Nonsense mutation in the LGR4 gene is associated with several human diseases and other traits.

Low bone mineral density (BMD) is used as a parameter of osteoporosis. Genome-wide association studies of BMD have hitherto focused on BMD as a quantitative trait, yielding common variants of small effects that contribute to the population diversity in BMD. Here we use BMD as a dichotomous trait, searching for variants that may have a direct effect on the risk of pathologically low BMD rather than on the regulation of BMD in the healthy population. Through whole-genome sequencing of Icelandic individuals, we found a rare nonsense mutation within the leucine-rich-repeat-containing G-protein-coupled receptor 4 (LGR4) gene (c.376C>T) that is strongly associated with low BMD, and with osteoporotic fractures. This mutation leads to termination of LGR4 at position 126 and fully disrupts its function. The c.376C>T mutation is also associated with electrolyte imbalance, late onset of menarche and reduced testosterone levels, as well as an increased risk of squamous cell carcinoma of the skin and biliary tract cancer. Interestingly, the phenotype of carriers of the c.376C>T mutation overlaps that of Lgr4 mutant mice.

Giant gastric lipoma successfully removed by endoscopic submucosal dissection: case report and systematic review.

OBJECTIVES: Gastric lipomas are rare adipose tumors that constitute less than 1% of gastric tumors. While lipomas generally do not need removal unless symptomatic, endoscopic resection has been proposed as safe for gastric lipomas smaller than 2 cm. Yet, there is no consensus on the optimal treatment method for larger lipomas. We report a case of a giant 7-cm gastric lipoma successfully removed by endoscopic submucosal dissection (ESD) and systematically review the literature for gastric lipomas removed by ESD. METHODS: Systematic review was conducted by searching PubMed and Scopus databases, up to 15 February 2018, using combinations of relevant terms. RESULTS: We report a 55-year-old male with known gastroesophageal reflux disease and asthma, who sought medical attention due to chronic heartburn and asthma exacerbations. These symptoms were attributed to a large 7 cm × 3 cm gastric lipoma that caused gastric outlet obstruction. The lipoma was safely removed by ESD, allowing quick recovery and alleviation of symptoms. In our review, we identified 20 gastric lipomas treated with ESD, with 15 (75%) being 2 cm or larger. The average size of the lipomas was 4 cm (range: 1.2-9 cm). All lipomas were limited to the submucosa, with 80% of the tumors located in the antrum. Three lipomas were removed by submucosal tunneling. All tumors were successfully removed en bloc and no major complications were reported. CONCLUSION: Our findings support the conclusion that ESD may be a safe alternative to conventional surgery for removal of large symptomatic gastric lipomas.

Why is colon cancer survival improving by time? A nationwide survival analysis spanning 35 years.

There is limited information present to explain temporal improvements in colon cancer survival. This nationwide study investigates the temporal changes in survival over a 35-year period (1970-2004) in Iceland and uses incidence, mortality, surgery rate, stage distribution, lymph node yield, tumor location and histological type to find explanations for these changes. Patients diagnosed with colon cancer in Iceland 1970-2004 were identified (n = 1962). All histopathology was reassessed. Proportions, age-standardized incidence and mortality, relative, cancer-specific and overall survival and conditional survival were calculated. When comparing first and last diagnostic periods (1970-1978 and 1997-2004), 5-year relative survival improved by 12% for men and 9% for women. At the same time surgery rate increased by 12% and the proportion of stage I increased by 9%. Stage-stratified, improved 5-year relative survival was mainly observed in stages II and III and coincided with higher lymph node yields, proportional reduction of stage II cancers and proportional increase of stage III cancers, indicating stage migration between these stages. Improvement in 1-year survival was mainly observed in stages III and IV. Five-year survival improvement for patients living beyond 1 year was minimum to none. There were no changes in histology that coincided with neither increased incidence nor possibly influencing improved survival. Concluding, as a novel finding, 1-year mortality, which previously has been identified as an important variable in explaining international survival differences, is in this study identified as also being important in explaining temporal improvements in colon cancer survival in Iceland.

Colon cancer in Iceland--a nationwide comparative study on various pathology parameters with respect to right and left tumor location and patients age.

