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Preoperative type and screen (TS) is routinely performed before elective thoracic surgery. We sought to evaluate the utility of this practice by examining our institutional data related to intraoperative and postoperative transfusions for two common, complex procedures.A single-center, retrospective review of a prospective thoracic surgery database was performed. Patients who underwent consecutive elective anatomic lung resection (ALR) and esophagectomy from January 2015 to April 2018 were included. Perioperative characteristics between patients who received transfusion of packed red blood cells and those who did not were compared. The rates of emergent and nonemergent transfusions were evaluated. Cost data were derived from institutional charges and Centers for MedicareMedicaid Services fee schedules.Of 370 patients, 16 (4.3%) received a transfusion and four (1.1%) were deemed emergent by the surgeons and 0 (0%) by blood bank criteria. For ALR (n = 321), 13 (4.0%) received a transfusion, and four (1.2%) were emergent. For esophagectomies (n = 49), three (6.1%) received a transfusion, and none were emergent. Patients who underwent ALR requiring a transfusion had a lower preoperative hemoglobin (11.7 versus 13.4 gm/dL, P = 0.001), higher estimated blood loss (1325 versus 196 mL, P 0.001), and longer operative time (291 versus 217 min, P = 0.003) than nontransfused patients. Based on current volumes, eliminating TS in these patients would save at least an estimated $60,100 per year.Emergent transfusion in ALR and esophagectomy is rare. Routine preoperative TS is most likely unnecessary for these cases. These results will be used in a quality improvement initiative to change practice at our institution.

Vitreoretinal mechanics plays an important role in retinal trauma and many sight-threatening diseases. In age-related pathologies, such as posterior vitreous detachment and vitreomacular traction, lingering vitreoretinal adhesions can lead to macular holes, epiretinal membranes, retinal tears and detachment. In age-related macular degeneration, vitreoretinal traction has been implicated in the acceleration of the disease due to the stimulation of vascular growth factors. Despite this strong mechanobiological influence on trauma and disease in the eye, fundamental understanding of the mechanics at the vitreoretinal interface is limited. Clarification of adhesion mechanisms and the role of vitreoretinal mechanics in healthy eyes and disease is necessary to develop innovative treatments for these pathologies. In this review, we evaluate the existing literature on the structure and function of the vitreoretinal interface to gain insight into age- and region-dependent mechanisms of vitreoretinal adhesion. We explore the role of vitreoretinal adhesion in ocular pathologies to identify knowledge gaps and future research areas. Finally, we recommend future mechanics-based studies to address the critical needs in the field, increase fundamental understanding of vitreoretinal mechanisms and disease, and inform disease treatments.

Background Smoking cessation programs for patients with cancer suggest 6-mo quit rates between 22% and 40%, and 1-y rates of 33%. We sought to investigate the long-term outcomes of an intensive, preoperative smoking cessation program in patients undergoing lung resection. Material and methods A retrospective analysis of an IRB-approved, prospective database was performed. Elective lung resections between January 1, 2015 and June 30, 2017 were identified. Demographics, smoking status, pack years, occurrence of smoking cessation counseling, complications, and quit date were obtained. Smoking cessation included face-to-face motivational interviewing, choice of nicotine replacement therapy, discussion that surgery may be canceled or delayed without cessation, and follow-up as needed. Results A total of 340 patients underwent lung resection. Of these, 82 patients were classified as current smokers. All were advised to quit and encouraged to meet with a certified tobacco treatment specialist. Sixty-three patients met with a tobacco treatment specialist and 19 did not. Overall, 60 patients (73%) were able to quit before surgery. At 2 y postoperatively, 15 (18%) were lost to follow-up and 9 (11%) had died. Excluding deaths and censoring those lost to follow-up, cessation rates at 6, 12, and 24 mo postoperatively were 55.3%, 55.6%, and 51.7%, respectively. Conclusions Implementation of an intensive smoking cessation program in the preoperative period demonstrated high initial, mid-term, and long-term success rates. The preoperative period, particularly one centered around lung cancer, is an effective time for smoking cessation intervention and can lead to a high rate of cessation up to 2 y after surgery.

The extraordinary demands of managing the COVID-19 pandemic has disrupted the world's ability to care for patients with thoracic malignancies. As a hospital's COVID-19 population increases and hospital resources are depleted, the ability to provide surgical care is progressively restricted, forcing surgeons to prioritize among their cancer populations. Representatives from multiple cancer, surgical, and research organizations have come together to provide a guide for triaging patients with thoracic malignancies as the impact of COVID-19 evolves as each hospital.

Dual-task gait can be a useful biomarker for cognitive decline and a sensitive predictor of future neurodegeneration in certain clinical populations, such as patients with idiopathic rapid eye movement sleep behavior disorder. Objectives The objective of this cross-sectional study was to determine the neural signature of dual-tasking deficits in idiopathic rapid eye movement sleep behavior disorder using a validated gait paradigm. Methods Fifty-eight participants (28 controls; 30 idiopathic rapid eye movement sleep behavior disorder patients) were recruited; 52 participants had functional MRI scans as they performed a validated dual-task virtual reality gait paradigm using foot pedals. Forty-one participants completed single- and dual-task "overground walking" on a pressure sensor carpet. Results Idiopathic rapid eye movement sleep behavior disorder patients showed deficits in dual-tasking (i.e., greater mean step time) compared to controls during "overground walking." Functional MRI revealed that idiopathic rapid eye movement sleep behavior disorder patients had reduced blood-oxygen-level-dependent signal change in the dorsal caudate nucleus, and significantly different corticostriatal functional connectivity patterns from controls, when dual-tasking in high versus low cognitive load. While controls showed greater connectivity between frontoparietal and motor networks, idiopathic rapid eye movement sleep behavior disorder patients exhibited less change in this connectivity as a function of cognitive load. Conclusions These findings demonstrate evidence of dual-task gait deficits in idiopathic rapid eye movement sleep behavior disorder patients, underpinned by disrupted corticostriatal connectivity. Minimal differences in the level of functional connectivity between dual-tasking conditions of high and low cognitive load suggest that idiopathic rapid eye movement sleep behavior disorder patients recruit cognitive networks to control gait even when the cognitive demands are low. This may indicate a compensatory strategy for early cognitive decline in idiopathic rapid eye movement sleep behavior disorder. © 2020 International Parkinson and Movement Disorder Society.

