Neurological Degeneration Research Articles

The correlation between structural attributes and magnetic shielding of some metal nanoparticles engineered polymeric surfaces

Polymeric structures for use in magnetic environments are of great importance for applications ranging from simple magnetic barriers to the design of high dimensions devices, or vehicles. The damage caused by magnetic radiations is invisible, slow, and accumulative. This can lead to genetic damage, reproductive defects, cancer, neurological degeneration and nervous system dysfunction. This research work has focused on the effects of magnetic radiations onto some polymeric supports coated with different molar ratios of Zn/Al oxides and their response to magnetic radiations. Of particular interest here was the adapting the coating conditions with the magnetic barrier of the coated polymeric supports.The engineered polymeric supports have been characterized using X-ray diffraction, UV–VIS spectroscopy, SEM techniques, and magnetic measurements. The XRD and SEM results are well correlated revealing the clustering of the Zn2+ cations and the forming of ZnO nanoparticles onto the surface of the polymeric support for all used cationic ratios. The magnetic measurements proved an average magnetic nature in ZnO/AlO NPs deposited onto polymeric supports.

Risk factors for incidence of dementia in primary care practice: a retrospective cohort study in older adults.

The dementias are long-term, chronic conditions caused by progressive neurological degeneration. Current literature suggests that cardiovascular disease risk factors may contribute to the onset of dementia; however, evidence of these associations is inconsistent. This study aimed to examine the impact of risk factors on dementia onset in older adults diagnosed and managed in Canadian primary care settings. A retrospective cohort study was employed utilizing electronic medical records data in the Canadian Primary Care Sentinel Surveillance Network (CPCSSN). Patients aged 65+ years with no dementia diagnosis at baseline who were followed from 2009 to 2017 with a run-in year to exclude existing undiagnosed dementia cases. Multivariate Cox proportional hazard models were used to estimate risk. Age was associated with an increased incidence risk of dementia in both examined age groups: 65-79 years (13%) and 80+ years (5%). History of depression increased dementia risk by 38% and 34% in the age groups. There were significant associations with lower social deprivation area quintile, smoking history, osteoarthritis, and diabetes mellitus in patients aged 65-79 years but not in those aged 80+ years. Sex, hypertension, obesity, dyslipidemia, and the use of antihypertensive medications and statins were not associated with risk of incident dementia diagnosis. The association between chronic health conditions and dementia onset is complicated. Primary care electronic medical record data might be useful for research in this topic, though follow-up time is still relatively short to observe a clear causal relationship. Future studies with more complete data may provide evidence for dementia preventive strategies within primary care practice.

Aging Does Not Exacerbate Muscle Loss During Denervation and Lends Unique Muscle-Specific Atrophy Resistance With Akt Activation.

Sarcopenia, or age-related skeletal muscle atrophy and weakness, imposes significant clinical and economic burdens on affected patients and societies. Neurological degeneration, such as motoneuron death, has been recognized as a key contributor to sarcopenia. However, little is known about how aged/sarcopenic muscle adapts to this denervation stress. Here, we show that mice at 27months of age exhibit clear signs of sarcopenia but no accelerated denervation-induced muscle atrophy when compared to 8-month-old mice. Surprisingly, aging lends unique atrophy resistance to tibialis anteria muscle, accompanied by an increase in the cascade of mammalian target of rapamycin complex 1 (mTORC1)-independent anabolic events involving Akt signaling, rRNA biogenesis, and protein synthesis during denervation. These results expand our understanding of age-dependent stress responses and may help develop better countermeasures to sarcopenia.

Differences in peripheral neuropathy in xeroderma pigmentosum complementation groups A and D as evaluated by nerve conduction studies

