Miracle-dz/UniFAR-FTUs huggingface dataset:
Deletion of the mouse RegIIIβ (Reg2) gene disrupts ciliary neurotrophic factor signaling and delays myelination of mouse cranial motor neurons

A large number of cytokines and growth factors support the development and subsequent maintenance of postnatal motor neurons. RegIIIβ, also known as Reg2 in rat and HIP/PAP1 in humans, is a member of a family of growth factors found in many areas of the body and previously shown to play an important role in both the development and regeneration of subsets of motor neurons. It has been suggested that RegIIIβ expressed by motor neurons is both an obligatory intermediate in the downstream signaling of the leukemia inhibitory factor/ciliary neurotrophic factor (CNTF) family of cytokines, maintaining the integrity of motor neurons during development, as well as a powerful influence on Schwann cell growth during regeneration of the peripheral nerve. Here we report that in mice with a deletion of the RegIIIβ gene, motor neuron survival was unaffected up to 28 weeks after birth. However, there was no CNTF-mediated rescue of neonatal facial motor neurons after axotomy in KO animals when compared with wild-type. In mice, RegIIIβ positive motor neurons are concentrated in cranial motor nuclei that are involved in the patterning of swallowing and suckling. We found that suckling was impaired in RegIIIβ KO mice and correlated this with a significant delay in myelination of the hypoglossal nerve. In summary, we propose that RegIIIβ has an important role to play in the developmental fine-tuning of neonatal motor behaviors mediating the response to peripherally derived cytokines and growth factors and regulating the myelination of motor axons.
Review article: monitoring for drug side-effects in inflammatory bowel disease.

The side-effects suitable for monitoring in patients with inflammatory bowel disease being treated with the four main groups of drugs (5-aminosalicylic acid preparations, azathioprine and 6-mercaptopurine, methotrexate, and corticosteroids) are reviewed. On the basis of the reported frequency, severity and timing of side-effects, a practical scheme of monitoring is recommended. This includes a baseline measurement of full blood count, creatinine and liver function tests in all patients. In the absence of worrying symptoms, we recommend the following: (i) no monitoring for sulfasalazine; (ii) for other 5-aminosalicylic acid preparations, the measurement of creatinine at 6 and 12 months and then annually; (iii) for azathioprine/6-mercaptopurine, thiopurine methyltransferase genotype/phenotype determination has no role in treatment monitoring, but a full blood count at 2 weeks, 1 month, 3 months and then every 3 months should be performed; (iv) for methotrexate, a full blood count and liver function tests should be performed every 3 months; (v) for steroids, dual energy X-ray absorptiometry bone scanning should be performed at the start of therapy, every year in which steroids are used if the T score is < 0, and every 3-5 years if the T score is > 0.
Regulation of Mammalian STE20-like Kinase 2 (MST2) by Protein Phosphorylation/Dephosphorylation and Proteolysis*

Mammalian STE20-like kinase 2 (MST2), a member of the STE20-like kinase family, has been shown in previous studies to undergo proteolytic activation by caspase-3 during cell apoptosis. A few studies have also implicated protein phosphorylation reactions in MST2 regulation. In this study, we examined the mechanism of MST2 regulation with an emphasis on the relationship between caspase-3 cleavage and protein phosphorylation. Both the full-length MST2 and the caspase-3-truncated form of MST2 overexpressed in 293T cells exist in a phosphorylated state. On the other hand, the endogenous full-length MST2 from rat thymus or from proliferating cells is mainly unphosphorylated whereas the caspase-3-truncated endogenous MST2 from apoptotic cells is highly phosphorylated. Cell transfection studies using mutant MST2 constructs indicate that MST2 depends on the autophosphorylation of a unique threonine residue, Thr180, for kinase activity. The autophosphorylation reaction shows strong dependence on MST2 concentration suggesting that it is an intermolecular reaction. While both the full-length MST2 and the caspase-3-truncated form of MST2 undergo autophosphorylation, the two forms of the phosphorylated MST2 display marked difference in susceptibility to protein phosphatases. The full-length phospho-MST2 is rapidly dephosphorylated by protein phosphatase 1 or protein phosphatase 2A whereas the truncated MST2 is remarkably resistant to the dephosphorylation. Based on the present results, a novel molecular mechanism for MST2 regulation in apoptotic cells is postulated. In normal cells, because of the low concentration and the ready reversal of the autophosphorylation by protein phosphatases, MST2 is present mainly in the unphosphorylated and inactive state. During cell apoptosis, MST2 is cleaved by caspase-3 and undergoes irreversible autophosphorylation, thus resulting in the accumulation of active MST2.
Transient hypoxia/hypoglycemia upregulates endothelin B receptors in cultured rat astrocytes

