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Clinical Genetics Jun 2024Multiple congenital contractures (MCC) due to fetal akinesia manifest across a broad spectrum of diseases, ranging from mild distal arthrogryposis to lethal fetal...
Multiple congenital contractures (MCC) due to fetal akinesia manifest across a broad spectrum of diseases, ranging from mild distal arthrogryposis to lethal fetal akinesia deformation sequence. We hereby present a series of 26 fetuses displaying severe MCC phenotypes from 18 families and describe detailed prenatal ultrasound findings, postmortem clinical evaluations, and genetic investigations. Most common prenatal findings were abnormal facial profile (65%), central nervous system abnormalities (62%), polyhydramnios (50%), increased nuchal translucency (50%), and fetal hydrops (35%). Postmortem examinations unveiled additional anomalies including facial dysmorphisms, dysplastic skeletal changes, ichthyosis, multiple pterygia, and myopathy, allowing preliminary diagnosis of particular Mendelian disorders in multiple patients. Evaluation of the parents revealed maternal grip myotonia in one family. By exome sequencing and targeted testing, we identified causative variants in ACTC1, CHST14, COG6, DMPK, DOK7, HSPG2, KLHL7, KLHL40, KIAA1109, NEB, PSAT1, RAPSN, USP14, and WASHC5 in 15 families, and one patient with a plausible diagnosis associated with biallelic NEB variants. Three patients received a dual diagnosis. Pathogenic alterations in newly discovered genes or in previously known genes recently linked to new MCC phenotypes were observed in 44% of the cohort. Our results provide new insights into the clinical and molecular landscape of lethal MCC phenotypes.
Topics: Humans; Female; Male; Arthrogryposis; Phenotype; Fetus; Exome Sequencing; Contracture; Pregnancy; Ultrasonography, Prenatal; Mutation; Abnormalities, Multiple
PubMed: 38278647
DOI: 10.1111/cge.14490 -
Frontiers in Neuroinformatics 2023Coordinated Reset Deep Brain Stimulation (CR DBS) is a novel DBS approach for treating Parkinson's disease (PD) that uses lower levels of burst stimulation through...
INTRODUCTION
Coordinated Reset Deep Brain Stimulation (CR DBS) is a novel DBS approach for treating Parkinson's disease (PD) that uses lower levels of burst stimulation through multiple contacts of the DBS lead. Though CR DBS has been demonstrated to have sustained therapeutic effects on rigidity, tremor, bradykinesia, and akinesia following cessation of stimulation, i.e., carryover effect, its effect on Parkinsonian gait has not been well studied. Impaired gait is a disabling symptom of PD, often associated with a higher risk of falling and a reduced quality of life. The goal of this study was to explore the carryover effect of subthalamic CR DBS on Parkinsonian gait.
METHODS
Three non-human primates (NHPs) were rendered Parkinsonian and implanted with a DBS lead in the subthalamic nucleus (STN). For each animal, STN CR DBS was delivered for several hours per day across five consecutive days. A clinical rating scale modified for NHP use (mUPDRS) was administered every morning to monitor the carryover effect of CR DBS on rigidity, tremor, akinesia, and bradykinesia. Gait was assessed quantitatively before and after STN CR DBS. The stride length and swing speed were calculated and compared to the baseline, pre-stimulation condition.
RESULTS
In all three animals, carryover improvements in rigidity, bradykinesia, and akinesia were observed after CR DBS. Increased swing speed was observed in all the animals; however, improvement in stride length was only observed in NHP B2. In addition, STN CR DBS using two different burst frequencies was evaluated in NHP B2, and differential effects on the mUPDRS score and gait were observed.
DISCUSSION
Although preliminary, our results indicate that STN CR DBS can improve Parkinsonian gait together with other motor signs when stimulation parameters are properly selected. This study further supports the continued development of CR DBS as a novel therapy for PD and highlights the importance of parameter selection in its clinical application.
