Introduction
MR-tractography is increasingly used in neurosurgical practice to evaluate the anatomical relationships between glioma and nearby subcortical tracts. In some patients, the subcortical ...tracts seem displaced by the glioma, while in other patients, the subcortical tracts seem infiltrated without displacement. At this point, it is unknown whether these different patterns are related to tumor type. The aim of this exploratory study was to investigate whether tumor type is related to the spatial tractography pattern of the frontal aslant tract (FAT) in low-grade gliomas (LGGs).
Methods
In 64 IDH-mutated LGG patients, the FAT was generated using a pipeline for automatic tractography. In 41 patients, the glioma adjoined the FAT, and four blinded reviewers independently assessed the following two dichotomous categories (yes/no): (i) glioma displaces the tract, and (ii) glioma infiltrates the tract.
Results
Fisher’s exact tests demonstrated strong and significant positive associations between displacement and astrocytomas (
p
= .002, φ = .497) and infiltration and oligodendrogliomas (
p
= .004, φ = .484). The interobserver agreement was good for both categories: (i) κ = 0.76 and (ii) κ = 0.71.
Conclusion
High sensitivity but low specificity for displacement in astrocytomas demonstrates that in the case of an astrocytoma, the tract is most likely displaced, but that displacement in itself is not necessarily predictive for astrocytomas, as oligodendrogliomas may both infiltrate and displace a tract. Overall, these results demonstrate that oligodendrogliomas tend to infiltrate the nearby subcortical tract, whereas astrocytomas only tend to displace it.
Chronic intestinal inflammation, as seen in inflammatory bowel disease (IBD), results from an aberrant and poorly understood mucosal immune response to the microbiota of the gastrointestinal tract in ...genetically susceptible individuals. Here we used serological expression cloning to identify commensal bacterial proteins that could contribute to the pathogenesis of IBD. The dominant antigens identified were flagellins, molecules known to activate innate immunity via Toll-like receptor 5 (TLR5), and critical targets of the acquired immune system in host defense. Multiple strains of colitic mice had elevated serum anti-flagellin IgG2a responses and Th1 T cell responses to flagellin. In addition, flagellin-specific CD4(+) T cells induced severe colitis when adoptively transferred into naive SCID mice. Serum IgG to these flagellins, but not to the dissimilar Salmonella muenchen flagellin, was elevated in patients with Crohn disease, but not in patients with ulcerative colitis or in controls. These results identify flagellins as a class of immunodominant antigens that stimulate pathogenic intestinal immune reactions in genetically diverse hosts and suggest new avenues for the diagnosis and antigen-directed therapy of patients with IBD.
We conducted a phase IIa, multi-centre, open label, single arm study (RADICAL; NCT01791985) of AZD4547 (a potent and selective inhibitor of Fibroblast Growth Factor Receptor (FGFR)-1, 2 and 3 ...receptor tyrosine kinases) administered with anastrozole or letrozole in estrogen receptor positive metastatic breast cancer patients who had become resistant to aromatase inhibitors. After a safety run-in study to assess safety and tolerability, we recruited 52 patients. The primary endpoint was change in tumour size at 12 weeks, and secondary endpoints were to assess response at 6 weeks, 20 weeks and every 8 weeks thereafter and tolerability of the combined treatment. Two partial responses (PR) and 19 stable disease (SD) patients were observed at the 12-week time point. At 28 weeks, according to centrally reviewed Response Evaluation Criteria in Solid Tumours (RECIST) criteria, five PR and 8 SD patients were observed in 50 assessable cases. Overall, objective response rate (5 PR) was of 10%, meeting the pre-specified endpoint. Fourteen patients discontinued due to adverse events. Eleven patients had retinal pigment epithelial detachments which was asymptomatic and reversible in all but one patient. Exploratory ribonucleic acid sequencing (RNA-Seq) analysis was done on patients' samples: 6 differentially-expressed-genes could distinguish those who benefited from the addition of AZD4547.
