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Clinical Genetics Feb 2024We report the third case of FADS due to biallelic DOK7 variants, which further strengthens the association of DOK7 with this lethal phenotype and lack of genotype... (Review)
Review
We report the third case of FADS due to biallelic DOK7 variants, which further strengthens the association of DOK7 with this lethal phenotype and lack of genotype phenotype correlation.
Topics: Humans; Arthrogryposis; Phenotype; Muscle Proteins
PubMed: 37849383
DOI: 10.1111/cge.14431 -
European Review For Medical and... Sep 2023Opicapone (OPC) is a third-generation peripheral catechol-O-methyl transferase inhibitor (COMT-i) approved as add-on therapy to levodopa/DOPA decarboxylase inhibitors...
OBJECTIVE
Opicapone (OPC) is a third-generation peripheral catechol-O-methyl transferase inhibitor (COMT-i) approved as add-on therapy to levodopa/DOPA decarboxylase inhibitors (DDCI) combinations in Parkinson's disease (PD) patients with end-of-dose motor fluctuations. While the OPC effectiveness on motor symptoms is well known, there is still uncertainty about the timing of introduction, the management of levodopa dose, and the efficacy on non-motor symptoms (NMS).
SUBJECTS AND METHODS
A group of PD experts participated in a consensus activity composed of the Nominal Group Technique (NGT) and the Delphi method to better define the role of OPC. A list of statements was defined with the NGT and voted on through an online Delphi process by a panel of 85 Italian clinicians.
RESULTS
24 statements were selected for the Delphi voting. Most statements (n=15, 62%) reached a consensus. A wide agreement was reached about the efficacy of OPC in treating motor fluctuations, including early morning akinesia and nocturnal akinesia. The panel widely agreed about the effectiveness of OPC in early fluctuating patients. The long-lasting inhibitory effect of OPC was recognized as an advantage over other COMT-i, resulting in a single daily dose and greater ease of introduction into the levodopa therapeutic regimen.
CONCLUSIONS
The efficacy of OPC observed in the clinical trials for the management of PD patients with motor fluctuations is also experienced in clinical practice. The review of the current positioning of OPC from the late to early stages of the disease may represent an important step in the evolution of the PD therapeutic approach.
Topics: Humans; Parkinson Disease; Levodopa; Catechol O-Methyltransferase; Consensus
PubMed: 37782207
DOI: 10.26355/eurrev_202309_33805 -
Saudi Pharmaceutical Journal : SPJ :... Oct 2023Parkinson's disease (PD) is one of the major neurodegenerative disorders and the prevalence is expected to increase during the next couple of decades. There is a need...
BACKGROUND
Parkinson's disease (PD) is one of the major neurodegenerative disorders and the prevalence is expected to increase during the next couple of decades. There is a need for safe and effective therapeutic regimen that can effectively manage this neurotoxicity. The leaves and several other parts of are known to possess number of medicinal properties. The purpose of this study was to examine the neuroprotective role of in an experimental model of haloperidol-induced P.D.
MATERIALS AND METHODS
Five groups of rats were randomly assigned into different groups. Intraperitoneal haloperidol 1 mg/kg was given to the inducer group and 0.5% CMC to the normal control. The reference standard was syndopa 10 mg/kg, p.o., and the test group animals received ethanolic extract at 200 and 400 mg/kg orally for one week. Rats exposed to haloperidol were assessed for behavioral, neurochemical, and histopathological parameters.
RESULTS
leaves extract dose-dependently increased behavioral activity and muscle coordination. The extract at 400 mg/kg was found to increase significantly ( < 0.001) the central square activity in open-field test, compared to haloperidol treated rats. In stepping test, both tested doses of (200 mg and 400 mg/kg) were found to significantly ( < 0.001) reduce akinesia, besides these doses also decreased the catatonic responses induced by haloperidol. Further, the extraction treatment (200 mg and 400 mg/kg) significantly ( < 0.001) decreased malonaldehyde and increased antioxidant enzymes like catalase compared to the control group. Histopathological changes in the test group showed a significant reduction in haloperidol damage to normal morphology in cortical, hippocampus, substantia nigra, and pyramidal.
CONCLUSION
The observations of the study suggest that attenuated the haloperidol-induced neurological changes, indicating that the plant might benefit in the treatment of Parkinson's disease. The activity of could be linked to its antioxidant property. Since, the drug is traditionally used in different parts of world; it could be a promising agent if more research establishes its safety and efficacy in other experimental models of Parkinson's Disease.