PubMed: 37692361
DOI: 10.3389/fninf.2023.1185723 -
Frontiers in Cardiovascular Medicine 2023The aim was to characterize the electrovectorcardiographic pattern of ventricular aneurysms in ischemic cardiopathy by analyzing the cardiac ventricular repolarization....
The aim was to characterize the electrovectorcardiographic pattern of ventricular aneurysms in ischemic cardiopathy by analyzing the cardiac ventricular repolarization. The medical records of 2,670 individuals were analyzed in this cross-sectional study. A test phase included 33 patients who underwent transthoracic echocardiogram with ultrasonic enhancing agent, electrocardiogram, and vectorcardiogram (aneurysm group - = 22, and akinesia group - = 11). In the validation phase, cardiac magnetic resonance imaging established the left ventricle segmental contractility in 16 patients who underwent electrocardiographic and vectorcardiographic tests (aneurysm group, = 8, and akinesia group, = 8). The variables studied were the presence of the T-wave plus-minus pattern and the T-wave loop anterior-posterior pattern in V2-V4. The diagnostic indices used were sensitivity, specificity, and predictive values, with their respective 95% confidence intervals. During the test and validation phases, the analysis of the presence of the T-wave plus-minus pattern identified the aneurysm group with a sensitivity of 91% vs. 87% and specificity of 91% vs. 87% ( < 0.0001 vs. = 0.01), respectively. Meanwhile, the T-wave loop anterior-posterior pattern evidenced sensitivity of 95% vs. 77% and specificity of 91% vs. 87% ( < 0.0001 vs. = 0.04), respectively. The electrovectorcardiographic parameters showed high accuracy for recognizing left ventricular aneurysms in ischemic heart disease.
PubMed: 38155984
DOI: 10.3389/fcvm.2023.1275194 -
Parkinsonism & Related Disorders Sep 2023Parkinson's disease which shows clinically heterogeneous motor derangement may also accompany various autonomic disorders, but results of previous research on incidence...
INTRODUCTION
Parkinson's disease which shows clinically heterogeneous motor derangement may also accompany various autonomic disorders, but results of previous research on incidence and degree of each autonomic dysfunction have been inconsistent. As for sudomotor dysfunction, some investigators emphasize hypo- or anhidrois, whereas others stress hyperhidrosis.
SUBJECTS AND METHODS
To elucidate sudomotor dysfunctions in Parkinson's disease (PD) with respect to subtypes, 225 clinically probable patients PD patients were stratified by motor phenotype (tremor-dominant group: 33; mixed group: 105; and akinesia-rigidity group: 87) and subjected to thermal and acetylcholine-induced (focal) sweating tests. Thermal sweating was qualitatively assessed with a modified version of Minor's colorimetric methods. Thermoregulatory and acetylcholine-induced focal sweat rates were measured with capacitance hydrometers.
RESULTS
Thermoregulatory sweating was almost normal without anhidrotic area in 29.8% of PD patients, slightly defective in 38.7%, with anhidrotic area across <1/4 of the body surface, moderately defective in 22.2% with anhidrotic area across approximately 1/2 of the body surface, and extremely defective in 9.3% with anhidrotic area across more than 3/4 of the body surface. Patchy sweating was observed in 104 patients, implicating involvement of the hypothalamo-spinal and/or preganglionic systems in the disease process. Hyperhidrosis was seen in 15% of patients. Tremor-dominant group showed least impairment.
CONCLUSION
This study suggests that PD is associated with various patterns and degree of sudomotor abnormalities, and that sudomotor sympathetic deficits may be related with the pathophysiology of akinesia and rigidity rather than that of resting tremor.
Topics: Humans; Parkinson Disease; Tremor; Acetylcholine; Hyperhidrosis; Primary Dysautonomias; Apraxias
PubMed: 37540935
DOI: 10.1016/j.parkreldis.2023.105489 -
Echocardiography (Mount Kisco, N.Y.) Jul 2023Using existing transthoracic echocardiographic indices to quantify left ventricular wall motion abnormalities (WMAs) can be difficult due to the variations in the...
