bluuebunny/crossref_metadata_2025_split huggingface dataset:
Case Report: Lennox–Gastaut Epileptic Encephalopathy Responsive to Cannabidiol Treatment Associated With a Novel de novo Mosaic SHANK1 Variant
Authors: Paprocka Justyna , Ziętkiewicz Szymon , Kosińska Joanna , Kaczorowska Ewa , Płoski Rafał 
Published: December 2021

The SH3 and multiple ankyrin repeat domains (SHANKs) are a family of scaffolding proteins located in excitatory synapses required for their development and function. Molecular defects of SHANK3 are a well-known cause of several neurodevelopmental entities, in particular autism spectrum disorders and epilepsy, whereas relatively little is known about disease associations of SHANK1. Here, we propose a novel de novo mosaic p.(Gly126Arg) SHANK1 variant as the monogenic cause of disease in a patient who presented, from the age of 2 years, moderate intellectual disability, autism, and refractory epilepsy of the Lennox–Gastaut type. The epilepsy responded remarkably well to cannabidiol add-on therapy. In silico analyses including homology modeling and molecular dynamics simulations indicated the deleterious effect of SHANK1 p.(Gly126Arg) on the protein structure and the related function associated with protein–protein interactions. In particular, the variant was predicted to disrupt a hitherto unknown conserved region of SHANK1 protein with high homology to a recently recognized functionally relevant domain in SHANK3 implicated in ligand binding, including the “non-canonical” binding of Rap1.
SRD5A3-CDG: Emerging Phenotypic Features of an Ultrarare CDG Subtype
Authors: Kamarus Jaman Nazreen , Rehsi Preeya , Henderson Robert H. , Löbel Ulrike , Mankad Kshitij , Grunewald Stephanie 
Published: December 2021

Background: SRD5A3-CDG is a rare N-glycosylation defect caused by steroid 5 alpha reductase type 3 deficiency. Its key feature is an early severe visual impairment with variable ocular anomalies often leading to diagnosis. Additional symptoms are still poorly defined. In this case study, we discuss 11 genetically confirmed cases, and report on emerging features involving other systems in addition to the eye phenotype.Methods: In total, 11 SRD5A3-CDG patients in five sets of sibships were included in the study. Data on 9 of 11 patients are as of yet unpublished. Patients’ results on biochemical and genetic investigations and on in-depth phenotyping are presented.Results: Key diagnostic features of SRD5A3-CDG are ophthalmological abnormalities with early-onset retinal dystrophy and optic nerve hypoplasia. SRD5A3-CDG is also characterized by variable neurological symptoms including intellectual disability, ataxia, and hypotonia. Furthermore, ichthyosiform skin lesions, joint laxity, and scoliosis have been observed in our cohort. We also report additional findings including dystonia, anxiety disorder, gastrointestinal symptoms, and MRI findings of small basal ganglia and mal-rotated hippocampus, whereas previous publications described dysmorphic features as a common finding in SRD5A3, which could not be confirmed in our patient cohort.Conclusion: The detailed description of the phenotype of this large cohort of patients with SRD5A3-CDG highlights that the key clinical diagnostic features of SRD5A3-CDG are an early onset form of ophthalmological problems in patients with a multisystem disorder with variable symptoms evolving over time. This should aid earlier diagnosis and confirms the need for long-time follow-up of patients.
Heart Failure and Ischemic Stroke: A Bidirectional and Multivariable Mendelian Randomization Study
Authors: Zhang Luyang , Liu Weishi , Sun Wenxian , Wang Xin , Tian Mengke , Pei Lu-Lu , Liu Kai , Liang Jing , Zhou Lue , Lu Jie , Ning Mingming , Buonanno Ferdinando S. , Xu Yuming , Song Bo 
Published: December 2021

