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This study uses a qualitative methodology to explore mental health literacy, specifically perceptions of prognosis, which is typically investigated with a quantitative, questionnaire-based approach. Two vignettes--one of a person with schizophrenia and one with depression--were shown to three mental health nurses and three psychiatrists. During semi-structured, open-ended interviews, they were asked to discuss their thoughts about the prognosis for the patient presented in each vignette. Participants tended to use the terms 'prognosis' and 'outcome' interchangeably. Psychiatrists tended to be more guarded in determining a prognosis than nurses. Both groups emphasized the importance of clinical experience in formulating views. However, nurses also discussed the role of the multidisciplinary team, whilst psychiatrists emphasized their reliance upon the scientific literature in shaping opinions. Participants identified information relevant for incorporating into future vignettes, to allow more informed research into literacy. The results of quantitative mental health literacy research should be interpreted with caution. Simplifying responses to allow comparative analysis is necessary, but masks more complex and important interpretations. Further qualitative research is recommended, the results of which can inform more comprehensive quantitative studies in the area. [ABSTRACT FROM AUTHOR]

Background: Because intrauterine devices (IUD) invoke acute and chronic inflammatory responses in the endometrium, it is possible that prolonged insertion of an IUD could induce endometrial cancer.Methods: We examined the relation between use of an IUD and endometrial cancer risk using data from a multicentre case-control study involving 405 endometrial cancer cases and 297 population controls.Results: A total of 20 (4.9%) cases and 34 (11.4%) controls reported any use of an IUD. After adjustment for potential confounders, IUD use was not associated with an increased risk of endometrial cancer (RR = 0.56 for ever use; 95% CI: 0.3-1.0). Little reduction in risk was observed among women who last used an IUD within 10 years of the index date (RR = 0.84; 95% CI: 0.3-2.4) but risk was decreased among women who used an IUD in the more distant past (RR = 0.45; 95% CI: 0.2-1.0). Risk did not vary consistently with number of years of IUD use or with years since first use. Risk was not increased among women who used inert devices (RR = 0.46; 95% CI: 0.3-3.6) or those who used devices containing copper (RR = 1.08; 95% CI: 0.1-3.6).Conclusion: These data are reassuring in that they do not provide any evidence of an increased risk of endometrial cancer among women who have used IUD. [ABSTRACT FROM AUTHOR]

Human induced pluripotent stem cell (hiPSC)-derived intestinal organoids are valuable tools for researching developmental biology and personalized therapies, but their closed topology and relative immature state limit applications. Here, we use organ-on-chip technology to develop a hiPSC-derived intestinal barrier with apical and basolateral access in a more physiological in vitro microenvironment. To replicate growth factor gradients along the crypt-villus axis, we locally expose the cells to expansion and differentiation media. In these conditions, intestinal epithelial cells self-organize into villus-like folds with physiological barrier integrity, and myofibroblasts and neurons emerge and form a subepithelial tissue in the bottom channel. The growth factor gradients efficiently balance dividing and mature cell types and induce an intestinal epithelial composition, including absorptive and secretory lineages, resembling the composition of the human small intestine. This well-characterized hiPSC-derived intestine-on-chip system can facilitate personalized studies on physiological processes and therapy development in the human small intestine., Competing Interests: Declaration of interests The authors declare no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Cardiovascular toxicity causes adverse drug reactions and may lead to drug removal from the pharmaceutical market. Cancer therapies can induce life-threatening cardiovascular side effects such as arrhythmias, muscle cell death, or vascular dysfunction. New technologies have enabled cardiotoxic compounds to be identified earlier in drug development. Human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (CMs) and vascular endothelial cells (ECs) can screen for drug-induced alterations in cardiovascular cell function and survival. However, most existing hiPSC models for cardiovascular drug toxicity utilize two-dimensional, immature cells grown in static culture. Improved in vitro models to mechanistically interrogate cardiotoxicity would utilize more adult-like, mature hiPSC-derived cells in an integrated system whereby toxic drugs and protective agents can flow between hiPSC-ECs that represent systemic vasculature and hiPSC-CMs that represent heart muscle (myocardium). Such models would be useful for testing the multi-lineage cardiotoxicities of chemotherapeutic drugs such as VEGFR2/PDGFR-inhibiting tyrosine kinase inhibitors (VPTKIs). Here, we develop a multi-lineage, fully-integrated, cardiovascular organ-chip that can enhance hiPSC-EC and hiPSC-CM functional and genetic maturity, model endothelial barrier permeability, and demonstrate long-term functional stability. This microfluidic organ-chip harbors hiPSC-CMs and hiPSC-ECs on separate channels that can be subjected to active fluid flow and rhythmic biomechanical stretch. We demonstrate the utility of this cardiovascular organ-chip as a predictive platform for evaluating multi-lineage VPTKI toxicity. This study may lead to the development of new modalities for the evaluation and prevention of cancer therapy-induced cardiotoxicity.

Purpose: To determine whether the addition of cisplatin-based chemotherapy (CT) to pelvic radiation therapy (RT) will improve the survival of early-stage, high-risk patients with cervical carcinoma., Patients and Methods: Patients with clinical stage IA 2 , IB, and IIA carcinoma of the cervix, initially treated with radical hysterectomy and pelvic lymphadenectomy, and who had positive pelvic lymph nodes and/or positive margins and/or microscopic involvement of the parametrium were eligible for this study. Patients were randomized to receive RT or RT + CT. Patients in each group received 49.3 GY RT in 29 fractions to a standard pelvic field. Chemotherapy consisted of bolus cisplatin 70 mg/m 2 and a 96-hour infusion of fluorouracil 1,000 mg/m 2 /d every 3 weeks for four cycles, with the first and second cycles given concurrent to RT., Results: Between 1991 and 1996, 268 patients were entered onto the study. Two hundred forty-three patients were assessable (127 RT + CT patients and 116 RT patients). Progression-free and overall survival are significantly improved in the patients receiving CT. The hazard ratios for progression-free survival and overall survival in the RT only arm versus the RT + CT arm are 2.01 ( P = .003) and 1.96 ( P = .007), respectively. The projected progression-free survivals at 4 years is 63% with RT and 80% with RT + CT. The projected overall survival rate at 4 years is 71% with RT and 81% with RT + CT. Grades 3 and 4 hematologic and gastrointestinal toxicity were more frequent in the RT + CT group., Conclusion: The addition of concurrent cisplatin-based CT to RT significantly improves progression-free and overall survival for high-risk, early-stage patients who undergo radical hysterectomy and pelvic lymphadenectomy for carcinoma of the cervix.

