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
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
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
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
The cytoplasmic polyadenylation element (CPE)-binding protein (CPEB) binds to CPE containing mRNAs on their 3' untranslated regions (3'UTRs). This RNA binding protein comes out many important tasks, especially in learning and memory, by modifying the translational efficiency of target mRNAs via poly (A) tailing. Overexpressed CPEB has been reported to induce the formation of stress granules (SGs), a sort of RNA granule in mammalian cell lines. RNA granule is considered to be a potentially important factor in learning and memory. However, there is no study about RNA granule in Aplysia. To examine whether an Aplysia CPEB, ApCPEB1, forms RNA granules, we overexpressed ApCPEB1-EGFP in Aplysia sensory neurons. Consistent with the localization of mammalian CPEB, overexpressed ApCPEB1 formed granular structures, and was colocalized with RNAs and another RNA binding protein, ApCPEB, showing that ApCPEB1 positive granules are RNA-protein complexes. In addition, ApCPEB1 has a high turnover rate in RNA granules which were mobile structures. Thus, our results indicate that overexpressed ApCPEB1 is incorporated into RNA granule which is a dynamic structure in Aplysia sensory neuron. We propose that ApCPEB1 granule might modulate translation, as other RNA granules do, and furthermore, influence memory.
Aplysia; CPEB protein; fluorescence recovery after photobleaching; mRNA cleavage and polyadenylation factors; neurons; protein biosynthesis
We report a case of pseudo-Duane's retraction syndrome with entrapment of the medial rectus muscle in an old medial orbital wall fracture presenting identical clinical symptoms as Duane's retraction syndrome. A 15-year-old boy presented with persistent limited right eye movement since a young age. Examination showed marked limited abduction, mildly limited adduction, and globe retraction accompanied by narrowing of the palpebral fissure during attempted adduction in the right eye. He showed a right esotropia of 16 prism diopters and his head turned slightly to the right. A slight enophthalmos was noted in his right eye. A computed tomography scan demonstrated entrapment of the medial rectus muscle and surrounding tissues in an old medial orbital wall fracture. A forced duction test revealed a marked restriction of abduction in the right eye. A 5 mm recession of the right medial rectus muscle was performed. Postoperatively, the patient's head turn and esotropia in the primary position were successfully corrected, but there was still some limitations to his ocular movement. The importance of several tests such as the forced duction test and an imaging study should be emphasized in making a diagnosis for limitation of eye movement.
Duane's retraction syndrome; Medial orbital wall fracture; Pseudo-Duane's retraction syndrome
To evaluate the effect of X-ray irradiation on apoptosis and change of expression of aquaporin 5 (AQP5) and transforming growth factor-β(TGF-β) in the rat submandibular gland (SMG).
Materials and Methods
SMGs of 120 male Sprague-Dawley rats were irradiated with a single X-ray dose (3, 10, 20, or 30 Gy). At the early and late post-irradiation phase, apoptosis was measured by the terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling (TUNEL) method, and expression of AQP5 and TGF-β was determined by immunohistochemical staining.
At the late post-irradiation phase, increased apoptosis was evident and marked decreases of expression of AQP5 expression by acinar cells and TGF-β expression by ductal cells were evident.
Apoptosis after X-ray irradiation develops relatively late in rat SMG. Irradiation reduces AQP5 and TGF-β expression in different SMG cell types.
Submandibular gland; Radiation; Apoptosis; AQP5; TGF-β
Human umbilical cord blood-derived mesenchymal stem cells (MSCs) are known to possess the potential for multiple differentiations abilities in vitro and in vivo. In canine system, studying stem cell therapy is important, but so far, stem cells from canine were not identified and characterized. In this study, we successfully isolated and characterized MSCs from the canine umbilical cord and its fetal blood. Canine MSCs (cMSCs) were grown in medium containing low glucose DMEM with 20% FBS. The cMSCs have stem cells expression patterns which are concerned with MSCs surface markers by fluorescence-activated cell sorter analysis. The cMSCs had multipotent abilities. In the neuronal differentiation study, the cMSCs expressed the neuronal markers glial fibrillary acidic protein (GFAP), neuronal class III β tubulin (Tuj-1), neurofilament M (NF160) in the basal culture media. After neuronal differentiation, the cMSCs expressed the neuronal markers Nestin, GFAP, Tuj-1, microtubule-associated protein 2, NF160. In the osteogenic & chondrogenic differentiation studies, cMSCs were stained with alizarin red and toluidine blue staining, respectively. With osteogenic differentiation, the cMSCs presented osteoblastic differentiation genes by RT-PCR. This finding also suggests that cMSCs might have the ability to differentiate multipotentially. It was concluded that isolated MSCs from canine cord blood have multipotential differentiation abilities. Therefore, it is suggested that cMSCs may represent a be a good model system for stem cell biology and could be useful as a therapeutic modality for canine incurable or intractable diseases, including spinal cord injuries in future regenerative medicine studies.