Increasing evidence suggests genetic, biological and demographical difference between right and left colon cancer. Studies have also indicated age differences in the pathology of colon cancer. There is a scarcity of large-scale studies that closely examine the pathological differences regarding age and tumor location. The aim of our study was to do an extensive comparison of right- and left- sided colon cancers as well as comparing patients <50 years with older patients. A retrospective, population-based study was carried out on all patients with colon cancer in Iceland between 1955 and 2004. A total of 2293 cases were analyzed (1148 men, 1145 women). All histopathology material was re-evaluated. Differences in tumor characteristics between right and left location and younger (<50) and older (≥50) patients was evaluated in particular. Higher TNM-stage, larger tumors, vessel invasion, mucinous type, high grade and expanding tumor border occurred more frequently in right- versus left-sided lesions while annular and polypoid tumors were more common in left-sided tumors (p < 0.05). Young patients had more frequent lymph node metastases, vessel invasion, nonpolypoid lesions and infiltrating tumor border (p < 0.05). Right-sided lesions show more aggressive features, reflected in morphology and stage. Younger patients present more frequently with adverse features than do older patients. Frequency of right- and left-sided colon cancer differs by age with pronounced age-location differences in females. This supports the assumption of differences in etiology and carcinogenesis of right- and left-sided colon cancer, and between young and old patients.

Immunoglobulin A deficiency and oral health status: a case-control study.

INTRODUCTION: Immunoglobulin A (IgA) is important for mucosal health. Selective IgA deficiency (IgAD) is the most common primary immunodeficiency but its effect on oral health is unclear. The aim of this study was to investigate dental, periodontal and oral mucosal health in IgAD individuals. MATERIAL AND METHODS: In total, 32 adult IgAD subjects were compared with 63 randomly selected individuals. Participants answered questionnaires regarding general and oral health and underwent oral examination, including examination using the periodontal screening and recording (PSR) system and dental examination using the DMF system. RESULTS: The IgAD individuals had significantly more often undergone tonsillectomy (44%versus 24%, p=0.046) and adenoidectomy (31%versus 8%, p=0.003) compared with the controls. Furthermore, the IgAD subjects reported having pharyngitis, stomatitis and herpes labialis significantly more often. There was no significant difference in periodontal health (mean PSR index; 1.87 versus 1.77) or dental health (mean DMFS; 51.3 versus 53.7) between the two cohorts. A positive correlation between Helicobacter pylori infection and severity of periodontitis was found (p=0.036). CONCLUSION: IgAD predisposes to oral mucosal infections but does not influence periodontal or dental health. This is the first controlled study to include detailed clinical history and investigations, together with full oral and dental examination, in adults with IgAD.

Large-scale whole-genome sequencing of the Icelandic population.

Here we describe the insights gained from sequencing the whole genomes of 2,636 Icelanders to a median depth of 20×. We found 20 million SNPs and 1.5 million insertions-deletions (indels). We describe the density and frequency spectra of sequence variants in relation to their functional annotation, gene position, pathway and conservation score. We demonstrate an excess of homozygosity and rare protein-coding variants in Iceland. We imputed these variants into 104,220 individuals down to a minor allele frequency of 0.1% and found a recessive frameshift mutation in MYL4 that causes early-onset atrial fibrillation, several mutations in ABCB4 that increase risk of liver diseases and an intronic variant in GNAS associating with increased thyroid-stimulating hormone levels when maternally inherited. These data provide a study design that can be used to determine how variation in the sequence of the human genome gives rise to human diversity.

[Colon cancer in Iceland 1955-2004. Study on epidemiology, histopathology and gender difference]. / Ristilkrabbamein á Islandi árin 1955-2004. Faraldsfraedileg og meinafraedileg athugun og samanburdur á kynjum.

