Maladaptive Changes Research Articles

Tracking Prostate Carcinogenesis over Time through Urine Proteome Profiling in an Animal Model: An Exploratory Approach.

Prostate cancer (PCa) is one of the most lethal diseases in men, which justifies the search for new diagnostic tools. The aim of the present study was to gain new insights into the progression of prostate carcinogenesis by analyzing the urine proteome. To this end, urine from healthy animals and animals with prostate adenocarcinoma was analyzed at two time points: 27 and 54 weeks. After 54 weeks, the incidence of pre-neoplastic and neoplastic lesions in the PCa animals was 100%. GeLC-MS/MS and subsequent bioinformatics analyses revealed several proteins involved in prostate carcinogenesis. Increased levels of retinol-binding protein 4 and decreased levels of cadherin-2 appear to be characteristic of early stages of the disease, whereas increased levels of enolase-1 and T-kininogen 2 and decreased levels of isocitrate dehydrogenase 2 describe more advanced stages. With increasing age, urinary levels of clusterin and corticosteroid-binding globulin increased and neprilysin levels decreased, all of which appear to play a role in prostate hyperplasia or carcinogenesis. The present exploratory analysis can be considered as a starting point for studies targeting specific human urine proteins for early detection of age-related maladaptive changes in the prostate that may lead to cancer.

Comparative Study of Intranasal Dexmedetomidine Versus Intranasal Ketamine as Premedicant in Children.

Background: Pre-operative anxiety in children not only makes induction difficult but it is also associated with an increase in the requirement of analgesics, the incidence of post-operative nausea and vomiting (PONV), emergence delirium (ED), and postoperative maladaptive behavioral changes. It can be reduced effectively by pharmacological interventions. In a quest to find the ideal premedicant and non-invasive way of its administration, we decided to compare intranasal (IN) dexmedetomidine with IN ketamine as a premedicant in pediatric patients.Aims and objectives: To compare sedation score, mask acceptance score (MAS) during induction, the incidence of ED, and other adverse events in both groups.Material and methods: Some 60 children, between 1 and 8 years of age of either sex undergoing surgical procedures were included in this study and randomly divided into two groups (Group D and Group K). Thirty minutes prior to induction of anesthesia, patients of Group D received dexmedetomidine 1 mcg kg-1 in 1 mL of 0.9% saline intranasally and patients of Group K received ketamine 5 mg kg-1 in 1 mL of 0.9% saline intranasally through calibrated dropper (0.5 mL in each nostril) in a recumbent position. Incidences of sneezing or coughing after IN administration of study drugs were recorded. The subsequent sedation scores were assessed using MOASS at 15 min, then at 30 min following premedication at the time of parental separation. After shifting patients to operation theater inhalation induction was done. MAS at induction and any adverse effects were recorded.Results: Children in Group K were found to be significantly more sedated at 30 min after administration of premedication and mask acceptance was also better (p value < 0.0001 with a confidence interval, CI=95%). But the incidence of ED and PONV was high.Conclusion: Intranasal dexmedetomidine (1 mcg kg-1) is clinically less effective as a premedicant in terms of sedation and mask acceptance in older children as compared to ketamine (5 mg kg-1), but associated with fewer incidence of ED and PONV. We recommend the usage of IN dexmedetomidine in a higher dose (1.5-2 mcg kg-1), through nebulization/atomizer for the desired level of sedation and mask acceptance.

A nerve injury-specific long noncoding RNA promotes neuropathic pain by increasing Ccl2 expression.

Maladaptive changes of nerve injury–associated genes in dorsal root ganglia (DRGs) are critical for neuropathic pain genesis. Emerging evidence supports the role of long noncoding RNAs (lncRNAs) in regulating gene transcription. Here we identified a conserved lncRNA, named nerve injury–specific lncRNA (NIS-lncRNA) for its upregulation in injured DRGs exclusively in response to nerve injury. This upregulation was triggered by nerve injury–induced increase in DRG ELF1, a transcription factor that bound to the NIS-lncRNA promoter. Blocking this upregulation attenuated nerve injury–induced CCL2 increase in injured DRGs and nociceptive hypersensitivity during the development and maintenance periods of neuropathic pain. Mimicking NIS-lncRNA upregulation elevated CCL2 expression, increased CCL2-mediated excitability in DRG neurons, and produced neuropathic pain symptoms. Mechanistically, NIS-lncRNA recruited more binding of the RNA-interacting protein FUS to the Ccl2 promoter and augmented Ccl2 transcription in injured DRGs. Thus, NIS-lncRNA participates in neuropathic pain likely by promoting FUS-triggered DRG Ccl2 expression and may be a potential target in neuropathic pain management.