Background Routine chest x-rays (CXRs) ordered on thoracic surgery inpatients are common, costly, and of unclear clinical utility. We sought to investigate CXR ordering practices and their impact on clinical care. Materials and methods A single-center, retrospective cohort study of adult patients admitted after undergoing thoracic surgery with an intraoperative chest tube (CT) placed was performed over a 1-y period. Our primary outcome was a CXR-driven change in care. We evaluated routine CXR orders immediately after surgery in the postanesthesia care unit (PACU) and after final CT removal. “Routine” was defined as not ordered during a workup for a clinical concern. Patients were excluded if they underwent pleurodesis, were discharged with a CT, or had an immediate post-CT removal clinical change prompting intervention. Results A total of 241 patients met inclusion. All patients received a routine PACU CXR, and 48% (117) had abnormal radiographic findings (e.g., pneumothorax, consolidation, effusion, etc). Secondary to this CXR, one patient (0.4%) experienced a change in care: a repeat CXR only. All patients received a routine final CT removal CXR, and 58% (140) had abnormal radiographic findings. After this CXR, 33 patients (14%) experienced a change in care: 32 underwent repeat CXR and one was clinically observed. Overall, no patients experienced a procedural intervention. Conclusions Routine post-thoracic surgery CXRs in the PACU and after CT removal have limited clinical impact. Quality initiatives should be pursued to decrease empiric CXR use and reserve ordering for specific clinical concerns.

Vaccine hesitancy is a significant impediment to global efforts to vaccinate against the SARS-CoV-2 virus at levels that generate herd immunity. In this article, we show the utility of an inductive approach – latent class analysis (LCA) – that allows us to characterize the size and nature of different vaccine attitude groups; and to compare how these groups differ across countries as well as across demographic subgroups within countries. We perform this analysis using original survey data collected in the US, UK, and Canada. We also show that these classes are strongly associated with SARS-CoV-2 vaccination intent and perceptions of the efficacy and safety of the COVID-19 vaccines, suggesting that attitudes about vaccines to fight the novel coronavirus pandemic are well explained by latent vaccine attitudes that precede the pandemic. More specifically, we find four substantive classes of vaccine attitudes: strong supporters, supporters with concerns, vaccine hesitant, and “anti-vax” as well as a fifth measurement error class. The strong “anti-vax” sentiment class is small in all three countries, while the strong supporter class is the largest across all three countries. We observe different distributions of class assignments in different demographic groups – most notably education and political leaning (partisanship and ideology).

Background: Motor impairments in those with isolated REM sleep behaviour disorder (iRBD) significantly increases the likelihood of developing Lewy body disease (e.g. Parkinson’s disease and Dementia with Lewy Bodies). Objective: This study sought to explore the prodromal process of neurodegeneration by examining the neural signature underlying motor deficits in iRBD patients. Methods: A virtual reality (VR) gait paradigm (which has previously been shown to elicit adaptive changes in gait performance whilst navigating doorways in Parkinson’s Disease - PD) was paired with fMRI to investigate whether iRBD patients demonstrated worsened motor performance and altered connectivity across frontoparietal, motor and basal ganglia networks compared to healthy controls. Forty participants (23 iRBD and 17 healthy controls) completed the virtual reality gait task whilst in the MRI scanner, and an additional cohort of 19 Early PD patients completed the behavioural virtual reality gait task. Results: As predicted, iRBD patients demonstrated slower and more variable stepping compared to healthy control participants and demonstrated an exaggerated response when navigating narrow compared to wide doorways, a phenomenon characteristically seen in PD. The iRBD patients also demonstrated less BOLD signal change in the left posterior putamen and right mesencephalic locomotor region, as well as reduced functional connectivity between the frontoparietal network and the motor network, when navigating narrow versus wide doorways compared to healthy control participants. Conclusions: Taken together, this study demonstrates that iRBD patients have altered task-related brain connectivity, which may represent the neural underpinnings of early motor impairments that are evident in iRBD.

Widespread misperceptions about COVID-19 and the novel coronavirus threaten to exacerbate the severity of the pandemic. We conducted preregistered survey experiments in the United States, Great Britain and Canada examining the effectiveness of fact-checks that seek to correct these false or unsupported beliefs. Across three countries with differing levels of political conflict over the pandemic response, we demonstrate that fact-checks reduce targeted misperceptions, especially among the groups who are most vulnerable to these claims, and have minimal spillover effects on the accuracy of related beliefs. However, these reductions in COVID-19 misperception beliefs do not persist over time in panel data even after repeated exposure. These results suggest that fact-checks can successfully change the COVID-19 beliefs of the people who would benefit from them most but that their effects are ephemeral.

There is emerging evidence indicating that color discrimination impairments can predict the development of Lewy body dementia in patients with rapid eye movement sleep behavior disorder, Parkinson disease, and in patients with mild cognitive impairment. Despite this clear relationship, color vision deficits are not seen uniformly in patients with dementia with Lewy bodies (DLB), suggesting a more nuanced association with the underlying neuropathology. Visual hallucinations represent a discriminating feature of DLB, and recent evidence implicates visual pathway dysfunction as a significant contributor to this phenomenon. In this study, we examined the relationship between color vision impairment and visual hallucinations, along with other clinical and neuropsychological features in 24 well-characterized patients with DLB alongside 25 healthy controls. Color discrimination impairment was seen in 16 (67%) of 24 DLB participants with a higher error score relative to controls ( P = .001). We demonstrate for the first time a strong association between color discrimination errors on the Farnsworth-Munsell 100 hue test and both the presence and severity of hallucinatory symptoms in DLB based on clinician-derived ( P = .008) and questionnaire-derived ( P = .03) measures. Correlation with clinical and neuropsychological variables revealed that color discrimination is significantly related to visuospatial difficulties measured by the clock-drawing task ( P = .02) but not to global measures of cognition, motor severity, age, or disease duration in our cohort. Factor analysis confirmed a unique relationship between color discrimination, visual hallucinations, and visuospatial function. Our results suggest that color discrimination does not simply relate to dementia but rather indexes higher order perceptual deficits that may predict visual hallucinations in Lewy body disorders and share a common pathophysiological substrate.

