Profile of a Multivariate Observation under Destructive Sampling-A Monte Carlo Approach to a Case of Spina Bifida.

A biodegradable hybrid polymer patch was invented at the University of Cincinnati to cover gaps on the skin over the spinal column of a growing fetus, characterized by the medical condition spina bifida. The inserted patch faces amniotic fluid (AF) on one side and cerebrospinal fluid on the other side. The goal is to provide a profile of the roughness of a patch over time at 0, 4, 8, 12, and 16 weeks with a 95% confidence band. The patch is soaked in a test tube filled with either amniotic fluid (AF) or phosphate-buffered saline (PBS) in the lab. If roughness is measured at any time point for a patch, the patch is destroyed. Thus, it is impossible to measure roughness at all weeks of interest for any patch. It is important to assess the roughness of a patch because the rougher the patch is, the faster the skin grows under the patch. We use a model-based approach with Monte Carlo simulations to estimate the profile over time with a 95% confidence band. The roughness profiles are similar with both liquids. The profile can be used as a template for future experiments on the composition of patches.

Reliability of Systematic and Targeted Biopsies versus Prostatectomy.

Systematic Biopsy (SBx) has been and continues to be the standard staple for detecting prostate cancer. The more expensive MRI guided biopsy (MRITBx) is a better way of detecting cancer. The prostatectomy can provide an accurate condition of the prostate. The goal is to assess how reliable SBx and MRITBx are vis à vis prostatectomy. Graded Gleason scores are used for comparison. Cohen's Kappa index and logistic regression after binarization of the graded Gleason scores are some of the methods used to achieve our goals. Machine learning methods, such as classification trees, are employed to improve predictability clinically. The Cohen's Kappa index is 0.31 for SBx versus prostatectomy, which means a fair agreement. The index is 0.34 for MRITBx versus prostatectomy, which again means a fair agreement. A direct comparison of SBx versus prostatectomy via binarized graded scores gives sensitivity 0.83 and specificity 0.50. On the other hand, a direct comparison of MRITBx versus prostatectomy gives sensitivity 0.78 and specificity 0.67, putting MRITBx on a higher level of accuracy. The SBx and MRITBx do not yet match the findings of prostatectomy completely, but they are useful. We have developed new biomarkers, considering other pieces of information from the patients, to improve the accuracy of SBx and MRITBx. From a clinical point of view, we provide a prediction model for prostatectomy Gleason grades using classification tree methodology.

Brown Slime Cap Mushroom (Chroogomphus rutilus, Agaricomycetes) Polysaccharide Resists Motion Sickness by Inhibiting the Activity of the Serotonin System in Mice.

Motion sickness (MS) is a disorder of the autonomic nervous system caused by abnormal exercise with symptoms such as nausea, vomiting and drowsiness. More than 90% of the human population has experienced different degrees of MS. At present, anticholinergics, antihistamines, and sympathomimetic drugs are used for treating MS, but these drugs generally have some adverse reactions and are not suitable for all people. Therefore, it is necessary to develop anti-MS drugs that have high efficiency and no adverse effects. Previous studies have found that Chroogomphus rutilus polysaccharide (CRP) is effective at preventing and treating MS in rats and mice. However, its mechanism of action is not clear. To clarify whether the CRP has anti-MS effects in mice, and to clarify its mechanism, we performed behavioral, biochemical, and morphological tests in a Kunming mouse model. Our results indicate that CRPs can significantly relieve the symptoms of MS, and their effect is equivalent to that of scopolamine, a commonly used anti-MS medicine. Our results indicate that CRPs may directly act on the gastrointestinal chromaffin cells to inhibit the synthesis and release of serotonin (5-hydroxytryptamine, or 5-HT) and thus reduce the signal from the gastrointestinal tract.

The putative protein kinase Stk36 is essential for ciliogenesis and CSF flow by associating with Ulk4.

