Efficacy of Constraint-Induced Movement Therapy Versus Bimanual Intensive Training on Motor and Psychosocial Outcomes in Children With Unilateral Cerebral Palsy: A Randomized Trial.

IMPORTANCE: Emerging research has demonstrated that constraint-induced movement therapy (CIMT) and bimanual intensive training (BIT) show promising effectiveness for children with unilateral cerebral palsy (UCP). Considering that neurorehabilitative programs have always been designed with long training periods, psychosocial outcomes have received scarce attention and thus have not been investigated sufficiently. OBJECTIVE: To compare the efficacy of CIMT and BIT with 36-hr interventional dosages for both motor and psychosocial outcomes. DESIGN: Randomized trial. SETTING: Community. PARTICIPANTS: Forty-eight children with UCP, ages 6 to 12 yr. INTERVENTION: Both CIMT and BIT delivered via individual intervention for 2.25 hr/day, twice a week, for 8 wk. OUTCOMES AND MEASURES: The Melbourne Assessment 2, Pediatric Motor Activity Log-Revised, Bruininks-Oseretsky Test of Motor Proficiency, ABILHAND-Kids measure, and Parenting Stress Index-Short Form were administrated at pretreatment, midterm, posttreatment, and 6 mo after intervention. An engagement questionnaire for investigating the child's engagement in the intervention was used to collect the perspectives of the children and the parents weekly. RESULTS: Children with UCP who received either CIMT or BIT achieved similar motor improvements. The only difference was that CIMT yielded larger improvements in frequency and quality of use of the more affected hand at the 6-mo follow-up. Similar child engagement and parental stress levels were found in the two groups. CONCLUSIONS AND RELEVANCE: This study comprehensively compared the efficacy of motor and psychosocial outcomes for 36-hr dosages of CIMT and BIT. The promising findings support the clinical efficacy and feasibility of the proposed protocols. What This Article Adds: The core therapeutic principle of CIMT (i.e., remind the child to use the more affected hand) may be more easily duplicated by parents. Parents may have overestimated their child's engagement and given relatively higher scores; therefore, occupational therapists should also consider the opinions of the children themselves.

Type I Interferon Orchestrates Demand-Adapted Monopoiesis during Influenza A Virus Infection via STAT1-Mediated Upregulation of Macrophage Colony-Stimulating Factor Receptor Expression.

Whether and how a local virus infection affects the hematopoietic system in the bone marrow is largely unknown, unlike with systemic infection. In this study, we showed that influenza A virus (IAV) infection leads to demand-adapted monopoiesis in the bone marrow. The beta interferon (IFN-ß) promoter stimulator 1 (IPS-1)-type I IFN-IFN-α receptor 1 (IFNAR1) axis-mediated signaling was found to induce the emergency expansion of the granulocyte-monocyte progenitor (GMP) population and upregulate the expression of the macrophage colony-stimulating factor receptor (M-CSFR) on bipotent GMPs and monocyte progenitors via the signal transducer and activator of transcription 1 (STAT1), leading to a scaled-back proportion of granulocyte progenitors. To further address the influence of demand-adapted monopoiesis on IAV-induced secondary bacterial infection, IAV-infected wild-type (WT) and Stat1-/- mice were challenged with Streptococcus pneumoniae. Compared with WT mice, Stat1-/- mice did not demonstrate demand-adapted monopoiesis, had more infiltrating granulocytes, and were able to effectively eliminate the bacterial infection. IMPORTANCE Our findings show that influenza A virus infection induces type I interferon (IFN)-mediated emergency hematopoiesis to expand the GMP population in the bone marrow. The type I IFN-STAT1 axis was identified as being involved in mediating the viral-infection-driven demand-adapted monopoiesis by upregulating M-CSFR expression in the GMP population. As secondary bacterial infections often manifest during a viral infection and can lead to severe or even fatal clinical complications, we further assessed the impact of the observed monopoiesis on bacterial clearance. Our results suggest that the resulting decrease in the proportion of granulocytes may play a role in diminishing the IAV-infected host's ability to effectively clear secondary bacterial infection. Our findings not only provide a more complete picture of the modulatory functions of type I IFN but also highlight the need for a more comprehensive understanding of potential changes in hematopoiesis during local infections to better inform clinical interventions.