ALCOHOL-INDUCED EXPRESSION OF VASCULAR ENDOTHELIAL GROWTH FACTOR AND STRUCTURAL CHANGES IN RAT CARDIOMYOCYTES

The aim of the study is to reveal the ethanol effects on the expression of hypoxia-associated factors (HIF-1α, VEGF-A) and structural changes in cardiomyocytes of healthy rats.&#x0D; Materials and methods. Ethanol-induced structural changes in cardiomyocytes were studied in 60 outbred mature rats. Control animals were intragastrically injected with sterile 0.9% saline, experimental animals – with 40 % ethanol. Ethanol exposure on myocardium lasted 4 and 8 days. Morphological study of the heart was carried out after decapitation preceded by ether anesthesia. PCR tests were used to determine mRNA expression of HIF-1α and VEGF-A genes from the left ventricle and serum concentration of vascular endothelial growth factor. Morphological studies of the left ventricle myocardium were carried out on histological sections using light microscopy.&#x0D; Results. A short ethanol exposure was accompanied by fatty and granular cytoplasm degeneration of cardiomyocytes with erythrocyte stasis in capillaries, arterioles and venules. VEGF-A serum concentration in control rats was lower if compared with ethanol-induced rats. Gender differences to ethanol response were revealed, in particular, a more pronounced HIF-1α and VEGF-A mRNA expression in females compared to males on the background of 4-day ethanol exposure, which correlated with VEGF-A level in blood serum. 8-day alcohol exposure was accompanied by an increase in VEGF-A mRNA expression in both female and male rats.&#x0D; Conclusion. Ethanol exposure causes activation of HIF-1α and VEGF-A transcription factors in cardiomyocytes of rats. It can be regarded as a mechanism of urgent adaptation without the development of pronounced structural maladaptive changes of the myocardium.

Functional Capaсities of Limb Muscles in Patients with Partial Damage to the Cervical Spinal Cord

INTRODUCTION: In the long-term course of traumatic spinal cord disease (TSCD), neuroplastic adaptive and maladaptive changes occurred on different structural levels of the nervous system, which leads to a shift in the activation and strength characteristics of the limb muscles. The standard neurological assessment is approximate; therefore, objective instrumental studies of the motor sphere of patients with partial damage to the cervical spinal cord have not lost their significance.&#x0D; AIM: To study the activation and strength characteristics of the limb muscles of patients with partial injury of the cervical spinal cord in the long-term course of the disease (type B on the American Spinal Cord Injury Association (ASIA) scale).&#x0D; MATERIALS AND METHODS: The study enrolled 28 patients with fractures of the cervical spinal cord vertebrae in the late period of the TSCD of ASIA type B. The amplitude of motor responses (M-responses) of the upper and lower limbs was assessed using electroneuromyography. The strength of the upper limb muscles was evaluated using manual dynamometers.&#x0D; RESULTS: M-responses were absent in 9% and 64% in the upper and lower limbs, respectively. The amplitude of the most recorded M-responses of the upper and lower limb muscles was reduced relative to the norm. The reduction was not uniform, with significant differences in different leads. The average values of the amplitude asymmetry of M-responses did not exceed the norm. Moreover, 61% of the patients could perform hand-grip functions and hold the wrist dynamometer. Only 59% of the patients could make an effort and the results of strength measurement were obtained, whereas in 41% of cases, zero values were obtained. Statistical analyses revealed a clear relationship between the motor deficiency index of the upper limb and hand-grip strength.&#x0D; CONCLUSION: The degree of preservation of M-responses and evident asymmetry of evoked electrical activities of the upper and lower limb muscles indicate the existence of a certain level of neurotrophic interaction in the muscle fibermotor neuron system. The level of reduction of the hand-grip strength and its relationship with the motor deficiency index allows discussion about the partial preservation of the voluntary control of the motor function of the upper limbs.

