Nationwide study of appendicitis in children.

BACKGROUND: Paediatric surgical care is increasingly being centralized away from low-volume centres, and prehospital delay is considered a risk factor for more complicated appendicitis. The aim of this study was to determine the incidence of paediatric appendicitis in Sweden, and to assess whether distance to the hospital was a risk factor for complicated disease. METHODS: A nationwide cohort study of all paediatric appendicitis cases in Sweden, 2001-2014, was undertaken, including incidence of disease in different population strata, with trends over time. The risk of complicated disease was determined by regression methods, with travel time as the primary exposure and individual-level socioeconomic determinants as independent variables. RESULTS: Some 38 939 children with appendicitis were identified. Of these, 16·8 per cent had complicated disease, and the estimated risk of paediatric appendicitis by age 18 years was 2·5 per cent. Travel time to the treating hospital was not associated with complicated disease (adjusted odds ratio (OR) 1·00 (95 per cent c.i. 0·96 to 1·05) per 30-min increase; P = 0·934). Level of education (P = 0·177) and family income (P = 0·120) were not independently associated with increased risk of complicated disease. Parental unemployment (adjusted OR 1·17, 95 per cent c.i. 1·05 to 1·32; P = 0·006) and having parents born outside Sweden (1 parent born in Sweden: adjusted OR 1·12, 1·01 to 1·25; both parents born outside Sweden: adjusted OR 1·32, 1·18 to 1·47; P < 0·001) were associated with an increased risk of complicated appendicitis. CONCLUSION: Every sixth child diagnosed with appendicitis in Sweden has a more complicated course of disease. Geographical distance to the surgical facility was not a risk factor for complicated appendicitis.

ANTECEDENTES: La atención quirúrgica pediátrica está cada vez más centralizada lejos de los centros de bajo volumen, y el retraso pre-hospitalario se considera un factor de riesgo para las apendicitis más complicadas. El objetivo de este estudio fue determinar la incidencia de apendicitis pediátrica en Suecia y evaluar si la distancia al hospital era un factor de riesgo para una enfermedad complicada. MÉTODOS: Se analizó un estudio de cohortes a nivel nacional que incluyó todos los casos de apendicitis pediátrica en Suecia durante el periodo 2001-2014, incluida la incidencia de la enfermedad en diferentes estratos de la población y las tendencias a lo largo del tiempo. El riesgo de enfermedad complicada se determinó mediante métodos de regresión, con el tiempo de viaje como exposición primaria y los determinantes socioeconómicos a nivel individual como variables independientes. RESULTADOS: Se identificaron 38.939 casos de apendicitis pediátrica. De estos, el 17% eran complicados y el riesgo estimado de apendicitis pediátrica a los 18 años era del 2,5%. El tiempo de viaje al hospital de tratamiento no se asoció con una enfermedad complicada (razón de oportunidades, odds ratio OR ajustada 1,00 (i.c. del 95%: 0,96 a 1,05) por aumentos de 30 minutos, P = 0,93). El nivel de educación (P = 0,18) y los ingresos familiares (P = 0,120) no se asociaron de forma independiente con un aumento del riesgo de enfermedad complicada. El desempleo de los padres (OR ajustada 1,17 (1,05 a 1,32), P = 0,006) y tener padres nacidos fuera de Suecia se asociaron con un mayor riesgo de apendicitis complicada (P < 0,001; un progenitor nacido en Suecia: OR ajustada 1,12 (1,01 a 1,25), ambos progenitores nacidos fuera de Suecia: OR ajustada 1,32 (1,18 a 1,47)). CONCLUSIÓN: Uno de cada seis niños diagnosticados de apendicitis en Suecia sufre un curso de enfermedad más complicado. La distancia geográfica al hospital donde se llevó a cabo la cirugía no fue un factor de riesgo para la apendicitis complicada.

Decreased physical health-related quality of life-a persisting state for older women with clinical vertebral fracture.