Management of Restenosis after Stenting in Left Main Coronary Artery Disease.

Background: The optimal alternative treatment strategy to coronary artery bypass graft surgery (CABG) for in-stent restenosis (ISR) in left main (LM) coronary artery disease remains uncertain. Methods: We retrospectively screened all intervention reports from an intervention database and extracted those mentioning an LM stent. We then manually confirmed reports involving LM ISR and divided them into two groups, those in which the patient received a new drug-eluting stent (new-DES) strategy, and those in which the patient received a drug-coated balloon (DCB) only. A composite endpoint of major adverse cardiovascular events (MACEs) and each individual endpoint were compared. We also performed a brief analysis of similar designed studies. Results: Between the new-DES (n = 40) and DCB-only (n = 22) groups, during median respective follow-up times of 581.5 and 642.5 days, no significant statistical differences were detected in MACEs (50.0% vs. 50.0%, p = 0.974), cardiovascular death (27.5% vs. 13.6%, p = 0.214), nonfatal myocardial infarction (30.0% vs. 31.8%, p = 0.835), or target lesion revascularization (35.0% vs. 45.5%, p = 0.542). We analyzed four similar studies and found comparable MACE findings (odds ratio: 0.85, 95% CI: 0.44-1.67). Conclusions: Our findings support both DCB angioplasty and repeat DES implantation for LMISR lesions in patients who were clinically judged to be unsuitable for CABG; the treatments achieved comparable clinical results in terms of MACEs in the medium term.

Association of leukocyte mitochondrial DNA copy number with longitudinal C-reactive protein levels and survival in older adults: a cohort study.

BACKGROUND: Systemic chronic inflammation occurs with age. The association of the leukocyte mitochondrial DNA copy number, a measure of mitochondrial function in aging, with the temporal profile of serum high-sensitivity C-reactive protein and mortality risk remains uncertain. The objectives of this study were to examine the association of the leukocyte mitochondrial DNA copy number with longitudinal high-sensitivity C-reactive protein levels and the association of the longitudinal high-sensitivity C-reactive protein levels with mortality risk. METHODS: This prospective cohort study included 3928 adults aged ≥ 55 years without systemic inflammation in the baseline examination of the Healthy Aging Longitudinal Study in Taiwan, which started in 2009. Each participant received leukocyte mitochondrial DNA copy number measurement using a fluorescence-based quantitative polymerase chain reaction at baseline, serum high-sensitivity C-reactive protein measurements at baseline and the follow-up examination five years later, and the ascertainment of all-cause death (until November 30, 2021). The relationships among the leukocyte mitochondrial DNA copy number, longitudinal serum high-sensitivity C-reactive protein levels, and time to all-cause mortality were examined using the joint longitudinal and survival modeling analysis. RESULTS: Of the 3928 participants (mean age: 69 years; 2060 [52%] were women), 837 (21%) died during follow-up. In the adjusted analysis, one standard deviation lower natural log-transformed baseline leukocyte mitochondrial DNA copy number was associated with an increase of 0.05 (95% confidence interval [CI], 0.02 to 0.08) standard deviation in serum high-sensitivity C-reactive protein in subsequent years. An increase of 1 standard deviation in instantaneous high-sensitivity C-reactive protein levels was associated with a hazard ratio (HR) for all-cause mortality of 1.22 (95% CI, 1.14 to 1.30). Similar results were obtained after further adjusting for baseline high-sensitivity C-reactive protein levels (HR [95% CI], 1.27 [1.16 to 1.38]) and after excluding those with serum high-sensitivity C-reactive protein above 10 mg/L (HR [95% CI], 1.21[1.11 to 1.31]) or 3 mg/L (HR [95% CI], 1.19 [1.06 to 1.31]) during follow-up. CONCLUSIONS: A lower leukocyte mitochondrial DNA copy number was associated with persistently higher high-sensitivity C-reactive protein levels. Moreover, these higher time-varying high-sensitivity C-reactive protein levels were instantaneously associated with a higher risk of death.

