bluuebunny/crossref_metadata_2025 huggingface dataset:
Does Soluble TREM2 Protect Against Alzheimer's Disease?
Authors: Brown Guy C. , St George-Hyslop Peter
Published: January 2022

Triggering Receptor Expressed in Myeloid Cells 2 (TREM2) is a pattern recognition receptor on myeloid cells, and is upregulated on microglia surrounding amyloid plaques in Alzheimer's disease (AD). Rare, heterozygous mutations in TREM2 (e.g., R47H) increase AD risk several fold. TREM2 can be cleaved at the plasma membrane by metalloproteases to release the ectodomain as soluble TREM2 (sTREM2). Wild-type sTREM2 binds oligomeric amyloid beta (Aβ) and acts as an extracellular chaperone, blocking and reversing Aβ oligomerization and fibrillization, and preventing Aβ-induced neuronal loss in vitro. Whereas, R47H sTREM2 increases Aβ fibrillization and neurotoxicity. AD brains expressing R47H TREM2 have more fibrous plaques with more neuritic pathology around these plaques, consistent with R47H sTREM2 promoting Aβ fibrillization relative to WT sTREM2. Brain expression or injection of wild-type sTREM2 reduces pathology in amyloid models of AD in mice, indicating that wild-type sTREM2 is protective against amyloid pathology. Levels of sTREM2 in cerebrospinal fluid (CSF) fall prior to AD, rise in early AD, and fall again in late AD. People with higher sTREM2 levels in CSF progress more slowly into and through AD than do people with lower sTREM2 levels, suggesting that sTREM2 protects against AD. However, some of these experiments can be interpreted as full-length TREM2 protecting rather than sTREM2, and to distinguish between these two possibilities, we need more experiments testing whether sTREM2 itself protects in AD and AD models, and at what stage of disease. If sTREM2 is protective, then treatments could be designed to elevate sTREM2 in AD.
Antileishmanial Activity of BNIPDaoct- and BNIPDanon-loaded Emulsomes on Leishmania infantum Parasites
Authors: Islek Zeynep , Ucisik Mehmet Hikmet , Keskin Elif , Sucu Bilgesu Onur , Gomes‐Alves Ana G. , Tomás Ana M. , Guzel Mustafa , Sahin Fikrettin
Published: January 2022

Among bisnaphthalimidopropyl (BNIP) derivatives, BNIPDaoct and BNIPDanon recently came forward with antileishmanial activities beyond the standard, commercialized antileishmanial therapies. However, high-level toxicity on macrophages plus poor aqueous solubility and poor bioavailability of the compounds limit their application in therapies. Addressing these limitations, the present study introduces BNIPDaoct- and BNIPDanon-loaded emulsomes as lipid-based nanocarrier systems. Accordingly, emulsome formulations were prepared with the presence of BNIP compounds. The average diameters of BNIPDaoct- and BNIPDanon-loaded emulsomes were found as 363.1 and 337.4 nm, respectively; while empty emulsomes differed with a smaller average particle diameter, i.e., 239.1 nm. All formulations exhibited a negative zeta potential value. The formulations achieved the encapsulation of BNIPDaoct and BNIPDanon at approximately 0.31 mg/ml (501 µM) and 0.24 mg/ml (387 µM), respectively. The delivery of BNIP within the emulsomes improved the antileishmanial activity of the compounds. BNIPDaoct-loaded emulsome with 50% inhibitory concentration (IC50) value of 0.59 ± 0.08 µM was in particular effective againstLeishmania infantumpromastigotes compared to free BNIPDaoct (0.84 ± 0.09 µM), free BNIPDanon (1.85 ± 0.01 µM), and BNIPDanon-loaded emulsome (1.73 ± 0.02 µM). Indicated by at least ≥ 2-fold higher 50% cytotoxic concentration (CC50) values, the incorporation of BNIP into emulsomes significantly reduced the toxicity of BNIPs against macrophages, corresponding to up to 16-fold improvement in selectivity index (CC50/IC50) forL. infantumpromastigotes. The infection rates of macrophages were determined using dual-fluorescent flow cytometry as 68.6%. Both BNIP formulations at concentration of 1.87 µM reduced the parasitic load nearly to 40%, whereas BNIPDaoct-loaded emulosmes could further decrease the parasitic load below 20% at 7.5 µM and above. In conclusion, the incorporation of BNIPDaoct and BNIPDanon into emulsomes results in water-soluble dispersed emulsome formulations that do not only successfully facilitate the delivery of BNIP compounds into the parasites and the Leishmania-infected macrophagesin vitrobut also enhance antileishmanial efficacy as proven by the decline in IC50values. The selectivity of the formulation forL. infantumparasites further contributes to the challenging safety profile of the compounds. The promisingin vitroantileishmanial efficacy of BNIP-loaded emulsomes highlights the potential of the system for the futurein vivostudies.
Measuring the Rate of Information Exchange in Point-Process Data With Application to Cardiovascular Variability
Authors: Mijatovic Gorana , Pernice Riccardo , Perinelli Alessio , Antonacci Yuri , Busacca Alessandro , Javorka Michal , Ricci Leonardo , Faes Luca
Published: January 2022