Background: Heart failure (HF) is a potential cause of ischemic stroke (IS), and previous studies have reported an association between HF and IS. This study aimed to analyze the causal link between HF and IS using bidirectional and multivariable Mendelian randomization (MR) studies.Methods: Genetic variants significantly associated with HF and IS were selected in the MR analysis from two large genome-wide association studies. Bidirectional and multivariable MR analyses were performed to evaluate the effect of HF on IS or the effect of IS on HF.Results: Two-sample MR analysis showed causal effects of HF on IS of all causes [odds ratio (OR) = 1.555, 95% confidence interval (CI): 1.343–1.799, p = 3.35 × 10−9] and large artery atherosclerosis stroke (LAS) (OR = 1.678, 95% CI: 1.044–2.696, p = 3.03 × 10−5), while there was a suggestive effect of HF on cardioembolic stroke (CES) (OR = 3.355, 95% CI: 1.031–10.919, p = 0.044). Genetically predicted HF was not associated with small artery occlusion stroke. Bidirectional MR analysis showed causal effects of IS of all causes (OR = 1.211, 95% CI: 1.040–1.410, p = 0.014) and CES (OR = 1.277, 95% CI: 1.213–1.344, p = 6.73 × 10−21) on HF, while there were no causal effects of LAS on HF.Conclusion: This MR analysis provided evidence of the causal links between genetically predicted HF and IS. Subgroup analysis highlighted the causal or suggestive relationship between genetically predicted HF and LAS or CES. The potential causal links need further investigation with genetic information about other ancestries or etiologies of HF.
The Second Study of Clinical and Immunological Findings in Anti-laminin 332-Type Mucous Membrane Pemphigoid Examined at Kurume University—Diagnosis Criteria Suggested by Summary of 133 Cases
Authors: Qian Hua , Natsuaki Yohei , Koga Hiroshi , Kawakami Tamihiro , Tateishi Chiharu , Tsuruta Daisuke , Ishii Norito , Li Xiaoguang , Hashimoto Takashi 
Published: December 2021

BackgroundRecently, we published an article retrospectively summarizing the results in 55 anti-laminin 332 (LM332)-type mucous membrane pemphigoid (MMP) cases examined at Kurume University, which were diagnosed by strict inclusion criteria, including positive reactivity in direct immunofluorescence and absence of antibodies to non-LM332 autoantigens. However, indirect immunofluorescence using 1M-NaCl-split normal human skin (ssIIF) is also valuable for diagnosis of anti-LM332-type MMP.MethodsIn this second study, we selected 133 anti-LM332-type MMP cases, which were diagnosed by our different inclusion criteria: (i) immunoglobulin G (IgG) deposition to basement membrane zone (BMZ) by direct immunofluorescence or IgG reactivity with dermal side of split skin by ssIIF, (ii) positivity for at least one of the three subunits of LM332 by immunoblotting of purified human LM332, and (iii) the presence of mucosal lesions. Clinical, histopathological, and immunological findings were summarized and analyzed statistically. Although these cases included the 55 previous cases, the more detailed study for larger scale of patients was conducted for further characterization.ResultsClinically, among the 133 patients, 89% and 43% patients had oral and ocular mucosal lesions, respectively, 71% had cutaneous lesions, and 17% had associated malignancies. Histopathologically, 93% patients showed subepidermal blisters. The sensitivities of ssIIF and direct immunofluorescence are similar but are significantly higher than indirect immunofluorescence using non-split human skin (both p &lt; 0.001). In immunoblotting of purified LM332, patient IgG antibodies most frequently reacted with LMγ2 subunit (58%), followed by LMα3 (49%) and LMβ3 (36%). Thirty-four percent patients recognized additional non-LM332 autoantigens. Statistical analysis revealed that autoantibodies against non-LM332 autoantigens might stimulate the production of anti-LMγ2 antibodies.ConclusionsThis retrospective study further characterized in more detail the clinical and immunological features of 133 cases of anti-LM332-type MMP, in which the new diagnostic criteria without positive direct immunofluorescence reactivity were useful for the diagnosis. Higher frequency with anti-LMγ2 antibodies suggested more significant pathogenic role of this subunit. Additional autoantibodies to non-LM332 autoantigens detected in one-third of the patients may contribute to complexity in anti-LM332-type MMP, including the induction of anti-LMγ2 antibodies.
Dl-3-n-Butylphthalide Rescues Dopaminergic Neurons in Parkinson’s Disease Models by Inhibiting the NLRP3 Inflammasome and Ameliorating Mitochondrial Impairment
Authors: Que Rongfang , Zheng Jialing , Chang Zihan , Zhang Wenjie , Li Hualing , Xie Zhenchao , Huang Zifeng , Wang Hai-Tao , Xu Jiangping , Jin Dana , Yang Wanlin , Tan Eng-King , Wang Qing 
Published: December 2021