Inter- and intra-observer variability in the echocardiographic evaluation of wall motion abnormality in patients with ST-elevation myocardial infarction or takotsubo syndrome - A novel approach.
INTRODUCTION AND OBJECTIVES
Using existing transthoracic echocardiographic indices to quantify left ventricular wall motion abnormalities (WMAs) can be difficult due to the variations in the location of the abnormalities within the left ventricle, the quality of examinations, and the inter-/intra-observer variability of available indices. This study aimed to evaluate a new approach for measuring the extent of WMA by calculating the percentage of abnormal wall motion and comparing it to the wall motion score index (WMSI). The study also sought to assess inter- and intra-observer variability.
METHODS
The study included 140 echocardiograms from 54 patients presenting with ST-elevation myocardial infarction or Takotsubo syndrome. All patients underwent an echocardiographic examination according to a standard protocol and the images were used to measure the extent of akinesia (proportion akinesia, PrA), akinesia and hypokinesia (proportion akinesia/hypokinesia, PrAH), and WMSI. The inter-observer variability between the two operators was analyzed. The intra-observer analysis was performed by one observer using the same images at least 1 month after the first measurement. The agreement was analyzed using the Pearson correlation coefficient and Bland-Altman plots.
RESULTS
Inter- and intra-observer variability for PrA and PrAH were low and comparable to those for WMSI.
CONCLUSION
PrA and PrAH are reliable and reproducible echocardiographic methods for the evaluation of left ventricular wall motion.
Topics: Humans; Observer Variation; ST Elevation Myocardial Infarction; Takotsubo Cardiomyopathy; Hypokinesia; Echocardiography
PubMed: 37363868
DOI: 10.1111/echo.15638 -
American Journal of Ophthalmology Aug 2023This network meta-analysis aims to determine the differences between adjuvants that are used in combination with local anesthetics for ophthalmic regional anesthesia. (Meta-Analysis)
Meta-Analysis Review
PURPOSE
This network meta-analysis aims to determine the differences between adjuvants that are used in combination with local anesthetics for ophthalmic regional anesthesia.
DESIGN
Systematic review and network meta-analysis.
METHODS
A systematic literature search for randomized controlled trials, comparing the impact of adjuvants in ophthalmic regional anesthesia, in Embase, CENTRAL, MEDLINE and Web of Science was performed. Risk of bias was evaluated using the Cochrane risk of bias tool. Frequentist network meta-analysis was performed using a random effects model with saline as the comparator. Primary endpoints were the onset and the duration of sensory block and globe akinesia, as well as the duration of analgesia. Summary measure was the ratio of means (ROM). Secondary endpoints were the rates of side effects and adverse events.
RESULTS
A total of 39 trials were identified as eligible for network meta-analysis, including 3046 patients. In all, 17 adjuvants were compared in the most extensive network (onset of globe akinesia). The addition of fentanyl (F), clonidine (C), or dexmedetomidine (D) showed the best overall results. Onset of sensory block was as follows: F 0.58 (CI = 0.47-0.72), C 0.75 (0.63-0.88), D 0.71 (0.61-0.84); onset of globe akinesia: F 0.71 (0.61-0.82), C 0.70 (0.61-0.82), D 0.81 (0.71-0.92); duration of sensory block: F 1.20 (1.14-1.26), C 1.22 (1.18-1.27), D 1.44 (1.34-1.55); duration of globe akinesia: F 1.38 (1.22-1.57), C 1.45 (1.26-1.67), D 1.41 (1.24-1.59); and duration of analgesia: F 1.46 (1.33-1.60), C 1.78 (1.63-1.96), D 1.41 (1.28-1.56).