Background: Intestinal fibrosis is a serious complication of Crohn's disease. Numerous cell types including intestinal epithelial and mesenchymal cells are implicated in this process, yet studies are hampered by the lack of personalized in vitro models. Human intestinal organoids (HIOs) derived from induced pluripotent stem cells (iPSCs) contain these cell types, and our goal was to determine the feasibility of utilizing these to develop a personalized intestinal fibrosis model., Methods: iPSCs from 2 control individuals and 2 very early onset inflammatory bowel disease patients with stricturing complications were obtained and directed to form HIOs. Purified populations of epithelial and mesenchymal cells were derived from HIOs, and both types were treated with the profibrogenic cytokine transforming growth factor β (TGFβ). Quantitative polymerase chain reaction and RNA sequencing analysis were used to assay their responses., Results: In iPSC-derived mesenchymal cells, there was a significant increase in the expression of profibrotic genes (Col1a1, Col5a1, and TIMP1) in response to TGFβ. RNA sequencing analysis identified further profibrotic genes and demonstrated differential responses to this cytokine in each of the 4 lines. Increases in profibrotic gene expression (Col1a1, FN, TIMP1) along with genes associated with epithelial-mesenchymal transition (vimentin and N-cadherin) were observed in TGFβ -treated epithelial cells., Conclusions: We demonstrate the feasibility of utilizing iPSC-HIO technology to model intestinal fibrotic responses in vitro. This now permits the generation of near unlimited quantities of patient-specific cells that could be used to reveal cell- and environmental-specific mechanisms underpinning intestinal fibrosis., (© 2021 Crohn’s & Colitis Foundation. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation.)

Human intestinal organoids (HIOs) are increasingly being used to model intestinal responses to various stimuli, yet few studies have confirmed the fidelity of this modeling system. Given that the interferon-gamma (IFN-γ) response has been well characterized in various other cell types, our goal was to characterize the response to IFN-γ in HIOs derived from induced pluripotent stem cells (iPSCs). To achieve this, iPSCs were directed to form HIOs and subsequently treated with IFN-γ. Our results demonstrate that IFN-γ phosphorylates STAT1 but has little effect on the expression or localization of tight and adherens junction proteins in HIOs. However, transcriptomic profiling by microarray revealed numerous upregulated genes such as IDO1 , GBP1 , CXCL9 , CXCL10 and CXCL11 , which have previously been shown to be upregulated in other cell types in response to IFN-γ. Notably, "Response to Interferon Gamma" was determined to be one of the most significantly upregulated gene sets in IFN-γ-treated HIOs using gene set enrichment analysis. Interestingly, similar genes and pathways were upregulated in publicly available datasets contrasting the gene expression of in vivo biopsy tissue from patients with IBD against healthy controls. These data confirm that the iPSC-derived HIO modeling system represents an appropriate platform to evaluate the effects of various stimuli and specific environmental factors responsible for the alterations in the intestinal epithelium seen in various gastrointestinal conditions such as inflammatory bowel disease.

In inflammatory bowel disease (IBD), the intestinal epithelium is characterized by increased permeability both in active disease and remission states. The genetic underpinnings of this increased intestinal permeability are largely unstudied, in part due to a lack of appropriate modelling systems. Our aim is to develop an in vitro model of intestinal permeability using induced pluripotent stem cell (iPSC)-derived human intestinal organoids (HIOs) and human colonic organoids (HCOs) to study barrier dysfunction. iPSCs were generated from healthy controls, adult onset IBD, and very early onset IBD (VEO-IBD) patients and differentiated into HIOs and HCOs. EpCAM+ selected cells were seeded onto Transwell inserts and barrier integrity studies were carried out in the presence or absence of pro-inflammatory cytokines TNFα and IFNγ. Quantitative real-time PCR (qRT-PCR), transmission electron microscopy (TEM), and immunofluorescence were used to determine altered tight and adherens junction protein expression or localization. Differentiation to HCO indicated an increased gene expression of CDX2 , CD147, and CA2 , and increased basal transepithelial electrical resistance compared to HIO. Permeability studies were carried out in HIO- and HCO-derived epithelium, and permeability of FD4 was significantly increased when exposed to TNFα and IFNγ. TEM and immunofluorescence imaging indicated a mislocalization of E-cadherin and ZO-1 in TNFα and IFNγ challenged organoids with a corresponding decrease in mRNA expression. Comparisons between HIO- and HCO-epithelium show a difference in gene expression, electrophysiology, and morphology: both are responsive to TNFα and IFNγ stimulation resulting in enhanced permeability, and changes in tight and adherens junction architecture. This data indicate that iPSC-derived HIOs and HCOs constitute an appropriate physiologically responsive model to study barrier dysfunction and the role of the epithelium in IBD and VEO-IBD.

DNA damage occurs as a result of environmental insults and aging and, if unrepaired, may lead to chromosomal instability and tumorigenesis. Because GH suppresses ataxia-telangiectasia mutated kinase phosphorylation, decreases DNA repair, and increases DNA damage accumulation, we elucidated whether GH effects on DNA damage are mediated through induced IGF-1. In nontumorous human colon cells, GH, but not IGF-1, increased DNA damage. Stably disrupted IGF-1 receptor (IGF-1R) by lentivirus-expressing short hairpin RNA in vitro or treatment with the IGF-1R phosphorylation inhibitor picropodophyllotoxin (PPP) in vitro and in vivo led to markedly induced GH receptor (GHR) abundance, rendering cells more responsive to GH actions. Suppressing IGF-1R triggered DNA damage in both normal human colon cells and three-dimensional human intestinal organoids. DNA damage was further increased when cells with disrupted IGF-1R were treated with GH. Because GH induction of DNA damage accumulation appeared to be mediated not by IGF-1R but probably by more abundant GH receptor expression, we injected athymic mice with GH-secreting xenografts and then treated them with PPP. In these mice, high circulating GH levels were associated with increased colon DNA damage despite disrupted IGF-1R activity (P < 0.01), whereas GHR levels were also induced. Further confirming that GH effects on DNA damage are directly mediated by GHR signaling, GHR-/- mice injected with PPP did not show increased DNA damage, whereas wild-type mice with intact GHR exhibited increased colon DNA damage in the face of IGF-1 signaling suppression. The results indicate that GH directly induces DNA damage independent of IGF-1., (Copyright © 2019 Endocrine Society.)

T helper 9 (T H 9) cells are important for the development of inflammatory and allergic diseases. The T H 9 transcriptional network converges signals from cytokines and antigen presentation but is incompletely understood. Here, we identified TL1A, a member of the TNF superfamily, as a strong inducer of mouse and human T H 9 differentiation. Mechanistically, TL1A induced the expression of the transcription factors BATF and BATF3 and facilitated their binding to the Il9 promoter leading to enhanced secretion of IL-9. BATF- and BATF3-deficiencies impaired IL-9 secretion under T H 9 and T H 9-TL1A-polarizing conditions. In vivo, using a T-cell transfer model, we demonstrated that TL1A promoted IL-9-dependent, T H 9 cell-induced intestinal and lung inflammation. Neutralizing IL-9 antibodies attenuated TL1A-driven mucosal inflammation. Batf3 -/- T H 9-TL1A cells induced reduced inflammation and cytokine expression in vivo compared to WT cells. Our results demonstrate that TL1A promotes T H 9 cell differentiation and function and define a role for BATF3 in T-cell-driven mucosal inflammation.