Seabird foraging behaviour can reflect prey abundance at sea, and is influenced by stress hormone levels, thus providing a potential indicator of at-sea conditions. Using common diving petrels (
...Pelecanoides urinatrix,
hereafter CDPs), a procellariform that preferentially forages on crustacean zooplankton, we sought to understand how spatially separate colonies responded behaviourally and physiologically to contrasting prey levels with a view to recruiting this species as an environmental indicator. In 2016, incubating CDPs from Tiritiri Matangi (− 36.59S; 174.88E, low levels of preferred prey) and Burgess (− 35.91S; 174.12E, high levels of preferred prey) Islands within the Hauraki Gulf, New Zealand, were tracked using GPS devices. We hypothesised that Tiritiri birds would exhibit greater foraging effort and higher stress hormone levels across the breeding season due to lower levels of available prey. Hidden Markov methods were used to model foraging effort, and prey trophic level (stable isotopes:
δ
13
C and
δ
15
N) and stress hormone levels (CORT) quantified in plasma samples. During incubation birds were spatially segregated when foraging. Tiritiri birds exerted more effort, chasing higher trophic level prey at larger distances from the colony, and had higher body weight and lower CORT than Burgess birds. However, bird CORT levels responded more to reproductive duties (peaking during chick rearing) as opposed to colony location, i.e. CORT was not consistently higher in Tiritiri birds. Although a snapshot, our findings illustrate the promise of integrating multiple parameters when recruiting seabirds as ocean indicators, resulting in improved resolution of future monitoring programmes based upon them.
Background & Aims:
Antibody responses to certain microbial antigens define heterogeneous groups of Crohn’s patients; multiple and high-level responses to these antigens are associated with aggressive ...clinical phenotypes. The flagellin, CBir1, identified by investigations in the C3H/HeJBir mouse model, has been identified as a dominant antigen capable of inducing colitis in mice and eliciting antibody responses in a subpopulation of patients with Crohn’s disease (CD). The aim of this study was to evaluate serum response to CBir1 flagellin in CD patients and to compare this response to responses defined previously to oligomannan (anti-
Saccharomyces cerevisiae antibody), I2, OmpC, and neutrophil nuclear autoantigens (pANCA), and to determine anti-CBir1-associated phenotypes.
Methods:
A total of 484 sera from the Cedars Sinai Medical Center repository, previously typed for anti-
Saccharomyces cerevisiae antibody, anti-I2, anti-OmpC, and pANCA were tested for anti-CBir1 by enzyme-linked immunosorbent assay, and results were assessed for clinical phenotype associations.
Results:
The presence and level of immunoglobulin G anti-CBir1 were associated with CD independently. Anti-CBir1 was present in all antibody subgroups and expression increased in parallel with increases in the number of antibody responses. pANCA
+ CD patients were more reactive to CBir1 than were pANCA
+ ulcerative colitis patients. Anti-CBir1 expression is associated independently with small-bowel, internal-penetrating, and fibrostenosing disease features.
Conclusions:
Serum responses to CBir1 independently identify a unique subset of patients with complicated CD. This bacterial antigen was identified in a murine model and has a similar pattern of aberrant reactivity in a subset of CD patients.
A massive hexanucleotide repeat expansion mutation (HREM) in C9ORF72 has recently been linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here we describe the frequency, ...origin and stability of this mutation in ALS+/-FTD from five European cohorts (total n=1347). Single-nucleotide polymorphisms defining the risk haplotype in linked kindreds were genotyped in cases (n=434) and controls (n=856). Haplotypes were analysed using PLINK and aged using DMLE+. In a London clinic cohort, the HREM was the most common mutation in familial ALS+/-FTD: C9ORF72 29/112 (26%), SOD1 27/112 (24%), TARDBP 1/112 (1%) and FUS 4/112 (4%) and detected in 13/216 (6%) of unselected sporadic ALS cases but was rare in controls (3/856, 0.3%). HREM prevalence was high for familial ALS+/-FTD throughout Europe: Belgium 19/22 (86%), Sweden 30/41 (73%), the Netherlands 10/27 (37%) and Italy 4/20 (20%). The HREM did not affect the age at onset or survival of ALS patients. Haplotype analysis identified a common founder in all 137 HREM carriers that arose around 6300 years ago. The haplotype from which the HREM arose is intrinsically unstable with an increased number of repeats (average 8, compared with 2 for controls, P<10(-8)). We conclude that the HREM has a single founder and is the most common mutation in familial and sporadic ALS in Europe.