BackgroundNeuroinflammation and mitochondrial impairment play important roles in the neuropathogenesis of Parkinson’s disease (PD). The activation of NLRP3 inflammasome and the accumulation of α-synuclein (α-Syn) are strictly correlated to neuroinflammation. Therefore, the regulation of NLRP3 inflammasome activation and α-Syn aggregation might have therapeutic potential. It has been indicated that Dl-3-n-butylphthalide (NBP) produces neuroprotection against some neurological diseases such as ischemic stroke. We here intended to explore whether NBP suppressed NLRP3 inflammasome activation and reduced α-Syn aggregation, thus protecting dopaminergic neurons against neuroinflammation.MethodsIn our study, we established a MPTP-induced mouse model and 6-OHDA-induced SH-SY5Y cell model to examine the neuroprotective actions of NBP. We then performed behavioral tests to examine motor dysfunction in MPTP-exposed mice after NBP treatment. Western blotting, immunofluorescence staining, flow cytometry and RT-qPCR were conducted to investigate the expression of NLRP3 inflammasomes, neuroinflammatory cytokines, PARP1, p-α-Syn, and markers of microgliosis and astrogliosis.ResultsThe results showed that NBP exerts a neuroprotective effect on experimental PD models. In vivo, NBP ameliorated behavioral impairments and reduced dopaminergic neuron loss in MPTP-induced mice. In vitro, treatment of SH-SY5Y cells with 6-OHDA (100uM,24 h) significantly decreased cell viability, increased intracellular ROS production, and induced apoptosis, while pretreatment with 5uM NBP could alleviated 6-OHDA-induced cytotoxicity, ROS production and cell apoptosis to some extent. Importantly, both in vivo and in vitro, NBP suppressed the activation of the NLRP3 inflammasome and the aggregation of α-Syn, thus inhibited neuroinflammation ameliorated mitochondrial impairments.ConclusionsIn summary, NBP rescued dopaminergic neurons by reducing NLRP3 inflammasome activation and ameliorating mitochondrial impairments and increases in p-α-Syn levels. This current study may provide novel neuroprotective mechanisms of NBP as a potential therapeutic agent.
Mid-Regional Proadrenomedullin (MR-proADM) and Microcirculation in Monitoring Organ Dysfunction of Critical Care Patients With Infection: A Prospective Observational Pilot Study
Authors: Domizi Roberta , Damiani Elisa , Scorcella Claudia , Carsetti Andrea , Giaccaglia Paolo , Casarotta Erika , Montomoli Jonathan , Gabbanelli Vincenzo , Brugia Marina , Moretti Marco , Adrario Erica , Donati Abele 
Published: December 2021

