Identifying Novel Subtypes of Functional Gastrointestinal Disorder by Analyzing Nonlinear Structure in Integrative Biopsychosocial Questionnaire Data.

Background/Objectives: Given the limited success in treating functional gastrointestinal disorders (FGIDs) through conventional methods, there is a pressing need for tailored treatments that account for the heterogeneity and biopsychosocial factors associated with FGIDs. Here, we considered the potential of novel subtypes of FGIDs based on biopsychosocial information. Methods: We collected data from 198 FGID patients utilizing an integrative approach that included the traditional Korean medicine diagnosis questionnaire for digestive symptoms (KM), as well as the 36-item Short Form Health Survey (SF-36), alongside the conventional Rome-criteria-based Korean Bowel Disease Questionnaire (K-BDQ). Multivariate analyses were conducted to assess whether KM or SF-36 provided additional information beyond the K-BDQ and its statistical relevance to symptom severity. Questions related to symptom severity were selected using an extremely randomized trees (ERT) regressor to develop an integrative questionnaire. For the identification of novel subtypes, Uniform Manifold Approximation and Projection and spectral clustering were used for nonlinear dimensionality reduction and clustering, respectively. The validity of the clusters was assessed using certain metrics, such as trustworthiness, silhouette coefficient, and accordance rate. An ERT classifier was employed to further validate the clustered result. Results: The multivariate analyses revealed that SF-36 and KM supplemented the psychosocial aspects lacking in K-BDQ. Through the application of nonlinear clustering using the integrative questionnaire data, four subtypes of FGID were identified: mild, severe, mind-symptom predominance, and body-symptom predominance. Conclusions: The identification of these subtypes offers a framework for personalized treatment strategies, thus potentially enhancing therapeutic outcomes by tailoring interventions to the unique biopsychosocial profiles of FGID patients.

Cerebellum as a kernel machine: A novel perspective on expansion recoding in granule cell layer.

Sensorimotor information provided by mossy fibers (MF) is mapped to high-dimensional space by a huge number of granule cells (GrC) in the cerebellar cortex's input layer. Significant studies have demonstrated the computational advantages and primary contributor of this expansion recoding. Here, we propose a novel perspective on the expansion recoding where each GrC serve as a kernel basis function, thereby the cerebellum can operate like a kernel machine that implicitly use high dimensional (even infinite) feature spaces. We highlight that the generation of kernel basis function is indeed biologically plausible scenario, considering that the key idea of kernel machine is to memorize important input patterns. We present potential regimes for developing kernels under constrained resources and discuss the advantages and disadvantages of each regime using various simulation settings.

A Novel Framework for Understanding the Pattern Identification of Traditional Asian Medicine From the Machine Learning Perspective.

Pattern identification (PI), a unique diagnostic system of traditional Asian medicine, is the process of inferring the pathological nature or location of lesions based on observed symptoms. Despite its critical role in theory and practice, the information processing principles underlying PI systems are generally unclear. We present a novel framework for comprehending the PI system from a machine learning perspective. After a brief introduction to the dimensionality of the data, we propose that the PI system can be modeled as a dimensionality reduction process and discuss analytical issues that can be addressed using our framework. Our framework promotes a new approach in understanding the underlying mechanisms of the PI process with strong mathematical tools, thereby enriching the explanatory theories of traditional Asian medicine.

Lessons From Deep Neural Networks for Studying the Coding Principles of Biological Neural Networks.

One of the central goals in systems neuroscience is to understand how information is encoded in the brain, and the standard approach is to identify the relation between a stimulus and a neural response. However, the feature of a stimulus is typically defined by the researcher's hypothesis, which may cause biases in the research conclusion. To demonstrate potential biases, we simulate four likely scenarios using deep neural networks trained on the image classification dataset CIFAR-10 and demonstrate the possibility of selecting suboptimal/irrelevant features or overestimating the network feature representation/noise correlation. Additionally, we present studies investigating neural coding principles in biological neural networks to which our points can be applied. This study aims to not only highlight the importance of careful assumptions and interpretations regarding the neural response to stimulus features but also suggest that the comparative study between deep and biological neural networks from the perspective of machine learning can be an effective strategy for understanding the coding principles of the brain.

Construction And Analysis Of The Time-Evolving Pain-Related Brain Network Using Literature Mining.

