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Objectives: Loneliness and social isolation are described similarly yet are distinct constructs. Numerous studies have examined each construct separately; however, less effort has been dedicated to exploring the impacts in combination. This study sought to describe the cumulative effects on late-life health outcomes., Method: Survey data collected in 2018-2019 of a randomly sampled population of US older adults, age 65+, were utilized ( N  = 6,994). Survey measures included loneliness and social isolation using the UCLA-3 Loneliness Scale and Social Network Index. Participants were grouped into four categories based on overlap. Groups were lonely only, socially isolated only, both lonely and socially isolated, or neither. Bivariate and adjusted associations were examined., Results: Among participants (mean age = 76.5 years), 9.8% ( n  = 684) were considered lonely only, 20.6% ( n  = 1,439) socially isolated only, 9.1% ( n  = 639) both lonely and socially isolated, and 60.5% ( n  = 4,232) neither. Those considered both lonely and socially isolated were more likely to be older, female, less healthy, depressed, with lower quality of life and greater medical costs in bivariate analyses. In adjusted results, participants who were both lonely and socially isolated had significantly higher rates of ER visits and marginally higher medical costs., Conclusion: Results demonstrate cumulative effects of these constructs among older adults. Findings not only fill a gap in research exploring the impacts of loneliness and social isolation later in life, but also confirm the need for approaches targeting older adults who are both lonely and socially isolated. As the COVID-19 pandemic continues, this priority will continue to be urgent for older adults.

Objective: To determine the nutrition risk prevalence and associated health and social risk factors amongst community-living Māori and non-Māori older adults in New Zealand., Methods: As part of the 2014 Health, Work and Retirement postal survey, 2914 community-living older adults (749 Māori) aged 49-87 years completed the Seniors in the Community: Risk Evaluation for Eating and Nutrition (SCREEN II-AB) to determine nutrition risk status and sociodemographic and health measures., Results: Half (50.2%) of Māori and 32.7% of non-Māori were at nutrition risk. Independent risk factors were as follows: for Māori, being unpartnered and rating general health as fair, and for non-Māori, being unpartnered and rating general health as fair or poor, lower life satisfaction, higher number of health conditions and emotional loneliness., Conclusions: Findings highlight the need for culturally appropriate intervention strategies, which provide opportunity for older adults to eat with others, especially for those who are unpartnered and lonely., (© 2021 AJA Inc.)

Objectives: Assess well-being among older adults through secondary analysis measured during an annual survey in 2018, 2019, and 2020, to determine trends from before and during the COVID-19 pandemic., Methods: Mailed surveys sent annually included measures related to various psychosocial factors., Main Findings: Response rates were 29% in 2018, 25% in 2019, and 24% in 2020. Most respondents reported average or high resilience (89% 2018-2020), high purpose (64% in 2018 and 2019, 63% in 2020), moderate optimism (46% in 2019, 44% in 2020) and low stress (88% in 2019 and 2020). Reported loneliness increased 13% from 2018 to 2020. In 2020, only 45% reported high comfort with technology, decreasing with age (>75)., Principal Conclusion: Psychosocial well-being of respondents were doing well despite changes related to COVID-19. However, increased loneliness may negatively impact long-term health outcomes; thus, a focus on technology options to stay socially connected and access healthcare are needed., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest with respect to the research, authorship, and/or publication of this article. The authors received no financial support for the research, authorship, and/or publication of this article., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Loss of functional mitochondrial complex I (MCI) in the dopaminergic neurons of the substantia nigra is a hallmark of Parkinson's disease 1 . Yet, whether this change contributes to Parkinson's disease pathogenesis is unclear 2 . Here we used intersectional genetics to disrupt the function of MCI in mouse dopaminergic neurons. Disruption of MCI induced a Warburg-like shift in metabolism that enabled neuronal survival, but triggered a progressive loss of the dopaminergic phenotype that was first evident in nigrostriatal axons. This axonal deficit was accompanied by motor learning and fine motor deficits, but not by clear levodopa-responsive parkinsonism-which emerged only after the later loss of dopamine release in the substantia nigra. Thus, MCI dysfunction alone is sufficient to cause progressive, human-like parkinsonism in which the loss of nigral dopamine release makes a critical contribution to motor dysfunction, contrary to the current Parkinson's disease paradigm 3,4 ., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Studies consistently demonstrate that older adults who are lonely have higher rates of depression and increased mortality risk. Pet ownership may be a solution for loneliness; however, challenges related to pet ownership exist for older adults. Therefore, researchers and practitioners are examining the use of animatronic pets to reduce loneliness., Objective: To determine the feasibility of an animatronic pet program, and whether ownership of animatronic pets would decrease loneliness and improve well-being among lonely older adults., Methods: Eligible individuals were identified as lonely through a prior survey. Participants were provided with the choice of an animatronic pet and completed T1/T2/T3 surveys., Results: Attrition was high; 168 (63%) participants completed T1/T2 surveys, and 125 (48%) also completed a T3 survey. Post survey data indicated that loneliness decreased, while mental well-being, resilience, and purpose in life improved. Frequent interactions with the pets were associated with greater improvement in mental well-being and optimism., Conclusions: Animatronic pets appear to provide benefits for the well-being of lonely older adults. Future studies should employ randomized controlled designs examining the impact of animatronic pets.

Risk of COVID-19 exposure and more severe illness are serious concerns for older adults. Social distancing has worsened existing social isolation, with severe impacts on connectedness among seniors. The pandemic is threatening to cause an extended health crisis, with impacts including serious health consequences. Our primary purpose is to summarize emerging research describing the impacts of the pandemic on social isolation among older adults. A streamlined search was conducted to fit the scope of this literature review. Common research databases and mainstream resources and websites were utilized to identify research published or released in 2020 to align with the pandemic. Early research indicates that the pandemic has worsened social isolation among older adults. Social isolation has become urgent, as seniors have lost their usual connections due to social distancing. While safety measures are critical to prevent virus exposure, this approach must be balanced with maintaining social connectedness. The pandemic highlights the importance of social connections, with significant impacts on both community-living older adults and those in nursing facilities. Safety protocols have created a paradox of reduced risk along with greater harm. Consequently, adapted approaches are urgently needed to address the consequences of a long-term social recession.