Peripheral mechanisms of chronic pain

Acutely, pain serves to protect us from potentially harmful stimuli, however damage to the somatosensory system can cause maladaptive changes in neurons leading to chronic pain. Although acute pain is fairly well controlled, chronic pain remains difficult to treat. Chronic pain is primarily a neuropathic condition, but studies examining the mechanisms underlying chronic pain are now looking beyond afferent nerve lesions and exploring new receptor targets, immune cells, and the role of the autonomic nervous system in contributing chronic pain conditions. The studies outlined in this review reveal how chronic pain is not only confined to alterations in the nervous system and presents findings on new treatment targets and for this debilitating disease.

Pressure Overload Activates DNA-Damage Response in Cardiac Stromal Cells: A Novel Mechanism Behind Heart Failure With Preserved Ejection Fraction?

Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome characterized by impaired left ventricular (LV) diastolic function, with normal LV ejection fraction. Aortic valve stenosis can cause an HFpEF-like syndrome by inducing sustained pressure overload (PO) and cardiac remodeling, as cardiomyocyte (CM) hypertrophy and fibrotic matrix deposition. Recently, in vivo studies linked PO maladaptive myocardial changes and DNA damage response (DDR) activation: DDR-persistent activation contributes to mouse CM hypertrophy and inflammation, promoting tissue remodeling, and HF. Despite the wide acknowledgment of the pivotal role of the stromal compartment in the fibrotic response to PO, the possible effects of DDR-persistent activation in cardiac stromal cell (C-MSC) are still unknown. Finally, this novel mechanism was not verified in human samples. This study aims to unravel the effects of PO-induced DDR on human C-MSC phenotypes. Human LV septum samples collected from severe aortic stenosis with HFpEF-like syndrome patients undergoing aortic valve surgery and healthy controls (HCs) were used both for histological tissue analyses and C-MSC isolation. PO-induced mechanical stimuli were simulated in vitro by cyclic unidirectional stretch. Interestingly, HFpEF tissue samples revealed DNA damage both in CM and C-MSC. DDR-activation markers γH2AX, pCHK1, and pCHK2 were expressed at higher levels in HFpEF total tissue than in HC. Primary C-MSC isolated from HFpEF and HC subjects and expanded in vitro confirmed the increased γH2AX and phosphorylated checkpoint protein expression, suggesting a persistent DDR response, in parallel with a higher expression of pro-fibrotic and pro-inflammatory factors respect to HC cells, hinting to a DDR-driven remodeling of HFpEF C-MSC. Pressure overload was simulated in vitro, and persistent activation of the CHK1 axis was induced in response to in vitro mechanical stretching, which also increased C-MSC secreted pro-inflammatory and pro-fibrotic molecules. Finally, fibrosis markers were reverted by the treatment with a CHK1/ATR pathway inhibitor, confirming a cause-effect relationship. In conclusion we demonstrated that, in severe aortic stenosis with HFpEF-like syndrome patients, PO induces DDR-persistent activation not only in CM but also in C-MSC. In C-MSC, DDR activation leads to inflammation and fibrosis, which can be prevented by specific DDR targeting.

Effect of Acupuncture on Blood Pressure and Metabolic Profile Among Patients With Essential Hypertension: Protocol of a Randomized Clinical Trial.

