Prognostic value of lymph node ratio and extramural vascular invasion on survival for patients undergoing curative colon cancer resection

There was no study funding. We are grateful to Tony Rafferty (Tailored Information for the People of Scotland, TIPs) for providing survival data.Peer reviewedPublisher PD

Spontaneous symmetry breaking in a two-lane model for bidirectional overtaking traffic

First we consider a unidirectional flux \omega_bar of vehicles each of which is characterized by its `natural' velocity v drawn from a distribution P(v). The traffic flow is modeled as a collection of straight `world lines' in the time-space plane, with overtaking events represented by a fixed queuing time tau imposed on the overtaking vehicle. This geometrical model exhibits platoon formation and allows, among many other things, for the calculation of the effective average velocity w=\phi(v) of a vehicle of natural velocity v. Secondly, we extend the model to two opposite lanes, A and B. We argue that the queuing time \tau in one lane is determined by the traffic density in the opposite lane. On the basis of reasonable additional assumptions we establish a set of equations that couple the two lanes and can be solved numerically. It appears that above a critical value \omega_bar_c of the control parameter \omega_bar the symmetry between the lanes is spontaneously broken: there is a slow lane where long platoons form behind the slowest vehicles, and a fast lane where overtaking is easy due to the wide spacing between the platoons in the opposite direction. A variant of the model is studied in which the spatial vehicle density \rho_bar rather than the flux \omega_bar is the control parameter. Unequal fluxes \omega_bar_A and \omega_bar_B in the two lanes are also considered. The symmetry breaking phenomenon exhibited by this model, even though no doubt hard to observe in pure form in real-life traffic, nevertheless indicates a tendency of such traffic.Comment: 50 pages, 16 figures; extra references adde

Evaluation of the endoplasmic reticulum-stress response in eIF2B-mutated lymphocytes and lymphoblasts from CACH/VWM patients

<p>Abstract</p> <p>Background</p> <p>Eukaryotic translation initiation factor 2B (eIF2B), a guanine nucleotide exchange factor (GEF) and a key regulator of translation initiation under normal and stress conditions, causes an autosomal recessive leukodystrophy of a wide clinical spectrum. EBV-immortalised lymphocytes (EIL) from eIF2B-mutated patients exhibit a decrease in eIF2B GEF activity. eIF2B-mutated primary fibroblasts have a hyper-induction of activating transcription factor 4 (ATF4) which is involved in the protective unfolded protein response (UPR), also known as the ER-stress response. We tested the hypothesis that EIL from eIF2B-mutated patients also exhibit a heightened ER-stress response.</p> <p>Methods</p> <p>We used thapsigargin as an ER-stress agent and looked at polysomal profiles, rate of protein synthesis, translational activation of <it>ATF4</it>, and transcriptional induction of stress-specific mRNAs (<it>ATF4, CHOP, ASNS, GRP78</it>) in normal and eIF2B-mutated EIL. We also compared the level of stress-specific mRNAs between EIL and primary lymphocytes (PL).</p> <p>Results</p> <p>Despite the low eIF2B GEF activity in the 12 eIF2B-mutated EIL cell lines tested (range 40-70% of normal), these cell lines did not differ from normal EIL in their ATF4-mediated ER-stress response. The absence of hyper-induction of ATF4-mediated ER-stress response in eIF2B-mutated EIL in contrast to primary fibroblasts is not related to their transformation by EBV. Indeed, PL exhibited a higher induction of the stress-specific mRNAs in comparison to EIL, but no hyper-induction of the UPR was noticed in the eIF2B-mutated cell lines in comparison to controls.</p> <p>Conclusions</p> <p>Taken together with work of others, our results demonstrate the absence of a major difference in ER-stress response between controls and eIF2B-mutated cells. Therefore, components of the ER-stress response cannot be used as discriminantory markers in eIF2B-related disorders.</p

Nervous system and Fabry disease, from symptoms to diagnosis: damage evaluation and follow-up in adult patients, enzyme replacement, and support therapy