Background: Faecal microbiota transplantation is an emerging therapeutic option, particularly for the treatment of recurrent Clostridioides difficile infection. Stool banks that organise recruitment and screening of faeces donors are being embedded within the regulatory frameworks described in the European Union Tissue and Cells Directive and the technical guide to the quality and safety of tissue and cells for human application, published by the European Council., Objective: Several European and international consensus statements concerning faecal microbiota transplantation have been issued. While these documents provide overall guidance, we aim to provide a detailed description of all processes that relate to the collection, handling and clinical application of human donor stool in this document., Methods: Collaborative subgroups of experts on stool banking drafted concepts for all domains pertaining to stool banking. During a working group meeting in the United European Gastroenterology Week 2019 in Barcelona, these concepts were discussed and finalised to be included in our overall guidance document about faecal microbiota transplantation., Results: A guidance document for all domains pertaining to stool banking was created. This document includes standard operating manuals for several processes involved with stool banking, such as handling of donor material, storage and donor screening., Conclusion: The implementation of faecal microbiota transplantation by stool banks in concordance with our guidance document will enable quality assurance and guarantee the availability of donor faeces preparations for patients., (© 2020 The Authors. United European Gastroenterology Journal published by Wiley Periodicals LLC. on behalf of United European Gastroenterology.)

Purpose: Current international guidelines recommend colonoscopy in patients with acromegaly at the time of diagnosis, even though the risk of developing colorectal neoplasm is still controversial. The main objective of this Argentine multicenter study was to analyze through screening colonoscopy the presence of advanced neoplastic lesions considered as precancerous, in patients with acromegaly compared to a control group., Methods: This is a case-control retrospective study. Full length colonoscopy of 70 acromegalic patients and 128 control subjects were studied. Polyps were classified into non pre-cancerous lesions and advance neoplastic lesions which included advanced adenomas (preneoplastic) and colorectal carcinomas., Results: Thirty three out of 70 acromegalic patients and 32 out of 128 subjects controls presented polyps in the colonoscopy [47.1% vs 25%, p = 0.002, OR 2.68]. Non precancerous polyps were found in 11 (15.7%) and 23 (17.9%) (p = 0.690), while advanced neoplastic lesions were found in 22 (31.4%) and 9 (7.0%) (p = 0,0001 - OR: 6.06) patients and controls respectively. Advanced adenomas and colorectal carcinomas were found in 18 (27.3%) and 9 (7.0%) (p = 0,0006-OR: 4,57), and 4 (5.7%) and 0 (0.0%) p = 0.0063) of patients and controls respectively. The presence of insulin resistance was the only statistically significant associated factor among acromegalic patients with and without colonic polyps., Conclusions: Our findings show an increased risk of preneoplastic colonic lesions and colorectal carcinoma in patients with chronic and sustained GH excess compared to a control group. This supports the recommendation to perform screening colonoscopy at diagnosis of acromegaly.

Background: Acromegaly is associated with higher morbidity and mortality mainly due to cardiovascular disease. Data on the incidence and evolution of thyroid cancer in acromegaly are controversial. Our objective was to describe the characteristics of a group of acromegalic patients with differentiated thyroid carcinoma (DTC) and analyze their evolution., Methods: This is a retrospective multicenter study of 24 acromegalic patients with DTC. The AJCC Staging System 8th Edition was used for TNM staging, and the initial risk of recurrence (RR), initial response and response at the end of follow-up (RFU) were defined according to the 2015 ATA Guidelines. As a control group, 92 patients with DTC without acromegaly were randomly included. Statistical analyses were done using SPSS Statistics 20.0., Results: Median age of patients at diagnosis of acromegaly was 49.5 years (range 12-69). The median delay in diagnosis of acromegaly was 3 years (range 0.5-23). Mean baseline IGF-1 level was 2.9 ± 1.1 ULN. Median age at DTC diagnosis was 51.5 years (18-69). At the moment of diagnosis of DTC, 58.3% of the patients had active acromegaly. Median time from DTC diagnosis to acromegaly control was 1.25 years (0.5-7). Mean DTC tumor diameter of the biggest lesion was 14.6 ± 9.2 mm, being multifocal in 37.5%. All tumors were papillary carcinomas, two cases being of an aggressive variety. Lymph node dissection was performed in 8 out of 24 patients and 62.5% had metastases. Only one patient had distant metastases. Radioiodine ablation was given to 87.5% of patients. Nineteen patients (79%) were stage I, four (17%) stage II and one (4%) stage IVb. Initial RR was low in 87% (21/24), intermediate in 9% (2/24) and high in 4% (1/24) patient. RFU was: 83% (19/23) patients with no evidence of disease, 9% (2/23) with indeterminate response, 4% (1/23) with biochemical incomplete response and 4% (1/23) with structural incomplete response, at a median time of FU of 36.5 months. When comparing RFU between acromegalics and controls no statistically significant differences were found., Conclusions: Patients with acromegaly and DTC mostly had a low initial RR. When compared with the control group, we found that DTC patients with acromegaly did not have a worse evolution.

Background: Mechanical circulatory support devices are being increasingly used as destination therapy in end-stage heart failure patients. Although current devices have significantly improved survival rates, the resulting hemodynamics remains nonphysiological. Spiral forms of blood flow are known to exist in the large arteries (eg, aorta) and serve as a biomimetic-motivation for generating these physiologically adapted flow regimes. We aimed to study the potential benefits of generating spiral flow at the mechanical circulatory support outflow graft and the resultant flow-fields in the aorta, including recirculation zones and endothelial wall shear stress (WSS) areas., Methods: A three-dimensional model of an outflow graft virtually anastomosed end-to-side to an image-derived aortic arch was used in computational fluid dynamic simulations. To study the impact of both spiral flow modulation (clockwise/counterclockwise helical-flow content) and the outflow graft anastomosis angle (inferiorly/superiorly directed, anteriorly/posteriorly directed), flow velocities were measured, low/high WSS were computed, and fluid streamlines were visualized., Results: Increased helical-flow content reduced regions of low velocity (<5 cm/s), minimized areas exhibiting low WSS (<3 dyn/cm 2 ), and concomitantly increased areas of high WSS (>80 dyn/cm 2 ). The outflow graft anastomosis angle was a key determinant of aortic root washout and fluid-jet wall impingement. Despite counterclockwise spiral flow predominance in diminishing the size of recirculation/stasis zones compared to straight/clockwise flow, exceptions to this were noted with the superiorly directed and posteriorly directed graft placements., Conclusions: Spiral flow-forms better tailored to the underlying three-dimensional aortic curvature and graft angle positioning is expected to help attenuate atherogenesis, preventing vascular remodeling and minimizing plaque formation/erosion in mechanically assisted circulation., (Copyright © 2020 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: While today's older adults experience longevity, they often manage several chronic conditions and increasingly serve as informal caregivers for aging parents, children with life-long disabilities, and spouses. Older adult caregivers managing personal chronic illness often experience significant psychosocial hardships., Objective: The primary purpose of this study was to explore the experiences of older adult caregivers in an online, interactive mindfulness intervention., Methods: Self-reported older caregivers who participated in an online-based mindfulness program (n = 20) were recruited for semi-structured interviews. Participants were asked to provide feedback about any previous experience with mindfulness and/or meditation, hopes or goals held prior to the start of the program, desired expectations, motivation for joining, impressions of sessions, most beneficial topics, potential application of content, and any perceived effects. Participants' responses were analyzed using qualitative content analysis., Results: Five themes emerged from the analysis: Managing the Comprehensive Effects of Caregiving, Openness to Meditation and Mindfulness, Course Engagement and Incremental Growth, Building Rapport through Shared Experiences, and Ongoing Application and Opportunities for Refinement. Participants reported both short-term post-exercise benefits such as increased calm, relaxation, and stress relief, as well as long-term positive outcomes. Notably, participants found the program's unique interactive feature to be particularly beneficial as a form of perceived social support., Conclusions: Caregivers for older adults may derive benefit and potentially experience reduced subjective caregiver burden as a result of participating in a Mindfulness-Based Stress Reduction (MBSR) program, particularly when the program is augmented with a self-compassion approach and perceived social support.

