This paper examines how clinicians promote pediatric patients’ symptom accounts at the beginning of visits in three pediatric tertiary care clinics at a university hospital in the US: pain, gastroenterology and neurology. Quantitative and qualitative data were collected for 69 patient-parent pairs, including videotaped intake visits. Two forms of child account promotion, together with their corresponding distribution across clinics, were identified: (1) Epistemic prefaces were used to upgrade the patient’s epistemic status and to establish the child as primary informant; and, (2) non-focused questioning was used to permit children latitude in the formulation of symptoms and experiences. In general, epistemic prefaces were characteristic of the gastroenterology and neurology visits, while non-focused questioning was found overwhelmingly in the pain encounters.
USA; Children; Chronic condition; Pain; Communication; Biopsychosocial; Patient Participation
Due to co-morbidities and treatment resistant nature of pervasive developmental disorder (PDD), diverse combinations of regimens have been tried. This retrospective study aimed to explore adjunctive use of aripiprazole in children with PDD. Changes in illness severity were measured by Clinical Global Impression of Severity (CGI-S) and Clinical Global Impression of Improvement (CGI-I) in 14 aripiprazole-treated patients with PDD. Improvement of illness severity was observed after aripiprazole add-on (5.8±0.8 to 4.9±1.0, Z=-2.75, p=0.001). Mean dosage was 7.7 mg/day [standard deviation (SD) 3.3, range 5-15]. A higher mean dosage was observed in group with improvement in symptoms (t=-2.33, df =12, p=0.004). The target symptoms most effectively improved after using aripiprazole were positive psychotic symptoms (mean CGI-I: 2.0±1.4, 3 responders/4 patients, 75% response) followed by aggressive behavior (2.5±1.7, 3/4, 75%), self-injurious behavior (2.0±1.0, 2/3, 67%), stereotypic behavior (2.7±1.2, 2/3, 67%), tic (2.8±1.0, 2/4, 50%), irritability (3.5±2.1, 1/2, 50%), obsessive behavior (2.5±2.1, 1/3, 33%), hyperactivity (3.4±1.6, 3/7, 43%) and mood fluctuation (3, 0/1, no response). Five patients (35%) discontinued aripiprazole due to treatment-emergent adverse effects (akathisia, insomnia, withdrawal). The results of this study suggest that aripiprazole augmentation may be used safely in maladaptive behaviors of some populations of PDD. However, future studies are required to confirm these preliminary findings.
Aripiprazole; Augmentation; Autism; Pervasive developmental disorder
The Wnt pathway effector gene TCF7L2 has been linked to type II diabetes, making it important to study the role of Wnt signaling in diabetes pathogenesis. We examined the expression of multiple Wnt pathway components in pancreases from normal individuals and type II diabetic individuals. Multiple members of the Wnt signaling pathway, including TCF7L2, Wnt2b, β-catenin, pGSK3β, TCF3, cyclinD1, and c-myc, were undetectable or expressed at low levels in islets from nondiabetic individuals, but were also upregulated specifically in islets of type II diabetic patients. Culture of pancreatic tissue and islet isolation led to Wnt activation that was reversed by the Wnt antagonist sFRP, demonstrating that Wnt activation in that setting was due to soluble Wnt factors. These data support a model in which the Wnt pathway plays a dynamic role in the pathogenesis of type II diabetes and suggest manipulation of Wnt signaling as a new approach to β-cell-directed diabetes therapy.
Platelet abnormalities are well-recognized complications of diabetes mellitus (DM). Mitochondria play a central role in platelet metabolism and activation. Mitochondrial dysfunction is evident in DM. The molecular pathway for hyperglycemia-induced mitochondrial dysfunction in DM platelets is unknown.