In a population-based study of older Swedish women, we investigated if clinical vertebral fracture was associated with lower health-related quality of life (HRQoL) and determined whether the association remained over time. Clinical vertebral fracture was associated with lower HRQoL and the effect persisted for up to 18.9 years. INTRODUCTION: Vertebral fractures are often associated with back pain and reduced physical function, which might result in isolation and depression. As a result, women with vertebral fractures often have lower health-related quality of life (HRQoL), but during what time frame the decrease lingers is unclear. Therefore, the aim of this study was to investigate if clinical vertebral fracture and hip fracture were associated with lower HRQoL and to determine whether the associations remained over time. METHODS: Vertebral fracture assessments (VFA) were performed using dual-energy X-ray absorptiometry. Data regarding prior fractures, medications, medical history, and physical activity was collected using a questionnaire. Self-rated physical HRQoL was assessed using the 12-Item Short-Form Health Survey (SF-12). Women with clinical vertebral fractures were divided into tertiles according to time since fracture onset and their HRQoL was compared with non-fractured women. RESULTS: In a population-based cross-sectional study of 3028 women aged 77.8 ± 1.63 (mean ± SD), a total of 130 (4.3%) women reported at least one clinical vertebral fracture. Women with a clinical vertebral fracture, divided into tertiles (T1-T3) depending on time since the fracture occurred, had lower HRQoL (T1: 36.3 ± 10.8; T2: 41.0 ± 9.94; and T3:41.6 ± 11.4) than women without fracture (46.2 ± 10.6; p < 0.001). Using linear regression analysis, clinical vertebral fracture was associated with reduced physical HRQoL for up to 18.9 years, independently of covariates (age, height, weight, smoking, prior stroke, mental HRQoL, grip strength, and lumbar spine BMD). CONCLUSIONS: Clinical vertebral fracture was associated with lower self-rated physical HRQoL, for up to 18.9 years after time of fracture.

The effects of person-centered or other supportive interventions in older women with osteoporotic vertebral compression fractures-a systematic review of the literature.

Vertebral compression fracture (VCF) is a common fragility fracture and the starting point of a lasting, painful, disabling condition. The aim was to summarize evidence of person-centered/non-medical interventions supporting women with VCF. Results show small numbers of studies with only probable effect on function, pain, QoL, fear of falling, and psychological symptoms. The vertebral compression fracture (VCF) caused by osteoporosis is the third most common fragility fracture worldwide. Previously, it was believed that the pain caused by VCF was self-subsiding within weeks or a few months post-fracture. However, this positive prognosis has been refuted by studies showing that, for the great majority of patients, the VCF was the starting point of a long-lasting, severely painful, and disabling condition. The low number of studies focusing on the experience of the natural course of VCF, and what support is available and how it is perceived by those affected, calls for further investigation. Strengthening older patients' sense of security and increasing confidence in their own abilities are of great importance for successful rehabilitation following VCF. More research is needed to identify resources, possibilities, and strategies that can assist older patients to reach their goals to improve well-being. The purpose of this systematic review was to identify and summarize the current evidence of person-centered or other structured non-medical/non-surgical interventions supporting older women after experiencing an osteoporotic VCF. A systematic literature search was conducted on the MeSH terms encompassing osteoporosis and vertebral compression fractures in the PubMed-MEDLINE and Cumulative Index for Nursing and Allied Health Literature (CINAHL) databases during March through June 2015. The initial search identified 8789 articles, but only seven articles (six randomized controlled trials and one observational study with a control group) met the inclusion criteria. It became evident from the current study that the availability of evidence on the effects of non-medical interventions aiming to support older women with VCF is limited, to say the least. The trials included in this review have few limitations and were mainly considered to be of moderate quality. This systematic literature review suggests that non-medical interventions aiming to support older women with VCF might decrease levels of pain and use of analgesic as well as promote improved physical mobility and function. These interventions would probably result in an improved difference in experiences of fear of falling and perceived psychological symptoms, but would only slightly improve quality of life. However, given the nature of the seven studies, potential biases in patient selection, issues around precision with small cohorts, and failure to control for confounders, makes it difficult to draw a definitive conclusion about the significant effects of non-medical interventions. Incurring a VCF is a complex and diverse event, necessitating equally complex interventions to identify new ways forward. However, to date, interventions struggle with a risk of selection bias in that only the needs of the healthiest of the population are addressed and the voices of the remaining majority of the people affected by VCF are unheard.

A painful, never ending story: older women's experiences of living with an osteoporotic vertebral compression fracture.