BackgroundXeroderma pigmentosum (XP) is a rare autosomal recessive genetic disorder with defective DNA nucleotide excision repair and associated with a high frequency of skin cancer. Approximately 25% of patients develop progressive neurological degeneration. Complementation groups XP-A and XP-D are most frequently associated with neurological disorders.Design/methodsThis is a retrospective review of patients with XP who were evaluated at NIH from 1986 to 2015 and had nerve conduction studies (NCS). In the complementation groups with peripheral neuropathy, further comparisons of the NCS were made with audiological, brain imaging, neuropsychological assessments that were also performed on most of the patients. Limited neuropathology of XP-A and XP-D patients were examined..ResultsThe 33 patients had NCS: XP-A (9 patients), XP-C (7 patients), XP-D (10 patients), XP-E (1 patient), XP-V (4 patients), and XP-unknown (2 patients). Peripheral neuropathy based on nerve conduction studies was documented only in two complementation groups: 78% (7/9) of XP-A patients had a sensorimotor neuropathy while 50% (5/10) of XP-D patients had a sensory neuropathy only. Analysis of sural sensory nerve amplitude in both complementation groups XP-A and XP-D correlated with sensorineural hearing loss (SNHL), MRI/CT severity, and Full-scale Intelligence Quotient (IQ). Analysis of fibular motor nerve amplitude in complementation XP-A correlated with SNHL and MRI/CT severity. Limited follow-up studies showed gradual loss of NCS responses compared to an earlier and more rapid progression of the hearing loss.ConclusionsDespite similar brain imaging and audiological findings patients, XP-A and XP-D complementation groups differ in the type of neuropathy, sensorimotor versus sensory alone. A few cases suggest that sensorineural hearing loss may precede abnormal NCS in XP and therefore serve as valuable clinical indicators of XP patients that will later develop peripheral neuropathy.

Who is this who is coming? From neurosis to neurodegeneration in television adaptations of M. R. James’s ‘Oh, Whistle and I’ll Come to You, My Lad’

This article discusses two BBC television adaptations of M. R. James’s classic ghost story ‘Oh, Whistle and I’ll Come to You, My Lad’ (1904), the first directed by Jonathan Miller (1968) and the second by Andy de Emmony (2010). Arguing that de Emmony’s film takes Miller’s as a point of departure, it attempts to track the progressive ‘psychologization’ of James’s tale, a development that it explores with reference to Sarah Cardwell’s notion of ‘meta-textual’ lineage. The article outlines how Miller knowingly reimagines James’s story as a Freudian parable by drawing on the resources of classical psychoanalysis and its understanding of neurosis as the expression of a dynamic interior conflict, one in which something repressed menacingly returns. It goes on to read de Emmony’s film, which reorganizes the story around a case of dementia, as an effort to extend the tale into the psychic terrain of the ‘new wounded’, a term coined by philosopher Catherine Malabou to describe emergent psychopathologies unique to neurological injury or degeneration. Taking conceptual support from Malabou, the article demonstrates both the self-consciousness with which the later adaptation builds from its antecedent and its reinscription of the story within a frame of reference that specifically exceeds the psychoanalytic ontology presupposed by Miller. The films reimagine and contemporize the Jamesian haunting – with its climactic coming of a mysterious other – in ways that are utterly distinct but also cumulatively psychological. Looked at in apposition, the article suggests, they exemplify adaptation not simply as a revival or reconstitution of a past text but as an ongoing, intertextual and incremental labour of reinvention.

Serum Neurofilament Light is elevated in COVID-19 Positive Adults in the ICU and is associated with Co-Morbid Cardiovascular Disease, Neurological Complications, and Acuity of Illness.

In critically ill COVID-19 patients, the risk of long-term neurological consequences is just beginning to be appreciated. While recent studies have identified that there is an increase in structural injury to the nervous system in critically ill COVID-19 patients, there is little known about the relationship of COVID-19 neurological damage to the systemic inflammatory diseases also observed in COVID-19 patients. The purpose of this pilot observational study was to examine the relationships between serum neurofilament light protein (NfL, a measure of neuronal injury) and co-morbid cardiovascular disease (CVD) and neurological complications in COVID-19 positive patients admitted to the intensive care unit (ICU). In this observational study of one-hundred patients who were admitted to the ICU in Tucson, Arizona between April and August 2020, 89 were positive for COVID-19 (COVID-pos) and 11 was COVID-negative (COVID-neg). A healthy control group (n=8) was examined for comparison. The primary outcomes and measures were subject demographics, serum NfL, presence and extent of CVD, diabetes, sequential organ failure assessment score (SOFA), presence of neurological complications, and blood chemistry panel data. COVID-pos patients in the ICU had significantly higher mean levels of Nfl (229.6 ± 163 pg/ml) compared to COVID-neg ICU patients (19.3 ± 5.6 pg/ml), Welch’s t-test, p =.01 and healthy controls (12.3 ± 3.1 pg/ml), Welch’s t-test p =.005. Levels of Nfl in COVID-pos ICU patients were significantly higher in patients with concomitant CVD and diabetes (n=35, log Nfl 1.6±.09), and correlated with higher SOFA scores (r=.5, p =.001). These findings suggest that in severe COVID-19 disease, the central neuronal and axonal damage in these patients may be driven, in part, by the level of systemic cardiovascular disease and peripheral inflammation. Understanding the contributions of systemic inflammatory disease to central neurological degeneration in these COVID-19 survivors will be important to the design of interventional therapies to prevent long-term neurological and cognitive dysfunction.

