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Nicholas L. Balderston ◽  
Joanne C. Beer ◽  
Darsol Seok ◽  
Walid Makhoul ◽  
Zhi-De Deng ◽  

AbstractResting state functional connectivity (rsFC) offers promise for individualizing stimulation targets for transcranial magnetic stimulation (TMS) treatments. However, current targeting approaches do not account for non-focal TMS effects or large-scale connectivity patterns. To overcome these limitations, we propose a novel targeting optimization approach that combines whole-brain rsFC and electric-field (e-field) modelling to identify single-subject, symptom-specific TMS targets. In this proof of concept study, we recruited 91 anxious misery (AM) patients and 25 controls. We measured depression symptoms (MADRS/HAMD) and recorded rsFC. We used a PCA regression to predict symptoms from rsFC and estimate the parameter vector, for input into our e-field augmented model. We modeled 17 left dlPFC and 7 M1 sites using 24 equally spaced coil orientations. We computed single-subject predicted ΔMADRS/HAMD scores for each site/orientation using the e-field augmented model, which comprises a linear combination of the following elementwise products (1) the estimated connectivity/symptom coefficients, (2) a vectorized e-field model for site/orientation, (3) rsFC matrix, scaled by a proportionality constant. In AM patients, our connectivity-based model predicted a significant decrease depression for sites near BA9, but not M1 for coil orientations perpendicular to the cortical gyrus. In control subjects, no site/orientation combination showed a significant predicted change. These results corroborate previous work suggesting the efficacy of left dlPFC stimulation for depression treatment, and predict better outcomes with individualized targeting. They also suggest that our novel connectivity-based e-field modelling approach may effectively identify potential TMS treatment responders and individualize TMS targeting to maximize the therapeutic impact.

2021 ◽  
Vol 12 ◽  
Gwenda F. Vasse ◽  
Lisette Van Os ◽  
Marina De Jager ◽  
Marnix R. Jonker ◽  
Theo Borghuis ◽  

Introduction: Idiopathic pulmonary fibrosis (IPF) is a fibrotic lung disease characterized by excess deposition and altered structure of extracellular matrix (ECM) in the lungs. The fibrotic ECM is paramount in directing resident cells toward a profibrotic phenotype. Collagens, an important part of the fibrotic ECM, have been shown to be structurally different in IPF. To further understand the disease to develop better treatments, the signals from the ECM that drive fibrosis need to be identified. Adipose tissue-derived stromal cell conditioned medium (ASC-CM) has demonstrated antifibrotic effects in animal studies but has not been tested in human samples yet. In this study, the collagen structural integrity in (fibrotic) lung tissue, its interactions with fibroblasts and effects of ASC-CM treatment hereon were studied.Methods: Native and decellularized lung tissue from patients with IPF and controls were stained for denatured collagen using a collagen hybridizing peptide. Primary lung fibroblasts were seeded into decellularized matrices from IPF and control subjects and cultured for 7 days in the presence or absence of ASC-CM. Reseeded matrices were fixed, stained and analyzed for total tissue deposition and specific protein expression.Results: In both native and decellularized lung tissue, more denatured collagen was observed in IPF tissue compared to control tissue. Upon recellularization with fibroblasts, the presence of denatured collagen was equalized in IPF and control matrices, whereas total ECM was higher in IPF matrices than in the control. Treatment with ASC-CM resulted in less ECM deposition, but did not alter the levels of denatured collagen.Discussion: Our data showed that ASC-CM can inhibit fibrotic ECM-induced profibrotic behavior of fibroblasts. This process was independent of collagen structural integrity. Our findings open up new avenues for ASC-CM to be explored as treatment for IPF.

Diagnostics ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 1347
Nivethitha Arunkumar ◽  
Dung Chi Vu ◽  
Shaukat Khan ◽  
Hironori Kobayashi ◽  
Thi Bich Ngoc Can ◽  