UNLABELLED: Vertebral compression fractures (VCF) cause pain and decreased physical ability, with no known well-established treatment. The aim of this study was to illuminate the experience of living with a VCF. The results show that fear and concerns are a major part of daily life. The women's initial contact with health-care providers should focus on making them feel acknowledged by offering person-centered and tailored support. INTRODUCTION: In the past decade, osteoporotic-related fractures have become an increasingly common and costly public health problem worldwide. Vertebral compression fracture (VCF) is the second most common osteoporotic fracture, and patients with VCF describe an abrupt descent into disability, with a subsequent desire to regain independence in everyday life; however, little is known of their situation. The aim of this study was to illuminate the lived experience of women with an osteoporotic VCF. METHODS: Ten women were interviewed during 2012-2013, starting with an open-ended question: could you tell me what it is like to live with a vertebral compression fracture? The verbatim transcribed interviews were analyzed using a phenomenological hermeneutical approach. RESULTS: The narrative provided descriptions of living in turmoil and chaos, unable to find stability in their life with little improvement regarding pain and physical function. Shifts from periods of constant pain to periods of fear of constant pain created a loss of confidence and an increased sense of confinement. The structural analysis revealed fear and concerns as the most prominent experience building on five themes: struggling to understand a deceiving body, breakthrough pain fueling fear, fearing a trajectory into isolation, concerns of dependency, and fearing an uncertain future. CONCLUSIONS: Until researchers find a successful prevention or medical/surgical treatment for osteoporotic VCFs, health-care providers and society abandon these women to remain in a painful and never ending story.

Design and structure-activity relationships of novel inhibitors of human rhinovirus 3C protease.

Human rhinovirus (HRV) is a primary cause of common cold and is linked to exacerbation of underlying respiratory diseases such as asthma and COPD. HRV 3C protease, which is responsible for cleavage of viral polyprotein in to proteins essential for viral life-cycle, represents an important target. We have designed proline- and azetidine-based analogues of Rupintrivir that target the P2 pocket of the binding site. Potency optimization, aided with X-ray crystallography and quantum mechanical calculations, led to compounds with activity against a broad spectrum of HRV serotypes. Altogether, these compounds represent alternative starting points to identify promising leads in our continual efforts to treat HRV infections.

Association of IFNL3 and IFNL4 polymorphisms with liver-related mortality in a multiracial cohort of HIV/HCV-coinfected women.

African Americans coinfected with HIV and hepatitis C virus (HCV) have lower liver-related mortality than Caucasians and Hispanics. While genetic polymorphisms near the IFNL3 and IFNL4 genes explain a significant fraction of racial differences in several HCV-related outcomes, the impact of these variants on liver-related mortality has not been investigated. We conducted a cohort study of HIV/HCV-coinfected women followed in the multicentre, NIH-funded Women's Interagency HIV Study (WIHS) to investigate whether 10 polymorphisms spanning the IFN-λ region were associated with liver-related mortality by dominant, recessive or additive genetic models. We also considered whether these polymorphisms contributed to previously reported differences in liver-related death by race/ethnicity (ascertained by self-report and ancestry informative markers). Among 794 coinfected women, there were 471 deaths including 55 liver-related deaths during up to 18 years of follow-up. On adjusted analysis, rs12980275 GG genotype compared to AG+AA hazards ratios [(HR) 0.36, 95% CI 0.14-0.90, P = 0.029] and rs8109886 AA genotype compared to CC+AC (HR 0.67, 95% CI 0.45-0.99, P = 0.047) were most strongly associated with liver-related death although these associations were no longer significant after adjusting for race/ethnicity (HR 0.41, 95% CI 0.16-1.04, P = 0.060 and HR 0.78, 95% CI 0.51-1.19, P = 0.25, respectively). African American women had persistently lower liver-related death independent of IFN-λ variants (HRs ≤ 0.44, P values ≤ 0.04). The lower risk of death among African American HIV/HCV-coinfected women is not explained by genetic variation in the IFN-λ region suggesting, that other genetic, behavioural and/or environmental factors may contribute to racial/ethnic differences in liver-related mortality.

Accurate T(1) mapping for oxygen-enhanced MRI in the mouse lung using a segmented inversion-recovery ultrashort echo-time sequence.

