Search

Targeted tissue ablation involving the anterior hippocampus is the standard of care for patients with drug-resistant mesial temporal lobe epilepsy. However, a substantial proportion continues to suffer from seizures even after surgery. We identified the fasciola cinereum (FC) neurons of the posterior hippocampal tail as an important seizure node in both mice and humans with epilepsy. Genetically defined FC neurons were highly active during spontaneous seizures in epileptic mice, and closed-loop optogenetic inhibition of these neurons potently reduced seizure duration. Furthermore, we specifically targeted and found the prominent involvement of FC during seizures in a cohort of six patients with epilepsy. In particular, targeted lesioning of the FC in a patient reduced the seizure burden present after ablation of anterior mesial temporal structures. Thus, the FC may be a promising interventional target in epilepsy.

The majority of the brain’s vasculature is composed of intricate capillary networks lined by capillary pericytes. However, it remains unclear whether capillary pericytes influence blood flow. Using two-photon microscopy to observe and manipulate brain capillary pericytes in vivo, we find that their optogenetic stimulation decreases lumen diameter and blood flow, but with slower kinetics than similar stimulation of mural cells on upstream pial and precapillary arterioles. This slow vasoconstriction was inhibited by the clinically used vasodilator fasudil, a Rho-kinase inhibitor that blocks contractile machinery. Capillary pericytes were also slower to constrict back to baseline following hypercapnia-induced dilation, and slower to dilate towards baseline following optogenetically induced vasoconstriction. Optical ablation of single capillary pericytes led to sustained local dilation and a doubling of blood cell flux selectively in capillaries lacking pericyte contact. These data indicate that capillary pericytes contribute to basal blood flow resistance and slow modulation of blood flow throughout the brain.

Langerhans cells are a subset of dendritic cells residing in the epidermis of the human skin. As such, they are key mediators of immune regulation and have emerged as prime targets for novel transcutaneous cancer vaccines. Importantly, the induction of protective T cell immunity by these vaccines requires the efficient and specific delivery of both tumor-associated antigens and adjuvants. Langerhans cells uniquely express Langerin (CD207), an endocytic C-type lectin receptor. Here, we report the discovery of a specific, glycomimetic Langerin ligand employing a heparin-inspired design strategy and structural characterization by NMR spectroscopy and molecular docking. The conjugation of this glycomimetic to liposomes enabled the specific and efficient targeting of Langerhans cells in the human skin. We further demonstrate the doxorubicin-mediated killing of a Langerin+monocyte cell line, highlighting its therapeutic and diagnostic potential in Langerhans cell histiocytosis, caused by the abnormal proliferation of Langerin+myeloid progenitor cells. Overall, our delivery platform provides superior versatility over antibody-based approaches and novel modalities to overcome current limitations of dendritic cell-targeted immuno- and chemotherapy.

Supplemental Digital Content is available in the text.

Direct contact and communication between pericytes and endothelial cells is critical for maintenance of cerebrovascular stability and blood-brain barrier function. Capillary pericytes have thin processes that reach hundreds of micrometers along the capillary bed. The processes of adjacent pericytes come in close proximity but do not overlap, yielding a cellular chain with discrete territories occupied by individual pericytes. Little is known about whether this pericyte chain is structurally dynamic in the adult brain. Using in vivotwo-photon imaging in adult mouse cortex, we show that while pericyte somata were immobile, the tips of their processes underwent extensions and/or retractions over days. The selective ablation of single pericytes provoked exuberant extension of processes from neighboring pericytes to contact uncovered regions of the endothelium. Uncovered capillary regions had normal barrier function but were dilated until pericyte contact was regained. Pericyte structural plasticity may be critical for cerebrovascular health and warrants detailed investigation.

In order to examine the way ethical decisions are made, we asked ethicists, regulatory officials, and experienced researchers to review a set of scenarios that depict important ethical tensions in research. The method employed was “protocol analysis,” a talk-aloud technique pioneered by cognitive scientists. Each individual was asked to make recommendations for courses of action. Later, we held a focus group of university faculty and staff with either institutional review board experience or research ethics training. They too were asked to recommend actions. The results show there are areas where the two data collection approaches agree, as well as areas of considerable difference. Implications for training in the responsible conduct of research are discussed.

As drug treatment courts developed over the past 20 years, they were increasingly and productively grounded in the philosophy of therapeutic jurisprudence and in the operational standards of the 10 key components. Both of these and particularly the growing literature on the efficacy of the key components offer guidance for the implementation and monitoring of programs and provide a logic for attributing outcomes to program operation. What then, if anything, might be gained by an explicit attention to what is generally called social science theory in understanding and modifying drug courts? This article addresses these questions and develops social learning theory as an example of the potential for this union of theoretical and practical concerns.