The amount of information exchanged per unit of time between two dynamic processes is an important concept for the analysis of complex systems. Theoretical formulations and data-efficient estimators have been recently introduced for this quantity, known as the mutual information rate (MIR), allowing its continuous-time computation for event-based data sets measured as realizations of coupled point processes. This work presents the implementation of MIR for point process applications in Network Physiology and cardiovascular variability, which typically feature short and noisy experimental time series. We assess the bias of MIR estimated for uncoupled point processes in the frame of surrogate data, and we compensate it by introducing a corrected MIR (cMIR) measure designed to return zero values when the two processes do not exchange information. The method is first tested extensively in synthetic point processes including a physiologically-based model of the heartbeat dynamics and the blood pressure propagation times, where we show the ability of cMIR to compensate the negative bias of MIR and return statistically significant values even for weakly coupled processes. The method is then assessed in real point-process data measured from healthy subjects during different physiological conditions, showing that cMIR between heartbeat and pressure propagation times increases significantly during postural stress, though not during mental stress. These results document that cMIR reflects physiological mechanisms of cardiovascular variability related to the joint neural autonomic modulation of heart rate and arterial compliance.
Prognostic Nomogram for Predicting Lower Extremity Deep Venous Thrombosis in Neurointensive Care Unit Patients: A Prospective Observational Study
Authors: Li Rongqing , Jiang Jinxia , Song Yu , Zhang Jianan , Wu Yawen , Wu Lingzhi , Zhu Xiaoping , Zeng Li
Published: January 2022

Background

Deep venous thrombosis (DVT) of the lower extremities is one of the common complications for neurointensive care unit patients, which leads to increased morbidity and mortality. The purpose of our study was to explore risk factors and develop a prognostic nomogram for lower extremity DVT in neurointensive care unit patients.

Methods

We prospectively collected and analyzed the clinical data of 420 neurointensive care unit patients who received treatment in our institution between January 2018 and September 2019. Stepwise logistic regression was used to select predictors. R software was used to develop the prognostic nomogram. The performance of the nomogram was validated using a validation cohort of patients with data collected between October 2019 and March 2020.

Results

Among 420 patients, 153 (36.4%) had lower extremity DVT and five (1.2%) had both DVT and pulmonary embolism (PE) in our study. Logistic regression analysis indicated that age [odds ratio (OR): 1.050; 95% confidence interval (CI): 1.029–1.071; P < 0.001], Glasgow Coma Scale (GCS) score (OR: 0.889; 95% CI: 0.825–0.959; P = 0.002), D-dimer level (OR: 1.040; 95% CI: 1.008–1.074; P = 0.014), muscle strength (OR: 2.424; 95% CI: 1.346–4.366; P = 0.003), and infection (OR: 1.778; 95% CI: 1.034–3.055; P = 0.037) were independent predictors for lower extremity DVT. These predictors were selected to be included in the nomogram model. The area under the curve values in the primary cohort and validation cohort were 0.817 (95% CI: 0.776–0.858) and 0.778 (95% CI: 0.688–0.868), respectively, and respective Brier scores were 0.167 and 0.183.

Conclusion

Age, GCS score, D-dimer level, muscle strength, and infection are independent predictors for lower extremity DVT. The nomogram is a reliable and convenient model to predict the development of lower extremity DVT in neurointensive care unit patients.
A Systematic Review and Meta-Analysis Comparing FAST and BEFAST in Acute Stroke Patients
Authors: Chen Xinjie , Zhao Xiaoxiao , Xu Fan , Guo Mingjin , Yang Yifan , Zhong Lianmei , Weng Xiechuan , Liu Xiaolei
Published: January 2022

Objective

To evaluate and compare the predictive value of Face, Arm, Speech Test (FAST) and Balance, Eyes, Face, Arm, Speech, Time (BEFAST) scale in the acute ischemic stroke (AIS).

Methods

We searched Medline and Ovid databases for relevant literature in the English language. There were no limitations on the date. The sensitivity, specificity, likelihood ratio, and diagnostic odds ratio were pooled for meta-analysis. The symmetric receiver operator characteristic curve and Fagan's Nomogram were drawn, and meta-regression and subgroup analysis were used to explore the source of heterogeneity.

Results

A total of 9 studies, including 6,151 participants, were analyzed. The combined sensitivity of FAST was 0.77 [95% CI (0.64–0.86)], specificity was 0.60 [95% CI (0.38–0.78)], the area under the ROC curve was 0.76, and the diagnostic ratio was 1.57, while the sensitivity of BEFAST was 0.68 [95% CI (0.23–0.93)], specificity was 0.85 [95% CI (0.72–0.92)], the area under the ROC curve was 0.86, and the diagnostic odds ratio was 2.44. No publication bias was detected in Deeks' funnel plot. For FAST, meta-regression analysis showed that the prospective design, satisfactory description of the index test, and a broad spectrum of disease contributed to the heterogeneity in sensitivity, while no sources contributed to the heterogeneity in sensitivity. When the pretest probability was set as 20%, the posterior probability in Fagan's Nomogram was 32%; however, when the pretest probability was set as 20% in BEFAST, the posterior probability in Fagan's Nomogram was 52%.