Loss of function of CMPK2 causes mitochondria deficiency and brain calcification.

Brain calcification is a critical aging-associated pathology and can cause multifaceted neurological symptoms. Cerebral phosphate homeostasis dysregulation, blood-brain barrier defects, and immune dysregulation have been implicated as major pathological processes in familial brain calcification (FBC). Here, we analyzed two brain calcification families and identified calcification co-segregated biallelic variants in the CMPK2 gene that disrupt mitochondrial functions. Transcriptome analysis of peripheral blood mononuclear cells (PBMCs) isolated from these patients showed impaired mitochondria-associated metabolism pathways. In situ hybridization and single-cell RNA sequencing revealed robust Cmpk2 expression in neurons and vascular endothelial cells (vECs), two cell types with high energy expenditure in the brain. The neurons in Cmpk2-knockout (KO) mice have fewer mitochondrial DNA copies, down-regulated mitochondrial proteins, reduced ATP production, and elevated intracellular inorganic phosphate (Pi) level, recapitulating the mitochondrial dysfunction observed in the PBMCs isolated from the FBC patients. Morphologically, the cristae architecture of the Cmpk2-KO murine neurons was also impaired. Notably, calcification developed in a progressive manner in the homozygous Cmpk2-KO mice thalamus region as well as in the Cmpk2-knock-in mice bearing the patient mutation, thus phenocopying the calcification pathology observed in the patients. Together, our study identifies biallelic variants of CMPK2 as novel genetic factors for FBC; and demonstrates how CMPK2 deficiency alters mitochondrial structures and functions, thereby highlighting the mitochondria dysregulation as a critical pathogenic mechanism underlying brain calcification.

Suppression of SREBP-1 Expression by Simvastatin Decreases Visfatin-Induced Chemoresistance to Sunitinib in Human Renal Carcinoma 786-O Cells.

The resistance of renal cell carcinoma (RCC) to sunitinib impedes the success of chemotherapy in cancer treatment. Although several sunitinib resistance mechanisms have been proposed, little is known concerning the impact of obesity and adipokines in RCC cells. The upregulation of sterol-regulatory element-binding protein-1 (SREBP-1) has been reported to modulate the progression of tumor cells. The present study investigated the effect of visfatin on sunitinib-induced cytotoxicity in RCC cells through SREBP-1 expression. We found that visfatin-induced Akt and p70S6K activation increased SREBP-1 expression in 786-O cells. The visfatin-induced SREBP-1 mRNA and protein levels were attenuated through the inactivation of Akt and p70S6K by pharmacological inhibitors. In addition, the SREBP-1 knockdown using siRNA enhanced the cytotoxic effects of sunitinib. Our results also revealed the roles of simvastatin in attenuating the effects of visfatin on 786-O cells by inhibiting the production of reactive oxygen species. In particular, simvastatin co-treatment increased the cell cytotoxicity of sunitinib in visfatin-treated 786-O cells, which were associated with down-regulation of SREBP-1 expression. Our results suggest an important role of SREBP-1 in visfatin-induced drug resistance of RCC cells to sunitinib. The cytotoxic mechanism of simvastatin on RCC cells may provide a new strategy to improve therapeutic outcomes for the RCC treatment.

Accelerated Corneal Endothelial Cell Loss after Phacoemulsification in Patients with Mildly Low Endothelial Cell Density.