Endothelins are potent vasoactive peptides that bind to their specific receptors, playing an important role in the CNS under physiological and pathophysiological conditions. Astrocytes, which have been shown to express these receptors, also have a considerable role to play under physiological and pathophysiological conditions, particularly those involved in delayed neuronal death. We carried out in vitro receptor autoradiographic binding experiments using specific ligands for endothelin receptors on cultured rat astrocytes. On astrocytes, the specific binding sites for 125I‐PD151242 (a selective endothelin A receptor antagonist) and 125I‐IRL 1620 (a selective endothelin B receptor agonist) were detected. We also characterized the qualitative and quantitative changes of endothelin receptors 24 h after subjecting cultured rat astrocytes to a transient 4‐h hypoxia/hypoglycemia insult, used as a model of delayed neuronal death. After transient hypoxia/hypoglycemia, the number of endothelin B receptors increased significantly on cultured astrocytes, but this did not occur among the endothelin A receptors. These findings suggest that the astrocytic effects associated with endothelin in delayed neuronal death include gliosis or the repair process or both, manifested primarily by an increase in the number of endothelin B receptors. This rise does not require interaction with other types of CNS cells. Endothelin A receptors might have a role taking their number into consideration on rat astrocytes under both physiological and pathophysiological conditions. GLIA 31:91–94, 2000. © 2000 Wiley‐Liss, Inc.
Calcification in retinoblastoma: histopathologic findings and statistical analysis of 302 cases

Aim To evaluate the histopathologic factors statistically associated with the presence of calcification in eyes with retinoblastoma. Methods Retrospective, consecutive and observational case series. Three hundred and two enucleated eyes with retinoblastoma examined between the years 1960 and 2008. Five representative histopathologic slides of the pupil–optic nerve section and three cross optic nerve sections were retrospectively reviewed. The presence and degree of calcification as well as other histopathologic features were evaluated. Demographic data including age, gender and country of origin of the case were also reviewed. Univariate and multivariate statistical analyses were performed to search for a possible correlation between calcification and the other histopathologic factors and/or demographic data. Results Calcification was present in 84.9% of cases. Age, tumour size, necrosis, basophilic staining, iris neovascularisation, choroidal, scleral and/or optic nerve invasion were correlated significantly with calcification. Multivariate analysis showed a significant correlation between the presence of calcification and the amount of necrosis and choroidal invasion only. Conclusions In this series, calcification was more frequent in cases with more necrosis and cases with choroidal invasion, a known poor histopathologic risk factor for metastatic disease. The possible clinical implication of the findings from this study deserves additional studies.
Effects of hormone therapy on blood pressure

ObjectiveAlthough hormone therapy remains the most efficacious option for the management of vasomotor symptoms of menopause, its effects on blood pressure remain unclear. This review scrutinizes evidence of the mechanisms of action of hormone therapy on signaling pathways affecting blood pressure and evidence from clinical studies. MethodsComprehensive Ovid MEDLINE searches were conducted for the terms “hypertension” and either of the following “hormone therapy and menopause” or “selective estrogen receptor modulator” from year 2000 to November 2013. ResultsIn vitro and physiologic studies did not reveal a clear deleterious effect of hormone therapy on blood pressure. The effect of oral therapy was essentially neutral in large trials conducted in normotensive women with blood pressure as primary outcome. Results from all other trials had several limitations. Oral therapy had a neutral effect on blood pressure in hypertensive women. Transdermal estrogen and micronized progesterone had a beneficial effect on blood pressure in normotensive women and, at most, a neutral effect on hypertensive women. In general, tibolone and raloxifene had a neutral effect on blood pressure in both hypertensive and normotensive women. ConclusionsLarge randomized trials are needed to assess the effect of oral hormone therapy on blood pressure as a primary outcome in hypertensive women and the effect of transdermal preparations on both normotensive and hypertensive women. Transdermal preparations would be the preferred mode of therapy for hypertensive women, in view of their favorable physiologic and clinical profiles. The decision regarding the use of hormone therapy should be individualized, and blood pressure should be monitored during the course of treatment.
Polypharmacy and Potentially Inappropriate Medication Use Among Community-dwelling Elders With Dementia