Spiral/helical forms of blood flow have been observed in large arteries of the cardiovascular system, but their benefits remain underappreciated. Spiral flow has been postulated to improve near-wall washout, promoting anti-atherothrombotic conditions. This research aims to study the washout characteristics of spiral flow, specifically, its ability to increase velocity and wall shear stress (WSS) in atherothrombotic-prone regions. Using 1.2 cm diameter angled test-conduits (45°, 90°, 135°) with known recirculation/stasis regions at the bend corners, spiral flow washout potential was evaluated in terms of low velocity and low WSS. Two sub-studies were conducted: the first utilized a spiral flow-inducing device to enable qualitative analysis of washout-potential in both computational fluid dynamic (CFD) simulations and benchtop ultrasound visualization; the second used CFD to study the impact of several induced helical wavelengths on the conduit-dependent recirculation/stasis zones. Physical models of the angled conduits and spiral flow-inducer were 3D-printed to facilitate ultrasound visualization. Compared to straight flow, spiral flow generated by the flow-inducer significantly cleared the recirculation/stasis zones at the corners of the angled conduits. CFD simulations demonstrated that past a geometry-dependent threshold, increased helical content improved washout, denoted by decreased regions of low velocity and low WSS. Overall, spiral flow markedly improved washout in difficult to reach areas in the angled conduits. This has several important clinical implications: spiral flow shows great promise in reducing blood-transport-related complications and can be used to enhance the performance of future medical devices (eg grafts, mechanical circulatory support devices, hemodialysis access ports)., (© 2019 International Center for Artificial Organs and Transplantation and Wiley Periodicals, Inc.)

Objective: To describe the long term safety and efficacy of pegvisomant (PEGV), and the predictors of treatment response in patients with acromegaly in the real life setting., Subjects and Methods: We retrospectively reviewed the clinical, hormonal and radiological data of acromegalic patients treated with PEGV in 17 Argentine centers., Results: Seventy-five patients (age range 22-77, 51 females) with acromegaly have been treated with PEGV for up to 118 months (median 27 months). Before PEGV, 97.3% of patients had been treated with medical therapy, surgery and/or radiotherapy, two patients had no previous treatment. At that time, all patients had an IGF-1 above the upper normal limit (ULN) (mean 2.4 x ULN ± 0.98, range 1.25-7). At diagnosis of acromegaly 84% presented macroadenomas, prior to PEGV only 23,5% of patients remained with tumor remnant > 1 cm, the remaining showed normal or less than 1 cm images. Disease control (IGF-1 ≤ 1.2 x ULN) was achieved in 62.9% of patients with a mean dose of 11.8 mg/day. Thirty-four patients (45%) received PEGV monotherapy, while 41 (55%) received combined therapy with either somatostatin analogues and/or cabergoline. Adverse events related to PEGV were: local injection site reaction in 5.3%, elevated liver enzymes in 9.3%, and tumor size growth in 9.8%. Pre-PEGV IGF-I level was the only predictor of treatment response: 2.1 x ULN vs 2.8 x ULN in controlled and uncontrolled patients respectively (p < 0.001)., Conclusion: this long term experience indicates PEGV treatment was highly effective and safe in our series of Argentine patients with acromegaly refractory to standard therapies. Arch Endocrinol Metab. 2019;63(4):320-7.

Local control of protein translation is a fundamental process for the regulation of synaptic plasticity. It has been demonstrated that the local protein synthesis occurring in axons and dendrites can be shaped by numerous mechanisms, including miRNA-mediated regulation. However, several aspects underlying this regulatory process have not been elucidated yet. Here, we analyze the differential miRNA profile in cell bodies and neurites of primary hippocampal neurons and find an enrichment of the precursor and mature forms of miR-218 in the neuritic projections. We show that miR-218 abundance is regulated during hippocampal development and by chronic silencing or activation of neuronal network. Overexpression and knockdown of miR-218 demonstrated that miR-218 targets the mRNA encoding the GluA2 subunit of AMPA receptors and modulates its expression. At the functional level, miR-218 overexpression increases glutamatergic synaptic transmission at both single neuron and network levels. Our data demonstrate that miR-218 may play a key role in the regulation of AMPA-mediated excitatory transmission and in the homeostatic regulation of synaptic plasticity.