Motile cilia lining on the ependymal cells are crucial for cerebrospinal fluid (CSF) flow and its dysfunction is often associated with hydrocephalus. Unc51-like-kinase 4 (Ulk4) was previously linked to CSF flow and motile ciliogenesis in mice, as the hypomorph mutant of Ulk4 (Ulk4tm1a/tm1a ) developed hydrocephalic phenotype resulted from defective ciliogenesis and disturbed ciliary motility, while the underling mechanism is largely obscure. Here, we report that serine/threonine kinase 36 (STK36), a paralog of ULK4, directly interacts with ULK4 and this was demonstrated by yeast two-hybrid (Y2H) in yeast and coimmunoprecipitation (co-IP) assays in HEK293T cells, respectively. The interaction region was confined to their respective N-terminal kinase domain. The hypomorph mutant of Stk36 (Stk36tmE4-/- ) also developed progressive hydrocephalus postnatally and dysfunctional CSF flow, with multiple defects of motile cilia, including reduced ciliary number, disorganized ciliary orientation, defected axonemal structure and inconsistent base body (BB) orientation. Stk36tmE4-/- also disturbed the expression of Foxj1 transcription factor and a range of other ciliogenesis-related genes. All these morphological changes, motile cilia defects and transcriptional dysregulation in the Stk36tmE4-/- are practically copied from that in Ulk4tm1a/tm1a mice. Taken together, we conclude that both Stk36 and Ulk4 are crucial for CSF flow, they cooperate by direct binding with their kinase domain to regulate the Foxj1 transcription factor pathways for ciliogenesis and cilia function, not limited to CSF flow. The underlying molecular mechanism probably conserved in evolution and could be extended to other metazoans.

Sample Size Calculations in Simple Linear Regression: A New Approach.

The problem tackled is the determination of sample size for a given level and power in the context of a simple linear regression model. The standard approach deals with planned experiments in which the predictor X is observed for a number n of times and the corresponding observations on the response variable Y are to be drawn. The statistic that is used is built on the least squares' estimator of the slope parameter. Its conditional distribution given the data on the predictor X is utilized for sample size calculations. This is problematic. The sample size n is already presaged and the data on X is fixed. In unplanned experiments, in which both X and Y are to be sampled simultaneously, we do not have data on the predictor X yet. This conundrum has been discussed in several papers and books with no solution proposed. We overcome the problem by determining the exact unconditional distribution of the test statistic in the unplanned case. We have provided tables of critical values for given levels of significance following the exact distribution. In addition, we show that the distribution of the test statistic depends only on the effect size, which is defined precisely in the paper.

Systemic Immune-Inflammation Index is Associated with Cerebral Small Vessel Disease Burden and Cognitive Impairment.

Objective: This study sought to explore the associations of the systemic immune-inflammation index (SII) with total cerebral small vessel disease (CSVD) burden and cognitive impairment. Methods: We enrolled 201 patients in the retrospective study with complete clinical and laboratory data. The SII was calculated as platelet count × neutrophil count/lymphocyte count. Cognitive function was evaluated by the Mini-Mental State Examination (MMSE). Total CSVD burden was assessed based on magnetic resonance imaging. We performed logistic regression models, Spearman correlation, and mediation analysis to evaluate the associations of SII with CSVD burden and cognitive impairment. Results: After adjustment for confounding factors in the multivariate binary logistic regression model, elevated SII (odds ratio [OR], 3.263; 95% confidence interval [CI], 1.577-6.752; P = 0.001) or severe CSVD burden (OR, 2.794; 95% CI, 1.342-5.817; P = 0.006) was significantly associated with the risk of cognitive impairment. Correlation analyses revealed that SII levels were negatively associated with MMSE scores (rs = -0.391, P < 0.001), and positively associated with the total CSVD burden score (rs = 0.361, P < 0.001). Moreover, SII was significantly related to the severity of the CSVD burden (OR, 2.674; 95% CI, 1.359-5.263; P = 0.004). The multivariable-adjusted odds ratios (95% CI) in highest tertile versus lowest tertile of SII were 8.947 (3.315-24.145) for cognitive impairment and 4.945 (2.063-11.854) for severe CSVD burden, respectively. The effect of higher SII on cognitive impairment development was partly mediated by severe CSVD burden. Conclusion: Elevated SII is associated with severe CSVD burden and cognitive impairment. The mediating role of severe CSVD burden suggests that higher SII may contribute to cognitive impairment through aggravating CSVD burden.

