Perturbations In Patients Research Articles

Response to photic stimulation as a measure of cortical excitability in epilepsy patients.

Studying states and state transitions in the brain is challenging due to nonlinear, complex dynamics. In this research, we analyze the brain's response to non-invasive perturbations. Perturbation techniques offer a powerful method for studying complex dynamics, though their translation to human brain data is under-explored. This method involves applying small inputs, in this case via photic stimulation, to a system and measuring its response. Sensitivity to perturbations can forewarn a state transition. Therefore, biomarkers of the brain's perturbation response or "cortical excitability" could be used to indicate seizure transitions. However, perturbing the brain often involves invasive intracranial surgeries or expensive equipment such as transcranial magnetic stimulation (TMS) which is only accessible to a minority of patient groups, or animal model studies. Photic stimulation is a widely used diagnostic technique in epilepsy that can be used as a non-invasive perturbation paradigm to probe brain dynamics during routine electroencephalography (EEG) studies in humans. This involves changing the frequency of strobing light, sometimes triggering a photo-paroxysmal response (PPR), which is an electrographic event that can be studied as a state transition to a seizure state. We investigate alterations in the response to these perturbations in patients with genetic generalized epilepsy (GGE), with (n = 10) and without (n = 10) PPR, and patients with psychogenic non-epileptic seizures (PNES; n = 10), compared to resting controls (n = 10). Metrics of EEG time-series data were evaluated as biomarkers of the perturbation response including variance, autocorrelation, and phase-based synchrony measures. We observed considerable differences in all group biomarker distributions during stimulation compared to controls. In particular, variance and autocorrelation demonstrated greater changes in epochs close to PPR transitions compared to earlier stimulation epochs. Comparison of PPR and spontaneous seizure morphology found them indistinguishable, suggesting PPR is a valid proxy for seizure dynamics. Also, as expected, posterior channels demonstrated the greatest change in synchrony measures, possibly reflecting underlying PPR pathophysiologic mechanisms. We clearly demonstrate observable changes at a group level in cortical excitability in epilepsy patients as a response to perturbation in EEG data. Our work re-frames photic stimulation as a non-invasive perturbation paradigm capable of inducing measurable changes to brain dynamics.

Immune system perturbations in patients with long COVID

Klein et al. report multimodal analyses of immune cells, proteins, and physiological parameters in patients with long COVID (LC). At the group level, LC subjects exhibited elevated antibody responses to SARS-CoV-2, but also to herpes viruses, pointing to a general suppression of viral control mechanisms in LC.

Whole-brain analyses indicate the impairment of posterior integration and thalamo-frontotemporal broadcasting in disorders of consciousness.

The study of the brain's dynamical activity is opening a window to help the clinical assessment of patients with disorders of consciousness. For example, glucose uptake and the dysfunctional spread of naturalistic and synthetic stimuli has proven useful to characterize hampered consciousness. However, understanding of the mechanisms behind loss of consciousness following brain injury is still missing. Here, we study the propagation of endogenous and in-silico exogenous perturbations in patients with disorders of consciousness, based upon directed and causal interactions estimated from resting-state fMRI data, fitted to a linear model of activity propagation. We found that patients with disorders of consciousness suffer decreased capacity for neural propagation and responsiveness to events, and that this can be related to severe reduction of glucose metabolism as measured with [18 F]FDG-PET. In particular, we show that loss of consciousness is related to the malfunctioning of two neural circuits: the posterior cortical regions failing to convey information, in conjunction with reduced broadcasting of information from subcortical, temporal, parietal and frontal regions. These results shed light on the mechanisms behind disorders of consciousness, triangulating network function with basic measures of brain integrity and behavior.