Cushing's disease (CD) is an endocrine disorder originated by a corticotroph tumor. It is linked with high mortality and morbidity due to chronic hypercortisolism. Treatment goals are to control cortisol excess and achieve long-term remission, therefore, reducing both complications and patient's mortality. First-line of treatment for CD is pituitary's surgery. However, 30% of patients who undergo surgery experience recurrence in long-term follow-up. Persistent or recurrent CD demands second-line treatments, such as pituitary radiotherapy, adrenal surgery, and/or pharmacological therapy. The latter plays a key role in cortisol excess control. Its targets are inhibition of adrenocorticotropic hormone (ACTH) production, inhibition of adrenal steroidogenesis, or antagonism of cortisol action at its peripheral receptor. Retinoic acid (RA) is a metabolic product of vitamin A (retinol) and has been studied for its antiproliferative effects on corticotroph tumor cells. It has been shown that this drug regulates the expression of pro-opiomelanocortin (POMC), ACTH secretion, and tumor growth in corticotroph tumor mouse cell lines and in the nude mice experimental model, via inhibition of POMC transcription. It has been shown to result in tumor reduction, normalization of cortisol levels and clinical improvement in dogs treated with RA for 6 months. The orphan nuclear receptor COUP-TFI is expressed in normal corticotroph cells, but not in corticotroph tumoral cells, and inhibits RA pathways. A first clinical human study demonstrated clinical and biochemical effectiveness in 5/7 patients treated with RA for a period of up to 12 months. In a recent second clinical trial, 25% of 16 patients achieved eucortisolemia, and all achieved a cortisol reduction after 6- to 12-month treatment. The goal of this review is to discuss in the context of the available and future pharmacological treatments of CD, RA mechanisms of action on corticotroph tumor cells, and future perspectives, focusing on potential clinical implementation.

Diabetes is a serious issue for African American women. The purpose of this project was to develop and test the feasibility of a culturally appropriate and faith-based healthy eating program for African American women at risk for developing diabetes. At total of 30 women from two churches completed a 12-week, faith-based program using a community-based approach with lay health educators in the church setting. Participants set healthy eating goals, attended weekly education classes, and received daily text messaging reminders related to their goals. Outcomes included high levels of social support, frequent engagement with the program, and improved healthy eating. This program demonstrated the ability to target African American women at risk for diabetes and engage them in a health-related program.

Older adult health is often defined in clinical terms. Research has demonstrated that many older adults self-report aging successfully regardless of clinical health status. This qualitative study used claims data to identify older adults on three levels of health status: healthy and active, managing diseases, or very sick, to better understand how health is defined and maintained. In total, 32 participants from two cities were interviewed. Interviews were audio- and video-recorded and then transcribed. Thematic analysis identified five themes: disconnectedness between objective and subjective health; health defined to include psychological and social components; resilience and coping mechanisms indicative of successful aging; social support systems integral to health; and the goal of maintaining functioning. These results indicate the importance of individual perceptions of health rather than just counts of chronic diseases. Health management programs should provide holistic approaches to maximize health outcomes and to promote successful aging., (Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.)

Interventions to reduce caregiver burden are of great interest as the number of informal family caregivers continues to grow. The purpose of this study was to test the feasibility of an online mindfulness meditation intervention for community-dwelling older adult caregivers and to evaluate its impact on quality of life, caregiver burden, and psychological well-being. A total of 40 caregivers were recruited from 2 community center support groups to participate in an 8-week online mindfulness intervention. Pre and post surveys were administered. Retention rates were high with 55% completing the post surveys and attending at least 5 out of 8 sessions. Matched pairs t test indicated that the intervention reduced caregiver burden, perceived stress, anxiety, and loneliness and improved mental well-being. Online interventions offer flexibility for caregivers regardless of their responsibilities. Future research should expand this opportunity and explore the scalability of online mindfulness interventions.

Inadequate health literacy (HL) is associated with impaired healthcare choices leading to poor quality-of-care. Our primary purpose was to estimate the prevalence of inadequate HL among two populations of AARP ® Medicare Supplement insureds: sicker and healthier populations; to identify characteristics of inadequate HL; and to describe the impact on patient satisfaction, preventive services, healthcare utilization, and expenditures. Surveys were mailed to insureds in 10 states. Multivariate regression models were used to identify characteristics and adjust outcomes. Among respondents (N = 7334), 23% and 16% of sicker and healthier insureds, respectively, indicated inadequate HL. Characteristics of inadequate HL included male gender, older age, more comorbidities, and lower education. Inadequate HL was associated with lower patient satisfaction, lower preventive service compliance, higher healthcare utilization and expenditures. Inadequate HL is more common among older adults in poorer health, further compromising their health outcomes; thus they may benefit from expanded educational or additional care coordination interventions., (Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.)

Key mitochondrial functions such as ATP production, Ca 2+ uptake and release, and substrate accumulation depend on the proton electrochemical gradient (ΔμH + ) across the inner membrane. Although several drugs can modulate ΔμH + , their effects are hardly reversible, and lack cellular specificity and spatial resolution. Although channelrhodopsins are widely used to modulate the plasma membrane potential of excitable cells, mitochondria have thus far eluded optogenetic control. Here we describe a toolkit of optometabolic constructs based on selective targeting of channelrhodopsins with distinct functional properties to the inner mitochondrial membrane of intact cells. We show that our strategy enables a light-dependent control of the mitochondrial membrane potential (Δψ m ) and coupled mitochondrial functions such as ATP synthesis by oxidative phosphorylation, Ca 2+ dynamics, and respiratory metabolism. By directly modulating Δψ m , the mitochondria-targeted opsins were used to control complex physiological processes such as spontaneous beats in cardiac myocytes and glucose-dependent ATP increase in pancreatic β-cells. Furthermore, our optometabolic tools allow modulation of mitochondrial functions in single cells and defined cell regions., Competing Interests: The authors declare no conflict of interest.

In the superior colliculus, visual stimuli can induce gamma frequency oscillations of neuronal activity. It has been shown that in cats, these oscillations are synchronized over distances of greater than 300 μm that may contribute toward visual information processing. We investigated the spatial properties of such oscillations in a rodent because the availability of molecular tools could enable future studies on the role of these oscillations in visual information processing. Using extracellular electrode array recordings in anesthetized rats, we found that visual stimuli-induced gamma and eta frequency (30-115 Hz) oscillations of the local field potential that were synchronized over distances of ∼ 600 μm. Multiple-unit events were phase locked to the local field potential signal and showed prominent oscillations during OFF responses. The rate of lower than 5 ms cross-electrode coincidences was in line with the response-corrected predictions for each electrode. These data suggest that the synchronized superior colliculus neuronal activity is largely network driven, whereas common synaptic inputs play a minor role.

The increased risk of genetic cancer mutations for Ashkenazi Jews is well known. However, little is known about the cancer-related health behaviors of a subset of Ashkenazi Jews, Orthodox Jews, who are a very religious and insular group. This study partnered with Rabbinical leadership and community members in an Orthodox Jewish community to investigate barriers to cancer screening in this community. Orthodox Jewish women were recruited to participate in focus groups designed to elicit their perspectives on barriers to cancer screening. A total of five focus groups were conducted, consisting of 3-5 members per group, stratified by age and family history of cancer. Focus groups were audio recorded and transcribed. Transcripts were coded using conventional content analysis. The resulting themes identified as barriers to cancer screening were: preservation of hidden miracles, fate, cost, competing priorities, lack of culturally relevant programming, lack of information, and fear. These results provide a unique perspective on barriers to cancer screening in a high risk but understudied population. Findings from this study may serve to inform culturally appropriate cancer education programs to overcome barriers to screening in this and other similar communities.