Pulmonary metastasectomy for colorectal cancer is an established means of treatment for select patients. This article will highlight the recent evidence published in the literature related to current practices for the surgical management of colorectal lung metastases and propose a diagnostic algorithm for use in clinical practice. It will also discuss controversies related to pulmonary metastasectomy, including the optimal timing of surgery, the extent of lymph node sampling/dissection, and the extent of surgical resection.

The programmed cell death 1 (PD-1) pathway represents a major immune checkpoint which may be engaged by cells in a tumor microenvironment to overcome active T-cell immune surveillance. Pembrolizumab (Keytruda®) is a potent and highly selective humanized monoclonal antibody (mAb) of the IgG4/κ isotype designed to directly block the interaction between PD-1 and its ligands, PD-L1 and PD-L2. The current work was focused on developing a mouse T-Dependent Antibody Response (TDAR) model using a murinized rat anti-mouse PD-1 antibody (muDX400; a rodent surrogate for pembrolizumab) to evaluate the potential impact of treatment with a PD-1 inhibitor on immune responses to an antigen challenge (e.g. HBsAg in Hepatitis B vaccine). Despite the lower binding affinity and T1/2 compared to pembrolizumab, ligand blocking data indicated muDX400 had appropriate pharmacological activity and demonstrated efficacy in mouse tumor models, thus was suitable for pharmacodynamic and vaccination studies in mice. In a vaccination study in which mice were concomitantly administered muDX400 and the Hepatitis B vaccine, muDX400 was well-tolerated and did not result in any immune-mediated adverse effects. The treatment with muDX400 was associated with a shift in the ratio between naive and memory cells in both CD4+ and CD8+ T-lymphocytes in the spleen but did not affect anti-HBsAg antibody response profile. The mouse TDAR model using the Hepatitis B vaccine and the surrogate anti-PD1 monoclonal antibody was a useful tool in the evaluation of the potential immune-mediated effects of pembrolizumab following vaccination and appears to be a suitable alternative for the nonhuman primate TDAR models utilized for other checkpoint inhibitors.

The nature of the anti-tumor immune response changes as primary tumors progress and metastasize. We investigated the role of resident memory (Trm) and circulating memory (Tcirm) cells in anti-tumor responses at metastatic locations using a mouse model of melanoma-associated vitiligo. We found that the transcriptional characteristics of tumor-specific CD8+ T cells were defined by the tissue of occupancy. Parabiosis revealed that tumor-specific Trm and Tcirm compartments persisted throughout visceral organs, but Trm cells dominated lymph nodes (LNs). Single cell RNA sequencing profiles of LN Trm and skin Trm cells in LN and skin were distinct, but shared clonotypes that occupied both tissues were preferentially overwhelmingly maintained as Trm in LNs. Whereas Tcirm cells prevented melanoma growth in the lungs, Trm afforded long-lived protection against melanoma seeding in LNs. Expanded Trm populations were also present in melanoma-involved LNs from patients, and their transcriptional signature predicted better survival. Thus tumor-specific Trm cells persist in LNs, restricting metastatic cancer.

Background Rural populations face many health disadvantages compared to urban areas. There is a critical need to better understand the current lung cancer screening landscape in these communities to identify targeted areas to improve the impact of this proven tool. Methods Data from the County Health Rankings of New Hampshire and Vermont was reviewed for population density, distribution of adult smokers, and level of education compared to the distribution of Lung Cancer Screening Facilities throughout these two states. Results Screening programs in southern counties of Vermont with lower levels of education have decreased access. In New Hampshire, there are no programs within 30 miles of the areas with the largest distribution of smokers, and decreased access in some areas with the lowest levels of education. Conclusions Improving equitable access to high-quality screening services in rural regions and the creation of targeted interventions to address decreased access in areas of high tobacco use and low education is vital to decreasing the incidence of latestage presentations of lung cancer within these populations.

Background Rural populations face many health disadvantages including higher rates of tobacco use and lung cancer than more populated areas. Given this, we specifically sought to understand the current screening landscape in a cohort of patients with resected lung cancer to help direct improvements in the screening process. Materials and methods We retrospectively reviewed our prospective database at a rural, quaternary, academic institution from January 2015 to June 2018. All patients who underwent resection for primary lung cancer were studied to assess the frequency of preoperative low-dose chest computed tomography per accepted guidelines. The intent was to evaluate participant demographics, clinical stage, frequency, and distribution of Lung-RADS reporting. Results About 446 patients underwent primary resection, of which 252 were deemed screening-eligible. About 57 (22.6%) underwent low-dose chest computed tomography screening and 195 (77.4%) did not. No significant demographic differences were identified between groups. However, 82.5% (47/57) of the screened patients presented with clinical stage IA disease, compared with 67.1% (131/195) of the nonscreened patients (P = 0.03). Among those screened, 36.8% (21/57) did not have a Lung-RADS score documented despite 52.3% (11/21) of those coming from accredited programs. Conclusions Our screening completion rate was only 22.6% of eligible patients and 36.8% of those patients did not have a documented Lung-RADS score. These findings, in combination with the increased rate of diagnosis of stage IA disease, provide compelling reasons to further investigate factors designed to improve access and screening practices at rural institutions.