PURPOSE: We aimed to quantitatively investigate how the neuroscience field developed over time in terms of its concept on how pain is represented in the brain and compare the research trends of pain with those of mental disorders through literature mining of accumulated published articles. METHODS: The abstracts and publication years of 137,525 pain-related articles were retrieved from the PubMed database. We defined 22 pain-related brain regions that appeared more than 100 times in the retrieved abstracts. Time-evolving networks of pain-related brain regions were constructed using the co-occurrence frequency. The state-space model was implemented to capture the trend patterns of the pain-related brain regions and the patterns were compared with those of mental disorders. RESULTS: The number of pain-related abstracts including brain areas steadily increased; however, the relative frequency of each brain region showed different patterns. According to the chronological patterns of relative frequencies, pain-related brain regions were clustered into three groups: rising, falling, and consistent. The network of pain-related brain regions extended over time from localized regions (mainly including brain stem and diencephalon) to wider cortical/subcortical regions. In the state-space model, the relative frequency trajectory of pain-related brain regions gradually became closer to that of mental disorder-related brain regions. CONCLUSION: Temporal changes of pain-related brain regions in the abstracts indicate that emotional/cognitive aspects of pain have been gradually emphasized. The networks of pain-related brain regions imply perspective changes on pain from the simple percept to the multidimensional experience. Based on the notable occurrence patterns of the cerebellum and motor cortex, we suggest that motor-related areas will be actively explored in pain studies.

Oxidative stress-induced inflammatory responses and effects of N-acetylcysteine in bovine mammary alveolar cells.

Bovine mastitis, an inflammation of the udder, results in reduced milk production and poor milk quality. Mastitis is usually, but not always, a response to pathogen infection. High milk yield can produce oxidative stress in the mammary tissue. High milk yield is also known to be associated with bovine mastitis. Thus, in the current study, we hypothesised that oxidative stress increases inflammatory responses in bovine mammary cells. To examine the hypothesis, we produced cellular oxidative stress and investigated resulting inflammatory responses in bovine mammary alveolar cells (MAC-T). To produce oxidative stress, cells were treated with the reactive oxygen species (ROS; e.g., superoxide anion)-producing agent, menadione (MD; 0-10 µm; 6 h). To ensure the ROS-induced responses, cells were pretreated with an antioxidant NAC (0-10 mm; 1 h). Results showed that MD elevated intracellular ROS levels and protein expression of cyclooxygenase-2 (COX-2), a biomarker of inflammation. Pretreatment of cells with NAC attenuated MD-induced COX-2 expression by scavenging intracellular ROS and enhancing intracellular glutathione levels. MD-induced COX-2 expression was mediated by activation of extracellular signal receptor-activated kinase 1/2 (ERK1/2), Akt, and nuclear factor-kappa B (NF-κB). NAC attenuated activation of these intracellular signalling molecules. Treatment of cells with pharmacological inhibitors for ERK1/2, Akt, and NF-κB confirmed the association of these signalling pathways in MD-induced COX-2 expression. These results support our hypothesis that oxidative stress, which is found in high-yielding dairy cows, can produce cellular inflammation in bovine mammary alveolar cells and prevention of oxidative stress can attenuate such pathological responses. This may be relevant for cases of clinical mastitis for which no pathogen can be isolated.

Bee Venom Decreases LPS-Induced Inflammatory Responses in Bovine Mammary Epithelial Cells.

The world dairy industry has long been challenged by bovine mastitis, an inflammatory disease, which causes economic loss due to decreased milk production and quality. Attempts have been made to prevent or treat this disease with multiple approaches, primarily through increased abuse of antibiotics, but effective natural solutions remain elusive. Bee venom (BV) contains a variety of peptides (e.g., melittin) and shows multiple bioactivities, including prevention of inflammation. Thus, in the current study, it was hypothesized that BV can reduce inflammation in bovine mammary epithelial cells (MAC-T). To examine the hypothesis, cells were treated with LPS (1 µg/ml) to induce an inflammatory response and the anti-inflammatory effects of BV (2.5 and 5 µg/ml) were investigated. The cellular mechanisms of BV against LPS-induced inflammation were also investigated. Results showed that BV can attenuate expression of an inflammatory protein, COX2, and pro-inflammatory cytokines such as IL-6 and TNF-α. Activation of NF-κB, an inflammatory transcription factor, was significantly downregulated by BV in cells treated with LPS, through dephosphorylation of ERK1/2. Moreover, pretreatment of cells with BV attenuated LPS-induced production of intracellular reactive oxygen species (e.g., superoxide anion). These results support our hypothesis that BV can decrease LPS-induced inflammatory responses in bovine mammary epithelial cells through inhibition of oxidative stress, NF-κB, ERK1/2, and COX-2 signaling.

Organized Comprehensive Stroke Center is Associated with Reduced Mortality: Analysis of Consecutive Patients in a Single Hospital.

