Collagenous Colitis Is Associated With HLA Signature and Shares Genetic Risks With Other Immune-Mediated Diseases.

BACKGROUND & AIMS: Collagenous colitis (CC) is an inflammatory bowel disorder with unknown etiopathogenesis involving HLA-related immune-mediated responses and environmental and genetic risk factors. We carried out an array-based genetic association study in a cohort of patients with CC and investigated the common genetic basis between CC and Crohn's disease (CD), ulcerative colitis (UC), and celiac disease. METHODS: DNA from 804 CC formalin-fixed, paraffin-embedded tissue samples was genotyped with Illumina Immunochip. Matching genotype data on control samples and CD, UC, and celiac disease cases were provided by the respective consortia. A discovery association study followed by meta-analysis with an independent cohort, polygenic risk score calculation, and cross-phenotype analyses were performed. Enrichment of regulatory expression quantitative trait loci among the CC variants was assessed in hemopoietic and intestinal cells. RESULTS: Three HLA alleles (HLA-B∗08:01, HLA-DRB1∗03:01, and HLA-DQB1∗02:01), related to the ancestral haplotype 8.1, were significantly associated with increased CC risk. We also identified an independent protective effect of HLA-DRB1∗04:01 on CC risk. Polygenic risk score quantifying the risk across multiple susceptibility loci was strongly associated with CC risk. An enrichment of expression quantitative trait loci was detected among the CC-susceptibility variants in various cell types. The cross-phenotype analysis identified a complex pattern of polygenic pleiotropy between CC and other immune-mediated diseases. CONCLUSIONS: In this largest genetic study of CC to date with histologically confirmed diagnosis, we strongly implicated the HLA locus and proposed potential non-HLA mechanisms in disease pathogenesis. We also detected a shared genetic risk between CC, celiac disease, CD, and UC, which supports clinical observations of comorbidity.

Grasping the world through words: from action to linguistic production of verbs in early childhood.

We investigated whether the bodily-mediated production of verbs emerges earlier than verb recognition and oral production during early language acquisition. Children (aged 18-22, 23-27, 28-32, and 33-37 months) viewed animated pictures representing actions related to transitive and intransitive verbs and were asked to (i) orally indicate the verb presented, (ii) recognize the target verb among other verbs, and (iii) perform the actions corresponding to the target verb enunciated by the experimenter. Children 18-22 months showed a capacity to enact the verbs, while their recognition and oral production abilities were not comparably developed. Until 27 months of age, children produced more transitive than intransitive verbs across tasks. The gap between verb recognition and verb oral production was found in all ages tested. This is the first study to directly demonstrate that the ability to produce verbs, especially transitive verbs, via overt body actions emerges ontogenetically earlier than recognition and oral production.

Recurrent Adult Sacrococcygeal Teratoma Developing Adenocarcinoma: A Case Report and Review of Literatures.

Sacrococcygeal teratomas (SCT) are most commonly seen in infants and children but are rare in adults. Most adult SCT are benign and mature with a minority of tumors having immature components or overt malignancy. Here, we report a 65-year-old female with a SCT developing adenocarcinoma. The patient was diagnosed with benign sacrococcygeal cystic teratoma on her initial hospital visit and was treated with surgical resection. She was followed up postoperatively and was noted to have a markedly elevated CA 19-9 level 13 months after the surgery. Radiological and clinical examination revealed thickening of the perirectal soft tissues, located near the inferior portion of her previous incision site. Histological evaluation of the lesion showed invasive, moderately differentiated adenocarcinoma. Immunohistochemical staining results were suggestive, but not diagnostic, of anal gland adenocarcinoma. This case report expands the knowledge regarding an adenocarcinoma arising from a previously benign, adult SCT.

Colonic Mucosubmucosal Elongated Polyp in the Sigmoid Colon on Surveillance Colonoscopy.

Colonic mucosubmucosal elongated polyp (CMSEP) is a newly designated colorectal polyp. It has unique endoscopic features of a worm- or drumstick-shaped appearance. Histologically, it is composed of normal colonic mucosa and expanded submucosa with a prominent vascular component and no significant inflammation. CMSEP is usually detected incidentally on screening colonoscopy or colonoscopy for other causes. Differential diagnoses that need to be considered include mucosal prolapse syndrome, filiform polyposis, hamartomatous polyp, colon leiomyoma, inverted diverticulum, and residual stalk of a pedunculated adenoma. We present a case of CMSEP on surveillance colonoscopy and literature review.