PURPOSE: A segmented inversion-recovery module combined with the 2D ultrashort echo time radial technique is proposed that allows accurate pixel level T(1) mapping of mouse lung in vivo. METHODS: Numerical simulations were performed to estimate T(1) measurement accuracy and precision versus flip angle and signal-to-noise ratio. Phantom measurements were used for protocol validation, where the segmented inversion-recovery ultrashort echo-time sequence was compared with the reference technique (inversion-recovery rapid acquisition with refocused echoes). The in vivo experiments were carried out on free-breathing C57 mice (n = 10), breathing first air and then oxygen. RESULTS: The simulations demonstrated the high potential of the technique for accurate and precise T(1) assessment. Phantom experiments showed good agreement for T(1) values measured with segmented inversion-recovery ultrashort echo-time and the reference technique. The in vivo experiment demonstrated the utility of the technique in oxygen-enhanced assessment, where small T(1) changes were detected with high precision. CONCLUSION: Segmented inversion-recovery ultrashort echo-time provides accurate, high resolution T(1) mapping of the lung parenchyma.

Socioeconomic inequalities in relative survival of rectal cancer most obvious in stage III.

INTRODUCTION: The association between socioeconomic status (SES) and relative survival of rectal cancer is little investigated. We hypothesized that the impact on risk of death by SES would be much smaller when differences in background mortality (comorbidity, lifestyle factors) were taken into account, i.e. in modelling relative survival of rectal cancer. METHODS: Individual data on civil status, education, and income were linked to the Swedish Rectal Cancer Registry 1995-2005 (n = 16,713). Specific life tables by socioeconomic group were used to calculate relative survival, and modelling included age, sex, stage, time period, and SES. The same covariates were applied in a Cox regression based on absolute survival. RESULTS: Stage distribution was associated with civil status, education, and income (p < 0.001). In spite of modelling based on relative survival, an increased risk of death was found for all other patients compared with those who were married, as well as for all other patients compared with those with the highest income. The pattern was fundamentally the same as in a Cox regression model, only the point estimates were slightly reduced using the relative approach. In stage-specific modelling of relative survival, income was of particular importance in stage III; the hazard ratio (HR) for lowest versus the highest income was 1.37 [95 % confidence interval (CI) 1.15-1.64]. There were also significant differences by income among patients who had a major surgical resection (stage IV excluded). CONCLUSION: Large and clinically relevant socioeconomic inequalities remained in stage-adjusted analyses of relative survival, also in a setting of universal healthcare and no screening program operating.

Heterogeneity of colon cancer patients reported as emergencies.

BACKGROUND: Up to one-fourth of all colon cancer patients are reported as emergencies, and the aim of the present study was to scrutinize mode of presentation in this group. MATERIALS AND METHODS: All reported cases of emergency (n = 263) and randomly selected elective controls (1:2) of colon cancer in four Swedish counties 2006-2008 were eligible (n = 854). Symptoms and aspects of management were retrieved from surgery and primary care records. Outcomes were compared using Kaplan-Meier estimates and Cox regression. RESULTS: Among patients reported as emergencies, 158/263 (60 %) underwent operation within three days (acute), and 105 (40 %) after more than 3 days (subacute). In the latter group, 20/94 (21 %) had reported two symptoms, and 31/94 (33 %) had reported three or more symptoms associated with colon cancer to primary care during the last 12 months prior to surgery. In total, 46/105 (44 %) had already had an examination of the large bowel, and 52/105 (50 %) were stage IV, as opposed to 36/158 (23 %) in the acute group and 83/577 (15 %) in the elective group (p < 0.001). Mortality at 30 and 90 days was 15.2 and 35.6 % in the subacute group, 8.2 and 14.9 % in the acute group (p = 0.001), and 1.9 and 4.3 % in the elective group (p < 0.001); 5-year survival was 28.3, 40.1, and 57.8 %, respectively, in the three groups (p < 0.001). The hazard ratio, adjusted for age, sex, and stage, was 1.88 95 % confidence interval (CI) 1.5-2.4) for the acute group and 2.29 (95 % CI 1.7-3.1) for the subacute group. CONCLUSIONS: Colon cancer patients reported as emergencies but operated upon more than three days after admission had the worst outcome. Efforts to decrease the interval between admission and surgery is one important aspect of care, but wider attention must also be paid to this group of patients.