Background and Aims: Human intestinal organoids derived from induced pluripotent stem cells have tremendous potential to elucidate the intestinal epithelium's role in health and disease, but it is difficult to directly assay these complex structures. This study sought to make this technology more amenable for study by obtaining epithelial cells from induced pluripotent stem cell-derived human intestinal organoids and incorporating them into small microengineered Chips. We then investigated if these cells within the Chip were polarized, had the 4 major intestinal epithelial subtypes, and were biologically responsive to exogenous stimuli., Methods: Epithelial cells were positively selected from human intestinal organoids and were incorporated into the Chip. The effect of continuous media flow was examined. Immunocytochemistry and in situ hybridization were used to demonstrate that the epithelial cells were polarized and possessed the major intestinal epithelial subtypes. To assess if the incorporated cells were biologically responsive, Western blot analysis and quantitative polymerase chain reaction were used to assess the effects of interferon (IFN)-γ, and fluorescein isothiocyanate-dextran 4 kDa permeation was used to assess the effects of IFN-γ and tumor necrosis factor-α on barrier function., Results: The optimal cell seeding density and flow rate were established. The continuous administration of flow resulted in the formation of polarized intestinal folds that contained Paneth cells, goblet cells, enterocytes, and enteroendocrine cells along with transit-amplifying and LGR5 + stem cells. Administration of IFN-γ for 1 hour resulted in the phosphorylation of STAT1, whereas exposure for 3 days resulted in a significant upregulation of IFN-γ related genes. Administration of IFN-γ and tumor necrosis factor-α for 3 days resulted in an increase in intestinal permeability., Conclusions: We demonstrate that the Intestine-Chip is polarized, contains all the intestinal epithelial subtypes, and is biologically responsive to exogenous stimuli. This represents a more amenable platform to use organoid technology and will be highly applicable to personalized medicine and a wide range of gastrointestinal conditions.

Study Design: Retrospective consecutive case series., Objective: The objective of this case series was to demonstrate the safety of a modified transfacet pedicle-sparing decompression and instrumented fusion in patients with thoracic disc herniations (TDHs)., Methods: Consecutive patients undergoing operative management of TDH from July 2007 to December 2011 using a posterior unilateral modified transfacet pedicle-sparing approach were identified. All patients underwent open or minimally invasive modified transfacet pedicle-sparing discectomy and segmental instrumentation with interbody fusion, performed by four different surgeons. Pre- and postoperative visual analog scale (VAS) pain scores, Nurick grade, and American Spinal Injury Association Impairment Scale (AIS) were analyzed from a retrospective chart review. Estimated blood loss and complications were also obtained., Results: Fifty-one patients were included that had operations for TDH. Thirty-nine patients had single level decompression and 12 had multilevel decompression. The total number of levels operated on was 64. Five patients were treated with minimally invasive surgery. A herniated disc level of T11-12 (n = 17) was treated most often. One major complication of epidural hematoma occurred. Minor complications such as malpositioned hardware, postoperative hematoma, wound infection, pseudoarthrosis, and pulmonary complications occurred in a few patients. Follow-up ranged from 1 to 46 months with 1 patient lost to follow-up. From preoperative to final postoperative: mean VAS scores improved from 8.31 to 4.05, AIS in all patients remained stable or improved, and Nurick scores improved from 3 to 2.6 on average. No intraoperative or permanent neurological deficit occurred., Conclusion: In our surgical series, 51 consecutive patients underwent modified transfacet pedicle-sparing approach to TDHs and experienced improvement of functional status as well as improvement of objective pain scales with no neurological complications. The posterior unilateral modified transfacet pedicle-sparing decompression and instrumented fusion approach to the thoracic spine is a safe and reproducible procedure for the treatment of TDHs., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Aim: To evaluate the feasibility of this novel surgical approach for treatment of cervical discitis and vertebral osteomyelitis., Material and Methods: This is a report of two patients who underwent anterior cervical decompression for discitis and vertebral osteomyelitis (DVO) with cervical spine reconstruction with polymethylmethacrylate impregnated with antibiotics (AI-PMMA)., Results: Both patients had successful procedures that were followed by 6 weeks of intravenous antibiotics. Stabilization and eradication of infection was achieved with clinical and radiographic stabilization seen in both. Follow-up is greater than 18 months and both patients remain off antibiotics., Conclusion: The described technique using AI-PMMA offers immediate structural stability and local delivery of high concentration of antibiotics. Use in two patients has demonstrated a cost effective, long-term biomechanically stable construct and infection control.

Objective: Genome-wide association studies have identified multiple Crohn's disease (CD) susceptibility loci, including association with non-coding intergenic single-nucleotide polymorphisms (SNPs) at 10q21., Design: To fine-map the 10q21 locus, the authors genotyped 86 SNPs in 1632 CD cases and 961 controls and performed single-marker and conditional analyses using logistic regression., Results: Association with CD risk spanning 11 SNPs (p<0.001) was observed. The most significant association observed was at the non-synonymous SNP, rs7076156 (Ala62Thr), in ZNF365. The alanine allele was over-represented in CD (p=5.23×10⁻⁷; OR=1.39 (95% CI 1.22 to 1.58)); allele frequency of 76% in CD and 69.7% in controls). Conditional analysis on rs7076156 nullified all other significant associations, suggesting that this is the causative variant at this locus. Four isoforms of ZNF365 have previously been identified, and rs7076156 is located in an exon unique to ZNF365 isoform D. The authors demonstrated, using reverse transcription-PCR, expression of ZNF365D in intestinal resections from both CD subjects and controls. Markedly reduced mean expression levels of ZNF365D were identified in Epstein-Barr virus-transformed lymphoblastoid cell lines from CD subjects homozygous for the risk allele (Ala). A whole-genome microarray expression study further suggested that the Ala62Thr change in ZNF365 isoform D is related to differential expression of the genes ARL4A, MKKS, RRAGD, SUMF2, TDR1 and ZNF148 in CD., Conclusions: Collectively, these data support the hypothesis that the non-synonymous Ala62Thr SNP, rs7076156, underlies the association between 10q21 and CD risk and suggest that this SNP acts by altering expression of genes under the control of ZNF365 isoform D.

