Miracle-dz/UniFAR-FTUs huggingface dataset:
Interobserver Agreement in Endometrial Carcinoma Histotype Diagnosis Varies Depending on The Cancer Genome Atlas (TCGA)-based Molecular Subgroup

The Cancer Genome Atlas recently identified a genomic-based molecular classification of endometrial carcinomas, with 4 molecular categories: (1) ultramutated (polymerase epsilon [POLE] mutated), (2) hypermutated (microsatellite instability), (3) copy number abnormalities-low, and (4) copy number abnormalities-high. Two studies have since proposed models to classify endometrial carcinomas into 4 molecular subgroups, modeled after The Cancer Genome Atlas, using simplified and more clinically applicable surrogate methodologies. In our study, 151 endometrial carcinomas were molecularly categorized using sequencing for the exonuclease domain mutations (EDM) of POLE, and immunohistochemistry for p53 and mismatch repair (MMR) proteins. This separated cases into 1 of 4 groups: (1) POLE EDM, (2) MMR-D, (3) p53 wildtype (p53 wt), or (4) p53 abnormal (p53 abn). Seven gynecologic pathologists were asked to assign each case to one of the following categories: grade 1 to 2 endometrioid carcinoma (EC), grade 3 EC, mucinous, serous carcinoma (SC), clear cell, dedifferentiated, carcinosarcoma, mixed, and other. Consensus diagnosis among all 7 pathologists was highest in the p53 wt group (37/41, 90%), lowest in the p53 abn group (14/36, 39%), and intermediate in the POLE EDM (22/34, 65%) and MMR-D groups (23/40, 58%). Although the majority of p53 wt endometrial carcinomas are grade 1 to 2 EC (sensitivity: 90%), fewer than half of grade 1 to 2 EC fell into the p53 wt category (positive predictive value: 42%). Pure SC almost always resided in the p53 abn group (positive predictive value: 96%), but it was insensitive as a marker of p53 abn (sensitivity 64%) and the reproducibility of diagnosing SC was suboptimal. The limitations in the precise histologic classification of endometrial carcinomas highlights the importance of an ancillary molecular-based classification scheme.
A clinical, genetic, and biochemical characterization of SPG7 mutations in a large cohort of patients with hereditary spastic paraplegia

Mutations in the SPG7 gene encoding a mitochondrial protein termed paraplegin, are responsible for a recessive form of hereditary spastic paraparesis. Only few studies have so far been performed in large groups of hereditary spastic paraplegia (HSP) patients to determine the frequency of SPG7 mutations. Here, we report the result of a mutation screening conducted in a large cohort of 135 Italian HSP patients with the identification of six novel point mutations and one large intragenic deletion. Sequence analysis of the deletion breakpoint, together with secondary structure predictions of the deleted region, indicate that a complex rearrangement, likely caused by extensive secondary structure formation mediated by the short interspersed nuclear element (SINE) retrotransposons, is responsible for the deletion event. Biochemical studies performed on fibroblasts from three mutant patients revealed mild and heterogeneous mitochondrial dysfunctions that would exclude a specific association of a complex I defect with the pathology at the fibroblast level. Overall, our data confirm that SPG7 point mutations are rare causes of HSP, in both sporadic and familial forms, while underlying the puzzling and intriguing aspects of histological and biochemical consequences of paraplegin loss. Hum Mutat 29(4), 522–531, 2008. © 2008 Wiley‐Liss, Inc.
Integration of hepatitis B virus DNA into the myeloid/lymphoid or mixed‐lineage leukemia (MLL4) gene and rearrangements of MLL4 in human hepatocellular carcinoma

Integration of hepatitis B virus (HBV) DNA into host DNA is detected in about 90% of HBV‐related hepatocellular carcinoma (HCC), but the preferential sites of the viral integration etiologically relevant to oncogenesis have been controversial. By using an adaptor‐ligation/suppression‐PCR, we identified four integrations into the myeloid/lymphoid or mixed‐lineage leukemia 4 (MLL4) gene from 10 HCC patients with positive HBV surface antigen (HBsAg). Determination of the cellular‐virus DNA junction demonstrated that various lengths of the virus were integrated within 300 bp of intron 3 flanked by the Alu element of MLL4. Chimeric hepatitis B virus X gene (HBx)/MLL4 transcripts and the HBx fusion proteins were detected. DNA microarray revealed that HBx/MLL4 fusion proteins suppressed unique genes in HepG2 cells. Finally, chromosomal translocations of intron 3 of MLL4 to the specific region of chromosome 17p11.2 in 22 out of 32 HCC patients were observed, showing that the intron 3 region of MLL4 gene would be a target of translocation breakpoint. In conclusion, the present data suggest that the translocation breakpoint of MLL4 gene is one of the preferential targets for HBV DNA integration into the MLL4 gene and the HBV DNA integration may be involved in liver oncogenesis. Hum Mutat 29(5), 703–708, 2008. © 2008 Wiley‐Liss, Inc.
SALL1 truncated protein expression in Townes‐Brocks syndrome leads to ectopic expression of downstream genes