Conclusions

Our findings indicated that FAST and BEFAST might be useful in the diagnosis of acute ischemic stroke. The diagnostic value of BEFAST in acute ischemic stroke was higher than in FAST; thus, it might have an important role in the fast recognition of acute ischemic stroke.
T2 FLAIR Hyperintensity Volume Is Associated With Cognitive Function and Quality of Life in Clinically Stable Patients With Lower Grade Gliomas
Authors: Luks Tracy L. , Villanueva-Meyer Javier E. , Weyer-Jamora Christina , Gehring Karin , Jakary Angela , Hervey-Jumper Shawn L. , Braunstein Steve E. , Bracci Paige M. , Brie Melissa S. , Smith Ellen M. , Chang Susan M. , Taylor Jennie W.
Published: January 2022

Survival outcomes for patients with lower grade gliomas (LrGG) continue to improve. However, damage caused both by tumor growth and by the consequences of treatment often leads to significantly impaired cognitive function and quality of life (QoL). While neuropsychological testing is not routine, serial clinical MRIs are standard of care for patients with LrGG. Thus, having a greater understanding of MRI indicators of cognitive and QoL impairment risk could be beneficial to patients and clinicians. In this work we sought to test the hypothesis that in clinically stable LrGG patients, T2 FLAIR hyperintensity volumes at the time of cognitive assessment are associated with impairments of cognitive function and QoL and could be used to help identify patients for cognitive and QoL assessments and interventions. We performed anatomical MR imaging, cognitive testing and QoL assessments cross-sectionally in 30 clinically stable grade 2 and 3 glioma patients with subjective cognitive concerns who were 6 or more months post-treatment. Larger post-surgical T2 FLAIR volume at testing was significantly associated with lower cognitive performance, while pre-surgical tumor volume was not. Older patients had lower cognitive performance than younger patients, even after accounting for normal age-related declines in performance. Patients with Astrocytoma, IDH mutant LrGGs were more likely to show lower cognitive performance than patients with Oligodendroglioma, IDH mutant 1p19q co-deleted LrGGs. Previous treatment with combined radiation and chemotherapy was associated with poorer self-reported QoL, including self-reported cognitive function. This study demonstrates the importance of appreciating that LrGG patients may experience impairments in cognitive function and QoL over their disease course, including during periods of otherwise sustained clinical stability. Imaging factors can be helpful in identifying vulnerable patients who would benefit from cognitive assessment and rehabilitation.
Poor Sleep Quality Associated With Enlarged Perivascular Spaces in Patients With Lacunar Stroke
Authors: Yang Shuna , Yin Jiangmei , Qin Wei , Yang Lei , Hu Wenli
Published: January 2022

Background and Objective

Enlarged perivascular spaces (EPVSs) are considered as an MRI marker of cerebral small vessel diseases and were reported to be associated with brain waste clearance dysfunction. A previous study found that interstitial fluid clearance in the mouse brain occurred mainly during sleep. However, the relationship between sleep quality and EPVS in humans has not been well-understood. Thus, we aimed to investigate the relationship between sleep and EPVS in humans.

Methods

This retrospective study was conducted in patients with lacunar stroke in the Neurology Department of Beijing Chaoyang Hospital. Patients with EPVS >10 on one side of the basal ganglia (BG) and white matter slice containing the maximum amount were defined as the BG-EPVS group and the white matter (WM)-EPVS group, respectively. Patients with EPVS <10 in the slice containing the maximum amount were defined as the control group. Sleep quality was evaluated by the Pittsburgh Sleep Quality Index (PSQI) including seven components, where a score of 6 or higher indicated poor sleep quality. Spearman's correlation analysis and the binary logistic regression analysis were performed to analyze the relationship between poor sleep quality and BG-EPVS and WM-EPVS, respectively.

Results

A total of 398 patients were enrolled in this study, including 114 patients in the BG-EPVS group and 85 patients in the WM-EPVS group. The proportion of poor sleep quality in the BG-EPVS group was higher than that in the control group (58.8 vs. 32.5%, p < 0.001). The score of PSQI, subjective sleep quality, sleep latency, sleep duration, and sleep efficiency were higher in the BG-EPVS group than that in the control group (p < 0.05). The proportion of poor sleep quality was also higher in the WM-EPVS group than that in the control group (50.6 vs. 35.3%, p = 0.031). The score of sleep duration and sleep disturbances was higher in the WM-EPVS group than that in the control group. Spearman's correlation analysis showed that poor sleep quality was positively associated with BG-EPVS (ρ = 0.264, p < 0.001) and WM-EPVS (ρ = 0.154, p = 0.044). The binary logistic regression analysis showed that poor sleep quality, longer sleep latency, and less sleep duration were independently related to BG-EPVS and poor sleep quality, less sleep duration, and more serious sleep disturbances were independently related to WM-EPVS after adjusting for confounders (P < 0.05).

Conclusion

Poor sleep quality was independently associated with EPVS in BG and WM.
Nerve Ultrasound Distinguishes Non-Inflammatory Axonal Polyneuropathy From Inflammatory Polyneuropathy With Secondary Axonal Damage
Authors: Brünger Jil , Motte Jeremias , Grüter Thomas , Mork Hannah , Bulut Yesim , Carolus Anne , Athanasopoulos Diamantis , Yoon Min-Suk , Gold Ralf , Pitarokoili Kalliopi , Fisse Anna Lena
Published: January 2022

Introduction

Chronic inflammatory demyelinating polyneuropathy (CIDP) may have a similar clinical and electrophysiological presentation to non-inflammatory axonal polyneuropathies (NIAPs) when secondary axonal damage occurs. We aimed to investigate if nerve ultrasound can help to differentiate CIDP with additional secondary axonal damage from NIAP.

Methods

In a retrospective analysis, the cross-sectional area (CSA) of the peripheral nerves measured by ultrasound at six suitable nerve sites was compared in 95 patients with CIDP and 82 patients with NIAP. We developed the adjusted Bochum ultrasound score (aBUS) ranging from 0 to 6 resulting from the number of sites with enlarged CSA (median, ulnar, radial, and sural nerve).