Hedgehog (HH) signaling is activated in various lymphoid malignancies, but conflicting results exist about its role in chronic lymphocytic leukemia (CLL). Here, we demonstrate that the expression of essential HH pathway components like GLI1, PTCH1, and the HH ligands is highly diverse in CLL. A subset of 36.7% of 60 tested CLL samples responded to all 3 SMOOTHENED (SMO) inhibitors, whereas 40% were completely resistant. Responsiveness correlated with elevated GLI1 and PTCH1 transcript levels and the presence of trisomy 12, whereas no other karyotype correlated with responsiveness. All trisomy 12 CLLs displayed constitutive HH pathway activation driven by autocrine DESERT HH (DHH) ligand secretion, which could be blocked by the HH-blocking Ab 5E1. Cocultures with DHH-expressing BM stromal cells reduced sensitivity of CLLs to SMO-inhibitor treatment by activation of noncanonical ERK phosphorylation directly downstream of the PTCH1 receptor without involvement of SMO and could be overcome by the HH-blocking Ab 5E1 or a combination of SMO and ERK inhibitors. Our results demonstrate that the HH-signaling pathway is an interesting therapeutic target for a subset of patients with CLL, characterized by high GLI1 and PTCH1 transcript levels, and all patients with trisomy 12 and indicate HH-blocking Abs to be favorable over SMO inhibitors in overcoming stroma-mediated protective effects.

Hedgehog (HH) signaling is activated in various lymphoid malignancies, but conflicting results exist about its role in chronic lymphocytic leukemia (CLL). Here, we demonstrate that the expression of essential HH pathway components like GLI1, PTCH1, and the HH ligands is highly diverse in CLL. A subset of 36.7% of 60 tested CLL samples responded to all 3 SMOOTHENED (SMO) inhibitors, whereas 40% were completely resistant. Responsiveness correlated with elevated GLI1and PTCH1transcript levels and the presence of trisomy 12, whereas no other karyotype correlated with responsiveness. All trisomy 12 CLLs displayed constitutive HH pathway activation driven by autocrine DESERT HH (DHH) ligand secretion, which could be blocked by the HH-blocking Ab 5E1. Cocultures with DHH-expressing BM stromal cells reduced sensitivity of CLLs to SMO-inhibitor treatment by activation of noncanonical ERK phosphorylation directly downstream of the PTCH1 receptor without involvement of SMO and could be overcome by the HH-blocking Ab 5E1 or a combination of SMO and ERK inhibitors. Our results demonstrate that the HH-signaling pathway is an interesting therapeutic target for a subset of patients with CLL, characterized by high GLI1and PTCH1transcript levels, and all patients with trisomy 12 and indicate HH-blocking Abs to be favorable over SMO inhibitors in overcoming stroma-mediated protective effects.

Cationic blue‐emitting complexes with (2,4‐difluoro)phenylpyridine and different 1,2,3‐triazole ligands are synthesized with different counterions. The influence of the substituents on the triazole ligand is investigated as well as the influence of the counterions. The substituents do not change the emission energy but, in some cases, slightly modify the excited‐state lifetimes and the emission quantum yields. The excited‐state lifetimes, in apolar solvents, are slightly dependent on the nature of the counterion. A crystal structure of one of the compounds confirms the geometry and symmetry postulated on the basis of the other spectroscopic data. Light‐emitting electrochemical cell devices are prepared and the recorded emission is the bluest with the fastest response time ever reported for iridium complexes.

In nur einer Stufewird Myrtucommulon A, ein entzündungshemmender und Apoptose induzierender Inhaltsstoff der gemeinen Myrte Myrtus communis, aus käuflichen oder literaturbekannten Verbindungen synthetisiert (siehe Schema). Die Synthesestrategie ermöglicht ebenfalls die Erzeugung von Myrtucommulon‐Bibliotheken.

No Abstract

The use of triangulated research designs is becoming increasingly popular, particularly in applied sociology and evaluation research. There is a substantial amount of literature on triangulated research methods, particularly in the fields of social research methods and nursing. This paper examines the uses of the concept of triangulation in applied sociological research. It does so first by reviewing uses of the term in various applied contexts. We then turn to whether and how the information derived from multiple methods is actually integrated by the applied researcher. Finally, we discuss the importance of triangulation for the quality of work in the field of applied sociology.