Methods and Results
Using both human and humanized mouse models, we report that hyperglycemia-induced aldose reductase (AR) activation, and subsequent reactive oxygen species (ROS) production, leads to increased p53 phosphorylation (Ser15), which promotes mitochondrial dysfunction, damage and rupture by sequestration of the anti-apoptotic protein Bcl-xL. In a glucose dose dependent manner, severe mitochondrial damage leads to loss of mitochondrial membrane potential and platelet apoptosis (cytochrome c release, caspase 3 activation and phosphatidylserine exposure). Although platelet hyperactivation, mitochondrial dysfunction, AR activation, ROS production and p53 phosphorylation are all induced by hyperglycemia, we demonstrate that platelet apoptosis and hyperactivation are two distinct states, dependent upon the severity of the hyperglycemia and mitochondrial damage. Combined, both lead to increased thrombus formation in a mouse blood stasis model.
AR contributes to diabetes-mediated mitochondrial dysfunction and damage through the activation of p53. The degree of mitochondrial dysfunction and damage determines whether hyperactivity (mild damage) or apoptosis (severe damage) will ensue. These signaling components provide novel therapeutic targets for DM thrombotic complications.
aldose reductase; p53; platelet; diabetes mellitus; mitochondria; apoptosis
We report three patients with normal karyotype (NK) ALL, who showed genetic aberrations as determined by high-resolution single nucleotide polymorphism array (SNP-A) analysis at both diagnosis and relapse. We evaluated the clinical relevance of the SNP-A assay for the detection of subtle changes in the size of affected genetic lesions at relapse as well as the prognostic value of the assay. In our patients, application of the SNP-A assay enabled sensitive detection of cryptic changes affecting clinically important genes in NK ALL. Therefore, this assay seems to be more advantageous compared to other conventional methods such as FISH assay, HemaVision (DNA Technology, Denmark), and conventional karyotyping for the detection of an "unstable genotype" at relapse, which may be associated with microscopic clonal evolution and poor prognosis. Further comprehensive studies are required to confirm the issues presented by our case patients in this report.
Acute lymphoblastic leukemia; Array; Clonal evolution; Normal karyotype; Prognosis; Single nucleotide polymorphism
The basal forebrain provides the primary source of cholinergic input to the cortex, and it plays a crucial role in promoting wakefulness and arousal. However, whether rapid changes in basal forebrain neuron spiking in awake animals can dynamically influence sensory perception is unclear. Here we show that basal forebrain cholinergic neurons rapidly regulate cortical activity and visual perception in awake, behaving mice. Optogenetic activation of the cholinergic neurons or their V1 axon terminals improved performance of a visual discrimination task on a trial-by-trial basis. In V1, basal forebrain activation enhanced visual responses and desynchronized neuronal spiking, which could partly account for the behavioral improvement. Conversely, optogenetic basal forebrain inactivation decreased behavioral performance, synchronized cortical activity and impaired visual responses, indicating the importance of cholinergic activity in normal visual processing. These results underscore the causal role of basal forebrain cholinergic neurons in fast, bidirectional modulation of cortical processing and sensory perception.
The principal finding of this study is that two drugs, alverine and benfluorex, used in vastly different clinical settings and previously unknown to share mechanistic or structural similarity, activated the nuclear receptor transcription factor HNF4α. Both were hits in a high-throughput screen for compounds that reversed the inhibitory effect of the fatty acid palmitate on human insulin promoter activity. Alverine is used in the treatment of irritable bowel syndrome, while benfluorex (Mediator) was used to treat hyperlipidemia and type II diabetes. Benfluorex was withdrawn from the market recently because of serious cardiovascular side effects related to fenfluramine-like activity. Strikingly, alverine and benfluorex have a previously unrecognized structural similarity, consistent with a common mechanism of action. Gene expression and biochemical studies revealed that they both activate HNF4α. This novel mechanism of action should lead to a reinterpretation of previous studies with these drugs and suggests a path towards the development of therapies for diseases such as inflammatory bowel and diabetes that may respond to HNF4α activators.
Poor accessibility to affordable healthy foods is associated with higher rates of obesity and diet-related chronic diseases. We present our process evaluation of a youth-targeted environmental intervention (Baltimore Healthy Eating Zones) that aimed to increase the availability of healthy foods and promote these foods through signage, taste tests and other interactive activities in low-income Baltimore City. Trained peer educators reinforced program messages. Dose, fidelity and reach—as measured by food stocking, posting of print materials, distribution of giveaways and number of interactions with community members—were collected in six recreation centers and 21 nearby corner stores and carryouts. Participating stores stocked promoted foods and promotional print materials with moderate fidelity. Interactive sessions were implemented with high reach and dose among both adults and youth aged 10–14 years, with more than 4000 interactions. Recreation centers appear to be a promising location to interact with low-income youth and reinforce exposure to messages.
