Miracle-dz/UniFAR-FTUs huggingface dataset:
The unbiased estimation of number and sizes of arbitrary particles using the disector

A three‐dimensional counting rule and its integral test system, the disector, for obtaining unbiased estimates of the number of arbitrary particles in a specimen is presented. Used in combination with ordinary and recently developed stereological methods unbiased estimates of various mean particle sizes and the variance of particle volume are obtainable on sets of two parallel sections with a known separation. The same principle allows the unbiased estimation of the distribution of individual particle volumes in sets of serial sections.
Comparison of Two Procedures for Analyzing Small Sets of Repeated Measures Data

This article compares two methods for analyzing small sets of repeated measures data under normal and non-normal heteroscedastic conditions: a mixed model approach with the Kenward-Roger correction and a multivariate extension of the modified Brown-Forsythe (BF) test. These procedures differ in their assumptions about the covariance structure of the data and in the method of estimation of the parameters defining the mean structure. Simulation results show that the BF test outperformed its competitor, in terms of Type I errors, particularly when the total sample size was small, and the data were normally distributed. Under non-normal distributions the BF test tended to err on the side of conservatism. Results also indicate that neither method was uniformly more powerful. With very few exceptions, the power differences between these two methods depended on the population covariance structure, the nature of the pairing of covariance matrices and group sizes, and the relationship between mean vectors and dispersion matrices.
Fibroblast Growth Factors and Epidermal Growth Factor Cooperate with Oocyte-Derived Members of the TGFbeta Superfamily to Regulate Spry2 mRNA Levels in Mouse Cumulus Cells1

Mouse oocytes produce members of the transforming growth factor beta (TGFbeta) superfamily, including bone morphogenetic protein 15 (BMP15) and growth differentiation factor 9 (GDF9), as well as fibroblast growth factors (FGFs). These growth factors cooperate to regulate cumulus cell function. To identify potential mechanisms involved in these interactions, the ability of fully grown oocytes to regulate expression of BMP or FGF antagonists in cumulus cells was examined. Oocytes promoted cumulus cell expression of transcripts encoding antagonists to TGFbeta superfamily members, including Grem2, Htra1, Htra3, and Nog mRNAs. In contrast, oocytes suppressed cumulus cell expression of Spry2 mRNA, which encodes a regulator of receptor tyrosine kinase signals, such as FGF and epidermal growth factor (EGF) receptor signals. The regulation of Spry2 mRNA levels in cumulus cells was studied further as a model for analysis of potential mechanisms for cooperativity of FGF/EGF signaling with oocyte-derived members of the TGFbeta superfamily. Oocytes suppressed basal and FGF-stimulated Spry2 mRNA levels in cumulus cells but promoted EGF-stimulated levels. Furthermore, recombinant TGFbeta superfamily proteins, including BMP15 and GDF9, mimicked these effects of oocytes. Elevated expression of Spry2 mRNA in cumulus and mural granulosa cells correlated with human chorionic gonadotropin-induced expression of mRNAs encoding EGF-like peptides. Therefore, oocyte-derived members of the TGFbeta superfamily suppress FGF-stimulated Spry2 mRNA levels before the luteinizing hormone surge but promote Spry2 mRNA levels stimulated by EGF receptor-mediated signals after the surge.
Low serum levels of alkaline phosphatase of bone origin: a good marker of adynamic bone disease in haemodialysis patients.

BACKGROUND Adynamic bone disease was recently described to be increasingly prevalent in the dialysis population. At present the diagnosis of this type of renal osteodystrophy can only be made by bone histomorphometry. We assessed the value of different biochemical serum markers in the diagnosis of adynamic bone disease. METHODS In 103 haemodialysis patients a bone biopsy was performed after double tetracycline labelling, and the serum levels of intact PTH, osteocalcin, and the bone isoenzyme of alkaline phosphatase were determined. Bone alkaline phosphatase was measured by an optimized agarose gel electrophoretic method, recently shown to have a high accuracy, precision and reproducibility, also in the lower range. RESULTS In 38 (37%) of the patients the diagnosis of adynamic bone disease was histologically established. Constructing receiver operator curves optimal cut-off levels for the diagnosis of adynamic bone disease were determined, being <=27 U/litre for the bone isoenzyme of alkaline phosphatase, <=14 microg/litre for osteocalcin and <=150 pg/ml for intact PTH. Concentrations of bone alkaline phosphatase or intact PTH below these cut-off levels, were shown to be the best performing tests in the detection of adynamic bone disease as indicated by a sensitivity of 78.1 and 80.6% and a specificity of 86.4 and 76.2% respectively. Applying Bayes' theorema, it was calculated that in the current haemodialysis population in which a prevalence of adynamic bone disease up to 35% has been described, the positive predictive values for the proposed cut-off values are 75% for bone alkaline phosphatase, 65% for intact PTH and 55% for osteocalcin. Moreover, in this population, levels of bone alkaline phosphatase and intact PTH below the optimal cut-off excluded hyperparathyroid bone disease. CONCLUSION In view of the relative easy and accurate methodology for bone alkaline phosphatase determination, the closer physiological link with osteoblast function and the lesser expense for its determination we suggest that this marker is a useful tool in the non-invasive diagnosis of the adynamic type of bone disease in the individual patient.
Genetic Assessment of Cortical Malformations

