Miracle-dz/UniFAR-FTUs huggingface dataset:
Early differentiation between good and poor response to growth hormone therapy in short children born small for gestational age (SGA) to improve the outcome of poor responders

Abstract Objective: The aim of this study was to examine height-gain response in relation to predicted good or poor response during first-year low or high growth hormone (GH) dose in short prepubertal children born small for gestational age. Patients and methods: The OPTIMA (Optimization of GH Treatment in Short Children Born Small for Gestational Age Based on a Growth Prediction Model) randomised study evaluated 12-month height standard deviation score (SDS) changes in patients receiving GH dose: fixed high (FH; 0.067 mg/kg/day) or 0.035 mg/kg/day individually adjusted (IA) after 3 months according to the Cologne early growth prediction. Results: Predicted 12-month height SDS gain was <0.75 for 21/89 FH-dose patients, considered poor responders; 11/21 reached a 12-month height SDS gain of ≥0.75. In IA-dose poor responders, increasing GH dose at 3 months maintained mean height velocity (HV), with 73.7% reaching a 12-month height SDS gain of ≥0.75 vs. 73.8% in IA-dose good responders who continued on low GH dose, where mean HV decreased after the initial 3-month period. Conclusion: GH dose increase at 3 months in patients with predicted poor response maintained catch-up growth. Even when on FH dose, some patients did not achieve a good response.
Prevalence of violent victimisation in severe mental illness

Background Since de-institutionalisation, much has been written about the risk posed to the community by those with severe mental illness. However, violent victimisation of people with mental illnesses has received little attention. Aims To establish the 1-year prevalence of violent victimisation in community-dwelling patients with psychosis and to identify the socio-demographic and clinical correlates of violent victimisation. Method A total of 691 subjects with established psychotic disorders were interviewed. The past-year prevalence of violent victimisation was estimated and compared with general population figures. Those who reported being violently victimised were compared with those who did not on a range of social and clinical characteristics. Results Sixteen per cent of patients reported being violently victimised. Victims of violence were significantly more likely to report severe psychopathological symptoms, homelessness, substance misuse and previous violent behaviour and were more likely to have a comorbid personality disorder. Conclusions Those with psychosis are at considerable risk of violent victimisation in the community. Victimisation experience should be recorded in the standard psychiatric interview.
Reference ranges for plasma cystatin C and creatinine measurements in premature infants, neonates, and older children

AIM To establish a reference range in the paediatric population for the new glomerular filtration rate (GFR) marker, cystatin C, and to compare it with that of creatinine. METHODS Cystatin C and creatinine were measured by particle enhanced nephelometric immunoassay (PENIA) and fixed interval Jaffé methods, respectively, in 291 children aged 1 day to 17 years, including 30 premature infants with gestational ages ranging from 24 to 36 weeks. RESULTS In the premature infants, concentrations of both cystatin C and creatinine were significantly raised compared with term infants, with cystatin C concentrations being between 1.10 and 2.06 mg/litre and creatinine between 32 and 135 μmol/litre. In premature infants, there was no significant relation between gestational age and cystatin C or creatinine concentration. Creatinine concentrations fell to a nadir at 4 months of age, rising gradually to adult values by about 15–17 years of age, in contrast to cystatin C, which fell to a mean concentration of 0.80 mg/litre by the 1st year of life, and remained constant throughout adulthood up to the age of 50 years. Neither analyte showed any influence of sex. CONCLUSION The measurement of cystatin C, rather than creatinine, is more practical for monitoring GFR changes in the paediatric population. Key messages Cystatin C is a better marker than creatinine of glomerular filtration rate (GFR) in preterm infants A single reference range for plasma cystatin C can be used, regardless of sex, from 1 year of age Cystatin C offers a more specific and practical measure for monitoring GFR in the paediatric population than does creatinine
Infusion of α-galactosidase A reduces tissue globotriaosylceramide storage in patients with Fabry disease