Purpose: The use of time in outpatient cancer clinics is a marker of quality and efficiency. Inefficiencies such as excessive patient wait times can have deleterious effects on clinic flow, functioning, and patient satisfaction. We propose a novel method of objectively measuring patient time in cancer clinic examination rooms and evaluating its impact on overall system efficiency., Methods: We video-recorded patient visits (N = 55) taken from a larger study to determine patient occupancy and flow in and out of examination rooms in a busy urban clinic in a National Cancer Institute-designated comprehensive cancer center. Coders observed video recordings and assessed patient occupancy time, patient wait time, and physician-patient interaction time. Patient occupancy time was compared with scheduled occupancy time to determine discrepancy in occupancy time. Descriptive and correlational analyses were conducted., Results: Mean patient occupancy time was 94.8 minutes (SD = 36.6), mean wait time was 34.9 minutes (SD = 28.8), and mean patient-physician interaction time was 29.0 minutes (SD = 13.5). Mean discrepancy in occupancy time was 40.3 minutes (range, 0.75 to 146.5 minutes). We found no correlation between scheduled occupancy time and patient occupancy time, patient-physician interaction time, and patient wait time, or between discrepancy in occupancy time and patient-physician interaction time., Conclusion: The method is useful for assessing clinic efficiency and patient flow. There was no relationship between scheduled and actual time patients spend in exam rooms. Such data can be used in the design of interventions that reduce patient wait times, increase efficient use of resources, and improve scheduling patterns., (Copyright © 2014 by American Society of Clinical Oncology.)

Racial disparities have been found in the use of chemotherapy as cancer treatment. These disparities may be, in part, due to well-documented differences in the quality of communication during clinical interactions with oncologists and Black versus White patients. In this study using a community-based participatory research approach, academic researchers, community members, and oncologists formed a partnership to develop a communication intervention to address racial disparities in cancer care. Partners developed a question prompt list (QPL), a simple tool that can be used to improve communication, and thus treatment, during clinical interactions in which oncologists and Black patients discuss chemotherapy. Partners endorsed the use of a QPL, provided specific suggestions for content and format, conducted and analyzed qualitative interviews with Black patients receiving chemotherapy, and approved the final version. The feasibility and effectiveness of the QPL that resulted from this research process are currently under evaluation in a separate study.

Synapsin I (SynI) is a synaptic vesicle (SV) phosphoprotein playing multiple roles in synaptic transmission and plasticity by differentially affecting crucial steps of SV trafficking in excitatory and inhibitory synapses. SynI knockout (KO) mice are epileptic, and nonsense and missense mutations in the human SYN1 gene have a causal role in idiopathic epilepsy and autism. To get insights into the mechanisms of epileptogenesis linked to SYN1 mutations, we analyzed the effects of the recently identified Q555X mutation on neurotransmitter release dynamics and short-term plasticity (STP) in excitatory and inhibitory synapses. We used patch-clamp electrophysiology coupled to electron microscopy and multi-electrode arrays to dissect synaptic transmission of primary SynI KO hippocampal neurons in which the human wild-type and mutant SynI were expressed by lentiviral transduction. A parallel decrease in the SV readily releasable pool in inhibitory synapses and in the release probability in excitatory synapses caused a marked reduction in the evoked synchronous release. This effect was accompanied by an increase in asynchronous release that was much more intense in excitatory synapses and associated with an increased total charge transfer. Q555X-hSynI induced larger facilitation and post-tetanic potentiation in excitatory synapses and stronger depression after long trains in inhibitory synapses. These changes were associated with higher network excitability and firing/bursting activity. Our data indicate that imbalances in STP and release dynamics of inhibitory and excitatory synapses trigger network hyperexcitability potentially leading to epilepsy/autism manifestations.

The RE-1-specific silencing transcription factor (REST or NRSF) is a transcription repressor that orchestrates differentiation and also operates in differentiated neurons and neurosecretory cells (neural cells). Its role in proliferation has been investigated so far only in rapidly growing tumors, with conflicting results: suppression in non-neural tumors, stimulation in medulloblastomas. Working with two clones of chromaffin-neuronal PC12 cells, which express different levels of REST, and using genetic complementation and knockdown approaches, we show that REST also promotes proliferation in differentiated neural cells. Mechanistically, this occurs by a signaling pathway involving REST, the GTPase-activating protein tuberin (TSC2) and the transcription co-factor β-catenin. In PC12 cells, raised expression of REST correlates with reduced TSC2 levels, nuclear accumulation and co-transcriptional activation of β-catenin, and increased expression of its target oncogenes Myc and Ccnd1, which might account for the proliferation advantage and the distinct morphology. Rest transcription is also increased, unveiling the existence of a self-sustaining, feed-forward REST-TSC2-β-catenin signaling loop that is also operative in another neural cell model, NT2/D1 cells. Transfection of REST, knockdown of TSC2 or forced expression of active β-catenin recapitulated the biochemical, functional and morphological properties of the high-expressing REST clone in wild-type PC12 cells. Upregulation of REST promoted proliferation and phenotypic changes, thus hindering neurosecretion. The new REST-TSC2-β-catenin signaling paradigm might have an important role in various aspects of neural cell physiology and pathology, including the regulation of proliferation and neurosecretion.

Objective: We tested the hypotheses that the number of close social network members and the health-related support provided by social network members are predictive of coping efficacy and health behaviors., Methods: Cross-sectional data were collected from 115 African Americans enrolled in cardiac rehabilitation. Measures included the social convoy model, SF-36, the Social Interaction Questionnaire, the Patient Self-Efficacy Questionnaire, and an investigator-developed assessment of health behaviors., Results: Bivariate relationships were found between the number of inner network members and coping efficacy (r = .19, P < .05) and health behaviors (r = .18, P < .06), and between health-related support and coping efficacy (r = .22, P < .05) and health behaviors (r = .28, P < .001). Regression analyses support the hypothesis that close network members predicted better coping efficacy (β = .18, P < .05) and health behaviors (β = .19, P < .05). Health-related support also predicted coping efficacy (β = .23, P < .05) and health behaviors (β = .30, P < .01)., Conclusion: African Americans with larger inner networks have more health support, better health behaviors, and higher coping efficacy. The number of close social network members and related health-support promote health through health behaviors and coping efficacy., (Copyright © 2011 Elsevier Inc. All rights reserved.)