canine umbilical cord blood; differentiation study; mesenchymal stem cell; stem cell characterization
Despite the current emphasis in the US on HIV testing and serostatus disclosure as HIV-prevention strategies, little is known about men who have sex with men's (MSM) perceptions of serostatus disclosure by sexual partners. This study used conversation analysis to examine recordings of HIV-test counseling sessions in order to understand how counselors and clients conceptualize and discuss sex partners' disclosure of HIV status. Of 50 test sessions audio-recorded in four publicly funded sites in Northern California, 47 sessions included a discussion about sexual partners' serostatus disclosure, in the vast majority of these (91.5%), counselors and clients avoided directly asserting their knowledge of partners' serostatus. Throughout the discussions, counselors and clients co-constructed the sense of distrust, uncertainty and unknowability of partners' serostatus. The implications of our findings for evaluating the effectiveness of HIV status disclosure as a prevention strategy are discussed.
serostatus disclosure; HIV test counseling; MSM
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.
The axon guidance cue netrin is importantly involved in neuronal development. DCC (deleted in colorectal cancer) is a functional receptor for netrin and mediates axon outgrowth and the steering response. Here we show that different regions of the intracellular domain of DCC directly interacted with the tyrosine kinases Src and focal adhesion kinase (FAK). Netrin activated both FAK and Src and stimulated tyrosine phosphorylation of DCC. Inhibition of Src family kinases reduced DCC tyrosine phosphorylation and blocked both axon attraction and outgrowth of neurons in response to netrin. Mutation of the tyrosine phosphorylation residue in DCC abolished its function of mediating netrin-induced axon attraction. On the basis of our observations, we suggest a model in which DCC functions as a kinase-coupled receptor, and FAK and Src act immediately downstream of DCC in netrin signaling.
The aim of this study was to evaluate the effect of lowering the fasting plasma glucose (FPG) criteria for impaired fasting glucose (IFG) on the prevalence of IFG and the risk for the development of diabetes associated with IFG in Koreans.
Materials and Methods
A total of 7,211 subjects who had normal glucose tolerance (NGT) or IFG were recruited. Subjects were evaluated at baseline and after two years follow up. Clinical data including total cholesterol, FPG and blood pressure were examined.
Lowering the criteria for IFG from 6.1 mmol/L (110 mg/dL) to 5.6 mmol/L (100 mg/dL) increased the prevalence of IFG from 6.6% (494 subjects) to 24.4% (1829 subjects). After the 2 years follow up period, 91 subjects (1.3%) developed diabetes. Twenty one (0.3%) subjects developed diabetes among 5,382 NGT subjects and 70 (3.8%) subjects developed diabetes among 1,829 IFG (5.6 - 7.0 mmol/L) subjects. Lowering the IFG threshold from 6.1 mmol/L to 5.6 mmol/L resulted in a 18.4% decrease in specificity and 23.9% increase in sensitivity for predicting diabetes. The baseline FPG for predicting the development of diabetes after 2 years at a point on the receiver operating characteristic curve that was closest to the ideal 100% sensitivity and 100% specificity was 5.7 mmol/L (103 mg/dL).
Lowering the FPG criterion of IFG should have benefits in predicting new onset type 2 diabetes mellitus in Koreans. The economic and health benefits of applying the new IFG criteria should be evaluated in future studies.
Impaired fasting glucose; normal glucose tolerance; type 2 diabetes mellitus