Essential hypertension is a polygenic cardiovascular disease that is associated with maladaptive metabolic changes. Acupuncture as a non-pharmacologic intervention is used to lower blood pressure and improve metabolic dysfunction. However, such effects have not been clinically characterized. We will conduct a randomized clinical trial to evaluate the antihypertensive effect of acupuncture among patients with essential hypertension and determine the associated metabolic improvements. This study is a phase II, two-arm, randomized, sham-controlled trial (Trial registration: ChiCTR2100043737), in which biospecimens will be collected for metabolic profiling. A total of 64 patients with a clinical diagnosis of essential hypertension will be randomly assigned to either the acupuncture or the sham acupuncture group in a 1:1 ratio. All participants will receive 10 treatments over 4 weeks, with three sessions per week for the first 2 weeks and two sessions per week for the remaining weeks. The primary outcome is the change of the systolic and diastolic blood pressure measured by the 24-h ambulatory blood pressure monitoring from baseline to 4 weeks. Secondary outcomes include the circadian rhythm of blood pressure, sleep quality measured by the Insomnia Severity Index, cognitive function measured by the Montreal Cognitive Assessment, and others. Fasting blood serum and urine samples will be collected at baseline and 4 weeks for targeted and untargeted metabolomics analysis. We will use the mixed-effects model and other related bioinformatics approaches to analyze the clinical and metabolome data. This metabolomic-based trial will provide important clinical data regarding the efficacy of acupuncture for essential hypertension to better inform evidence-based care delivery for hypertension patients. Moreover, the findings will offer important insights into the mechanism of action of acupuncture for hypertension by revealing its effect on metabolism. The results of this study will be used to inform the design of a statistically powered, multicenter, randomized trial. We will publish the study findings in peer-reviewed journals. The ethical approval of this study has been reviewed and approved by the Sichuan Regional Ethics Review Committee on Traditional Chinese Medicine (ID: 2021KL-006). The outcomes of the trial will be disseminated through peer-reviewed publications.

Sex-specific effects of daily tadalafil on diabetic heart kinetics in RECOGITO, a randomized, double-blind, placebo-controlled trial.

Cyclic GMP-phosphodiesterase type 5 (PDE5) inhibition has been shown to counteract maladaptive cardiac changes triggered by diabetes in some but not all studies. We performed a single-center, 20-week, double-blind, randomized, placebo-controlled trial (NCT01803828) to assess sex differences in cardiac remodeling after PDE5 inhibition in patients with diabetic cardiomyopathy. A total of 122 men and women (45 to 80 years) with long-duration (>3 years) and well-controlled type 2 diabetes mellitus (T2DM; HbA1c < 86 mmol/mol) were selected according to echocardiographic signs of cardiac remodeling. Patients were randomly assigned (1:1) to placebo or oral tadalafil (20 mg, once daily). The primary outcome was to evaluate sex differences in cardiac torsion change. Secondary outcomes were changes in cardiovascular, metabolic, immune, and renal function. At 20 weeks, the treatment-by-sex interaction documented an improvement in cardiac torsion (-3.40°, -5.96; -0.84, P = 0.011) and fiber shortening (-1.19%, -2.24; -0.14, P = 0.027) in men but not women. The primary outcome could not be explained by differences in cGMP concentrations or tadalafil pharmacodynamics. In both sexes, tadalafil improved hsa-miR-199-5p expression, biomarkers of cardiovascular remodeling, albuminuria, renal artery resistive index, and circulating Klotho concentrations. Immune cell profiling revealed an improvement in low-grade chronic inflammation: Classic CD14++CD16- monocytes reduced, and Tie2+ monocytes increased. Nine patients (14.5%) had minor adverse reactions after tadalafil administration. Continuous PDE5 inhibition could offer a strategy to target cardiorenal complications of T2DM, with sex- and tissue-specific responses. Further studies are needed to confirm Klotho and hsa-miR-199-5p as markers for T2DM complications.

Motor response vigour and visual fixation patterns reflect subjective valuation during intertemporal choice.

Value-based decision-making is of central interest in cognitive neuroscience and psychology, as well as in the context of neuropsychiatric disorders characterised by decision-making impairments. Studies examining (neuro-)computational mechanisms underlying choice behaviour typically focus on participants' decisions. However, there is increasing evidence that option valuation might also be reflected in motor response vigour and eye movements, implicit measures of subjective utility. To examine motor response vigour and visual fixation correlates of option valuation in intertemporal choice, we set up a task where the participants selected an option by pressing a grip force transducer, simultaneously tracking fixation shifts between options. As outlined in our preregistration (https://osf.io/k6jct), we used hierarchical Bayesian parameter estimation to model the choices assuming hyperbolic discounting, compared variants of the softmax and drift diffusion model, and assessed the relationship between response vigour and the estimated model parameters. The behavioural data were best explained by a drift diffusion model specifying a non-linear scaling of the drift rate by the subjective value differences. Replicating previous findings, we found a magnitude effect for temporal discounting, such that higher rewards were discounted less. This magnitude effect was further reflected in motor response vigour, such that stronger forces were exerted in the high vs. the low magnitude condition. Bayesian hierarchical linear regression further revealed higher grip forces, faster response times and a lower number of fixation shifts for trials with higher subjective value differences. An exploratory analysis revealed that subjective value sums across options showed an even more pronounced association with trial-wise grip force amplitudes. Our data suggest that subjective utility or implicit valuation is reflected in motor response vigour and visual fixation patterns during intertemporal choice. Taking into account response vigour might thus provide deeper insight into decision-making, reward valuation and maladaptive changes in these processes, e.g. in the context of neuropsychiatric disorders.