Mutations in SALL1 lead to the dominant multiorgan congenital anomalies that define Townes‐Brocks syndrome (TBS). The majority of these mutations result in premature termination codons that would be predicted to trigger nonsense‐mediated decay (NMD) of mutant mRNA and cause haploinsufficiency. Our previous studies using a gene targeted mouse model (Sall1‐ΔZn) suggested that TBS phenotypes are due to expression of a truncated mutant protein, not haploinsufficiency. In this report, we strengthen this hypothesis by showing that expression of the mutant protein alone in transgenic mice is sufficient to cause limb phenotypes that are characteristic of TBS patients. We prove that the same pathogenetic mechanism elucidated in mice is occurring in humans by demonstrating that truncated SALL1 protein is expressed in cells derived from a TBS patient. TBS mutant protein is capable of dominant negative activity that results in ectopic activation of two downstream genes, Nppa and Shox2, in the developing heart and limb. We propose a model for the pathogenesis of TBS in which truncated Sall1 protein causes derepression of Sall‐responsive target genes. Hum Mutat 0,1–8, 2008. Published 2008 Wiley‐Liss, Inc.
Intronic variants in BRCA1 and BRCA2 that affect RNA splicing can be reliably selected by splice‐site prediction programs

A large number of sequence variants identified in BRCA1 and BRCA2 cannot be distinguished as either disease‐causing mutations or neutral variants. These so‐called unclassified variants (UVs) include variants that are located in the intronic sequences of BRCA1 and BRCA2. The purpose of this study was to assess the use of splice‐site prediction programs (SSPPs) to select intronic variants in BRCA1 and BRCA2 that are likely to affect RNA splicing. We performed in vitro molecular characterization of RNA of six intronic variants in BRCA1 and BRCA2. In four cases (BRCA1, c.81–6T>A and c.4986+5G>T; BRCA2, c.7617+2T>G and c.8754+5G>A) a deleterious effect on RNA splicing was seen, whereas the c.135‐15_‐12del variant in BRCA1 showed no effect on RNA splicing. In the case of the BRCA2 c.68–7T>A variant, RNA analysis was not sufficient to establish the clinical significance. Six SSPPs were used to predict whether an effect on RNA splicing was expected for these six variants as well as for 23 intronic variants in BRCA1 for which the effect on RNA splicing has been published. Out of a total of 174 predictions, 161 (93%) were informative (i.e., the wild‐type splice‐site was recognized). No false‐negative predictions were observed; an effect on RNA splicing was always predicted by these programs. In four cases (2.5%) a false‐positive prediction was observed. For DNA diagnostic laboratories, these programs are therefore very useful to select intronic variants that are likely to affect RNA splicing for further analysis. Hum Mutat 0,1–8, 2008. © 2008 Wiley‐Liss, Inc.
Mutations in TREM2 lead to pure early‐onset dementia without bone cysts

A genome‐wide screen using 382 STR markers to localize and identify the gene implicated in early‐onset dementia (EOD) without bone cysts in a Lebanese family with three affected subjects was conducted. A unique locus homozygous by descent at chromosome 6p21.2 locus was identified. Candidate genes were explored by fluorescent sequencing and the effect of the identified mutation was confirmed by qualitative and quantitative RT‐PCR. The genetic analysis revealed a novel deletion, c.40+3delAGG, in the 5' consensus donor splice site in intron 1 of TREM2 gene which is known to be responsible for PLOSL (Polycystic Lipomembranous Osteodysplasia with Sclerosing Leukoencephalopathy) also designated as Nasu‐Hakola disease. In silico analysis predicted a lower strength for the novel donor splice site. Qualitative RT‐PCR revealed normal transcript while quantitative RT‐PCR showed over twofold down‐regulation of TREM2 transcripts. The expression profile of six genes SPP1, NEDD9, FSCN, BCL3, NFKBIA and CCL2 known as disrupted in TREM2‐deficient samples was studied and showed same expression profile as TREM2‐mutated samples except for CCL2 which was normally regulated. The significantly‐reduced expression of TREM2 in our patients and the expression profiles of the six studied genes confirm a role for TREM2 in this distinct phenotype of EOD without bone cysts. To our knowledge, this is the first report of mutations in TREM2 causing a pure dementia. © 2008 Wiley‐Liss, Inc.
Perceptions of team athletes on the importance of recovery modalities