Exploring the neurological exposome for precision prevention of neurodegenerative diseases – the role of diet

BACKGROUND AND AIM: The exposome represents the totality of exposures from conception onwards. Unravelling it requires to simultaneously identify, characterize and quantify exogenous and endogenous exposures and modifiable risk factors that predispose to and predict disease throughout the human life span. METHODS: Exposome science will help us understand the intricate web of relationships between environmental exposures, lifestyle, genetics and disease, contributing significantly to the determination of causal associations between environmental factors and human health. Determination of causality would support targeted interventions towards precision prevention, contributing significantly towards healthy aging. RESULTS:Aging brings a lot of physiological changes, usually accompanied by deterioration in cognitive function as a result of neurological degeneration, mediated by oxidative stress and inflammatory processes. However, this process does not follow a standardized course for all individuals, as a result of multiple factors. These factors include genetic susceptibility, exposure to environmental chemicals, lifestyle aspects such as poor nutrition, excessive alcohol ingestion, lack of exercise and stress, health status (e.g. hypertension or diabetes), as well as exposure to chemicals. Although diet is considered as a major exogenous factor, up-regulation of the inflammatory metabolic pathway and in many cases the oxidative stress pathway is triggered or amplified by other exogenous exposures such as exposure to man-made chemicals. Thus, exploring the role of diet in triggering and accelerating the progression of Alzheimer’s disease, should account for both the beneficial nutrients and the neurotoxicants associated with specific food items. High dimension biology tools based on a combination of omics technologies are able to identify the molecular fingerprints and pathway changes associated with specific dietary patterns, exposure to chemicals inducing oxidative stress (ambient air PM) and neuroinflammation (Hg) and genetic factors (ApoE e4 carriers). CONCLUSIONS:Exposomic analysis of the effect of diet on AD is expected to facilitate the coining and implementation of precision prevention strategies. KEYWORDS: Neurodegenerative outcomes, Exposome, Food/nutrition, Metabolomics

Residual olfactory dysfunction in coronavirus disease 2019 patients after long term recovery

IntroductionHyposmia is among the most common symptoms of COVID-19 patients. Previous research has mainly described this issue at the disease’s early stages. Because olfactory impairment can indicate neurological degeneration, we investigated the possibility of permanent olfactory damage by assessing hyposmia during the late recovery stage of COVID-19 patients. MethodsNinety-five patients were assessed with the Brief Smell Identification Test for Chinese (B-SITC) and Hyposmia Rating Scale (HRS) after 16 weeks from disease onset. Five weeks later, 41 patients were retested with B-SITC. ResultsAt the first visit, hyposmia was identified in 26/82 (31.7%) and 22/95 (23.2%) of participants by HRS (HRS score ≤22) and B-SITC (B-SITC score <8), respectively. The rates of hyposmia in patients who performed B-SITC after 14–15 weeks, 16–17 weeks, and ≥18 weeks from disease onset were 7/25 (28%), 8/35 (23%) and 7/35 (20%), respectively, which demonstrated a trend of olfaction improvement as recovery time prolonging. Hyposmia percentages decreased from the first visit (34.1%) to the second visit (24.4%) for the 41 patients who completed 2 visits. B-SITC scores of the first-visit hyposmia participants increased significantly at the second visit (5.29 ± 2.02 to 8.29 ± 2.40; n = 14, P = 0.001). Severe cases tended to recover less than common cases. ConclusionsHyposmia was present in up to one-third of COVID-19 patients after about 3 months from disease onset. Notable recovery of olfactory function was observed at a next 5-weeks follow-up. Clinical severity had little influence on olfactory impairment and recovery.