This cross-sectional study examines the association between total prescription medication use and potentially inappropriate medication use (PIRx) among community-dwelling elderly patients with and without dementia. Data (September 2005 to September 2007) were from the National Institute on Aging-funded National Alzheimer's Coordinating Center Uniform Data Set. The study analyzed the Uniform Data Set initial visits of 4518 community-dwelling subjects aged 65 years and above with and without dementia (2665 and 1853, respectively). PIRx was defined using a partial list of the 2003 Beers criteria. Generalized linear mixed models were applied to estimate the association between PIRx and polypharmacy. In both groups (with and without dementia), subjects who received PIRx on average took more medications than those taking no PIRx. As the total number of medications used increased, the odds of having PIRx also increased, controlling for dementia diagnosis and other subject characteristics. Our key findings were consistent after considering 2 definitions of PIRx (with or without oral estrogens) and accounting for missing data. In summary, the total number of medications used is associated with PIRx among Alzheimer's Disease Centers community-dwelling elderly patients with and without dementia, with polypharmacy increasing the risk of PIRx. Ensuring appropriate medication use in this population is clinically important because of the significant risks for institutionalization.
Intra-network knowledge roles and division performance in multi-business firms

Purpose – The purpose of this study is to deal with the performance consequences of business units that adopt varying knowledge roles within the internal multi-business network. Multi-business firms are distributed knowledge systems in which business units are extensively involved in internal knowledge transfer processes. Business units play different roles within their respective corporate knowledge networks as knowledge providers, knowledge receivers, both or neither. Design/methodology/approach – Survey data from a sample of 225 business divisions were analyzed using a multivariate analysis of covariance (ANCOVA). Findings – Results indicate that divisions which occupy knowledge roles that reveal the possession of unique knowledge (knowledge signaling) or guarantee the accumulation of new knowledge (knowledge learning) outperform those divisions that have access to spilled knowledge (knowledge depreciation) or have no access to any kind of knowledge (knowledge insulation). Practical implications – Four.
The Natural History of Juvenile or Subacute GM2 Gangliosidosis: 21 New Cases and Literature Review of 134 Previously Reported