Baicalin facilitates remyelination and suppresses neuroinflammation in rats with chronic cerebral hypoperfusion by activating Wnt/ß-catenin and inhibiting NF-κB signaling.

One main factor contributing to the cognitive loss in vascular dementia (VD) is white matter lesions (WMLs) carried on by chronic cerebral hypoperfusion (CCH). A secondary neuroinflammatory response to CCH accelerates the loss and limits the regeneration of oligodendrocytes, leading to progressive demyelination and insufficient remyelination in the white matter. Thus, promoting remyelination and inhibiting neuroinflammation may be an ideal therapeutic strategy. Baicalin (BAI) is known to exhibit protective effects against various inflammatory and demyelinating diseases. However, whether BAI has neuroprotective effects against CCH has not been investigated. To determine whether BAI inhibits CCH-induced demyelination and neuroinflammation, we established a model of CCH in rats by occluding the two common carotid arteries bilaterally. Our results revealed that BAI could remarkably ameliorate cognitive impairment and mitigate CA1 pyramidal neuron damage and myelin loss. BAI exhibited enhancement of remyelination by increasing the expression of myelin basic protein (MBP) and oligodendrocyte transcription factor 2 (Olig2), inhibiting the loss of oligodendrocytes and promoting oligodendrocyte regeneration in the corpus callosum of CCH rats. Furthermore, BAI modified microglia polarization to the anti-inflammatory phenotype and inhibited the release of pro-inflammatory cytokines. Mechanistically, BAI treatment significantly induced phosphorylation of glycogen synthase kinase 3ß (GSK3ß), enhanced the expression of ß-catenin and its nuclear translocation. Simultaneously, BAI reduced the expression of nuclear NF-κB. Collectively, our results suggest that BAI ameliorates cognitive impairment in CCH-induced VD rats through its pro-remyelination and anti-inflammatory capacities, possibly by activating the Wnt/ß-catenin and suppressing the NF-κB signaling.

Dulaglutide Improves Gliosis and Suppresses Apoptosis/Autophagy Through the PI3K/Akt/mTOR Signaling Pathway in Vascular Dementia Rats.

Dulaglutide is a new type of hypoglycemic agent that agonizes glucagon-like peptide-1 receptor (GLP-1RA). It can be concluded from previous studies that a GLP-1RA can reduce apoptosis and regulate autophagy in the nervous system, while related research on dulaglutide in vascular dementia (VD) has not been reported. In our study, the VD rat model was established by bilateral carotid artery occlusion, and the results of the Morris water maze test (MWM) and open-field test showed that the application of dulaglutide could effectively reduce the cognitive decline of VD rats without changing the behavior in the open-field test, which was used to assess an anxiety-like phenotype. We applied HE staining and immunofluorescence labeling to show that dulaglutide treatment significantly alleviated neuronal damage in the hippocampal region of VD rats, and reduced microglial and astrocyte proliferation. Western blot results showed that dulaglutide reduced VD-induced neuronal apoptosis (BCL2/BAX, c-caspase3) and autophagy (P62, LC3B, Beclin-1), and upregulated phosphorylation of PI3K/Akt/mTOR signaling pathway. KEGG pathway analysis of RNA-Sequence results showed that the differentially expressed genes in the dulaglutide treatment group were significantly enriched in the mTOR signaling pathway, and the repressor of mTOR, Deptor, was down-regulated. In conclusion, this study suggested that dulaglutide may alleviate learning and memory impairment and neuron damage in VD rats by attenuating apoptosis, regulating autophagy, and activating the PI3K/Akt/mTOR signaling pathway in neurons, which may make it a promising candidate for the simultaneous treatment of VD and diabetes.

