Summary
Background Crohn's disease is associated with small bowel cancer whilst risk of colorectal cancer is less clear.
Aim To ascertain the combined estimates of relative risk of these cancers in ...Crohn's disease.
Methods MEDLINE was searched to identify relevant papers. Exploding references identified additional publications. When two papers reviewed the same cohort, the later study was used.
Results Meta‐analysis showed overall colorectal cancer relative risk in Crohn's disease as 2.5 (1.3–4.7), 4.5 (1.3–14.9) for patients with colonic disease and 1.1 (0.8–1.5) in ileal disease. Meta‐regression showed reduction in relative risk over the past 30 years. Subgroup analysis showed Scandinavia had significantly lower colorectal cancer relative risk than the UK and North America. Cumulative risk analysis showed 10 years following diagnosis of Crohn's disease relative risk of colorectal cancer is 2.9% (1.5%–5.3%). Meta‐analysis showed small bowel cancer relative risk in Crohn's disease is 33.2 (15.9–60.9). Small bowel cancer relative risk has not significantly reduced over the last 30 years.
Conclusion Relative risk of colorectal and small bowel cancers are significantly raised in Crohn's disease. Cumulative risk of colorectal cancer of 2.9% at 10 years suggests a potential benefit from routine screening. However, the value of screening requires rigorous appraisal.
Connexins are members of a family of integral membrane proteins that provide a pathway for both electrical and metabolic coupling between cells. Astroglia express connexin 30 (Cx30)-
and Cx43-
, ...while oligodendroglia express Cx29/Cx31.3-
, Cx32-
, and Cx47-
. Connexins organize into hexameric hemichannels (homomeric if all subunits are identical or heteromeric if one or more differs). Hemichannels from one cell then form cell-cell channels with a hemichannel from an apposed cell. (These are termed homotypic if the hemichannels are identical and heterotypic if the hemichannels differ). Oligodendrocytes couple to each other through Cx32/Cx32 or Cx47/Cx47 homotypic channels and they couple to astrocytes via Cx32/Cx30 or Cx47/Cx43 heterotypic channels. Astrocytes couple via Cx30/Cx30 and Cx43/Cx43 homotypic channels. Though Cx32 and Cx47 may be expressed in the same cells, all available data suggest that Cx32 and Cx47 cannot interact heteromerically. Animal models wherein one or in some cases two different CNS glial connexins have been deleted have helped to clarify the role of these molecules in CNS function. Mutations in a number of different CNS glial connexin genes cause human disease. Mutations in
lead to three distinct phenotypes, Pelizaeus Merzbacher like disease, hereditary spastic paraparesis (SPG44) and subclinical leukodystrophy.
BACKGROUND AND AIMS Controversy surrounds the risk of colorectal cancer (CRC) in ulcerative colitis (UC). Many studies have investigated this risk and reported widely varying rates. METHODS A ...literature search using Medline with the explosion of references identified 194 studies. Of these, 116 met our inclusion criteria from which the number of patients and cancers detected could be extracted. Overall pooled estimates, with 95% confidence intervals (CI), of cancer prevalence and incidence were obtained using a random effects model on either the log odds or log incidence scale, as appropriate. RESULTS The overall prevalence of CRC in any UC patient, based on 116 studies, was estimated to be 3.7% (95% CI 3.2–4.2%). Of the 116 studies, 41 reported colitis duration. From these the overall incidence rate was 3/1000 person years duration (pyd), (95% CI 2/1000 to 4/1000). The overall incidence rate for any child was 6/1000 pyd (95% CI 3/1000 to 13/1000). Of the 41 studies, 19 reported results stratified into 10 year intervals of disease duration. For the first 10 years the incidence rate was 2/1000 pyd (95% CI 1/1000 to 2/1000), for the second decade the incidence rate was estimated to be 7/1000 pyd (95% CI 4/1000 to 12/1000), and in the third decade the incidence rate was 12/1000 pyd (95% CI 7/1000 to 19/1000). These incidence rates corresponded to cumulative probabilities of 2% by 10 years, 8% by 20 years, and 18% by 30 years. The worldwide cancer incidence rates varied geographically, being 5/1000 pyd in the USA, 4/1000 pyd in the UK, and 2/1000 pyd in Scandinavia and other countries. Over time the cancer risk has increased since 1955 but this finding was not significant (p=0.8). CONCLUSIONS Using new meta-analysis techniques we determined the risk of CRC in UC by decade of disease and defined the risk in pancolitics and children. We found a non-significant increase in risk over time and estimated how risk varies with geography.