PubMed: 37771955
DOI: 10.1016/j.jsps.2023.101791 -
The Journal of Pharmacy Technology :... Oct 2023Acute encephalopathy is a common symptom encountered in critically ill patients and may be associated with Wernicke's encephalopathy (WE) or serotonin syndrome (SS). We...
Acute encephalopathy is a common symptom encountered in critically ill patients and may be associated with Wernicke's encephalopathy (WE) or serotonin syndrome (SS). We describe a patient who presented with clinical manifestations of both WE and SS and who responded to treatment for both pathologies. A 56-year-old male presented after being found unresponsive and in a questionable tonic-clonic state. Past medical history was significant for depression managed with fluoxetine 20 mg by mouth daily and alcohol use disorder. A physical exam revealed severe clonus in the bilateral lower extremities; diffuse hyperreflexia along with akinesia on the left upper extremity; ophthalmoplegia; and persistent tachycardia despite pharmacologic interventions. It was learned that the patient had been taking his fluoxetine 3 times per day rather than daily as prescribed. Oral cyproheptadine was administered at a 12 mg initial dose followed by 4 mg every 6 hours. A thiamine regimen of 500 mg intravenous (IV) every 8 hours in addition to folic acid 1 mg IV every 24 hours was initiated to treat WE. Physical symptoms of both WE and SS resolved within 48 hours, and the patient was ultimately discharged to home in stable condition. The clinical diagnosis of both WE and SS in this case is supported by the Caine and Hunter criteria, respectively, as well as the resolution of symptoms with accepted treatment modalities for each. It is important for clinicians to be cognizant of potential overlapping pathologies when patients present with nonspecific symptoms, especially acute encephalopathy, in the intensive care unit.
PubMed: 37745730
DOI: 10.1177/87551225231195536 -
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 -
Neurotherapeutics : the Journal of the... Oct 2023Traumatic brain injury (TBI), a neurovascular injury caused by external force, is a common diagnosis among veterans and those experiencing homelessness (HL). There is a... (Review)
Review
Traumatic brain injury (TBI), a neurovascular injury caused by external force, is a common diagnosis among veterans and those experiencing homelessness (HL). There is a significant overlap in the veteran and homeless population, possibly accounting for the two to seven times greater incidence of TBI among those experiencing HL than the general population. Despite these statistics, individuals experiencing HL are often underdiagnosed and ineffectively treated for TBI. We introduced a novel model of HL. Over 5 weeks, adult Sprague-Dawley rats were randomly assigned to one of the following conditions: TBI only, HL only, TBI + HL, or control (n = 9 per group). To emulate HL, animals (2 animals per cage) were exposed to soiled beddings for 5 weeks. Subsequently, animals were introduced to TBI by using the moderate controlled cortical impact model, then underwent 4 consecutive days of behavioral testing (beam walk (BW), elevated body swing test (EBST), forelimb akinesia (FA), paw grasp (PG), Rotorod, and elevated T-maze). Nissl staining was performed to determine the peri-impact cell survival and the integrity of corpus callosum area. Motor function was significantly impaired by TBI, regardless of housing (beam walk or BW 85.0%, forelimb akinesia or FA 104.7%, and paw grasp or PG 100% greater deficit compared to control). Deficits were worsened by HL in TBI rats (BW 93.3%, FA 40.5%, and PG 50% greater deficit). Two-way ANOVA revealed BW (F(4, 160) = 31.69, p < 0.0001), FA (F(4, 160) = 13.71, p < 0.0001), PG (F(4, 160) = 3.873, p = 0.005), Rotorod (F(4, 160), p = 1.116), and EBST (F(4, 160) = 6.929, p < 0.0001) showed significant differences between groups. The Rotorod and EBST tests showed TBI-induced functional deficits when analyzed by day, but these deficits were not exacerbated by HL. TBI only and TBI + HL rats exhibited typical cortical impact damage (F(3,95) = 51.75, p < 0.0001) and peri-impact cell loss compared to control group (F(3,238) = 47.34, p < 0.0001). Most notably, TBI + HL rats showed significant alterations in WM area measured via the corpus callosum (F(3, 95) = 3.764, p = 0.0133). Worsened behavioral outcomes displayed by TBI + HL rats compared to TBI alone suggest HL contributes to TBI functional deficits. While an intact white matter, such as the corpus callosum, may lessen the consequent functional deficits associated with TBI by enhancing hemispheric communications, there are likely alternative cellular and molecular pathways mitigating TBI-associated inflammatory or oxidative stress responses. Here, we showed that the environmental condition of the patient, i.e., HL, participates in white matter integrity and behavioral outcomes, suggesting its key role in the disease diagnosis to aptly treat TBI patients.