CONCLUSIONS
The addition of fentanyl, clonidine, or dexmedetomidine showed beneficial effects regarding onset and duration of sensory block and globe akinesia.
Topics: Humans; Anesthesia, Conduction; Anesthetics, Local; Clonidine; Dexmedetomidine; Fentanyl; Network Meta-Analysis
PubMed: 36906095
DOI: 10.1016/j.ajo.2023.02.023 -
Frontiers in Public Health 2023This study aims to provide a comprehensive analysis of clinical and epidemiological data related to Chronic Chagas Cardiomyopathy (CCC) in the Amazon region of Brazil. (Review)
Review
OBJECTIVES
This study aims to provide a comprehensive analysis of clinical and epidemiological data related to Chronic Chagas Cardiomyopathy (CCC) in the Amazon region of Brazil.
METHODS
A review of observational, retrospective, and cross-sectional studies related to Chagas Disease in the Amazon region of Brazil was conducted, and a case series addressing CCC in patients treated at the FMT-HVD outpatient clinic, a reference center for Chagas disease in Brazil, was carried out.
RESULTS
Clinical characteristics of 55 patients from the Amazon region with CCC were described. The most common electrocardiographic alteration observed was abnormal ventricular repolarization (AVR), present in 40% of cases. The most common echocardiographic finding was left ventricular systolic dysfunction (49%), followed by akinesia or hypokinesia of the inferior and/or inferolateral walls (38.1%) and the presence of an apical aneurysm (32.7%).
CONCLUSIONS
Overall, this study demonstrates that CCC in the Amazon region presents clinical characteristics and severity that are similar to those observed in other regions. However, certain peculiarities, such as the frequency of right bundle branch block (RBBB) and anterior and septal involvement during the acute phase, require additional investigation to better comprehend the disease in the region. Overall, the study provides crucial clinical insights for the diagnosis and treatment of CCC in the Amazon region.
Topics: Humans; Chagas Cardiomyopathy; Brazil; Retrospective Studies; Cross-Sectional Studies; Chagas Disease
PubMed: 38089032
DOI: 10.3389/fpubh.2023.1284639 -
Biomedicines Jul 2023Dopamine (DA) is the critical neurotransmitter involved in the unconscious control of muscle tone and body posture. We evaluated the general motor capacities and muscle...
Dopamine (DA) is the critical neurotransmitter involved in the unconscious control of muscle tone and body posture. We evaluated the general motor capacities and muscle responses to postural disturbance in three conditions: normal DA level (wild-type rats, WT), mild DA deficiency (WT after administration of α-methyl-p-tyrosine-AMPT, that blocks DA synthesis), and severe DA depletion (DAT-KO rats after AMPT). The horizontal displacements in WT rats elicited a multi-component EMG corrective response in the flexor and extensor muscles. Similar to the gradual progression of DA-related diseases, we observed different degrees of bradykinesia, rigidity, and postural instability after AMPT. The mild DA deficiency impaired the initiation pattern of corrective responses, specifically delaying the extensor muscles' activity ipsilaterally to displacement direction and earlier extensor activity from the opposite side. DA depletion in DAT-KO rats after AMPT elicited tremors, general stiffness, and akinesia, and caused earlier response to horizontal displacements in the coactivated flexor and extensor muscles bilaterally. The data obtained show the specific role of DA in postural reactions and suggest that this experimental approach can be used to investigate sensorimotor control in different dopamine-deficient states and to model DA-related diseases.
PubMed: 37509596
DOI: 10.3390/biomedicines11071958 -
Cell & Bioscience Aug 2023Parkinson's disease (PD), a highly prevalent neuro-motor disorder is caused due to progressive loss of dopaminergic (DAergic) neurons at substantia nigra region of...