Background: Dural injury is a common complication of lumbar spine surgery. Primary closure is the "gold standard.", Objective: This technical note describes a failed primary closure of a durotomy revised using an aneurysm clip., Methods: From 2005 to 2009, 5 patients underwent repair of a durotomy with the use of aneurysm clips. Resolution of the cerebrospinal fluid leak was seen in all patients. An 84-year-old woman underwent a laminectomy with an inadvertent dural tear that was primarily repaired with suture. On postoperative day 8, the patient presented with new incisional drainage. The wound was explored, and the dura had torn around the previous sutured closure. A curved aneurysm clip was used to obtain dural closure. Postoperatively, the patient's incision remained dry., Results: Microsurgical closure with suture is the primary modality in durotomy repair. Difficulty arises when the dura is friable and multiple small tears are present. Suturing worsens the durotomy. Also, the durotomy is often caused along a bony edge with limited visualization, requiring additional bone removal to suture, therefore risking destabilization of the spine., Conclusion: We describe the application of an aneurysm clip to treat a recurrent durotomy where the standard practice of sutured closure failed. Aneurysm clips offer a quick, safe, and secure manner to close dura without risking spinal destabilization. They offer significant benefit to already torn, friable dura. Postoperatively, patients have no limitations and are therefore prevented from being exposed to additional risks associated with bed rest. Aneurysm clips are cost and clinically effective in the management of dural injuries.

Background: The pharmacological stress agents adenosine and dipyridamole are contraindicated in asthma patients because of the risk of adenosine receptor-mediated bronchospasm. Binodenoson, a selective adenosine A(2A) receptor agonist, produces maximal coronary hyperemia during pharmacological stress testing yet has a low affinity for the adenosine A(1), A(2B), and A(3) receptors that are probably responsible for bronchospasm. This study was conducted to assess the safety of binodenoson in 87 healthy young adult volunteers with documented mild, intermittent asthma., Methods and Results: This study consisted of a dose-escalating, single-blinded phase and a placebo-controlled, double-blinded phase conducted in healthy, young adults with documented mild, intermittent, asthma. In the single-blinded phase, 3 sequential cohorts of 8 subjects received intravenous binodenoson (0.5, 1.0, and 1.5 microg/kg). In the double-blinded phase, commenced after medical review of results from the single-blinded phase, subjects were randomly assigned 2:1 to either binodenoson 1.5 microg/kg (n=41) or placebo (n=22). The primary end point was clinically significant bronchoconstriction, defined as a decrease in forced expiratory volume in 1 second of >/=20% from the preinjection measure. Secondary safety end points were changes from preinjection measure in forced expiratory volume in 1 second, forced vital capacity, and forced expiratory flow during the middle 50% of the forced vital capacity; vital signs; pulse oximetry; and adverse events. Binodenoson caused no clinically significant bronchoconstriction or alterations in pulmonary function parameters and transiently increased heart rate and systolic blood pressure. The most common treatment-emergent adverse events were tachycardia, dizziness, and flushing., Conclusions: Binodenoson was safe, well tolerated, and caused no clinically significant bronchoconstriction or pulmonary responses in a small population of healthy subjects with mild, intermittent asthma.

Background: Drugs used to induce stress for cardiac imaging studies often cause discomfort. Patient-reported intensity of discomfort should be considered when comparing such agents., Objective: The purpose of this study was to assess the psychometric properties of a modified visual analog scale (VAS) symptom-intensity measure and an overall-bother measure adapted to assess patient-reported intensity of the adverse events (AEs) associated with pharmacologic stress testing with adenosine, a pharmacologic stress myocardial perfusion imaging (PS-MPI) agent., Methods: Data were based on 2 complementary, open-label, multicenter, naturalistic, observational studies among patients completing a PS-MPI procedure. Content, concurrent, and discriminant validity was examined by correlating modified VAS symptom-intensity scores obtained from patients with investigator-rated intensity at time of event, overall bother, and patient-reported measures obtained during a structured interview. Test-retest reliability of the overall-bother measure was examined using 1- and 2-hour assessments, and concurrent validity was assessed by correlating counts of symptoms and other patient-reported measures. Responsiveness was examined by calculating change scores of the VAS symptom-intensity measures from baseline to 1 hour among patients who reported symptoms during the 1-hour monitoring period after PS infusion. Low to moderate correlation was defined as a coefficient between 0.3 and 0.5., Results: A total of 324 patients enrolled in the 2 studies. Content validity of the VAS symptom-intensity and overall-bother measures was established, with nearly all patients reporting that they were a useful way to rate symptom intensity and overall bother. VAS ratings were moderately to highly correlated with physician-rated AE intensity, and patient-reported assessments of symptom intensity, discomfort, and concern (r(s) = 0.21 r(s) = 0.84). Findings to support discriminant validity were inconclusive because of small sample size. Responsiveness was demonstrated with VAS symptom-intensity change scores ranging from 2.8 for headache to 4.9 for chest pain; effect sizes for these differences were large, ranging from 1.6 to 7.3, respectively., Conclusion: Findings support the validity, reliability, and responsiveness of the modified VAS symptom-intensity measure, and the reliability and validity of the overall-bother measure for use in patients completing PS procedures.

Increased transgene expression per vector genome is an important goal in the optimization of viral vectors for gene therapy. Herein we demonstrate that herpes simplex virus type 1 (HSV1) thymidine kinase (TK) gene sequences (1,131 bp) fused to the 3' end of lacZ increase transgene expression from high-capacity adenoviral vectors (HCAd), but not from first-generation (Ad) vectors. The woodchuck hepatitis virus posttranscriptional regulatory element (WPRE), in contrast, increased transgene expression levels from Ad but not HCAd vectors. The differential activity of the HSV1 TK gene and WPRE sequences was detected both in vitro and in vivo and suggests potentially different mechanisms of action or the interaction of these elements with vector genomic sequences.

Introduction: The authors present a 31-year-old man with a Chiari type I malformation (CM-1) occurring in conjunction with LEOPARD syndrome. He presented with severe dysphagia requiring placement of a percutaneous endoscopic gastrostomy (PEG) tube. Evaluation included magnetic resonance imaging (MRI) of the brain and cervical spine that revealed CM-1 with an extensive cervical syrinx. The patient underwent a suboccipital craniectomy with C1 laminectomy and duraplasty. His symptoms quickly resolved and his PEG tube was removed., Discussion: The occurrence of a CM-1 with LEOPARD syndrome has only been reported once, whereas CM-1 and Noonan syndrome have been linked in several cases. The similarity between LEOPARD and Noonan syndromes has been reported and many propose they represent 2 entities along a spectrum., Conclusion: In light of this spectrum, we propose that CM-1 should be considered in all patients presenting with LEOPARD-Noonan syndrome.