Immune system perturbations in patients with severe long COVID

Abstract SARS-CoV-2 infections have different outcomes ranging from mild to severe acute infection as well as post-infectious multi-system inflammatory syndromes (MIS-C/A). Post-acute sequelae of COVID-19 (PASC) or long COVID is another outcome, which is poorly understood and range from mild to very severe persistent organ dysfunction and damages. To maximize our chances of identifying underlying mechanisms of long COVID we focus on the most severe cases with objective measures of disease such as lung damages, microvascular and autonomic nerve dysfunction. We are testing the following hypotheses that I) long COVID is a super-antigen mediated disease, II) an autoimmune condition driven by pathogenic autoantibodies, and/or III) a disease caused by viral persistence. A cohort of over 100 long COVID patients, 24 recovered long COVID patients as well as 9 COVID convalescent controls have been recruited thus far and blood samples analyzed for plasma proteome (Olink assays), immune cell composition and phenotypes (mass cytometry), T-cell repertoire (scTCR-seq), innate cell activation (circulating nucleosomes), and auto-antibody analyses (Luminex arrays) in order to understand immune perturbations in severe long COVID patients. Unlike children with hyperinflammatory MIS-C, we have not found any evidence of superantigen-mediated T-cell activation in long COVID, but instead substantial clonal expansion of memory T cell clones with effector memory states and shared clonality across patients. Additionally, cytokine perturbations such as elevated levels of IL8 and elevated levels of circulating nucleosomes indicate persistent activation of neutrophils in severe long COVID.

Compensatory Responses During Slip-Induced Perturbation in Patients With Knee Osteoarthritis Compared With Healthy Older Adults: An Increased Risk of Falls?

Background: Functional impairment of the knee joint affected by osteoarthritis and loss of muscle strength leads to a significant increase in the number of falls. Nevertheless, little is known about strategies for coping with gait perturbations in patients with knee osteoarthritis (KOA). Thus, this study aimed to examine the compensatory strategies of patients with KOA in response to a backward slip perturbation compared with healthy older adults. Methods: An automated perturbation program was developed by using D-Flow software based on the Gait Real-time Analysis Interactive Lab, and an induced backward slip perturbation was implemented on nine patients with severe KOA (68.89 ± 3.59 years) and 15 age-matched healthy older adults (68.33 ± 3.29 years). Step length, gait speed, range of motion, vertical ground reaction forces, lower extremity joint angles, and joint moments were computed and analyzed. Results: Compared with older adults, patients with KOA had significantly lower step length, gait speed, and vertical ground reaction forces in both normal walking and the first recovery step following backward slip perturbations. Inadequate flexion and extension of joint angles and insufficient generation of joint moments predispose patients with KOA to fall. Hip extension angle and flexion moment, knee range of motion, and vertical ground reaction forces are key monitoring variables. Conclusion: The risk of falls for patients with KOA in response to backward slip perturbations is higher. Patients with KOA should focus not only on quadriceps muscle strength related to knee range of motion but also on improving hip extensor strength and activation through specific exercises. Targeted resistance training and perturbation-based gait training could be better options.

Association between knee extensor force steadiness and postural stability against mechanical perturbation in patients with Parkinson’s disease

ObjectiveLower extremity force steadiness has been shown to decrease with aging and neuromotor dysfunction and to be associated with physical function and fall. Although patients with Parkinson’s disease (PD) experience decreased force steadiness, whether the extent of force steadiness differs according to target force or whether this steadiness is associated with postural control remain unclear. Therefore, this study aimed to compare the force steadiness while steadily exerting low and moderate levels of knee extensor force between individuals with and without PD and to examine the association between force steadiness and postural instability against mechanical perturbation in PD. MethodsA total of 33 patients with PD (mean age, 71.7 years) and 33 healthy controls (72.2 years) participated in this study. Participants with PD were classified into postural stability or instability groups based on the Movement Disorder Society-sponsored revision of the Unified Parkinson’s Disease Rating Scale motor exam item 12. Participants performed steady task of the knee isometric extension at two levels (10% and 50% of maximal voluntary contraction [MVC]). ResultsForce steadiness at 10% MVC was lower in postural instability group than that in the control and postural stability groups (P < 0.05) after adjusting for age, sex, and body mass index, whereas it was not significantly different at 50% MVC among the three groups. DiscussionThese results suggest that the knee extensor force steadiness is affected in patients with PD having postural instability against mechanical perturbation during low intensity force exertion and is not affected regardless of the presence of postural instability during moderate intensity force exertion.