Abstract The aim of this study was to determine how elite team athletes perceive the importance of various recovery modalities. Differences between men and women, players from various team sports and different levels of participation were determined. A total of 890 athletes who volunteered to participate in the study were team players from field hockey (n=213; mean age 21.8±3.3 years), netball (n=215; mean age 22.0±4.0 years), rugby union (n=317; mean age 23.2±3 years) and soccer (n=145; mean age 21.3±2.2 years). The total group of players consisted of 507 (57%) men and 383 (43%) women. At the time of the study, players who participated in the study competed at the highest level of the major competitions and tournaments in their sport, both locally and internationally. Data were collected by means of a questionnaire specifically designed for the study. A one-page, alphabetical list consisted of 32 words or phrases relating to physiological, psychological, social as well as complimentary and alternative strategies, which could be used for the recovery of athletes. Recovery modalities that were rated as important by all players, regardless of gender, type of sport or level of participation, were sleep, fluid replacement and socialise with friends. Gender differences could play a role in how the importance of recovery modalities was perceived. Men rated an ice bath and supplements as significantly more important (P<0.001) than women. Women rated discussions with their teammates and coaches after training and matches as significantly more important (P<0.001) than men. Significant differences were also found between the different sport codes and levels of participation in regard to the perceived importance of various modalities that could affect recovery of team sport players.
Cardiorespiratory Fitness after Stroke: A Systematic Review

Cardiorespiratory fitness programs are increasingly used in stroke rehabilitation. Maximal oxygen uptake is the gold standard measurement of cardiorespiratory fitness; however, no recent publications have collated evidence about maximal oxygen uptake levels following stroke. We therefore performed a systematic review of maximal oxygen uptake in stroke survivors, aiming to observe changes in levels over time, and associations with severity of stroke. We searched Medline and Embase until April 2011, and included cross-sectional studies, longitudinal studies, and baseline data from intervention trials. Studies had to recruit at least 10 stroke survivors, and report direct measurement of maximal/peak oxygen uptake. We then compared maximal oxygen uptake with published data from age and gender-matched controls. The search identified 3357 articles. Seventy-two full texts were retrieved, of which 41 met the inclusion criteria. Time since stroke ranged from 10 days to over seven-years. Peak oxygen uptake ranged from 8 to 22 ml/kg/min, which was 26–87% of that of healthy age- and gender-matched individuals. Stroke severity was mild in most studies. Three studies reported longitudinal changes; there was no clear evidence of change in peak oxygen uptake over time. Most studies recruited participants with mild stroke, and it is possible that cardiorespiratory fitness is even more impaired after severe stroke. Maximal oxygen uptake might have been overestimated, as less healthy and older stroke survivors may not tolerate maximal exercise testing. More studies are needed describing mechanisms of impaired cardiorespiratory fitness and longitudinal changes over time to inform the optimal ‘prescription’ of cardiorespiratory fitness programs for stroke survivors.
Histologic Features of Gastrointestinal Tract Biopsies in IgA Vasculitis (Henoch-Schönlein Purpura)

