The role of demographic, perinatal/developmental, and acquired subject characteristics in determining neuropsychological (NP) performance was investigated in 22 alcoholics with Antisocial Personality ...Disorder (ASPD) and 84 non-ASPD alcoholics. Results of stepwise multiple regression analyses revealed that in ASPD subjects, poor NP performance was predicted by less education, childhood symptoms of Conduct Disorder, drinks per drinking day. and history of head injury, accounting for 80% of the explained variance (
p < .0001). In non-ASPD subjects. NP performance was predicted by self-reported history of diagnosed Attention Deficit Disorder, Verbal Learning Disability, and symptoms of Nonverbal Learning Disability, accounting for 24% of the explained variance (
p < .0001). These results suggest the presence of potentially different lifelong paths to NP impairment among ASPD and non-ASPD alcoholics. Further exploration of the multivariate predictors of neuropsychological performance in subgroups of alcoholics is warranted.
Obsessive-compulsive disorder (OCD) affects 2-3% of the population. One-third of patients are poorly responsive to conventional therapies, and for a subgroup, gamma knife capsulotomy (GKC) is an ...option. We examined lesion characteristics in patients previously treated with GKC through well-established programs in Providence, RI (Butler Hospital/Rhode Island Hospital/Alpert Medical School of Brown University) and São Paulo, Brazil (University of São Paolo). Lesions were traced on T1 images from 26 patients who had received GKC targeting the ventral half of the anterior limb of the internal capsule (ALIC), and the masks were transformed into MNI space. Voxel-wise lesion-symptom mapping was performed to assess the influence of lesion location on Y-BOCS ratings. General linear models were built to compare the relationship between lesion size/location along different axes of the ALIC and above or below-average change in Y-BOCS ratings. Sixty-nine percent of this sample were full responders (≥35% improvement in OCD). Lesion occurrence anywhere within the targeted region was associated with clinical improvement, but modeling results demonstrated that lesions occurring posteriorly (closer to the anterior commissure) and dorsally (closer to the mid-ALIC) were associated with the greatest Y-BOCS reduction. No association was found between Y-BOCS reduction and overall lesion volume. GKC remains an effective treatment for refractory OCD. Our data suggest that continuing to target the bottom half of the ALIC in the coronal plane is likely to provide the dorsal-ventral height required to achieve optimal outcomes, as it will cover the white matter pathways relevant to change. Further analysis of individual variability will be essential for improving targeting and clinical outcomes, and potentially further reducing the lesion size necessary for beneficial outcomes.
Deep brain stimulation (DBS) of the anterior limb of the internal capsule has been shown to be beneficial in the short term for obsessive-compulsive disorder (OCD) patients who exhaust conventional ...therapies. Nuttin et al, who published the first DBS for OCD series, found promising results using a capsule target immediately rostral to the anterior commissure extending into adjacent ventral capsule/ventral striatum (VC/VS). Published long-term outcome data are limited to four patients. In this collaborative study, 10 adult OCD patients meeting stringent criteria for severity and treatment resistance had quadripolar stimulating leads implanted bilaterally in the VC/VS. DBS was activated openly 3 weeks later. Eight patients have been followed for at least 36 months. Group Yale-Brown Obsessive Compulsive Scale (YBOCS) scores decreased from 34.6+/-0.6 (mean+/-SEM) at baseline (severe) to 22.3+/-2.1 (moderate) at 36 months (p < 0.001). Four of eight patients had a > or =35% decrease in YBOCS severity at 36 months; in two patients, scores declined between 25 and 35%. Global Assessment of Functioning scores improved from 36.6+/-1.5 at baseline to 53.8+/-2.5 at 36 months (p < 0.001). Depression and anxiety also improved, as did self-care, independent living, and work, school, and social functioning. Surgical adverse effects included an asymptomatic hemorrhage, a single seizure, and a superficial infection. Psychiatric adverse effects included transient hypomanic symptoms, and worsened depression and OCD when DBS was interrupted by stimulator battery depletion. This open study found promising long-term effects of DBS in highly treatment-resistant OCD.