OBJECTIVE: Colon cancer is the third most common cancer in Iceland. The aim of this study was to analyze the epidemiology and histopathology of colon cancer in Iceland, resection rate and the difference between men and women. MATERIAL AND METHODS: Pathology and autopsy reports for all patients diagnosed with colon cancer between 1955 and 2004 where reviewed. All the histopathology material was re-evaluated. Demographical information and pathological findings were registered. Age-standardized incidence was calculated for both men and women. Gender difference was evaluated. Time trend was evaluated by linear regression. RESULTS: After re-evaluation 2293 cases remained (1148 males and 1145 females). The incidence increased for men from 7.5, to 22.2/105 and for women from 8.6 to 15.1/105. Most tumors were located in the sigmoid colon (35%). Surgical rate increased from 50% to 85%. Adenocarcinomas where 84% and mucinous adenocarcinoma 7%. Altogether 7% of cases were TNM-stage I, 32% were stage II, 24% stage III, 21% in stage IV and stage was unknown in 16% of cases. Slight gender difference was observed regarding grade, vessel invasion, depth of invasion and anatomic subsite. CONCLUSION: Incidence of colon cancer increased considerably, mainly for men. Surgical rate and pathology of colon cancer is similar to that reported elsewhere except that there are somewhat fewer cases in TNM-stage I. Little gender difference was observed in the pathological parameters analysed.

[Endoscopic drainage of posttraumatic pancreatic pseudocyst in a child]. / Holsjármedferd á sýndarblödru í briskirtli.

This case report describes endoscopic drainage of posttraumatic pancreatic pseudocyst in a eleven year old boy. Pancreatic pseudocyst is a well known complication of pancreatitis and pancreatic trauma. Traditional methods of draining them consists of open surgery or transcutanous emptying. In recent years endoscopic treatment has been used more often and is now a well established treatment in the adult population. In children this kind of treatment is less well established. Our experience with this case demonstrated that endoscopic drainage is successful and safe procedure.

[The relationship of gastrointestinal symptoms and menstrual cycle phase in young healthy women]. / Tengsl meltingarfaeraeinkenna vid hluta tídahrings hjá ungum, hraustum konum.

BACKGROUND: Abdominal discomfort is a common complaint by women and may vary with the menstrual cycle. The aim of this study was to investigate abdominal symptoms and general well being of women in relation to different phases of the menstrual cycle as well as gastrointestinal transit time. METHODS: Fourteen young women who were not using any contraceptive medications were recruited. Questionnaire was used to exclude functional gastrointestinal problems. Questionnaires on abdominal symptoms and general well being were used. Gastric emptying time, small intestinal transit time and colonic transit time were measured and serum sex hormone concentrations were measured at three points in the menstrual cycle. RESULTS: Abdominal symptoms were significantly more pronounced at the beginning of the follicular phase. Gastric emptying and colonic transit times were not significantly different between the follicular and the luteal phase of the menstrual cycle. Small bowel transit was faster in the luteal phase (75,7 min) compared with the follicular phase (99,3 min). There was no correlation between the transit times, symptoms or hormone concentrations. CONCLUSIONS: Results indicate that women experience more abdominal symptoms at the beginning of the follicular phase compared to the early luteal phase. Small bowel transit appears to be faster in the luteal phase than in the follicular phase. Further studies on the relationship of gastrointestinal symptoms and the menstrual cycle are needed.

A quantitative analysis of NSAID-induced small bowel pathology by capsule enteroscopy.

BACKGROUND & AIMS: Conventional acidic nonsteroidal anti-inflammatory drugs frequently cause small bowel inflammation. Diagnosis is largely based on assay of surrogate markers of inflammation in stool, such as fecal calprotectin. However, stool markers are not widely available and the precise nature of this inflammation is uncertain. We used wireless capsule enteroscopy to quantitate and assess the nature of the small bowel damage caused by nonsteroidal anti-inflammatory drugs when taken on a short-term basis. METHODS: Forty healthy volunteers underwent a baseline capsule enteroscopy and fecal calprotectin test. After taking diclofenac slow-release 75 mg twice a day (with omeprazole 20 mg twice a day for gastroprotection) for a total of 14 days, both investigations were repeated. RESULTS: After drug treatment, 30 subjects (75%) had increased repeat fecal calprotectin concentrations above the upper limit of normal. Capsule enteroscopy showed new pathology in 27 subjects (68%). The commonest lesions were mucosal breaks, seen in 16 (40%), which were seen to be bleeding in 2 (5%); reddened folds in 14 (35%); petechiae or red spots in 13 (33%); denuded mucosa in 8 (20%); and blood in the lumen without a visualized source in 3 (8%). Fifteen of the 27 subjects had more than one lesion concurrently. CONCLUSIONS: This study provides both biochemical and direct evidence of macroscopic injury to the small intestine in 68%-75% of volunteers resulting from 2 weeks' ingestion of slow-release diclofenac.