Fabry disease is a lysosomal storage disorder caused by a deficiency of the lysosomal enzyme α-galactosidase A (α-gal A). This enzymatic defect results in the accumulation of the glycosphingolipid globotriaosylceramide (Gb3; also referred to as ceramidetrihexoside) throughout the body. To investigate the effects of purified α-gal A, 10 patients with Fabry disease received a single i.v. infusion of one of five escalating dose levels of the enzyme. The objectives of this study were: (i) to evaluate the safety of administered α-gal A, (ii) to assess the pharmacokinetics of i.v. -administered α-gal A in plasma and liver, and (iii) to determine the effect of this replacement enzyme on hepatic, urine sediment and plasma concentrations of Gb3. α-Gal A infusions were well tolerated in all patients. Immunohistochemical staining of liver tissue approximately 2 days after enzyme infusion identified α-gal A in several cell types, including sinusoidal endothelial cells, Kupffer cells, and hepatocytes, suggesting diffuse uptake via the mannose 6-phosphate receptor. The tissue half-life in the liver was greater than 24 hr. After the single dose of α-gal A, nine of the 10 patients had significantly reduced Gb3 levels both in the liver and shed renal tubular epithelial cells in the urine sediment. These data demonstrate that single infusions of α-gal A prepared from transfected human fibroblasts are both safe and biochemically active in patients with Fabry disease. The degree of substrate reduction seen in the study is potentially clinically significant in view of the fact that Gb3 burden in Fabry patients increases gradually over decades. Taken together, these results suggest that enzyme replacement is likely to be an effective therapy for patients with this metabolic disorder.
Protein Kinase Dyrk1 Activates cAMP Response Element-binding Protein during Neuronal Differentiation in Hippocampal Progenitor Cells*

Dyrk is a dual specific protein kinase thought to be involved in normal embryo neurogenesis and brain development. Defects/imperfections in this kinase have been suggested to play an important role in the mental retardation of patients with Down's syndrome. The transcriptional factor cAMP response element-binding protein (CREB) has been implicated in the formation of many types of synaptic plasticity, such as learning and memory. In the present study we show that Dyrk1 activity is markedly induced during the differentiation of immortalized hippocampal progenitor (H19-7) cells. The addition of a neurogenic factor, basic fibroblast growth factor, to the H19-7 cells results in an increased specific binding of Dyrk1 to active CREB. In addition, Dyrk1 directly phosphorylates CREB, leading to the stimulation of subsequent CRE-mediated gene transcription during the neuronal differentiation in H19-7 cells. Blockade of Dyrk1 activation significantly inhibits the neurite outgrowth as well as CREB phosphorylation induced by basic fibroblast growth factor. These findings suggest that Dyrk1 activation and subsequent CREB phosphorylation is important in the neuronal differentiation of central nervous system hippocampal cells.
Parotid MALT lymphoma in an HIV positive child

Sir: We found the study of the distinction of follicular non-Hodgkin’s lymphomas and follicular hyperplasia by Ashton-Key et al. very interesting. However, we were surprised by the authors’ contention that all of the germinal centre cells expressing bcl-2 protein were T lymphocytes. The precise role of bcl-2, and the stages at which it acts, within the normal germinal centre reaction remain unresolved. However, the in vitro evidence that many of the signals mediating germinal centre B-cell survival induce bcl-2 protein expression suggests that bcl-2 protein would be identifiable in centrocytes surviving the negative and positive selection processes in the apical light zones of germinal centres. In our routinely stained lymphoid tissues, we believe that at least some bcl-2 positive germinal centre cells show typical centrocyte morphology. More convincingly, however, double-labelling immunohistochemistry has shown that the bcl-2 positive germinal centre cells co-express CD22 but not CD3.
Constitutive negative regulation in the processing of the anti-Müllerian hormone receptor II

ABSTRACT The levels and intracellular localization of wild-type transforming growth factor &bgr; superfamily (TGF&bgr;-SF) receptors are tightly regulated by endocytic trafficking, shedding and degradation. In contrast, a main regulatory mechanism of mutation-bearing receptors involves their intracellular retention. Anti-Müllerian hormone receptor II (AMHRII, also known as AMHR2) is the type-II receptor for anti-Müllerian hormone (AMH), a TGF&bgr;-SF ligand that mediates Müllerian duct regression in males. Here, we studied AMHRII processing and identified novel mechanisms of its constitutive negative regulation. Immunoblot analysis revealed that a significant portion of AMHRII was missing most of its extracellular domain (ECD) and, although glycosylated, was unfolded and retained in the endoplasmic reticulum. Exogenous expression of AMHRII, but not of type-II TGF-&bgr; receptor (T&bgr;RII, also known as TGFR2), resulted in its disulfide-bond-mediated homo-oligomerization and intracellular retention, and in a decrease in its AMH-binding capacity. At the plasma membrane, AMHRII differed from T&bgr;RII, forming high levels of non-covalent homomeric complexes, which exhibited a clustered distribution and restricted lateral mobility. This study identifies novel mechanisms of negative regulation of a type-II TGF&bgr;-SF receptor through cleavage, intracellular retention and/or promiscuous disulfide-bond mediated homo-oligomerization.
Is subclinical hypothyroidism a cardiovascular risk factor in the elderly?