Results

The mean CSA of patients with CIDP was enlarged at all six nerve sites compared with the mean CSA of patients with NIAP. A total of 21 patients with CIDP did not meet 2010 electrophysiological diagnostic criteria (European Academy of Neurology/Peripheral Nerve Society Guideline, EFNS/PNS criteria) for CIDP at examination timepoint but only in further follow-up, while 25 patients with NIAP fulfilled electrophysiological EFNS/PNS criteria for CIDP as “possible” or “probable” CIDP. To increase diagnostic power, we included aBUS measured by ultrasound in patients classified as “possible” or “probable” resulting in an improved specificity of 94% and a sensitivity of 59%, compared to a specificity of the EFNS/PNS criteria alone of 60% and sensitivity of 78%.

Conclusion

Using nerve ultrasound and the aBUS as a complementary method to distinguish CIDP from NIAP in case of secondary axonal damage can facilitate the diagnosis of CIDP.
Case Report: Overlap Between Long COVID and Functional Neurological Disorders
Authors: Gilio Luana , Galifi Giovanni , Centonze Diego , Stampanoni Bassi Mario
Published: January 2022

Long lasting symptoms have been reported in a considerable proportion of patients after a severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) infection. This condition, defined as either “post-acute coronavirus disease (COVID),” “long COVID,” or “long-haul COVID,” has also been described in outpatients and in individuals who are asymptomatic during the acute infection. A possible overlap exists between this condition and the functional neurological disorders (FNDs). We report a 23-year-old man who developed, after asymptomatic COVID-19, a complex symptomatology characterized by fatigue, episodic shortness of breath, nocturnal tachycardia, and chest pain. He also complained of attention and memory difficulties, fluctuating limb dysesthesia, and weakness of his left arm. After neurological examination, a diagnosis of FND was made. Notably, the patient was also evaluated at a post-COVID center and received a diagnosis of long COVID-19 syndrome. After 4 months of psychoanalytic psychotherapy and targeted physical therapy in our center for FNDs, dysesthesia and motor symptoms had resolved, and the subjective cognitive complaints had improved significantly. However, the patient had not fully recovered as mild symptoms persisted limiting physical activities. Long-term post COVID symptoms and FNDs may share underlying biological mechanisms, such as stress and inflammation. Our case suggests that functional symptoms may coexist with the long COVID symptoms and may improve with targeted interventions. In patients presenting with new fluctuating symptoms after SARS-CoV-2 infection, the diagnosis of FNDs should be considered, and the positive clinical signs should be carefully investigated.
Effects of Spatial Speech Presentation on Listener Response Strategy for Talker-Identification
Authors: Uhrig Stefan , Perkis Andrew , Möller Sebastian , Svensson U. Peter , Behne Dawn M.
Published: January 2022

This study investigates effects of spatial auditory cues on human listeners' response strategy for identifying two alternately active talkers (“turn-taking” listening scenario). Previous research has demonstrated subjective benefits of audio spatialization with regard to speech intelligibility and talker-identification effort. So far, the deliberate activation of specific perceptual and cognitive processes by listeners to optimize their task performance remained largely unexamined. Spoken sentences selected as stimuli were either clean or degraded due to background noise or bandpass filtering. Stimuli were presented via three horizontally positioned loudspeakers: In a non-spatial mode, both talkers were presented through a central loudspeaker; in a spatial mode, each talker was presented through the central or a talker-specific lateral loudspeaker. Participants identified talkers via speeded keypresses and afterwards provided subjective ratings (speech quality, speech intelligibility, voice similarity, talker-identification effort). In the spatial mode, presentations at lateral loudspeaker locations entailed quicker behavioral responses, which were significantly slower in comparison to a talker-localization task. Under clean speech, response times globally increased in the spatial vs. non-spatial mode (across all locations); these “response time switch costs,” presumably being caused by repeated switching of spatial auditory attention between different locations, diminished under degraded speech. No significant effects of spatialization on subjective ratings were found. The results suggested that when listeners could utilize task-relevant auditory cues about talker location, they continued to rely on voice recognition instead of localization of talker sound sources as primary response strategy. Besides, the presence of speech degradations may have led to increased cognitive control, which in turn compensated for incurring response time switch costs.
Computer-Assisted Dental Implant Placement Following Free Flap Reconstruction: Virtual Planning, CAD/CAM Templates, Dynamic Navigation and Augmented Reality
Authors: Ochandiano Santiago , García-Mato David , Gonzalez-Alvarez Alba , Moreta-Martinez Rafael , Tousidonis Manuel , Navarro-Cuellar Carlos , Navarro-Cuellar Ignacio , Salmerón José Ignacio , Pascau Javier
Published: January 2022

