The minimal detectable change cannot reliably replace the minimal important difference.

Objective: We compared the minimal important difference (MID) with the minimal detectable change (MDC) generated by distribution-based methods.

Study Design: Studies of two quality-of-life instruments (Chronic Respiratory Questionnaire [CRQ] and Rhinoconjunctivitis Quality of Life Questionnaire [RQLQ]) and two physician-rated disease-activity indices (Pediatric Ulcerative Colitis Activity Index [PUCAI] and Pediatric Crohn's Disease Activity Index [PCDAI]) provided longitudinal data. The MID values were calculated from global ratings of change (small change for CRQ and RQLQ; moderate for PUCAI and PCDAI) using receiver-operating characteristic (ROC) curve and mean change.

Multipathway kinase signatures of multipotent stromal cells are predictive for osteogenic differentiation: tissue-specific stem cells.

Bone marrow-derived multipotent stromal cells (MSCs) offer great promise for regenerating tissue. Although certain transcription factors have been identified in association with tendency toward particular MSC differentiation phenotypes, the regulatory network of key receptor-mediated signaling pathways activated by extracellular ligands that induce various differentiation responses remains poorly understood. Attempts to predict differentiation fate tendencies from individual pathways in isolation are problematic due to the complex pathway interactions inherent in signaling networks.

Why psychotherapy helps the patient in chronic pain.

Psychiatrists frequently see patients in their practices who struggle with issues of chronic physical pain. This can present diagnostic and therapeutic dilemmas. These patients require an approach that allows them to talk about their pain and feel supported while simultaneously being nudged to develop a meaningful life alongside their pain.

Multimodal sensory integration of courtship stimulating cues in Drosophila melanogaster.

Mechanisms for identifying appropriate mating partners are required for any species to survive. In many types of animals, males employ multiple sensory modalities to initially search for females and to subsequently determine if they are fit and/or receptive. In this paper we will detail the multiple types of sensory information that are used to initiate and drive courtship in Drosophila melanogaster and discuss the importance of context in the interpretation of chemosensory cues.

Three-kinase inhibitor combination recreates multipathway effects of a geldanamycin analogue on hepatocellular carcinoma cell death.

Multitarget compounds that act on a diverse set of regulatory pathways are emerging as a therapeutic approach for a variety of cancers. Toward a more specified use of this approach, we hypothesize that the desired efficacy can be recreated in terms of a particular combination of relatively more specific (i.e.

Liver tissue engineering in the evaluation of drug safety.

Assessment of drug-liver interactions is an integral part of predicting the safety profile of new drugs. Existing model systems range from in vitro cell culture models to FDA-mandated animal tests. Data from these models often fail, however, to predict human liver toxicity, resulting in costly failures of clinical trials.

Sustained epidermal growth factor receptor levels and activation by tethered ligand binding enhances osteogenic differentiation of multi-potent marrow stromal cells.

Epidermal growth factor receptor (EGFR)-mediated signaling helps regulate bone development and healing through its effects on osteogenic cells. Here, we show how EGFR activity and osteogenic differentiation responses in primary human bone marrow-derived multipotent stromal cells (MSCs) are influenced by presenting covalently tethered epidermal growth factor (tEGF) on the culture substratum, a presentation mode that reduces EGFR internalization and restricts signaling to the cell surface. In both absence and presence of tEGF, MSCs increase expression levels of EGFR and its heterodimerization partner HER2 during the course of osteogenic differentiation.

The influence of tethered epidermal growth factor on connective tissue progenitor colony formation.

Strategies to combine aspirated marrow cells with scaffolds to treat connective tissue defects are gaining increasing clinical attention and use. In situations such as large defects where initial survival and proliferation of transplanted connective tissue progenitors (CTPs) are limiting, therapeutic outcomes might be improved by using the scaffold to deliver growth factors that promote the early stages of cell function in the graft. Signaling by the epidermal growth factor receptor (EGFR) plays a role in cell survival and has been implicated in bone development and homeostasis.

High-resolution video tracking of locomotion in adult Drosophila melanogaster.