Mucopolysaccharidoses (MPS) and mucolipidosis (ML II/III) are a group of lysosomal storage disorders (LSDs) that occur due to a dysfunction of the lysosomal hydrolases responsible for the catabolism of glycosaminoglycans (GAGs). However, ML is caused by a deficiency of the enzyme uridine-diphosphate N-acetylglucosamine:lysosomal-enzyme-N-acetylglucosamine-1-phosphotransferase (GlcNAc-1-phosphotransferase, EC2.7.8.17), which tags lysosomal enzymes with a mannose 6-phosphate (M6P) marker for transport to the lysosome. A timely diagnosis of MPS and ML can lead to appropriate therapeutic options for patients. To improve the accuracy of diagnosis for MPS and ML in a high-risk population, we propose a combination method based on known biomarkers, enzyme activities, and specific GAGs. We measured five lysosomal enzymes (α-L-iduronidase (MPS I), iduronate-2-sulfatase (MPS II), α-N-acetylglucosaminidase (MPS IIIB), N-acetylglucosamine-6-sulfatase (MPS IVA), and N-acetylglucosamine-4-sulfatase (MPS VI)) and five GAGs (two kinds of heparan sulfate (HS), dermatan sulfate (DS), and two kinds of keratan sulfate (KS)) in dried blood samples (DBS) to diagnose suspected MPS patients by five-plex enzyme and simultaneous five GAGs assays. We used liquid chromatography-tandem mass spectrometry (LC-MS/MS) for both assays. These combined assays were tested for 43 patients with suspected MPS and 103 normal control subjects. We diagnosed two MPS I, thirteen MPS II, one MPS IIIB, three MPS IVA, two MPS VI, and six ML patients with this combined method, where enzymes, GAGs, and clinical manifestations were compatible. The remaining 16 patients were not diagnosed with MPS or ML. The five-plex enzyme assay successfully identified MPS patients from controls. Patients with MPS I, MPS II, and MPS IIIB had significantly elevated HS and DS levels in DBS. Compared to age-matched controls, patients with ML and MPS had significantly elevated mono-sulfated KS and di-sulfated KS levels. The results indicated that the combination method could distinguish these affected patients with MPS or ML from healthy controls. Overall, this study has shown that this combined method is effective and can be implemented in larger populations, including newborn screening.

2021 ◽  
Vol 17 ◽  
Yu-Feng Qing ◽  
Quan-Bo Zhang ◽  
Fei Dai ◽  
Yu-Qin Huang ◽  
Jian-Xiong Zheng ◽  

Background: Previous studies demonstrated that MicroRNA-146a (miR-146a) plays an important role in the regulation of autoinflammatory diseases including primary gout. The G/C polymorphism (rs2910164) in the precursor sequence of miR-146a caused its stem region to change from G: U to C: U,which can contribute to the susceptibility of human diseases. however, no genetic relevance studies of miR-146a gene polymorphisms to gout have been reported by now. Objective: The purpose of this study was to analyze the association between the miR-146a rs2910164 genetic polymorphism and the susceptibility of Chinese Han population to primary gout. Method:1130 Chinese Han participants (including 606 primary gout patients and 524 gender and age-matched healthy control subjects) were recruited and the 5'exonuclease TaqMan® technology was used to perform miR-146a rs2910164 genotyping. Method: 1130 Chinese Han participants (including 606 primary gout patients and 524 gender and age-matched healthy control subjects) were recruited and the 5'exonuclease TaqMan® technology was used to perform miR-146a rs2910164 genotyping. Result: After statistical analysis, no significant differences were observed between gout patients and healthy controls in genotype and allele frequency. Conclusion: Our results indicate that there is no evidence for the involvement of the miR-146a rs2910164 polymorphisms in susceptibility to primary gout in the Chinese Han population.

2021 ◽  
Mansoor Shahriari ◽  
Afshin Karimzadeh ◽  
Hadi Esmaily ◽  
Saman Rezanejad ◽  
Homayoun Nikkhah ◽  

Abstract Purpose To assess the occurrence and severity of electrodiagnostic signs of carpal tunnel syndrome (ED-CTS) in patients with ocular pseudoexfoliation (PEX) and compare them with normal subjects.Method A 1:1 case-control study was designed and 60 patients with PEX were recruited from May 2019 to February 2021, and the findings were compared with 59 age- and gender-matched healthy controls. All patients underwent complete ophthalmologic examination and nerve conduction velocity test at the median nerve was used to assess the occurrence and severity of ED-CTS in both hands.Results The mean age of participants was 59.8 ± 4.5 years. Occurrence of ED-CTS was 38.3% in PEX patients and 20.3% in control subjects (P = 0.025). There was also a significant difference in the severity, and presence of asymptomatic CTS (P < 0.05). Adjusting other variables, including; age, sex and job difficulty, having severe ED-CTS showed a 3.49-fold higher chance in the PEX group (P = 0.002). Conclusion There is a direct relation between PEX and the occurrence, as well as severity of ED-CTS.