Mitsugumin 53 (MG53) negatively regulates skeletal myogenesis by targeting insulin receptor substrate 1 (IRS-1). Here, we show that MG53 is a ubiquitin E3 ligase that induces IRS-1 ubiquitination with the help of an E2-conjugating enzyme UBE2H. Molecular manipulations that disrupt the E3 ligase function of MG53 abolishes IRS-1 ubiquitination and enhances skeletal myogenesis. Skeletal muscles derived from the MG53−/− mice show an elevated IRS-1 level with enhanced insulin signaling, which protects the MG53−/− mice from developing insulin resistance when challenged with a high fat/high sucrose diet. Muscle samples derived from human diabetic patients and mice with insulin resistance show normal expression of MG53, indicating that altered MG53 expression does not serve as a causative factor for the development of metabolic disorders. Thus, therapeutic interventions that target the interaction between MG53 and IRS-1 may be a novel approach for the treatment of metabolic diseases that are associated with insulin resistance.
We established a method for creation of an anatomic femoral tunnel with minimal damage to the remnant bundle in remnant-preserving anterior cruciate ligament (ACL) reconstruction. The goals of this surgical technique were to preserve the remnant bundle as much as possible, especially at the femoral insertion, and to make the tunnel at the anatomic position. The critical points are that the posterior side of the femoral footprint of the ACL is observed through the posterolateral portal using a 70° arthroscope and a femoral tunnel is made by use of an outside-in technique with remnant preservation. This technique allows for easy viewing of the posterior side of the ACL and enables performance of an anatomic ACL reconstruction.
Introduction: Clarification of the relationship between external stimuli and brain response has been an important topic in neuroscience and brain rehabilitation. In the current study, using functional near infrared spectroscopy (fNIRS), we attempted to investigate cortical activation patterns generated during execution of a rehabilitation robotic hand.
Methods: Ten normal subjects were recruited for this study. Passive movements of the right fingers were performed using a rehabilitation robotic hand at a frequency of 0.5 Hz. We measured values of oxy-hemoglobin (HbO), deoxy-hemoglobin (HbR) and total-hemoglobin (HbT) in five regions of interest: the primary sensory-motor cortex (SM1), hand somatotopy of the contralateral SM1, supplementary motor area (SMA), premotor cortex (PMC), and prefrontal cortex (PFC).
Results: HbO and HbT values indicated significant activation in the left SM1, left SMA, left PMC, and left PFC during execution of the rehabilitation robotic hand (uncorrected, p < 0.01). By contrast, HbR value indicated significant activation only in the hand somatotopic area of the left SM1 (uncorrected, p < 0.01).
Conclusions: Our results appear to indicate that execution of the rehabilitation robotic hand could induce cortical activation.
functional NIRS; robot; cortical activation; brain plasticity; rehabilitation
Switches between different behavioral states of the animal are associated with prominent changes in global brain activity, between sleep and wakefulness or from inattentive to vigilant states. What mechanisms control brain states, and what are the functions of the different states? Here we summarize current understanding of the key neural circuits involved in regulating brain states, with a particular emphasis on the subcortical neuromodulatory systems. At the functional level, arousal and attention can greatly enhance sensory processing, whereas sleep and quiet wakefulness may facilitate learning and memory. Several new techniques developed over the past decade promise great advances in our understanding of the neural control and function of different brain states.