Transcriptome of HPβCD-treated Niemann-Pick disease type C1 cells highlights GPNMB as a biomarker for therapeutics

The rare, fatal neurodegenerative disorder Niemann-Pick disease type C1 (NPC1) arises from lysosomal accumulation of unesterified cholesterol and glycosphingolipids. These subcellular pathologies lead to phenotypes of hepatosplenomegaly, neurological degeneration and premature death. The timing and severity of NPC1 clinical presentation is extremely heterogeneous. This study analyzed RNA-Seq data from 42 NPC1 patient-derived, primary fibroblast cell lines to determine transcriptional changes induced by treatment with 2-hydroxypropyl-β-cyclodextrin (HPβCD), a compound currently under investigation in clinical trials. A total of 485 HPβCD-responsive genes were identified. Pathway enrichment analysis of these genes showed significant involvement in cholesterol and lipid biosynthesis. Furthermore, immunohistochemistry of the cerebellum as well as measurements of plasma from Npc1m1N null mice treated with HPβCD and adeno-associated virus gene therapy suggests that one of the identified genes, GPNMB, may serve as a useful biomarker of treatment response in NPC1 disease. Overall, this large NPC1 patient-derived dataset provides a comprehensive foundation for understanding the genomic response to HPβCD treatment.

Nucleotide Excision Repair: From Molecular Defects to Neurological Abnormalities.

Nucleotide excision repair (NER) is the most versatile DNA repair pathway, which can remove diverse bulky DNA lesions destabilizing a DNA duplex. NER defects cause several autosomal recessive genetic disorders. Xeroderma pigmentosum (XP) is one of the NER-associated syndromes characterized by low efficiency of the removal of bulky DNA adducts generated by ultraviolet radiation. XP patients have extremely high ultraviolet-light sensitivity of sun-exposed tissues, often resulting in multiple skin and eye cancers. Some XP patients develop characteristic neurodegeneration that is believed to derive from their inability to repair neuronal DNA damaged by endogenous metabolites. A specific class of oxidatively induced DNA lesions, 8,5′-cyclopurine-2′-deoxynucleosides, is considered endogenous DNA lesions mainly responsible for neurological problems in XP. Growing evidence suggests that XP is accompanied by defective mitophagy, as in primary mitochondrial disorders. Moreover, NER pathway is absent in mitochondria, implying that the mitochondrial dysfunction is secondary to nuclear NER defects. In this review, we discuss the current understanding of the NER molecular mechanism and focuses on the NER linkage with the neurological degeneration in patients with XP. We also present recent research advances regarding NER involvement in oxidative DNA lesion repair. Finally, we highlight how mitochondrial dysfunction may be associated with XP.

TBC1D24 and Its Related Epileptic Encephalopathy

Abstract TBC1D24, mapped to 16p13.3, encodes a protein containing a Tre2/Bub2/Cdc16 (TBC) domain, belonging to the super-family of Rab GTPase activating proteins (Rab-GAP). These proteins regulate various functions, including the regulation of the traffic of the vesicular membrane. Several TBC1D24 mutations have been related to autosomal recessive neurological disorders, including severe developmental encephalopathies with malignant early childhood epilepsy, benign epilepsy, epileptic encephalopathy, and a complex neurological syndrome characterized by deafness, onychodystrophy, bone and neurological degeneration. Mutations of TBC1D24 have also been reported in patients with nonsyndromic deafness with dominant or recessive inheritance. Mechanisms underlying TBC1D24-associated disorders and the functions of TBC1D24 products in the generation of such complex spectrum of diseases remain partly unclear and future studies are needed to clarify this aspect, in order to improve the management of seizures and for the prevention of complication (including death) of newly diagnosed patients affected by TBC1D24-related disorders.

Identification of mutations in the ATP7B gene in 14 Wilson disease children: Case series.

Introduction:Wilson Disease (WD) is an autosomal recessive inherited metabolic disease caused by mutations in the ATPase copper transporting beta gene (ATP7B). WD can cause fatal neurological and hepatic disorders if not diagnosed and treated.Objective:To analyze the disease-causing mutations of 14 Chinese WD children, 11 of whom are diagnosed with hepatic disorders, 2 with neurological degeneration and 1 with both hepatic and neurological disorders.Methods:All ATP7B coding regions were analyzed by Sanger sequencing. Single nucleotide polymorphisms (SNPs) functional impacts were assessed by combining the results of four bioinformatics tools (Poly-phen-2, SIFT, PANTHER-PSEP and PhD-SNPs) in an index that reflects the combined probability (cPdel) of an amino acid change to be deleterious to the protein function.Results:Two novel variants involved in WD development, c.1448_1455del (p.Arg483SerfsX19) and c.4144G>T (p.Glu1382Stop), and 11 previously reported mutations were detected. Both new variants result in shortened and dysfunctional ATP7B proteins. cPdel score suggests that SNPs may be deleterious to the ATP7B functionality.Conclusions:This study enriches the library of the ATP7B mutations that lead to WD and can be used as a basis for genetic counseling, for WD prevention and clinical and prenatal diagnosis. Those SNPs that are believed to be harmless to ATP7B protein may be involved in the pathogenesis of WD.