MRI in radiotherapy - Is it time to rethink the current radiotherapy fixation solutions?

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Alcohol consumption is associated with reduced risk of Type 2 diabetes and autoimmune diabetes in adults: results from the Nord-Trøndelag health study.

AIMS: We investigated the influence of different aspects of alcohol consumption on the risk of Type 2 diabetes and autoimmune diabetes in adults. METHODS: We used data from the Nord-Trøndelag Health Survey (HUNT) study, in which all adults aged ≥ 20 years from Nord-Trondelag County were invited to participate in three surveys in 1984-1986, 1995-1997 and 2006-2008. Patients with diabetes were identified using self-reports, and participants with onset age ≥ 35 years were classified as having Type 2 diabetes if they were negative for anti-glutamic acid decarboxylase (n = 1841) and as having autoimmune diabetes if they were positive for anti-glutamic acid decarboxylase (n = 140). Hazard ratios of amount and frequency of alcohol use, alcoholic beverage choice, and binge drinking and alcohol use disorders were estimated. RESULTS: Moderate alcohol consumption (adjusted for confounders) was associated with a reduced risk of Type 2 diabetes in men, but not in women (hazard ratio for men 10-15 g/day 0.48, 95% CI 0.28-0.77; hazard ratio for women ≥ 10 g/day 0.81, 95% CI 0.33-1.96). The reduced risk was primarily linked to consumption of wine [hazard ratio 0.93, 95% CI 0.87-0.99 (per g/day)]. No increased risk was seen in participants reporting binge drinking or in problem drinkers. The results were also compatible with a reduced risk of autoimmune diabetes associated with alcohol consumption [hazard ratio 0.70, 95% CI 0.45-1.08 (frequent consumption) and hazard ratio 0.36, 95% CI 0.13-0.97 (2-7 g/day)]. CONCLUSIONS: Moderate alcohol consumption associates with reduced risk of both Type 2 diabetes and autoimmune diabetes. A protective effect of alcohol intake may be limited to men. High alcohol consumption does not seem to carry an increased risk of diabetes.

A population-based audit of the clinical use of faecal occult blood testing in primary care for colorectal cancer.

AIM: Symptoms related to colorectal cancer (CRC) are common. We investigated the value of the faecal occult blood test (FOBT), when administered in primary care, in the diagnosis of CRC. METHOD: All patients who underwent a FOBT (Hemoccult II) at 20 public primary care centres in Sörmland County, Sweden, during 2000-2005, were included (n=9048). Linkage to the Swedish Cancer Registry identified all cases of CRC. Symptoms recorded at the time of the FOBT were retrieved from the patient records. The outcome from the FOBT to diagnosis and subsequent survival was compared between patients who were FOBT negative and patients who were FOBT positive. RESULTS: One-hundred and sixty-one patients were diagnosed with CRC within 2 years after undergoing a FOBT in primary care. These comprised 18% of all 917 patients diagnosed with CRC in the county during the study period. In 41 (25.4%) of the 161 patients the test was negative. Symptoms related to CRC were documented for 158 (98%) patients at the time the FOBT was administered. The median investigation time from the FOBT test to the diagnosis of CRC was 91 days: 80 days for FOBT-positive patients and 188 days for FOBT-negative patients (P<0.001). This difference was significant independent of age, sex and site of tumour. The hazard ratio for FOBT negativity, 3 years after the FOBT, when adjusted for age and sex, was 1.47 (95% CI, 0.81-2.68). CONCLUSION: Despite having suggestive symptoms, 41 (4.5%) of 917 CRC patients had a negative FOBT result in primary care. This was associated with diagnostic delay and, potentially, a worse outcome.

Risk alleles for chronic hepatitis B are associated with decreased mRNA expression of HLA-DPA1 and HLA-DPB1 in normal human liver.