The X-linked genetic Fabry disease causes multiorgan lesions due to intracellular storage of the substrate globotriaosylceramide. Neurological involvement ranges from painful, small fiber neuropathy to cerebrovascular disorders to multifocal aggressive forms. Disease identification through proper differential diagnosis and timely assessment of organ damage should guide a careful treatment planning. Mainstay treatment, include enzyme replacement and support therapy. Neurologists have a pivotal role in early instrumental and clinical detection of organ damage. A panel of experts has developed a set of consensus recommendations to guide the approach of neurologists to Fabry disease

Developmental Splicing Deregulation in Leukodystrophies Related to EIF2B Mutations

Leukodystrophies (LD) are rare inherited disorders that primarily affect the white matter (WM) of the central nervous system. The large heterogeneity of LD results from the diversity of the genetically determined defects that interfere with glial cells functions. Astrocytes have been identified as the primary target of LD with cystic myelin breakdown including those related to mutations in the ubiquitous translation initiation factor eIF2B. EIF2B is involved in global protein synthesis and its regulation under normal and stress conditions. Little is known about how eIF2B mutations have a major effect on WM. We performed a transcriptomic analysis using fibroblasts of 10 eIF2B-mutated patients with a severe phenotype and 10 age matched patients with other types of LD in comparison to control fibroblasts. ANOVA was used to identify genes that were statistically significantly differentially expressed at basal state and after ER-stress. The pattern of differentially expressed genes between basal state and ER-stress did not differ significantly among each of the three conditions. However, 70 genes were specifically differentially expressed in eIF2B-mutated fibroblasts whatever the stress conditions tested compared to controls, 96% being under-expressed. Most of these genes were involved in mRNA regulation and mitochondrial metabolism. The 13 most representative genes, including genes belonging to the Heterogeneous Nuclear Ribonucleoprotein (HNRNP) family, described as regulators of splicing events and stability of mRNA, were dysregulated during the development of eIF2B-mutated brains. HNRNPH1, F and C mRNA were over-expressed in foetus but under-expressed in children and adult brains. The abnormal regulation of HNRNP expression in the brain of eIF2B-mutated patients was concomitant with splicing dysregulation of the main genes involved in glial maturation such as PLP1 for oligodendrocytes and GFAP in astrocytes. These findings demonstrate a developmental deregulation of splicing events in glial cells that is related to abnormal production of HNRNP, in eIF2B-mutated brains

Impact of age on outcome after colorectal cancer surgery in the elderly - a developing country perspective

<p>Abstract</p> <p>Background</p> <p>Colorectal cancer (CRC) is a major source of morbidity and mortality in the elderly population and surgery is often the only definitive management option. The suitability of surgical candidates based on age alone has traditionally been a source of controversy. Surgical resection may be considered detrimental in the elderly solely on the basis of advanced age. Based on recent evidence suggesting that age alone is not a predictor of outcomes, Western societies are increasingly performing definitive procedures on the elderly. Such evidence is not available from our region. We aimed to determine whether age has an independent effect on complications after surgery for colorectal cancer in our population.</p> <p>Methods</p> <p>A retrospective review of all patients who underwent surgery for pathologically confirmed colorectal cancer at Aga Khan University Hospital, Karachi between January 1999 and December 2008 was conducted. Using a cut-off of 70 years, patients were divided into two groups. Patient demographics, tumor characteristics and postoperative complications and 30-day mortality were compared. Multivariate logistic regression analysis was performed with clinically relevant variables to determine whether age had an independent and significant association with the outcome.</p> <p>Results</p> <p>A total of 271 files were reviewed, of which 56 belonged to elderly patients (≥ 70 years). The gender ratio was equal in both groups. Elderly patients had a significantly higher comorbidity status, Charlson score and American society of anesthesiologists (ASA) class (all p < 0.001). Upon multivariate analysis, factors associated with more complications were ASA status (95% CI = 1.30-6.25), preoperative perforation (95% CI = 1.94-48.0) and rectal tumors (95% CI = 1.21-5.34). Old age was significantly associated with systemic complications upon univariate analysis (p = 0.05), however, this association vanished upon multivariate analysis (p = 0.36).</p> <p>Conclusion</p> <p>Older patients have more co-morbid conditions and higher ASA scores, but increasing age itself is not independently associated with complications after surgery for CRC. Therefore patient selection should focus on the clinical status and ASA class of the patient rather than age.</p