2021 ◽  
Vol 10 (15) ◽  
pp. 3277
Ramón Martín-Brufau ◽  
Manuel Nombela Gómez ◽  
Leyre Sanchez-Sanchez-Rojas ◽  
Cristina Nombela

Objective: The identification of a complementary test to confirm the diagnosis of FM. The diagnosis of fibromyalgia (FM) is based on clinical features, but there is still no consensus, so patients and clinicians might benefit from such a test. Recent findings showed that pain lies in neuronal bases (pain matrices) and, in the long term, chronic pain modifies the activity and dynamics of brain structures. Our hypothesis is that patients with FM present lower levels of brain activity and therefore less connectivity than controls. Methods: We registered the resting state EEG of 23 patients with FM and compared them with 23 control subjects’ resting state recordings from the PhysioBank database. We measured frequency, amplitude, and functional connectivity, and conducted source localization (sLORETA). ROC analysis was performed on the resulting data. Results: We found significant differences in brain bioelectrical activity at rest in all analyzed bands between patients and controls, except for Delta. Subsequent source analysis provided connectivity values that depicted a distinct profile, with high discriminative capacity (between 91.3–100%) between the two groups. Conclusions: Patients with FM show a distinct neurophysiological pattern that fits with the clinical features of the disease.

2021 ◽  
Vol 16 (1) ◽  
pp. 105-114
Amos Dangana ◽  
Ifeoma Miracle Okoronkwo ◽  
Solomon Oloche Onoja ◽  
Innocent Nwabueze Okonkwo ◽  
Nonye Bibiana Egenti ◽  

Background: Albuminuria and Albumin-Creatinine Ratio (ACR) has been identified as early indices of cardiovascular diseases (CVD), Hypertension and are at great risk of hypertensive nephropathy, but this not so for the apparently healthy individuals. Objectives: This study was therefore carried out to evaluate and quantitate albuminuria and urine ACR among apparently healthy individual and to compare values with the hypertensive attending University of Nigeria Teaching Hospital, Ituku-Ozalla Enugu State. Materials and method: The study was carried out on eighty-nine (89) volunteers (50 tests and 39 controls) age 21-77 years between August and September 2019. A structured questionnaire was used to get vital information, anthropometric measurements were taken while blood and urine samples were collected and analyzed for serum creatinine (Scr), urine creatinine (UCr) and urine albumin using Jaffe modified kinetic method and Enzyme Linked Immunosorbent Assay (ELISA) method respectively. Body mass index (BMI) in Kg/m2, urine ACR in mg/mmol and estimated glomerular filtration rate (eGFR) using Chronic Disease Epidemiology Equation were calculated. Data were analyzed using student’s T-test and one-way Analysis of variance (ANOVA). Results: Generally, results showed that males have higher (p<0.05) height, Scr, eGFR, and UCr but lower (p<0.05) BMI) when compared with the females, but no significant difference (P>0.05) between systolic blood pressure (SBP), diastolic BP (DBP), pulse, weight, urine albumin and ACR. Also, the study revealed that the test subjects have higher SBP, DBP, weight, BMI, SCr, urine albumin, and ACR but lower (p<0.05) eGFR and UCr when compared with the control subjects, but no significant difference (P>0.05) between pulse and height. Furthermore, intra gender analysis of the results showed that males tests have higher SBP, DBP, weight, BMI and urine ACR but lower (p<0.05) eGFR and UCr when compared with male controls, but no significant difference (P>0.05) was observed for pulse, height, Scr and urine albumin. Finally, the results showed that female tests have higher (P<0.05) SBP, pulse, Scr, urine albumin and ACR but lower (p<0.05) eGFR when compared with the female controls Conclusion: Findings and results from this study suggest that the hypertensives stand a higher risk of kidney damage, consequently cardiovascular disease (CVD).

2021 ◽  
pp. 1-11
Sven J. van der Lee ◽  
Inger van Steenoven ◽  
Marleen van de Beek ◽  
Niccolo Tési ◽  
Iris E. Jansen ◽  

Background: Dementia with Lewy bodies (DLB) is a complex, progressive neurodegenerative disease with considerable phenotypic, pathological, and genetic heterogeneity. Objective: We tested if genetic variants in part explain the heterogeneity in DLB. Methods: We tested the effects of variants previously associated with DLB (near APOE, GBA, and SNCA) and polygenic risk scores for Alzheimer’s disease (AD-PRS) and Parkinson’s disease (PD-PRS). We studied 190 probable DLB patients from the Alzheimer’s dementia Cohort and compared them to 2,552 control subjects. The p-tau/Aβ 1–42 ratio in cerebrospinal fluid was used as in vivo proxy to separate DLB cases into DLB with concomitant AD pathology (DLB-AD) or DLB without AD (DLB-pure). We studied the clinical measures age, Mini-Mental State Examination (MMSE), and the presence of core symptoms at diagnosis and disease duration. Results: We found that all studied genetic factors significantly associated with DLB risk (all-DLB). Second, we stratified the DLB patients by the presence of concomitant AD pathology and found that APOE ɛ4 and the AD-PRS associated specifically with DLB-AD, but less with DLB-pure. In addition, the GBA p.E365K variant showed strong associated with DLB-pure and less with DLB-AD. Last, we studied the clinical measures and found that APOE ɛ4 associated with reduced MMSE, higher odds to have fluctuations and a shorter disease duration. In addition, the GBA p.E365K variant reduced the age at onset by 5.7 years, but the other variants and the PRS did not associate with clinical features. Conclusion: These finding increase our understanding of the pathological and clinical heterogeneity in DLB.