BACKGROUND AND PURPOSE: Organized inpatient stroke care is one of the most effective therapies for improving patient outcomes. Many stroke centers have been established to meet this need, however, there are limited data on the effectiveness of these organized comprehensive stroke center (CSC) in the real-world setting. Our aim is to determine whether inpatient care following the establishment of CSC lowers mortality of patients with acute ischemic stroke (AIS). METHODS: Based on a prospective stroke registry, we identified AIS patients hospitalized before and after the establishment of a CSC. We observed all-cause mortality within 30 days from time of admission. Logistic regression was used to determine whether the establishment of the CSC affects independently the 30-day all-cause mortality. RESULTS: A total of 3,117 consecutive patients with AIS were admitted within seven days after the onset of the symptoms. Unadjusted 30-day mortality was lower for patients admitted to our hospital after the establishment of the CSC than before (5.9% vs. 8.2%, P=0.012). Advanced age, female gender, previous coronary artery disease, non-smoking, stroke subtype, admission on a holiday, referral from other hospitals, high NIHSS on admission, and admission before the establishment of CSC were associated with increased 30-day stroke case fatality. After adjustment for these factors, stroke inpatient care subsequent to the establishment of the CSC was independently associated with lower 30-day mortality (OR, 0.57; 95% CI, 0.412-0.795). CONCLUSIONS: Patients treated after the establishment of a CSC had lower 30-mortality rates than ever before, even adjusting for the differences in the baseline characteristics. The present study reveals that organized stroke care in a CSC might improve the outcome after AIS.

Leukoaraiosis on magnetic resonance imaging is related to long-term poor functional outcome after thrombolysis in acute ischemic stroke.

OBJECTIVE: Leukoaraiosis (LA) has been suggested to be related to the poor outcome or the occurrence of symptomatic intracerebral hemorrhage (sICH) after acute ischemic stroke. We retrospectively investigated the influences of LA on long-term outcome and the occurrence of sICH after thrombolysis in acute ischemic stroke (AIS). METHODS: In this study, we recruited 164 patients with AIS and magnetic resonance image (MRI)-detected thrombolysis. The presence and extent of LA were assessed using the Fazekas grading system. The National Institutes of Health Stroke Scale score was used to assess the baseline measure of neurologic severity, and the modified Rankin Scale score assessment was used up to 1 year after thrombolysis. RESULTS: Of 164 subjects, 56 (34.2%) showed LA on MRI. Compared to the 108 patients without LA, the patients with LA were of much older age (p<0.01), had a higher prevalence of hypertension (p<0.01), and had a much poorer outcome at 90 days (p=0.05) and 1 yr (p=0.01) after thrombolysis. There were no significant differences in sICH between patients with and without LA on MRI. In univariate analysis for the occurrence of poor outcome at 90 days after thrombolysis, the size of ischemic lesion on diffusion weighted images (DWI), [odds ratio (OR), 1.03; 95% confidence interval (95% CI), 1.01-1.04; p<0.01], recanalization (OR, 0.03; 95% CI, 0.01-0.10; p<0.01), sICH (OR, 12.2; 95% CI, 1.54-95.8), neurologic severity (OR, 1.17; 95% CI, 1.09-1.25; p<0.01), blood glucose level (OR, 1.01; 95% CI, 1.00-1.02; p=0.03), and the presence of LA on MRI (OR, 2.01; 95% CI, 1.04-3.01; p=0.04) were statistically significant. In multivariate analysis, neurologic severity (OR, 1.14; 95% CI, 1.04-1.24; p<0.01), recanalization (OR, 0.03; 95% CI, 0.01-0.11; p<0.01), lesion size on DWI (OR, 1.02; 95% CI, 1.01-1.03; p=0.02), serum glucose level (OR, 1.01; 95% CI; 1.01-1.02; p=0.03), and the presence of LA on MRI (OR, 3.2; 95% CI, 1.22-8.48; p<0.01) showed statistically significant differences. These trends persisted up to 1 yr after thrombolysis. CONCLUSION: In this study, we demonstrated that the presence of LA on MRI might be related to poor outcome after use of intravenous tissue plasminogen activator in AIS.

Orthostatic hypotension in drug-naïve patients with Parkinson's disease.