Strategic alterations of posture are delayed in Parkinson\u2019s disease patients during deep brain stimulation

Parkinson’s disease (PD) is characterized by rigidity, akinesia, postural instability and tremor. Deep brain stimulation (DBS) of the subthalamic nucleus (STN) reduces tremor but the effects on postural instability are inconsistent. Another component of postural control is the postural strategy, traditionally referred to as the ankle or hip strategy, which is determined by the coupling between the joint motions of the body. We aimed to determine whether DBS STN and vision (eyes open vs. eyes closed) affect the postural strategy in PD in quiet stance or during balance perturbations. Linear motion was recorded from the knee, hip, shoulder and head in 10 patients with idiopathic PD with DBS STN (after withdrawal of other anti-PD medication), 25 younger adult controls and 17 older adult controls. Correlation analyses were performed on anterior–posterior linear motion data to determine the coupling between the four positions measured. All participants were asked to stand for a 30 s period of quiet stance and a 200 s period of calf vibration. The 200 s vibration period was subdivided into four 50 s periods to study adaptation between the first vibration period (30–80 s) and the last vibration period (180–230 s). Movement was recorded in patients with PD with DBS ON and DBS OFF, and all participants were investigated with eyes closed and eyes open. DBS settings were randomized and double-blindly programmed. Patients with PD had greater coupling of the body compared to old and young controls during balance perturbations (p ≤ 0.046). Controls adopted a strategy with greater flexibility, particularly using the knee as a point of pivot, whereas patients with PD adopted an ankle strategy, i.e., they used the ankle as the point of pivot. There was higher flexibility in patients with PD with DBS ON and eyes open compared to DBS OFF and eyes closed (p ≤ 0.011). During balance perturbations, controls quickly adopted a new strategy that they retained throughout the test, but patients with PD were slower to adapt. Patients with PD further increased the coupling between segmental movement during balance perturbations with DBS ON but retained a high level of coupling with DBS OFF throughout balance perturbations. The ankle strategy during balance perturbations in patients with PD was most evident with DBS OFF and eyes closed. The increased coupling with balance perturbations implies a mechanism to reduce complexity at a cost of exerting more energy. Strategic alterations of posture were altered by DBS in patients with PD and were delayed. Our findings therefore show that DBS does not fully compensate for disease-related effects on posture.

TDCS application for postural control in Parkinson's disease: Effects are associated with baseline characteristics

IntroductionTranscranial direct current stimulation (tDCS) improves postural response to perturbation in patients with Parkinson's disease (PwPD). However, the influence of baseline characteristics such as clinical/cognitive and postural performance on the response to tDCS remains unclear. ObjectiveTo investigate whether baseline level of postural control (performance during sham condition) and clinical/cognitive characteristics are associated with tDCS-related changes in postural responses to external perturbations in PwPD. MethodsTwenty-four PwPD participated in this study. Clinical assessment included disease severity, disease duration, levodopa equivalent dose and global cognition. Anodal tDCS protocols targeting the primary motor cortex were applied in two separate sessions (at least 2 weeks apart): active (2 mA for 20 min) and sham stimulation. Seven trials with the backward translation of the support base (20 cm/s and 5 cm) were performed after tDCS. Postural outcomes included the recovery time to stable position and onset latency of the medial gastrocnemius (MG). Pearson and Spearman correlation tests were performed. ResultsNo significant correlations were observed between clinical/cognitive characteristics and tDCS-related changes in postural responses. Negative associations were observed between the baseline level of postural control and tDCS-related changes in postural responses for the recovery time (r = −0.657; p < 0.001) and the MG onset latency (rs = −0.539; p = 0.007). PwPD with worse baseline postural control demonstrated greater improvement after active stimulation. ConclusionsFindings suggest that tDCS-related effects on postural response to perturbation are related to the baseline level of postural control, but not to clinical characteristics in PwPD. Those with worse baseline postural control responded better to tDCS.