Selective Inhibitory Circuit Dysfunction after Chronic Frontal Lobe Contusion.

Traumatic brain injury (TBI) is a leading cause of neurologic disability; the most common deficits affect prefrontal cortex-dependent functions such as attention, working memory, social behavior, and mental flexibility. Despite this prevalence, little is known about the pathophysiology that develops in frontal cortical microcircuits after TBI. We investigated whether alterations in subtype-specific inhibitory circuits are associated with cognitive inflexibility in a mouse model of frontal lobe contusion in both male and female mice that recapitulates aberrant mental flexibility as measured by deficits in rule reversal learning. Using patch-clamp recordings and optogenetic stimulation, we identified selective vulnerability in the non-fast-spiking and somatostatin-expressing (SOM+) subtypes of inhibitory neurons in layer V of the orbitofrontal cortex 2 months after injury. These subtypes exhibited reduced intrinsic excitability and a decrease in their synaptic output onto pyramidal neurons, respectively. By contrast, the fast-spiking and parvalbumin-expressing interneurons did not show changes in intrinsic excitability or synaptic output, respectively. Impairments in non-fast-spiking/SOM+ inhibitory circuit function were also associated with network hyperexcitability. These findings provide evidence for selective disruptions within specific inhibitory microcircuits that may guide the development of novel therapeutics for TBI.SIGNIFICANCE STATEMENT TBI frequently leads to chronic deficits in cognitive and behavioral functions that involve the prefrontal cortex, yet the maladaptive changes that occur in these cortical microcircuits are unknown. Our data indicate that alterations in subtype-specific inhibitory circuits, specifically vulnerability in the non-fast-spiking/somatostatin-expressing interneurons, occurs in the orbitofrontal cortex in the context of chronic deficits in reversal learning. These neurons exhibit reduced excitability and synaptic output, whereas the other prominent inhibitory population in layer V, the fast-spiking/parvalbumin-expressing interneurons as well as pyramidal neurons are not affected. Our work offers mechanistic insight into the subtype-specific function of neurons that may contribute to mental inflexibility after TBI.

Involvement of PKMζ in Stress Response and Depression.

The stress system in the brain plays a pivotal role in keeping humans and animals from harmful stimuli. However, excessive stress will cause maladaptive changes to the stress system and lead to depression. Despite the high prevalence of depression, the treatment remains limited. PKMζ, an atypical PKC isoform, has been demonstrated to play a crucial role in maintaining long-term potentiation and memory. Recent evidence shows that PKMζ is also involved in stress response and depressive-like behavior. In particular, it was demonstrated that stress that resulted in depressive-like behavior could decrease the expression of PKMζ in the prefrontal cortex, which could be reversed by antidepressants. Importantly, modulation of PKMζ expression could regulate depressive-like behaviors and the actions of antidepressants. These data suggested that PKMζ could be a molecular target for developing novel antidepressants. Here, I review the advance on the role of PKMζ in mediating stress response and its involvement in the development of depression.

Voluntary exercise ameliorates neuropathic pain by suppressing calcitonin gene-related peptide and ionized calcium-binding adapter molecule 1 overexpression in the lumbar dorsal horns in response to injury to the cervical spinal cord