The activity patterns of subthalamic nucleus (STN) neurons are intimately related to motor function/dysfunction and modulated directly by dopaminergic neurons that degenerate in Parkinson's disease (PD). To understand how dopamine and dopamine depletion influence the activity of the STN, the functions/signaling pathways/substrates of D2-like dopamine receptors were studied using patch-clamp recording. In rat brain slices, D2-like dopamine receptor activation depolarized STN neurons, increased the frequency/irregularity of their autonomous activity, and linearized/enhanced their firing in response to current injection. Activation of D2-like receptors in acutely isolated neurons reduced transient outward currents evoked by suprathreshold voltage steps. Modulation was inhibited by a D2-like receptor antagonist and occluded by voltage-dependent Ca2+ (Cav) channel or small-conductance Ca2+-dependent K+ (SKCa) channel blockers or Ca2+-free media. Because Cav channels are targets of G(i/o)-linked receptors, actions on step- and action potential waveform-evoked Cav channel currents were studied. D2-like receptor activation reduced the conductance of Cav2.2 but not Cav1 channels. Modulation was mediated, in part, by direct binding of Gbetagamma subunits because it was attenuated by brief depolarization. D2 and/or D3 dopamine receptors may mediate modulation because a D4-selective agonist was ineffective and mRNA encoding D2 and D3 but not D4 dopamine receptors was detectable. Brain slice recordings confirmed that SKCa channel-mediated action potential afterhyperpolarization was attenuated by D2-like dopamine receptor activation. Together, these data suggest that D2-like dopamine receptors potently modulate the negative feedback control of firing that is mediated by the functional coupling of Cav2.2 and SKCa channels in STN neurons.

We determined the expression of Kv2 channel subunits in rat somatosensory and motor cortex and tested for the contributions of Kv2 subunits to slowly inactivating K+ currents in supragranular pyramidal neurons. Single cell RT-PCR showed that virtually all pyramidal cells expressed Kv2.1 mRNA and approximately 80% expressed Kv2.2 mRNA. Immunocytochemistry revealed striking differences in the distribution of Kv2.1 and Kv2.2 subunits. Kv2.1 subunits were clustered and located on somata and proximal dendrites of all pyramidal cells. Kv2.2 subunits were primarily distributed on large apical dendrites of a subset of pyramidal cells from deep layers. We used two methods for isolating currents through Kv2 channels after excluding contributions from Kv1 subunits: intracellular diffusion of Kv2.1 antibodies through the recording pipette and extracellular application of rStromatoxin-1 (ScTx). The Kv2.1 antibody specifically blocked the slowly inactivating K+ current by 25-50% (at 8 min), demonstrating that Kv2.1 subunits underlie much of this current in neocortical pyramidal neurons. ScTx (300 nM) also inhibited approximately 40% of the slowly inactivating K+ current. We observed occlusion between the actions of Kv2.1 antibody and ScTx. In addition, Kv2.1 antibody- and ScTx-sensitive currents demonstrated similar recovery from inactivation and voltage dependence and kinetics of activation and inactivation. These data indicate that both agents targeted the same channels. Considering the localization of Kv2.1 and 2.2 subunits, currents from truncated dissociated cells are probably dominated by Kv2.1 subunits. Compared with Kv2.1 currents in expression systems, the Kv2.1 current in neocortical pyramidal cells activated and inactivated at relatively negative potentials and was very sensitive to holding potential.

Dendritically placed, voltage-sensitive ion channels are key regulators of neuronal synaptic integration. In several cell types, hyperpolarization/cyclic nucleotide gated (HCN) cation channels figure prominently in dendritic mechanisms controlling the temporal summation of excitatory synaptic events. In prefrontal cortex, the sustained activity of pyramidal neurons in working memory tasks is thought to depend on the temporal summation of dendritic excitatory inputs. Yet we know little about how this is accomplished in these neurons and whether HCN channels play a role. To gain a better understanding of this process, layer V-VI pyramidal neurons in slices of mouse prelimbic and infralimbic cortex were studied. Somatic voltage-clamp experiments revealed the presence of rapidly activating and deactivating cationic currents attributable to HCN1/HCN2 channels. These channels were open at the resting membrane potential and had an apparent half-activation voltage near -90 mV. In the same voltage range, K+ currents attributable to Kir2.2/2.3 and K+-selective leak (Kleak) channels were prominent. Computer simulations grounded in the biophysical measurements suggested a dynamic interaction among Kir2, Kleak, and HCN channel currents in shaping membrane potential and the temporal integration of synaptic potentials. This inference was corroborated by experiment. Blockade of Kir2/Kleak channels caused neurons to depolarize, leading to the deactivation of HCN channels, the initiation of regular spiking (4-5 Hz), and enhanced temporal summation of EPSPs. These studies show that HCN channels are key regulators of synaptic integration in prefrontal pyramidal neurons but that their functional contribution is dependent on a partnership with Kir2 and Kleak channels.

Neurons express multiple types of voltage-gated calcium (Ca2+) channels. Two subtypes of neuronal L-type Ca2+ channels are encoded by CaV1.2 and CaV1.3 pore-forming subunits. Both CaV1.2 and CaV1.3 subunits contain class I PDZ (postsynaptic density-95/Discs large/zona occludens-1) domain-binding consensus at their C termini. In yeast two-hybrid screen of rat brain cDNA library with the C-terminal bait of CaV1.3a (long C-terminal splice variant) L-type Ca2+ channel subunit, we isolated multiple clones of postsynaptic adaptor protein Shank. We demonstrated a specific association of CaV1.3a C termini, but not of CaV1.2 C termini, with Shank PDZ domain in vitro. We further demonstrated that the proline-rich region present in C termini of CaV1.3a subunit binds to Shank Src homology 3 domain. We established that CaV1.3a and Shank localized to postsynaptic locations in cultured rat hippocampal neurons. By expressing epitope-tagged recombinant CaV1.3 subunits in rat hippocampal neuronal cultures, we demonstrated that the presence of Shank-binding motifs in CaV1.3a sequence is both necessary and sufficient for synaptic clustering of CaV1.3 L-type Ca2+ channels. In experiments with dominant-negative peptides and dihydropyridine-resistant CaV1.3a mutants, we demonstrated an importance of Shank-binding motif in CaV1.3a sequence for phosphorylated cAMP response element-binding protein (pCREB) signaling in cultured hippocampal neurons. Our results directly link CaV1.3 neuronal L-type Ca2+ channels to macromolecular signaling complex formed by Shank and other modular adaptor proteins at postsynaptic density and provide novel information about the role played by CaV1.3 L-type Ca2+ channels in pCREB signaling.