Moderate Intensity Exercise Causes a Shift in the Relative Importance of the Endothelium‐Dependent Relaxing Factors in Mesenteric Arteries of Male UC Davis Type‐2 Diabetes Mellitus (UCD‐T2DM) Rats

Over the past decade obesity and type 2 diabetes (T2D) have reached epidemic levels worldwide. Cardiovascular disease (CVD) is one of the leading causes of mortality and morbidity in diabetic patients. Regular aerobic exercise is a well-characterized lifestyle intervention that improves endothelial dysfunction, insulin resistance, and CVD risk in T2D. However, there are still debates regarding the duration and intensity of exercise required to ameliorate the deleterious metabolic perturbations in patients with T2D. The objective of this study was to investigate the effects of moderate intensity exercise (MIE) on vascular reactivity of mesenteric artery (MA) of male UC Davis Type-2 Diabetes Mellitus Rat (UCD-T2DM) model. Specifically, we examined whether there were changes in the relative contributions of endothelium-derived relaxing factors in modulating vascular reactivity of MA from exercise-trained compared with control sedentary UCD-T2DM rats. Age-matched male control and UCD-T2DM rats underwent forced treadmill exercise (E) or remained sedentary (S) for 8 weeks. Endothelium-dependent vasorelaxation (EDV) to acetylcholine (ACh, 10-8 to 10-5 M) were measured in precontracted MA before and after indomethacin (10µM), a cyclooxygenase (COX) inhibitor; followed by addition of L-NAME (200µM), a nitric oxide synthase (NOS) inhibitor; followed by combination of apamin (1 µM) and TRAM-34 (1 µM) (SKCa and IKCa blockers, respectively). The diabetic exercise trained (DE) rats exhibited decreased visceral adiposity and plasma triglyceride levels compared with the diabetic sedentary (DS) group. However, MIE did not alter plasma glucose or insulin concentrations in either nondiabetic or diabetic UCD-T2DM Rats. Both sensitivity and maximal responses (Emax) to ACh were significantly reduced in MA from DS rats compared with those in control sedentary (CS). MIE improved the Emax to ACh only in MA of DE group. Inhibition of COX enhanced Emax to ACh in DS arteries suggesting the elevation of contractile COX metabolites in the DS group. The addition of L-NAME resulted in a reduction in ACh relaxation of arteries from both CS and DS rats, however the effect was more prominent in DS group, suggesting the contribution of NO was enhanced (or endothelium-dependent hyperpolarizing factor (EDHF)-type relaxation was diminished) in DS arteries. Remarkably, MIE reversed the loss of EDHF-type relaxation in UCD-T2DM Rats. Unlike in the DS group, inhibition of COX had no effect on ACh response in MA of the DE group, suggesting that MIE may cause a shift from contractile COX to NO and EDHF-type relaxation in UCD-T2DM Rats. In conclusion, we provide the first evidence for a positive impact of moderate exercise on mesenteric arterial function in male UCD-T2DM Rats, likely mediated by a contribution of EDHF-type (NO and prostanoid-independent) responses.