Cardiomyopathy and Response to Enzyme Replacement Therapy in a Male Mouse Model for Fabry Disease

Fabry disease is an X-linked disorder of glycosphingolipid metabolism that results in progressive accumulation of neutral glycosphingolipids, (predominately globotriaosylceramide; GL-3) in lysosomes, as well as other cellular compartments and the extracellular space. Our aim was to characterize the cardiac phenotype of male knock-out mice that are deficient in alpha-galactosidase A activity, as a model for Fabry disease and test the efficacy of Enzyme Replacement Therapy with agalsidase-beta. Male mice (3–4 months of age) were characterized with awake blood pressure and heart rate measurements, cardiac echocardiography and electrocardiography measurements under light anesthesia, histological studies and molecular studies with real-time polymerase chain reaction. The Fabry knock-out mouse has bradycardia and lower blood pressure than control wild type (CB7BL/6J) mice. In Fabry knock-out mice, the cardiomyopathy associated mild hypertrophy at echography with normal systolic LV function and mild diastolic dysfunction. Premature atrial contractions were more frequent in without conduction defect. Heart weight normalized to tibial length was increased in Fabry knock-out mice. Ascending aorta dilatation was observed. Molecular studies were consistent with early stages of cardiac remodeling. A single dose of agalsidase-beta (3 mg/kg) did not affect the LV hypertrophy, function or heart rate, but did improve the mRNA signals of early cardiac remodeling. In conclusion, the alpha-galactosidase A deficient mice at 3 to 4 months of age have cardiac and vascular alterations similar to that described in early clinical stage of Fabry disease in children and adolescents. Enzyme replacement therapy affects cardiac molecular remodeling after a single dose

Early indicators of disease progression in Fabry disease that may indicate the need for disease-specific treatment initiation: findings from the opinion-based PREDICT-FD modified Delphi consensus initiative.

OBJECTIVES: The PRoposing Early Disease Indicators for Clinical Tracking in Fabry Disease (PREDICT-FD) initiative aimed to reach consensus among a panel of global experts on early indicators of disease progression that may justify FD-specific treatment initiation. DESIGN AND SETTING: Anonymous feedback from panellists via online questionnaires was analysed using a modified Delphi consensus technique. Questionnaires and data were managed by an independent administrator directed by two non-voting cochairs. First, possible early indicators of renal, cardiac and central/peripheral nervous system (CNS/PNS) damage, and other disease and patient-reported indicators assessable in routine clinical practice were compiled by the cochairs and administrator from panellists' free-text responses. Second, the panel scored indicators for importance (5-point scale: 1=not important; 5=extremely important); indicators scoring ≥3 among >75% of panellists were then rated for agreement (5-point scale: 1=strongly disagree; 5=strongly agree). Indicators awarded an agreement score ≥4 by >67% of panellists achieved consensus. Finally, any panel-proposed refinements to consensus indicator definitions were adopted if >75% of panellists agreed. RESULTS: A panel of 21 expert clinicians from 15 countries provided information from which 83 possible current indicators of damage (kidney, 15; cardiac, 15; CNS/PNS, 13; other, 16; patient reported, 24) were compiled. Of 45 indicators meeting the importance criteria, consensus was reached for 29 and consolidated as 27 indicators (kidney, 6; cardiac, 10; CNS/PNS, 2; other, 6; patient reported, 3) including: (kidney) elevated albumin:creatinine ratio, histological damage, microalbuminuria; (cardiac) markers of early systolic/diastolic dysfunction, elevated serum cardiac troponin; (CNS/PNS) neuropathic pain, gastrointestinal symptoms suggestive of gastrointestinal neuropathy; (other) pain in extremities/neuropathy, angiokeratoma; (patient-reported) febrile crises, progression of symptoms/signs. Panellists revised and approved proposed chronologies of when the consensus indicators manifest. The panel response rate was >95% at all stages. CONCLUSIONS: PREDICT-FD captured global opinion regarding current clinical indicators that could prompt FD-specific treatment initiation earlier than is currently practised