Voltage-gated L-type Ca2+ channels are key determinants of synaptic integration and plasticity, dendritic electrogenesis, and activity-dependent gene expression in neurons. Fulfilling these functions requires appropriate channel gating, perisynaptic targeting, and linkage to intracellular signaling cascades controlled by G-protein-coupled receptors (GPCRs). Surprisingly, little is known about how these requirements are met in neurons. The studies described here shed new light on how this is accomplished. We show that D2 dopaminergic and M1 muscarinic receptors selectively modulate a biophysically distinctive subtype of L-type Ca2+ channels (CaV1.3) in striatal medium spiny neurons. The splice variant of these channels expressed in medium spiny neurons contains cytoplasmic Src homology 3 and PDZ (postsynaptic density-95 (PSD-95)/Discs large/zona occludens-1) domains that bind the synaptic scaffolding protein Shank. Medium spiny neurons coexpressed CaV1.3-interacting Shank isoforms that colocalized with PSD-95 and CaV1.3a channels in puncta resembling spines on which glutamatergic corticostriatal synapses are formed. The modulation of CaV1.3 channels by D2 and M1 receptors was disrupted by intracellular dialysis of a peptide designed to compete for the CaV1.3 PDZ domain but not with one targeting a related PDZ domain. The modulation also was disrupted by application of peptides targeting the Shank interaction with Homer. Upstate transitions in medium spiny neurons driven by activation of glutamatergic receptors were suppressed by genetic deletion of CaV1.3 channels or by activation of D2 dopaminergic receptors. Together, these results suggest that Shank promotes the assembly of a signaling complex at corticostriatal synapses that enables key GPCRs to regulate L-type Ca2+ channels and the integration of glutamatergic synaptic events.

Striatal cholinergic interneurons are critical elements of the striatal circuitry controlling motor planning, movement, and associative learning. Intrastriatal release of dopamine and inhibition of interneuron activity is thought to be a critical link between behaviorally relevant events, such as reward, and alterations in striatal function. However, the mechanisms mediating this modulation are unclear. Using a combination of electrophysiological, molecular, and computational approaches, the studies reported here show that D2 dopamine receptor modulation of Na+ currents underlying autonomous spiking contributes to a slowing of discharge rate, such as that seen in vivo. Four lines of evidence support this conclusion. First, D2 receptor stimulation in tissue slices reduced the autonomous spiking in the presence of synaptic blockers. Second, in acutely isolated neurons, D2 receptor activation led to a reduction in Na+ currents underlying pacemaking. The modulation was mediated by a protein kinase C-dependent enhancement of channel entry into a slow-inactivated state at depolarized potentials. Third, the sodium channel blocker TTX mimicked the effects of D2 receptor agonists on pacemaking. Fourth, simulation of cholinergic interneuron pacemaking revealed that a modest increase in the entry of Na+ channels into the slow-inactivated state was sufficient to account for the slowing of pacemaker discharge. These studies establish a cellular mechanism linking dopamine and the reduction in striatal cholinergic interneuron activity seen in the initial stages of associative learning.

Objective: To explore the relationship between maternal obesity and shoulder dystocia while controlling for the potential confounding effects of other variables associated with obesity., Methods: We performed a case-control study of provincial delivery records audited by the Northern and Central Alberta Perinatal Outreach Program. Risk factors evaluated were selected based on previously published studies. Cases and controls were drawn from 45,877 live singleton cephalic vaginal deliveries weighing more than 2500 g between January 1995 and December 1997. There were 413 cases of shoulder dystocia (0.9% incidence). Controls (n = 845) were randomly chosen from the remainder of the target population to create a 1:2 case/control ratio. Univariate analysis with calculation of odds ratios (ORs) was used to determine which of the chosen risk factors were significantly related to the incidence of shoulder dystocia. Multivariable regression analyses were then used to determine the independently associated variables, and the adjusted ORs were obtained for each relevant risk factor., Results: Maternal obesity was not significant as an independent risk factor for shoulder dystocia after adjusting for confounding variables (adjusted OR 0.9; 95% confidence interval [CI] 0.5, 1.6). Fetal macrosomia was the single most powerful predictor. The adjusted ORs were 39.5 (95% CI 19.1, 81.4) for birth weight greater than 4500 g and 9.0 (95% CI 6.5, 12.6) for birth weight between 4000 and 4499 g., Conclusion: The strongest predictors of shoulder dystocia are related to fetal macrosomia. For obese nondiabetic women carrying fetuses whose weights are estimated to be within normal limits, there is no increased risk of shoulder dystocia.

Dopamine (DA) is a well established modulator of prefrontal cortex (PFC) function, yet the cellular mechanisms by which DA exerts its effects in this region are controversial. A major point of contention is the consequence of D(1) DA receptor activation. Several studies have argued that D(1) receptors enhance the excitability of PFC pyramidal neurons by augmenting voltage-dependent Na(+) currents, particularly persistent Na(+) currents. However, this conjecture is based on indirect evidence. To provide a direct test of this hypothesis, we combined voltage-clamp studies of acutely isolated layer V-VI prefrontal pyramidal neurons with single-cell RT-PCR profiling. Contrary to prediction, the activation of D(1) or D(5) DA receptors consistently suppressed rapidly inactivating Na(+) currents in identified corticostriatal pyramidal neurons. This modulation was attenuated by a D(1)/D(5) receptor antagonist, mimicked by a cAMP analog, and blocked by a protein kinase A (PKA) inhibitor. In the same cells the persistent component of the Na(+) current was unaffected by D(1)/D(5) receptor activation-suggesting that rapidly inactivating and persistent Na(+) currents arise in part from different channels. Single-cell RT-PCR profiling showed that pyramidal neurons coexpressed three alpha-subunit mRNAs (Nav1.1, 1.2, and 1.6) that code for the Na(+) channel pore. In neurons from Nav1.6 null mice the persistent Na(+) currents were significantly smaller than in wild-type neurons. Moreover, the residual persistent currents in these mutant neurons-which are attributable to Nav1.1/1.2 channels-were reduced significantly by PKA activation. These results argue that D(1)/D(5) DA receptor activation reduces the rapidly inactivating component of Na(+) current in PFC pyramidal neurons arising from Nav1.1/1.2 Na(+) channels but does not modulate effectively the persistent component of the Na(+) current that is attributable to Nav1.6 Na(+) channels.