Abstract Malformations of cortical development comprise a clinically and etiologically heterogeneous group of distinct structural abnormalities of the cerebral cortex, commonly identified during MR imaging of patients with seizure disorders and/or developmental delay. MR imaging is crucial for further classification and together with additional clinical information and family history guiding specific genetic testing, which today is an integral part of the interdisciplinary diagnostic work-up and allows identification of an underlying genetic alteration in a significant subset of patients. Results of genetic testing may provide important prognostic information and subsequently support prospective therapeutic decisions. Furthermore, genetic forms of cortical malformations may be associated with a significantly increased recurrence risk for further siblings or other relatives and require genetic counselling of the family on individual risks and the options of prenatal or even preimplantation genetic diagnosis.
Disability and Survival of Multiple Sclerosis in Saskatoon, Saskatchewan

Background: A population-based prevalent group of 150 clinical definite patients ascertained on 1 January 1977, in Saskatoon, Saskatchewan, was followed for 30 years. Objectives: To outline the clinical characteristics, determine the levels of disability at 15, 25, 35, 40, and 45 years after onset, to estimate the survival after onset and life expectancy. Methods: Clinical records were maintained, and the cohort reviewed each decade for 30 years. The disability levels according to the Kurtzke Extended Disability Status Scale were recorded and survival times were estimated. SPSS and Kaplan-Meier methods were used for analysis. Results: On prevalence day, 1 January 1977, there were 48(32%) men and 102(68%) women, with an average age of onset of 32.2±10 years and 28.4±8.6 years. The average duration of disease was 15.7 years. On 1 January 2007, 39(26%) patients were living, 105(70%) deceased, and 6(4%) were missing The disability levels recorded in 1977 and 2007, at 15 and 45 years after onset, were mild (EDSS≤2.5), 33.3% and 8.0%; moderate (EDSS3-5.5), 17.3% and 2.7%; severe (EDSS6-7.5), 6.6% and 4.7%; maximum (EDSS8-9.5), 22.7% and 10.7%. The median survival time after onset was 33 (95% CI: 27.3-38.6) years for men and 38 (95% CI: 34.1-41.9) years for women. The median duration of life was 68.9 years for men and 69.5 years for women, and a decreased life expectancy of 7.7 and 12.8 years. Conclusions: Multiple sclerosis is a progressive neurological disorder and long-term survival is associated with moderate to severe disability and decreased life expectancy.
Absent or Shortened Nasal Bone Length and the Detection of Down Syndrome in Second-Trimester Fetuses

OBJECTIVE: To estimate the accuracy of evaluating nasal bone length, expressed as multiples of the median (MoM), for the detection of Down syndrome in second- trimester fetuses. METHODS: Expected normal median nasal bone measurements were established for an initial cohort of women receiving fetal ultrasound examinations at 15–24 weeks of gestation. Nasal bone lengths were converted to MoM with adjustment for maternal race and ethnicity using whites as the referent group. Nasal bone MoM were compared in euploid and Down syndrome fetuses. The sensitivity and specificity were evaluated in this initial cohort and in a second cohort in which all ultrasound measurements were carried out prospectively. RESULTS: For the combined data set, 10 of 21 affected pregnancies had an absence of the nasal bone (sensitivity 47.6%), but absence was noted in only 1 of 2,515 unaffected pregnancies (false-positive rate 0.04%). Using less than 0.80 MoM as a cutoff, the sensitivity was 20 of 21 (95.2%), and the false-positive rate was 185 of 2,515 (7.4%). Changing the cutoff to 0.75 MoM resulted in 18 of 21 (85.7%) sensitivity and 74 of 2,515 (2.9%) false-positive rate. Using medians derived from whites to calculate MoM for the entire population resulted in higher false-positive rates. CONCLUSION: Nasal bone length expressed as MoM seems to be an useful ultrasound marker for Down syndrome in second-trimester fetuses with a high sensitivity and a low false-positive rate. LEVEL OF EVIDENCE: III
Accuracy of the Diagnosis of GORD by Questionnaire, Physicians and a Trial of Proton Pump Inhibitor Treatment: The Diamond Study (Gut 2010;59:714-721)