48352 Mechanisms Underlying Lipidomic Changes in Major Depressive Disorder

ABSTRACT IMPACT: Lipidomics is emerging as a powerful strategy to identify biomarkers for Major Depressive Disorder, as well as therapeutic targets in lipid metabolic pathways. OBJECTIVES/GOALS: Lipidomics is increasingly recognized in precision psychiatry for global lipid perturbations in patients suffering from Major Depressive Disorder (MDD). We will test the hypothesis that lipid metabolism dysregulation is associated with familial risk of depression. METHODS/STUDY POPULATION: Patients with MDD (G1), children (G2), and grandchildren (G3) have been part of a longitudinal study since 1982. If a parent G2 and grandparent G1 have MDD, G3 is considered a high risk of depression. Biospecimens (saliva and serum) were collected for full exome sequencing and RNA analysis. Samples will also be extracted for lipid content and lipids will be identified by mass spectrometry. A panel of nearly 600 lipid species can reliably be identified and quantified using liquid chromatography paired with tandem mass spectrometry (LC-MS/MS). Dysregulated lipids will be correlated with familial risk of depression in samples of G3. RESULTS/ANTICIPATED RESULTS: We hypothesize that dysregulation of lipids and lipid metabolism will be apparent in biospecimens from the high risk compared to the low risk of depression. Also, alterations in RNA transcriptomics of genes involved in lipid metabolic networks are associated with familial risk of depression. Several differential lipid species were previously identified to be associated with MDD. Reduced phosphatidylcholine(PC), phosphatidylethanolamine(PE), phosphatidylinositol(PI), and increased LysoPC, LysoPE, ceramide, triacylglycerol, and diacylglycerol levels have been correlated to MDD. However, these results need to be replicated in independent studies using lipidomics analysis. DISCUSSION/SIGNIFICANCE OF FINDINGS: It is highly likely that completely novel cellular targets will emerge from these studies by uncovering the convergence of lipidomics and genetic variance of lipid metabolic enzymes as biomarkers for predisposition to MDD as well as potential targets for therapeutic development for MDD.

Association of D-dimer and Fibrinogen With Hypercoagulability in COVID-19 Requiring Extracorporeal Membrane Oxygenation.

Background:D-dimer concentration has been used by institutions to identify candidates for intensified anticoagulant treatment for venous thromboembolism prevention and for the mitigation of the microthrombotic complications associated with COVID-19. Thromboelastography (TEG) maximum amplitude (MA) has been validated as a marker of hypercoagulability and MA ≥68 mm has been utilized as a marker of hypercoagulability in other conditions.Methods:The goal of this study was to evaluate the relationship between coagulation, inflammatory, and TEG parameters in patients with COVID-19 on extracorporeal membrane oxygenation (ECMO). We performed a single-center retrospective analysis of consecutive patients that received ECMO for the treatment of COVID-19. TEG, inflammatory, and coagulation markers were compared in patients with and without a thrombotic complication. Correlation tests were performed to identify the coagulation and inflammatory markers that best predict hypercoagulability as defined by an elevated TEG MA.Results:A total of 168 TEGs were available in 24 patients. C-reactive protein and fibrinogen were significantly higher in patients that developed a thrombotic event versus those that did not (P = 0.04 and P = 0.04 respectively). D-dimer was negatively correlated with TEG MA (P < 0.01), while fibrinogen was positively correlated (P < 0.01). A fibrinogen >441 mg/dL was found to have a sensitivity of 91.2% and specificity of 85.7% for the detection of MA ≥68 mm.Conclusions:In critically ill patients with COVID-19 treated with ECMO, D-dimer concentration had an inverse relationship with degree of hypercoagulability as measured by TEG MA. D-dimer elevation may potentially reflect hemostatic perturbation in patients on ECMO or the severity of COVID-19 related sepsis rather than designate patients likely to benefit from anticoagulation. Fibrinogen concentration may represent a more useful marker of hypercoagulability in this population.

Effect of Different Intensities of Transcranial Direct Current Stimulation on Postural Response to External Perturbation in Patients With Parkinson’s Disease