Review of COVID-19 Vaccines and the Risk of Chronic Adverse Events Including Neurological Degeneration

Many have argued that the outbreak of COVID-19 is the result of the release of a viral based bioweapon. Vaccines to COVID-19 have been developed and a policy of universal immunization has been initiated with total disregard to the fact that the virus may be a bioweapon. The potential risk of a catastrophe exists in part because all the vaccines contain the spike protein and or the mRNA/DNA encoding for the COVID-19 associated spike protein. These vaccines were designed and placed on the market with little knowledge of how the spike protein or its nucleic acid causes disease and without knowledge of long-term adverse effects of the vaccines. This paper reviews many of the potential long-term risks that could result from receiving one of the COVID-19 vaccines. The potential for the spike protein and its mRNA to cause prion disease is reviewed as well as reasons why the vaccine could be much more dangerous than the natural infection. Adenoviral derived COVID-19 vaccines are particularly risky because of their potential to recombine with human DNA or viruses already in the human recipient. The result could be new infectious adenoviral species containing spike proteins that could infect humans and farm animals used for food. Some of the COVID-19 vaccines utilize novel technology including nanotechnology and novel adjuvants that increase intracellular penetration of cells and can potentially exacerbate chronic toxicity from the spike protein. Governments should consider suspending sale of the COVID-19 vaccines until they have a better understanding of their risks.

Niemann-Pick disease type A: a case report

BACKGROUND&#x0D; Niemann-Pick disease (NPD) types A result from the deficient activity of sphingomyelinase. NPD type A is characterized by early-onset, progressive neurodegenerative course; systemic disease manifestations, including massive hepatosplenomegaly, interstitial lung disease, and cherry-red macula; and death in early childhood. The objective: to enhance the recognition of health care providers about the potential undiagnosed NPD because nonspecific clinical manifestation&#x0D; &#x0D; CASE PRESENTATION &#x0D; A 18-months-old boy was admitted to Dr. Kariadi Hospital with enlarged abdomen since seventh month old with failure to thrive. He also showed progressive loss of neurologic function, microcephaly with open major fontanelle, recurrent pulmonary and systemic infection. Physical examination revealed facial dysmorphic, milestone regression, under-nutrition, crackles in both lungs, hepatosplenomegaly with petechial in extremities and floppy infants. Laboratory investigations showed anemia (9.4 g/dL) and thrombocytopenia (73.000/mm3). The lactate dehydrogenase (482 U/L) and alkaline phosphatase (159, 03 IU/L) were higher than normal. Abdominal ultrasound revealed hepatomegaly with normal parenchyma and splenomegaly without nodule. Skeletal survey revealed Erlenmeyer flask deformity. Foam cell are detected in bone marrow puncture. Retcam examination showed cherry red spot at the macula. Bera revealed auditory neuropathy. The enzyme activity showed normal ?–Glucosidase (5.55 uM/hr) and chitotriosidase (105,8 nmol/ml) but low sphingomyelinases activity (0.30 uM/hr) which confirmed the diagnosis of NPD.&#x0D; DISCUSSION&#x0D; Niemann-Pick disease (NPD) types A result from the deficient activity of sphingomyelinase. NPD type A is characterized by early-onset, progressive neurodegenerative course; systemic disease manifestations, including massive hepatosplenomegaly, interstitial lung disease, and cherry-red macula; and death in early childhood. Type A is very rare and a severe infantile form with neurologic degeneration resulting in death usually by 3 years of age. No treatment available for type A and It’s a rare disease in Indonesia. &#x0D; CONCLUSION &#x0D; These investigations were able to diagnose this child as a NPD-Type A. Patient was closely monitored and symptomatic treatment was provided.

