moreover, patients with invisible PS had lower peak LH and FSH in GnRH stimulation test, and higher peak cortisol in ITT while peak GH remained unchanged between two groups.ConclusionsThe prevalence of multiple anterior pituitary hormone deficiency was high in adult patients with PSIS. And more importantly, we found the visibility of PS shown on MRI might be an indication of the severity of PSIS.
A systematic review of sacral nerve stimulation for low anterior resection syndrome
Authors: Ramage L. , Qiu S. , Kontovounisios C. , Tekkis P. , Rasheed S. , Tan E. 
Published: April 2015

AbstractAimThe efficacy of sacral nerve stimulation (SNS) in low anterior resection syndrome (LARS) is largely undocumented. A review of the literature was carried out to study this question.MethodPubmed, Medline and Cochrane databases were searched for relevant articles up to August 2014. Studies were included if they evaluated the use ofSNSfollowing rectal resection and assessed at least one of the following end‐points: bowel function, quality of life and ano‐neorectal physiology. No restrictions on language or study size were made.ResultsSeven papers were identified including one case report and six prospective case series. These included 43 patients with a median follow‐up of 15 months. After peripheral nerve evaluation definitive implantation was carried out in 34 (79.1%) patients. Overall, 32 (94.1%) of the 34 patients experienced improvement of symptoms which, based on intention to treat, was 32/43 (74.4%).ConclusionThe review suggests thatSNSfor faecal incontinence inLARShas success rates comparable to its use for other forms of faecal incontinence.
Ups and Downs in Auditory Development: Preschoolers’ Sensitivity to Pitch Contour and Timbre
Authors: Creel Sarah C. 
Published: April 2015

AbstractMuch research has explored developing sound representations in language, but less work addresses developing representations of other sound patterns. This study examined preschool children's musical representations using two different tasks: discrimination and sound–picture association. Melodic contour—a musically relevant property—and instrumental timbre, which is (arguably) less musically relevant, were tested. In Experiment 1, children failed to associate cartoon characters to melodies with maximally different pitch contours, with no advantage for melody preexposure. Experiment 2 also used different‐contour melodies and found good discrimination, whereas association was at chance. Experiment 3 replicated Experiment 2, but with a large timbre change instead of a contour change. Here, discrimination and association were both excellent. Preschool‐aged children may have stronger or more durable representations of timbre than contour, particularly in more difficult tasks. Reasons for weaker association of contour than timbre information are discussed, along with implications for auditory development.
The over‐pruning hypothesis of autism
Authors: Thomas Michael S.C. , Davis Rachael , Karmiloff‐Smith Annette , Knowland Victoria C.P. , Charman Tony 
Published: April 2015

AbstractThis article outlines the over‐pruning hypothesis of autism. The hypothesis originates in a neurocomputational model of the regressive sub‐type (Thomas, Knowland & Karmiloff‐Smith, 2011a, 2011b). Here we develop a more general version of the over‐pruning hypothesis to address heterogeneity in the timing of manifestation of ASD, including new computer simulations which reconcile the different observed developmental trajectories (early onset, late onset, regression) via a single underlying atypical mechanism; and which show how unaffected siblings of individuals with ASD may differ from controls either by inheriting a milder version of the pathological mechanism or by co‐inheriting the risk factors without the pathological mechanism. The proposed atypical mechanism involves overly aggressive synaptic pruning in infancy and early childhood, an exaggeration of a normal phase of brain development. We show how the hypothesis generates novel predictions that differ from existing theories of ASD including that (1) the first few months of development in ASD will be indistinguishable from typical, and (2) the earliest atypicalities in ASD will be sensory and motor rather than social. Both predictions gain cautious support from emerging longitudinal studies of infants at‐risk of ASD. We review evidence consistent with the over‐pruning hypothesis, its relation to other current theories (including C. Frith's under‐pruning proposal; C. Frith, 2003, 2004), as well as inconsistent data and current limitations. The hypothesis situates causal accounts of ASD within a framework of protective and risk factors (Newschaffer et al., 2012); clarifies different versions of the broader autism phenotype (i.e. the implication of observed similarities between individuals with autism and their family members); and integrates data from multiple disciplines, including behavioural studies, neuroscience studies, genetics, and intervention studies.
Australian hip surveillance guidelines for children with cerebral palsy: 5‐year review
Authors: Wynter Meredith , Gibson Noula , Willoughby Kate L , Love Sarah , Kentish Megan , Thomason Pam , Graham H Kerr ,   the National Hip Surveillance Working Group
Published: April 2015

AimTo ensure hip surveillance guidelines reflect current evidence of factors influencing hip displacement in children with cerebral palsy (CP).MethodA three‐step review process was undertaken: (1) systematic literature review, (2) analysis of hip surveillance databases, and (3) national survey of orthopaedic surgeons managing hip displacement in children with CP.ResultsFifteen articles were included in the systematic review. Quantitative analysis was not possible. Qualitative review indicated hip surveillance programmes have decreased the incidence of hip dislocation in populations with CP. The Gross Motor Function Classification System was confirmed as the best indicator of risk for displacement, and evidence was found of hip displacement occurring at younger ages and in young adulthood. Femoral geometry, pelvic obliquity, and scoliosis were linked to progression of hip displacement. A combined data pool of 3366 children from Australian hip surveillance databases supported the effectiveness of the 2008 Consensus Statement to identify hip displacement early. The survey of orthopaedic surgeons supported findings of the systematic review and database analyses.InterpretationThis review rationalized changes to the revised and renamed Australian Hip Surveillance Guidelines for Children with Cerebral Palsy 2014, informing frequency of radiographic examination in lower risk groups and continuation of surveillance into adulthood for adolescents with identified risk factors.
Collaborative Learning Using a Project across Multiple Business Courses: A Cognitive Load and Knowledge Convergence Approach
Authors: Bhowmick Sandeep , Chandra Aruna , Harper Jeffrey S. , Sweetin Vernon 
Published: April 2015

ABSTRACTFour business professors at a state university in the Midwestern United States launched a collaborative learning project grounded in cognitive learning theory and knowledge convergence theory with the objective of assessing student learning gains in cross‐functional knowledge (CFK), course‐related knowledge (CRK), and overall satisfaction with this teaching approach. The project involved the start‐up and operation of an entrepreneurial campus lunch delivery service from local restaurants to university faculty, students, and staff.A total of 46 students participated in the project, and comprised seven groups across four business courses: Strategy, Project Management, Marketing Promotion, and Marketing Research. A survey instrument was developed comprising 21 items. Survey results indicated significant increases in cross‐functional and course‐related knowledge, and in student involvement and teamwork when using this cross‐functional, multicourse approach to an entrepreneurial endeavor.