The value of serologic markers in indeterminate colitis: a prospective follow-up study

BACKGROUND & AIMS: In the absence of pathognomonic markers for Crohn's disease (CD) and ulcerative colitis (UC), the diagnosis of inflammatory bowel disease depends on a compendium of clinical, radiographic, endoscopic, and histologic criteria that bears imperfect specificity to the individual disorders. In 10% of cases of colitis, no differentiation can be made between CD and UC; these patients are diagnosed with indeterminate colitis (IC). We evaluated the value of anti-Saccharomyces cerevisiae antibodies (ASCA) and perinuclear antineutrophil cytoplasmic antibodies (pANCA) to increase diagnostic accuracy in categorizing IC. METHODS: Since 1996, 97 patients with IC from 3 centers (Leuven, Lille, and Vienna) were enrolled, analyzed for pANCA and ASCA, and followed up prospectively. RESULTS: A definitive diagnosis has been reached for 31 of 97 patients (32%). In these patients, ASCA+/pANCA- correlated with CD in 8 of 10 patients, whereas ASCA-/pANCA+ correlated with UC in 7 of 11 patients. The remaining 4 cases became CD, clinically behaving as UC-like CD. Almost half of the patients (47 of 97 [48.5%]) were negative for ASCA and pANCA, and 40 remain diagnosed with IC to date. Only 7 seronegative cases (14.9%) became CD or UC compared with 48% (24 of 50) of seropositive patients (P < 0.001). CONCLUSIONS: Results so far show that ASCA+/pANCA- predicts CD in 80% of patients with IC and ASCA-/pANCA+ predicts UC in 63.6%. Interestingly, 48.5% of patients do not show antibodies against ASCA or pANCA. Most of these patients remain diagnosed with IC during their further clinical course, perhaps reflecting a distinct clinicoserological entity.     

Lack of C9ORF72 coding mutations supports a gain of function for repeat expansions in amyotrophic lateral sclerosis

Hexanucleotide repeat expansions in C9ORF72 are a common cause of familial and apparently sporadic amyotrophic lateral sclerosis (ALS) and frontal temporal dementia (FTD). The mechanism by which expansions cause neurodegeneration is unknown, but current evidence supports both loss-of-function and gain-of-function mechanisms. We used pooled next-generation sequencing of the C9ORF72 gene in 389 ALS patients to look for traditional loss-of-function mutations. Although rare variants were identified, none were likely to be pathogenic, suggesting that mutations other than the repeat expansion are not a common cause of ALS, and providing supportive evidence for a gain-of-function mechanism. We also show by repeat-primed PCR genotyping that the C9ORF72 expansion frequency varies by geographical region within the United States, with an unexpectedly high frequency in the Mid-West. Finally we also show evidence of somatic instability of the expansion size by Southern blot, with the largest expansions occurring in brain tissue.     

CHOP‐mediated hepcidin suppression modulates hepatic iron load

The liver is the central regulator of iron metabolism and accordingly, chronic liver diseases often lead to systemic iron overload due to diminished expression of the iron‐regulatory hormone hepcidin. To study the largely unknown regulation of iron metabolism in the context of hepatic disease, we used two established models of chronic liver injury, ie repeated carbon tetrachloride (CCl₄) or thioacetamide (TAA) injections. To determine the impact of CCAAT/enhancer‐binding protein (C/EBP)‐homologous protein (CHOP) on hepcidin production, the effect of a single TAA injection was determined in wild‐type and CHOP knockout mice. Furthermore, CHOP and hepcidin expression was assessed in control subjects and patients with alcoholic liver disease. Both chronic injury models developed a distinct iron overload in macrophages. TAA‐, but not CCl₄‐ injected mice displayed additional iron accumulation in hepatocytes, resulting in a significant hepatic and systemic iron overload which was due to suppressed hepcidin levels. C/EBPα signalling, a known hepcidin inducer, was markedly inhibited in TAA mice, due to lower C/EBPα levels and overexpression of CHOP, a C/EBPα inhibitor. A single TAA injection resulted in a long‐lasting (> 6 days) suppression of hepcidin levels and CHOP knockouts (compared to wild‐types) displayed significantly attenuated hepcidin down‐regulation in response to acute TAA administration. CHOP mRNA levels increased 5‐fold in alcoholic liver disease patients versus controls (p < 0.005) and negatively correlated with hepcidin expression. Our results establish CHOP as an important regulator of hepatic hepcidin expression in chronic liver disease. The differences in iron metabolism between the two widely used fibrosis models likely reflect the differential regulation of hepcidin expression in human liver disease. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Cognitive function and its relationship with brain structure in myotonic dystrophy type 1