Introduction: Microvascular alterations are involved in the development of organ injury in critical care patients. Mid-regional proadrenomedullin (MR-proADM) may predict organ damage and its evolution. The main objective of this study was to assess the correlation between MR-proADM and microvascular flow index (MFI) in a small cohort of 20 adult critical care patients diagnosed with infection, sepsis, or septic shock. Further objectives were to evaluate the correlation between the clearance of MR-proADM and the variables of microcirculation and between MR-proADM and the Sequential Organ Failure Assessment (SOFA) score.Materials and Methods: This is a prospective observational pilot study. Inclusion criteria: consecutive adult patients admitted to intensive care unit (ICU) for or with infection-related illness. Daily measurement of MR-proADM and calculation of the SOFA score from admission in ICU to day 5. Repeated evaluations of sublingual microcirculation, collection of clinical data, and laboratory tests.Results: Primary outcome: MR-proADM was not significantly correlated to the MFI at admission in ICU. A clearance of MR-proADM of 20% or more in the first 24 h was related to the improvement of the MFIs and MFIt [percentual variation of the MFIs + 12.35 (6.01–14.59)% vs. +2.23 (−4.45–6.01)%, p = 0.005; MFIt +9.09 (4.53–16.26)% vs. −1.43 (−4.36–3.12)%, p = 0.002].Conclusion: This study did not support a direct correlation of MR-proADM with the MFI at admission in ICU; however, it showed a good correlation between the clearance of MR-proADM, MFI, and other microvascular variables. This study also supported the prognostic value of the marker. Adequately powered studies should be performed to confirm the findings.
Elevated Serum Tenascin-C Predicts Mortality in Critically Ill Patients With Multiple Organ Dysfunction
Authors: Xu Yunyu , Li Nanyang , Gao Jiamin , Shang Da , Zhang Min , Mao Xiaoyi , Chen Ruiying , Zheng Jianming , Shan Ying , Chen Mingquan , Xie Qionghong , Hao Chuan-Ming 
Published: December 2021

Background: Multiple organ dysfunction is a complex and lethal clinical feature with heterogeneous causes and is usually characterized by tissue injury of multiple organs. Tenascin-C (TNC) is a matricellular protein that is rarely expressed in most of the adult tissues, but re-induced following injury. This study aimed to evaluate serum TNC in predicting mortality in critically ill patients with multiple organ dysfunction.Methods: Adult critically ill patients with at least two organs dysfunction and an increase of Sequential Organ Failure Assess (SOFA) score ≥ 2 points within 7 days were prospectively enrolled into two independent cohorts. The emergency (derivation) cohort was a consecutive series and the patients were from Emergency Department. The inpatient (validation) cohort was a convenience series and the patients were from medical wards. Their serum samples at the first 24 h after enrollment were collected and subjected to TNC measurement using ELISA. The association between serum TNC level and 28-day all-cause mortality was investigated, and then the predictive value of serum TNC was analyzed.Results: A total of 110 patients with a median age of 64 years (53, 73) were enrolled in the emergency cohort. Compared to the survivors, serum TNC in the non-survivors was significantly higher (467.7 vs. 197.5 ng/ml, p &lt; 0.001). Multivariate logistic regression analysis revealed that the association between serum TNC and 28-day mortality was independent of sepsis or critical illness scores such as SOFA, Acute Physiology and Chronic Health Evaluation (APACHE II), and Simplified Acute Physiology Score (SAPS II), respectively (p &lt; 0.001 for each). The area under receiver operating characteristic curve of serum TNC for predicting mortality was 0.803 (0.717–0.888) (p &lt; 0.001), similar with SOFA 0.808 (0.725–0.891), APACHE II 0.762 (0.667–0.857), and SAPS II 0.779 (0.685–0.872). The optimal cut-off value of serum TNC was 298.2 ng/ml. Kaplan–Meier analysis showed that the survival of patients with serum TNC ≥ 300 ng/ml was significantly worse than that of patients with serum TNC &lt; 300 ng/ml. This result was validated in the inpatient cohort. The sensitivity and specificity of serum TNC ≥ 300 ng/ml for predicting mortality were 74.3 and 74.7% in the emergency cohort, and 63.0 and 70.1% in the inpatient cohort, respectively.Conclusion: Serum TNC was associated with mortality in critically ill patients with multiple organ dysfunction, and would be used as a prognostic tool for predicting mortality in this population.
Metabolomic Profiling of Amino Acids in Human Plasma Distinguishes Diabetic Kidney Disease From Type 2 Diabetes Mellitus
Authors: Zhou Chunyu , Zhang Qing , Lu Liqian , Wang Jiao , Liu Dongwei , Liu Zhangsuo 
Published: December 2021

