👤 Nitesh Malhotra

The progressive neurodegenerative disease known as Parkinson's Disease (PD) is represented by deficits in both motor and non-motor functions. Levodopa and dopamine agonists are examples of pharmaceutical treatments that mainly reduce symptoms without having any discernible neuroprotective effects. The potential of exercise-based physical therapy to improve neuroplasticity and slow disease progression has drawn increasing attention. To provide awareness of their complementary roles in enhancing outcomes for people with PD, this narrative review examines the combined neuroprotective effects of pharmaceutical medicines and physical therapy. The aim of the review was to evaluate the effects of both physical and pharmaceutical therapies in the management of Parkinson's disease to enhance motor recovery and retard disease progression. The evidence from previous research is compiled in this review, which focuses on preclinical and clinical trials examining the neuroprotective benefits of medication and exercise-based physical therapy. We searched databases such as PubMed, Scopus, Embase, the Cochrane Library, and Web of Science to identify relevant peer-reviewed articles. The review discusses therapeutic synergies, underlying mechanisms, and how these affect clinical practice. Aerobic, resistance, and balance training are examples of exercise-based physiotherapy that reduce oxidative stress, increase brain-derived neurotrophic factor (BDNF) levels, and promote neuroplasticity. These effects enhance the ability of pharmacological drugs to relieve symptoms. Research indicates that, compared to stand-alone treatments, combined therapies produce superior outcomes in motor function, non-motor symptom management, and overall quality of life. The review also highlights important mechanisms of interaction between various medicines, including neuroprotective signaling pathways and improved dopamine utilization. Combined therapy in Parkinson's disease enhances neuroprotection by boosting BDNF and other neurotrophic factors, reducing oxidative stress and inflammation, and promoting neurogenesis. Exercise and medications work synergistically to improve neuronal survival, cognition, and motor function. However, challenges include poor patient adherence, limited access to structured programs, limited clinical integration, and the need to tailor treatment to disease stage. A possible method for improving neuroprotection in PD is the combination of pharmaceutical therapies and exercise-based physical therapy. Further research is needed to optimize therapy regimens and develop individualized approaches to enhance patient outcomes and slow disease progression. This combined method offers a multifaceted and comprehensive approach to managing Parkinson's disease. Show less

Resistance and resilience are pathways through which modifiable behaviors may reduce Alzheimer's disease (AD) risk. Sleep - a known modifiable factor - is understudied in this context, especially among older women at elevated risk for AD. Forty-five functionally intact older women (≥65 years) at heightened risk for AD completed wrist actigraphy to capture average nocturnal sleep duration. Tau positron emission tomography imaging ( Shorter sleep duration amplified the association between APOE ε4 status and tau, while longer sleep mitigated it. Similarly, tau burden was related to worse memory performance only among those with short sleep duration. Longer sleep duration may promote resistance and resilience to AD in at-risk older women, highlighting sleep as a critical intervention target. Sleep was measured via wrist actigraphy, tau via PET imaging, and memory with a composite score. Longer sleep attenuated the link between APOE ε4 carriership and tau PET across Braak regions. Greater sleep duration weakened the negative impact of tau on memory performance. This is the first study to examine sleep in AD resistance and resilience among older women at heightened risk. Show less

A low respiratory arousal threshold (ArTH) has been linked to reduced continuous positive airway pressure (CPAP) adherence in obstructive sleep apnea (OSA) via a multi-trait model developed in the RICCADSA trial. Our objective was to validate the prior model in a large, real-world cohort and explore alternative linear and non-linear approaches for predicting CPAP adherence. Does a previously derived multi-trait model linking low ArTH to poor CPAP adherence remain valid in a diverse real-world population and do alternative linear or non-linear approaches offer improved predictive performance? Adults with OSA from the SNOOzzzE-cohort who initiated CPAP within 1 year of in-lab polysomnography (2017-2019) were included. Pathophysiological traits (Vpassive, Vactive, loop gain, ArTH, ventilatory response to arousal) were estimated from polysomnography. Poor (vs good) adherence was defined as ≤2.48h/night at month 1 (1 Among 744 participants (45% women, 47% non-White), median CPAP adherence was 4.8 h/night at 1 month. The prior model's AUC was 0.51 (95%-CI 0.46-0.55), with no usage differences between predicted poor vs good adherers. A new linear model overfit in training (AUC=0.85) but failed in testing (AUC=0.55). LPA identified a "Low ArTH Driven" cluster with persistently lower adherence at months 2-3 (P<.05) and a "Low ArTH & High loop gain" cluster whose usage stabilized after month 1. The prior model did not generalize to this diverse clinical cohort. LPA identified a "Low ArTH Driven" endotype with persistently low CPAP adherence, suggesting potential for targeted interventions pending external validation. Show less

