Background
Primary small bowel adenocarcinoma (SBA) is a rare, chemoresistant tumor with an aggressive clinical nature. Surgery is the mainstay of therapy, but the extent of lymph node (LN) recovery ...necessary for optimal care of jejunoileal SBA is unknown.
Materials and Methods
The SEER database was queried to identify patients whose primary jejunoileal SBA was diagnosed between 1995 and 2005. Patients were grouped by AJCC stage and number of LNs recovered from the surgical specimen.
Results
Of 1444 patients with primary SBA, 93 (6.4%), 529 (36.6%), 356 (24.7%), and 466 (32.3%) were initially diagnosed with stage I, II, III, and IV disease, respectively. Five-year overall survival (OS) rate was 59.8%, 39.5%, 27.0%, and 3.2% for patients with stage I, II, III, and IV SBA, respectively. When ≥10 nodes were recovered, OS rate increased nonsignificantly in stage I (73.2% vs. 55.6%) and significantly in stage II (61.8% vs. 32.9%,
P
< .001) but was unchanged in stage III (27.4% vs. 27.3%,
P
= .13). Recovery of ≥10 nodes occurred in 26.9%, 23.6%, and 42.1% of patients with stage I, II, and III SBA, respectively. Multivariate analysis identified age, AJCC stage, site of primary tumor, recovery of ≥10 LNs, and number of positive nodes as significant for OS.
Conclusions
We have found SBA staging is largely inadequate. Our results suggest recovery of ≥10 LNs ensures accurate staging. Improvement in stage II SBA OS after adequate LN may reflect a high degree of understaging in this dataset rather than a therapeutic effect of LAD.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Background and Purpose
Ionotropic GABA receptors are evolutionarily conserved proteins that mediate cellular and network inhibition in both vertebrates and invertebrates. A unique class of excitatory ...GABA receptors has been identified in several nematode species. Despite well‐characterized functions in Caenorhabditis elegans, little is known about the pharmacology of the excitatory GABA receptors EXP‐1 and LGC‐35. Using a panel of compounds that differentially activate and modulate ionotropic GABA receptors, we investigated the agonist binding site and allosteric modulation of EXP‐1 and LGC‐35.
Experimental Approach
We used two‐electrode voltage clamp recordings to characterize the pharmacological profile of EXP‐1 and LGC‐35 receptors expressed in Xenopus laevis oocytes.
Key Results
The pharmacology of EXP‐1 and LGC‐35 is different from that of GABAA and GABAA‐ρ receptors. Both nematode receptors are resistant to the competitive orthosteric antagonist bicuculline and to classical ionotropic receptor pore blockers. The GABAA‐ρ specific antagonist, TPMPA, was the only compound tested that potently inhibited EXP‐1 and LGC‐35. Neurosteroids have minimal effects on GABA‐induced currents, but ethanol selectively potentiates LGC‐35.
Conclusions and Implications
The pharmacological properties of EXP‐1 and LGC‐35 more closely resemble the ionotropic GABAA‐ρ family. However, EXP‐1 and LGC‐35 exhibit a unique profile that differs from vertebrate GABAA and GABAA‐ρ receptors, insect GABA receptors and nematode GABA receptors. As a pair, EXP‐1 and LGC‐35 may be utilized to further understand the differential molecular mechanisms of agonist, antagonist and allosteric modulation at ionotropic GABA receptors and may aid in the design of new and more specific anthelmintics that target GABA neurotransmission.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
IntroductionFrailty and multimorbidity are common in type 2 diabetes (T2D), including people <65 years. Guidelines recommend adjustment of treatment targets in people with frailty or multimorbidity, ...however guidelines do not differentiate these two related states. It is unclear how recommendations to adjust treatment targets in people with frailty or multimorbidity should be applied to different ages. It is also not known if the relationship between HbA1c and outcomes is similar in people with and without frailty. We assess implications of frailty/multimorbidity in middle/older-aged people with T2D.
MethodsAnalysis of UK Biobank participants (n = 20,566) with T2D aged 40-72 years comparing two frailty measures (frailty phenotype and frailty index) and two multimorbidity measures (Charlson comorbidity index and a simply count of 40 long-term conditions (LTCs)). Outomes: mortality (all-cause, cardiovascular- and cancer-related mortality), Major Adverse Cardiovascular Event (MACE), hospitalization with hypoglycaemia or fall/fracture.
ResultsMeasure choice influenced the population identified: 42% of participants were identified as frail/multimorbid by at least one measure; only 2.2% were identified by all four measures. Both frailty and multimorbidity, by all measures, were prevalent throughout the age range studied. Each measure was associated with mortality, MACE, hypoglycaemia and falls. The absolute 5-year mortality risk was higher in older versus younger participants with a given level of frailty (e.g. 1.9%, and 9.9% in men aged 45 and 65, respectively, using frailty phenotype) or multimorbidity (e.g. 1.3%, and 7.8% in men with 4 LTCs aged 45 and 65, respectively). Using frailty phenotype, the relationship between higher HbA1c and mortality was stronger in frail compared with pre-frail or robust participants.