Background Habituation of postural response to perturbations is impaired in people with Parkinson’s disease (PD) due to deficits in cortico-basal pathways. Although transcranial direct current stimulation (tDCS) modulate cortico-basal networks, it remains unclear if it can benefit postural control in PD. Objective To analyze the effect of different intensities of anodal tDCS on postural responses and prefrontal cortex (PFC) activity during the habituation to the external perturbation in patients with PD (n = 24). Methods Anodal tDCS was applied over the primary motor cortex (M1) with 1 mA, 2 mA, and sham stimulation in 3 different sessions (~2 weeks apart) during 20 minutes immediately before the postural assessment. External perturbation (7 trials) was applied by a support base posterior translation (20 cm/s and 5 cm). Primary outcome measures included lower limb electromyography and center of pressure parameters. Measures of PFC activity are reported as exploratory outcomes. Analyses of variance (Stimulation Condition × Trial) were performed. Results Habituation of perturbation was evidenced independent of the stimulation conditions. Both active stimulation intensities had shorter recovery time and a trend for lower cortical activity in the stimulated hemisphere when compared to sham condition. Shorter onset latency of the medial gastrocnemius as well as lower cortical activity in the nonstimulated hemisphere were only observed after 2 mA concerning the sham condition. Conclusions tDCS over M1 improved the postural response to external perturbation in PD, with better response observed for 2 mA compared with 1 mA. However, tDCS seems to be inefficient in modifying the habituation of perturbation.

Rigid head-neck responses to unpredictable perturbations in patients with long standing neck pain does not change with treatment.

In a previous study we have shown that patients with long standing non-specific neck-pain display more rigid neck movement behavior than controls in response to unpredictable perturbations. In the present study we investigated head/neck motor control in patients with neck-pain during a course of physiotherapy intervention and the associations with pain, neck disability and kinesiophobia. In this longitudinal observational study, 72 patients with non-specific neck-pain were exposed to unpredictable horizontal rotations by means of an actuated chair in three conditions; with a visual reference, and without vision with and without a cognitive task before first consultation with physiotherapist, after 2 weeks and 2 months of intervention. The neck movements were analyzed in the frequency domain to cover voluntarily and reflex controlled responses. Questionnaires encompassed Neck Disability Index, Tampa Scale of Kinesiophobia, and the Numerical Rating Scale for current pain. The results showed that the response pattern for the amplitudes of movement between head and trunk across frequencies did not change over time, whereas some changes in timing were found for some frequencies. Pain, neck disability, and kinesiophobia improved after intervention, but were not significantly associated with neck movement responses to perturbations across time or condition. Although physiotherapy intervention improved self-reported function, the rigid responses to unpredictable perturbations remained unchanged. This indicates altered function in reflex mediated control mechanisms, i.e., the vestibulocollic and the cervicocollic reflex systems that control the head in space and on the trunk. Future research should further investigate pain related changes in reflex systems and whether alterations in these systems are modifiable.

Abstract CT198: Efficacy of metfOrmin in PrevenTIng glucocorticoid-induced diabetes in Melanoma, breAst or Lung Cancer patients with brain metastases: The phase II OPTIMAL study