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Cognitive fluctuations (CFs) are a core diagnostic feature of dementia with Lewy bodies (DLB). Detection of CF is still mostly based on subjective reports from the patient or informant; more quantitative measures are likely to improve the accuracy for the diagnosis of DLB. The purpose of the current study is to test whether performance on the Sustained Attention Response Task (SART) could distinguish those patients with DLB with and without CF. Twenty-four patients with DLB were tested on the SART and performance was related to scores on the Clinical Assessment of Fluctuations (CAFs) and One Day Fluctuation Assessment Scale (ODFAS). The number of “misses” made was a significant predictor of their fluctuation severity, attentional performance, disorganized thinking, and language production ratings on the ODFAS. However, measures on the SART did not correlate with measures on the CAF scale. In conclusion, these findings suggest that SART is a feasible measure of sustained attention in this population and has clinical and diagnostic relevance to the measurement of CF, particularly those aspects measured by the ODFAS.

A 49-year-old woman with a medical history of essential hypertension presented to the ED with severe pain in the left superior chest and dull aching pain in the upper flank, lasting for the last 2 days.

Objective Although previous studies have identified variation in quality lung cancer care, existing quality metrics may not fully capture the complexity of cancer care. The Thoracic Surgery Outcomes Research Network recently developed quality measures to address this. We evaluated baseline adherence to these measures and identified factors associated with adherence. Methods Patients with pathologic stage I and II non–small cell lung cancer from 2010 to 2015 were identified in the National Cancer Database. Patient-level and hospital-level adherence to 7 quality measures was calculated. Goal hospital adherence threshold was 85%. Factors influencing adherence were identified using multilevel logistic regression. Results We identified 253,182 patients from 1324 hospitals. Lymph node sampling was performed in 91% of patients nationally, but only 76% of hospitals met the 85% adherence mark. Similarly, 89% of T1b (seventh edition staging) tumors had anatomic resection, with 69% hospital-level adherence. Sixty-nine percent of pathologic stage II patients were recommended chemotherapy, with only 23% hospitals adherent. Eighty-three percent of patients had biopsy before primary radiation, with 64% hospitals adherent. Higher volume and academic institutions were associated with nonadherence to adjuvant chemotherapy and radiation therapy measures. Conversely, lower volume and nonacademic institutions were associated with inadequate nodal sampling and nonanatomic resection. Conclusions Significant gaps continue to exist in the delivery of quality care to patients with early-stage lung cancer. High-volume academic hospitals had higher adherence for surgical care measures, but lower rates for coordination of care measures. This requires further investigation, but suggests targets for quality improvement may vary by institution type.

Parkinson’s disease (PD) is primarily a motor disorder that involves the gradual loss of motor function. Symptoms are observed initially in the extremities, such as hands and arms, while advanced stages of the disease can effect blinking, swallowing, speaking, and breathing. PD is a neurodegenerative disease, with dopaminergic neuronal loss occurring in the substantia nigra pars compacta, thus disrupting basal ganglia functions. This leads to downstream effects on other neurotransmitter systems such as glutamate, γ-aminobutyric acid, and serotonin. To date, one of the main treatments for PD is levodopa. While it is generally very effective, prolonged treatments lead to levodopa-induced dyskinesia (LID). LID encompasses a family of symptoms ranging from uncontrolled repetitive movements to sustained muscle contractions. In many cases, the symptoms of LID can cause more grief than PD itself. The purpose of this review is to discuss the possible clinical features, cognitive correlates, neural substrates, as well as potential psychopharmacological and surgical (including nondopaminergic and deep brain stimulation) treatments of LID.

Mesenchymal stem cells (MSCs) are promising candidates for cell-based therapy to treat several diseases and are compelling to consider as vehicles for delivery of biological agents. However, MSCs appear to act through a seemingly limited "hit-and-run" mode to quickly exert their therapeutic impact, mediated by several mechanisms, including a potent immunomodulatory secretome. Furthermore, MSC immunomodulatory properties are highly variable and the secretome composition following infusion is uncertain. To determine whether a transiently controlled antiinflammatory MSC secretome could be achieved at target sites of inflammation, we harnessed mRNA transfection to generate MSCs that simultaneously express functional rolling machinery (P-selectin glycoprotein ligand-1 [PSGL-1] and Sialyl-Lewis(x) [SLeX]) to rapidly target inflamed tissues and that express the potent immunosuppressive cytokine interleukin-10 (IL-10), which is not inherently produced by MSCs. Indeed, triple-transfected PSGL-1/SLeX/IL-10 MSCs transiently increased levels of IL-10 in the inflamed ear and showed a superior antiinflammatory effect in vivo, significantly reducing local inflammation following systemic administration. This was dependent on rapid localization of MSCs to the inflamed site. Overall, this study demonstrates that despite the rapid clearance of MSCs in vivo, engineered MSCs can be harnessed via a "hit-and-run" action for the targeted delivery of potent immunomodulatory factors to treat distant sites of inflammation.

Cancer stem cells (CSC) represent a malignant subpopulation of cells in hierarchically organized tumors. They constitute a sub-population of malignant cells within a tumor mass and possess the ability to self-renew giving rise to heterogeneous tumor cell populations with a complex set of differentiated tumor cells. CSC may be the cause of metastasis and therapeutic refractory disease. Because few markers exist to identify and isolate pure CSC, we used cell-based Systematic Evolution of Ligands by EXponential enrichment (cell-SELEX) to create DNA aptamers that can identify novel molecular targets on the surfaces of live CSC. Out of 22 putative DNA sequences, 3 bound to ~90% and 5 bound to ~15% of DU145 prostate cancer cells. The 15% of cells that were positive for the second panel of aptamers expressed high levels of E-cadherin and CD44, had high aldehyde dehydrogenase 1 activity, grew as spheroids under non-adherent culture conditions, and initiated tumors in immune-compromised mice. The discovery of the molecular targets of these aptamers could reveal novel CSC biomarkers.

Gastric cancer is common worldwide. Tumor location and disease stage differ between Asian and Western countries. Western patients often have higher BMIs and comorbidities that may make laparoscopic resections challenging. Multiple trials from Asian countries demonstrate the benefits of laparoscopic gastrectomy for early gastric cancer while maintaining equivalent short-term and long-term oncologic outcomes compared with open surgery. The outcomes of laparoscopy seem to offer equivalent results to open surgery. In the United States, laparoscopic gastrectomy remains in its infancy and is somewhat controversial. This article summarizes the literature on the epidemiology, operative considerations and approaches, and outcomes for laparoscopic gastrectomy.