Inhibitory interneurons are essential components of the neural circuits underlying various brain functions. In the neocortex, a large diversity of GABAergic interneurons have been identified based on their morphology, molecular markers, biophysical properties, and innervation pattern1,2,3. However, how the activity of each subtype of interneurons contributes to sensory processing remains unclear. Here we show that optogenetic activation of parvalbumin-positive (PV+) interneurons in mouse V1 sharpens neuronal feature selectivity and improves perceptual discrimination. Using multichannel recording with silicon probes4,5 and channelrhodopsin 2 (ChR2)-mediated optical activation6, we found that elevated spiking of PV+ interneurons markedly sharpened orientation tuning and enhanced direction selectivity of nearby neurons. These effects were caused by the activation of inhibitory neurons rather than decreased spiking of excitatory neurons, since archaerhodopsin-3 (Arch)-mediated optical silencing7 of calcium/calmodulin-dependent protein kinase IIα-positive (CaMKIIα+) excitatory neurons caused no significant change in V1 stimulus selectivity. Moreover, the improved selectivity specifically required PV+ neuron activation, since activating somatostatin (SOM+) or vasointestinal peptide (VIP+) interneurons had no significant effect. Notably, PV+ neuron activation in awake mice caused a significant improvement in their orientation discrimination, mirroring the sharpened V1 orientation tuning. Together, these results provide the first demonstration that visual coding and perception can be improved by elevated spiking of a specific subtype of cortical inhibitory interneurons.
Elucidating mechanisms of cell cycle control in normally quiescent human pancreatic β-cells has the potential to impact regeneration strategies for diabetes. Previously we demonstrated that Id3, a repressor of basic Helix-Loop-Helix (bHLH) proteins, was sufficient to induce cell cycle entry in pancreatic duct cells, which are closely related to β-cells developmentally. We hypothesized that Id3 might similarly induce cell cycle entry in primary human β-cells. To test this directly, adult human β-cells were transduced with adenovirus expressing Id3. Consistent with a replicative response, β-cells exhibited BrdU incorporation. Further, Id3 potently repressed expression of the cyclin dependent kinase inhibitor p57Kip2, a gene which is also silenced in a rare β-cell hyperproliferative disorder in infants. Surprisingly, however, BrdU positive β-cells did not express the proliferation markers Ki67 and pHH3. Instead, BrdU uptake reflected a DNA damage response, as manifested by hydroxyurea incorporation, γH2AX expression and 53BP1 subcellular relocalization. The uncoupling of BrdU uptake from replication raises a cautionary note about interpreting studies relying solely upon BrdU incorporation as evidence of β-cell proliferation. The data also establish that loss of p57Kip2 is not sufficient to induce cell cycle entry in adult β-cells. Moreover, the differential responses to Id3 between duct and β-cells reveal that β-cells possess intrinsic resistance to cell cycle entry not common to all quiescent epithelial cells in the adult human pancreas. The data provide a much needed comparative model for investigating the molecular basis for this resistance in order to develop a strategy for improving replication competence in β-cells.
DNA damage; regeneration; replication
Hepatocyte Nuclear Factor (HNF)4α is a central regulator of gene expression in cell types that play a critical role in metabolic homeostasis, including hepatocytes, enterocytes, and pancreatic β-cells. Although fatty acids were found to occupy the HNF4α ligand-binding pocket and proposed to act as ligands, there is controversy about both the nature of HNF4α ligands as well as the physiological role of the binding. Here, we report the discovery of potent synthetic HNF4α antagonists through a high-throughput screen for effectors of the human insulin promoter. These molecules bound to HNF4α with high affinity and modulated the expression of known HNF4α target genes. Notably, they were found to be selectively cytotoxic to cancer cell lines in vitro and in vivo, although in vivo potency was limited by suboptimal pharmacokinetic properties. The discovery of bioactive modulators for HNF4α raises the possibility that diseases involving HNF4α, such as diabetes and cancer, might be amenable to pharmacologic intervention by modulation of HNF4α activity.