With the growing rise in utilization of CT perfusion for selecting patients for thrombectomy in acute ischemic stroke from large vessel occlusion, some potential pitfalls are becoming more commonly ...seen particularly when it comes to estimating the core infarct size on CT perfusion. Ghost infarct core has been described to account for overestimating core infarct size in the early time period (<3 hours). Herein, we describe the phenomenon of underestimating core infarct size on CT perfusion in the later time period (>6 hours), which we have termed perfusion scotoma.
Fully covered self-expanding removable stents (SERS) have been considered a viable alternative to serial bougienage. The primary aim of this meta-analysis was to determine the efficacy of SERS for ...refractory esophageal strictures.
Medline, Embase, and PubMed databases were searched using the keywords "esophageal stricture," "esophageal stents," "benign stricture," "dysphagia," "caustic," "peptic stricture," "anastomotic," "radiation," and "dysphagia" for the period from January 1965 to June 2010. Articles were selected for review independently by two authors (T. T. and J. M.) on the basis of predefined inclusion criteria, and the data collected. A meta-analysis using a random effects model was done.
Eight studies with a total of 199 patients were included in the final analysis (104-males, average age 56 years, range: 49 - 68 years). Overall, 46.2 % of patients (95 %CI: 38.3 % - 54.1 %) had dysphagia improvement at an average follow up of 74 weeks. There was a significant difference ( P = 0.019) in dysphagia improvement for patients with Polyflex stents (55.3 %; 95 %CI: 44.4 % - 65.9 %) versus nitinol stents (21.8 %; 95 %CI: 13.7 % - 33.7 %). On meta-regression, patient sex ( P = 0.80), patient age ( P = 0.725), corrosive etiology ( P = 0.30), stricture location ( P = 0.273), stricture length ( P = 0.32), time of removal ( P = 0.056), and duration of follow-up (0.35) had no significance influence on the outcome. The migration rate was 26.4 % (95 %CI: 25.3 % - 39.3 %).
Although the efficacy of SERS placement in benign refractory strictures is 46.2 %, it is associated with migration rate of 26.4 %. Nevertheless, the use of these temporary stents, which can be successfully removed in 87 % of patients, is an alluring prospect for treating patients with this difficult condition.
CNS glia and neurons express connexins, the proteins that form gap junctions in vertebrates. We review the connexins expressed by oligodendrocytes and astrocytes, and discuss their proposed ...physiologic roles. Of the 21 members of the human connexin family, mutations in three are associated with significant central nervous system manifestations. For each, we review the phenotype and discuss possible mechanisms of disease. Mutations in GJB1, the gene for connexin 32 (Cx32) cause the second most common form of Charcot–Marie–Tooth disease (CMT1X). Though the only consistent phenotype in CMT1X patients is a peripheral demyelinating neuropathy, CNS signs and symptoms have been found in some patients. Recessive mutations in GJC2, the gene for Cx47, are one cause of Pelizaeus–Merzbacher-like disease (PMLD), which is characterized by nystagmus within the first 6months of life, cerebellar ataxia by 4years, and spasticity by 6years of age. MRI imaging shows abnormal myelination. A different recessive GJC2 mutation causes a form of hereditary spastic paraparesis, which is a milder phenotype than PMLD. Dominant mutations in GJA1, the gene for Cx43, cause oculodentodigital dysplasia (ODDD), a pleitropic disorder characterized by oculo-facial abnormalities including micropthalmia, microcornia and hypoplastic nares, syndactyly of the fourth to fifth fingers and dental abnormalities. Neurologic manifestations, including spasticity and gait difficulties, are often but not universally seen. Recessive GJA1 mutations cause Hallermann–Streiff syndrome, a disorder showing substantial overlap with ODDD. This article is part of a Special Issue entitled: The Communicating junctions, composition, structure and functions.
► Astrocytes express Cx30 and Cx43 and Oligodendrocytes express Cx29, Cx32, and Cx47. ► Mutations in GJB1, cause a form of Charcot–Marie–Tooth disease (CMT1X). Some patients have CNS signs and symptoms. ► Recessive mutations in GJC2, the gene for Cx47, are one cause of Pelizaeus–Merzbacher-like disease. ► A different recessive GJC2 mutation causes a form of hereditary spastic paraparesis. ► Dominant mutations in GJA1, cause oculodentodigital dysplasia (ODDD). Spasticity and gait difficulties may be seen.
Objective
To assess construct validity of the Patient Global Impression scales (Severity PGI‐S, Bother PGI‐B and Improvement PGI‐I) for symptoms of detrusor overactivity (DO).