Severe hypertriglyceridemia (HTG) is a relatively common form of dyslipidemia with a complex pathophysiology and serious health complications. HTG can develop in the presence of rare genetic factors ...disrupting genes involved in the triglyceride (TG) metabolic pathway, including large-scale copy-number variants (CNVs). Improvements in next-generation sequencing technologies and bioinformatic analyses have better allowed assessment of CNVs as possible causes of or contributors to severe HTG. We screened targeted sequencing data of 632 patients with severe HTG and identified partial deletions of the LPL gene, encoding the central enzyme involved in the metabolism of TG-rich lipoproteins, in four individuals (0.63%). We confirmed the genomic breakpoints in each patient with Sanger sequencing. Three patients carried an identical heterozygous deletion spanning the 5′ untranslated region (UTR) to LPL exon 2, and one patient carried a heterozygous deletion spanning the 5′UTR to LPL exon 1. All four heterozygous CNV carriers were determined to have multifactorial severe HTG. The predicted null nature of our identified LPL deletions may contribute to relatively higher TG levels and a more severe clinical phenotype than other forms of genetic variation associated with the disease, particularly in the polygenic state. The identification of novel CNVs in patients with severe HTG suggests that methods for CNV detection should be included in the diagnostic workup and molecular genetic evaluation of patients with high TG levels.
Data from 30 elderly inpatients with major depression were analyzed to explore the relationship between subcortical hyperintensities (SH) on MRI and activities of daily living (ADLs). A comparison of ...subjects based on a median split of the severity of SH revealed that subjects with greater SH performed worse on both instrumental and physical ADLs. A hierarchical multiple regression revealed that age, depression severity, neuropsychological test performance, and SH variables accounted for a total of 53% of the variance in ADL functioning. Severity of SH accounted for an additional 18% of the variance over and above the other three variables. Results suggest that severity of subcortical disease measured by MRI improves prediction of functional impairment in elderly individuals.
White matter hyperintensities (WMHs) are frequently found on MRI studies of vascular dementia (VaD) patients. As several studies have demonstrated that WMHs are often associated with severity of ...illness, cognitive impairment, and functional decline, the accurate and reliable measurement of WMHs on MRI is an important, yet often overlooked, prerequisite for accurate interpretation of neuroimaging studies. Using a sample of 39 VaD patients, we evaluated the reliability and validity of a visual ordinal rating scale and a computer-mediated thresholding technique to evaluate WMHs. Results indicated the computer-mediated technique had slightly stronger inter-rater reliability than the visual ordinal rating scale. Furthermore, the computer-mediated thresholding technique was correlated with measures of neuropsychological functioning believed to be compromised in VaD (i.e., psychomotor speed, executive functioning) while the visual rating scale was not. Results suggest that this computer-mediated thresholding technique is superior to visual ratings of WMHs.
The ATR-CHK1 DNA damage response pathway becomes activated by the exposure of RPA-coated single-stranded DNA (ssDNA) that forms as an intermediate during DNA damage and repair, and as a part of the ...replication stress response. Here, we identify ZNF827 as a component of the ATR-CHK1 kinase pathway. We demonstrate that ZNF827 is a ssDNA binding protein that associates with RPA through concurrent binding to ssDNA intermediates. These interactions are dependent on two clusters of C2H2 zinc finger motifs within ZNF827. We find that ZNF827 accumulates at stalled forks and DNA damage sites, where it activates ATR and promotes the engagement of homologous recombination-mediated DNA repair. Additionally, we demonstrate that ZNF827 depletion inhibits replication initiation and sensitizes cancer cells to the topoisomerase inhibitor topotecan, revealing ZNF827 as a therapeutic target within the DNA damage response pathway.
Parkinson's disease (PD) is often accompanied by stigma, which could contribute to a worse prognosis. The objective of this study is to identify the variables associated with stigma in PD patients ...who are candidates for deep brain stimulation (DBS).
We investigated sociodemographic and clinical variables associated with stigma in a sample of 54 PD patients indicated for DBS. The independent variables were motor symptoms assessed by the Movement Disorder Society-sponsored revision of the Unified Parkinson Disease Rating Scale (MDS-UPDRS III), depressive symptoms measured by the Hospital Anxiety and Depression Scale, age, disease duration and the presence of a general medical condition. The Mobility, Activities of daily living and Emotional well-being domains of the 39-item Parkinson's Disease Questionnaire (PDQ-39) were also investigated as independent variables, and the Stigma domain of the PDQ-39 scale was considered the outcome variable.
After multiple linear regression analysis, activities of daily living remained associated with the Stigma domain (B = 0.42 95%CI 0.003-0.83, p = 0.048). The full model accounted for 15% of the variance in the Stigma domain (p = 0.03).