To review the meniscus from a historical perspective especially on surgical management and general guidelines for arthroscopic meniscectomy procedures for various types of meniscal tears. We searched MEDLINE and PubMed for the years of 1980-2010 using the terms meniscus, meniscal repair, menisectomy, and arthroscopy. Orthopedic surgeons frequently encounter patients with pain or functional impairment of the knee joint and repair or resection of the injured meniscus is one of the most common orthopedic operative procedures. The object of meniscal surgery is to reduce pain, restore functional meniscus and prevent the development of degenerative osteoarthritis in the involved knee. Historically, total meniscectomy was a common procedure performed for meniscus tear symptoms. However, it has been reported that total meniscectomy has deleterious effects on the knee. In the past, the menisci were thought as a functionless remnant tissue. Currently, it is known that the meniscus is an important structure for knee joint function. Menisci provide several vital functions including mechanical support, localized pressure distribution, and lubrication to the knee joint. It is widely accepted that the function of the meniscus can be preserved through minimal excision. An arthroscopic partial meniscectomy preserving more of the meniscus is preferred over total meniscectomy. In recent decades, this shift toward arthroscopic partial meniscectomy has led to the development of new surgical techniques.
Menisectomy; Arthroscopy; Prognosis
A number of diabetogenic stimuli interact to influence insulin promoter activity, making it an attractive target for both mechanistic studies and therapeutic interventions. High-throughput screening (HTS) for insulin promoter modulators has the potential to reveal novel inputs into the control of that central element of the pancreatic β-cell. A cell line from human islets in which the expression of insulin and other β-cell-restricted genes are modulated by an inducible form of the bHLH transcription factor E47 was developed. This cell line, T6PNE, was adapted for HTS by transduction with a vector expressing green fluorescent protein under the control of the human insulin promoter. The resulting cell line was screened against a library of known drugs for those that increase insulin promoter activity. Members of the phenothiazine class of neuroleptics increased insulin gene expression upon short-term exposure. Chronic treatment, however, resulted in suppression of insulin promoter activity, consistent with the effect of phenothiazines observed clinically to induce diabetes in chronically treated patients. In addition to providing insights into previously unrecognized targets and mechanisms of action of phenothiazines, the novel cell line described here provides a broadly applicable platform for mining new molecular drug targets and central regulators of β-cell differentiated function.
diabetes; chlorpromazine; ethopropazine
We describe the effects of structural intervention to enhance the quality of HIV test counseling interaction with men who have sex with men (MSM) in San Francisco.
Audio recordings of 28 rapid HIV test sessions by seven counselors were collected in two phases: before and after implementation of a waiting room intervention prior to the session. The sessions were analyzed using sequence maps to visualize and compare the sequence and distribution of four activities: counseling, information delivery, data collection, and sample collection.
Prior to the intervention, counselors and clients often oriented to data collection about the client’s past risk as if it were a survey. In sessions recorded after the intervention, questions about past risk were dispersed throughout the session and embedded within an elaborated discussion of the client’s particular life circumstances.
Direct observation with the aid of sequence maps illuminates the ways that counselors and clients collaboratively orient to various tasks.
We demonstrated the feasibility of a structural intervention that improved the quality of both counseling and the accuracy of client risk data without requiring additional session time or counselor training.
To compare the menopausal symptom experiences of sub-ethnic groups of Asian American midlife women.
A cross-sectional study among 91 Asian American women online. Questions about background characteristics, ethnic identity, and health and menopausal status, and the Midlife Women’s Symptom Index were used. The data were analyzed using descriptive and inferential statistics.
The most frequently reported and the most severe symptoms differed by sub-ethnicity. The total number of symptoms differed by sub-ethnicity, as did total severity scores for the symptoms.
Discussion, Conclusion, and Implications for Practice
Researchers and clinicians should be aware of sub-ethnic differences.
Asian; Menopausal Symptom; Experience; Culture
The food environment is associated with obesity risk and diet-related chronic diseases. Despite extensive research conducted on retail food stores, little is known about prepared food sources (PFSs). We conducted an observational assessment of all PFSs (N = 92) in low-income neighborhoods in Baltimore. The most common PFSs were carry-outs, which had the lowest availability of healthy food choices. Only a small proportion of these carry-outs offered healthy sides, whole wheat bread, or entrée salads (21.4%, 7.1%, and 33.9%, respectively). These findings suggest that carry-out-specific interventions are necessary to increase healthy food availability in low-income urban neighborhoods.
food environment; prepared food; restaurants; carry-outs; low-income neighborhoods
Beta-cell replication dramatically declines with age. Here, we report that the level of CENP-A, a protein required for cell division, declines precipitously with age in an islet-specific manner. CENP-A is essentially undetectable after age 29 in humans. However, exocrine cells retain CENP-A expression. The decline in islet-cell CENP-A expression is more striking in humans than in mice, where CENP-A expression continues to be detectable at low levels even in elderly mice. The mechanism by which CENP-A declines appears to be post-transcriptional, as there was no correlation between CENP-A mRNA levels and age or islet purity. This finding has implications for efforts to induce beta-cell replication as a treatment for diabetes.