Capture and isolation of flowing cells and particulates from body fluids has enormous implications in diagnosis, monitoring, and drug testing, yet monovalent adhesion molecules used for this purpose result in inefficient cell capture and difficulty in retrieving the captured cells. Inspired by marine creatures that present long tentacles containing multiple adhesive domains to effectively capture flowing food particulates, we developed a platform approach to capture and isolate cells using a 3D DNA network comprising repeating adhesive aptamer domains that extend over tens of micrometers into the solution. The DNA network was synthesized from a microfluidic surface by rolling circle amplification where critical parameters, including DNA graft density, length, and sequence, could readily be tailored. Using an aptamer that binds to protein tyrosine kinase-7 (PTK7) that is overexpressed on many human cancer cells, we demonstrate that the 3D DNA network significantly enhances the capture efficiency of lymphoblast CCRF-CEM cells over monovalent aptamers and antibodies, yet maintains a high purity of the captured cells. When incorporated in a herringbone microfluidic device, the 3D DNA network not only possessed significantly higher capture efficiency than monovalent aptamers and antibodies, but also outperformed previously reported cell-capture microfluidic devices at high flow rates. This work suggests that 3D DNA networks may have broad implications for detection and isolation of cells and other bioparticles.

Postural instability (PI) is one of the most debilitating motor symptoms of Parkinson’s disease (PD), as it is associated with an increased risk of falls and subsequent medical complications (e.g. fractures), fear of falling, decreased mobility, self-restricted physical activity, social isolation, and decreased quality of life. The pathophysiological mechanisms underlying PI in PD remain elusive. This short review provides a critical summary of the literature on PI in PD, covering the clinical features, the neural and cognitive substrates, and the effects of dopaminergic medications and deep brain stimulation. The delayed effect of dopaminergic medication combined with the success of extrastriatal deep brain stimulation suggests that PI involves neurotransmitter systems other than dopamine and brain regions extending beyond the basal ganglia, further challenging the traditional view of PD as a predominantly single-system neurodegenerative disease.

Monitoring the location, distribution and long-term engraftment of administered cells is critical for demonstrating the success of a cell therapy. Among available imaging-based cell tracking tools, magnetic resonance imaging (MRI) is advantageous due to its noninvasiveness, deep penetration, and high spatial resolution. While tracking cells in preclinical models via internalized MRI contrast agents (iron oxide nanoparticles, IO-NPs) is a widely used method, IO-NPs suffer from low iron content per particle, low uptake in nonphagocytotic cell types (e.g., mesenchymal stem cells, MSCs), weak negative contrast, and decreased MRI signal due to cell proliferation and cellular exocytosis. Herein, we demonstrate that internalization of IO-NP (10 nm) loaded biodegradable poly(lactide-co-glycolide) microparticles (IO/PLGA-MPs, 0.4-3 μm) in MSCs enhances MR parameters such as the r(2) relaxivity (5-fold), residence time inside the cells (3-fold) and R(2) signal (2-fold) compared to IO-NPs alone. Intriguingly, in vitro and in vivo experiments demonstrate that internalization of IO/PLGA-MPs in MSCs does not compromise inherent cell properties such as viability, proliferation, migration and their ability to home to sites of inflammation.

Parkinson’s disease (PD) is characterized by a range of motor symptoms. Besides the cardinal symptoms (tremor, bradykinesia/akinesia, and rigidity), PD patients also show other motor deficits, including gait disturbance, speech deficits, and impaired handwriting. However, along with these key motor symptoms, PD patients also experience cognitive deficits in attention, executive function, working memory, and learning. Recent evidence suggests that these motor and cognitive deficits of PD are not completely dissociable, as aspects of cognitive dysfunction can impact motor performance in PD. In this article, we provide a review of behavioral and neural studies on the associations between motor symptoms and cognitive deficits in PD, specifically akinesia/bradykinesia, tremor, gait, handwriting, precision grip, and speech production. This review paves the way for providing a framework for understanding how treatment of cognitive dysfunction, for example cognitive rehabilitation programs, may in turn influence the motor symptoms of PD.

Mechanistic insights into visual hallucinations (VH) in Parkinson’s disease (PD) have suggested a role for impaired attentional processes. The current study tested 25 PD patients with and 28 PD patients without VH on the attentional network test. Hallucinators had significantly lower accuracy rates compared to non-hallucinators, but no differences were found in reaction times. This suggests that hallucinators show deficits in attentional processes and conflict monitoring. Our findings provide novel behavioural insights that dovetail with current neurobiological frameworks of VH.

The rational design of DNA/RNA aptamers for use as molecular probes depends on a clear understanding of their structural elements in relation to target-aptamer binding interactions. We present a simple method to create aptamer probes that can occupy two different structural states. Then, based on the difference in binding affinity between these states, target-aptamer binding interactions can be elucidated. The basis of our two-state system comes from the incorporation of azobenzene within the DNA strand. Azobenzene can be used to photo-regulate the melting of DNA-duplex structures. When incorporated into aptamers, the light-regulated conformational change of azobenzene can be used to analyze how aptamer secondary structure is involved in target binding. Azobenzene modified aptamers showed no change in target selectivity, but showed differences in binding affinity as a function of the number, position, and conformation of azobenzene modifications. Aptamer probes that can change binding affinity on demand may have future uses in targeted drug delivery and photodynamic therapy.

Measuring distances at molecular length scales in living systems is a significant challenge. Methods like Förster resonance energy transfer (FRET) have limitations due to short detection distances and strict orientations. Recently, surface energy transfer (SET) has been used in bulk solutions; however, it cannot be applied to living systems. Here, we have developed an SET nanoruler, using aptamer-gold nanoparticle conjugates with different diameters, to monitor the distance between binding sites of a receptor on living cells. The nanoruler can measure separation distances well beyond the detection limit of FRET. Thus, for the first time, we have developed an effective SET nanoruler for live cells with long distance, easy construction, fast detection, and low background. This is also the first time that the distance between the aptamer and antibody binding sites in the membrane protein PTK7 was measured accurately. The SET nanoruler represents the next leap forward to monitor structural components within living cell membranes.