Dent et al1 reported a study entitled "Accuracy of the diagnosis of GORD by questionnaire, physicians and a trial of proton pump inhibitor treatment: The Diamond Study" in the June 2010 issue of Gut. Patients with symptoms considered by their family practitioner to be of upper gastrointestinal origin were enrolled from 6 countries (n = 308). The Reflux Disease Questionnaire (RDQ) was completed and a symptom-based diagnosis was made by the family practitioner.2 Placebo esomeprazole was started after the diagnosis. Gastroenterologists made a symptom-based diagnosis and then performed endoscopy and wireless 48 hour esophageal pH recordings with monitoring of associated symptoms; the findings were used to determine the reference standard for the presence or absence of gastroesophageal reflux disease (GERD). Symptoms were recorded during treatment with 40 mg of esomeprazole for 2 weeks. The main outcome measure was RDQ scoring for the presence of GERD compared to the symptom-based diagnosis by family physicians and gastroenterologists. GERD was present in 203/308 (66%) of the patients. Only 49% of the patients with GERD reported either heartburn or regurgitation as their most troublesome symptom. The sensitivity and specificity of the symptom-based diagnosis of GERD, were 62% and 67% for the RDQ, 63% and 63% for the family practitioners, 67% and 70% for the gastroenterologists and 54% and 65% for the 2-week trial of proton pump inhibitor (PPI) treatment. The symptom-based diagnosis of GERD by the RDQ, family practitioners and gastroenterologists had moderate and similar accuracy. Symptom response to a 2-week course of 40 mg of esopmeprazole did not increase the diagnostic accuracy.
Different sensitivity of recombinant Aspergillus niger phytase (r-PhyA) and Escherichia coli pH 2.5 acid phosphatase (r-AppA) to trypsin and pepsin in vitro.

Proteolysis of two purified recombinant enzymes, namely, the Aspergillus niger phytase (r-PhyA) and the Escherichia coli pH 2.5 acid phosphatase (r-AppA), by pepsin and trypsin was investigated in this study. After r-PhyA and r-AppA were incubated with different concentrations of pepsin or trypsin, their residual phytase activities and amounts of inorganic phosphorus released from soybean meal were determined. Both enzymes retained more than 85% of their original activities at the trypsin/phytase ratios (w/w) 0.001 and 0. 005, while r-AppA and r-PhyA lost 60 and 20% of the original activity at the ratio of 0.01 or 0.025, respectively. In contrast, there was a 30% increase in phytase activity after r-AppA was incubated with pepsin at the ratios of 0.005 or 0.01. Meanwhile, r-PhyA lost 58 to 77% of its original activity under the same conditions. Trypsin and pepsin affected the hydrolysis of phytate phosphorus from soybean meal by r-AppA and r-PhyA in a similar way to their residual phytase activities. All of these in vitro proteolyses were confirmed by SDS-PAGE analysis. Our results demonstrate different sensitivities of r-AppA and r-PhyA to trypsin and pepsin, suggesting active trypsin resistant r-PhyA and pepsin resistant r-AppA polypeptides.
Attentional skills 10 years post-paediatric traumatic brain injury (TBI)

Objective: To date no study has reported findings regarding attentional deficits following pre-school paediatric traumatic brain injury (TBI), as long as 10 years post-injury. It was predicted that more severe TBI would be associated with generalized deficits at 10 years post-TBI, particularly for skills not mastered at time of injury. Research design: The sample comprised 40 prospectively-recruited children (42% of the original sample) who had sustained a mild, moderate or severe traumatic brain injury (TBI) between the ages of 1–7 years and 19 non-injured control participants. Children were assessed 10 years post-TBI, with a focus on measures of attentional ability. Outcomes/results: While attentional deficits were not evident across all components of attentional ability, both early- and later-established attention skills were compromised, particularly following severe TBI. Environmental predictors were generally not successful predictors of attentional outcome at 10 years post-TBI. Age at injury and acute IQ were identified as contributing to attention at 10 years. Conclusions/implications: The present study shows that attentional deficits do occur and persist to 10 years following serious TBI. Clinicians may be able to screen for such deficits and so intervene in order to prevent or lessen the consequences of such difficulties.
Studies with a Growth Hormone Antagonist and Dual-fluorescent Confocal Microscopy Demonstrate that the Full-length Human Growth Hormone Receptor, but Not the Truncated Isoform, Is Very Rapidly Internalized Independent of Jak2-Stat5 Signaling*