A genome-wide association study identified single nucleotide polymorphisms (SNPs) rs3077 and rs9277535 located in the 3' untranslated regions of human leukocyte antigen (HLA) class II genes HLA-DPA1 and HLA-DPB1, respectively, as the independent variants most strongly associated with chronic hepatitis B. We examined whether these SNPs are associated with mRNA expression of HLA-DPA1 and HLA-DPB1. We identified gene expression-associated SNPs (eSNPs) in normal liver samples obtained from 651 individuals of European ancestry by integrating genotype (~650 000 SNPs) and gene expression (>39 000 transcripts) data from each sample. We used the Kruskal-Wallis test to determine associations between gene expression and genotype. To confirm findings, we measured allelic expression imbalance (AEI) of complementary DNA compared with DNA in liver specimens from subjects who were heterozygous for rs3077 and rs9277535. On a genome-wide basis, rs3077 was the SNP most strongly associated with HLA-DPA1 expression (p=10(-48)), and rs9277535 was strongly associated with HLA-DPB1 expression (p=10(-15)). Consistent with these gene expression associations, we observed AEI for both rs3077 (p=3.0 × 10(-7); 17 samples) and rs9277535 (p=0.001; 17 samples). We conclude that the variants previously associated with chronic hepatitis B are also strongly associated with mRNA expression of HLA-DPA1 and HLA-DPB1, suggesting that expression of these genes is important in control of HBV.

No effect by the common gene variant rs10830963 of the melatonin receptor 1B on the association between sleep disturbances and type 2 diabetes: results from the Nord-Trøndelag Health Study.

AIMS/HYPOTHESIS: Genetic variation in the melatonin receptor 1B (MTNR1B) is associated with type 2 diabetes. Melatonin contributes to the regulation of sleep, and sleep problems are a documented risk factor for type 2 diabetes. The aim of this study was to investigate whether the MTNR1B gene variant rs10830963 is associated with sleep problems and whether this variant contributes to the association between sleep disturbances and type 2 diabetes. METHODS: This was a case-control study nested within the population-based Nord-Trøndelag Health Study, including 1,322 prevalent cases of type 2 diabetes and 1,447 controls. In addition, prospective data were available for 838 incident cases and 1,133 controls. Genotyping was done by TaqMan single-nucleotide polymorphism allelic discrimination analysis. ORs and 95% CIs were calculated using logistic regression models. RESULTS: Our findings confirm an association between sleep disturbances and type 2 diabetes (OR 1.69, 95% CI 1.22-2.33, p = 0.0016) and between the risk allele of rs10830963 and type 2 diabetes (OR 1.12, 95% CI 1.00-1.27, p = 0.0579). There was a tendency for an association between the risk allele and prevalence of sleep problems (specifically early awakening). However, the risk allele did not influence the association of sleep problems with diabetes, which was unaltered after adjustment for the MTNR1B risk allele (OR 1.69, 95% CI 1.23-2.34, p = 0.0014). Results based on prospective data were similar, although non-significant. CONCLUSIONS/INTERPRETATION: Our findings do not support participation of the MTNR1B gene variant rs10830963 in the well documented association between sleep disturbances and type 2 diabetes.

Emergency presentation of colon cancer is most frequent during summer.

AIM: The frequency of emergency colon cancer (ECC) was determined using a reproducible definition of 'emergency' to analyse the impact of mode of presentation on long-term prognosis and to search for risk factors for an emergency presentation. METHOD: All patients with colon cancer treated at one Swedish GDH between 1996 and 2005 (N = 604) were eligible. Patients admitted through the emergency room, operated on within three days and with an emergency condition confirmed at surgery were classified as ECC. Survival was analysed by Kaplan-Meier estimates and risk of death by Cox regression. RESULTS: The rate of ECC was 97/585 (17%). Patients with ECC were older (median 77 vs 74, P = 0.02), they had more stage III and IV cancers (65%vs 47%; χ(2) = 9.4, P < 0.001) and had a cancer located in the caecum less often (20%vs 33%, χ(2) = 4.3 P = 0.04). ECC were most frequent between June and August (36%), whereas elective cases were evenly distributed throughout the year (χ(2) = 7.8; P = 0.049), Crude 5-year survival was 18% in ECC and 38% in the elective group (P < 0.001). The hazard ratio for death within five years in ECC, with 30-day mortality excluded and adjusted for age and sex was 2.25 (95% CI; 1.42-3.55). CONCLUSION: Emergency presentation of colon cancer is an independent and adverse risk factor for long-term survival. The causes of a seasonal variation need to be clarified.