β-cell; replication; pancreas; diabetes
Using a feminist approach, we examined the menopausal symptom experience of Hispanic midlife women in the U.S. This was a qualitative online forum study among 27 Hispanic midlife women in the U.S. Seven topics related to menopausal symptom experience were used to administer the 6-month online forum. The data were analyzed using thematic analysis. Four themes were identified: (a) “Cambio de vida (change of life),” (b) “being silent about menopause,” (c) “trying to be optimistic,” and (d) “getting support.” More in-depth studies with diverse groups of Hispanic women are needed while considering family as a contextual factor.
Hispanic; Midlife Women; Menopause; Symptoms
Islet transplantation is limited by the need for chronic immunosuppression and the paucity of donor tissue. As new sources of human β-cells are developed (e.g., stem cell-derived tissue), transplanting them in a durable device could obviate the need for immunosuppression, while also protecting the patient from any risk of tumorigenicity. Here, we studied (1) the survival and function of encapsulated human β-cells and their progenitors and (2) the engraftment of encapsulated murine β-cells in allo- and autoimmune settings.
Human islets and human fetal pancreatic islet-like cell clusters were encapsulated in polytetrafluorethylene devices (TheraCyte) and transplanted into immunodeficient mice. Graft survival and function was measured by immunohistochemistry, circulating human C-peptide levels, and blood glucose levels. Bioluminescent imaging was used to monitor encapsulated neonatal murine islets.
Encapsulated human islet-like cell clusters survived, replicated, and acquired a level of glucose responsive insulin secretion sufficient to ameliorate hyperglycemia in diabetic mice. Bioluminescent imaging of encapsulated murine neonatal islets revealed a dynamic process of cell death followed by regrowth, resulting in robust long-term allograft survival. Further, in the non-obese diabetic (NOD) mouse model of type I diabetes, encapsulated primary β-cells ameliorated diabetes without stimulating a detectable T-cell response.
We demonstrate for the first time that human β-cells function is compatible with encapsulation in a durable, immunoprotective device. Moreover, our study suggests that encapsulation of β-cells before terminal differentiation will be a successful approach for new cell-based therapies for diabetes, such as those derived from stem cells.
Encapsulation; Diabetes; Islet transplantation; Immunoisolation
Cultural values and beliefs related to cancer and pain have been used to explain ethnic differences in cancer pain experience. Yet, very little is known about similarities and differences in cancer pain experience among different ethnic groups.
To explore similarities and differences in cancer pain experience among four major ethnic groups in the United States.
A feminist approach by Hall and Stevens was used. This was a cross-sectional qualitative study among 22 White, 15 Hispanic, 11 African American, and 27 Asian cancer patients recruited through both Internet and community settings. Four ethnic-specific online forums were conducted for 6 months. Nine topics related to cancer pain experience were used to guide the online forums. The collected data were analyzed using thematic analysis involving line-by-line coding, categorization, and thematic extraction.
All participants across ethnic groups reported “communication breakdowns” with their health care providers and experienced “changes in perspectives.” All of them reported that their cancer pain experience was “gendered experience.” White patients focused on how to control their pain and treatment selection process, while ethnic minority patients tried to control pain by minimizing and normalizing it. White patients sought out diverse strategies of pain management; ethnic minority patients tried to maintain normal lives and use natural modalities for pain management. Finally, the cancer pain experience of White patients was highly individualistic and independent, while that of ethnic minority patients was family-oriented.
These findings suggest that nurses need to use culturally competent approaches to cancer pain management for different ethnic groups. Also, the findings suggest further in-depth cultural studies on the pain experience of multiethnic groups of cancer patients.
cancer; ethnic minority; experience; pain