We report an aptamer-nanoparticle strip biosensor (ANSB) for the rapid, specific, sensitive and low-cost detection of circulating cancer cells. Known for their high specificity and affinity, aptamers were first selected from live cells by the cell-SELEX (systematic evolution of ligands by exponential enrichment) process. When next combined with the unique optical properties of gold nanoparticles (Au-NPs), ANSBs were prepared on a lateral flow device. Ramos cells were used as a model target cell to demonstrate proof of principle. Under optimal conditions, the ANSB was capable of detecting a minimum of 4000 Ramos cells without instrumentation (visual judgment) and 800 Ramos cells with a portable strip reader within 15 minutes. Importantly, ANSB has successfully detected Ramos cells in human blood, thus providing a rapid, sensitive and low-cost quantitative tool for the detection of circulating cancer cells. ANSB therefore shows great promise for in-field and point-of-care cancer diagnosis and therapy.

The ability to inhibit an enzyme in a specific tissue with high spatial resolution combined with a readily available antidote should find many biomedical applications. We have accomplished this by taking advantage of the cis–trans photoisomerization of azobenzene molecules. Specifically, we positioned azobenzene moieties within the DNA sequence complementary to a 15-base-long thrombin aptamer and then linked the azobenzene-modified cDNA to the aptamer by a polyethylene glycol (PEG) linker to make a unimolecular conjugate. During the photoisomerization of azobenzene by visible light, the inhibition of thrombin is disabled because the probe hybridizes with the cDNA in the trans -azobenzene conformation so that the aptamer cannot bind its target thrombin. However, when UV light is applied, melting of the hairpin structure (duplex) is induced via trans- to- cis conversion, thereby changing conformation of the aptamer and making the aptamer free to bind to and inhibit its target thrombin. By using standard clotting assays, we measured the IC 200 of various probe designs in both states and concluded the feasibility of using photon energy to temporally and spatially regulate these enzymatic reactions. Thus, we can report the development of DNA probes in the form of photon-controllable (thrombin) inhibitors, termed PCIs, and we expect that this approach will be highly beneficial in future biomedical and pharmaceutical applications.

The conjugation of antitumor drugs to targeting reagents such as antibodies is a promising method that can increase the efficacy of chemotherapy and reduce their overall toxicity. In this paper, we covalently link an antitumor agent doxorubicin (Dox) to the DNA aptamer sgc8c, which was selected by the cell-SELEX method. In doing so, we expected that this sgc8c-Dox conjugate would specifically kill the target CCRF-CEM (T-cell Acute Lymphoblastic Leukemia, T-cell ALL) cells, but with minimal toxicity towards non-target cells. The results demonstrated that sgc8c-Dox conjugate possesses many of the properties of the sgc8c aptamer, including high binding affinity (Kd = 2.0 ± 0.2 nM), and the capability to be efficiently internalized by target cells. Moreover, due to the specific conjugation method, the acid-labile linkage connecting the sgc8c-Dox conjugate can be cleaved inside the acidic endosomal environment. Cell viability tests demonstrate that the sgc8c-Dox conjugates not only possess potency similar to the unconjugated Dox, but also have the required molecular specificity which is lacking in most current targeted drug delivery strategies. Furthermore, we found that nonspecific uptake of membrane-permeable Dox to non-target cell lines could also be inhibited by linking the drug with the aptamer, thus, it makes the conjugates selective to the cells which express higher amounts of target proteins. Compared to the less effective reported Dox-immunoconjugates, this sgc8c-Dox conjugates make targeted chemotherapy more feasible with drugs having various potencies. When combined with the large number of recently created DNA aptamers that specifically target a wide variety of cancer cells, this drug-aptoconjugation method will have broad implications for targeted drug delivery.

Cell surface proteins can play important roles in cancer pathogenesis. Comprehensive understanding of the surface protein expression patterns of tumor cells and, consequently, the pathogenesis of tumor cells, depends on molecular probes against these proteins. To be effectively used for tumor diagnosis, classification and therapy, such probes would be capable of specific binding to targeted tumor cells. Molecular aptamers, designer DNA/RNA probes, can address this challenge by recognizing proteins, peptides and other small molecules with high affinity and specificity. Through a process known as cell-SELEX, we used live acute myeloid leukemia (AML) cells to select a group of DNA aptamers that can recognize acute myeloid leukemia cells with dissociation constants (Kds) in the nanomolar range. Interestingly, one aptamer (KH1C12), compared with two control cell lines (K562 and NB4), showed significant selectivity to the target AML cell line (HL60) and could recognize the target cells within a complex mixture of normal bone marrow aspirates. The other two aptamers KK1B10 and KK1D04 recognize targets associated with monocytic differentiation. Our studies demonstrate that the selected aptamers can be used as a molecular tool for further understanding surface protein expression patterns on tumor cells and thus providing a foundation for effective molecular analysis of leukemia and its subcategories.

Intravascular delivery (1.5 x 10(9) particles and higher) of recombinant adenovirus (rAd) induces myeloid cell mediated, self-limiting hemodynamic responses in normal mice. However, we observed anaphylactoid-type reactions and exacerbated hemodynamic events following rAd injection in mice bearing malignant 4T1 mammary carcinoma. Because 4T1 tumors induce significant CD11b(+)Gr-1(+) myeloid cell expansion and activation, we set to determine whether this causes rAd-induced exaggerated responses. When treated with a single intravenous dose (1 x 10(10) particles) of rAd, mice implanted with 4T1 carcinoma succumbed due to the anaphylactoid-type reactions. In contrast, normal mice and mice implanted with a related mammary carcinoma (66cl4) that does not induce CD11b(+)Gr-1(+) cell expansion, showed minimal responses. Depletion of phagocytic CD11b(+)Gr-1(+) cells prior to rAd delivery protected 4T1 tumor-bearing animals, whereas passive transfer of CD11b(+)Gr-1(+) cells from 4T1 tumor-bearing animals was sufficient to convey susceptibility to anaphylactoid-type reactions in normal animals. We further show that there is upregulation of nitric oxide and leukotriene signaling pathways in the 4T1 tumor-induced CD11b(+)Gr-1(+) myeloid cells and that pretreating mice with inhibitors of nitric oxide synthetase and leukotrienes can attenuate the anaphylactoid-type reactions. These data show that malignant tumor growth can alter CD11b(+)Gr-1(+) myeloid cells, rendering hosts susceptible to anaphylactoid-type reactions upon intravascular treatment with rAd.

