Drug-Induced Parkinsonism: Too Many Cooks in the Kitchen.

Drug-induced parkinsonism (DIP) is a condition characterized by the development of parkinsonian symptoms as a result of medication use. It is often misdiagnosed and can be challenging to differentiate from Parkinson's disease (PD). In this case presentation, we describe the clinical course of a 64-year-old male who presented with parkinsonian symptoms while using atypical antipsychotics, which was originally misdiagnosed as PD. The case highlights the importance of recognizing the potential iatrogenic effects of medications with antidopaminergic properties, such as antipsychotics and antiepileptic drugs, which are common culprits in causing DIP. We discuss DIP management, long-term impacts, and differentiating DIP from PD through clinical findings and imaging, emphasizing the utility of the (123)I-ioflupane single-photon emission computerized tomography (SPECT) scan in aiding diagnosis. This case serves as a reminder to healthcare providers to remain vigilant in monitoring patients for adverse effects, polypharmacy, and harmful medication interactions.

Fully sequencing the cassava full-length cDNA library reveals unannotated transcript structures and alternative splicing events in regions with a high density of single nucleotide variations, insertions-deletions, and heterozygous sequences.

The primary transcript structure provides critical insights into protein diversity, transcriptional modification, and functions. Cassava transcript structures are highly diverse because of alternative splicing (AS) events and high heterozygosity. To precisely determine and characterize transcript structures, fully sequencing cloned transcripts is the most reliable method. However, cassava annotations were mainly determined according to fragmentation-based sequencing analyses (e.g., EST and short-read RNA-seq). In this study, we sequenced the cassava full-length cDNA library, which included rare transcripts. We obtained 8,628 non-redundant fully sequenced transcripts and detected 615 unannotated AS events and 421 unannotated loci. The different protein sequences resulting from the unannotated AS events tended to have diverse functional domains, implying that unannotated AS contributes to the truncation of functional domains. The unannotated loci tended to be derived from orphan genes, implying that the loci may be associated with cassava-specific traits. Unexpectedly, individual cassava transcripts were more likely to have multiple AS events than Arabidopsis transcripts, suggestive of the regulated interactions between cassava splicing-related complexes. We also observed that the unannotated loci and/or AS events were commonly in regions with abundant single nucleotide variations, insertions-deletions, and heterozygous sequences. These findings reflect the utility of completely sequenced FLcDNA clones for overcoming cassava-specific annotation-related problems to elucidate transcript structures. Our work provides researchers with transcript structural details that are useful for annotating highly diverse and unique transcripts and alternative splicing events.

Src family kinase targeting in head and neck tumor cells using SU6656, PP2 and dasatinib.

BACKGROUND: We have recently shown a frequent upregulation of Src-family kinases (SFK) in head and neck squamous cell carcinoma (HNSCC). Here we tested, if SFK targeting is effective especially in HNSCC cells with upregulated SFK signaling. METHODS: The impact of SFK inhibitors SU6656, PP2 and dasatinib on three HNSCC cell lines with different SFK activity levels was analyzed using proliferation and colony formation assays, Western blot and functional kinomics. RESULTS: Proliferation was blocked by all inhibitors in a micro-molar range. With respect to cell kill, dasatinib was most effective, while SU6656 showed moderate and PP2 minor effects. Cellular signaling was affected differently, with PP2 having no effect on SFK signaling while dasatinib probably has non-SFK specific effects. Only SU6656 showed clear SFK specific effects on signaling. CONCLUSION: The results demonstrate potential benefit of SFK inhibition in HNSCC but they also highlight challenges due to non-specificities of the different drugs.

Ethanol treatment enhances drought stress avoidance in cassava (Manihot esculenta Crantz).

External application of ethanol enhances tolerance to high salinity, drought, and heat stress in various plant species. However, the effects of ethanol application on increased drought tolerance in woody plants, such as the tropical crop "cassava," remain unknown. In the present study, we analyzed the morphological, physiological, and molecular responses of cassava plants subjected to ethanol pretreatment and subsequent drought stress treatment. Ethanol pretreatment induced a slight accumulation of abscisic acid (ABA) and stomatal closure, resulting in a reduced transpiration rate, higher water content in the leaves during drought stress treatment and the starch accumulation in leaves. Transcriptomic analysis revealed that ethanol pretreatment upregulated the expression of ABA signaling-related genes, such as PP2Cs and AITRs, and stress response and protein-folding-related genes, such as heat shock proteins (HSPs). In addition, the upregulation of drought-inducible genes during drought treatment was delayed in ethanol-pretreated plants compared with that in water-pretreated control plants. These results suggest that ethanol pretreatment induces stomatal closure through activation of the ABA signaling pathway, protein folding-related response by activating the HSP/chaperone network and the changes in sugar and starch metabolism, resulting in increased drought avoidance in plants.

Ethanol-Mediated Novel Survival Strategy against Drought Stress in Plants.