Mutational load may predict risk of progression in patients with Barrett's oesophagus and indefinite for dysplasia: a pilot study.

BACKGROUND AND AIMS: Mutational load (ML) has been shown to help risk-stratify those that may progress from non-dysplastic Barrett's oesophagus (BE) to dysplastic disease. Management of patients with BE and indefinite for dysplasia (BE-IND) is challenging and risk stratification tools are lacking. The aim of this pilot study is to evaluate the utility of ML for risk stratification in patients with BE-IND. METHODS: This is a single-centre, retrospective pilot study evaluating ML quantification in patients with BE-IND. Histology at follow-up endoscopy at least 1 year after the baseline endoscopy was used to determine if a patient progressed to low or high dysplasia. The ML levels were then compared among patients who progressed to dysplasia versus those who did not. RESULTS: Thirty-five patients who met the inclusion criteria were identified, and seven met the exclusion criteria. Twenty-eight patients were analysed, of whom eight progressed to low-grade dysplasia (6) and high-grade dysplasia (2). Seven of these eight patients had some level of genomic instability detected in their IND biopsy (ML ≥0.5). Ten of the 20 (50%) who did not progress had no ML level. At an ML cut-off above 1.5, the risk of progression to high-grade dysplasia was 33% vs 0% (p=0.005), with a sensitivity of 100% and a specificity of 85%. CONCLUSION: These results indicate that ML may be able to risk-stratify progression to high-grade dysplasia in BE-IND. Larger studies are needed to confirm these findings.

Dynamic time warping: a new method in the study of poor handwriting.

Poor handwriting is a diagnostic criterion for developmental coordination disorder. Typical of poor handwriting is its low overall quality and the high variability of the spatial characteristics of the letters, usually assessed with a subjective handwriting scale. Recently, Dynamic Time Warping (DTW), a technique originally developed for speech recognition, was introduced for pattern recognition in handwriting. The present study evaluates its application to analyze poor handwriting. Forty children attending Dutch mainstream primary schools were recruited and based on their scores on the Concise Evaluation Scale for Children's Handwriting (Dutch abbreviation: BHK), 20 good and 20 poor writers (of whom 13 were scheduled for handwriting intervention) were identified. The groups were matched for age (7-9 years), school grade (grades 2 and 3) and handedness. The children subsequently wrote sequences of the letter "a" on a graphics tablet in three conditions (normal, fast, and accurate). Classical kinematics were obtained and for each individual letter DTW was used to calculate the distance from the mean shape. The DTW data revealed much higher variability in the letter forms of the poor writers that was independent of the kinematic results of larger trajectories, faster movements, and higher pen pressure. The current results suggest that DTW is a valid and objective technique for letter-form analysis in handwriting and may hence be useful to evaluate the rehabilitation treatments of children suffering from poor handwriting. In education research it may be exploited to explore how children (should) learn to write.

Intestinal low-grade tubuloglandular adenocarcinoma in inflammatory bowel disease.