Image-guided surgery, prosthetic-based virtual planning, 3D printing, and CAD/CAM technology are changing head and neck ablative and reconstructive surgical oncology. Due to quality-of-life improvement, dental implant rehabilitation could be considered in every patient treated with curative intent. Accurate implant placement is mandatory for prosthesis long-term stability and success in oncologic patients. We present a prospective study, with a novel workflow, comprising 11 patients reconstructed with free flaps and 56 osseointegrated implants placed in bone flaps or remnant jaws (iliac crest, fibula, radial forearm, anterolateral thigh). Starting from CT data and jaw plaster model scanning, virtual dental prosthesis was designed. Then prosthetically driven dental implacement was also virtually planned and transferred to the patient by means of intraoperative infrared optical navigation (first four patients), and a combination of conventional static teeth supported 3D-printed acrylic guide stent, intraoperative dynamic navigation, and augmented reality for final intraoperative verification (last 7 patients). Coronal, apical, and angular deviation between virtual surgical planning and final guided intraoperative position was measured on each implant. There is a clear learning curve for surgeons when applying guided methods. Initial only-navigated cases achieved low accuracy but were comparable to non-guided freehand positioning due to jig registration instability. Subsequent dynamic navigation cases combining highly stable acrylic static guides as reference and registration markers result in the highest accuracy with a 1–1.5-mm deviation at the insertion point. Smartphone-based augmented reality visualization is a valuable tool for intraoperative visualization and final verification, although it is still a difficult technique for guiding surgery. A fixed screw-retained ideal dental prosthesis was achieved in every case as virtually planned. Implant placement, the final step in free flap oncological reconstruction, could be accurately planned and placed with image-guided surgery, 3D printing, and CAD/CAM technology. The learning curve could be overcome with preclinical laboratory training, but virtually designed and 3D-printed tracer registration stability is crucial for accurate and predictable results. Applying these concepts to our difficult oncologic patient subgroup with deep anatomic alterations ended in comparable results as those reported in non-oncologic patients.
Loss of SMAD4 Is Associated With Poor Tumor Immunogenicity and Reduced PD-L1 Expression in Pancreatic Cancer
Authors: Principe Daniel R. , Underwood Patrick W. , Kumar Sandeep , Timbers Kaytlin E. , Koch Regina M. , Trevino Jose G. , Munshi Hidayatullah G. , Rana Ajay
Published: January 2022

Transforming Growth Factor β (TGFβ) is a key mediator of immune evasion in pancreatic ductal adenocarcinoma (PDAC), and the addition of TGFβ inhibitors in select immunotherapy regimens shows early promise. Though the TGFβ target SMAD4 is deleted in approximately 55% of PDAC tumors, the effects of SMAD4 loss on tumor immunity have yet to be fully explored. Using a combination of genomic databases and PDAC specimens, we found that tumors with loss of SMAD4 have a comparatively poor T-cell infiltrate. SMAD4 loss was also associated with a reduction in several chemokines with known roles in T-cell recruitment, which was recapitulated using knockdown of SMAD4 in PDAC cell lines. Accordingly, JURKAT T-cells were poorly attracted to conditioned media from PDAC cells with knockdown of SMAD4 and lost their ability to produce IFNγ. However, while exogenous TGFβ modestly reduced PD-L1 expression in SMAD4-intact cell lines, SMAD4 and PD-L1 positively correlated in human PDAC samples. PD-L1 status was closely related to tumor-infiltrating lymphocytes, particularly IFNγ-producing T-cells, which were more abundant in SMAD4-expressing tumors. Low concentrations of IFNγ upregulated PD-L1 in tumor cells in vitro, even when administered alongside high concentrations of TGFβ. Hence, while SMAD4 may have a modest inhibitory effect on PD-L1 in tumor cells, SMAD4 indirectly promotes PD-L1 expression in the pancreatic tumor microenvironment by enhancing T-cell infiltration and IFNγ biosynthesis. These data suggest that pancreatic cancers with loss of SMAD4 represent a poorly immunogenic disease subtype, and SMAD4 status warrants further exploration as a predictive biomarker for cancer immunotherapy.
Inhibition of Gasdermin D-Mediated Pyroptosis Attenuates the Severity of Seizures and Astroglial Damage in Kainic Acid-Induced Epileptic Mice
Authors: Xia Lu , Liu Lu , Cai Yiying , Zhang Yiying , Tong Fangchao , Wang Qiang , Ding Jing , Wang Xin
Published: January 2022

Objective: Our study aimed to explore whether gasdermin D (GSDMD)-mediated pyroptosis is involved in the mechanism of kainic acid-induced seizures.

Methods: C57BL/6 mice were randomly divided into sham and epilepsy groups. The epilepsy group was intrahippocampally injected with kainic acid to induce status epilepticus (SE), and the sham group was injected with an equal volume of saline. Dimethyl fumarate (DMF) was used as the GSDMD N-terminal fragments (GSDMD-N) inhibitor and suspended in 0.5% sodium carboxymethyl cellulose (CMC) for orally administration. The epilepsy group was divided into SE + CMC and SE + DMF groups. In the SE + DMF group, DMF was orally administered for 1 week before SE induction and was continued until the end of the experiment. An equal volume of CMC was administered to the sham and SE + CMC groups. Recurrent spontaneous seizures (SRSs) were monitored for 21 days after SE. Western blot analysis and immunofluorescent staining was performed.

Results: The expression of GSDMD increased at 7–21 days post-SE, and GSDMD-N expression was significantly elevated 7 days after SE in both ipsilateral and contralateral hippocampus. GSDMD-positive cells were co-labeled with astrocytes, but not neurons or microglia. Astroglial damage occurs following status epilepticus (SE). Damaged astrocytes showed typical clasmatodendrosis in the CA1 region containing strong GSDMD expression at 7–21 days post-SE, accompanied by activated microglia. In the SE + DMF group, the expression of GSDMD-N was significantly inhibited compared to that in the SE + CMC group. After administration of DMF, SRSs at 7–21 days after SE were significantly decreased, and the number of clasmatodendritic astrocytes, microglia, and the expression of inflammatory factors such as IL-1β and IL-18 were significantly attenuated.