Background: A prospective, international, multicenter, observational study was conducted to investigate patient and population characteristics; utilization of radiopharmaceuticals and pharmacologic stress (PS) agents; imaging protocols; clinical outcomes; the incidence, intensity, and time to onset of adverse events; and the prognostic value of single photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI) procedures. The rationale, study methods, and data on presenting populations are described., Methods and Results: Investigators recorded the demographics, American College of Cardiology/American Heart Association pretest likelihood for coronary artery disease, cardiovascular risk factors, antianginal drug use, use of PS agents and associated adverse events, and radiopharmaceutical(s) and imaging protocol for each patient enrolled. SPECT images were reconstructed at each site; investigators assigned summed stress and summed rest scores using a 17-segment model (rating perfusion on a scale ranging from 0 to 4). Patients were followed up for 1 year for clinical outcomes of revascularization, nonfatal myocardial infarction, or death., Conclusion: The design offers a unique opportunity to study the characteristics of patients referred for SPECT imaging over a period of time consistent with the laboratories' usual practices, provides an up-to-date PS safety registry, and allows assessment of the prognostic value of PS SPECT MPI across a wide number of covariables, as well as relationships between patient and population characteristics, SPECT MPI results, and clinical outcomes.

Background: Astrocytes usually respond to trauma, stroke, or neurodegeneration by undergoing cellular hypertrophy, yet, their response to a specific immune attack by T cells is poorly understood. Effector T cells establish specific contacts with target cells, known as immunological synapses, during clearance of virally infected cells from the brain. Immunological synapses mediate intercellular communication between T cells and target cells, both in vitro and in vivo. How target virally infected astrocytes respond to the formation of immunological synapses established by effector T cells is unknown., Findings: Herein we demonstrate that, as a consequence of T cell attack, infected astrocytes undergo dramatic morphological changes. From normally multipolar cells, they become unipolar, extending a major protrusion towards the immunological synapse formed by the effector T cells, and withdrawing most of their finer processes. Thus, target astrocytes become polarized towards the contacting T cells. The MTOC, the organizer of cell polarity, is localized to the base of the protrusion, and Golgi stacks are distributed throughout the protrusion, reaching distally towards the immunological synapse. Thus, rather than causing astrocyte hypertrophy, antiviral T cells cause a major structural reorganization of target virally infected astrocytes., Conclusions: Astrocyte polarization, as opposed to hypertrophy, in response to T cell attack may be due to T cells providing a very focused attack, and thus, astrocytes responding in a polarized manner. A similar polarization of Golgi stacks towards contacting T cells was also detected using an in vitro allogeneic model. Thus, different T cells are able to induce polarization of target astrocytes. Polarization of target astrocytes in response to immunological synapses may play an important role in regulating the outcome of the response of astrocytes to attacking effector T cells, whether during antiviral (e.g. infected during HIV, HTLV-1, HSV-1 or LCMV infection), anti-transplant, autoimmune, or anti-tumor immune responses in vivo and in vitro.

Kupfer-type immunological synapses are thought to mediate intercellular communication between antiviral T cells and virally infected target Ag-presenting brain cells in vivo during an antiviral brain immune response. This hypothesis predicts that formation of Kupfer-type immunological synapses is necessary for polarized distribution of effector molecules, and their directed secretion toward the target cells. However, no studies have been published testing the hypothesis that cytokines can only form polarized clusters at Kupfer-type immunological synapses. Here, we show that IFN-gamma and granzyme-B cluster in a polarized fashion at contacts between T cells and infected astrocytes in vivo. In some cases these clusters were found in Kupfer-type immunological synapses between T cells and infected astrocytes, but we also detected polarized IFN-gamma at synaptic immunological contacts which did not form Kupfer-type immunological synaptic junctions, i.e., in the absence of polarization of TCR or LFA-1. This indicates that TCR signaling, which leads to the production, polarization, and eventual directed secretion of effector molecules such as IFN-gamma, occurs following the formation of both Kupfer-type and non-Kupfer type immunological synaptic junctions between T cells and virally infected target astrocytes in vivo.

Background: Recent reports suggest that when thrombolytic agents are administered within the clot, lysis rate accelerates at the expense of increased risk of worsening edema. To test this hypothesis, we report on the volumetric analysis of (1) the intraparenchymal hematoma and, (2) perihematomal edema in a cohort of ICH patients treated with intraclot rtPA., Methods: A convenience sample of highly selected ICH patients underwent frameless stereotactic aspiration and thrombolysis (FAST) of the clot. Two milligrams of rtPA were administered every 12 h until ICH volume < or =10 cc, or catheter fenestrations were no longer in continuity with the clot. ICH and perihematomal edema volumes were calculated from CT scans. Using random effects linear regression we estimated the rate of hematoma and edema volume resolution as well as their relationship during the first 8 days of lytic therapy., Results: Fifteen patients were treated, mean age: 60.7 years, median time from ictus to FAST: 1 (range 0-3) day. Using a random effects model that considered volume resolution over the first 8 days following lytic therapy we found that the both percentage hematoma and percentage perihematoma edema resolution per day were quadratic with respect to time. Percentage residual hematoma volume on day K = 97.7% - [24.36%*K] + [1.89%*K (2)]; P < 0.001 for both terms. Percentage residual edema on day K = 97.4% - [13.94%*K] + [1.30%*K (2)]; P < 0.001 for K and P = 0.01 for K (2). Examination of each patient's volume data suggests that there exists a strong direct relationship between perihematoma edema volume and same day hematoma volume., Conclusions: In this cohort of ICH patients treated using FAST, volumetric analysis of ICH and perihematomal edema seems to suggest that local use of rtPA does not exacerbate brain edema formation. Furthermore, there seems to be a strong association between reduction in ICH volume and reduction in edema volume, as would be expected following the concept of "hemotoxicity" postulated by some investigators.

The purpose of this study was to define binodenoson dosing regimens that produce coronary hyperemia comparable to those of adenosine and that are tolerated well by patients. An open-label, randomized, parallel-group, multicenter study enrolled adult patients who had completed diagnostic cardiac catheterization. Coronary blood flow velocity (CBFV) was measured with a Doppler flow wire, and CBFV reserve was determined before binodenoson administration. Patients (n = 133) received a 3-minute infusion of 0.3, 0.5, or 1 microg/kg/min or a bolus intravenous injection of 1.5 or 3 microg/kg. Coronary hyperemic responses were evident within seconds of administering binodenoson, and the magnitudes and durations of coronary hyperemic responses were dose related. The 1.5- and 3-microg/kg doses, by infusion or bolus, produced maximal coronary hyperemia equivalent to CBFV reserve. All doses transiently decrease blood pressure and increased heart rate and rate-pressure product. In conclusion, the 1.5-microg/kg binodenoson bolus dose produced nearly maximal coronary hyperemia by 4.5 +/- 3.7 minutes that was sustained for 7.4 +/- 6.86 minutes, was accompanied by modest changes in blood pressure, heart rate, and rate-pressure product, and produced no adverse changes on electrocardiogram, including no second- or third-degree atrioventricular block.