BACKGROUND AND PURPOSE: Orthostatic hypotension (OH) is known to be present even in patients with early Parkinson's disease (PD). To affirm the presence of OH and find correlation between OH and other dysautonomic symptoms in PD, this study has done in newly-diagnosed PD patients. METHODS: Forty-five non-demented patients with no prior history of treatment for PD were recruited (17 men, 63.8 ± 10.1 years of age). All the patients were evaluated for OH before starting medications. Autonomic symptoms were evaluated with structured questionnaires. Clinical characteristics of PD were evaluated (median Hoehn and Yahr stage 2.0 (1-3), 1.3 ± 1.1 years of disease duration), and comorbid medical conditions that could affect blood pressure were also recorded. RESULTS: OH was prevalent, and eighteen patients (40%) showed orthostatic hypotension, and twenty-seven (60%) did not (normotensive group). There was no significant difference in demographic and clinical characteristics between groups. The presence or severity of symptoms of autonomic dysfunction in the OH group also not differed from those of the normotensive group. CONCLUSIONS: OH was prevalent even in the early stage of PD, and was not related to presence or severity of any other symptoms of autonomic dysfunction. Our findings suggest that clinicians should pay attention to OH from the early stage of disease.

Prehospital notification from the emergency medical service reduces the transfer and intra-hospital processing times for acute stroke patients.

BACKGROUND AND PURPOSE: There is little information available about the effects of Emergency Medical Service (EMS) hospital notification on transfer and intrahospital processing times in cases of acute ischemic stroke. METHODS: This study retrospectively investigated the real transfer and imaging processing times for cases of suspected acute stroke (AS) with EMS notification of a requirement for intravenous (IV) tissue-type plasminogen activator (t-PA) and for cases without notification. Also we compared the intra-hospital processing times for receiving t-PA between patients with and without EMS prehospital notification. RESULTS: Between December 2008 and August 2009, the EMS transported 102 patients with suspected AS to our stroke center. During the same period, 33 patients received IV t-PA without prehospital notification from the EMS. The mean real transfer time after the EMS call was 56.0±32.0 min. Patients with a transfer distance of more than 40 km could not be transported to our center within 60 min. Among the 102 patients, 55 were transferred via the EMS to our emergency room for IV t-PA. The positive predictive value for stroke (90.9% vs. 68.1%, p=0.005) was much higher and the real transfer time was much faster in patients with an EMS t-PA call (47.7±23.1 min, p=0.004) than in those without one (56.3±32.4 min). The door-to-imaging time (17.8±11.0 min vs. 26.9±11.5 min, p=0.01) and door-to-needle time (29.7±9.6 min vs. 42.1±18.1 min, p=0.01) were significantly shorter in the 18 patients for whom there was prehospital notification and who ultimately received t-PA than in those for whom there was no prehospital notification. CONCLUSIONS: Our results indicate that prehospital notification could enable the rapid dispatch of AS patients needing IV t-PA to a stroke centre. In addition, it could reduce intrahospital delays, particularly, imaging processing times.

Autonomic dysfunctions in parkinsonian disorders.

BACKGROUND AND PURPOSE: Symptoms of autonomic dysfunctions are common in the patients with parkinsonian disorders. Because clinical features of autonomic dysfunctions are diverse, the comprehensive evaluation is essential for the appropriate management. For the appreciation of autonomic dysfunctions and the identification of differences, patients with degenerative parkinsonisms are evaluated using structured questionnaire for autonomic dysfunction (ADQ). METHODS: Total 259 patients, including 192 patients with [idiopathic Parkinson's disease (IPD, age 64.6 ± 9.6 years)], 37 with [multiple system atrophy (MSA, 62.8 ± 9.1)], 9 with [dementia with Lewy body (DLB, 73.9 ± 4.3)], and 21 with [progressive supranuclear palsy (PSP, 69.4 ± 9.6)]. The ADQ was structured for evaluation of the presence of symptoms and its severity due to autonomic dysfunction, covering gastrointestinal, urinary, sexual, cardiovascular and thermoregulatory domains. Patients were also evaluated for the orthostatic hypotension. RESULTS: Although dementia with Lewy body (DLB) patients were oldest and duration of disease was longest in IPD, total ADQ scores of MSA and PSP (23.9 ± 12.6 and 21.1 ± 7.8) were significantly increased than that of IPD (15.1 ± 10.6). Urinary and cardiovascular symptom scores of MSA and gastrointestinal symptom score of PSP were significantly worse than those of IPD. The ratio of patient with orthostatic hypotension in IPD was 31.2% and not differed between groups (35.1% in MSA, 33.3% in DLB and 33.3% in PSP). But the systolic blood pressure dropped drastically after standing in patients with MSA and DLB than in patients with IPD and PSP. CONCLUSIONS: Patients with degenerative parkinsonism showed widespread symptoms of autonomic dysfunctions. The severity of those symptoms in patients with PSP were comparing to that of MSA patients and worse than that of IPD.