Conclusion: GSDMD-mediated pyroptosis is involved in the mechanism of kainic acid-induced seizures. Our study provides a new potential therapeutic target for seizure control.
Kratom Abuse Potential 2021: An Updated Eight Factor Analysis
Authors: Henningfield Jack E. , Wang Daniel W. , Huestis Marilyn A.
Published: January 2022

Drugs are regulated in the United States (US) by the Controlled Substances Act (CSA) if assessment of their abuse potential, including public health risks, show such control is warranted. An evaluation via the 8 factors of the CSA provides the comprehensive assessment required for permanent listing of new chemical entities and previously uncontrolled substances. Such an assessment was published for two kratom alkaloids in 2018 that the Food and Drug Administration (FDA) have identified as candidates for CSA listing: mitragynine (MG) and 7-hydroxymitragynine (7-OH-MG) (Henningfield et al., 2018a). That assessment concluded the abuse potential of MG was within the range of many other uncontrolled substances, that there was not evidence of an imminent risk to public health, and that a Schedule I listing (the only option for substances that are not FDA approved for therapeutic use such as kratom) carried public health risks including drug overdoses by people using kratom to abstain from opioids. The purpose of this review is to provide an updated abuse potential assessment reviewing greater than 100 studies published since January 1, 2018. These include studies of abuse potential and physical dependence/withdrawal in animals;in-vitroreceptor binding; assessments of potential efficacy treating pain and substance use disorders; pharmacokinetic/pharmacodynamic studies with safety-related findings; clinical studies of long-term users with various physiological endpoints; and surveys of patterns and reasons for use and associated effects including dependence and withdrawal. Findings from these studies suggest that public health is better served by assuring continued access to kratom products by consumers and researchers. Currently, Kratom alkaloids and derivatives are in development as safer and/or more effective medicines for treating pain, substances use disorders, and mood disorders. Placing kratom in the CSA via scheduling would criminalize consumers and possession, seriously impede research, and can be predicted to have serious adverse public health consequences, including potentially thousands of drug overdose deaths. Therefore, CSA listing is not recommended. Regulation to minimize risks of contaminated, adulterated, and inappropriately marketed products is recommended.
Anti-HCV Tannins From Plants Traditionally Used in West Africa and Extracted With Green Solvents
Authors: Bamba Moussa , Bordage Simon , Sahuc Marie-Emmanuelle , Moureu Sophie , Samaillie Jennifer , Roumy Vincent , Vauchel Peggy , Dimitrov Krasimir , Rouillé Yves , Dubuisson Jean , Tra Bi Fézan Honora , Séron Karin , Sahpaz Sevser
Published: January 2022

Millions of people are still infected with hepatitis C virus (HCV) nowadays. Although recent antivirals targeting HCV proteins are very efficient, they are not affordable for many people infected with this virus. Therefore, new and more accessible treatments are needed. Several Ivorian medicinal plants are traditionally used to treat “yellow malaria”, a nosological category including illness characterized by symptomatic jaundice such as hepatitis. Therefore, some of these plants might be active against HCV. An ethnobotanical survey in Côte d’Ivoire allowed us to select such medicinal plants. Those were first extracted with methanol and tested for their anti-HCV activity. The most active ones were further studied to specify their IC50 and to evaluate their toxicity in vitro. Greener solvents were tested to obtain extracts with similar activities. Following a phytochemical screening, tannins of the most active plants were removed before re-testing on HCV. Some of these tannins were identified by UPLC-MS and pure molecules were tested against HCV. Out of the fifteen Ivorian medicinal plants selected for their putative antiviral activities, Carapa procera DC. and Pericopsis laxiflora (Benth. ex Baker) Meeuwen were the most active against HCV (IC50: 0.71 and 0.23 μg/ml respectively) and not toxic for hepatic cells. Their crude extracts were rich in polyphenols, including tannins such as procyanidins A2 which is active against HCV. The same extracts without tannin lost their anti-HCV activity. Replacing methanol by hydro-ethanolic solvent led to tannins-rich extracts with similar antiviral activities, and higher than that of aqueous extracts.
Effect of Polysaccharides From Enteromorpha intestinalis on Intestinal Function in Sprague Dawley Rats
Authors: Li Xia , Zhang Miao , Khoo Hock Eng , Jiang Tiemin , Guan Yuan , Li Peijun
Published: January 2022

This study aims to determine the effect of polysaccharides extracted from Enteromorpha intestinalis (EI) on the intestinal function of Sprague Dawley (SD) rats. The polysaccharides were extracted from the green alga using water and alkaline solution, where these extracts were named WPEI and APEI, respectively. The dried powder of EI was labeled as DPEI. Proximate compositions, minerals, and amino acids of the DPEI, WPEI, and APEI were determined. The growth-promoting effect of the polysaccharides on selected intestinal microflora was determined based on the plate count method. In contrast, the in vivo effect of DPEI and its polysaccharides on the intestinal function of the SD rats was determined. These rats were fed with 1% WPEI, APEI, and DPEI. The result showed that APEI had lower total sugars and total proteins content than the WPEI. WPEI did not contain arabinose. The WPEI and APEI also had a better ability to promote microbial growth than the DPEI. The in vivo study showed that WPEI improved intestinal peristalsis and other intestinal functions compared with the other rat groups. The average final body weight of the experimental rats treated with DPEI was also lower than the other groups. The pH value of the feces of all treated rats was lower than the control rats, and the moisture content of the fecal samples of these experimental groups was higher than the control group. Also, the intestinal activated carbon propulsion of the WPEI, APEI, and DPEI fed rats increased. Among the short-chain fatty acids content determined in the fecal samples, the propionic acid content of the WPEI group was significantly highest. Therefore, WPEI had the best effect in improving intestinal digestion.
Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) Protects Striatal Cells and Improves Motor Function in Huntington’s Disease Models: Role of PAC1 Receptor
Authors: Solés-Tarrés Irene , Cabezas-Llobet Núria , Lefranc Benjamin , Leprince Jérôme , Alberch Jordi , Vaudry David , Xifró Xavier
Published: January 2022