Diagnostics ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 1326
Pilar Cañadas ◽  
Yrbani Lantigua ◽  
Amalia Enríquez-de-Salamanca ◽  
Itziar Fernandez ◽  
Salvador Pastor-Idoate ◽  

Purpose: To report the ocular surface pathology of patients suffering from acute/subacute mercury vapor intoxication. Design: Cross-sectional study. Participants: Male workers intoxicated with inorganic mercury referred for ophthalmic involvement and healthy control subjects. Methods: The following tests were performed: dry eye (DE)-related symptoms indicated by the ocular surface disease (OSDI) index questionnaire; tear osmolarity; analysis of 23 tear cytokine concentrations and principal component and hierarchical agglomerative cluster analyses; tear break-up time (T-BUT); corneal fluorescein and conjunctival lissamine green staining; tear production by Schirmer and tear lysozyme tests; mechanical and thermal corneal sensitivity (non-contact esthesiometry); and corneal nerve analysis and dendritic cell density by in vivo confocal microscopy (IVCM). Results: Twenty-two out of 29 evaluated patients entered the study. Most had DE-related symptoms (OSDI values > 12), that were severe in 63.6% of them. Tear osmolarity was elevated (>308 mOsms/L) in 83.4% of patients (mean 336.23 (28.71) mOsm/L). Corneal and conjunctival staining were unremarkable. T-BUT was low (<7 s) in 22.7% of patients. Schirmer test and tear lysozyme concentration were low in 13.6% and 27.3% of cases, respectively. Corneal esthesiometry showed patient mechanical (mean 147.81 (53.36) mL/min) and thermal thresholds to heat (+2.35 (+1.10) °C) and cold (−2.57 (−1.24) °C) to be significantly higher than controls. Corneal IVCM revealed lower values for nerve density ((6.4 (2.94) n/mm2), nerve branching density (2 (2.50) n/mm2), and dendritic cell density (9.1 (8.84) n/mm2) in patients. Tear levels of IL-12p70, IL-6, RANTES, and VEGF were increased, whereas EGF and IP-10/CXCL10 were decreased compared to controls. Based on cytokine levels, two clusters of patients were identified. Compared to Cluster 1, Cluster 2 patients had significantly increased tear levels of 18 cytokines, decreased tear lysozyme, lower nerve branching density, fewer dendritic cells, and higher urine mercury levels. Conclusions: Patients suffering from systemic mercury intoxication showed symptoms and signs of ocular surface pathology, mainly by targeting the trigeminal nerve, as shown by alterations in corneal sensitivity and sub-basal nerve morphology.

Tingting Feng ◽  
Ping Miao ◽  
Bin Liu ◽  
Yao Liu ◽  
Ximing Bao ◽  

Chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by Th2-skewed inflammation and increased colonization by Staphylococcus aureus. CRSwNP can be distinguished as eosinophilic (ECRSwNP) and non-eosinophilic (NECRSwNP) by the infiltration of eosinophils. The local microbiota plays an important role in the persistent inflammation of CRSwNP. To evaluate the bacterial community composition on the distinct types of CRSwNP patients, we collected nasal swabs from 16 ECRSwNP patients, 18 NECRSwNP patients, and 39 healthy control subjects. The microbiome structure for all the samples were analyzed by high-throughput 16S rRNA gene sequencing. Concentration of S. aureus was determined using TaqMan quantitative polymerase chain reaction (qPCR) targeting the nuclease (nuc) gene. The result showed significant differences in the sinus microbiome among healthy control subjects and CRSwNP patients. Microbiota community diversity was significantly lower in NECRSwNP samples compared to that of healthy control subjects. Interestingly, the abundance of several pathogenic bacteria was diverse between ECRSwNP and NECRSwNP patients. Although Staphylococcus prevailed in all groups, the abundance of Staphylococcus was significantly higher in the healthy control group than the ECRSwNP group. More importantly, the abundance of S. aureus was much higher in NECRSwNP patients. This study highlights that microbiota composition may contribute to the different clinical types of CRSwNP, inspiring new therapeutic strategies to resolve this chronic inflammation process.

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