We have investigated trafficking of two negative regulators of growth hormone receptor (GHR) signaling: a human, truncated receptor, GHR1–279, and a GH antagonist, B2036. Fluorescent-labeled growth hormone (GH) was rapidly internalized by the full-length GHR, with >80% of the hormone internalized within 5 min of exposure to GH. In contrast, <5% of labeled GH was internalized by cells expressing truncated GHR1–279. Using another truncated receptor, GHR1–317 fused to enhanced green fluorescent protein (EGFP), we have exploited fluorescence energy transfer to monitor the trafficking of ligand-receptor complexes. The data confirmed that internalization of this truncated receptor is very inefficient. It was possible to visualize the truncated GHR1–317-EGFP packaged in the endoplasmic reticulum, its rapid movement in membrane bound vesicles to the Golgi apparatus, and subsequent transport to the cell membrane. The GH antagonist, B2036, blocked Jak2-Stat5-mediated GHR signaling but was internalized with a similar time course to native GH. The results: 1) demonstrate the rapid internalization of GH when studied under physiological conditions; 2) confirm the hypothesis that internalization of cytoplasmic domain truncated human GHRs is very inefficient, which explains their dominant negative action; and 3) show that the antagonist action of B2036 is independent of receptor internalization.
Structural and Functional Characterization of Disulfide Isoforms of the Human IgG2 Subclass*

In the accompanying report ( Wypych, J., Li, M., Guo, A., Zhang, Z., Martinez, T., Allen, M. J., Fodor, S., Kelner, D. N., Flynn, G. C., Liu, Y. D., Bondarenko, P. V., Ricci, M. S., Dillon, T. M., and Balland, A. (2008) J. Biol. Chem. 283, 16194-16205 ), we have identified that the human IgG2 subclass exists as an ensemble of distinct isoforms, designated IgG2-A, -B, and -A/B, which differ by the disulfide connectivity at the hinge region. In this report, we studied the structural and functional properties of the IgG2 disulfide isoforms and compared them to IgG1. Human monoclonal IgG1 and IgG2 antibodies were designed with identical antigen binding regions, specific to interleukin-1 cell surface receptor type 1. In vitro biological activity measurements showed an increased activity of the IgG1 relative to the IgG2 in blocking interleukin-1β ligand from binding to the receptor, suggesting that some of the IgG2 isoforms had lower activity. Under reduction-oxidation conditions, the IgG2 disulfide isoforms converted to IgG2-A when 1 m guanidine was used, whereas IgG2-B was enriched in the absence of guanidine. The relative potency of the antibodies in cell-based assays was: IgG1 > IgG2-A > IgG2 ≫ IgG2-B. This difference correlated with an increased hydrodynamic radius of IgG2-A relative to IgG2-B, as shown by biophysical characterization. The enrichment of disulfide isoforms and activity studies were extended to additional IgG2 monoclonal antibodies with various antigen targets. All IgG2 antibodies displayed the same disulfide conversion, but only a subset showed activity differences between IgG2-A and IgG2-B. Additionally, the distribution of isoforms was influenced by the light chain type, with IgG2λ composed mostly of IgG2-A. Based on crystal structure analysis, we propose that IgG2 disulfide exchange is caused by the close proximity of several cysteine residues at the hinge and the reactivity of tandem cysteines within the hinge. Furthermore, the IgG2 isoforms were shown to interconvert in whole blood or a “blood-like” environment, thereby suggesting that the in vivo activity of human IgG2 may be dependent on the distribution of isoforms.
Interrelationship between chromosome 8 aneuploidy, C-MYC amplification and increased expression in individuals from northern Brazil with gastric adenocarcinoma.