Immunoglobulin A (IgA) vasculitis or Henoch-Schönlein purpura (HSP) typically occurs in the pediatric population, although rare cases also occur in adults. Gastrointestinal (GI) involvement is common. The “classic” histologic finding in IgA vasculitis (HSP) is leukocytoclastic vasculitis (LCV); other histologic features in biopsies of IgA vasculitis (HSP) have only been rarely described. The pathology archival files at our institution were searched for GI biopsies from patients with IgA vasculitis (HSP). Slides were retrieved and histologic and clinical features were reviewed. We identified 16 patients with IgA vasculitis (HSP) with a GI biopsy series, including both adult and pediatric patients. The most common histologic abnormality was lamina propria hemorrhage (all cases) with many cases also showing lamina propria fibrin deposition with red cell sludging and nuclear debris (7 cases). Twelve of the 16 duodenal biopsies had acute duodenitis; 3 of which were severe and erosive. Several also had an eosinophilic infiltrate. Seven of the 9 jejunal and/or ileal biopsies had acute jejunitis or ileitis. An acute colitis or proctitis was observed in 9/12 colorectal biopsies. Four biopsies contained LCV; in each of these cases, the involved vessels were small capillaries within the lamina propria. Only 1 biopsy contained deeper submucosal vessels, but they were uninvolved. Sites involved by LCV included the colorectum (2 cases), colorectum and terminal ileum, terminal ileum only, duodenum, and jejunum (1 case each). All patients presented with abdominal pain; 13/16 developed a rash, 1 following the index biopsy. Other presenting symptoms included diarrhea and/or hematochezia (8 cases), nausea/vomiting (5 cases), and intussusception (1 case). Four patients had concurrent skin biopsies showing LCV; only 1 of these patients had LCV on GI biopsy. Indications for biopsy included nonspecific presenting symptoms, absence of rash at presentation, and/or failure to respond adequately to steroid therapy. Biopsies are commonly performed in patients with or without suspected IgA vasculitis (HSP) to rule out infection, inflammatory bowel disease, and less commonly, vasculitis. In general, vasculitis is not commonly observed in GI biopsies of patients with IgA vasculitis (HSP), and the spectrum of findings includes neutrophilic infiltrate within the small bowel and colon, with the duodenum most commonly affected. While the clinical and histologic findings may mimic early inflammatory bowel disease, the presence of predominant small bowel involvement, especially erosive duodenitis, should raise suspicion for IgA vasculitis (HSP). Biopsies should be obtained before steroid therapy is initiated, if possible.
Comprehensive Stroke Units: A Review of Comparative Evidence and Experience

Background Stroke unit care offers significant benefits in survival and dependency when compared to general medical ward. Most stroke units are either acute or rehabilitation, but comprehensive (combined acute and rehabilitation) model (comprehensive stroke unit) is less common. Aim To examine different levels of evidence of comprehensive stroke unit compared to other organized inpatient stroke care and share local experience of comprehensive stroke units. Methods Cochrane Library and Medline (1980 to December 2010) review of English language articles comparing stroke units to alternative forms of stroke care delivery, different types of stroke unit models, and differences in processes of care within different stroke unit models. Different levels of comparative evidence of comprehensive stroke units to other models of stroke units are collected. Results There are no randomized controlled trials directly comparing comprehensive stroke units to other stroke unit models (either acute or rehabilitation). Comprehensive stroke units are associated with reduced length of stay and greatest reduction in combined death and dependency in a meta-analysis study when compared to other stroke unit models. Comprehensive stroke units also have better length of stay and functional outcome when compared to acute or rehabilitation stroke unit models in a cross-sectional study, and better length of stay in a ‘before-and-after’ comparative study. Components of stroke unit care that improve outcome are multifactorial and most probably include early mobilization. A comprehensive stroke unit model has been successfully implemented in metropolitan and rural hospital settings. Conclusions Comprehensive stroke units are associated with reductions in length of stay and combined death and dependency and improved functional outcomes compared to other stroke unit models. A comprehensive stroke unit model is worth considering as the preferred model of stroke unit care in the planning and delivery of metropolitan and rural stroke services.
Aberrant Diffuse Expression of p63 in Adenocarcinoma of the Prostate on Needle Biopsy and Radical Prostatectomy: Report of 21 Cases