Water scarcity is a serious agricultural problem causing significant losses to crop yield and product quality. The development of technologies to mitigate the damage caused by drought stress is essential for ensuring a sustainable food supply for the increasing global population. We herein report that the exogenous application of ethanol, an inexpensive and environmentally friendly chemical, significantly enhances drought tolerance in Arabidopsis thaliana, rice and wheat. The transcriptomic analyses of ethanol-treated plants revealed the upregulation of genes related to sucrose and starch metabolism, phenylpropanoids and glucosinolate biosynthesis, while metabolomic analysis showed an increased accumulation of sugars, glucosinolates and drought-tolerance-related amino acids. The phenotyping analysis indicated that drought-induced water loss was delayed in the ethanol-treated plants. Furthermore, ethanol treatment induced stomatal closure, resulting in decreased transpiration rate and increased leaf water contents under drought stress conditions. The ethanol treatment did not enhance drought tolerance in the mutant of ABI1, a negative regulator of abscisic acid (ABA) signaling in Arabidopsis, indicating that ABA signaling contributes to ethanol-mediated drought tolerance. The nuclear magnetic resonance analysis using 13C-labeled ethanol indicated that gluconeogenesis is involved in the accumulation of sugars. The ethanol treatment did not enhance the drought tolerance in the aldehyde dehydrogenase (aldh) triple mutant (aldh2b4/aldh2b7/aldh2c4). These results show that ABA signaling and acetic acid biosynthesis are involved in ethanol-mediated drought tolerance and that chemical priming through ethanol application regulates sugar accumulation and gluconeogenesis, leading to enhanced drought tolerance and sustained plant growth. These findings highlight a new survival strategy for increasing crop production under water-limited conditions.

Accelerated Implementation of a Virtual Neurology Clerkship Amid a Global Crisis.

The standard neurology clinical experience in medical school focuses primarily on bedside patient encounters; however, the limitations of the clinical environment due to the current COVID-19 pandemic have accelerated the need for virtual curriculum development. To provide guidance to Neurology clerkship directors during this unprecedented time, the American Academy of Neurology (AAN) Undergraduate Education Subcommittee (UES) formed a workgroup to develop an outline for a virtual curriculum, provide recommendations, and describe models of integrating virtual curricula into the neurology clerkship. In this overview, we discuss different methods of virtual instruction, hybrid models of clerkship training and the challenges to its implementation, professionalism issues, and modification of feedback and assessment techniques specific to the virtual learning environment. We also offer suggestions for implementation of a hybrid virtual curriculum into the neurology clerkship. The virtual curriculum is intended to supplement the core neurology in-person clinical experience and should not be used for shortening or replacing the required neurology clinical clerkship.

Rehabilitation Outcomes of Cortical Blindness and Characteristics Secondary to Cardiac Arrest: A Review.

We reviewed the published literature on rehabilitation outcomes in patients with cortical blindness (CB) and highlighted the characteristic features and prognosis of CB due to cardiac arrest. The studies excluded were those involving the pediatric population (

Analyzing tyrosine kinase activity in head and neck cancer by functional kinomics: Identification of hyperactivated Src family kinases as prognostic markers and potential targets.

Signal transduction via protein kinases is of central importance in cancer biology and treatment. However, the clinical success of kinase inhibitors is often hampered by a lack of robust predictive biomarkers, which is also caused by the discrepancy between kinase expression and activity. Therefore, there is a need for functional tests to identify aberrantly activated kinases in individual patients. Here we present a systematic analysis of the tyrosine kinases in head and neck cancer using such a test-functional kinome profiling. We detected increased tyrosine kinase activity in tumors compared with their corresponding normal tissue. Moreover, we identified members of the family of Src kinases (Src family kinases [SFK]) to be aberrantly activated in the majority of the tumors, which was confirmed by additional methods. We could also show that SFK hyperphosphorylation is associated with poor prognosis, while inhibition of SFK impaired cell proliferation, especially in cells with hyperactive SFK. In summary, functional kinome profiling identified SFK to be frequently hyperactivated in head and neck squamous cell carcinoma. SFK may therefore be potential therapeutic targets. These results furthermore demonstrate how functional tests help to increase our understanding of cancer biology and support the expansion of precision oncology.

Receptor tyrosine kinase MET as potential target of multi-kinase inhibitor and radiosensitizer sorafenib in HNSCC.

BACKGROUND: The multi-kinase inhibitor sorafenib displays antitumoral effects in head and neck squamous cell carcinoma (HNSCC); however, the targeted kinases are unknown. Here we aimed to identify those kinases to determine the mechanism of sorafenib-mediated effects and establish candidate biomarkers for patient stratification. METHODS: The effects of sorafenib and MET inhibitors crizotinib and SU11274 were analyzed using a slide-based antibody array, Western blotting, proliferation, and survival assays. X-rays were used for irradiations. RESULTS: Sorafenib inhibited auto-phosphorylation of epidermal growth factor receptor and MET, which has not been described previously. MET expression in HNSCC cells was not always associated with activity/phosphorylation. Furthermore, sorafenib-dependent cell kill and radiosensitization was not associated with MET level. Although MET inhibitors blocked proliferation, they caused only mild cytotoxicity and no radiosensitization. CONCLUSION: We identified MET as a new potential target of sorafenib. However, MET inhibition is not the cause for sorafenib-mediated cytotoxicity or radiosensitization.