BACKGROUND
Parkinson's disease (PD), a highly prevalent neuro-motor disorder is caused due to progressive loss of dopaminergic (DAergic) neurons at substantia nigra region of brain. This leads to depleted dopamine (DA) content at striatum, thus affecting the fine tuning of basal ganglia. In patients, this imbalance is manifested by akinesia, catalepsy and tremor. PD associated behavioral dysfunctions are frequently mitigated by l-DOPA (LD) therapy, a precursor for DA synthesis. Due to progressive neurodegeneration, LD eventually loses applicability in PD. Although DA is cytotoxic, it is unclear whether LD therapy can accelerate PD progression or not. LD itself does not lead to neurodegeneration in vivo, but previous reports demonstrate that LD treatment mediated excess DA can potentiate neurotoxicity when PD associated genetic or epigenetic aberrations are involved. So, minimizing DA toxicity during the therapy is an absolute necessity to halt or slowdown PD progression. The two major contributing factors associated with DA toxicity are: degradation by Monoamine oxidase and DAquinone (DAQ) formation.
RESULTS
Here, we report that apoptotic mitochondrial fragmentation via Calcineurin (CaN)-DRP1 axis is a common downstream event for both these initial cues, inhibiting which can protect cells from DA toxicity comprehensively. No protective effect is observed, in terms of cell survival when only PxIxIT domain of CaN is obstructed, demonstrating the importance to block DRP1-CaN axis specifically. Further, evaluation of the impact of DA exposure on PD progression in a mice model reveal that LD mediated behavioral recovery diminishes with time, mostly because of continued DAergic cell death and dendritic spine loss at striatum. CaN inhibition, alone or in combination with LD, offer long term behavioral protection. This protective effect is mediated specifically by hindering CaN-DRP1 axis, whereas inhibiting interaction between CaN and other substrates, including proteins involved in neuro-inflammation, remained ineffective when LD is co-administered.
CONCLUSIONS
In this study, we conclude that DA toxicity can be circumvented by CaN inhibition and it can mitigate PD related behavioral aberrations by protecting neuronal architecture at striatum. We propose that CaN inhibitors might extend the therapeutic efficacy of LD treatment.
PubMed: 37528492
DOI: 10.1186/s13578-023-01068-6 -
Movement Disorders : Official Journal... Jun 2024Isolated Rapid Eye Movement (REM) sleep Behavior Disorder (iRBD) requires quantitative tools to detect incipient Parkinson's disease (PD).
BACKGROUND
Isolated Rapid Eye Movement (REM) sleep Behavior Disorder (iRBD) requires quantitative tools to detect incipient Parkinson's disease (PD).
METHODS
A motor battery was designed and compared with the Movement Disorder Society-Unified Parkinson's Disease Rating Scale part III (MDS-UPDRS-III) in people with iRBD and controls. This included two keyboard-based tests (BRadykinesia Akinesia INcoordination tap test and Distal Finger Tapping) and two dual tasking tests (walking and finger tapping).
RESULTS
We included 33 iRBD patients and 29 controls. The iRBD group performed both keyboard-based tapping tests more slowly (P < 0.001, P = 0.020) and less rhythmically (P < 0.001, P = 0.006) than controls. Unlike controls, the iRBD group increased their walking duration (P < 0.001) and had a smaller amplitude (P = 0.001) and slower (P = 0.007) finger tapping with dual task. The combination of the most salient motor markers showed 90.3% sensitivity for 89.3% specificity (area under the ROC curve [AUC], 0.94), which was higher than the MDS-UPDRS-III (minus action tremor) (69.7% sensitivity, 72.4% specificity; AUC, 0.81) for detecting motor dysfunction.
CONCLUSION
Speed, rhythm, and dual task motor deterioration might be accurate indicators of incipient PD in iRBD. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Topics: Humans; REM Sleep Behavior Disorder; Male; Female; Aged; Middle Aged; Parkinson Disease; Psychomotor Performance; Walking; Severity of Illness Index
PubMed: 38470080
DOI: 10.1002/mds.29779