OBJECTIVE. Juvenile GM2 gangliosidosis is a group of inherited neurodegenerative diseases caused by deficiency of lysosomal β-hexosaminidase resulting in GM2 ganglioside accumulation in brain. The purpose of this study was to delineate the natural history of the condition and identify genotype-phenotype correlations that might be helpful in predicting the course of the disease in individual patients. METHODS. A cohort of 21 patients with juvenile GM2 gangliosidosis, 15 with the Tay-Sachs variant and 6 with the Sandhoff variant, was studied prospectively in 2 centers. Our experience was compared with previously published reports on 134 patients. Information about clinical features, β-hexosaminidase enzyme activity, and mutation analysis was collected. RESULTS. In our cohort of patients, the mean (±SD) age of onset of symptoms was 5.3 ± 4.1 years, with a mean follow-up time of 8.4 years. The most common symptoms at onset were gait disturbances (66.7%), incoordination (52.4%), speech problems (28.6%), and developmental delay (28.6%). The age of onset of gait disturbances was 7.1 ± 5.6 years. The mean time for progression to becoming wheelchair-bound was 6.2 ± 5.5 years. The mean age of onset of speech problems was 7.0 ± 5.6 years, with a mean time of progression to anarthria of 5.6 ± 5.3 years. Muscle wasting (10.6 ± 7.4 years), proximal weakness (11.1 ± 7.7 years), and incontinence of sphincters (14.6 ± 9.7 years) appeared later in the course of the disease. Psychiatric disturbances and neuropathy were more prevalent in patients with the Sandhoff variant than in those with the Tay-Sachs variant. However, dysphagia, sphincter incontinence, and sleep problems occurred earlier in those with the Tay-Sachs variant. Cerebellar atrophy was the most common finding on brain MRI (52.9%). The median survival time among the studied and reviewed patients was 14.5 years. The genotype-phenotype correlation revealed that in patients with the Tay-Sachs variant, the presence of R178H and R499H mutations was predictive of an early onset and rapidly progressive course. The presence of either G269S or W474C mutations was associated with a later onset of symptoms along with a more slowly progressive disease course. CONCLUSIONS. Juvenile GM2 gangliosidosis is clinically heterogeneous, not only in terms of age of onset and clinical features but also with regard to the course of the disease. In general, the earlier the onset of symptoms, the more rapidly the disease progresses. The Tay-Sachs and Sandhoff variants differed somewhat in the frequency of specific clinical characteristics. Speech deterioration progressed more rapidly than gait abnormalities in both the Tay-Sachs variant and Sandhoff variant groups. Among patients with the Tay-Sachs variant, the HEXA genotype showed a significant correlation with the clinical course.
Adult-onset spinocerebellar dysfunction caused by a mutation in the gene for the alpha-tocopherol-transfer protein.

BACKGROUND Patients with isolated vitamin E deficiency have an impaired ability to incorporate alpha-tocopherol into lipoproteins in the liver and usually have symptoms and signs of spinocerebellar dysfunction before adolescence. Accumulated evidence suggests that the alpha-tocopherol-transfer protein, which is presumed to function in the intracellular transport of alpha-tocopherol, is abnormal in these patients. METHODS We studied a patient from an isolated Japanese island who began to have ataxia, dysarthria, and sensory disturbances in the sixth decade of life. His serum vitamin E concentration was low (1.2 micrograms per milliliter [2.8 mumol per liter]). Exons of his gene for the alpha-tocopherol-transfer protein were analyzed by DNA sequencing. We also screened an additional 801 inhabitants of the island for the mutation. Both the normal and mutant alpha-to-copherol-transfer proteins were expressed in COS-7 cells and studied by immunoblot analysis and assay for alpha-tocopherol-transfer activity. RESULTS The patient was homozygous for a point mutation that replaces histidine (CAT) with glutamine (CAG) at position 101 of the gene for the alpha-tocopherol-transfer protein. When expressed in COS-7 cells, the missense mutation produced a functionally defective alpha-tocopherol-transfer protein with approximately 11 percent of the transfer activity of the wild-type protein. Of the 801 island inhabitants examined, 21 were heterozygous for the His101Gln mutation. In all affected subjects, including the patient, this mutation cosegregated with an intron-sequence polymorphism. The heterozygotes were phenotypically normal and had serum vitamin E concentrations that were on average 25 percent lower than those of normal subjects (mean [+/- SD], 7.5 +/- 2.2 vs. 10.1 +/- 2.8 micrograms per milliliter [17.4 +/- 5.1 vs. 23.4 +/- 6.5 mumol per liter]; P = 0.002). CONCLUSIONS alpha-Tocopherol-transfer protein is a determinant of serum vitamin E concentrations. An abnormality in this protein is a cause of spinocerebellar dysfunction.
Social anxiety in childhood: the relationship with self and observer rated social skills.