AIM To investigate chromosome 8 numerical aberrations, C-MYC oncogene alterations and its expression in gastric cancer and to correlate these findings with histopathological characteristics of gastric tumors. METHODS Specimens were collected surgically from seven patients with gastric adenocarcinomas. Immunostaining for C-MYC and dual-color fluorescence in situ hybridization (FISH) for C-MYC gene and chromosome 8 centromere were performed. RESULTS All the cases showed chromosome 8 aneuploidy and C-MYC amplification, in both the diffuse and intestinal histopathological types of Lauren. No significant difference (P < 0.05) was observed between the level of chromosome 8 ploidy and the site, stage or histological type of the adenocarcinomas. C-MYC high amplification, like homogeneously stained regions (HSRs) and double minutes (DMs), was observed only in the intestinal-type. Structural rearrangement of C-MYC, like translocation, was observed only in the diffuse type. Regarding C-MYC gene, a significant difference (P < 0.05) was observed between the two histological types. The C-MYC protein was expressed in all the studied cases. In the intestinal-type the C-MYC immunoreactivity was localized only in the nucleus and in the diffuse type in the nucleus and cytoplasm. CONCLUSION Distinct patterns of alterations between intestinal and diffuse types of gastric tumors support the hypothesis that these types follow different genetic pathways.
Risk Prediction of Cervical Cancer and Precancers by Type-Specific Human Papillomavirus: Evidence from a Population-Based Cohort Study in China

Risk stratification of human papillomavirus (HPV)-positive women is needed to avoid excessive colposcopy and overtreatment in cervical cancer screening. We aimed to evaluate the predictive value of type-specific HPV in detecting cervical cancer and precancers in a Chinese population–based cohort and provide evidence of HPV genotyping to triage HPV-positive women. We typed all Hybrid Capture 2–positive cytologic samples of 1,742 women in Shanxi Province Cervical Cancer Screening Study cohort. Cumulative risks of cervical intraepithelial neoplasia grade 2 or worse (CIN2+) among HPV-positive women and cumulative detection rates of CIN2+ among general women by type-specific HPV were estimated during the course of 10-year follow-up. HPV 16 and HPV 52 were most prevalent types among the screening population. Ten-year cumulative risk of CIN2+ was 47.5% [95% confidence interval (CI), 31.6–62.3] for HPV 16–positive women and 46.3% (95% CI, 15.3–75.4) for HPV 31–positive women. Ten-year cumulative risks of CIN2+ among HPV 58, 39, 33, 18, and 52 positive women ranged from 34.3% to 12.0% in a decreasing order. CIN2+ risks were found to be positively associated with infection times of the same genotypes of HPV 16, 31, 33, and 58 (all Ptrend < 0.001). Cumulative detection rates of CIN2+ within 10 years were predominantly contributed by HPV 16, 31, and 58. Our results support the risk-based management of HPV-positive women using HPV genotyping and also indicate the significance of including HPV 31 and 58 apart from commonly acknowledged HPV 16 and HPV 18 in achieving better risk stratification. Cancer Prev Res; 10(12); 745–51. ©2017 AACR.
Risk Factors for Injury in Child and Adolescent Sport: A Systematic Review of the Literature

ObjectiveThe objective of this systematic review of the literature is to identify risk factors and potential prevention strategies that may modify risk factors for injury in child and adolescent sport. Data SourcesSeven electronic databases were searched to identify potentially relevant articles. A combination of Medical Subject Headings and text words were used (athletic injuries, sports injury, risk factors, adolescent, and child). Study SelectionThis review is based on epidemiological evidence in which the data are original, an exposure and outcome are objectively measured, and an attempt is made to create a comparison group. Forty-five studies were selected for this review. Data ExtractionThe data summarized include study design, study population, exposures, outcomes, and results. Estimates of odds ratios or relative risks were calculated where study data were adequate to do so. The quality of evidence is based on internal validity, external validity, and causal association. Data SynthesisThere is some evidence that potentially modifiable risk factors including poor endurance, lack of preseason training, and some psychosocial factors are important risk factors for injury in child and adolescent sport. Concerns with study design, internal validity, and generalizability persist. The evidence is consistent, however, with more convincing evidence from adult population studies. The evidence for nonmodifiable risk factors for injury in adolescent sport (ie, age, sex, previous injury) is consistent among studies. ConclusionsSport participation and injury rates in child and adolescent sport are high. This review will assist in targeting the relevant groups and designing future research examining risk factors and prevention strategies in child and adolescent sport. Future clinical trials addressing modifiable risk factors to reduce the incidence of sports injury in this population are necessary.