cometadata/datacite-titles-descriptions-related-identifiers huggingface dataset:
DOI: 10.6084/m9.figshare.5126836.v1
title: Supplementary Material for: Mutation and Clinical Characteristics of Autosomal-Dominant Hereditary Spastic Paraplegias in China

description: <b><i>Background:</i></b> Hereditary spastic paraplegias constitute a heterogeneous group of inherited neurodegenerative disorders. To date, there has been no systematic mutation and clinical analysis for a large group of autosomal-dominant hereditary spastic paraplegias in China. <b><i>Objective:</i></b> The purpose of this study was to investigate the mutation frequencies and the clinical phenotypes of Chinese spastic paraplegia patients. <b><i>Methods:</i></b> Direct sequencing and a multiplex ligation-dependent probe amplification assay were applied to detect the mutations of <i>SPAST</i> and <i>ATL1</i> in 54 autosomal-dominant hereditary spastic paraplegia probands and 66 isolated cases. Next, mutations in <i>NIPA1</i>, <i>KIF5A</i>, <i>REEP1</i> and <i>SLC33A1</i> were detected in the negative patients. Subsets of spastic paraplegia patients were genotyped for the modifying variants. Further, detailed clinical data regarding the genetically diagnosed families were analysed. <b><i>Results:</i></b> Altogether, 27 families were diagnosed as SPG4, 3 as SPG3A and 1 as SPG6. No mutations in <i>KIF5A</i>, <i>REEP1</i> or <i>SLC33A1 </i>were found; 9 <i>SPAST</i> mutations were novel. There was no p.S44L or p.P45Q variant in <i>SPAST</i> and no p.G563A variant in<i> HSPD1</i> in either the 120 spastic paraplegia patients or the 500 controls. There was a remarkable clinical difference between the SPG4 and non-SPG4 patients and even between genders among the SPG4 patients. Non-penetrance and remarkable gender difference were observed in some SPG4 and SPG3A families. <b><i>Conclusions:</i></b> Our data confirm that hereditary spastic paraplegias in China represent a heterogeneous group of genetic neurodegenerative disorders in autosomal-dominant and apparently sporadic forms. Novel genotype-phenotype correlations were established.
DOI: 10.6084/m9.figshare.5126830
title: Supplementary Material for: Endogenous Kisspeptin Tone Is a Critical Excitatory Component of Spontaneous GnRH Activity and the GnRH Response to NPY and CART

description: <b><i>Background/Aims:</i></b> Kisspeptin is the major excitatory regulator of gonadotropin-releasing hormone (GnRH) neurons and is responsible for basal GnRH/LH release and the GnRH/LH surge. Although it is widely assumed, based on mutations in kisspeptin and Kiss1R, that kisspeptin acts to sustain basal GnRH neuronal activity, there have been no studies to investigate whether endogenous basal kisspeptin tone plays a direct role in basal spontaneous GnRH neuronal excitability. It is also of interest to examine possible interactions between endogenous kisspeptin tone and other neuropeptides that have direct effects on GnRH neurons, such as neuropeptide Y (NPY) or cocaine- and amphetamine-regulated transcript (CART), since the activity of all these neuropeptides changes during states of negative energy balance. <b><i>Methods:</i></b> Loose cell-attached and whole-cell current patch-clamp recordings were made from GnRH-GFP neurons in hypothalamic slices from female and male rats. <b><i>Results:</i></b> Kisspeptin activated GnRH neurons in a concentration-dependent manner with an EC<sub>50</sub> of 3.32 ± 0.02 nM. Surprisingly, a kisspeptin antagonist, Peptide 347, suppressed spontaneous activity in GnRH neurons, demonstrating the essential nature of the endogenous kisspeptin tone. Furthermore, inhibition of endogenous kisspeptin tone blocked the direct activation of GnRH cells that occurs in response to antagonism of NPY Y5 receptor or by CART. <b><i>Conclusions:</i></b> Our electrophysiology studies suggest that basal endogenous kisspeptin tone is not only essential for spontaneous GnRH neuronal firing, but it is also required for the net excitatory effects of other neuropeptides, such as CART or NPY antagonism, on GnRH neurons. Therefore, endogenous kisspeptin tone could serve as the linchpin in GnRH activation or inhibition.
DOI: 10.6084/m9.figshare.5126833
title: Supplementary Material for: Recurrent Stroke in the Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction (WARCEF) Trial