d-Lysergic acid diethylamide (LSD), an indoleamine hallucinogen, produces profound alterations in mood, thought, and perception in humans. The brain site(s) that mediates the effects of LSD is currently unknown. In this study, we combine the drug discrimination paradigm with intracerebral microinjections to investigate the anatomical localization of the discriminative stimulus of LSD in rats. Based on our previous findings, we targeted the anterior cingulate cortex (ACC) to test its involvement in mediating the discriminative stimulus properties of LSD. Rats were trained to discriminate systemically administered LSD (0.085 mg/kg s.c.) from saline. Following acquisition of the discrimination, bilateral cannulae were implanted into the ACC (AP, +1.2 mm; ML, +/-1.0 mm; DV, -2.0 mm relative to bregma). Rats were tested for their ability to discriminate varying doses of locally infused LSD (0.1875, 0.375, and 0.75 microg/side) or artificial cerebrospinal fluid (n = 3-7). LSD locally infused into ACC dose-dependently substituted for systemically administered LSD, with 0.75 microg/side LSD substituting completely (89% correct). Systemic administration of the selective 5-hydroxytryptamine (serotonin) (5-HT)(2A) receptor antagonist R-(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidine-methanol (M100907; 0.4 mg/kg) blocked the discriminative cue of LSD (0.375 microg/side) infused into ACC (from 68 to 16% drug lever responding). Furthermore, M100907 (0.5 microg/microl/side) locally infused into ACC completely blocked the stimulus effects of systemic LSD (0.04 mg/kg; from 80 to 12% on the LSD lever). Taken together, these data indicate that 5-HT(2A) receptors in the ACC are a primary target mediating the discriminative stimulus properties of LSD.

Objective: To study the symbolism of community as understood and practised in a mental health Crisis and Assessment Service in an Australian city., Theoretical Approaches: The paper draws on anthropological theories of symbolism and boundary work., Method: Ethnographic fieldwork techniques were employed for data collection. Ethnographic analysis was then applied to these data., Results: In mental health practice, community is primarily defined in contradistinction to hospital. Narratives about community, including an orthodox version and a sceptical counter-narrative, revolve around this community-hospital boundary., Conclusions: This analysis identifies a key symbol, which we have designated community, and enumerates the social values that comprise it.

Tolerance is defined as a decrease in responsiveness to a drug after repeated administration. Tolerance to the behavioral effects of hallucinogens occurs in humans and animals. In this study, we used drug discrimination to establish a behavioral model of lysergic acid diethylamide (LSD) tolerance and examined whether tolerance to the stimulus properties of LSD is related to altered serotonin receptor signaling. Rats were trained to discriminate 60 microg/kg LSD from saline in a two-lever drug discrimination paradigm. Two groups of animals were assigned to either chronic saline treatment or chronic LSD treatment. For chronic treatment, rats from each group were injected once per day with either 130 microg/kg LSD or saline for 5 days. Rats were tested for their ability to discriminate either saline or 60 microg/kg LSD, 24 h after the last chronic injection. Rats receiving chronic LSD showed a 44% reduction in LSD lever selection, while rats receiving chronic vehicle showed no change in percent choice on the LSD lever. In another group of rats receiving the identical chronic LSD treatment, LSD-stimulated [35S]GTPgammaS binding, an index of G-protein coupling, was measured in the rat brain by autoradiography. After chronic LSD, a significant reduction in LSD-stimulated [35S]GTPgammaS binding was observed in the medial prefrontal cortex and anterior cingulate cortex. Furthermore, chronic LSD produced a significant reduction in 2,5-dimethoxy-4-iodoamphetamine-stimulated [35S]GTPgammaS binding in medial prefrontal cortex and anterior cingulate cortex, which was blocked by MDL 100907, a selective 5-HT2A receptor antagonist, but not SB206553, a 5-HT2C receptor antagonist, indicating a reduction in 5-HT2A receptor signaling. 125I-LSD binding to 5-HT2A receptors was reduced in cortical regions, demonstrating a reduction in 5-HT2A receptor density. Taken together, these results indicate that adaptive changes in LSD-stimulated serotonin receptor signaling may mediate tolerance to the discriminative stimulus effects of LSD.

Object: Slit-ventricle syndrome (SVS) is a confusing description of presentations in patients with chronic shunt-treated hydrocephalus. These patients are prone to acute deterioration with recurrent malfunction. The authors describe the clinical profile and management outcome of using lumboperitoneal (LP) shunts in this population of patients., Methods: Thirty-three patients with slit ventricles and recurrent malfunctions were converted to LP shunts (mean age 12 years). The initial ventricular shunt was placed at a mean age of 16.5 months. Ten patients had failed endoscopic third ventriculostomies prior to placement of their LP shunt. At a previous presentation, in 11 patients suspected to have SVS following revision of the shunt, intracranial pressure normalized after insertion of a contralateral shunt, suggesting that their ventricles were isolated. The rate of infection and malfunction was compared before and after conversion to an LP shunt. Twenty-seven patients were successfully converted to LP shunts. Four of the 11 patients with isolated ventricles required ventricular shunts in addition to the LP shunt. During a mean follow-up period of 16.7 months, the malfunction rate per patient decreased from 4.81 for ventriculoperitoneal shunts, prior to conversion to 1.48 after conversion to LP shunts, a statistically significant reduction (p < 0.000). No significant difference was found in the rate of shunt infections (7.1% for VP shunts and 9.6% for LP shunts, p = 0.44). No patient presented with acute symptoms following malfunction of an LP shunt or suffered from a Chiari I malformation., Conclusions: Conversion to an LP shunt is a safe and effective procedure in patients prone to rapid decompensation and recurrent shunt malfunctions from small, slitlike ventricles. The term SVS is confusing. The condition is a manifestation of an unrecognized slitlike isolated ventricle and should be abandoned.

Rationale: The drug discrimination procedure is the most frequently used in vivo model of hallucinogen activity. Historically, most drug discrimination studies have been conducted in the rat. With the development of genetically modified mice, a powerful new tool has become available for investigating the mechanisms of drug-induced behavior. The current paper is part of an ongoing effort to determine the utility of the drug discrimination technique for evaluating hallucinogenic drugs in mice., Objective: To establish the training procedures and characterize the stimulus properties of (+)lysergic acid diethylamide (LSD) in mice., Methods: Using a two-lever drug discrimination procedure, C57Bl/6J mice were trained to discriminate 0.45 mg/kg LSD vs saline on a VI30 sec schedule of reinforcement, with vanilla-flavored Ensure serving as the reinforcer., Results: As in rats, acquisition was orderly, but the training dose was nearly five-fold higher for mice than rats. LSD lever selection was dose-dependent. Time-course studies revealed a rapid loss of the LSD stimulus effects. The 5-HT(2A/2C) receptor agonist, 2,5-dimethoxy-4-bromoamphetamine [(-)DOB] (1.0 mg/kg), substituted fully for LSD and the 5-HT(1A) receptor agonist, 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) (1.6 mg/kg), substituted partially for LSD. Pretreatment with the 5-HT(2A) receptor-selective antagonist, MDL 100907, or the 5-HT(1A)-selective antagonist WAY 100635, showed that each antagonist only partially blocked LSD discrimination. Substitution of 1.0 mg/kg (-)DOB for LSD was fully blocked by pretreatment with MDL 100907 but unaltered by WAY 100635 pretreatment., Conclusions: These data suggest that in mice the stimulus effects of LSD have both a 5-HT(2A) receptor and a 5-HT(1A) receptor component.