BackgroundNeuropathic pain (NP) is a frequent finding in patients diagnosed with spinal cord injuries (SCIs). To improve our understanding of the maladaptive changes taking place in the lumbar spinal cord that can lead to the development of NP and to find alternative options to treat this condition, we aimed to investigate the effects of voluntary exercise on NP after SCI and to elucidate its potential mechanisms. MethodsA rat model of post-SCI NP induced by compression of the posterior or lateral cervical spinal cord was used to evaluate the effects of voluntary exercise by measuring the bilateral withdrawal of the hind paws using the Von Frey filament and Hargreaves tests. The place escape/avoid paradigm was used to evaluate supraspinal pain processing and somatosensory evoked potentials (SEPs) were used to examine disturbances in proprioception. Locomotor function was evaluated using Basso, Beattie, and Bresnahan (BBB) scoring. Pathologic findings in hematoxylin and eosin-stained tissue and magnetic resonance imaging were used to evaluate the morphological changes after SCI. The lesion size within the cervical spinal cord was evaluated by staining with Eriochrome cyanine R. Quantitative polymerase chain reaction and immunohistochemistry were used to assess the expression of calcitonin gene-related peptide (CGRP) and ionized calcium-binding adapter molecule 1 (Iba-1) in the lumbar dorsal horns. ResultsAll injured rats developed mechanical hypersensitivity, hyposensitivity, and thermal hyperalgesia in the contralateral hind paws at 1 week post-injury. Rats that underwent lateral compression injury developed NP in the ipsilateral hind paws 1 week later than rats with a posterior compression injury. Our findings revealed that voluntary exercise ameliorated mechanical allodynia and thermal hyperalgesia, and significantly improved proprioception as measured by SEP, but had no impact on mechanical hypoalgesia or motor recovery and provided no significant neuroprotection after recovery from an acute SCI. SCI-induced NP was accompanied by increased expression of CGRP and Iba-1 in the lumbar dorsal horn. These responses were reduced in rats that underwent voluntary exercise. ConclusionsVoluntary exercise ameliorates NP that develops in rats after compression injury. Increased expression of CGRP and Iba-1 in the lumbar dorsal horns of rats exhibiting symptoms of NP suggests that microglial activation might play a crucial role in its development. Collectively, voluntary exercise may be a promising therapeutic modality to treat NP that develops clinically in response to SCI.

Minocycline Blunts Isoproterenol‐Induced Cardiac Hypertrophy

IntroductionExcess and chronic activation of the sympathetic nervous system often results in progressive adverse remodeling and heart failure development. Here we investigated whether chronic administration of isoproterenol (Iso), a β‐AR agonist, would promote hypertrophy, fibrosis, and dysfunction, and whether these maladaptive changes are prevented by minocycline, an FDA‐approved antibiotic, that has been shown to have cardioprotective effects outside of its antibacterial properties.MethodsWild‐type male C57BL/6J mice were subcutaneously implanted with osmotic minipumps, delivering either 30 mg/kg body weight per day of isoproterenol, or vehicle control. Following pump implantation, mice received daily intraperitoneal (I.P.) injections of either sterile saline or 50 mg/kg of minocycline. After 21 days, cardiac function was assessed by echocardiography, and hearts were collected for further analysis. A transverse slice of the ventricles was fixed for histology, and a portion of the left ventricle was used for RNA isolation, and mRNA and miRNA sequencing.ResultsEchocardiography revealed that isoproterenol increased heart rate, heart weight (hypertrophy), ejection fraction and fractional shortening, without leading to significant changes in fibrosis. Minocycline prevented the hypertrophic remodeling and changes in systolic function without affecting heart rate. While mRNA sequencing revealed that isoproterenol enriched gene networks associated with changes in inflammation, the miRNA sequencing showed that minocycline enhanced miR‐26b expression, which is reported to suppress GATA4‐mediated hypertrophy.ConclusionMinocycline mitigates isoproterenol‐induced cardiac hypertrophy while preserving contractility, as well as induces changes in RNA and miRNA pathways involved with inflammation and cardiac remodeling

Neurophysiological mechanisms of gait disturbance in advanced Parkinson's disease patients

This review considers pathophysiological mechanisms of posture-gait disturbances in Parkinson's disease (PD). Clinical studies have shown that posture-gait disturbance attributes to the dysfunction of the whole neuraxis in addition to the musculoskeletal system. The cerebral cortex, basal ganglia (BG), cerebellum, brainstem, and spinal cord temporally and spatially integrate and coordinate multisensory feedback and efferent copies of the motor command. Therefore, the extensive repertoire of voluntary movements can be coupled with anticipatory and reactive postural adjustments to provide the framework for supporting and stabilizing the goal-directed gait activity. Redundancies in the system allow adaptation and compensation through reward-oriented and error-based learning processes implemented through the BG and cerebellar pathways, respectively. However, the impairment of these systems in PD may considerably compromise the capacity to adapt and lead to maladaptive changes impairing posture-gait control. When these impairments occur, the risk of falls can significantly increase, and interventions are required to reduce morbidity. The damage in dopamine (DA) neurons is the primary cause of PD. Insufficient DA supply in the striatum disturbs the operation of intrinsic networks in the BG. This also pathologically increases GABAergic BG output to the cerebral cortex and brainstem, resulting in functional disconnection of other structures from the BG. The disconnection makes PD patients disable to achieve habitually acquired automatized gait control. Moreover, Lewy body degeneration in most brain areas, particularly in cholinergic and other monoaminergic systems vulnerable to neurodegeneration, further disturbs posture-gait control and alters non-motor symptoms of PD.