Design
Secondary ...analysis of a randomised trial of onabotulinum toxin A.
Setting
Eight UK urogynaecology departments.
Population
A total of 240 women with DO refractory to medical treatment randomised to receive 200 iu onabotulinum toxin A or placebo in the RELAX trial and followed up for 6 months.
Main outcome measures
Urinary diaries and disease‐specific quality of life (QoL) questionnaires were completed at baseline and during follow up. Discriminatory ability of the PGI‐S, PGI‐B and PGI‐I scales to identify symptom severity and change in severity was assessed by comparing mean diary and QoL outcomes across the response categories, analysed by one‐way analysis of variance.
Results
Data were available from 237 women (98.8%) for validation of PGI‐S and PGI‐B at baseline, and 192 women (80%) at 6 weeks follow up for validation of PGI‐I. Leakage episodes (P = 0.01), urgency episodes (P = 0.019), urgency severity (P = 0.012), and QoL scores (all P < 0.001) were greater in women with more severe problems on PGI‐S. Similar results were seen for PGI‐B: leakage (P = 0.051), urgency episodes (P < 0.001), urgency severity (P < 0.001), and QoL scores (all P < 0.001). PGI‐I responses demonstrated significant relationships with size of change of all variables (P < 0.001). The generic instrument EQ‐5D had weaker relationships (PGI‐S, P = 0.09; PGI‐B, P = 0.004; PGI‐I, P = 0.06), suggesting that it was less sensitive.
Conclusions
The PGI scales are robust and valid instruments to assess disease severity, bother and improvement after treatment in women with detrusor overactivity.
Treatment switching is common in randomised trials of oncology treatments, with control group patients switching onto the experimental treatment during follow-up. This distorts an intention-to-treat ...comparison of the treatments under investigation. Two-stage estimation (TSE) can be used to estimate counterfactual survival times for patients who switch treatments - that is, survival times that would have been observed in the absence of switching. However, when switchers do not die during the study, counterfactual censoring times are estimated, inducing informative censoring. Re-censoring is usually applied alongside TSE to resolve this problem, but results in lost longer-term information - a major concern if the objective is to estimate long-term treatment effects, as is usually the case in health technology assessment. Inverse probability of censoring weights (IPCW) represents an alternative technique for addressing informative censoring but has not before been combined with TSE. We aim to determine whether combining TSE with IPCW (TSEipcw) represents a valid alternative to re-censoring.
We conducted a simulation study to compare TSEipcw to TSE with and without re-censoring. We simulated 48 scenarios where control group patients could switch onto the experimental treatment, with switching affected by prognosis. We investigated various switching proportions, treatment effects, survival function shapes, disease severities and switcher prognoses. We assessed the alternative TSE applications according to their estimation of control group restricted mean survival (RMST) that would have been observed in the absence of switching up to the end of trial follow-up.
TSEipcw performed well when its weights had a low coefficient of variation, but performed poorly when the coefficient of variation was high. Re-censored analyses usually under-estimated control group RMST, whereas non-re-censored analyses usually produced over-estimates, with bias more serious when the treatment effect was high. In scenarios where TSEipcw performed well, it produced low bias that was often between the two extremes associated with the re-censoring and non-recensoring options.
Treatment switching adjustment analyses using TSE should be conducted with re-censoring, without re-censoring, and with IPCW to explore the sensitivity in results to these application options. This should allow analysts and decision-makers to better interpret the results of adjustment analyses.
Abstract The X-linked form of Charcot – Marie – Tooth disease (CMT1X) is the second most common form of hereditary motor and sensory neuropathy. The clinical phenotype is characterized by progressive ...weakness, atrophy, and sensory abnormalities that are most pronounced in the distal extremities. Some patients have CNS manifestations. Affected males have moderate to severe symptoms, whereas heterozygous females are usually less affected. Neurophysiology shows intermediate slowing of conduction and length-dependent axonal loss. Nerve biopsies show more prominent axonal degeneration than de/remyelination. Mutations in GJB1 , the gene that encodes the gap junction (GJ) protein connexin32 (Cx32) cause CMT1X; more than 400 different mutations have been described. Many Cx32 mutants fail to form functional GJs, or form GJs with abnormal biophysical properties. Schwann cells and oligodendrocytes express Cx32, and the GJs formed by Cx32 play an important role in the homeostasis of myelinated axons. Animal models of CMT1X demonstrate that loss of Cx32 in myelinating Schwann cells causes a demyelinating neuropathy. Effective therapies remain to be developed. This article is part of a Special Issue entitled Electrical Synapses.
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