By evaluating preoperative endothelial cell density (ECD), ECD loss after phacoemulsification can be predicted. In this retrospective cross-sectional study, we compared outcomes of phacoemulsification with different levels of preoperative ECD. Three-hundred-and-fifty-three patients aged between 18 and 90 years received phacoemulsification at Chang Gung Memorial Hospital. Age (p = 0.003), preoperative logMAR (p = 0.048), cataract grade (p = 0.005), preoperative ECD (p < 0.001), operation time (p = 0.043), phacoemulsification time (p = 0.001), and phacoemulsification energy (p < 0.001) were significantly associated with postoperative ECD change (%). Patients were divided into three groups according to preoperative ECD levels. Level of ECD, coefficient of variation (CV), cell hexagonality (HEX), central corneal thickness (CCT), visual acuity, underlying diseases, and complications were analyzed. With regard to groups, 29, 71, and 252 patients were respectively allocated into the markedly low (group A; ECD below 1000 cells/mm2), mildly low (group B; ECD between 1000 to 2000 cells/mm2), and normal (group C; ECD above 2000 cells/mm2) ECD level groups. The highest CV (40.8 ± 13.9%; p < 0.001) and lowest HEX (58.4 ± 14.6%; p < 0.001) were found in group A. Significant ECD loss was found in group B (28.9 ± 9.2%) as compared to group A (19.9 ± 5.4%) and C (15.0 ± 12.0%) (p < 0.001). No significant differences were found with regard to changes in CV (p = 0.941), HEX (p = 0.937), CCT (p = 0.346), and logMAR (p = 0.557) among the three groups. In conclusion, preoperative ECD level could be a novel predictive value for postoperative cell loss, which was the most prominent in mildly low ECD level group. Less phacoemulsification energy, earlier surgical intervention, or novel topical medications could be suggested for patients with an ECD range from 1000 to 2000 cells/mm2.

Clinical features of gingivostomatitis due to primary infection of herpes simplex virus in children.

BACKGROUND: Primary herpetic gingivostomatitis (PHGS) in children, though usually self-limited, might mimic bacterial and enteroviral pharyngitis clinically. We conducted a study to define the clinical features of PHGS in children. METHODS: Between January 2012 and December 2016, 282 inpatients aged less than 19 years with cell culture-confirmed herpes simplex virus (HSV) infection in a medical center were identified from the virologic laboratory logbook. Clinical data were retrospectively collected. RESULTS: Among the 282 inpatients, 185 cases were considered as PHGS and were included for analysis. Fever was present in 99.5%. The mean duration of fever was 5.11 days (±2.24) with the longest being 17 days. Common oral manifestations included oral ulcers (84.3%), which equally resided in the anterior and posterior part of the oral cavity (65.4% vs. 63.2%), gum swelling and/or bleeding (67.6%), and exudate coated tonsils (16.8%). Leukocytosis (WBC count > 15,000/uL3) was noted in 52 patients (28.1%) and a serum C-reactive protein level > 40 mg/L in 55 patients (29.7%). Fixty-five patients (35%) were diagnosed with PHGS on admission and were significantly more likely to have ulcers over the anterior oral cavity (76.1% vs. 26.7%) and gum swelling/bleeding (76.2% vs. 7.5%, p-value all < 0.001) on admission and were significantly less likely to receive antibiotic treatment (16.9 vs. 36.7%, p-value < 0.01) than others. Forty-six patients (25%) undiagnosed as PHGS on discharge were significantly more likely to have exudate coated on the tonsils, to receive antibiotic treatment and significantly less likely to have gum swelling/bleeding and oral ulcers (all p-values < 0.01). CONCLUSIONS: Meticulously identifying specific oral manifestations of gum swelling/bleeding and ulcers over the anterior oral cavity in children can help making the diagnosis of PHGS earlier and subsequently reduce unnecessary prescription of antibiotics.

Promotion of Bone Formation by Red Yeast Rice in Experimental Animals: A Systematic Review and Meta-Analysis.

OBJECTIVE: To systematically evaluate the effects of red yeast rice (RYR) and its extract on bone formation in experimental animals and to provide reference data for clinical research on the treatment of osteoporosis. METHODS: Chinese and English language databases, including Web of Science, PubMed, the Cochrane Library, Elsevier, Google Scholar, SpringerLink, Embase, China National Knowledge Infrastructure (CNKI), Weipu Chinese Sci-tech periodical full-text database (VIP), and Wanfang Data Knowledge Service Platform (Wanfang), were searched from their establishment to February 2020 using the following terms: "hongqu," "red yeast rice," "Monascus purpureus-fermented rice," "bone mineral density," "osteoblast," "osteoporosis," and "animal models." After excluding nonrelevant articles, Review Manager 5.2 was used to evaluate article quality and to analyze the data. Outcome indicators included bone mineral density (BMD), osteoblast proliferation, and the expression of alkaline phosphatase (ALP). RESULTS: A total of 11 randomized controlled trials were included in the meta-analysis, all of which were animal studies. Six studies included data on BMD, five on osteoblast proliferation, and six on the expression of ALP. The results of the meta-analysis showed that RYR can significantly improve BMD (standardized mean difference (SMD) = 3.12, 95% confidence interval (CI) 1.41 to 4.83, P = 0.0003), promote osteoblast proliferation (SMD = 1.64, 95% CI 1.04 to 2.23, P < 0.00001), and increase ALP expression in rats (SMD = 1.25, 95% CI 0.69 to 1.80, P < 0.00001). CONCLUSIONS: RYR can promote bone formation in experimental animals and may be useful for the treatment of osteoporosis.