Vascular calcification (VC), a common complication associated with diabetes mellitus (DM), substantially increases the risk of cardiovascular diseases and is associated with elevated mortality in individuals with DM. Endothelial-to-mesenchymal transition (EndMT) imparts phenotypic plasticity to vascular endothelial cells (VECs), granting them the potential for osteogenic differentiation, which is a crucial mechanism in regulating VC. Notably, adenosine-ADORA2A-mediated endothelial dysfunction plays a pivotal regulatory role in cardiovascular diseases. However, the specific role of endothelial ADORA2A in diabetic VC remains to be elucidated. In this study, we found that ADORA2A was upregulated in the endothelium of diabetic mice and cultured human aortic endothelial cells (HAECs) with high glucose treatment. Deletion of endothelial Adora2a or pharmacologic inhibition of ADORA2A with KW6002 attenuated EndMT, osteogenic differentiation, and calcium deposit in diabetic aortas of Ins2 Show less

Single exon duplications account for disease in a minority of Duchenne muscular dystrophy patients. Exon skipping in these patients has the potential to be highly therapeutic through restoration of full-length dystrophin expression. We conducted a 48-week open label study of casimersen and golodirsen in 3 subjects with an exon 45 or 53 duplication. Two subjects (aged 18 and 23 years) were non-ambulatory at baseline. Upper limb, pulmonary, and cardiac function appeared stable in the 2 subjects in whom they could be evaluated. Dystrophin expression increased from 0.94 % ±0.59% (mean±SD) of normal to 5.1% ±2.9% by western blot. Percent dystrophin positive fibers also rose from 14% ±17% at baseline to 50% ±42% . Our results provide initial evidence that the use of exon-skipping drugs may increase dystrophin levels in patients with single-exon duplications. Show less

Philadelphia chromosome (Ph)-like B-acute lymphoblastic leukemia (B-ALL) is a clinically significant, high-risk genetic subtype of B-ALL cases. There are few data on the incidence, characterization, and treatment outcomes of Ph-like ALL cases from low- and middle-income countries. There is a pressing need to establish a well-organized/cost-effective approach for identifying Ph-like ALL instances. Multiplex reverse transcriptase polymerase chain reaction, nCounter NanoString, and fluorescence in situ hybridization were used to detect and characterize Ph-like ALL cases among recurrent genetic abnormalities (RGA) Of 130 newly diagnosed B-ALL cases, 25% (BCR::ABL1), 4% (ETV6::RUNX1), 5% (TCF3::PBX1), 2% (KM2TA::AFF1), and 65% RGA This study showed the high incidence of Ph-like ALL cases with kinase activating alterations and treatment outcomes from low- and middle-income region. Furthermore, a surrogate cost-effective multiplex panel of 11 overexpressed genes for the prompt detection of Ph-like ALL cases is proposed. Identification of recurrent gene abnormalities (RGA) Show less