[The effect of diclofenac on the small intestine studied by wireless endoscopy.].

INTRODUCTION: It is well known that NSAIDs cause erosions and ulcers in the stomach and duodenum but little is known about a possible damage to the small intestine. Direct visualization of the small intestine has not been possible until recently with the introduction of wireless endoscopy. OBJECTIVES OF STUDY: Primary. To assess the effect of diclofenac on the small intestine using wireless endoscopy and measurement of calprotectin in the stools. Secondary. To assess the possible effect of diclofenac on gastro-intestinal symptoms and on the level of hemoglobin. METHODS: Twenty healthy volunteers 21-61 years of age, 10 males and 10 women, received diclofenac 75 mg twice daily for 14 days. Wireless endoscopy was performed before and after diclofenac and also measurements of calprotectin in the stools. The volunteers kept a diary of gastro-intestinal related symptoms during the treatment. In order to eliminate injury and symptoms from the stomach and duodenum, omeprazole 20 mg twice daily was given with the diclofenac. RESULTS: Wireless endoscopy before diclofenac showed no abnormalities in the 20 volunteers. After diclofenac treatment wireless endoscopy showed injuries in 14 volunteers but six had no injury. The number of small intestinal injuries found in each volunteer varied from 2-30. The injuries were equally distributed throughout the small intestine. Two volunteers had an injury in the caecum (ulcer, free blood). Stool calprotectin (normal value <60 mg/L) before diclofenac was 29 mg/L (+/-28) but increased to 148 mg/L (+/-108) (p<0.01) after diclofenac. Fourteen volunteers had gastro-intestinal related symptoms. The mean Hemoglobin concentration decreased from 145.1 to 136.8 g/L (p<0.05) with diclofenac treatment. CONCLUSIONS: The administration of diclofenac is associated with injuries in the small intestine similar as have been described in the stomach and duodenum. The symptoms associated with diclofenac in this study could be related to the small intestinal injury.

[Carcinoma of the colon in Iceland 1955-1989. An investigation of survival according to various pathological parameters.].

OBJECTIVE: The purpose of this study was to estimate various pathological parameters of colon carcinoma over a 35 year time period and evaluate their effect on survival of the patients. MATERIAL AND METHODS: All pathological specimens from patients diagnosed with colon carcinoma in Iceland in the period 1955 to 1989 were re-evaluated in order to determine the following pathological parameters: Tumour size, gross appearance, tissue type, grade, Dukes stage, lymphatic and/or blood vessel invasion, lateral margin involvement, Jass-group of tumour, peritumoural lymphocytic infiltrate, limitation of tumour growth to bowel wall, lymph node metastases, invasive tumour margin and colloid component in adenocarcinoma. Also the following parameters were determined in every case: Age at diagnosis, sex, year of diagnosis and tumour location within the bowel. All these parameters were evaluated with respect to survival of the patients. RESULTS: According to the Icelandic Cancer Registry 1265 patients were diagnosed with colon cancer in Iceland in the period under investigation. After re-evaluation 1205 patients fulfilled the criteria of a primary colon cancer and of those we were able to re-evaluate specimens from 1109 patients to determine histopathological parameters. In a univariable analysis most of the parameters investigated proved significant with respect to survival, except sex, anatomical location of tumour within the bowel, and the proportion of colloid component of tumour. In a multivariable analysis the age at diagnosis proved important as well as the year/period of diagnosis. The following pathological parameters evaluated had a significant prognostic input with regard to survival: Tumour grade, Dukes stage, number of lymph nodes with metastases, peritumoral lymphocytic infiltrate, lateral margin involvement in the surgical specimen and invasive growth pattern of tumour margin. CONCLUSIONS: Many pathological parameters are important in regard with prognostic evaluation of patients diagnosed with colon cancer. We suggest that pathologists should include in their surgical pathology specimen reports of colon cancer, in addition to traditional parameters, an evaluation of peritumoral lymphocytic infiltrate, lateral margin involvement with tumour and the growth pattern of tumour at the invasive margin.