CONTEXT The negative impact of subclinical hypothyroidism (sHT) on cardiovascular risk, widely recognized in young adults (aged <55-60 y), is still debated in the elderly (>65 y), especially in the oldest olds (>80 y). EVIDENCE ACQUISITION We searched Medline for reports published with the following search terms: "hypothyroidism," "subclinical hypothyroidism," "ageing," "elderly," "L-thyroxin," "thyroid," "guidelines," "treatment," "quality of life," "cardiovascular risk," "heart failure," "coronary heart disease" (CHD), "atherosclerosis," and "endothelial dysfunction. " We limited our search to reports in English published after 1980, although we incorporated some reports published before 1980. We supplemented the search with records from personal files, textbooks, and relevant articles. Analyzed parameters included the epidemiology of thyroid failure, the effect of thyroid hormone on the aging process, cardiovascular function, and CHD risk factors. We also included the potential benefits of L-T4 therapy on the quality of life, cardiovascular events, and survival. EVIDENCE SYNTHESIS TSH levels increase with age, even in older people without thyroid disease. Most longitudinal studies show an increased risk for CHD events and mortality in sHT participants. This increase is less evident in the elderly, mainly in cases of serum TSH values above 10 mIU/L. Lower mortality rate in a cohort of the oldest olds (>85 y) has been reported. CONCLUSIONS sHT in older people should be not regarded as a unique condition, and moderately old patients (aged <70-75 y) could be considered clinically similar to the adult population, albeit with a higher optimal TSH target value. Conversely, the oldest old subjects should be carefully followed with a wait-and-see strategy, generally avoiding hormonal treatment. The decision to treat elderly people is still an unresolved clinical challenge--first, due to a lack of appropriately powered randomized controlled trials of L-T4 in sHT patients, examining cardiovascular hard endpoints in various classes of age; and second, because of the negative effects of possible overtreatment.
p38 and OGT Sequestration into Viral Inclusion Bodies in Cells Infected with Human Respiratory Syncytial Virus Suppresses MK2 Activities and Stress Granule Assembly

ABSTRACT Respiratory syncytial virus (RSV) forms cytoplasmic inclusion bodies (IBs) that are thought to be sites of nucleocapsid accumulation and viral RNA synthesis. The present study found that IBs also were the sites of major sequestration of two proteins involved in cellular signaling pathways. These are phosphorylated p38 mitogen-activated protein kinase (MAPK) (p38-P), a key regulator of cellular inflammatory and stress responses, and O-linked N-acetylglucosamine (OGN) transferase (OGT), an enzyme that catalyzes the posttranslational addition of OGN to protein targets to regulate cellular processes, including signal transduction, transcription, translation, and the stress response. The virus-induced sequestration of p38-P in IBs resulted in a substantial reduction in the accumulation of a downstream signaling substrate, MAPK-activated protein kinase 2 (MK2). Sequestration of OGT in IBs was associated with suppression of stress granule (SG) formation. Thus, while the RSV IBs are thought to play an essential role in viral replication, the present results show that they also play a role in suppressing the cellular response to viral infection. The sequestration of p38-P and OGT in IBs appeared to be reversible: oxidative stress resulting from arsenite treatment transformed large IBs into a scattering of smaller bodies, suggestive of partial disassembly, and this was associated with MK2 phosphorylation and OGN addition. Unexpectedly, the RSV M2-1 protein was found to localize in SGs that formed during oxidative stress. This protein was previously shown to be a viral transcription elongation factor, and the present findings provide the first evidence of possible involvement in SG activities during RSV infection.
Subjective Well-Being in University Students