Aberrant diffuse expression of p63 in prostate carcinoma cells is a rare and poorly understood phenomenon. We studied 19 cases of prostate cancer with aberrant diffuse expression of p63 on needle biopsy and reviewed the subsequent radical prostatectomies in 6 cases. In 19/21 cases, 100% of the cancer nuclei stained intensely for p63, with 70% staining in the remaining 2 cases. Two additional radical prostatectomies with aberrant p63 staining with no needle biopsies available for review were also analyzed. On the hematoxylin and eosin-stained slides, 19/21 cases (90.5%) showed a distinctive morphology composed predominantly of glands, nests, and cords with atrophic cytoplasm, hyperchromatic nuclei, and visible nucleoli. Needle biopsy cases ranged from Gleason patterns 3 to 5 with tumor identified on one or more cores, ranging from a minute focus to 80% of the core. In all 8 radical prostatectomies p63 positive cancer was present, with in 2/8 cases both p63 positive cancer and usual p63 negative acinar prostate cancer. In all 8 cases, the tumors were organ confined with negative margins and there was no seminal vesicle involvement or lymph node metastasis. The presence of p63 positive atypical glands with an infiltrative pattern and perineural invasion on radical prostatectomy confirmed the needle biopsy diagnosis of carcinoma. Rarely, prostate cancer can aberrantly express diffuse p63 staining in a nonbasal cell distribution leading to the erroneous diagnosis of atrophy or atypical basal cell proliferation. The diagnosis of prostate cancer is based on the morphology and confirmed by the absence of high molecular weight cytokeratin staining and positivity for α-methylacyl-CoA racemase in the atypical glands. Pathologists need to be aware of this rare and unusual phenomenon, which is a potential pitfall in prostate cancer diagnosis.
The cadence and water temperature effect on physiological responses during water cycling

Abstract The aim of the study was to compare the maximal physiological responses during three protocols: maximal test on land cycle ergometer, maximal test on water cycling in an indoor pool at 27 °C (WC27) and at 31 °C (WC31). Moreover, the submaximal physiological responses were compared according cycling cadences and water temperatures during the water protocols. Ten young men were included and performed the protocols in separate days. Blood lactate (BL) concentration, heart rate (HR), oxygen uptake ( O2), ventilation (VE) and thermal comfort (TC) were collected during the exercise. The maximal HR and O2 showed no significant differences between the protocols: HRmax: 189±7 (Land), 188±14 (WC27), 185±9 bpm (WC31) and O2max: 4.2±0.4 (Land), 4.1±0.5 (WC27) and 4.3±0.5 l min−1 (WC31). However, the maximal BL demonstrated significant lower values during the water protocols compared to the land protocol (p=0.018). All the submaximal physiological responses showed significant differences between the cadences (60, 70, 80 and 90 rpm). The effect of water temperature was significant for TC response (p=0.001) showing higher values at 31 °C than 27 °C (TCW27: 7±1 and TCW31:9±1). In conclusion, higher physiological responses were showed by increasing the cadence by 10 rpm and the subjects were more comfortable when cycling in the lower water temperature.
Demographics, Socio-Economic Characteristics, and Risk Factor Prevalence in Patients with Non-Cardioembolic Ischaemic Stroke in Low- and Middle-Income Countries: The OPTIC Registry

Background There is a paucity of data on patients with stroke/transient ischaemic attack in low- and middle-income countries. We sought to describe the characteristics and management of patients with an ischaemic stroke and recent transient ischaemic attack or minor ischaemic strokes in low- or middle-income countries. Methods The Outcomes in Patients with TIA and Cerebrovascular disease registry is an international, prospective study. Patients ≥45 years who required secondary prevention of stroke (either following an acute transient ischaemic attack or minor ischaemic strokes (National Institutes of Health Stroke Scale <4) of <24 h duration, or recent (<6 months), stable, first-ever, non-disabling ischaemic stroke) were enrolled in 17 countries in Latin America, the Middle East, and Africa. The main measures of interest were risk factors, comorbidities, and socio-economic variables. Results Between January 2007 and December 2008, 3635 patients were enrolled in Latin America (n =1543), the Middle East (n =1041), North Africa (n = 834), and South Africa (n = 217). Of these, 63% had a stable, first-ever ischaemic stroke (median delay from symptom onset to inclusion, 25 days interquartile range, 7–77); 37% had an acute transient ischaemic attack or minor ischaemic stroke (median delay, two-days; interquartile range, 0–6). Prevalence of diabetes was 46% in the Middle East, 29% in Latin America, 35% in South Africa, and 38% in North Africa; 72% had abdominal obesity (range, 65–78%; adjusted P < 0·001); prevalence of metabolic syndrome was 78% (range, 72–84%, P < 0·001). Abnormal ankle brachial index (<0·9) was present in 22%, peripheral artery disease in 7·6%, and coronary artery disease in 13%. Overall, 24% of patients had no health insurance and 27% had a low educational level. Interpretation In this study, patients in low- and middle-income countries had a high burden of modifiable risk factors. High rates of low educational level and lack of health insurance in certain regions are potential obstacles to risk factor control. Funding The Outcomes in Patients with TIA and Cerebrovascular disease registry is supported by Sanofi-Aventis, Paris, France.