Gene expression profiling is the criterion standard for recognizing Ph-like ALL signatures among B-ALLs. The prerequisite of GEP is the accurate normalization of target genes with stable expression of housekeeping genes in a quantitative PCR. HKGs exhibit differential expression in the different experimental conditions and affect the target genes' expression, leading to imprecise qPCR results. The selection of stable HKGs is crucial in GEP experiments, especially in identifying high-risk Ph-like ALL cases. We have evaluated the expression stability of nine HKGs (GAPDH, ACTB, GUSB, RNA18S, EEF2, PGK1, B2M, TBP and ABL1) in identified Ph-like ALLs and Ph-negative (n = 23 each) using six algorithms, 4 traditional softwares; geNorm, BestKeeper, NormFinder, Delta Cq value method, and two algorithms, RefFinderTM and ComprFinder. Further, we have validated the expression of 8 overexpressed normalized genes in Ph-like ALL cases (JCHAIN, CA6, MUC4, SPATS2L, BMPR1B, CRLF2, ADGRF1 and NRXN3). GeNorm, BestKeeper, NormFinder, Delta Cq value method, RefFinderTM and ComprFinder algorithm analysis revealed that EEF2, GAPDH, and PGK1 form the best representative HKGs in Ph-like ALL cases, while RNA18s, ß-actin, and ABL1 in Ph-negative ALLs. Lastly, we performed a correlation analysis and found that the combination of EEF2, GAPDH, and PGK1 represents the best combination with a very high correlation in Ph-like ALL cases. This is the first report that shows EEF2, GAPDH, and PGK1 are the best HKG genes and can be used in the diagnostic panel of Ph-like ALL cases using qPCR at baseline diagnosis. Show less

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with limited treatment options. Despite endothelial cells (ECs) comprising 30% of the lung cellular composition, the role of EC dysfunction in pulmonary fibrosis (PF) remains unclear. We hypothesize that sterol regulatory element-binding protein 2 (SREBP2) plays a critical role in the pathogenesis of PF via EC phenotypic modifications. Transcriptome data demonstrate that SREBP2 overexpression in ECs led to the induction of the TGF, Wnt, and cytoskeleton remodeling gene ontology pathways and the increased expression of mesenchymal genes, such as snail family transcriptional repressor 1 (snai1), α-smooth muscle actin, vimentin, and neural cadherin. Furthermore, SREBP2 directly bound to the promoter regions and transactivated these mesenchymal genes. This transcriptomic change was associated with an epigenetic and phenotypic switch in ECs, leading to increased proliferation, stress fiber formation, and ECM deposition. Mice with endothelial-specific transgenic overexpression of SREBP2 (EC-SREBP2[N]-Tg mice) that were administered bleomycin to induce PF demonstrated exacerbated vascular remodeling and increased mesenchymal transition in the lung. SREBP2 was also found to be markedly increased in lung specimens from patients with IPF. These results suggest that SREBP2, induced by lung injury, can exacerbate PF in rodent models and in human patients with IPF. Show less

T-wave inversion (TWI) is common in patients with cardiomyopathy. However, up to 25% of athletes of African/Afro-Caribbean descent (black athletes) and 5% of white athletes also have TWI of unclear clinical significance despite comprehensive clinical evaluation and long-term follow-up. The aim of this study was to determine the diagnostic yield from genetic testing, beyond clinical evaluation, when investigating athletes with TWI. We investigated 50 consecutive asymptomatic black and 50 white athletes 14 to 35 years of age with TWI and a normal echocardiogram who were referred to a UK tertiary center for cardiomyopathy and sports cardiology. Subjects underwent exercise testing, 24-hour ambulatory ECG, signal-averaged ECG, cardiac magnetic resonance imaging, and a blood-based analysis of a comprehensive 311-gene panel for cardiomyopathies and ion channel disorders associated with TWI, including hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, dilated cardiomyopathy, left ventricular noncompaction, long-QT syndrome, and Brugada syndrome. In total, 21 athletes (21%) were diagnosed with cardiac disease on the basis of comprehensive clinical investigations. Of these, 8 (38.1%) were gene positive (myosin binding protein C[ MYBPC3], myosin heavy chain 7 [ MYH7], galactosidase alpha [ GLA], and actin alpha, cardiac muscle 1 [ ACTC1] genes) and 13 (61.9%) were gene negative. Of the remaining 79 athletes (79%), 2 (2.5%) were gene positive (transthyretin [ TTR] and sodium voltage-gated channel alpha subunit 5 [ SCN5A] genes) in the absence of a clinical phenotype. The prevalence of newly diagnosed cardiomyopathy was higher in white athletes compared with black athletes (30.0% versus 12%; P=0.027). Hypertrophic cardiomyopathy accounted for 90.5% of all clinical diagnoses. All black athletes and 93.3% of white athletes with a clinical diagnosis of cardiomyopathy or a genetic mutation capable of causing cardiomyopathy exhibited lateral TWI as opposed to isolated anterior or inferior TWI; the genetic yield of diagnoses from lateral TWI was 12.3%. Up to 10% of athletes with TWI revealed mutations capable of causing cardiac disease. Despite the substantial cost, the positive diagnostic yield from genetic testing was one half that from clinical evaluation (10% versus 21%) and contributed to additional diagnoses in only 2.5% of athletes with TWI in the absence of a clear clinical phenotype, making it of negligible use in routine clinical practice. Show less