Although causal assumptions are not appropriate for cross-sectional studies, the results suggest that ADL difficulties could contribute to greater stigma in PD patients with refractory motor symptoms who are candidates for DBS.
•Patients with head and neck cancer experience substantial financial toxicity.•Younger age is predictive of worse financial toxicity.•Lower median household income by county is predictive of worse ...financial toxicity.•Financial toxicity is associated with increased feeding tube rates and infusions.•1/3 of patients endorse moderate, significant, or catastrophic financial burdens.
Financial toxicity (FT) is a significant barrier to high-quality cancer care, and patients with head and neck cancer (HNCA) are particularly vulnerable given their need for intensive support, daily radiotherapy (RT), and management of long-term physical, functional, and psychosocial morbidities following treatment. We aim to identify predictors of FT and adverse consequences in HNCA following RT.
We performed a prospective survey study of patients with HNCA seen in follow-up at an academic comprehensive cancer center (CCC) or Veterans Affairs hospital between 05/2016 and 06/2018. Surveys included validated patient-reported functional outcomes and the COST measure, a validated instrument for measuring FT.
The response rate was 86% (n = 63). Younger age and lower median household income by county were associated with lower COST scores (i.e., worse FT) on multivariable analysis (p = .045 and p = .016, respectively). Patients with worse FT were more likely to skip clinic visits (RR (95% CI) 2.13 (1.23–3.67), p = .007), be noncompliant with recommended supplements or medications (1.24 (1.03–1.48), p = .02), and require supportive infusions (1.10 (1.02–1.20), p = .02). At the CCC, patients with worse FT were more likely to require feeding tubes (1.62 (1.14–2.31), p = .007). Overall, 36% reported that costs were higher than expected, 48% were worried about paying for treatment, and 33% reported at least a moderate financial burden from treatment.
HNCA patients experience substantial FT from their diagnosis and/or therapy, with potential implications for medical compliance, QOL, and survivorship care.
IMPORTANCE: The identification of a patient with a rare form of severe dysbetalipoproteinemia allowed the study of the consequences of total absence of apolipoprotein E (apoE). OBJECTIVES: To ...discover the molecular basis of this rare disorder and to determine the effects of complete absence of apoE on neurocognitive and visual function and on lipoprotein metabolism. DESIGN, SETTING, AND PARTICIPANTS: Whole-exome sequencing was performed on the patient’s DNA. He underwent detailed neurological and visual function testing and lipoprotein analysis. Lipoprotein analysis was also performed in the Cardiovascular Research Institute, University of California, San Francisco, on blood samples from the proband’s mother, wife, 2 daughters, and normolipidemic control participants. MAIN OUTCOME MEASURES: Whole-exome sequencing, lipoprotein analysis, and neurocognitive function. RESULTS: The patient was homozygous for an ablative APOE frameshift mutation (c.291del, p.E97fs). No other mutations likely to contribute to the phenotype were discovered, with the possible exception of two, in ABCC2 (p.I670T) and LIPC (p.G137R). Despite complete absence of apoE, he had normal vision, exhibited normal cognitive, neurological, and retinal function, had normal findings on brain magnetic resonance imaging, and had normal cerebrospinal fluid levels of β-amyloid and tau proteins. He had no significant symptoms of cardiovascular disease except a suggestion of myocardial ischemia on treadmill testing and mild atherosclerosis noted on carotid ultrasonography. He had exceptionally high cholesterol content (760 mg/dL; to convert to millimoles per liter, multiply by 0.0259) and a high cholesterol to triglycerides ratio (1.52) in very low-density lipoproteins with elevated levels of small-diameter high-density lipoproteins, including high levels of prebeta-1 high-density lipoprotein. Intermediate-density lipoproteins, low-density lipoproteins, and very low-density lipoproteins contained elevated apoA-I and apoA-IV levels. The patient’s apoC-III and apoC-IV levels were decreased in very low-density lipoproteins. Electron microscopy revealed large lamellar particles having electron-opaque cores attached to electron-lucent zones in intermediate-density and low-density lipoproteins. Low-density lipoprotein particle diameters were distributed bimodally. CONCLUSIONS AND RELEVANCE: Despite a profound effect on lipoprotein metabolism, detailed neurocognitive and retinal studies failed to demonstrate any defects. This suggests that functions of apoE in the brain and eye are not essential or that redundant mechanisms exist whereby its role can be fulfilled. Targeted knockdown of apoE in the central nervous system might be a therapeutic modality in neurodegenerative disorders.
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