description: <b><i>Background and Purpose:</i></b> WARCEF randomized 2,305 patients in sinus rhythm with ejection fraction (EF) ≤35% to warfarin (INR 2.0-3.5) or aspirin 325 mg. Warfarin reduced the incident ischemic stroke (IIS) hazard rate by 48% over aspirin in a secondary analysis. The IIS rate in heart failure (HF) is too low to warrant routine anticoagulation but epidemiologic studies show that prior stroke increases the stroke risk in HF. In this study, we explore IIS rates in WARCEF patients with and without baseline stroke to look for risk factors for IIS and determine if a subgroup with an IIS rate high enough to give a clinically relevant stroke risk reduction can be identified. <b><i>Methods:</i></b> We compared potential stroke risk factors between patients with baseline stroke and those without using the exact conditional score test for Poisson variables. We looked for risk factors for IIS, by comparing IIS rates between different risk factors. For EF we tried cut-off points of 10, 15 and 20%. The cut-off point 15% was used as it was the highest EF that was associated with a significant increase in IIS rate. IIS and EF strata were balanced as to warfarin/aspirin assignment by the stratified randomized design. A multiple Poisson regression examined the simultaneous effects of all risk factors on IIS rate. IIS rates per hundred patient years (/100PY) were calculated in patient groups with significant risk factors. Missing values were assigned the modal value. <b><i>Results:</i></b> Twenty of 248 (8.1%) patients with baseline stroke and 64 of 2,048 (3.1%) without had IIS. IIS rate in patients with baseline stroke (2.37/100PY) was greater than patients without (0.89/100PY) (rate ratio 2.68, p &lt; 0.001). Fourteen of 219 (6.4%) patients with ejection fraction (EF) &lt;15% and 70 of 2,079 (3.4%) with EF ≥15% had IIS. In the multiple regression analysis stroke at baseline (p &lt; 0.001) and EF &lt;15% vs. ≥15% (p = 0.005) remained significant predictors of IIS. IIS rate was 2.04/100PY in patients with EF &lt;15% and 0.95/100PY in patients with EF ≥15% (p = 0.009). IIS rate in patients with baseline stroke and reduced EF was 5.88/100PY with EF &lt;15% decreasing to 2.62/100PY with EF &lt;30%. <b><i>Conclusions:</i></b> In a WARCEF exploratory analysis, prior stroke and EF &lt;15% were risk factors for IIS. Further research is needed to determine if a clinically relevant stroke risk reduction is obtainable with warfarin in HF patients with prior stroke and reduced EF.
DOI: 10.6084/m9.figshare.5126842.v1
title: Supplementary Material for: Expression, Regulation and Function of Human Metallothioneins in Endothelial Cells

description: Metallothioneins (MTs) are small cysteine-rich proteins which are involved in e.g. metal homeostasis, metal detoxification and protection against oxidative stress. In addition, several MTs have been shown to regulate expression of proangiogenic growth factors like vascular endothelial growth factor. Detailed information about the expression and regulation of specific MT isoforms in endothelial cells (EC) is limited. We therefore performed extensive mRNA expression profiling of all known human MTs in EC. We found that the basal endothelial expression is restricted to MT1E, MT1X, MT2A, and MT3. Physiological activation of EC by exposure to serum increased the expression of MT1E and MT2A and induced the expression of MT1M. Furthermore, exposure to zinc or copper induced the expression of most MT1 isoforms, while hypoxia specifically increased the expression of MT1E, MT1M, MT1X, and MT3. Finally, knockdown of the dominant MT isoform in EC, i.e. MT2A, resulted in decreased proliferation and sprouting as well as in increased migration of human umbilical vein EC. Together, these findings provide a link between MTs and angiogenesis.
DOI: 10.6084/m9.figshare.5126824
title: Supplementary Material for: Expression of MIG/CXCL9 in Cystic Fibrosis and Modulation of Its Activities by Elastase of <b><i>Pseudomonas aeruginosa</i></b>