Two research questions were addressed in this study. First, what are the dimensions of the concept of control orientation with respect to substance-abusing behaviors as measured by Keyson and Janda's 1972 Drinking-related Locus of Control Scale and by an adaptation of that scale developed for users of other drugs. Second, utilizing a large sample of both male and female clients who abused both alcohol and other drugs, how does that dimensional structure differ from the one presented by Donovan and O'Leary in 1978 for male alcoholics at a VA hospital. Since the present sample was a large (N = 542) representative sample of publicly subsidized clients in Missouri, it provided an opportunity to extend earlier work across type of drug abused and sex. Like Donovan and O'Leary we used a principal components analysis with a varimax rotation to examine the dimensions of the 25-item locus of control scales. Like those authors, the analysis for male alcohol users produced a three-factor solution with interpretations resembling their “intrapersonal” and “interpersonal” factors but with a more fully developed third factor interpretable as a fate or luck dimension. These dimensions were apparent for the other groups as well, although the first two factors were reversed for male users of other drugs and the analysis for female alcohol abusers showed a more consistent sociability dimension than for males. While the derived structures are therefore similar to Donovan and O'Leary's results and consistent with the theoretical uses of control orientation in discussion of alcohol and other drug abuse, they also show some differences for type of drug abused and by sex. These are necessary but not sufficient conditions for including such measures in more specific models relating clients' motivation and propensity for change to outcomes.

This paper describes a retirement village community chorus of 49 with the goal of understanding the place of choral activities in the lives of these older people. Group musical activity provides a link to previous satisfying experiences and serves as a preventive measure against alienation. However, the nature of the activity may be consistent with a willingness to give up some inner directedness. Additional research is recommended since the present design with a comparison group of 49 non-choral members did not allow separation of effects of selection from those of activity.

Case management has been identified as an important addition to traditional services offered in drug and alcohol treatment. Implementation of case-management services requires a new array of managerial behaviors by middle managers. The Missouri Department of Mental Health, Division of Alcohol and Drug Abuse, introduced case management as a central component of the innovative Comprehensive Substance Treatment and Rehabilitation Program. The authors, drawing from the experience in Missouri, describe the challenge of effectively implementing case management in existing programs.

Empirical research indicates that posttreatment factors, including employment, residential stability, and social and family support, influence the resiliency of treatment outcomes. The degree to which current treatment methods affect such outcomes is the subject of much research and debate. The authors argue that case management should be considered complementary to traditional treatment services. By focusing directly on community functioning and social rehabilitation, case management can positively affect factors associated with relapse and alcohol-related problems. A strengths-based, outreach model of case management is described.

Pure carbon has been used clinically for percutaneous passage at Rancho Los Amigos Hospital. In the first phase, from 1968 to early 1972. over 40 carbon devices were implanted in the skin of volunteer patients and staff to test the potential use of this material for a dry, infection-free skin intrusion. In the second phase, during the past year, 20 functional devices were implanted in patients and volunteers for muscle stimulation and the control of pain. The success of the devices to achieve infection-free skin passage has given us sufficient confidence to propose an extensive clinical trial for biomedical connector systems.

The authors report the results from a study of a residential crisis program house in Missouri. Like other programs of its kind, the program is designed to provide a home-like atmosphere for consumers experiencing acute episodes. The study contributes to a quantitative comparative evaluation of the effectiveness of such programs; it suggests that a residential crisis program is a less expensive alternative to hospitalization and appears to serve the short-term stabilization needs of its clientele. Client self- reports confirm return to preadmission functioning and high levels of satisfaction.

Internal validity refers to the confidence with which changes in a dependent variable can be isolated from the effects of extraneous factors and causally attributed to the effects of an independent variable. While a randomized design is commonly recommended as the best way to preserve internal validity, random assignment of subjects to groups is not always feasible in evaluations of correctional programs. This paper argues that the biased assignment design, whereby subjects are assigned to groups according to controlled criteria, is a viable alternative means of preserving internal validity which should be employed more frequently by corrections researchers. The steps for using the biased assignment design are presented, as is a strategy for proper data analysis.

A 67-year-old woman was admitted to our hospital for progressive weakness, dysphagia, muscle pain, and weight loss. Here we detail the clinical problem solving involved in diagnosing and treating her immune-mediated necrotizing myopathy caused by anti-HMGCoA reductase autoantibodies. Interestingly, this diagnosis coincided with discovery of a gastrointestinal stromal tumor (GIST) and positivity for anti-nuclear matrix protein (anti-NXP2), another myositis specific autoantibody.