Chronic Binge Alcohol Differentially Affects Extracellular Matrix Phenotype in Omental and Subcutaneous Adipose Tissue of SIV‐infected Macaques

The incidence of at‐risk alcohol use among people living with HIV (PLWH) is two times greater than in the general population. Though antiretroviral therapy (ART) has significantly reduced HIV‐associated mortality, increased survival of PLWH on ART is associated with increased incidence of metabolic comorbidities. Adipose tissue maladaptation is central to metabolic alterations in PLWH and at‐risk alcohol use. This involves adipokine disruption, adipocyte dysfunction, inflammation, and dysregulation of the extracellular milieu. Using a relevant preclinical model of HIV‐infection, the objective of our study was to investigate the effects of chronic binge alcohol (CBA) administration on omental adipose tissue (OmAT) and subcutaneous adipose tissue (SAT) extracellular matrix (ECM) phenotype. Rhesus macaques were administered CBA or isovolumetric water (VEH) through an intragastric catheter for 30 min, 5 days a week, with blood alcohol concentrations reaching 50‐60 mM. Three months after initiation of CBA or VEH administration, macaques were inoculated with SIVMac251, and 2.5 months later animals were initiated on ART. CBA or VEH administration was continued throughout the duration of the study (14.5 mo). Animals were euthanized at 11.5 mo of SIV infection, and adipose (OmAT and SAT) samples excised. Collagen content, adipocyte diameter and adipocyte numbers were measured by Picrosirius Red Staining (PSR). A custom PCR Array was used to assess differential expression of 41 ECM‐related genes. CBA administration significantly increased collagen expression and decreased adipocyte diameter in the OmAT without altering adipocyte numbers. There was a strong negative correlation of OmAT adipocyte diameter and collagen expression. CBA administration did not result in significant differences in collagen expression, adipocyte diameter or number in SAT. CBA administration significantly upregulated expression of transforming growth factor beta‐1 (TGFB1), platelet‐derived growth factor receptor alpha (PDGFRA) and secreted protein acidic and rich in cysteine (SPARC), mediators of a pro‐fibrotic milieu in OmAT. In contrast, CBA did not significantly alter expression of ECM‐related genes in the SAT. These data suggest that the maladaptive adipose changes associated with CBA in SIV infection are depot specific. We speculate that changes in the ECM contribute to altered gene expression and impaired adipocyte metabolic capacity.

Continuous Dopaminergic Stimulation Improves Cortical Maladaptive Changes in Advanced Parkinson's Disease.

With the progression of Parkinson's disease (PD), pulsatile treatment with oral levodopa causes maladaptive changes within basal ganglia-thalamo-cortical circuits, which are clinically expressed as motor fluctuations and dyskinesias. At the level of the motor cortex, these changes may be detected using transcranial magnetic stimulation (TMS), as abnormal corticospinal and intracortical excitability and absent response to plasticity protocols. We investigated the effect of continuous dopaminergic stimulation on cortical maladaptive changes related to oral levodopa treatment. Twenty patients with advanced PD were tested using TMS within 1 week before and again 6 months after the introduction of levodopa-carbidopa intestinal gel. We measured resting and active motor thresholds, input/output curve, short interval intracortical inhibition curve, cortical silent period, and response to intermittent theta burst stimulation. Patients were clinically assessed with Part III and Part IV of the Movement Disorders Society Unified Parkinson's Disease Rating Scale. Six months after the introduction of levodopa-carbidopa intestinal gel, motor fluctuations scores (P = 0.001) and dyskinesias scores (P < 0.001) were reduced. Resting and active motor threshold (P=0.012 and P = 0.015) and x-intercept of input/output curve (P=0.005) were also decreased, while short-interval intracortical inhibition and response to intermittent theta bust stimulation were improved (P=0.026 and P=0.031, respectively). Changes in these parameters correlated with clinical improvement. In patients with advanced PD, switching from intermittent to continuous levodopa delivery increased corticospinal excitability and improved deficient intracortical inhibition and abnormal motor cortex plasticity, along with amelioration of motor fluctuations and dyskinesias. Continuous dopaminergic stimulation ameliorates maladaptive changes inflicted by chronic pulsatile dopaminergic stimulation. © 2022 International Parkinson and Movement Disorder Society.