Abstract Background: Brain metastases frequently occur in patients with late-stage cancers. Treatment with high-dose glucocorticoids (GCs) is usually started to prevent or reduce tumor-related edema and its deadly complications. However, treatment with high-dose GCs is associated with serious side effects, including diabetes and immunosuppression, which could promote tumor growth or reduce the effectiveness of antitumor therapies. Based on its potential antitumor properties and on its ability to prevent GC-induced diabetes, the antidiabetic compound Metformin could reduce short-term mortality in patients with brain metastases taking high-dose GCs. Methods: The OPTIMAL study is a monocentric, open label, randomized Phase II trial in patients with brain metastases from melanoma, lung or breast cancer, who require treatment with high-dose dexamethasone, as defined as a minimum of 8 mg daily based on the clinician judgment, for at least three consecutive weeks. At enrollment, patients are randomized in a 1:1 ratio to receive high-dose dexamethasone +/- metformin 2550 mg/day for 30 days. At randomization, patients are stratified according to: tumor origin, dose of dexamethasone (8-12 vs. &amp;gt; 12 mg/day) and baseline fasting glycemia (&amp;lt; 100 vs. 100-125 mg/dl). Patients may receive concomitant radiotherapy based on the judgment of the physician. The primary study endpoint is the rate of precocious (14 days) dexamethasone-induced diabetes, as defined as fasting plasma glucose levels ≥ 126 mg/dl. Discussion: The OPTIMAL study aims to evaluate the efficacy of upfront use of metformin in preventing the onset of GCs-induced diabetes and other metabolic perturbations in patients with brain metastases from melanoma, lung or breast cancer. Other clinical objectives consist in investigating the impact of metformin on precocious mortality, deterioration of ECOG PS and local (brain) disease control rate at one month after dexamethasone initiation. The effect of dexamethasone +/- metformin on other metabolites or growth factors, including amino acids, fatty acids, ketone bodies, IGF-1, as well as on the number, activation status and metabolism of peripheral blood immune cell populations will be evaluated as well. Trial registration: The OPTIMAL trial is registered at ClinicalTrials.gov (NCT04001725, June 28, 2019) and EudraCT (2019-000105-73, January 8, 2019). Citation Format: Claudio Vernieri, Federico Nichetti, Francesca Ligorio, Emma Zattarin, Teresa Beninato, Riccardo Lobefaro, Giulia Bianchi, Giuseppe Capri, Marina Garassino, Giuseppe Lo Russo, Michele Del Vecchio, Paola Corsetto, Licia Rivoltini, Chiara Castelli, Filippo de Braud. Efficacy of metfOrmin in PrevenTIng glucocorticoid-induced diabetes in Melanoma, breAst or Lung Cancer patients with brain metastases: The phase II OPTIMAL study [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT198.

Aging increases the systemic molecular degree of inflammatory perturbation in patients with tuberculosis

Tuberculosis (TB) is a chronic infection that can affect individuals of all ages. The description of determinants of immunopathogenesis in TB is of tremendous interest due to the perspective of finding a reliable host-directed therapy to reduce disease burden. The association between specific biomarker profiles related to inflammation and the diverse clinical disease presentations in TB has been extensively studied in adults. However, relatively scarce data on profiling the inflammatory responses in pediatric TB are available. Here, we employed the molecular degree of perturbation (MDP) score adapted to plasma biomarkers in two distinct databanks from studies that examined either adults or children presenting with pulmonary or extrapulmonary disease. We used multidimensional statistical analyses to characterize the impact of age on the overall changes in the systemic inflammation profiles in subpopulation of TB patients. Our findings indicate that TB results in significant increases in molecular perturbation, with the highest values being detected in adult patients. Furthermore, there were unique differences in the biomarker perturbation patterns and the overall degree of inflammation according to disease site and age. Importantly, the molecular degree of perturbation was not influenced by sex. Our results revealed that aging is an important determinant of the differences in quality and magnitude of systemic inflammatory perturbation in distinct clinical forms of TB.

Investigation of Adaptation to Successive Postural Perturbations in Patients with Multiple Sclerosis

Investigation of Adaptation to Successive Postural Perturbations in Patients with Multiple Sclerosis

Investigation of Adaptation to Successive Postural Perturbations in Patients with Multiple Sclerosis

Investigation of Adaptation to Successive Postural Perturbations in Patients with Multiple Sclerosis

The efficacy of intramuscular ephedrine in preventing hemodynamic perturbations in patients with spinal anesthesia and dexmedetomidine sedation.

Dexmedetomidine is used for sedation during spinal anesthesia. The sympatholytic effect of dexmedetomidine may exacerbate hypotension and bradycardia with spinal anesthesia. This study investigated the effects of prophylactic intramuscular injection of ephedrine in preventing hypotension and bradycardia occurring through combined use of spinal anesthesia and dexmedetomidine. One hundred sixteen patients scheduled for lower extremity orthopedic surgery were randomized into two groups receiving either ephedrine 20 mg intramuscularly or equivalent amount of 0.9% NaCl, both with dexmedetomidine and spinal anesthesia. The primary endpoint was the incidence of hemodynamic perturbations (hypotension or bradycardia event). The secondary endpoint was a rescue doses of ephedrine and atropine. The incidence of hemodynamic perturbations was significantly lower in the ephedrine group compared with to the saline group (26.3% versus 55.9%, p = 0.001). The rescue doses of atropine (0.09 ± 0.21 versus 0.28 ± 0.41, p = 0.001) and ephedrine (1.04 ± 2.89 versus 2.03 ± 3.25, p = 0.007) were also significantly lower in the ephedrine group. There was no differences in number of patients with hypertensive (7.0% versus 11.9%, p = 0.375) or tachycardia (1.8% versus 3.4% p = 0.581) episodes. The use of ephedrine intramuscular injections may be a safe and efficacious option in preventing hemodynamic perturbations in patients who received spinal anesthesia and sedation using dexmedetomidine.