Chronic idiopathic inflammatory bowel disease (IBD) with extensive colonic involvement predisposes to the development of colorectal adenocarcinoma. Among the types of cancer occurring in this setting is an unusually well-differentiated low-grade tubuloglandular adenocarcinoma (LGTGA) that has not been studied systematically thus far. A review of 149 IBD-associated cancer resections performed at our institution yielded 17 patients (11%) with 21 tumors classified as LGTGA based on the following histologic characteristics: very well-differentiated small to medium diameter glands with round or tubular profiles, low-grade cytologic characteristics and absence or paucity of desmoplastic reaction. Twelve patients had ulcerative colitis, 4 Crohn disease, and 1 indeterminate colitis. Their median age was 41.5 years (range, 28 to 58 y). Five patients had separate synchronous cancers of conventional types. LGTGAs ranged from 0.4 to 10 cm in size and varied in gross appearance. They included 5 flat lesions that were not identified visually but were detected either by palpation of the unfixed surgical specimen (1 case) or histologically in random sections (4 cases). The invasive glands usually bore a close histologic resemblance to overlying low-grade or indefinite dysplastic crypts. Twelve carcinomas (57%) with well-defined superficial regions of LGTGA progressed histologically to conventional adenocarcinoma in deeper regions. These tumors were significantly more advanced than 9 carcinomas that maintained low-grade histology throughout. Follow-up of 13 patients (76%) for a mean 4.0 years (range, 0.75 to 9.0 y) disclosed 10 (77%) with favorable outcomes and 3 (23%) with adverse outcomes. Two adverse outcomes were attributable to synchronous advanced-stage conventional cancers and the third to progression from LGTGA to poorly differentiated adenocarcinoma. The mucosa overlying and surrounding LGTGA showed low-grade dysplasia (LGD) in 18 cases (86%), indefinite dysplasia with focal LGD in 1 case (5%), and LGD with focal high-grade dysplasia (HGD) in 2 cases (10%). Immunohistochemical studies disclosed expression of MUC2 in 72%, MUC6 in 0%, CK7 in 69%, and CK20 in 100%. Coexpression of CK7 and CK20 was conserved in regions of conventional adenocarcinoma derived from LGTGA. Silencing of immunohistochemical expression of hMLH1 occurred in 6 of 11 tumors tested (55%), implicating defective DNA replication error repair in their pathogenesis. We conclude that LGTGA is a distinct clinicopathologic entity characterized by direct derivation from LGD mucosa of IBD, very well-differentiated morphology, frequent coexpression of CK7 and CK20, and frequent silencing of hMLH1. Histologic progression from LGTGA to conventional types of adenocarcinoma parallels clinical progression to more aggressive neoplasia. The potential of LGD to give rise directly to LGTGA, and by way of LGTGA to more aggressive cancers, reinforces recommendations in favor of aggressive management of IBD patients diagnosed with LGD.

Dexamethasone mediates protection against acute pancreatitis via upregulation of pancreatitis-associated proteins.

AIM: To examine the influence of dexamethasone on pancreatitis-associated protein (PAP) gene expression using both in vitro and in vivo models of acute pancreatitis and to study how PAP gene expression correlates with severity of pancreatitis. METHODS: In vitro, IL-6 stimulated pancreas acinar AR42J cells were cultured with increasing concentrations of dexamethasone and assayed for PAP expression (RT-PCR). In vivo, pancreatitis was induced in rats by retrograde injection of 40 g/L taurocholate into the pancreatic duct. Animals were pretreated with dexamethasone (2 mg/kg) daily or saline for 4 d. Pancreata and serum were harvested after 24 h and gene expression levels of PAP I, II and III were measured by RT-PCR. Severity of pancreatitis was based on serum amylase, pancreatic wet weight, and histopathological score. RESULTS: In vitro, dexamethasone and IL-6 induced a marked transcription of PAP I, II and III genes in AR42J cells at 24 h (P < 0.05 for all comparisons). In vivo, pancreas mRNA levels of PAP I, II or III increased by 2.6-fold, 1.9-fold, and 1.3-fold respectively after dexamethasone treatment, compared with saline treated animals. Serum amylase levels and edema were significantly lower in the dexamethasone group compared with the saline group. Histopathologic evaluation revealed less inflammation and necrosis in pancreata obtained from dexamethasone treated animals (P < 0.05). CONCLUSION: Dexamethasone significantly decreases the severity of pancreatitis. The protective mechanism of dexamethasone may be via upregulating PAP gene expression during injury.

When words lead to solutions: executive function deficits in preschool children with specific language impairment.

Several studies indicate that school-age children with specific language impairment (SLI) have difficulties with tasks that rely on executive functions. Whether executive function deficits in children with SLI emerge during preschool age remains unclear. Our aim was to fill this gap by investigating executive function performances in two age groups of preschoolers with and without SLI. Children with SLI (N=60; young: 53.6±5.3 months; old: 65.4±3.8 months) and age-matched control children (N=58) were tested for problem-representation ability, using the Flexible Item Selection Task (FIST), rule-use skills, using a Stroop-like Day-Night test (D/N), and planning skills, using the Tower of London test (TOL). Older children performed better than younger children did across tasks. Children with SLI had poorer performance, compared to typically developing children, on measures of problem representation, planning skills, and use of rules. Our results clearly indicate that executive function impairment is evident during the preschool period. Although old children with SLI performed better than young children with SLI, their performances were still poor, compared to those of control peers. These findings suggest that children with SLI have altered executive functioning at 53.6 months.

Building words on actions: verb enactment and verb recognition in children with specific language impairment.