Background: Diabetic kidney disease (DKD) is a highly prevalent complication in patients with type 2 diabetes mellitus (T2DM). Patients with DKD exhibit changes in plasma levels of amino acids (AAs) due to insulin resistance, reduced protein intake, and impaired renal transport of AAs. The role of AAs in distinguishing DKD from T2DM and healthy controls has yet to be elucidated. This study aimed to investigate the metabolomic profiling of AAs in the plasma of patients with DKD.Methods: We established an ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method to detect the plasma levels of the 20 AAs in healthy controls (n = 112), patients with T2DM (n = 101), and patients with DKD (n = 101). The key AAs associated with DKD were identified by orthogonal partial least-squares discriminant analysis (OPLS-DA) models with loading plots, shared and unique structures (SUS) plots, and variable importance in projection (VIP) values. The discrimination accuracies of these key AAs were then determined by analyses of receiver-operating characteristic (ROC) curves.Results: Metabolomic profiling of plasma revealed significant alterations in levels of the 20 AAs in patients with DKD when compared to those in either patients with T2DM or healthy controls. Metabolomic profiling of the 20 AAs showed a visual separation of patients with DKD from patients with T2DM and healthy controls in OPLS-DA models. Based on loading plots, SUS plots, and VIP values in the OPLS-DA models, we identified valine and cysteine as potential contributors to the progression of DKD from patients with T2DM. Histidine was identified as a key mediator that could distinguish patients with DKD from healthy controls. Plasma levels of histidine and valine were decreased significantly in patients with DKD with a decline in kidney function, and had excellent performance in distinguishing patients with DKD from patients with T2DM and healthy controls according to ROC curves.Conclusion: Plasma levels of histidine and valine were identified as the main AAs that can distinguish patients with DKD. Our findings provide new options for the prevention, treatment, and management of DKD.
Does Preoperative Halo-Gravity Traction Reduce the Degree of Deformity and Improve Pulmonary Function in Severe Scoliosis Patients With Pulmonary Insufficiency? A Systematic Review and Meta-Analysis
Authors: Yang Zhao , Liu Yang , Qi Longtao , Wu Shanshan , Li Jingwen , Wang Yu , Jiang Bin 
Published: December 2021

Background: Halo-gravity traction is a commonly used clinical intervention to reduce surgical risk in patients with scoliosis before surgical correction. Some previous studies have focused on the application of halo-gravity traction on patients with severe spinal deformity and pulmonary insufficiency, but the overall effect of halo-gravity traction has not been fully understood. The object of the present study was to perform a meta-analysis exploring the efficacy of preoperative halo-gravity traction on radiographic measurement and pulmonary function in severe scoliosis patients with pulmonary insufficiency.Methods: We searched the medical works of literature completed before January 17, 2021, in the databases of Pubmed, Embase, and Cochrane Library. Studies that quantitatively analyzed the effects of halo-gravity traction on the deformity and pulmonary functions of patients with severe scoliosis were included. Two researchers independently conducted the literature search, data extraction, and quality assessment. We used the Review Manager Software (version 5.4) for statistical analysis and data analysis. Mean difference (MD) with 95% confidence intervals (CIs) were calculated to evaluate the effects of halo-gravity traction.Results: Seven studies involving 189 patients received halo-gravity traction therapy preoperatively were analyzed in our study. Preoperative halo-gravity traction significantly ameliorated the degree of deformity in severe scoliosis patients with pulmonary insufficiency, especially reduced coronal Cobb angle and sagittal Cobb angle effectively [mean deviation (MD) = 2 7.28 (95%CI 21.16–33.4), p &lt; 0.001; MD = 22.02 (95%CI 16.8–27.23), p &lt; 0.001]. Preoperative halo-gravity traction also improved the pulmonary functions in patients, especially increasing %FVC and %FEV1 [MD = −0.0662 (95%CI −0.0672–−0.0652), p &lt; 0.001; MD = −0.0824 (95%CI −0.0832–−0.081), p &lt; 0.001].Conclusions: Preoperative halo-gravity traction for severe scoliosis patients shows significant improvement in the degree of deformity and pulmonary functions. Halo-gravity traction is an effective method to improve the tolerance of patients to surgery in the perioperative period.
Dialysis Adequacy and Risk of Dementia in Elderly Hemodialysis Patients
Authors: Kim Hyung Woo , Jhee Jong Hyun , Joo Young Su , Yang Ki Hwa , Jung Jin Ju , Shin Ji Hyeon , Han Seung Hyeok , Yoo Tae-Hyun , Kang Shin-Wook , Park Jung Tak 
Published: December 2021