description: In cystic fibrosis (CF), colonization of the airways with <i>Pseudomonas aeruginosa </i>is associated with disease deterioration. The mechanism behind the disease progression is not fully understood. The present work shows that the antibacterial chemokine MIG/CXCL9 is present in the airways and in sputum of CF patients. MIG/CXCL9 showed high bactericidal activity against. <i>P. aeruginosa, </i>including some strains from the airways of CF patients. Full-length MIG/CXCL9 was detected in sputum from healthy controls and CF patients colonized with <i>P. aeruginosa. </i>However, degraded MIG/CXCL9 was only found in CF sputum. In vitro, elastase of <i>P. aeruginosa </i>cleaved off a fragment of similar size and two additional fragments from MIG/CXCL9. The fragments showed less bactericidal activity against <i>P. aeruginosa </i>compared with the full-length protein. The fragments did not activate the MIG/CXCL9 receptor CXCR3 (expressed e.g. by NK cells, mast cells, and activated T cells) but instead displayed noncompetitive inhibition. In vitro, a decrease in CXCR3-bearing cells was found within and in the proximity of the bronchial epithelium of CF lung tissue compared with controls. Taken together, both bactericidal and cell-recruiting activities of MIG/CXCL9 are corrupted by <i>P. aeruginosa </i>through release of elastase, and this may contribute to impaired airway host defense in CF.
DOI: 10.6084/m9.figshare.5126827
title: Supplementary Material for: Die Wirksamkeit einzelner Therapieelemente in Routinetherapien bei Panikstörung und Agoraphobie

description: <b><i>Hintergrund: </i></b>Die Wirksamkeit der kognitiven Verhaltenstherapie bei der Panikstörung mit oder ohne Agoraphobie gilt als gesichert. Mehrere Studien weisen zudem darauf hin, dass die In-vivo-Exposition das möglicherweise wirkungsstärkste Behandlungselement darstellt. An der naturalistischen Stichprobe einer Hochschulambulanz wurden die Effektivität der durchgeführten Therapien sowie insbesondere die Frequenz und Wirksamkeit einzelner Behandlungselemente der kognitiven Verhaltenstherapie überprüft. <b><i>Methode: </i></b>Die Intention-to-Treat (ITT)-Stichprobe setzte sich aus N = 104 konsekutiven Patienten mit Panikstörung/Agoraphobie als Hauptdiagnose zusammen, von denen 84 die Therapie regulär beendeten. Als Outcome-Maße wurden das Brief Symptom Inventory (BSI) sowie die 4 Skalen des Fragebogens zu körperbezogenen Ängsten, Kognitionen und Vermeidung (AKV) eingesetzt. Mittels einer retrospektiven Aktenanalyse wurde geprüft, wie oft und wie konsequent einzelne Therapieelemente realisiert worden waren. <b><i>Ergebnisse: </i></b>Es ergaben sich Prä-Post-Effektstärken (Cohens d) zwischen d = 0,53 und d = 0,78 für die ITT-Stichprobe und zwischen d = 0,73 und d = 1,08 für die Completer. Katamnestisch erwiesen sich die Therapieeffekte auch nach 6 und 12 Monaten als stabil. Die Respon-seraten lagen bei 51% (ITT-Stichprobe) und 60,7% (Completer). Es zeigten sich folgende Häufigkeiten für die Durchführung der Therapieelemente: kognitive Therapie 73,0%, interozeptive Exposition 62,0%, In-vivo-Exposition 59,8%, Entspannungstraining 69,2%. Im Falle der Realisierung von In-vivo-Expositionen waren die Therapieergebnisse erheblich besser, während es bei der Realisierung von kognitiver Therapie und der interozeptiven Exposition nur mäßige Effektsteigerungen gab. Als nicht relevant für das Therapieergebnis erwies sich Entspannung. <b><i>Schlussfolgerung: </i></b>Die Ergebnisse bestätigen die herausragende Bedeutung der In-vivo-Exposition für den Behandlungserfolg. Zukünftige Forschung sollte sich mit der Frage beschäftigen, warum auf diese wichtige Therapiekomponente in naturalistischen Therapien in nicht wenigen Fällen verzichtet wird und durch welche Maßnahmen ein häufigerer Einsatz erreicht werden könnte.
DOI: 10.6084/m9.figshare.5126821
title: Supplementary Material for: Somatic Mutations Are Not Observed by Exome Sequencing of Lymphocyte DNA from Monozygotic Twins Discordant for Congenital Hypothyroidism due to Thyroid Dysgenesis