Recent studies have shown that language processing is grounded in actions. Multiple independent research findings indicate that children with specific language impairment (SLI) show subtle difficulties beyond the language domain. Uncertainties remain on possible association between body-mediated, non-linguistic expression of verbs and early manifestation of SLI during verb acquisition. The present study was conducted to determine whether verb production through non-linguistic modalities is impaired in children with SLI. Children with SLI (mean age 41 months) and typically developing children (mean age 40 months) were asked to recognize target verbs while viewing video clips showing the action associated with the verb (verb-recognition task) and to enact the action corresponding to the verb (verb-enacting task). Children with SLI performed more poorly than control children in both tasks. The present study demonstrates that early language impairment emerges at the bodily level. These findings are consistent with the embodied theories of cognition and underscore the role of action-based representations during language development.

Highly cross-linked polyethylene in posterior stabilized total knee arthroplasty: early results.

This article examines whether any new complications were associated with highly cross-linked polyethylene in posterior stabilized total knee arthroplasty (TKA) due to its altered mechanical properties. Average preoperative Knee Society Scores (KSS) were 49.7 and 51.5, with a range of movement (ROM) of 3° to 116°, and average postoperative KSS were 87.7 clinical and 89.7, with ROM of 0° to 123°. Postoperative alignment averaged 3.8° of valgus. There were no cases of polyethylene or post failure. Short-term results of posterior stabilized TKAs using highly cross-linked polyethylene show good functional outcomes with no evidence of loosening or tibial post failure.

Bilateral pseudogout 8 years after bilateral total knee arthroplasty.

This article presents the clinical features of crystal arthropathy after knee replacement. The current literature on pseudogout and gout after both total and partial knee replacement is summarized. A case of bilateral pseudogout 8 years after initial total knee arthroplasty (TKA) is used to highlight the clinical characteristics and treatment options for this underrecognized condition. Presentation mimicked a late septic joint arthroplasty with sudden onset of pain and effusion. The patient was treated successfully with an arthrotomy, debridement, synovectomy, polyethylene insert exchange, oral steroids, and nonsteroidal anti-inflammatories. There are no other reported cases of bilateral pseudogout after bilateral TKA.

Colonic-type adenocarcinoma of the base of the tongue: a case report of a rare neoplasm.

Lingual adenocarcinomas (ADC), either primary or metastatic to the tongue are extraordinarily rare neoplasms. Primary lingual adenocarcinomas are primarily of minor salivary gland origin. Two cases of primary colonic-type adenocarcinomas of the base of the tongue were recently reported for the first time in the English literature. We present an additional case of lingual intestinal-type adenocarcinoma with mucinous features that occurred in association with cervical node metastasis and discuss the clinicopathologic features and histogenetic aspects of this rare entity.

Serrated adenoma is a risk factor for subsequent adenomatous polyps.

BACKGROUND: Serrated adenomas (SA) are histologically defined by the presence of both hyperplastic and adenomatous features. These uncommon polyps are thought to play an important role in the development of sporadic colorectal cancers (CRC) with microsatellite instability (MSI). There is paucity of data on the risk of progression of SA to CRC. This study was undertaken to define the relationship between SA and the future development of adenomatous polyps. METHODS: Colonoscopic biopsies that contained a pathologic diagnosis of SA were identified from a pathology database of a major urban academic medical center. Those patients with absence of concomitant malignancy, complete colonoscopy, good or adequate prep and presence of at least one follow-up procedures were identified. These were matched to controls by age, sex, indication for colonoscopy, polyp type and number and duration of follow-up. Outcomes of the follow-up procedures were compared. RESULTS: Between January 1997 and June 2005 17,226 colonoscopic biopsies and polypectomies were performed. Of these, 80 patients (0.5%) with SA were found, and of these SA, 80% were found in the left colon. The average age of patients undergoing colonoscopy was 58.5 years, and the average age of patients with SA was 68 years (P = 0.004). Of all patients with SA, 7 (9%) had concomitant CRC. The final groups contained 17 patients and 17 controls, respectively, and were well matched. The mean follow-up interval in the patient group was 29 months vs. 31 months in the control group (P = 0.82). On follow-up examination four patients (24%) and no controls had adenomatous polyps (P = 0.01). CONCLUSIONS: While SA are uncommon, they are commonly associated with colorectal cancer. Serrated adenomas appear to be found more commonly in the left colon and in older patients. This study found a significant association between SA and the subsequent development of adenomatous polyps. Further studies are needed to define appropriate preventive strategies for these patients.