Huntington’s disease (HD) is a hereditary neurodegenerative disorder caused by the expression of mutant huntingtin (mHtt). One of the main features of HD is the degeneration of the striatum that leads to motor discoordination. Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide that acts through three receptors named PAC1R, VPAC1R, and VPAC2R. In the present study, we first investigated the effect of PACAP on STHdhQ7/Q7 and STHdhQ111/Q111 cells that express wild-type Htt with 7 and mHtt with 111 glutamines, respectively. Then we explored the capacity of PACAP to rescue motor symptoms in the R6/1, a murine model of HD. We found that PACAP treatment (10–7 M) for 24 h protects STHdhQ111/Q111 cells from mHtt-induced apoptosis. This effect is associated with an increase in PAC1R transcription, phosphorylation of ERK and Akt, and an increase of intracellular c-fos, egr1, CBP, and BDNF protein content. Moreover, the use of pharmacological inhibitors revealed that activation of ERK and Akt mediates these antiapoptotic and neurotrophic effects of PACAP. To find out PAC1R implication, we treated STHdh cells with vasoactive intestinal peptide (VIP), which exhibits equal affinity for VPAC1R and VPAC2R, but lower affinity for PAC1R, in contrast to PACAP which has same affinity for the three receptors. VIP reduced cleaved caspase-3 protein level, without promoting the expression of c-fos, egr1, CBP, and the neurotrophin BDNF. We next measured the protein level of PACAP receptors in the striatum and cortex of R6/1 mice. We observed a specific reduction of PAC1R at the onset of motor symptoms. Importantly, the intranasal administration of PACAP to R6/1 animals restored the motor function and increased the striatal levels of PAC1R, CBP, and BDNF. In conclusion, PACAP exerts antiapoptotic and neurotrophic effects in striatal neurons mainly through PAC1R. This effect in HD striatum allows the recovery of motor function and point out PAC1R as a therapeutic target for treatment of HD.
The Protective Effects of Lipid-Lowering Agents on Cardiovascular Disease and Mortality in Maintenance Dialysis Patients: Propensity Score Analysis of a Population-Based Cohort Study
Authors: Tsai Ming-Hsien , Chen Mingchih , Huang Yen-Chun , Liou Hung-Hsiang , Fang Yu-Wei
Published: January 2022

Lipid-lowering agents display limited benefits on cardiovascular diseases and mortality in patients undergoing dialysis. Therefore, they are not routinely recommended for dialysis patients. The aim of this study was to assess the effects of lipid-lowering agents on clinical outcomes in dialysis patients on the basis of real-world evidence. This research used Taiwan’s National Health Insurance Research Database to identify dialysis patients from January 2009 to December 2015; patients were then categorized into a case group treated with lipid-lowering agents (n = 3,933) and a control group without lipid-lowering agents (n = 24,267). Patients were matched by age, sex, and comorbidities in a 1:1 ratio. This study used the Cox regression model to estimate the hazard ratios (HRs) for mortality and major adverse cardiovascular events (MACEs) for events recorded until December 2017. During a mean follow-up period of approximately 3.1 years, 1726 [43.9%, incidence 0.123/person-year (PY)] deaths and 598 (15.2%, incidence 0.047/PY) MACEs occurred in the case group and 2031 (51.6%, incidence 0.153/PY) deaths and 649 (16.5% incidence 0.055/PY) MACEs occurred in the control group. In the multivariable analysis of the Cox regression model, lipid-lowering agent users showed a significantly lower risk of death [HR: 0.75; 95% confidence interval (CI): 0.70–0.80] and MACEs (HR: 0.88; 95% CI: 0.78–0.98) than lipid-lowering agent non-users. Moreover, the survival benefit of lipid-lowering agents was significant across most subgroups. Dialysis patients treated with lipid-lowering agents display a 25 and 12% reduction in their risk of mortality and MACEs, respectively. Therefore, lipid-lowering agents might be considered when treating dialysis patients with hyperlipidemia.
Association Between Regular Use of Gastric Acid Suppressants and Subsequent Risk of Cholelithiasis: A Prospective Cohort Study of 0.47 Million Participants
Authors: Yang Man , Xia Bin , Lu Yawen , He Qiangsheng , Lin Yanyan , Yue Ping , Bai Bing , Dong Chunlu , Meng Wenbo , Qi Jian , Yuan Jinqiu
Published: January 2022

Background: Gastric acid suppressants have a major impact on gut microbiome which in turn, may increase the risk of cholelithiasis, but epidemiological evidence remains unclear. We undertook this research to evaluate the association between regular use of proton pump inhibitors (PPIs) and H2-receptor antagonists (H2RAs) with risk of cholelithiasis.

Methods: Prospective cohort study included 477,293 UK residents aged 37–73 years from the UK Biobank. We included the participants reported PPI or H2RA use, and were free of cholelithiasis or cancer. We evaluated hazard ratios (HRs) of regular use of PPIs or H2RAs and risk of cholelithiasis adjusting for demographic factors, lifestyle habits, the presence of comorbidities, use of other medications, and clinical indications.