Does the type of biopsy used for diagnosis impact subsequent treatment selection in prostate cancer patients?

PURPOSE: Multiparametric magnetic resonance imaging (mpMRI) targeted biopsy has emerged as an augmentation to systematic prostate biopsy (SBx) with improved diagnostic accuracy. The purpose of this study was to determine whether biopsy modality impacted management of prostate cancer (PCa). METHODS: We performed a retrospective review of patients with newly diagnosed non-metastatic PCa at our institution (2014-2020). Either ultrasound-guided 12-core SBx or SBx plus ≥1targeted biopsy cores from identifiable lesions on mpMRI were performed. Patients were managed with active surveillance (AS), radiation therapy (RT), or radical prostatectomy (RP). Multivariate logistic and multinomial regression analyses were performed. RESULTS: Of 578 patients, 221(38%) proceeded with AS, 121(21%) received RT, and 236(41%) underwent RP. Median age and prostate-specific antigen (PSA) were 65.4 years and 7.2 ng/mL, respectively. On multivariate analysis, biopsy type did not predict decision to pursue treatment (p=.951). On multinomial regression analysis, biopsy type did not predict selection of AS over RP (p=.973) or RT over RP (p=.813). Alternatively, age, grade group, and PSA were significant predictors of management selection. CONCLUSIONS: Biopsy technique did not impact management for patients with new PCa diagnosis. Despite paradigm shifts in obtaining tissue diagnosis, age, PSA, and grade group remain valuable indices for shared decision-making and counseling patients with PCa.

Liraglutide Regulates Mitochondrial Quality Control System Through PGC-1α in a Mouse Model of Parkinson's Disease.

Parkinson's disease (PD) is a multifactorial disorder, and there is strong evidence that mitochondria play an essential role in the disorder. Factors that regulate the mechanism of the mitochondrial quality control system have been drawing more and more attention. PGC-1α (peroxisome proliferator-activated receptor-γ coactivator-1α) is a powerful transcription factor involved in regulation of mitochondrial function. Glucagon-like peptide 1 (GLP-1), a brain-gut peptide, can enter the central nervous system through the blood-brain barrier and play neuroprotective role. However, whether the GLP-1R agonist liraglutide regulates mitochondrial quality control system through PGC-1α is still unclear. We administered different doses of liraglutide to intervene MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-induced PD model, and then immunofluorescence, Western blot, and stereotactic injection of lentivirus to downregulate PGC-1α were used to explore the mechanisms underlying the protective effect of liraglutide in PD. The results showed that MPTP lead to decreased mitochondrial biogenesis, disrupted mitochondrial dynamics, inhibited mitochondrial autophagy, and promoted cell apoptosis. While liraglutide effectively attenuated the neurotoxicity of MPTP, including reversing the dyskinesia caused by MPTP and preserving the expression of GLP-1R, TH, and PGC-1α in the substantia nigra (SN), further experiments showed that downregulation of PGC-1α expression via stereotactic injection PGC-1α lentivirus into the SN reversed the liraglutide protective effects. By PGC-1α downregulation, we found that PGC-1α can not only regulate mitochondria biogenesis, mitochondria dynamics, and autophagy, but also regulate cell apoptosis. In summary, liraglutide has a neuroprotective effect in the PD model induced by MPTP. This protective effect is accomplished by activating PGC-1α, which regulates the mitochondrial quality control system.

A Comparison of Cancer Detection Rates Between Template Systematic Biopsies Obtained Using Magnetic Resonance Imaging-Ultrasound Fusion Machine and Freehand Transrectal Ultrasound-Guided Systematic Biopsies.