The present study used a two-lever, drug-discrimination procedure to train rats to discriminate between the cues associated with 5 mg/kg of the anxiolytic, chlordiazepoxide (CDP) and 15 mg/kg of the anxiogenic, pentylenetetrazol (PTZ), to investigate the relationship between withdrawal and acute tolerance. Training doses of the two drugs were chosen so that rats responded about equally on both levers when tested on saline (SAL). Following acquisition of the discrimination, rats were injected with 10 mg/kg CDP and tested for lever choice at various intervals from 6 h to 192 h. These tests revealed that cues associated with CDP withdrawal lasted approximately three times longer than the cues associated with the drug's primary effects. At the shortest retest interval (6 h) after treatment with 10 mg/kg CDP, rats responded primarily on the CDP lever, followed by a shift to predominant responding on the PTZ lever at the 16 h and 24 h intervals before returning to predrug, baseline levels at the longer intervals (48-192 h). In order to investigate the relationship between tolerance and withdrawal to the cue properties of CDP, CDP dose-response curves were determined 24 h following treatment with SAL or 10 mg/kg CDP. Acute tolerance, as defined by a rightward, parallel shift in the dose-response function, was observed in the rats pretreated with CDP. Furthermore, it was evident that the baseline shift associated with CDP withdrawal, rather than a weaker drug cue, accounted for acute tolerance. The results from this study are relevant to evaluating the role positive and negative reinforcement play in motivating compulsive drug use.

In the present experiment rats were trained on a three-lever, drug-discrimination task to discriminate the cues associated with 0.30 mg/kg of the indirect dopamine (DA) agonist, amphetamine (AMPH), saline (SAL), and 0.03 mg/kg of the DA, D2 receptor antagonist, haloperidol (HAL). Choice behavior determined from tests on 0.30 and 0.15 mg/kg AMPH, SAL 0.03 and 0.015 mg/kg HAL provided a behavioral baseline presumed to represent changes along a continuum of DA mediated, interoceptive cues. Results from separate groups tested on 0.30 and 0.15 mg/kg AMPH, SAL, 0.03 and 0.015 mg/kg HAL, 24 h post-treatment with an acute 7.5 mg/kg dose of AMPH, showed rapid tolerance and withdrawal to the AMPH cue and sensitization to the HAL cue. The same tests 24 h following treatment with 1.0 mg/kg HAL showed rapid tolerance to the HAL cue, sensitization to the AMPH cue, but not AMPH-like withdrawal cues. Analysis of the results showed that tolerance to the AMPH and HAL cues reflected neuroadaptive baseline shifts and not weaker cue properties. These findings are consistent with predictions from opponent process theory of motivation and provide an animal model to study the motivational consequences that aversive symptoms of AMPH withdrawal such as dysphoria and anhedonia can have on drug-taking behavior.

Objective: To retrospectively analyze data from a previously reported randomized trial of either pelvic radiation (RT) or RT + chemotherapy (CT) in patients undergoing radical hysterectomy and pelvic lymphadenectomy with positive pelvic lymph nodes, parametrial involvement, or surgical margins; to explore associations between RT + CT; and to investigate histopathologic and clinical factors which might be predictive of recurrence., Methods: Histopathologic sections from biopsies and hysterectomies and clinical data were reviewed from patients with stage IA2, IB, or IIA cervical cancer treated with RT or RT + CT (cisplatin 70 mg/m2 plus fluorouracil 1000 mg/m2 every 3 weeks for four cycles). A univariate analysis was performed because the relatively small sample size limited the interpretation of a multivariate analysis., Results: Of the 268 enrolled women, 243 (RT = 116; RT + CT = 127) were evaluable. The beneficial effect of adjuvant CT was not strongly associated with patient age, histological type, or tumor grade. The prognostic significance of histological type, tumor size, number of positive nodes, and parametrial extension in the RT group was less apparent when CT was added. The absolute improvement in 5-year survival for adjuvant CT in patients with tumors < or =2 cm was only 5% (77% versus 82%), while for those with tumors >2 cm it was 19% (58% versus 77%). Similarly, the absolute 5-year survival benefit was less evident among patients with one nodal metastasis (79% versus 83%) than when at least two nodes were positive (55% versus 75%)., Conclusions: In this exploratory, hypothesis-generating analysis, adding CT to RT after radical hysterectomy, appears to provide a smaller absolute benefit when only one node is positive or when the tumor size is < 2 cm. Further study of the role of CT after radical hysterectomy in patients with a low risk of recurrence may be warranted.

Background: Binodenoson, a highly selective agonist of the adenosine A 2A receptor, is being developed as a short-acting coronary vasodilator as an adjunct to radiotracers for use in myocardial stress imaging. This study was designed to assess the single-dose pharmacokinetics, safety, and tolerability of intravenous binodenoson., Methods and Results: This was a single-center, open-label, nonrandomized, dose-escalation study in 24 healthy volunteers. Each subject received 3 successive intravenous doses of binodenoson (0.1, 0.2, 0.4, 0.6, 1, 2, 3, 4, 5, and 6 microg/kg), each infused over a period of 10 minutes and separated by washout periods of at least 120 minutes. Generally, binodenoson was well tolerated. There were no serious adverse events. However, there was a dose-related increase in adverse events (e.g., headache, nausea, vasodilation, chest pain), consistent with the pharmacology of the drug. Binodenoson exhibited linear pharmacokinetics as indicated by a dose-proportional increase in peak concentration (C max ) and area under the concentration-time curve (AUC). Systemic clearance was independent of dose but was correlated with body weight. The mean terminal half-life of binodenoson across all doses was 10 +/- 4 minutes., Conclusions: Overall, binodenoson was well tolerated and exhibited linear pharmacokinetics when administered intravenously over a 60-fold dose range from 0.1 to 6 microg/kg.