Results: We identified 12,870 cases of cholelithiasis over a median follow-up of 8.1 years. Regular use of PPIs (HR 1.22 95% CI 1.16–1.29) or H2RAs (HR 1.16, 95% CI 1.05–1.28) was associated with an increased risk of cholelithiasis after confounding adjustment. There were no major differences among individual PPIs/H2RAs. The absolute risk of PPI-associated cholelithiasis was increased with the baseline predicted risk evaluated by known environmental and genetic risk factors (Risk differences in the lowest vs. the highest quartile: 1.37 vs. 4.29 per 1,000 person-years).

Conclusion: Regular use of PPIs and H2RAs was associated with increased risk of cholelithiasis. Future prospective studies are required to confirm whether the observed associations are casual.
Expression and Characterization of Relaxin Family Peptide Receptor 1 Variants
Authors: Speck David , Kleinau Gunnar , Meininghaus Mark , Erbe Antje , Einfeldt Alexandra , Szczepek Michal , Scheerer Patrick , Pütter Vera
Published: January 2022

G-protein coupled receptors (GPCR) transduce extracellular stimuli into the cell interior and are thus centrally involved in almost all physiological-neuronal processes. This essential function and association with many diseases or pathological conditions explain why GPCRs are one of the priority targets in medical and pharmacological research, including structure determination. Despite enormous experimental efforts over the last decade, both the expression and purification of these membrane proteins remain elusive. This is attributable to specificities of each GPCR subtype and the finding of necessary experimental in vitro conditions, such as expression in heterologous cell systems or with accessory proteins. One of these specific GPCRs is the leucine-rich repeat domain (LRRD) containing GPCR 7 (LGR7), also termed relaxin family peptide receptor 1 (RXFP1). This receptor is characterized by a large extracellular region of around 400 amino acids constituted by several domains, a rare feature among rhodopsin-like (class A) GPCRs. In the present study, we describe the expression and purification of RXFP1, including the design of various constructs suitable for functional/biophysical studies and structure determination. Based on available sequence information, homology models, and modern biochemical and genetic tools, several receptor variations with different purification tags and fusion proteins were prepared and expressed in Sf9 cells (small-scale), followed by an analytic fluorescence-detection size-exclusion chromatography (F-SEC) to evaluate the constructs. The most promising candidates were expressed and purified on a large-scale, accompanied by ligand binding studies using surface plasmon resonance spectroscopy (SPR) and by determination of signaling capacities. The results may support extended studies on RXFP1 receptor constructs serving as targets for small molecule ligand screening or structural elucidation by protein X-ray crystallography or cryo-electron microscopy.
Metabolomics Analysis Coupled With UPLC/MS on Therapeutic Effect of Jigucao Capsule Against Dampness-Heat Jaundice Syndrome
Authors: He Yanmei , Zhang Mengli , Li Taiping , Tan Zhien , Zhang Aihua , Ou Min , Huang Danna , Wu Fangfang , Wang Xijun
Published: January 2022

Dampness-heat Jaundice Syndrome (DHJS) is a complex Chinese medicine syndrome, while Jigucao capsule (JGCC) is an effective compound preparation of Chinese medicine for the treatment of DHJS about liver and gallbladder, but its mechanism is not clear yet. The purpose of this study is to clarify the pathogenesis of DHJS and the treatment mechanism of JGCC. We used ultra-high performance liquid chromatography/mass spectrometry (UPLC/MS) combined with pattern recognition, accompanied the advanced software and online database for the urine metabolomics of rats. The potential biomarkers disturbing metabolism were identified and the metabolic pathway was analyzed. We investigated the callback of biomarkers after treatment with JGCC. Finally, A total of 25 potential urine biomarkers were identified, including Arachidonic acid, Phenylpyruvic acid, L-Urobilin and so on, and 14 related metabolic pathways were disturbed. After treatment with JGCC, the clinical biochemical indexes and histopathological were significantly improved, and the disturbed biomarkers were also obviously adjusted. It is proved that JGCC has remarkable effect on the treatment of DHJS.
The Potential Relationship Between Environmental Endocrine Disruptor Exposure and the Development of Endometriosis and Adenomyosis
Authors: Stephens Victoria R. , Rumph Jelonia T. , Ameli Sharareh , Bruner-Tran Kaylon L. , Osteen Kevin G.
Published: January 2022

Women with endometriosis, the growth of endometrial glands and stroma outside the uterus, commonly also exhibit adenomyosis, the growth of endometrial tissues within the uterine muscle. Each disease is associated with functional alterations in the eutopic endometrium frequently leading to pain, reduced fertility, and an increased risk of adverse pregnancy outcomes. Although the precise etiology of either disease is poorly understood, evidence suggests that the presence of endometriosis may be a contributing factor to the subsequent development of adenomyosis as a consequence of an altered, systemic inflammatory response. Herein, we will discuss the potential role of exposure to environmental toxicants with endocrine disrupting capabilities in the pathogenesis of both endometriosis and adenomyosis. Numerous epidemiology and experimental studies support a role for environmental endocrine disrupting chemicals (EDCs) in the development of endometriosis; however, only a few studies have examined the potential relationship between toxicant exposures and the risk of adenomyosis. Nevertheless, since women with endometriosis are also frequently found to have adenomyosis, discussion of EDC exposure and development of each of these diseases is relevant. We will discuss the potential mechanisms by which EDCs may act to promote the co-development of endometriosis and adenomyosis. Understanding the disease-promoting mechanisms of environmental toxicants related to endometriosis and adenomyosis is paramount to designing more effective treatment(s) and preventative strategies.