Introduction: There are reports that the 12-core template systematic biopsies (SBx) obtained by using software registration machines (e.g., Artemis) have higher cancer detection rates (CDRs) of prostate cancer (PCa) than the standard, freehand 12-core transrectal ultrasound (TRUS)-guided biopsies. The goal of our study is to compare the clinically significant (CS) CDRs of SBx in two independent cohorts who underwent freehand TRUS-SBx alone (Cohort A) or machine-guided SBx as part of a combined MRI-ultrasound (MRI-US) fusion biopsy (FBx) (Cohort B). Materials and Methods: A retrospective review of all patients undergoing prostate biopsies over a 4-year period at the University of Cincinnati Medical Center was performed. CS cancer was defined as having a Gleason score ≥7. MRI-US FBx were obtained by using an Artemis software registration device (ARTEMIS™, Eigen, Inc., Grass Valley, CA). Statistical significance was considered at p < 0.05. Results: Nine hundred and thirty men underwent SBx (Cohort A: 474, Cohort B: 456). There were no statistical differences between cohort A and B in CS CDRs in the overall population (39.3% vs 33.8%; p = 0.093), biopsy naive patients (40.4% vs 39.8%; p = 0.951), or patients with a prior negative biopsy (22.7% vs 25.0%; p = 0.910). Multivariate logistic regression controlling for age, race, prostate-specific antigen level, prostate volume, abnormal digital rectal exam, and family history of PCa demonstrated comparable CS CDRs, which was maintained when further stratified by prior biopsy history (all patients: odds ratio [OR] 0.99, 95% confidence interval [CI] 0.71-1.38, p = 0.958; biopsy naive: OR 0.79, 95% CI 0.51-1.22, p = 0.291; prior negative biopsy: OR 0.64, 95% CI 0.21-1.75, p = 0.403). Conclusions: Our study did not find a significant difference in the CS CDRs of machine-guided SBx compared with the freehand TRUS-SBx. Unless the SBx is done at the time of FBx, the use of these machines for obtaining SBx only is unlikely to result in any increase of CS CDRs.

Correction to: miRNAs and target genes in the blood as biomarkers for the early diagnosis of Parkinson's disease.

AbstractIt was highlighted that the original article [1] contained some typesetting mistakes in the first paragraph of the Background section.

miRNAs and target genes in the blood as biomarkers for the early diagnosis of Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) is the second most common neurodegenerative disease, and it is a multifactorial disease with no definite diagnostic index. The aim of this study is to construct a molecular network to find molecules that play important roles in the progression of PD with the goal of using them diagnostically and for early intervention. RESULTS: We downloaded two gene expression profiles (GSE54536 and GSE100054) from the Expression Omnibus (GEO) database to analyze possible markers. The Genes were analyzed with GEO2R. There were 1790 and 967 differentially expressed genes (DEGs) in GSE54536 and GSE100054 respectively. A total of 125 genes co-exist in the DEGs of the two data sets. KEGG pathway analysis showed that 125 DEGs were enriched in Aldosterone synthesis and secretion, Gap junctions, Platelet activation, Rap1 signaling pathway, and Estrogen signaling pathway. There were 20 hub genes among 125 DEGs analyzed by PPI that involved in Platelet activation, Inflammatory response, Innate immune response, B cell receptor signaling, Stimulatory C-type lectin receptor signaling, Lipopolysaccharide response, Leukocyte migration, and Regulation of cell proliferation. Additionally, 42 differences in miRNAs were found in GSE100054. We constructed a miRNA-mRNA regulatory network depicting interactions between the predicted genes and the 125 DEGs. 34 miRNA-mRNA pairs were obtained. We found GNAQ and TMTC2 were the most important mRNAs in the network analyzed by Cytoscape APP centiscape, and their degrees in centiscape2.2 were all 10. has-miR-142 was the most important miRNA (the highest degree is 4 in centiscape2.2), which forms miRNA-mRNA pairs with GNAQ, TMTC2, BEND2, and KYNU. CONCLUSIONS: This study provides data of potential biomarkers and therapeutic targets for PD diagnosis and treatment. Among them, hsa-miR-142 is a critical miRNA in the PD network, and may be involved in PD progression by regulating GNAQ, TMTC2, BEND2, and KYNU.