Defenestrated endothelium delays liver-directed gene transfer in hemophilia A mice

AbstractHemophilia A is an inherited bleeding disorder caused by defective or deficient coagulation factor VIII (FVIII) activity. Until recently, the only treatment for prevention of bleeding involved IV administration of FVIII. Gene therapy with adeno-associated vectors (AAVs) has shown some efficacy in patients with hemophilia A. However, limitations persist due to AAV-induced cellular stress, immunogenicity, and reduced durability of gene expression. Herein, we examined the efficacy of liver-directed gene transfer in FVIII knock-out mice by AAV8-GFP. Surprisingly, compared with control mice, FVIII knockout (F8TKO) mice showed significant delay in AAV8-GFP transfer in the liver. We found that the delay in liver-directed gene transfer in F8TKO mice was associated with absence of liver sinusoidal endothelial cell (LSEC) fenestration, which led to aberrant expression of several sinusoidal endothelial proteins, causing increased capillarization and decreased permeability of LSECs. This is the first study to link impaired liver-directed gene transfer to liver-endothelium maladaptive structural changes associated with FVIII deficiency in mice.

Whose self-control development suffers or benefits in the face of adversity? A longitudinal study of Mexican-origin youth followed from age 10 to 16.

This study assessed the co-development of adversity and effortful control based on a sample of Mexican-origin youth (N = 674) and their parents. We used a four-wave longitudinal design and followed target participants from age 10 to 16. At each time point, we measured adversity experienced by the children and their parents and children's effortful control (self- and parent-reported). We also assessed children's shift-and-persist coping strategies at ages 14 and 16. Across time, we found slight decreases in child-adversity and slight increases in parent-adversity. Based on bivariate LGC analyses, we found that the strongest effects surfaced for child- (vs. parent-) adversity. Specifically, we found that greater increases in child-adversity were associated with greater decreases in effortful control from ages 10 to 16. Moreover, we found a positive association between initial levels of child-adversity and the slope of effortful control, as well as a cross-sectional negative association between child- and parent-adversity and effortful control (at age 10). We found no evidence of moderation by shift-and-persist coping strategies. In sum, our results suggest that, on average, Mexican-origin youth exposed to more adversity might experience more maladaptive change with respect to effortful control.

The Scaffold Protein PICK1 as a Target in Chronic Pain.

Well-tolerated and effective drugs for treating chronic pain conditions are urgently needed. Most chronic pain patients are not effectively relieved from their pain and suffer from debilitating drug side effects. This has not only drastic negative consequences for the patients’ quality of life, but also constitute an enormous burden on society. It is therefore of great interest to explore new potent targets for effective pain treatment with fewer side effects and without addiction liability. A critical component of chronic pain conditions is central sensitization, which involves the reorganization and strengthening of synaptic transmission within nociceptive pathways. Such changes are considered as maladaptive and depend on changes in the surface expression and signaling of AMPA-type glutamate receptors (AMPARs). The PDZ-domain scaffold protein PICK1 binds the AMPARs and has been suggested to play a key role in these maladaptive changes. In the present paper, we review the regulation of AMPARs by PICK1 and its relation to pain pathology. Moreover, we highlight other pain-relevant PICK1 interactions, and we evaluate various compounds that target PICK1 and have been successfully tested in pain models. Finally, we evaluate the potential on-target side effects of interfering with the action of PICK1 action in CNS and beyond. We conclude that PICK1 constitutes a valid drug target for the treatment of inflammatory and neuropathic pain conditions without the side effects and abuse liability associated with current pain medication.