This work describes the development and investigation of an aptamer modified microfluidic device that captures rare cells to achieve a rapid assay without pre-treatment of cells. To accomplish this, aptamers are first immobilized on the surface of a poly (dimethylsiloxane) microchannel, followed by pumping a mixture of cells through the device. This process permits the use of optical microscopy to measure the cell-surface density from which we calculate the percentage of cells captured as a function of cell and aptamer concentration, flow velocity, and incubation time. This aptamer-based device was demonstrated to capture target cells with > 97% purity and > 80% efficiency. Since the cell capture assay is completed within minutes and requires no pre-treatment of cells, the device promises to play a key role in the early detection and diagnosis of cancer where rare diseased cells can first be enriched and then captured for detection.

To protect against nuclease digestion, or single-strand binding protein interactions, oligonucleotides for targeted delivery into intracellular systems must be stable. To accomplish this, we have developed single-walled carbon nanotubes as a carrier for single-stranded DNA probe delivery. This has resulted in superior biostability for intracellular application, and, hence, has achieved the desired protective attributes, which are particularly important when DNA probes are used for intracellular measurements. Specifically, when bound to single-walled carbon nanotubes, DNA probes are protected from enzymatic cleavage and interference from nucleic acid binding proteins. Moreover, and equally important, our study shows that a single-walled carbon nanotube-modified DNA probe, which targets a specific mRNA inside living cells, has increased self-delivery capability and intracellular biostability when compared to free DNA probes. Therefore, this new conjugate provides significant advantages for basic genomic studies in which DNA probes are used to monitor intracellular levels of molecules.

Identifying cells associated with specific disease states is critically important for the early detection and diagnosis of cancer. To facilitate this task, molecular probes, which bind biomarkers that are either specifically or differentially expressed in diseased cells relative to healthy cells, provide a simple and effective method. This review focuses on the use of DNA aptamers as molecular probes for cancer cells. These aptamers are created by means of the cell-based Systematic Evolution of Ligands by EXponential enrichment (SELEX) process, which uses whole disease cells as targets. We describe at length the steps of the cell-SELEX process and discuss several applications for the aptamers, including profiling leukemia patient samples and discovering cell-surface cancer biomarkers. We conclude with a discussion of an aptamer-conjugated nanoparticle enrichment and detection scheme.

Parkinson’s disease (PD) is characterized by a range of motor symptoms. Besides the cardinal symptoms (akinesia and bradykinesia, tremor and rigidity), PD patients show additional motor deficits, including: gait disturbance, impaired handwriting, grip force and speech deficits, among others. Some of these motor symptoms (e.g., deficits of gait, speech, and handwriting) have similar clinical profiles, neural substrates, and respond similarly to dopaminergic medication and deep brain stimulation (DBS). Here, we provide an extensive review of the clinical characteristics and neural substrates of each of these motor symptoms, to highlight precisely how PD and its medical and surgical treatments impact motor symptoms. In conclusion, we offer a unified framework for understanding the range of motor symptoms in PD. We argue that various motor symptoms in PD reflect dysfunction of neural structures responsible for action selection, motor sequencing, and coordination and execution of movement.

The immune system has evolved to tolerate what is self and reject what is foreign. The recognition of self from non-self is performed by activating and inhibitory receptors, which signal immune cells via adapter molecules, determining the outcome of the immune response. DAP10, a transmembrane adapter protein expressed broadly in hematopoietic cells, associates with NKG2D activating receptor forming a multisubunit complex, which recognizes self-proteins upregulated during tumorigenesis, infection, and autoimmune response. Analysis of immune reactions against syngeneic tumors, as well as autoimmune responses in the DAP10-deficient mice, revealed an important physiological role of DAP10 signaling in maintaining tolerance to self, probably by controlling the development and activation threshold of autoreactive T cells.

Purpose Leukotrienes and prostaglandins, products of arachidonic acid metabolism, sustain both systemic and lesion-localized inflammation. Tumor-associated Inflammation can also contribute to the pathogenesis of colon cancer. Patients with inflammatory bowel disease (IBD) have increased risk of developing colon cancer. The levels of 5-lipoxygenase (5-LO), the key enzyme for leukotrienes production, are increased in colon cancer specimens and colonic dysplastic lesions. Here we report that Zileuton, a specific 5-LO inhibitor, can prevent polyp formation by efficiently reducing the tumor-associated and systemic inflammation in APCΔ468 mice. Experimental Design In the current study, we inhibited 5-LO by dietary administration of Zileuton in the APCΔ468 mouse model of polyposis and analyzed the effect of in vivo 5-LO inhibition on tumor-associated and systemic inflammation. Results Zileuton-fed mice developed fewer polyps and displayed marked reduction in systemic and polyp-associated inflammation. Pro-inflammatory cytokines and pro-inflammatory innate and adaptive immunity cells were reduced both in the lesions and systemically. As part of tumor-associated inflammation Leukotriene B4 (LTB4), product of 5-LO activity, is increased focally in human dysplastic lesions. The 5-LO enzymatic activity was reduced in the serum of Zileuton treated polyposis mice. Conclusions This study demonstrates that dietary administration of 5-LO specific inhibitor in the polyposis mouse model decreases polyp burden, and suggests that Zileuton may be a potential chemo-preventive agent in patients that are high-risk of developing colon cancer.