BACKGROUND Social anxiety of childhood is a common and pervasive problem. Traditional approaches to treating these difficulties have focused on providing afflicted children with social skills training. This approach has met with some, but not complete success. Recent reconceptualisations of social anxiety in the adult literature have emphasised the role of negative cognition regarding one's own social skills. Experimental evidence has demonstrated that a misperception of social skills, rather than a skills deficit per se, may be most pertinent to the understanding of social anxiety. This study set out to examine the relationship between self and observer ratings of social skill, and social anxiety in children. METHOD One hundred and ten non-referred schoolchildren aged 8-11 years were asked to give a two-minute speech to a video camera, after which they were asked to rate their performance on a number of social skill dimensions. Neutral observers also watched the videos and rated each child on the same dimensions. RESULTS There was very little correlation between social anxiety level and observer ratings of children's social skills. Indeed, some very anxious children achieved high observer rated social skill scores. State socially anxious children self-reported that their social skills were poorer than less anxious children. However, other than looking more nervous than less anxious children, the social skills of the high anxious children were indistinguishable from those of their less anxious peers. CONCLUSIONS Socially anxious children may not necessarily lack social skills. Rather, their deficits may relate to nervousness and appraisals of their skills. Treatment programmes for these children should take care to assess social skills carefully before prescribing social skill remediation, and should consider employing a cognitive element to tackle negative misperceptions of subjective social skill.
The efficacy of influenza vaccination in healthcare workers in a tropical setting: a prospective investigator blinded observational study.

INTRODUCTION Influenza vaccine has been shown to be highly effective in temperate regions with well-defined seasonal influenza. Healthcare workers (HCWs) are advised to receive regular influenza vaccination to protect themselves and their patients. However, there are limited data on the efficacy of influenza vaccine in HCWs in the tropics. MATERIALS AND METHODS In this observational, investigator blinded cohort study, bi-monthly questionnaires recording influenza-like illness (ILI) episodes and medical leave were administered to 541 HCWs at the Singapore National University Hospital and KK Women's and Children's Hospital from 2004 to 2005. ILI was defined according to a standard symptom score. RESULTS Baseline characteristics were comparable in both the vaccinated and non-vaccinated groups. Overall, the relative risk of self-reported ILI in vaccinated HCWs was 1.13 [95% confidence interval (CI), 0.98-1.13; P=0.107]; medical leave taken was lower in the vaccinated group [mean 0.26+/-0.6 days per visit, compared with 0.30+/-0.5 days in the non-vaccinated group (P=0.40)]. Because of the reported Northern Hemisphere 2003/04 vaccine mismatch, we stratified the cohort and determined that the group which received a matched vaccine had a relative risk of ILI of 0.49 (95% CI, 0.37-0.66; P<0.001), achieving a vaccine efficacy of 51%. Mean medical leave decreased significantly in HCWs who received the matched vaccine, compared with those who did not receive vaccination (0.13+/-0.3 vs 0.30+/-0.5; P<0.001) and with HCWs vaccinated with mismatched strains (0.13+/-0.3 vs 0.39+/-0.9; P=0.01). CONCLUSIONS A well-matched influenza vaccine is effective in preventing ILI and reducing sickness absence in healthcare workers in tropical settings. Efforts need to be made to increase influenza vaccination rates and to improve the currently available vaccines.
Neudesin, a novel secreted protein with a unique primary structure and neurotrophic activity

We identified a novel secreted protein and named it neudesin. Mouse neudesin of 171 amino acids is unique with no primary structural similarity to any known proteins. The neudesin protein produced in cultured cells was secreted efficiently into the culture medium. Mouse neudesin mRNA was expressed abundantly in the developing brain and spinal cord in embryos, but was expressed widely in postnatal tissues including brain, heart, lung, and kidney. Mouse neudesin mRNA was expressed in neurons but not glial cells of the brain. The protein exhibited significant neurotrophic activity in primary cultured mouse neurons but not mitogenic activity in primary cultured mouse astrocytes. Neudesin activated the mitogen‐activated protein (MAP) and phosphatidylinositol‐3 (PI‐3) kinase pathways. The activity of neudesin was inhibited by the inhibitor pertussis toxin for Gi/Go‐protein but not by inhibitors for receptor tyrosine kinases. These results indicated that the activity was mediated via the activation of the MAP and PI‐3 kinase pathways, potentially by the activation of a Gi/Go‐protein‐coupled receptor. Human neudesin of 172 amino acids with high similarity (∼91% identity) to mouse neudesin was also identified. The human neudesin gene was mapped to chromosome 1p33. The identification of neudesin, a novel secreted protein with a unique primary structure and neurotrophic activity, will provide new insights into the development and maintenance of neurons. © 2004 Wiley‐Liss, Inc.