ConclusionAssessment of frailty/multimorbidity should be embedded within routine management of middle-aged and older people with T2D. Method of identification as well as features such as age impact baseline risk and should influence clinical decisions (e.g. glycaemic control).
Human immunodeficiency virus encephalitis causes dementia in acquired immune deficiency syndrome patients. Using proteomic analysis of postmortem cerebrospinal fluid (CSF) and brain tissue from the ...simian immunodeficiency virus primate model, we demonstrate here a specific increase in YKL-40 that was tightly associated with lentiviral encephalitis. Longitudinal analysis of CSF from simian immunodeficiency virus-infected pigtailed macaques showed an increase in YKL-40 concentration 2 to 8 weeks before death from encephalitis. This increase in YKL-40 correlated with an increase in CSF viral load; it may therefore represent a biomarker for the development of encephalitis. Analysis of banked human CSF from human immunodeficiency virus-infected patients also demonstrated a correlation between YKL-40 concentration and CSF viral load. In vitro studies demonstrated increased YKL-40 expression and secretion by macrophages and microglia but not by neurons or astrocytes. We found that YKL40 displaced extracellular matrix-bound basic fibroblast growth factor (bFGF) as well as inhibited the mitogenic activity of both fibroblast growth factor receptor 1-expressing BaF3 cells and bFGF-induced axonal branching in hippocampal cultures. Taken together, these findings demonstrate that during lentiviral encephalitis, YKL-40 may interfere with the biological activity of bFGF and potentially of other heparin-binding growth factors and chemokines that can affect neuronal function or survival.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract The mortality associated with primary and metastatic hepatic malignancies remains high because few patients are candidates for hepatic resection or transplantation. Resection is the most ...effective treatment for liver tumors but may be contraindicated by factors such as the tumor's location; hepatic transplantation can cure primary hepatocellular carcinoma and underlying cirrhosis, but a donor may not be immediately available. When resection or transplantation is not possible, thermal ablation is a reasonable therapeutic option. Effective destruction of tumors can be achieved with low recurrence rates and minimal complications or risk of death. In patients with primary hepatic malignancy, ablation treatment does not preclude subsequent transplantation. Although radiofrequency ablation is currently the most widely used thermal ablative technique for hepatic malignancy, microwave ablation is gaining popularity and eventually may prove to be more effective.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
This article offers evidence from a classroom-based research study in English secondary schools which developed an innovative approach to teaching in Design and Technology based on inclusive design ...(also known as universal design). The research evidence highlights how creative, problem-solving approaches in Design and Technology can be used to provide authentic, engaging learning experiences for students. This study, entitled 'Designing our Tomorrows', introduced secondary school teachers and students to the principles and practices of inclusive design through an intervention using specially designed resources. In this article, findings from the study's qualitative pre- and post-intervention interviews are presented to illustrate how this type of approach can stimulate students' creativity and understanding of design.
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DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Pancreatic dermoid cysts are rare, benign, germ cell tumors and part of the differential diagnosis for cystic neoplasms of the pancreas.
A 35-year-old man presented with an incidentally discovered, 2 ...cm cystic pancreatic neoplasm of the pancreatic tail identified on CT scan. Endoscopic ultrasound (EUS) revealed a complex, honeycomb lesion. Fine needle aspiration (FNA) yielded a sample of whitish, necrotic material containing histiocytes, benign epithelial cells, and lymphocytes. After distal pancreatectomy and splenectomy was performed, histology revealed a cyst lined by stratified squamous epithelium with benign sebaceous units consistent with a pancreatic dermoid cysts.
Although axial imaging reliably detects cystic neoplasms of the pancreas, diagnostic criteria for rare lesions are lacking; therefore alternative modalities such as EUS/FNA can be utilized. This case report highlights the EUS and FNA findings associated with pancreatic dermoid cysts.
The clustered regularly interspersed palindromic repeats (CRISPR)-CRISPR-associated protein 9 (Cas9) prokaryotic adaptive immune defense system has been co-opted as a powerful tool for precise ...eukaryotic genome engineering. Here, we present a rapid and simple method using chimeric single guide RNAs (sgRNA) and CRISPR-Cas9 Ribonucleoproteins (RNPs) for the efficient and precise generation of genomic point mutations in C. elegans. We describe a pipeline for sgRNA target selection, homology-directed repair (HDR) template design, CRISPR-Cas9-RNP complexing and delivery, and a genotyping strategy that enables the robust and rapid identification of correctly edited animals. Our approach not only permits the facile generation and identification of desired genomic point mutant animals, but also facilitates the detection of other complex indel alleles in approximately 4 - 5 days with high efficiency and a reduced screening workload.
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