Evaluation of family drawings of physically and sexually abused children.

OBJECTIVE: The aim of this study is to analyse the family drawings of two groups of physically and/or sexually abused children as compared to the drawings of non-abused children of a matched control group. METHODS: The drawings by 12 physically abused, 12 sexually abused and 12 non-abused children, all aged between 5 years-old and 10 years-old, were assessed and compared. Family drawings were analysed using a specific Screening Inventory (FDI-Family Drawing Inventory). This Inventory takes into consideration such qualitative and quantitative variables as the quality of drawing, the children's perception of their family members and their own perception of themselves within the family system. RESULTS: The results have shown significant differences between the abused minors and the control group. Abused children are more likely to draw distorted bodies, the human figure is usually represented devoid of details, their drawings generally show clear signals of trauma and the majority of the abused children are likely to exclude their primary caregiver from the drawings. CONCLUSIONS: The "drawings of the family" of physically and/or sexually abused children significantly evidence a greater emotional distress then the drawings of the non-abused children of the matched control group.

Transurethral bladder cryoablation in the porcine model.

OBJECTIVES: To examine the feasibility of transurethral, focal, full-thickness bladder wall cryoablation in the porcine model using a novel 38-cm cryoablation probe. METHODS: A total of 18 pigs were divided into three groups. Groups 1 (n = 6) and 2 (n = 6) underwent transurethral bladder wall cryoablation in a saline environment with two freeze-thaw cycles. The pigs in groups 1 and 2 were killed after 1 and 3 weeks, respectively. The pigs in group 3 (n = 6) underwent transurethral cryoablation after the bladder had been insufflated with carbon dioxide gas. The pigs in group 3 were killed after 1 week. In all groups, laparoscopic access was obtained to protect the abdominal contents from the transmural cryoablation process. Bladder integrity was evaluated with cystography and laparoscopic visualization, and each cryolesion was excised en bloc for extensive histopathologic evaluation. RESULTS: All 18 pigs successfully underwent bladder wall cryoablation. For all groups, the preoperative, postoperative, and sacrifice cystograms were without evidence of extravasation. No urinomas, hematomas, or adhesions were present in groups 1 and 2. Minimal adhesions were identified in 3 (50%) of 6 pigs in group 3. For groups 1, and 2, the mean length and width of the area of complete necrosis on histopathologic evaluation was 6.5 and 3.0 mm and 2.3 and 1.3 mm, respectively. For group 3, the mean diameter of the cryolesion was 8.2 mm. Full-thickness necrosis was confirmed in all groups. CONCLUSIONS: The results of our study have shown that, in this model, complete full-thickness transurethral bladder wall cryoablation, with maintenance of bladder wall integrity, is feasible.

Relationship between HIV viral load and Langerhans cells of the cervical epithelium.

AIM: To determine the relationship between the density of cervical mucosa Langerhans cells, cervical histology, and HIV viral load. METHODS: Eighty-four HIV-infected and 17 women at high risk for HIV had cervical biopsies assessed for squamous intraepithelial lesions and Langerhans cell density. Langerhans cells were identified using the S-100 immunohistochemical stain and were counted manually. Polymerase chain reaction assays were used to detect cervical human papillomavirus (HPV)-DNA. T-cell subsets were determined using immunofluorescent flow cytometry. Plasma HIV RNA levels were measured using a nucleic acid sequence-based amplification technique. The associations between cervical Langerhans cell density, cervical histology, CD4 counts, HIV viral loads, HPV-DNA detection, and smoking status were assessed using multivariate statistical models. RESULTS: In multivariate analysis among women infected with HIV, the mean Langerhans cell density per high-powered field was 4.00 among women with no detectable plasma HIV-RNA, and 1.92 among those with detectable HIV-RNA (P = 0.01). The mean cervical Langerhans cell density was increased in women with high-grade squamous intraepithelial lesions compared with those with low-grade squamous intraepithelial lesions and normal/metaplastic histology (3.87 vs 2.11; P = 0.05). Neither HPV-DNA detection, smoking status, nor CD4 count was significantly associated with Langerhans cell density. CONCLUSIONS: The decrease in cervical Langerhans cell density in women with detectable HIV-RNA suggests an impaired mucosal immune response to local infections, such as HPV. Conversely, HPV infection resulting in high-grade dysplasia might be associated with an enhanced local immune response.