Follistatin-induced muscle hypertrophy in aged mice improves neuromuscular junction innervation and function

Sarcopenia, or age-related loss of muscle mass and strength, is an important contributor to loss of physical function in older adults. The pathogenesis of sarcopenia is likely multifactorial, but recently the role of neurological degeneration, such as motor unit loss, has received increased attention. Here, we investigated the longitudinal effects of muscle hypertrophy (via overexpression of human follistatin, a myostatin antagonist) on neuromuscular integrity in C57BL/6J mice between the ages of 24 and 27 months. Following follistatin overexpression (delivered via self-complementary adeno-associated virus subtype 9 injection), muscle weight and torque production were significantly improved. Follistatin treatment resulted in improvements of neuromuscular junction innervation and transmission but had no impact on age-related losses of motor units. These studies demonstrate that follistatin overexpression-induced muscle hypertrophy not only increased muscle weight and torque production but also countered age-related degeneration at the neuromuscular junction in mice.

Simultaneously Detecting Monoamine Oxidase A and B in Disease Cell/Tissue Samples Using Paper-Based Devices.

As enzymes in the outer membrane of the mitochondrion, monoamine oxidases (MAOs) can catalyze the oxidative deamination of monoamines in the human body. According to different substrates, MAOs can be divided into MAO-A and MAO-B. The imbalance of the MAO-A is associated with neurological degeneration, while excess MAO-B activity is closely connected with Parkinson's disease (PD) and Alzheimer's disease (AD); therefore, detection of MAOs is of great significance for the diagnosis and treatment of these diseases. This work reports the multiplexed detection of MAO-A and MAO-B using paper-based devices based on chemiluminescence (CL). The detection limits were 5.01 pg/mL for MAO-A and 8.50 pg/mL for MAO-B in human serum. In addition, we used paper-based devices to detect MAOs in human cells and tissue samples and found that the results of paper-based detection and Western blotting (WB) showed the same trend. While only one antibody can be incubated on the same membrane by WB, multiple antibodies incubated on the same paper enabled simultaneous detection of MAO-A and MAO-B by paper-based devices. The paper-based assay could be used for preliminary early screening of clinical samples for MAOs and can be extended as an alternative to WB for multiplexed detection of various proteins in disease cell or tissue samples.

Lucidity in the Context of Advanced Neurodegenerative Disorders: A Concept Analysis.

Individuals with advanced dementias resulting from neurodegenerative disorders (NDs) occasionally surprise caregivers with episodes of clarity and cognitive function that are not usually present. Lucid episodes-aptly named paradoxical lucidity in the literature-seem to involve a return of the "old self" during advanced neurodegenerative changes. Lucid episodes pose a problem for theories of neurological degeneration, which position dementias as progressive, incurable, and irreversible. In addition, lucid episodes raise ethical questions about whether information gleaned during lucid episodes is appropriate to direct future patient-centered care. The concept requires analysis and clarification if it is to guide future theorizing and research. The underlying goals of the current concept analysis are twofold: (a) to clarify the meaning of lucidity in the context of advanced NDs; and (b) to develop a theoretical definition that can guide future practice, research, and policy development. Walker and Avant's method is used to identify uses of the concept, defining attributes, antecedents, consequences, and empirical referents. [Journal of Gerontological Nursing, 46(12), 42-50.].

SMTP-44D improves diabetic neuropathy symptoms in mice through its antioxidant and anti-inflammatory activities.

Diabetic neuropathy (DN) is one of the major complications of diabetes. However, there are few approved effective therapies for painful or insensate DN. Recent studies have implicated oxidative stress and inflammation in the pathogenesis of DN, and suppressing these could be an important therapeutic strategy. We previously reported that Stachybotrys microspora triprenyl phenol‐44D (SMTP‐44D) exhibits both antioxidant and anti‐inflammatory activities. The aim of this study was to evaluate the effects of SMTP‐44D in a mouse model of streptozotocin‐induced DN. SMTP‐44D was administered for 3 weeks after the disease induction, and its effects were evaluated on the basis of mechanical and thermal thresholds, blood flow in the bilateral hind paw, and blood flow and conduction velocity in the sciatic nerve. Furthermore, the levels of inflammatory factors, such as tumor necrosis factor (TNF)‐α, interleukin (IL)‐1β, IL‐6 and malondialdehyde (MDA), in the sciatic nerve were assessed. Neurological degeneration was assessed by measuring myelin thickness and g‐ratio in the sciatic nerve. SMTP‐44D treatment significantly improved allodynia, hyperalgesia, blood flow, and conduction velocity in DN model mice in a dose‐dependent manner. Neurological degeneration was also significantly improved, accompanied by decreased levels of inflammatory factors (TNF‐α, 57.8%; IL‐1β, 51.4%; IL‐6, 62.8%; and MDA, 40.7% reduction rate against the diabetes mellitus + normal saline group). Thus, SMTP‐44D can improve allodynia and hyperalgesia in DN without affecting the body weight and blood glucose levels, which may be due to its antioxidant and anti‐inflammatory properties. In conclusion, SMTP‐44D could be a potential therapeutic agent for the treatment of DN.