Identity-by-descent mapping using empirical estimates of identity-by-descent allele sharing may be useful for studies of complex traits in founder populations, where hidden relationships may augment the inherent genetic information that can be used for localization. Through identity-by-descent mapping, using ≈400 000 single-nucleotide polymorphisms (SNPs), of serum lipid profiles, we identified a major linkage signal for triglycerides in 1007 Pima Indians (LOD=9.23; Show less

This study was designed to identify significant differences in gene expression profiles of human papillomavirus (HPV)-positive and HPV-negative oropharyngeal squamous cell carcinomas (OPSCC) and to better understand the functional and biological effects of HPV infection in the premalignant pathway. Twenty-four consecutive patients with locally advanced primary OPSCC were included in a prospective clinical trial. Fresh tissue samples (tumor vs. matched normal epithelium) were subjected to whole transcriptome analysis and the results validated on the same cohort with RT-quantitative real-time PCR. In a separate retrospective cohort of 27 OPSCC patients, laser capture microdissection of formalin-fixed, paraffin-embedded tissue allowed RNA extraction from adjacent regions of normal epithelium, carcinoma in situ (premalignant) and invasive SCC tissue. The majority of patients showed evidence of high-risk HPV16 positivity (80.4%). Predictable fold changes of RNA expression in HPV-associated disease included multiple transcripts within the p53 oncogenic pathway (e.g. CDKN2A/CCND1). Other candidate transcripts found to have altered levels of expression in this study have not previously been established (SFRP1, CRCT1, DLG2, SYCP2, and CRNN). Of these, SYCP2 showed the most consistent fold change from baseline in premalignant tissue; aberrant expression of this protein may contribute to genetic instability during HPV-associated cancer development. If further corroborated, this data may contribute to the development of a non-invasive screening tool. This study is registered with the UK Clinical Research Network (ref.: 11945). Show less

Evolutionarily significant selective sweeps may result in long stretches of homozygous polymorphisms in individuals from outbred populations. We developed whole-genome homozygosity association (WGHA) methodology to characterize this phenomenon in healthy individuals and to use this genomic feature to identify genetic risk loci for schizophrenia (SCZ). Applying WGHA to 178 SCZ cases and 144 healthy controls genotyped at 500,000 markers, we found that runs of homozygosity (ROHs), ranging in size from 200 kb to 15 mb, were common in unrelated Caucasians. Properties of common ROHs in healthy subjects, including chromosomal location and presence of nonancestral haplotypes, converged with prior reports identifying regions under selective pressure. This interpretation was further supported by analysis of multiethnic HapMap samples genotyped with the same markers. ROHs were significantly more common in SCZ cases, and a set of nine ROHs significantly differentiated cases from controls. Four of these 9 "risk ROHs" contained or neighbored genes associated with SCZ (NOS1AP, ATF2, NSF, and PIK3C3). Several of these risk ROHs were very rare in healthy subjects, suggesting that recessive effects of relatively high penetrance may explain a proportion of the genetic liability for SCZ. Other risk ROHs feature haplotypes that are also common in healthy individuals, possibly indicating a source of balancing selection. Show less