Evidence for neuroendocrine function of a unique splicing form of TCF7L2 in human brain, islets and gut.

AIMS/HYPOTHESIS: Variants in the TCF7L2 gene remain the strongest genetic associations with increased risk of type 2 diabetes. Recently, we identified a unique splicing form of TCF7L2 expressed in pancreatic islets, pancreas and colon and detected by assay 'ex13-13b'. The expression of ex13-13b strongly correlated with proinsulin in glucose-stimulated pancreatic islets, suggesting a potential role for this form in the development of type 2 diabetes. The goal of this study was to further characterise this unique TCF7L2 splicing form in human tissues. METHODS: We used a panel of 34 human tissues and 80 human cell lines to measure the expression of assay ex13-13b with use of quantitative RT-PCR. RESULTS: The highest expression of assay ex13-13b was detected in several areas of the brain (hypothalamus/thalamus, occipital lobe) and in neuronal cell line SHS5Y5. Low expression was confirmed in pancreatic islets, small intestine, pancreas and colon, while no expression was detected in other human tissues and cell lines. The expression of assay ex13-13b correlated with the gene for cocaine- and amphetamine-regulated transcript (CART, also known as CARTPT) in a panel of human tissues (n = 12, r = 0.85, p = 0.00046), pancreatic islets (n = 23, r = 0.62, p = 0.0016) and colon (n = 98, r = 0.54, p < 0.0001). CONCLUSIONS/INTERPRETATION: The significant correlation between expression of a unique splicing form of TCF7L2, named here TCF7L2-NE, and CART, the gene for an anorexigenic neurohormone expressed in the central and peripheral nervous system, suggests that these transcripts may share neuroendocrine functions important for brain, gut and pancreatic islets.

Expression analysis of loci associated with type 2 diabetes in human tissues.

AIMS/HYPOTHESIS: Genetic mapping has identified over 20 loci contributing to genetic risk of type 2 diabetes. The next step is to identify the genes and mechanisms regulating the contributions of genetic risk to disease. The goal of this study was to evaluate the effect of age, height, weight and risk alleles on expression of candidate genes in diabetes-associated regions in three relevant human tissues. METHODS: We measured transcript abundance for WFS1, KCNJ11, TCF2 (also known as HNF1B), PPARG, HHEX, IDE, CDKAL1, CDKN2A, CDKN2B, IGF2BP2, SLC30A8 and TCF7L2 by quantitative RT-PCR in human pancreas (n = 50), colon (n = 195) and liver (n = 50). Tissue samples were genotyped for single nucleotide polymorphisms (SNPs) associated with type 2 diabetes. The effects of age, height, weight, tissue and SNP on RNA expression were tested by linear modelling. RESULTS: Expression of all genes exhibited tissue bias. Immunohistochemistry confirmed the findings for HHEX, IDE and SLC30A8, which showed strongest tissue-specific mRNA expression bias. Neither age, height nor weight were associated with gene expression. We found no evidence that type 2 diabetes-associated SNPs affect neighbouring gene expression (cis-expression quantitative trait loci) in colon, pancreas and liver. CONCLUSIONS/INTERPRETATION: This study provides new evidence that tissue-type, but not age, height, weight or SNPs in or near candidate genes associated with increased risk of type 2 diabetes are strong contributors to differential gene expression in the genes and tissues examined.

Antibody producing human-human hybridomas. II. Derivation and characterization of an antibody specific for human leukemia cells.