Objective: Dementia is prevalent among elderly patients undergoing hemodialysis. However, the association between dialysis adequacy and the risk of dementia is uncertain.Methods: A total of 10,567 patients aged &gt;65 years undergoing maintenance hemodialysis who participated in a national hemodialysis quality assessment program were analyzed. The patients were classified into quartile groups based on single-pool Kt/V levels. The associations between single-pool Kt/V and the development of dementia, Alzheimer's disease (AD), and vascular dementia (VD) were examined.Results: The mean age of the patients was 72.9 years, and 43.4% were female. The mean baseline single-pool Kt/V level was 1.6 ± 0.3. During a median follow-up of 45.6 (45.6–69.9) months, there were 27.6, 23.9, and 2.8 events/1,000 person-years of overall dementia, AD, and VD, respectively. The incidences of overall dementia, AD, and VD were lowest in the highest single-pool Kt/V quartile group. Compared with the lowest single-pool Kt/V quartile, the risks of incident overall dementia and AD were significantly lower in the highest quartile [sub-distribution hazard ratio (sHR): 0.69, 95% confidence interval (CI): 0.58–0.82 for overall dementia; sHR: 0.69, 95% CI: 0.57–0.84 for AD]. Inverse relationships were found between the risks of developing overall dementia and AD, and single-pool Kt/V. However, no significant relationship was observed between single-pool Kt/V levels and VD development.Conclusions: Increased dialysis clearance was associated with a lower risk of developing dementia in elderly hemodialysis patients.
Effects of Baduanjin Exercise on Physical Function and Health-Related Quality of Life in Peritoneal Dialysis Patients: A Randomized Trial
Authors: Zhang Fan , Liao Jing , Zhang Weihong , Wang Hui , Huang Liuyan , Shen Qiyun , Zhang Huachun 
Published: December 2021

Background and Aims: Exercise is an efficient non-pharmacological intervention for chronic kidney disease. The study aims to evaluate the effects of Baduanjin exercise on physical function and health-related quality of life (HRQOL) in peritoneal dialysis (PD) patients.Methods: Seventy PD patients were randomly assigned to either the Baduanjin exercise group or the control group. Fifty-seven patients completed the study (exercise group, 25; control group, 32). The exercise group received the Baduanjin exercise program for 12 weeks. The control group received usual care. Three well-established performance-based tests determined physical function: five times sit-to-stand test (FTSST), timed up and go test (TUGT), and handgrip strength (HGS). HRQOL was assessed by the Kidney Disease Quality of Life-Short Form.Results: At baseline, no differences in physical function and HRQOL were observed between the Baduanjin exercise and the control group. At follow-up, the Baduanjin exercise group showed a marginally significant improvement in FTSST (P = 0.008) and TUGT (P = 0.040) over the 12 weeks compared to the control group. HRQOL in the Baduanjin exercise group was significantly higher than that of the control group.Conclusions: A 12-week Baduanjin exercise program may improve physical function and HRQOL in PD patients. Longer follow-up is needed to determine if these findings will translate into clinical application.