The subjective well-being concerns peoples’ self-reported assessment of their own wellbeing, namely both health and quality of life (1, 2). It is an issue of concern for university students (3, 4). The aim of the current study was to examine the level of subjective wellbeing among students in maritime business administration departments fol-lowed in university. We have performed this descriptive study in Kocaeli University in Kocaeli, Turkey, during Oc-tober 2013. The study was conducted by a sample of convenience students following in maritime business administration departments. Participants volunteered to take part in the study, who were over 18 years of age, and being a first-, second-, third- or fourth-year student Data were gathered using Personal Information Form and The BBC subjective well-being (BBC-SWB) scale (2). Partic-ipants’ consent was obtained to use their answers for the purpose of this study. The BBC-SWB scales have been used to identify populations' the general wellbeing. Respondents were required to select their answer from one of five options that best describes their experience. One item, asking about anxiety and depression, was reversed scored. Higher scores reflect a higher degree of general wellbeing. Cronbach’s alpha coefficients calculated using the whole sample (n = 178) revealed high levels of internal consistency for the total 24-item scale (Cronbach’s alpha = .84, 24 items). Statistical analysis was performed using the SPSS (SPSS for Windows, version 16.0). Mean age of the study participants was 20.52 ± 6.0 years (range: 18-24 years), 63.5% (n=113) of the students were man. %97.8 (n=174) of them was not married. The mean score was 3.27 ± 0.54; ranging from 2.44±1.08 to 4.19±0.84. Mean scores were psy-chological well-being 3.34 ± 0.53, physical health and well-being 3.13 ± 0.57, relationships 3.59 ± 0.70. The mean item score for the BBC-SWB was 3.27 ± 0.54
Stage at breast cancer diagnosis and distance from diagnostic hospital in a periurban setting: A South African public hospital case series of over 1,000 women

Advanced stage at diagnosis contributes to low breast cancer survival rates in sub‐Saharan Africa. Living far from health services is known to delay presentation, but the effect of residential distance to hospital, the radius at which this effect sets in and the women most affected have not been quantified. In a periurban South African setting, we examined the effect of a geographic information system (GIS)‐measured straight‐line distance, from a patient's residence to diagnostic hospital, on stage at diagnosis in 1,071 public‐sector breast cancer patients diagnosed during 2006–2012. Generalized linear models were used to estimate risk ratios for late stage (stage III/IV vs. stage I/II) associated with distance, adjusting for year of diagnosis, age, race and socioeconomic indicators. Mean age of patients was 55 years, 90% were black African and diagnoses were at stages I (5%), II (41%), III (46%) and IV (8%). Sixty‐two percent of patients with distances >20 km (n = 338) had a late stage at diagnosis compared to 50% with distances <20 km (n = 713, p = 0.02). Risk of late stage at diagnosis was 1.25‐fold higher (95% CI: 1.09, 1.42) per 30 km. Effects were pronounced in an underrepresented group of patients over age 70. This positive stage–distance association held to 40 km, and plateaued or slightly reversed in patients (9%) living beyond this distance. Studies of woman and the societal and healthcare‐level influences on these delays and on the late stage at diagnosis distribution are needed to inform interventions to improve diagnostic stage and breast cancer survival in this and similar settings.
Hypoxia reduces the output of matrix metalloproteinase‐9 (MMP‐9) in monocytes by inhibiting its secretion and elevating membranal association