Flies provide an important model for studying complex behavior due to the plethora of genetic tools available to researchers in this field. Studying locomotor behavior in Drosophila melanogaster relies on the ability to be able to quantify changes in motion during or in response to a given task. For this reason, a high-resolution video tracking system, such as the one we describe in this paper, is a valuable tool for measuring locomotion in real-time.

Synergistic drug-cytokine induction of hepatocellular death as an in vitro approach for the study of inflammation-associated idiosyncratic drug hepatotoxicity.

Idiosyncratic drug hepatotoxicity represents a major problem in drug development due to inadequacy of current preclinical screening assays, but recently established rodent models utilizing bacterial LPS co-administration to induce an inflammatory background have successfully reproduced idiosyncratic hepatotoxicity signatures for certain drugs. However, the low-throughput nature of these models renders them problematic for employment as preclinical screening assays. Here, we present an analogous, but high-throughput, in vitro approach in which drugs are administered to a variety of cell types (primary human and rat hepatocytes and the human HepG2 cell line) across a landscape of inflammatory contexts containing LPS and cytokines TNF, IFN gamma, IL-1 alpha, and IL-6.

Temporal dynamics of neuronal activation by Channelrhodopsin-2 and TRPA1 determine behavioral output in Drosophila larvae.

In recent years, a number of tools have become available for remotely activating neural circuits in Drosophila. Despite widespread and growing use, very little work has been done to characterize exactly how these tools affect activity in identified fly neurons. Using the GAL4-UAS system, we expressed blue light-gated Channelrhodopsin-2 (ChR2) and a mutated form of ChR2 (H134R-ChR2) in motor and sensory neurons of the Drosophila third-instar locomotor circuit.

Channelrhodopsin2 mediated stimulation of synaptic potentials at Drosophila neuromuscular junctions.

The Drosophila larval neuromuscular preparation has proven to be a useful tool for studying synaptic physiology. Currently, the only means available to evoke excitatory junctional potentials (EJPs) in this preparation involves the use of suction electrodes. In both research and teaching labs, students often have difficulty maneuvering and manipulating this type of stimulating electrode.

Transport-mediated angiogenesis in 3D epithelial coculture.

Increasing interest has focused on capturing the complexity of tissues and organs in vitro as models of human pathophysiological processes. In particular, a need exists for a model that can investigate the interactions in three dimensions (3D) between epithelial tissues and a microvascular network since vascularization is vital for reconstructing functional tissues in vitro. Here, we implement a microfluidic platform to analyze angiogenesis in 3D cultures of rat primary hepatocytes and rat/human microvascular endothelial cells (rMVECs/hMVECs).

Alternative splicing of the eag potassium channel gene in Drosophila generates a novel signal transduction scaffolding protein.

The Drosophila eag gene has been shown to regulate neuronal excitability, olfaction, associative learning and larval locomotion. Not all of the roles of this gene in these processes can be explained by its function as a voltage-gated potassium channel. In this study, we show that the eag gene is spliced in a PKA- and PKC-regulated manner to produce a protein lacking channel domains.

Light-arousal and circadian photoreception circuits intersect at the large PDF cells of the Drosophila brain.

The neural circuits that regulate sleep and arousal as well as their integration with circadian circuits remain unclear, especially in Drosophila. This issue intersects with that of photoreception, because light is both an arousal signal in diurnal animals and an entraining signal for the circadian clock. To identify neurons and circuits relevant to light-mediated arousal as well as circadian phase-shifting, we developed genetic techniques that link behavior to single cell-type resolution within the Drosophila central brain.

PDF cells are a GABA-responsive wake-promoting component of the Drosophila sleep circuit.

Daily sleep cycles in humans are driven by a complex circuit within which GABAergic sleep-promoting neurons oppose arousal. Drosophila sleep has recently been shown to be controlled by GABA, which acts on unknown cells expressing the Rdl GABAA receptor. We identify here the relevant Rdl-containing cells as PDF-expressing small and large ventral lateral neurons (LNvs) of the circadian clock.

Using the entire cohort in the receiver operating characteristic analysis maximizes precision of the minimal important difference.