Studies have shown relationships between white matter abnormalities and cognitive dysfunction in myotonic dystrophy type 1 (DM1), but comprehensive analysis of potential structure–function relationships are lacking. Fifty adult‐onset DM1 individuals (33 female) and 68 unaffected adults (45 female) completed the Wechsler Adult Intelligence Scale‐IV (WAIS‐IV) to determine the levels and patterns of intellectual functioning. Neuroimages were acquired with a 3T scanner and were processed with BrainsTools. Regional brain volumes (regions of interest, ROIs) were adjusted for inter‐scanner variation and intracranial volume. Linear regression models were conducted to assess if group by ROI interaction terms significantly predicted WAIS‐IV composite scores. Models were adjusted for age and sex. The DM1 group had lower Perceptual Reasoning Index (PRI), Working Memory Index (WMI), and Processing Speed Index (PSI) scores than the unaffected group (PRI t₍₁₁₃₎ = ?3.28, p = 0.0014; WMI t₍₁₁₄₎ = ?3.49, p = 0.0007; PSI t₍₁₁₄₎ = ?2.98, p = 0.0035). The group by hippocampus interaction term was significant for both PRI and PSI (PRI (t₍₁₁₁₎ = ?2.82, p = 0.0057; PSI (t₍₁₁₂₎ = ?2.87, p = 0.0049)). There was an inverse association between hippocampal volume and both PRI and PSI in the DM1 group (the higher the volume, the lower the intelligence quotient scores), but no such association was observed in the unaffected group. Enlarged hippocampal volume may underlie some aspects of cognitive dysfunction in adult‐onset DM1, suggesting that increased volume of the hippocampus may be pathological.     

Resettling into a new life: Exploring aspects of acculturation that could enhance the mental health of young refugees resettled under the humanitarian programme

Globally, the exodus of individuals who have been forced to flee their home and seek refuge in countries of safety has led to a refugee crisis. The United Kingdom (UK) has engaged with the United Nations High Commissioner for Refugees (UNHCR) in playing a significant role in the long‐term resettlement of refugees, half of whom are children and young people. One initiative of such humanitarian resettlement is the Gateway Protection Programme (GPP). To date, there is a dearth of studies investigating aspects of acculturation that affect the mental health of young refugees resettled under the UNHCR humanitarian programme. This study aimed to explore aspects of acculturation that could enhance the mental health of GPP young refugees several years after resettlement. Using narrative research, a purposive sample of 31 GPP young refugees, who had a minimum of three‐year stay in the UK, were recruited from local refugee community organizations. Data were collected through a multi‐method design combining focus group discussions (FGDs) with visual arts‐based narrative research (VABNR) and analysed thematically. Three overarching themes emerged: People and places; Its nearly all new to me; and Finding self. This study contributes important knowledge regarding the mental well‐being of young people who have engaged in a resettlement programme and offers valuable information for policymakers and mental health professionals working with GPP young refugees.     

Innovative Approaches to Educating Future Clinicians about Opioids,Pain, Addiction and Health Policy

BackgroundOpioid use disorder and overdose have reached unprecedented levels in many countries across the globe, including the United States, and pain is one of the most common reasons American adults seek healthcare. To address the interrelated public health crises of opioid use disorder and chronic pain, it is vital that clinicians practicing in diverse roles and settings possess the ability and knowledge to effectively manage pain, responsibly prescribe and monitor opioid analgesics, educate patients about harm reduction techniques, and treat opioid use disorder. However, future healthcare professionals are not receiving the training needed to competently provide this care. This gap in curriculum may lead to clinicians being unwilling and unprepared to address the current opioid and overdose crises, which requires a clinical understanding of pain and substance use disorders as well as knowledge about public health and policy interventions. To address this gap, we designed and are teaching an innovative transdisciplinary elective course titled “Opioids: From Receptors to Epidemic” for undergraduate nursing and premedical students.AimIn this paper, we present the course curriculum in detail, with the hope that educators at other institutions will design similar courses for their health professions students.