Cellular hypoxia, characterizing tumors, ischemia, and inflammation induce recruitment of monocytes/macrophages, immobilize them at the hypoxic site, and alter their function. To migrate across the extracellular matrix and as part of their inflammatory functions, monocytes and macrophages secrete proteases, including matrix metalloproteinase‐9 (MMP‐9), whose expression is induced by proinflammatory cytokines [e.g., tumor necrosis factor α (TNF‐α)]. We show that hypoxia (<0.3% O2 for 48 h) reduced the output of TNF‐α‐induced proMMP‐9 by threefold (P<0.01) in the U937 monocytic cell line and in primary human monocytes. TNF‐α induced MMP‐9 transcription by threefold, but no significant difference was observed in MMP‐9 mRNA steady‐state between normoxia and hypoxia, which inhibited the trafficking of proMMP‐9 via secretory vesicles and increased the intracellular accumulation of proMMP‐9 in the cells by 47% and 62% compared with normoxia (P<0.05), as evaluated by zymography of cellular extracts and confocal microscopy, respectively. Secretion of proMMP‐9 was reduced by the addition of cytochalazin B or nocodazole, which inhibits the polymerization of actin and tubulin fibers, or by the addition of the Rho kinase inhibitor Y27632, suggesting the involvement of the cytoskeleton and the Rho GTPases in the process of enzyme secretion. Furthermore, attachment of proMMP‐9 to the cell membrane increased after hypoxia via its interactions with surface molecules such as CD44. In addition, the reduced migration of monocytes in hypoxia was shown to be mediated, at least partially, by secreted MMP‐9. Thus, hypoxia post‐translationally reduced the secreted amounts of proMMP‐9 by using two mutually nonexclusive mechanisms: mostly, inhibition of cellular trafficking and to a lesser extent, attachment to the membrane.
Referential Choice: Predictability and Its Limits

We report a study of referential choice in discourse production, understood as the choice between various types of referential devices, such as pronouns and full noun phrases. Our goal is to predict referential choice, and to explore to what extent such prediction is possible. Our approach to referential choice includes a cognitively informed theoretical component, corpus analysis, machine learning methods and experimentation with human participants. Machine learning algorithms make use of 25 factors, including referent’s properties (such as animacy and protagonism), the distance between a referential expression and its antecedent, the antecedent’s syntactic role, and so on. Having found the predictions of our algorithm to coincide with the original almost 90% of the time, we hypothesized that fully accurate prediction is not possible because, in many situations, more than one referential option is available. This hypothesis was supported by an experimental study, in which participants answered questions about either the original text in the corpus, or about a text modified in accordance with the algorithm’s prediction. Proportions of correct answers to these questions, as well as participants’ rating of the questions’ difficulty, suggested that divergences between the algorithm’s prediction and the original referential device in the corpus occur overwhelmingly in situations where the referential choice is not categorical.
Routing protocols for efficient communication in wireless ad-hoc networks

In this paper we demonstrate the significant impact of the user mobility rates on the performance on two different approaches for designing routing protocols for ad-hoc mobile networks: (a) the route creation and maintenance approach and (b) the "support" approach, that forces few hosts to move acting as "helpers" for message delivery. We study a set of representative protocols for each approach, i.e. DSR and ZRP for the first approach and RUNNERS for the second. We have implemented the three protocols and performed a large scale and detailed simulation study of their performance. Our findings are: (i) DSR achieves low message delivery rates but manages to deliver messages very fast; (ii) ZRP behaves well in networks of low mobility rate, while its performance drops for networks of highly mobile users; (iii) RUNNERS seem to tolerate well (and in fact benefit from) high mobility rates. Based on our investigation, we design and implement two new protocols that result from the synthesis of the investigated routing approaches. We conducted an extensive, comparative simulation study of their performance. The new protocols behave well both in networks of diverse mobility motion rates, and in some cases they even outperform the original ones by achieving lower message delivery delays
Targeting the efficacy of a dendrimer-based nanotherapeutic in heterogeneous xenograft tumors in vivo

Our earlier studies have shown the in vitro and in vivo targeting of a generation 5 (G5) dendrimer-based multifunctional conjugate that contained folic acid (FA) as the targeting agent and methotrexate (MTX) as the chemotherapeutic drug. To clinically apply the synthesized G5-FA-MTX nanotherapeutic, it is important that the anticancer conjugate elicits cytotoxicity specifically and consistently. Toward this objective, we evaluated the large-scale synthesis of a G5-FA-MTX conjugate (Lot # 123–34) for its cytotoxic potential and specificity in vitro and in vivo. The cytotoxicity and specificity were tested by using a coculture assay in which FA receptor-expressing and nonexpressing cells (KB and SK-BR-3 cells, respectively) were cultured together and preferential killing was examined. The in-vitro data were compared with the in-vivo data obtained from a heterogeneous xenograft tumor model. The animal model of the artificial heterogeneous xenograft tumor showed that the nanotherapeutic was preferentially cytotoxic to KB cells.