description: <b><i>Background/Aims:</i></b> Congenital primary hypothyroidism (CH) is a rare pediatric disorder estimated to occur in about 1:2,500 live births. Approximately half of these cases entail ectopic thyroid tissue, which is believed to result from a migration defect during embryogenesis. Approximately 3% of CH cases are explained by mutation(s) in known genes, most of which are transcription factors implicated in the embryology of the thyroid gland. Surprisingly, monozygotic (MZ) twins are usually discordant for CH due to thyroid dysgenesis, suggesting that most cases are not caused by transmitted genetic variation. One possible explanation is somatic mutation in genes involved in thyroid migration occurring after zygotic twinning. Such mutations should be observed only in the affected twin. <b><i>Methods:</i></b> To test the hypothesis of somatic mutation, we performed whole exome sequencing of DNA from three pairs of MZ twins discordant for CH with ectopic glands. <b><i>Results:</i></b> We found no somatic mutations exclusive to any of the three affected twins or in any of the unaffected twins. <b><i>Conclusion:</i></b> Either somatic mutations are not significant for the etiology of CH or else such mutations lie outside regions of the genome accessible by exome sequencing technology.
DOI: 10.6084/m9.figshare.5126818
title: Supplementary Material for: Achievement of NKF/K-DOQI Recommended Target Values for Bone and Mineral Metabolism in Incident Hemodialysis Patients: Results of the FARO-2 Cohort

description: <b><i>Background:</i></b> Mineral Bone Disorders (MBD) is prevalent in hemodialysis (HD) patients and associated with increased cardiovascular mortality. The FARO-2 study evaluated the achievement of the NKF/K-DOQI guidelines on recommended target values for serum calcium (Ca), phosphorous (P) and intact parathyroid hormone (PTH) levels on survival in incident HD patients. <b><i>Methods:</i></b> Data were collected by questionnaire from 568 incident HD patients followed prospectively over a 3-year period from 26 Italian dialysis units. The cumulative probability of time-to-death for CKD-MBD treatment characteristics was determined by the Kaplan-Meier curves. <b><i>Results:</i></b> Serum PTH levels (median values at 6 months vs. 36 months; 225 vs. 254 pg/ml), Ca (8.8 vs. 8.9 g/dl) and P (5.1 vs. 4.8 mg/dl) were not significantly different at 6 months versus follow-up. The majority of incident HD patients (60-70%) who were followed up for 36 months did not achieve the NKF/K-DOQI recommended target values. Survival rates were higher in patients on target for three parameters versus patients off target (survival at 24 months: at target 95.7% (95% CI: 84.0-98.9) versus not on target 71.1% (95% CI: 66.3-75.4, p &lt; 0.01)). The 30.1% of patients on target for three MBD parameters at least once during the follow-up period had better survival rates compared to those not reaching these targets (survival at 24 months: at least once 88.0% (95% CI: 81.9-92.1); 67.7% (95% CI: 61.9-72.8, p &lt; 0.01)). <b><i>Conclusion:</i></b> Our findings indicate that incident HD patients who achieved target levels (for three MBD parameters) for at least one visit have a lower risk of mortality.
DOI: 10.6084/m9.figshare.5126815
title: Supplementary Material for: Changes in the Small Bowel of Symptomatic Kidney Transplant Recipients Converted from Mycophenolate Mofetil to Enteric-Coated Mycophenolate Sodium