Objective: We compared the minimal important difference (MID) values obtained by the receiver operating characteristics (ROC) curve approach using different strategies on four outcome measures to guide the optimal use of ROC curve.

Study Design And Setting: Studies of two psychometric scales (Rhinoconjunctivitis Quality-of-Life Questionnaire [RQLQ] and Chronic Respiratory Questionnaire [CRQ]) and two clinimetric indices (Pediatric Ulcerative Colitis Activity Index [PUCAI] and Pediatric Crohn's Disease Activity Index [PCDAI]) instruments provided prospective longitudinal data. The MID was calculated from 7- and 15-point global ratings of change dichotomized in multiple ways, using the ROC curve method.

Allogeneic hematopoietic cell transplantation for primary immune deficiency diseases: current status and critical needs.

Allogeneic hematopoietic cell transplantation (HCT) has been used for 40 years to ameliorate or cure primary immune deficiency (PID) diseases, including severe combined immunodeficiency (SCID) and non-SCID PID. There is a critical need for evaluation of the North American experience of different HCT approaches for these diseases to identify best practices and plan future investigative clinical trials. Our survey of incidence and prevalence of PID in North American practice sites indicates that such studies are feasible.

A study of the physiologic responses to a lung recruitment maneuver in acute lung injury and acute respiratory distress syndrome.

Objective: To determine the magnitude, duration, and consistency of the effects of lung recruitment maneuvers (RMs) on oxygenation, lung mechanics, and comfort in patients with acute lung injury (ALI) and acute respiratory distress syndrome (ARDS).

Methods: We conducted a prospective physiologic study at 3 tertiary-care hospitals. We enrolled 28 consecutive eligible patients with ARDS or ALI and a ratio of P(aO(2)) to fraction of inspired oxygen (P(aO(2))/F(IO(2))) or= 0.

Courtship initiation is stimulated by acoustic signals in Drosophila melanogaster.

Finding a mating partner is a critical task for many organisms. It is in the interest of males to employ multiple sensory modalities to search for females. In Drosophila melanogaster, vision is thought to be the most important courtship stimulating cue at long distance, while chemosensory cues are used at relatively short distance.

An inducible autocrine cascade regulates rat hepatocyte proliferation and apoptosis responses to tumor necrosis factor-alpha.

Unlabelled: Tumor necrosis factor-alpha (TNF) is an inflammatory cytokine that induces context-dependent proliferation, survival, and apoptosis responses in hepatocytes. TNF stimulates and enhances growth factor-mediated hepatocyte proliferation and survival following partial hepatectomy, but also acts in concert with other inflammatory cytokines of the innate immune response during viral infection to induce apoptosis in hepatocytes. In other epithelial cell types, TNF has recently been shown to stimulate autocrine release of transforming growth factor-alpha (TGF-alpha) and interleukin-1 (IL-1) family ligands.

CaMKII: new tricks for an old dog.

Calcium/calmodulin-dependent protein kinase II (CaMKII) is a pivotal signaling molecule in both the brain and the heart. In this issue of Cell, Erickson et al. (2008) demonstrate a mechanism for CaMKII activation by reactive oxygen species that provides a direct link between kinase activation and cardiac dysfunction.

The Psychiatrist's Guide to Motivational Interviewing.

Motivational interviewing (MI) is a technique that can be used to inspire patients who have virtually any level of enthusiasm for change, from almost none to nearly enough, to move toward improvements that can make their life better. The driving goal in MI is to move the patient from a position of complacency to one of more ambivalence about their particular version of toxic habit and then on to a personal desire for change. The approach of MI is one of collaboration in which the psychiatrist seeks to evoke the patient's own recognition of the desirability of change.

Cellular strategies for enhancement of fracture repair.

Tissue engineering seeks to translate scientific knowledge into tangible products to advance the repair, replacement, or regeneration of organs and tissues. Current tissue engineering strategies have progressed recently from a historical approach that is based primarily on biomaterials to a cell and tissue-based approach that includes understanding of cell-sourcing and bioactive stimuli. New options include methods for harvest and transplantation of tissue-forming cells, bioactive matrix materials that act as tissue scaffolds, and delivery of bioactive molecules within scaffolds.