Topics: Humans; Adult; Rats; Animals; Rats, Sprague-Dawley; Brain Injuries, Traumatic; White Matter; Ill-Housed Persons; Comorbidity
PubMed: 37639189
DOI: 10.1007/s13311-023-01419-8 -
Neurology and Therapy Dec 2023Foslevodopa/foscarbidopa, a soluble formulation of levodopa/carbidopa (LD/CD) prodrugs for the treatment of Parkinson's disease (PD), is administered as a 24-hour/day...
INTRODUCTION
Foslevodopa/foscarbidopa, a soluble formulation of levodopa/carbidopa (LD/CD) prodrugs for the treatment of Parkinson's disease (PD), is administered as a 24-hour/day continuous subcutaneous infusion (CSCI) with a single infusion site. The efficacy and safety of foslevodopa/foscarbidopa versus oral immediate-release LD/CD was previously demonstrated in patients with PD in a 12-week, randomized, double-blind, phase 3 trial (NCT04380142). We report the results of a separate 52-week, open-label, phase 3 registrational trial (NCT03781167) that evaluated the safety/tolerability and efficacy of 24-hour/day foslevodopa/foscarbidopa CSCI in patients with advanced PD.
METHODS
Male and female patients with levodopa-responsive PD and ≥ 2.5 hours of "Off" time/day received 24-hour/day foslevodopa/foscarbidopa CSCI at individually optimized therapeutic doses (approximately 700-4250 mg of LD per 24 hours) for 52 weeks. The primary endpoint was safety/tolerability. Secondary endpoints included changes from baseline in normalized "Off" and "On" time, percentage of patients reporting morning akinesia, Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS), Parkinson's Disease Sleep Scale-2 (PDSS-2), 39-item Parkinson's Disease Questionnaire (PDQ-39), and EuroQol 5-dimension questionnaire (EQ-5D-5L).
RESULTS
Of 244 enrolled patients, 107 discontinued, and 137 completed treatment. Infusion site events were the most common adverse events (AEs). AEs were mostly nonserious (25.8% of patients reported serious AEs) and mild/moderate in severity. At week 52, "On" time without troublesome dyskinesia and "Off" time were improved from baseline (mean [standard deviation (SD)] change in normalized "On" time without troublesome dyskinesia, 3.8 [3.3] hours; normalized "Off" time, -3.5 [3.1] hours). The percentage of patients experiencing morning akinesia dropped from 77.7% at baseline to 27.8% at week 52. Sleep quality (PDSS-2) and quality of life (PDQ-39 and EQ-5D-5L) also improved.
CONCLUSION
Foslevodopa/foscarbidopa has the potential to provide a safe and efficacious, individualized, 24-hour/day, nonsurgical alternative for patients with PD.
TRIAL REGISTRATION NUMBER
ClinicalTrials.gov identifier NCT03781167.
PubMed: 37632656
DOI: 10.1007/s40120-023-00533-1 -
Life (Basel, Switzerland) Aug 2023Takotsubo cardiomyopathy (TCM) is a reversible form of cardiomyopathy characterized by transient regional systolic dysfunction of the left ventricle.
INTRODUCTION
Takotsubo cardiomyopathy (TCM) is a reversible form of cardiomyopathy characterized by transient regional systolic dysfunction of the left ventricle.
CASE OUTLINE
A 78-year-old woman was admitted to the general hospital due to acute inferior STEMI late presentation. Two days after admission, the patient reported intense chest pain and an ECG registered diffuse ST-segment elevation in all leads with ST-segment denivelation in aVR. The patient also showed clinical signs of cardiogenic shock and was referred to a reference institution for further evaluation. Echocardiography revealed akinesia of all medioapical segments, dynamic obstruction of the left ventricular outflow tract (LVOT), moderate mitral regurgitation, and pericardial effusion. Coronary angiography showed the suboccluded right coronary artery, and a primary percutaneous coronary intervention was performed, which involved implanting a drug-eluting stent. The patient's condition worsened as pericardial effusion increased and led to tamponade. Pericardiocentesis was performed, resulting in the patient's stabilization. At this point, significant gradients at the LVOT and pericardial effusion were not registered. After eight days without symptoms and stable status, the patient was discharged.
CONCLUSIONS
The simultaneous presence of AMI and TCM increases the risk of developing cardiogenic shock. The cardio-circulatory profile of these patients is different from those with AMI.
PubMed: 37629626
DOI: 10.3390/life13081770