Investigation of sensorimotor dysfunction in Parkinson disease by resting-state fMRI

PurposeFunctional MRI has played a fundamental role in Parkinson's disease(PD) study. In this paper, we performed an independent component analysis (ICA) based on functional networks to reveal the intricate variations on the morphology and functional properties of brain. Our analysis aims at discovering the differences between PD patients with sensorimotor function impairment and normal controls(NC), thus helping to understand the coordination neurological function degeneration in PD objectively. MethodWe investigated the blood oxygen level dependent(BOLD) functional MRI obtained at a 3.0 T MRI scanner. 30 PD patients and 28 NC subjects underwent the scan in resting state. The signals of sensory and motor coordinative control areas in the sensorimotor, insula and cerebellum networks acquired by ICA(Independent Component Analysis)were applied to analyze the functional alterations. Specifically, intra-network analysis was performed with signals in local networks, and inter-network analysis was conducted by functional network connectivity (FNC) with signals across different networks. Two sample T test was carried out to detect the significant (p < 0.05, FDR p < 0.05) functional abnormality in PD patients. ConclusionWe identified an obvious increase in bilateral posterior insula, but decrease in bilateral cerebellum hemisphere, supplementary motor area(SMA) and precentral gyrus paracentral lobule of left postcentral gyrus. Besides, we found a significantly increased connection between independent component (IC) 13 which was located in right postcentral gyrus and cerebellum. Decreased connections were detected between sensory and motor cortex in sensorimotor network and between cerebellum and insula network by FNC analysis in PD patients as well. DiscussionParkinson's disease derives from the degeneration of the dopaminergic neurons in substantia nigra, and results in decreased secretion of inhibitory neurotransmitter. The significant differences between PD and NC groups in our research maybe explain the clinical manifestations of prominent bradykinesia and multiple extrapyramidal symptoms.

Alzheimer's Dementia After Exposure to Anesthesia and Surgery in the Elderly: A Matched Natural Experiment Using Appendicitis.

The aim of this study was to determine whether surgery and anesthesia in the elderly may promote Alzheimer disease and related dementias (ADRD). There is a substantial conflicting literature concerning the hypothesis that surgery and anesthesia promotes ADRD. Much of the literature is confounded by indications for surgery or has small sample size. This study examines elderly patients with appendicitis, a common condition that strikes mostly at random after controlling for some known associations. A matched natural experiment of patients undergoing appendectomy for appendicitis versus control patients without appendicitis using Medicare data from 2002 to 2017, examining 54,996 patients without previous diagnoses of ADRD, cognitive impairment, or neurological degeneration, who developed appendicitis between ages 68 through 77 years and underwent an appendectomy (the ''Appendectomy'' treated group), matching them 5:1 to 274,980 controls, examining the subsequent hazard for developing ADRD. The hazard ratio (HR) for developing ADRD or death was lower in the Appendectomy group than controls: HR = 0.96 [95% confidence interval (CI) 0.94-0.98], P < 0.0001, (28.2% in Appendectomy vs 29.1% in controls, at 7.5 years). The HR for death was 0.97 (95% CI 0.95-0.99), P = 0.002, (22.7% vs 23.1% at 7.5 years). The HR for developing ADRD alone was 0.89 (95% CI 0.86-0.92), P < 0.0001, (7.6% in Appendectomy vs 8.6% in controls, at 7.5 years). No subgroup analyses found significantly elevated rates of ADRD in the Appendectomy group. In this natural experiment involving 329,976 elderly patients, exposure to appendectomy surgery and anesthesia did not increase the subsequent rate of ADRD.