The recently discovered cytokine IL-27 belongs to the IL-6/IL-12 family of cytokines and induced proliferation of naive CD4+ T cells and the generation of a Th1-type adaptive immune response. Although binding of IL-27 to the cytokine receptor WSX-1 was demonstrated, this interaction proved insufficient to mediate cellular effects. Hence, IL-27 was believed to form a heteromeric signaling receptor complex with WSX-1 and another, yet to be identified, cytokine receptor subunit. In this study, we describe that WSX-1 together with gp130 constitutes a functional signal-transducing receptor for IL-27. We show that neither of the two subunits itself is sufficient to mediate IL-27-induced signal transduction, but that the combination of both is required for this event. Expression analysis of WSX-1 and gp130 by quantitative PCR suggests that IL-27 might have a variety of cellular targets besides naive CD4+ T cells: we demonstrate gene induction of a subset of inflammatory cytokines in primary human mast cells and monocytes in response to IL-27 stimulation. Thus, IL-27 not only contributes to the development of an adaptive immune response through its action on CD4+ T cells, it also directly acts on cells of the innate immune system.

CD200 (OX2) is a broadly distributed cell surface glycoprotein that interacts with a structurally related receptor (CD200R) expressed on rodent myeloid cells and is involved in regulation of macrophage function. We report the first characterization of human CD200R (hCD200R) and define its binding characteristics to hCD200. We also report the identification of a closely related gene to hCD200R, designated hCD200RLa, and four mouse CD200R-related genes (termed mCD200RLa-d). CD200, CD200R, and CD200R-related genes were closely linked in humans and mice, suggesting that these genes arose by gene duplication. The distributions of the receptor genes were determined by quantitative RT-PCR, and protein expression was confirmed by a set of novel mAbs. The distribution of mouse and human CD200R was similar, with strongest labeling of macrophages and neutrophils, but also other leukocytes, including monocytes, mast cells, and T lymphocytes. Two mCD200 receptor-like family members, designated mCD200RLa and mCD200RLb, were shown to pair with the activatory adaptor protein, DAP12, suggesting that these receptors would transmit strong activating signals in contrast to the apparent inhibitory signal delivered by triggering the CD200R. Despite substantial sequence homology with mCD200R, mCD200RLa and mCD200RLb did not bind mCD200, and presently have unknown ligands. The CD200 receptor gene family resembles the signal regulatory proteins and killer Ig-related receptors in having receptor family members with potential activatory and inhibitory functions that may play important roles in immune regulation and balance. Because manipulation of the CD200-CD200R interaction affects the outcome of rodent disease models, targeting of this pathway may have therapeutic utility.

The human leukocyte receptor complex (LRC) on chromosome 19q13.4 encodes Ig superfamily receptors expressed on hemopoietic cells. Killer Ig-like receptors (KIR) are expressed in cytotoxic lymphocytes but other LRC molecules (Ig-like transcript(ILT)/leukocyte Ig-like receptor (LIR)) are more ubiquitous. We investigated expression of the ILT2/LIR1 inhibitory receptor compared with the related KIR. Both ILT2/LIR1 and KIR were expressed by peripheral CD8+ T cells with a memory/effector phenotype. ILT2/LIR1+ T cells demonstrated diverse TCRBV repertoires in contrast to KIR+ T cells, while numbers of peripheral ILT2/LIR1+ T cells were greater than KIR+ T cells and the majority of ILT2/LIR1+ T cells did not coexpress KIR. Analysis of CD8+ T cells with specific HLA class I tetramers confirmed this pattern of expression, indicating differential regulation of LRC gene expression in T lymphocytes. Only a minor proportion of ILT2/LIR1+ KIR− clones survived in vitro cloning, were more susceptible to anti-CD3 or cognate peptide induced cell death than KIR+ T cells and exhibited lower levels of the Bcl-2 survival molecule. Our results indicate a sequential program of LRC-encoded receptor expression with initial ILT2/LIR1 expression in effector T cells and KIR gene transcription in the minor proportion of expanded clones which survives activation-induced cell death to become long term memory T cells.

Human leukocyte-associated immunoglobulin-like receptor (LAIR)-1 is expressed on many cells of the immune system and is predicted to mediate inhibitory functions based on the presence of immunoreceptor tyrosine-based inhibitory motifs (ITIMs) in its cytoplasmic domain. Although the role of LAIR-1 in the regulation of immune responses in vivo is unknown, LAIR-1 cross-linking by monoclonal antibody inhibits various immune cell functions in vitro. Here, we identify the coloncarcinoma-associated epithelial cellular adhesion molecule (Ep-CAM) as a ligand for LAIR-1 and LAIR-2, a related soluble LAIR-1 family member. Ep-CAM interacts with the LAIR molecules through its first epidermal growth factor domain; Ep-CAM–specific antibodies can abrogate the binding. Intraepithelial T lymphocytes express LAIR-1 and thus may interact with Ep-CAM present on human intestinal epithelium. We propose that LAIR-1–Ep-CAM interaction may contribute to mucosal tolerance and that LAIR-2 possibly modulates this function.

Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL; MIM 221770), also known as Nasu-Hakola disease, is a recessively inherited disease characterized by a combination of psychotic symptoms rapidly progressing to presenile dementia and bone cysts restricted to wrists and ankles. PLOSL has a global distribution, although most of the patients have been diagnosed in Finland and Japan, with an estimated population prevalence of 2x10-6 (ref. 2) in the Finns. We have previously identified a shared 153-kb ancestor haplotype in all Finnish disease alleles between markers D19S1175 and D19S608 on chromosome 19q13.1 (refs 5,6). Here we characterize the molecular defect in PLOSL by identifying one large deletion in all Finnish PLOSL alleles and another mutation in a Japanese patient, both representing loss-of-function mutations, in the gene encoding TYRO protein tyrosine kinase binding protein (TYROBP; formerly DAP12). TYROBP is a transmembrane protein that has been recognized as a key activating signal transduction element in natural killer (NK) cells. On the plasma membrane of NK cells, TYROBP associates with activating receptors recognizing major histocompatibility complex (MHC) class I molecules. No abnormalities in NK cell function were detected in PLOSL patients homozygous for a null allele of TYROBP.