Introduction: To test the feasibility and safety of a minimally invasive technique, we report our experience in treating spontaneous intracerebral hemorrhage (ICH) patients by using frameless stereotactic clot aspiration-thrombolysis and its effects on their 30-day survival. We compared the observed cohort mortality with its predicted 30-day ICH mortality, by using previously validated methods., Methods: Selection criteria were diagnosis of hypertensive ICH > or =35 cc, reduced level of consciousness, and no brainstem compression. Frameless stereotactic puncture/clot aspiration followed by intraclot external catheter placement was performed. Two milligrams of recombinant tissue plasminogen activator (rtPA) was administered q12 hours until ICH volume < or =10 cc, or the catheter fenestrations were no longer in continuity with the clot., Results: Fifteen patients were treated, mean age was 60.7 years. Hemorrhage locations included basal ganglia (13), thalamic (1), and lobar (1); mean systolic blood pressure; and admission ICH volumes were 229.3 mmHg and 59.1 cc, respectively. Median time from ictus to clot aspiration/thrombolysis was 1 (range 0-3) day. Mean hematoma volume was reduced to 17% of pretreatment size. Complications were ventriculitis (6.6%) and clot enlargement (13.3%). Two patients were dead at 30 days. Median Glasgow Coma Scale (GCS) scores were 10.5 (4-15) at admission and 11.0 (3-15) at discharge. By using the most conservative estimate for analysis, probability of observing two or fewer deaths among 15 patients with an overall probability of dying calculated at 0.33 was p = 0.079., Conclusions: In this selected cohort of patients with ICH, stereotactic aspiration and thrombolytic washout seemed to be feasible and to have a trend towards improved 30-day survival, when using their predicted mortality data as "historical control." Complications did not exceed expected incidence rates. Based on the experience presented here as well as previous similar reports, a larger, randomized study addressing dose escalation, patient selection, and best therapeutic window is needed.

Rationale: Previous drug-discrimination studies have focused on characterizing the cue properties associated with amphetamine's (AMPH) primary effect. Results from recent experiments indicate that equally prominent cues are associated with AMPH withdrawal., Objectives: The purpose of the present study was to investigate the extent to which AMPH-induced withdrawal cues, opposite to those associated with AMPH's primary effect are observed., Methods: Since dopamine (DA) has been implicated in mediating the AMPH cue, rats were trained to discriminate between 0.25 mg/kg AMPH, an indirect DA agonist, and 0.033 mg/kg haloperidol (HAL), a DA antagonist at the D2 receptor site. Training doses were chosen so that rats responded about equally on both levers when tested on saline (SAL) providing a behavioral baseline sensitive to assessing AMPH-related bidirectional changes in cue state. Following acquisition of the discrimination, rats were tested for choice of responding on the AMPH and HAL levers at intervals from 6 to 72 h following treatment with a single dose of 3.0 mg/AMPH. Also, in order to investigate the relationship between withdrawal and tolerance to AMPH's cue properties, AMPH dose-response curves were determined 24 h following treatment with SAL, 1.5 and 3.0 mg/kg AMPH., Results: At short intervals after treatment with 3.0 mg/kg AMPH, rats responded primarily on the AMPH lever followed by a shift to predominant responding on the HAL lever 16-30 h post-treatment, before returning to predrug levels. Treatment with 1.5 and 3.0 mg/kg AMPH produced parallel dose-response curve shifts to the right., Conclusions: Following a single dose of AMPH, robust cues associated with AMPH withdrawal were observed that lasted approximately three times longer than the cues associated with the drug's primary effects. Furthermore, results from the tolerance tests indicate that tolerance reflects a baseline shift rather than a loss in drug efficacy.

Objective: To assess whether circulating insulin-like growth factor-1 (IGF-1), IGF-2, insulin-like growth factor-binding protein-1 (IGFBP-1), or IGFBP-3 were associated with endometrial cancer in postmenopausal women., Study Design: Between 1987 and 1990, we conducted a case-control study of 405 women with endometrial cancer and 297 matched population-based controls. This analysis included 174 postmenopausal cases and 136 controls., Results: In logistic regression models adjusted for potential confounders, higher IGF-1 levels were not positively associated with endometrial cancer: odds ratio (OR) for the highest tertile versus the lowest tertile = 0.63, 95% confidence interval (CI) = 0.30-1.32. Endometrial cancer was inversely associated with IGF-2 (OR for the highest tertile = 0.35, 95% CI = 0.18-0.69) and IGFBP-3 (OR for the highest tertile = 0.40, 95% CI = 0.21-0.77), and not associated with IGFBP-1., Conclusion: Serum IGF-1, IGF-2, and IGFBP-3, but not IGFBP-1, were inversely associated with endometrial cancer in postmenopausal women. These associations and the potential role of the IGF system in endometrial proliferation and carcinogenesis warrant further research.

Background: Dipyridamole and adenosine cause frequent side effects as a result of nonspecific adenosine receptor stimulation. Selective agonism of the adenosine A2A receptor should result in a similar degree of coronary vasodilation (and thus similar perfusion images) with fewer side effects., Methods and Results: In a multicenter, randomized, single-blind, 2-arm crossover trial, 240 patients underwent 2 single photon emission computed tomographic (SPECT) imaging studies in random order, first after pharmacological stress with adenosine and a second study with the selective adenosine A2A receptor agonist binodenoson, using 1 of 4 dosing regimens. Safety, tolerability, and SPECT image concordance between the 2 agents were examined. Exact categorical agreement in the extent and severity of reversible perfusion defects ranged from 79% to 87%, with kappa values from 0.69 to 0.85, indicating very good to excellent agreement between binodenoson and adenosine. The risk of any safety event/side effect was significantly lower with any dose of binodenoson than with adenosine (P< or =0.01) because of a dose-related reduction in subjective side effects, as objective events were infrequent. There was a reduction in the severity of chest pain, dyspnea, and flushing in all binodenoson doses compared with adenosine (P<0.01), and the magnitude of severity reduction was dose-related., Conclusions: The selective adenosine A2A receptor agonist binodenoson results in an extent and severity of reversible perfusion defects on SPECT imaging similar to nonselective adenosine receptor stimulation, accompanied by a dose-related reduction in the incidence and severity of side effects.

An analysis is presented of psychiatric research interviews conducted among the Iban, a longhouse dwelling people of Sarawak, Malaysia. It draws on transcripts of interviews recorded in the course of carrying out research into schizophrenia in this group. The article examines three different interview spaces within the longhouse--public, family, and private--in order to explore the interplay between ethnographic context and interview conversation. The public setting is notable for the number of relatives who join in and transform the communication from dyadic to collective interlocution; the role of repetition in recruiting them into the conversation is explored. Indirect contrast is the private space, which allows for a level of confidentiality commensurate with Western psychiatric research practice. Intermediate between the two is the family space. The communicative forms that correspond to these settings influence the way symptoms of schizophrenia are experienced and expressed in the Iban. Implications for the practice of psychiatry cross-culturally are examined.