Study of Electronic and Vibrational Structures of Reduced, Neutral, and Oxidized Ni3(dpa)4X2 Using Density Functional Theory and Raman Spectroscopy.

The electronic and vibrational structures of trinickel metal string complexes [Ni3(dpa)4X2]1-,0,1+ (X = Cl, NCS) were investigated using both theoretical calculations and spectroscopic methods. We used the density functional theory (DFT) method B3LYP*-D3, including less exact exchange energy and the van der Waals interaction of metal ions, to obtain the geometries and vibrational structures, which were found to be in excellent agreement with the experimental data. The ground state of Ni3(dpa)4X2 is an antiferromagnetic (AF) singlet state, and the next state is a quintet state, which was detected using temperature-dependent Raman spectroscopy under a magnetic field. The vibrational structure of the quintet state is nearly identical to that of the AF state, according to the measured Raman spectra, except that the stretching of Ni-Cl is blue-shifted from 282.5 cm-1 in the AF state to 283.8 cm-1 in the quintet state. Two oxidized Ni3 complexes were found to have [Ni3]7+ cores, the doublet [Ni3(dpa)4]3+ without axial ligands and the quartet [Ni3(dpa)4X2]+. Complex [Ni3(dpa)4X2]-, which was produced from a reduction reaction by gold nanoparticles at room temperature, consists of a quartet state as the ground state and a doublet state lying nearby.

Associations between estimated glomerular filtration rate and cardiac biomarkers.

BACKGROUND: Chronic kidney disease (CKD) is associated with an increased cardiovascular disease (CVD) mortality risk. Elevation of cardiac biomarkers in patients with renal dysfunction is ambiguous in the diagnosis of CVD. The purpose of this study was to investigate the associations between estimated glomerular filtration rate (eGFR) and cardiac biomarkers, and the influence of renal dysfunction on the cardiac biomarkers. METHODS: We examined the cross-sectional associations of eGFR with cardiac troponin I (cTnI), creatine kinase (CK), CK-MB, lactic dehydrogenase (LDH), hydroxybutyrate dehydrogenase (HBDH), and brain natriuretic peptide (BNP) in 812 adults and 215 child. Spearman correlation and logistic regression analysis were performed to evaluate the associations. RESULTS: For adults, lower eGFR CKD-EPI had significantly higher cTnI, CK-MB, LDH, HBDH, and BNP. There were negative correlations between eGFRCKD-EPI and cTnI, CK-MB, LDH, HBDH, and BNP. After adjustment for potential confounders, as compared with eGFRCKD-EPI  ≥ 90 mL/min/1.73 m2 , eGFRCKD-EPI  < 60 mL/min/1.73 m2 remained associated with a 2.83 (1.08-7.41) [ratio (95% CI)] times higher cTnI and a 6.50 (2.32-18.22) [ratio (95% CI)] times higher HBDH. For child, lower eGFRSchwartz had significant higher CK and CK-MB. There were negative correlations between eGFRSchwartz and CK, and eGFRSchwartz and CK-MB. After adjustment for potential confounders, as compared with eGFRSchwartz  ≥ 90 mL/min/1.73 m2 , eGFRSchwartz  < 90 mL/min/1.73 m2 revealed no significant higher CVD biomarkers. CONCLUSION: Reduced eGFR is associated with elevated cTnI and HBDH among adults without clinically evident CVD, but not child.

Spatial Attention Disregard in Children With Hemiplegic Cerebral Palsy.