Despite impressive strides in health, social protection, and education, children continue to experience high rates of child maltreatment in Malaysia. This mixed-methods study assessed the feasibility ...of a five-session, social learning-based parenting program delivered by government staff in a community setting to reduce violence against children.
Parents of children from birth to 17 years were recruited from two communities near Kuala Lumpur to participate in the government-run program called the Naungan Kasih Positive Parenting Program ("Protecting through Love" in Bahasa Melayu). Quantitative data from female caregivers (N = 74) and children ages 10-17 (N = 26) were collected along with qualitative interviews and focus groups with parents, children, and facilitators. The primary outcome was child maltreatment with secondary outcomes including neglect, positive parenting, acceptability of corporal punishment, harsh parenting, positive discipline, and child behavior problems. Multilevel Poisson regression and multilevel linear regression were conducted to compare baseline and post-test outcomes. Qualitative interviews and focus groups examined how participants experienced the program utilizing a thematic analysis approach.
Quantitative analyses found pre-post reductions in overall child maltreatment, physical abuse, emotional abuse, attitudes supporting corporal punishment, parent sense of inefficacy, and child behavior problems. There were no reported changes on positive and harsh parenting, parental mental health, and marital satisfaction, nor were there any other significant changes reported by children. Qualitative findings suggested that the program had tangible benefits for female caregivers involved in the program, with the benefits extending to their family members.
This feasibility study is one of the few studies in Southeast Asia that examined the feasibility and initial program impact of a parenting program delivered by government staff to families with children across the developmental spectrum from birth to 17 years. Promising results suggest that the program may reduce child maltreatment across a range of child ages. Findings also indicate areas for program improvement prior to further delivery and testing, including additional training and content on sexual and reproductive health, parenting children with disabilities, and online child protection.
In the quest for markers of expression and progression for prostate cancer (PCa), the majority of studies have focussed on molecular data exclusively from primary tumours. Although expression in ...metastases is inferred, a lack of correlation with secondary tumours potentially limits their applicability diagnostically and therapeutically. Molecular targets were identified by examining expression profiles of prostate cell lines using cDNA microarrays. Those genes identified were verified on PCa cell lines and tumour samples from both primary and secondary tumours using real-time RT-PCR, western blotting and immunohistochemistry. Claudin-4, coding for an integral membrane cell-junction protein, was the most significantly (P<0.00001) upregulated marker in both primary and metastatic tumour specimens compared with benign prostatic hyperplasia at both RNA and protein levels. In primary tumours, claudin-4 was more highly expressed in lower grade (Gleason 6) lesions than in higher grade (Gleason >or=7) cancers. Expression was prominent throughout metastases from a variety of secondary sites in fresh-frozen and formalin-fixed specimens from both androgen-intact and androgen-suppressed patients. As a result of its prominent expression in both primary and secondary PCas, together with its established role as a receptor for Clostridium perfringens enterotoxin, claudin-4 may be useful as a potential marker and therapeutic target for PCa metastases.
A glass microdevice has been constructed for the on-line integration of solid-phase extraction (SPE) of DNA and polymerase chain reaction (PCR) on a single chip. The chromatography required for SPE ...in the microfluidic sample preparation device (μSPD) was carried out in a silica bead/sol−gel SPE bed, where the purified DNA was eluted directly into a downstream chamber where conventional thermocycling allowed for PCR amplification of specific DNA target sequences. Through rapid, simple passivation of the PCR chamber with a silanizing reagent, reproducible DNA extraction and amplification was demonstrated from complex biological matrixes in a manner amenable to any research laboratory, using only a syringe pump and a conventional thermocycler. The μSPD allowed for SPE concentration of DNA from 600 nL of blood coupled to subsequent on-chip amplification that yielded a detectable amplicon; this simple device can be applied to a variety of routine genetic analyses without the need for sophisticated instrumentation. In addition, the applicability of these developments to nonconventional thermocycling was demonstrated through the use of noncontact, IR-mediated heating. This was exemplified with the isolation of DNA from an anthrax spore-spiked nasal swab and the subsequent on-chip amplification of target DNA sequences in a total processing time of only 25 min.
PDF