description: <b><i>Background/Aims:</i></b> Gastrointestinal (GI) symptoms in renal transplant recipients may be caused due to mycophenolic acid (MPA) toxicity. Using small bowel capsule endoscopy (SBCE) we examined the impact of conversion from Mycophenolate Mofetil (MMF) to enteric-coated formulation of Mycophenolate Sodium (<i>EC-MPS) </i>given to treat GI mucosal lesions. <b><i>Methods:</i></b> Adult kidney-only recipients at least 30 days after transplant, presenting with GI symptoms while receiving MMF completed a Gastrointestinal Symptom Rating Scale (GSRS) questionnaire, underwent SBCE, and had MMF substituted by <i>EC-MPS</i>. After 30 days, GSRS and SBCE were repeated and findings were compared to baseline values. Patients who were still on EC-MPS 6-24 months post-conversion were contacted for completing a follow-up GSRS questionnaire and SBCE. <b><i>Results:</i></b> Eighteen out of 23 subjects completed the first part of the study. Subjects' median ages and post-transplant time were 47.5 years old and 4.5 months, respectively. Tacrolimus, MMF and prednisone was the main regimen (94%), with a median MMF dose of 750 mg BID. The average baseline GSRS was 2.99 ± 0.81; it significantly decreased to 2.19 ± 0.8 at 30 days post-conversion. At baseline, 50 had gastric and 89% had small bowel lesions. At 30 days, 29 and 62% of the SBCE were still showing gastric and small bowel lesions, respectively. Of 5 patients in the study extension, 4 had abnormal SBCE findings but have been reporting improvement in their symptoms. <b><i>Conclusion:</i></b> Stomach and small bowel mucosal lesions are common in kidney recipients with GI symptoms when treated with MMF. Conversion to <i>EC-MPS </i>for 30 days significantly alleviated the GI symptoms; however, no evident correlation with SBCE findings was found.
DOI: 10.6084/m9.figshare.5126818.v1
title: Supplementary Material for: Achievement of NKF/K-DOQI Recommended Target Values for Bone and Mineral Metabolism in Incident Hemodialysis Patients: Results of the FARO-2 Cohort

description: <b><i>Background:</i></b> Mineral Bone Disorders (MBD) is prevalent in hemodialysis (HD) patients and associated with increased cardiovascular mortality. The FARO-2 study evaluated the achievement of the NKF/K-DOQI guidelines on recommended target values for serum calcium (Ca), phosphorous (P) and intact parathyroid hormone (PTH) levels on survival in incident HD patients. <b><i>Methods:</i></b> Data were collected by questionnaire from 568 incident HD patients followed prospectively over a 3-year period from 26 Italian dialysis units. The cumulative probability of time-to-death for CKD-MBD treatment characteristics was determined by the Kaplan-Meier curves. <b><i>Results:</i></b> Serum PTH levels (median values at 6 months vs. 36 months; 225 vs. 254 pg/ml), Ca (8.8 vs. 8.9 g/dl) and P (5.1 vs. 4.8 mg/dl) were not significantly different at 6 months versus follow-up. The majority of incident HD patients (60-70%) who were followed up for 36 months did not achieve the NKF/K-DOQI recommended target values. Survival rates were higher in patients on target for three parameters versus patients off target (survival at 24 months: at target 95.7% (95% CI: 84.0-98.9) versus not on target 71.1% (95% CI: 66.3-75.4, p &lt; 0.01)). The 30.1% of patients on target for three MBD parameters at least once during the follow-up period had better survival rates compared to those not reaching these targets (survival at 24 months: at least once 88.0% (95% CI: 81.9-92.1); 67.7% (95% CI: 61.9-72.8, p &lt; 0.01)). <b><i>Conclusion:</i></b> Our findings indicate that incident HD patients who achieved target levels (for three MBD parameters) for at least one visit have a lower risk of mortality.
DOI: 10.6084/m9.figshare.5126830.v1
title: Supplementary Material for: Endogenous Kisspeptin Tone Is a Critical Excitatory Component of Spontaneous GnRH Activity and the GnRH Response to NPY and CART