In spite of the recognition that striatal D(2) receptors are critical determinants in a variety of psychomotor disorders, the cellular mechanisms by which these receptors shape neuronal activity have remained a mystery. The studies presented here reveal that D(2) receptor stimulation in enkephalin-expressing medium spiny neurons suppresses transmembrane Ca(2+) currents through L-type Ca(2+) channels, resulting in diminished excitability. This modulation is mediated by G(beta)(gamma) activation of phospholipase C, mobilization of intracellular Ca(2+) stores, and activation of the calcium-dependent phosphatase calcineurin. In addition to providing a unifying mechanism to explain the apparently divergent effects of D(2) receptors in striatal medium spiny neurons, this novel signaling linkage provides a foundation for understanding how this pivotal receptor shapes striatal excitability and gene expression.

A-type K(+) currents are key determinants of repetitive activity and synaptic integration. Although several gene families have been shown to code for A-type channel subunits, recent studies have suggested that Kv4 family channels are the principal contributors to A-type channels in the somatodendritic membrane of mammalian brain neurons. If this hypothesis is correct, there should be a strong correlation between Kv4 family mRNA and A-type channel protein or aggregate channel currents. To test this hypothesis, quantitative single-cell reverse transcription-PCR analysis of Kv4 family mRNA was combined with voltage-clamp analysis of A-type K(+) currents in acutely isolated neurons. These studies revealed that Kv4.2 mRNA abundance was linearly related to A-type K(+) current amplitude in neostriatal medium spiny neurons and cholinergic interneurons, in globus pallidus neurons, and in basal forebrain cholinergic neurons. In contrast, there was not a significant correlation between estimates of Kv4.1 or Kv4.3 mRNA abundance and A-type K(+) current amplitudes. These results argue that Kv4.2 subunits are major constituents of somatodendritic A-type K(+) channels in these four types of neuron. In spite of this common structural feature, there were significant differences in the voltage dependence and kinetics of A-type currents in the cell types studied, suggesting that other determinants may create important functional differences between A-type K(+) currents.

Adenosine is a potent regulator of acetylcholine release in the striatum, yet the mechanisms mediating this regulation are largely undefined. To begin to fill this gap, adenosine receptor expression and coupling to voltage-dependent Ca(2+) channels were studied in cholinergic interneurons by combined whole cell voltage-clamp recording and single-cell reverse transcription-polymerase chain reaction. Cholinergic interneurons were identified by the presence of choline acetyltransferase mRNA. Nearly all of these interneurons (90%, n = 28) expressed detectable levels of A(1) adenosine receptor mRNA. A(2a) and A(2b) receptor mRNAs were less frequently detected. A(3) receptor mRNA was undetectable. Adenosine rapidly and reversibly reduced N-type Ca(2+) currents in cholinergic interneurons. The A(1) receptor antagonist 8-cyclopentyl-1, 3-dimethylxanthine completely blocked the effect of adenosine. The IC(50) of the A(1) receptor selective agonist 2-chloro-N6-cyclopentyladenosine was 45 nM, whereas it was near 30 microM for the A(2a) receptor agonist CGS-21680. Dialysis with GDPbetaS or brief exposure to the G protein (G(i/o)) alkylating agent N-ethylmaleimide also blocked the adenosine modulation. The reduction in N-type currents was partially reversed by depolarizing prepulses. A membrane-delimited pathway mediated the modulation, because it was not seen in cell-attached patches when agonist was applied to the bath. Activation of protein kinase C attenuated the adenosine modulation. Taken together, our results argue that activation of A(1) adenosine receptors in cholinergic interneurons reduces N-type Ca(2+) currents via a membrane-delimited, G(i/o) class G-protein pathway that is regulated by protein kinase C. These observations establish a cellular mechanism by which adenosine may serve to reduce acetylcholine release.

In brain neurons, P- and Q-type Ca(2+) channels both appear to include a class A alpha1 subunit. In spite of this similarity, these channels differ pharmacologically and biophysically, particularly in inactivation kinetics. The molecular basis for this difference is unclear. In heterologous systems, alternative splicing and ancillary beta subunits have been shown to alter biophysical properties of channels containing a class A alpha1 subunit. To test the hypothesis that similar mechanisms are at work in native systems, P- and Q-type currents were characterized in acutely isolated rat neostriatal, medium spiny neurons and cortical pyramidal neurons using whole-cell voltage-clamp techniques. Cells were subsequently aspirated and subjected to single-cell RT-PCR (scRT-PCR) analysis of calcium channel alpha(1) and beta (beta(1-4)) subunit expression. In both cortical and neostriatal neurons, P- and Q-type currents were found in cells expressing class A alpha(1) subunit mRNA. Although P-type currents in cortical and neostriatal neurons were similar, Q-type currents differed significantly in inactivation kinetics. Notably, Q-type currents in neostriatal neurons were similar to P-type currents in inactivation rate. The variation in Q-type channel biophysics was correlated with beta subunit expression. Neostriatal neurons expressed significantly higher levels of beta(2a) mRNA and lower levels of beta(1b) mRNA than cortical neurons. These findings are consistent with the association of beta(2a) and beta(1b) subunits with slow and fast inactivation, respectively. Analysis of alpha(1A) splice variants in the linker between domains I and II failed to provide an alternative explanation for the differences in inactivation rates. These findings are consistent with the hypothesis that the biophysical properties of Q-type channels are governed by beta subunit isoforms and are separable from toxin sensitivity.

In summary, both G-CSF and GM-CSF have been identified, cloned, and produced for pharmacologic use in humans. While both G-CSF and GM-CSF have had significant impact in the treatment of neutropenic states, G-CSF appears to be more advantageous than GM-CSF in overall efficacy and paucity of side effects. Much has been discovered about the structure of the G-CSF receptor but further work is necessary to determine its mechanism of signal transduction. As our understanding of G-CSF signaling advances, the therapeutic impact of our knowledge about G-CSF biology will evolve from the current focus on enhancing its effects in hematologic and oncologic illnesses to decreasing its effects in inflammatory conditions where overexhuberant neutrophil infiltration and activation cause disease.