IMPORTANCE: Children with hemiplegic cerebral palsy (CP) demonstrate spatial attention disregard, but the rehabilitation approach to CP is traditionally motor oriented. OBJECTIVE: To explore spatial attention disregard in children with hemiplegic CP and its relationship to their motor performance in daily activities. DESIGN: Cross-sectional study. SETTING: Community. PARTICIPANTS: Twenty-five children with hemiplegic CP and 25 age-matched typically developing children. OUTCOMES AND MEASURES: For spatial attention performance, the Random Visual Stimuli Detection Task; for developmental disregard, the Observatory Test of Capacity, Performance, and Developmental Disregard; and for motor performance, the Melbourne Assessment 2. RESULTS: Children with hemiplegic CP evidenced spatial attention disregard on their more affected sides, and this phenomenon was correlated with developmental disregard. CONCLUSIONS AND RELEVANCE: Children with hemiplegic CP demonstrate developmental disregard in both the motor and the visual-spatial attention domains. Including evaluation of and intervention for visual-spatial attention for children with hemiplegic CP in the traditionally motor-oriented rehabilitation approach is recommended. WHAT THIS ARTICLE ADDS: This research provides evidence that children with hemiplegic CP demonstrate disregard in the domain of visual-spatial attention. The findings suggest that evaluation of and intervention for visual-spatial attention should be included in CP rehabilitation in addition to the traditionally motor-oriented approach.

Investigation of the cis-trans structures and isomerization of oligoprolines by using Raman spectroscopy and density functional theory calculations: solute-solvent interactions and effects of terminal positively charged amino acid residues.

Using low-wavenumber Raman spectroscopy in combination with theoretical calculations via solid-state density functional theory (DFT)-D3, we studied the vibrational structures and interaction with solvent of poly-l-proline and the oligoproline P12 series. The P12 series includes P12, the positively charged amino acid residue (arginine and lysine) N-terminus proline oligomers RP11 and KP11, and the C-terminus P11R and P11K. We assigned the spring-type phonon mode to 74-76 cm-1 bands for the PPI and PPII conformers and the carbonyl group ring-opening mode 122 cm-1 in the PPI conformer of poly-l-proline. Amide I and II were assigned based on the results of mode analysis for O, N, and C atom displacements. The broad band feature of the H-bond transverse mode in the Raman spectra indicates that the positively charged proline oligomers PPII form H-bonds with water in the solid phase, whereas P12 is relatively more hydrophobic. In propanol, the PPI conformer of the P12 series forms less H-bond network with the solvent. The PPII conformer exhibits a distinct Raman band at 310 cm-1, whereas the PPI has bands at 365, 660, and 960 cm-1 with reasonable intensity that can be used to quantitatively determine these two conformational forms. The 365 cm-1 mode comprising the motion of a C[double bond, length as m-dash]O group turning to the helix axis was used to monitor the isomerization reaction PPI ↔ PPII. In pure propanol, RP11 and KP11 were found to have mostly PPI present, but P11R and P11K preferred PPII. After adding 20% water, the PPI in P11R and P11K was completely converted to PPII, whereas a small fraction of PPI remained in RP11 and KP11. The substituted positively charged amino acid affected the balance of the PPI/PPII population ratio.

A performance guide for major risk factors control in patients with atherosclerotic cardiovascular disease in Taiwan.

Atherosclerotic cardiovascular disease (ASCVD), including coronary artery disease, cerebrovascular disease, and peripheral artery disease, carries a high morbidity and mortality. Risk factor control is especially important for patients with ASCVD to reduce recurrent cardiovascular events. Clinical guidelines have been developed by the Taiwan Society of Cardiology, Taiwan Society of Lipids and Atherosclerosis, and Diabetes Association of Republic of China (Taiwan) to assist health care professionals in Taiwan about the control of hypertension, hypercholesterolemia and diabetes mellitus. This article is to highlight the recommendations about blood pressure, cholesterol, and sugar control for ASCVD. Some medications that are beneficial for ASCVD were also reviewed. We hope the clinical outcomes of ASCVD can be improved in Taiwan through the implementation of these recommendations.