Human-human hybridoma technology was used to immortalize human B lymphocytes from patients with acute myeloid leukemia (AML) to study the antigenic repertoire of the humoral immune response against the patients' own leukemia cells and against leukemic cells from other patients. Nine fusions were done with lymphocytes from seven AML patients, and all with the human RH-L4 B lymphoma line as malignant fusion partner. A total of 305 Ig-producing hybrids were obtained. 26 reacted with cell surface components on AML cells, but 21 were found not to be specific for leukemia cells, when screened for reactivity against a panel of normal and malignant cells of both human and murine origin. Five hybridomas secreted Ig with high specificity for human leukemia cells, but only one hybridoma culture, aml-18, was stable in respect to Ig-production and growth upon repeated clonings and expansion in liquid cultures. A method was developed to grow human hybridomas as ascites tumors in nude mice, but the ascites fluid did not contain increased amount of antibody. The reactivity of the aml-18 antibody (gamma, kappa) was analyzed against samples of mononuclear cells from peripheral blood of 63 patients with leukemia and with cytologically verified leukemia cells in the blood. 22 of 54 AML samples reacted with aml-18. The reactivity pattern was not correlated to any categories of the French-American-British (FAB) classification; two of four ALL were positive. Moreover, a pronounced intratumoral antigenic heterogeneity in regard to aml-18 reactivity was seen and indicates a high degree of diversity in the immunological phenotype within individual AML cell populations. The study demonstrates that some patients with AML generate an immune response against their autologous malignant cells, and that the antigenic determinant in the case of aml-18 is also expressed specifically on leukemic cells from other patients.

Association studies on 11 published colorectal cancer risk loci.

BACKGROUND: Recently, several genome-wide association studies (GWAS) have independently found numerous loci at which common single-nucleotide polymorphisms (SNPs) modestly influence the risk of developing colorectal cancer. The aim of this study was to test 11 loci, reported to be associated with an increased or decreased risk of colorectal cancer: 8q23.3 (rs16892766), 8q24.21 (rs6983267), 9p24 (rs719725), 10p14 (rs10795668), 11q23.1 (rs3802842), 14q22.2 (rs4444235), 15q13.3 (rs4779584), 16q22.1 (rs9929218), 18q21.1 (rs4939827), 19q13.1 (rs10411210) and 20p12.3 (rs961253), in a Swedish-based cohort. METHODS: The cohort was composed of 1786 cases and 1749 controls that were genotyped and analysed statistically. Genotype-phenotype analysis, for all 11 SNPs and sex, age of onset, family history of CRC and tumour location, was performed. RESULTS: Of eleven loci, 5 showed statistically significant odds ratios similar to previously published findings: 8q23.3, 8q24.21, 10p14, 15q13.3 and 18q21.1. The remaining loci 11q23.1, 16q22.1, 19q13.1 and 20p12.3 showed weak trends but somehow similar to what was previously published. The loci 9p24 and 14q22.2 could not be confirmed. We show a higher number of risk alleles in affected individuals compared to controls. Four statistically significant genotype-phenotype associations were found; the G allele of rs6983267 was associated to older age, the G allele of rs1075668 was associated with a younger age and sporadic cases, and the T allele of rs10411210 was associated with younger age. CONCLUSIONS: Our study, using a Swedish population, supports most genetic variants published in GWAS. More studies are needed to validate the genotype-phenotype correlations.

Sphincter preservation in rectal cancer is associated with patients' socioeconomic status.

BACKGROUND: Decision making regarding the choice of surgical procedure in rectal cancer is complex. It was hypothesized that, in addition to clinical factors, several aspects of patients' socioeconomic background influence this process. METHODS: Individually attained data on civil status, education and income were linked to the Swedish Rectal Cancer Registry 1995-2005 (16 713 patients) and analysed by logistic regression. RESULTS: Anterior resection (AR) was performed in 7433 patients (44.5 per cent), abdominoperineal resection (APR) in 3808 (22.8 per cent) and Hartmann's procedure in 1704 (10.2 per cent). Unmarried patients were least likely (odds ratio (OR) 0.76, 95 per cent confidence interval (c.i.) 0.64 to 0.88) and university-educated men were most likely (OR 1.30, 1.04 to 1.62) to have an AR. Patients with the highest income were more likely to undergo AR (OR 0.80, 0.85 and 0.86 respectively for first, second and third income quartiles). Socioeconomic differences in the use of AR were smallest among the youngest patients. Unmarried patients were more likely (OR 1.21, 95 per cent c.i. 1.00 to 1.48) and university-educated patients less likely (OR 0.78, 95 per cent c.i. 0.63 to 0.98) to have an APR. CONCLUSION: The choice of surgical strategy in rectal cancer is not socioeconomically neutral. Confounding factors, such as co-morbidity or smoking, may explain some of the differences but inequality in treatment is also plausible.