Hospitalizations of Children with Huntington's Disease in the United States.

BACKGROUND: Juvenile Huntington's disease (JHD) is a childhood-onset neurodegenerative disorder. Although it is caused by the same pathologic expansion of CGA repeats as adult-onset Huntington's disease, JHD has distinct clinical features. Most clinical research in HD focuses in the adult-onset disease; therefore, little is known about acute care outcomes for patients with JHD. METHODS: The Kids' Inpatient Database (KID) was used to examine hospitalizations of children with JHD and to determine the diagnoses and procedures associated with inpatient care for JHD. Regression models were built to examine acute care outcomes, including death, length of stay, and disposition at discharge in patients with JHD compared with patients in the general KID data. RESULTS: The proportion of JHD cases among hospitalized children was 1.23 per 100,000 KID inpatient stays. Seizures/convulsions (58.5%) and psychiatric conditions (26.1%) were the most common primary or secondary diagnoses among JHD patient hospitalizations. The most common procedure was percutaneous endoscopic gastrostomy tube placement (8.6%). Compared with hospitalizations of the general population, hospitalizations of patients with JHD had a lower odds of discharge to home (adjusted odds ratio [AOR], 0.23; 95% confidence interval [CI], 0.14-0.37) and an increased likelihood of death (AOR, 8.03; 95% CI, 2.98-21.60) or discharge to a short-term care facility (AOR, 4.44; 95% CI, 2.59-7.61). A diagnosis of JHD was associated with increased length of stay (7.04 vs. 3.75 days; P < 0.01). CONCLUSIONS: Children with JHD have unique acute care patterns. Future studies are needed to determine the extent to which coordinated care may impact inpatient and disposition needs.

Analysis of methylated circulating DNA in cancer patients' blood.

Circulating extracellular nucleic acids derived from body fluids such as blood are commonly analyzed to assess malignant diseases. Efficient isolation, extraction, quantification, modification, and analysis methods remain important for utilizing circulating nucleic acids as potential molecular biomarkers. Our refined techniques of DNA isolation from serum, sodium bisulfite modification of extracted DNA, and methylation analysis provide a robust approach for quantitative analysis of circulating tumor-related DNA. The approach allows direct comparison of methylated and nonmethylated genomic sequences in a specimen.

Quantification of LINE1 in circulating DNA as a molecular biomarker of breast cancer.

Developing a noninvasive test for detecting and monitoring breast cancer progression would help in providing better procedures for the treatment of breast cancer. Increases in the absolute quantity of circulating DNA and DNA integrity have been previously reported in breast cancer patients. LINE1 is one of the most abundant sequences in the human genome, with about 520,000 copies per genome. To assess the combination of circulating DNA quantity and DNA integrity, we developed a long LINE1 (about 300-bp amplicon size) quantitative method. A quantitative real-time PCR (qPCR) technique was used to detect long LINE1. Breast cancer patients' sera was assessed preoperatively before primary tumor surgery. LINE1 could be detected in high levels of breast cancer patients' sera and in limited levels in normal females. We demonstrated that long LINE1 quantification of circulating DNA was useful for detecting early-stage breast cancer, and that copy number correlated with tumor size. This preliminary study demonstrates the potential clinical utility of LINE1 copy numbers in breast cancer patients.

Estrogen receptor and HER2/neu status affect epigenetic differences of tumor-related genes in primary breast tumors.

INTRODUCTION: Estrogen receptor (ER)-positive breast cancers are considered prognostically more favorable than ER-negative tumors, whereas human epidermal growth factor receptor (HER)2/neu-positive breast cancers are associated with worse prognosis. The objective of the present study was to determine whether ER-positive and ER-negative status relates to epigenetic changes in breast cancer-related genes. To evaluate epigenetic differences in tumor-related genes relating to ER and HER2/neu status of primary tumors, we examined the promoter methylation status of the promoter region CpG islands of eight major breast tumor-related genes (RASSF1A, CCND2, GSPT1, TWIST, APC, NES1, RARbeta2, and CDH1). METHODS: Paired ER-positive (n = 65) and ER-negative (n = 65) primary breast tumors (n = 130) matched for prognostic factors were assessed. DNA was extracted from paraffin-embedded tumor tissue after microdissection, and methylation-specific PCR and capillary-array electrophoresis analysis were performed. RESULTS: In early stages of tumor progression (T1 and N0), RASSF1A and CCND2 were significantly (P < 0.05) more methylated in ER-positive than in ER-negative tumors. GSTP1 hypermethylation was more frequent in the lymph node metastasis positive group than in the negative group. Double negative (ER-negative, HER2/neu-negative) breast cancers had significantly lesser frequencies of RASSF1A, GSTP1, and APC methylation (P < 0.0001, P < 0.0001, and P = 0.0035, respectively). Both ER and HER2/neu status correlated independently with these epigenetic alterations. CONCLUSION: We demonstrated significant differences in tumor-related gene methylation patterns relevant to ER and HER2/neu status of breast tumors. This may be of significance in the assessment of targeted therapy resistance related to ER and HER2/neu status in breast cancer patients.