description: <b><i>Background/Aims:</i></b> Kisspeptin is the major excitatory regulator of gonadotropin-releasing hormone (GnRH) neurons and is responsible for basal GnRH/LH release and the GnRH/LH surge. Although it is widely assumed, based on mutations in kisspeptin and Kiss1R, that kisspeptin acts to sustain basal GnRH neuronal activity, there have been no studies to investigate whether endogenous basal kisspeptin tone plays a direct role in basal spontaneous GnRH neuronal excitability. It is also of interest to examine possible interactions between endogenous kisspeptin tone and other neuropeptides that have direct effects on GnRH neurons, such as neuropeptide Y (NPY) or cocaine- and amphetamine-regulated transcript (CART), since the activity of all these neuropeptides changes during states of negative energy balance. <b><i>Methods:</i></b> Loose cell-attached and whole-cell current patch-clamp recordings were made from GnRH-GFP neurons in hypothalamic slices from female and male rats. <b><i>Results:</i></b> Kisspeptin activated GnRH neurons in a concentration-dependent manner with an EC<sub>50</sub> of 3.32 ± 0.02 nM. Surprisingly, a kisspeptin antagonist, Peptide 347, suppressed spontaneous activity in GnRH neurons, demonstrating the essential nature of the endogenous kisspeptin tone. Furthermore, inhibition of endogenous kisspeptin tone blocked the direct activation of GnRH cells that occurs in response to antagonism of NPY Y5 receptor or by CART. <b><i>Conclusions:</i></b> Our electrophysiology studies suggest that basal endogenous kisspeptin tone is not only essential for spontaneous GnRH neuronal firing, but it is also required for the net excitatory effects of other neuropeptides, such as CART or NPY antagonism, on GnRH neurons. Therefore, endogenous kisspeptin tone could serve as the linchpin in GnRH activation or inhibition.
DOI: 10.6084/m9.figshare.5126809
title: Supplementary Material for: Proteomic Analysis of Barley Cell Nuclei Purified by Flow Sorting

description: Many proteins are present in the nucleus; some are involved with its structural and functional organization, some with gene expression, and some with cell division. The plant nuclear proteome has not been well explored. Its characterization requires extraction methods which minimize both the artifactual alteration of the proteins and the extent of contamination with non-nuclear proteins. The conventional multi-step fractionation procedure is both laborious and prone to contamination. Here, we describe a single-step method based on flow sorting. The method allows the separation of G1, S and G2 phase nuclei and minimizes the risk of contamination by non-nuclear proteins. Preliminary results obtained using G1 phase cell nuclei from barley root tips indicate that flow sorting coupled with a protein/peptide separation and mass spectrometry will permit a comprehensive characterization of the plant nuclear proteome.
DOI: 10.6084/m9.figshare.5126812
title: Supplementary Material for: Adjusting Hemodialysis Dose for Protein Catabolic Rate

description: <b><i>Background:</i></b> Patients dialyzed with equal eKt/V may have huge variations in their urea concentrations. <b><i>Methods:</i></b> Urea generation rate, distribution volume and renal clearance were determined in 205 hemodialysis sessions of 33 patients with double pool urea kinetic modeling using dialyzer clearance from online monitoring. From these data, optimized prescriptions were computed. <b><i>Results:</i></b> In simulated dialysis sessions, the HEMO standard-dose equivalent clearance was not sufficient to keep time-averaged concentration (TAC) and average predialysis concentration (PAC) of urea below the defined upper limits (20 and 30 mmol/l), if normalized protein catabolic rate (nPCR) was greater than 1.3 g/kg/day. Protein catabolic rate was taken into account in the optimized prescription by cutting high urea concentrations. <b><i>Conclusions:</i></b> If patients having high urea concentrations with conventional clearance will benefit from higher dialysis dose - an unconfirmed hypothesis - this approach helps in identifying those who need more than three sessions per week.