Muscle activity during backward perturbation response in patients with clinical vertebral compression fractures

The present study examined muscle activity in response to backward perturbation in patients with clinical vertebral compression fracture (CVCF). The subjects were 32 patients aged 65 years and above consisting of 16 each with (CVCF group) and without (control group) CVCF. The time to peak activity, and time of onset of muscle activity of the anterior tibial, vastus medialis, and rectus abdominis muscles when unexpected backward perturbation was applied were evaluated by surface electromyography. The strength of perturbation was 4% or 6% of the subject’s body weight. In addition, the presence of the stepping reaction to perturbation, severity of low back pain, and vertebral alignment were evaluated. Each item was compared between the two groups. In the CVCF group, kyphosis and severity of low back pain were significantly more severe, the time to peak activity of the anterior tibial muscle after the application of perturbation at 6% of the body weight was significantly shorter, and the time of onset of activity of the rectus abdominis muscle was significantly delayed. This suggests that the time to peak activity of the anterior tibial muscle is shortened and the time of onset of activity of the rectus abdominis muscle is delayed in unexpected backward perturbation in patients with CVCF.

Fatigue changes neck muscle control and deteriorates postural stability during arm movement perturbations in patients with chronic neck pain

BACKGROUND CONTEXTMultisensory afferent inputs to the cervical spine affect the generation of neck muscle control. Chronic neck pain (CNP) and muscle fatigue are factors that disturb somatosensory function. Whether they affect postural control under self-initiated perturbation in daily activities is still unclear. PURPOSETo investigate the effect of CNP and neck flexor muscle fatigue on muscle control strategy and postural control in young patients performing voluntary shoulder flexion movements. STUDY DESIGNCross-sectional case-control study. PATIENT SAMPLETwenty-five patients with CNP and 25 age-matched asymptomatic controls. OUTCOME MEASURESThe postural sway, muscle onset time, and activation level of the erector spinae, rectus abdominal, semispinalis capitis (SSC), and sternocleidomastoid (SCM) muscles were recorded and analyzed using two-way ANOVA to evaluate the interaction of CNP and muscle fatigue on standing balance and muscle control upon self-initiated perturbations. METHODSAll participants were instructed to perform shoulder flexion movements in the standing position before and after a neck flexor muscle fatigue exercise under either the eyes-open or eyes-closed condition. RESULTSThe CNP group exhibited significantly larger body sway, greater neck muscle activation (SCM and SSC), and longer onset time of neck flexor muscle (SCM) compared with the control group. The CNP group also demonstrated a trend of greater postural sway and shorter muscle onset under the eyes-closed condition than those under the eyes-open condition. After muscle fatigue, the CNP group further exhibited (1) greater body sway during the eyes-open condition but decreased body sway during the eyes-closed condition, (2) higher activation of the neck flexor (SCM) and lower activation of the trunk extensor (erector spinae), and (3) early onset of the neck muscles (SCM and SSC). CONCLUSIONSCNP causes poor postural control and altered neck muscle control patterns. The addition of neck flexor muscle fatigue further decreases balance stability and provokes a protective neck muscle control strategy during the shoulder flexion movement. Those findings facilitate the understanding of the strategies adopted by patients and suggest that neck endurance training programs may be beneficial to improve whole postural control in patients with CNP.