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What Is Known on the Subject: Research suggests that the Dynamic Appraisal of Situational Aggression (DASA) is a useful risk assessment instrument to identify individuals who might be at risk of aggression in mental health inpatient units. Although, risk assessment research has typically focused on an individual's risk of aggression, recent research has begun exploring whether the DASA could be used to assess the likelihood that a group of patients would be aggressive., What the Paper Adds to Existing Knowledge: While the DASA was useful for assessing whether an individual was likely to be aggressive, the group average score was not a useful indicator for the likelihood of aggression once the individual DASA score was taken into consideration. Unexpectedly, patients who were assessed as high risk on the DASA were more likely to be aggressive on settled units compared to unsettled units, which included other individuals whose risk was elevated., What Are the Implications for Practice: There is not enough evidence to suggest that the group DASA average improves the identification of aggression above the individual DASA score., Abstract: INTRODUCTION: The Dynamic Appraisal of Situational Aggression (DASA) is an inpatient aggression risk assessment instrument. Recently, research explored whether the unit atmosphere, as indicated by a unit's average DASA score, was related to inpatient aggression risk, but failed to control for individual risk., Aim: Investigate whether the DASA unit average score or an interaction between the unit average and an individual patient's DASA score was related to the likelihood that an individual would act aggressively., Method: Cox regression with repeated assessments and recurrent events was used to analyse 11,243 DASA risk assessments of 113 inpatients collected via retrospective file review., Results: The unit DASA average score was not related to aggression towards staff. There was a negative interaction between the individual and the unit DASA average scores when identifying patient-to-patient aggression; high-risk patients engaged in less aggression when the unit average was heightened relative to units with lower DASA average scores., Discussion: It is possible that there were more nursing interventions and/or patients engaged in greater self-regulation on unsettled units, thus reducing aggression., Implications for Practice: Currently, there is insufficient evidence to suggest that the unit average score should be used to supplement individual DASA scores to identify aggression risk., (© 2023 The Authors. Journal of Psychiatric and Mental Health Nursing published by John Wiley & Sons Ltd.)

Readministration of multiple risk assessment instruments to determine the risk of aggression over the short, medium, and long term is common practice in many forensic mental health settings. Justification for the repeated administration and use of multiple instruments is based on purported differences in discriminative validity of risk factors according to whether they are characterized as static, stable, or acute, and the composition of these tools, in terms of the relative balance of different types of risk factors, which can impact the discriminative validity of these instruments over different follow-up periods. However, research has yet to determine whether the use of multiple and repeated administration of risk assessment instruments improves identification of risk, and it may be the case that the heavy burden on service providers to administer multiple instruments is unwarranted. In this study, time-dependent cox regression with repeated assessments and recurrent events was used to investigate the dynamic nature and incremental validity of the dynamic appraisal of situational aggression (DASA), short-term assessment of risk and treatability (START), and HCR-20 v3 , which were repeatedly rated on a sample of forensic mental health inpatients ( N = 240) over a 2-year period. Results suggest that using the rolling mean or the most recent risk assessment yielded the most accurate characterization of change in aggression risk. Repeated administration of dynamic risk instrument instruments improved the identification of aggression beyond the initial risk assessment. Although static, stable, and acute factors were significantly related to aggression, the combination of data from multiple risk assessment instruments may not result in clinically meaningful improvements in risk identification. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Background: A team approach is one of the most effective ways to lower blood pressure (BP) in uncontrolled hypertension, but different models for organizing team-based care have not been compared directly., Methods: A pragmatic, cluster-randomized trial compared 2 interventions in adult patients with moderately severe hypertension (BP≥150/95 mm Hg): (1) clinic-based care using best practices and face-to-face visits with physicians and medical assistants; and (2) telehealth care using best practices and adding home BP telemonitoring with home-based care coordinated by a clinical pharmacist or nurse practitioner. The primary outcome was change in systolic BP over 12 months. Secondary outcomes were change in patient-reported outcomes over 6 months., Results: Participants (N=3071 in 21 primary care clinics) were on average 60 years old, 47% male, and 19% Black. Protocol-specified follow-up within 6 weeks was 32% in clinic-based care and 27% in telehealth care. BP decreased significantly during 12 months of follow-up in both groups, from 157/92 to 139/82 mm Hg in clinic-based care patients (adjusted mean difference -18/-10 mm Hg) and 157/91 to 139/81 mm Hg in telehealth care patients (adjusted mean difference -19/-10 mm Hg), with no significant difference in systolic BP change between groups (-0.8 mm Hg [95% CI, -2.84 to 1.32]). Telehealth care patients were significantly more likely than clinic-based care patients to report frequent home BP measurement, rate their BP care highly, and report that BP care visits were convenient., Conclusions: Telehealth care that includes extended team care is an effective and safe alternative to clinic-based care for improving patient-centered care for hypertension., Registration: URL: https://www., Clinicaltrials: gov; Unique identifier: NCT02996565.

Purpose: The case of a pediatric patient with treatment refractory anti-N-methyl-d-aspartate (NMDA) receptor encephalitis treated with the plasma cell-depleting therapy bortezomib is reported., Summary: A 5-year-old female presented to the hospital with a 1-week history of altered mental status, agitation, and possible seizure-like activity. She was admitted to the hospital for suspected meningitis or meningoencephalitis and an extensive workup was completed, including sending blood and cerebrospinal fluid (CSF) for testing for NMDA receptor antibodies. While test results were pending, the patient was treated initially with intravenous immunoglobulin (IVIG) for 4 days followed by high-dose methylprednisolone for 5 days. The patient's serum and CSF studies were positive for NMDA receptor antibodies, confirming the diagnosis of anti-NMDA receptor encephalitis. She was then treated with plasmapheresis therapy every other day for 5 treatments, without any clinical improvement. The patient then received rituximab once weekly for 6 weeks. Three weeks after completion of rituximab therapy, the patient was started on her first cycle of bortezomib therapy. She received a total of 6 cycles, with improvement in her clinical status beginning with the third cycle. Upon completion of 6 cycles, the patient's mental status and level of functioning had greatly improved. She was discharged to an inpatient rehabilitation facility and ultimately able to return home to her family., Conclusion: A 5-year-old female with anti-NMDA receptor encephalitis was successfully treated with bortezomib after having shown no clinical improvement during treatment with IVIG, high-dose methylprednisolone, plasmapheresis, and rituximab., (© American Society of Health-System Pharmacists 2021. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The Sex Offender Registration Act 2004 was introduced in Victoria to decrease recidivism and aid in future investigations and prosecutions. This article reviews literature to evaluate four assumptions inherent to the Act: (a) sexual offenders are more dangerous than non-sexual offenders; (b) sexual offenders who target children are more dangerous than those who target adults; (c) recidivism risk can be accurately assessed for sexual offenders who target adults; and (d) the Act is a useful tool for investigations and prosecutions. The findings suggest that there is little evidence that supports the assumptions. Further, given the relatively narrow scope of the Act, it is unlikely to have a positive impact on the safety of the community., (© 2019 The Australian and New Zealand Association of Psychiatry, Psychology and Law.)

The diagnosis of a new onset movement disorder after a stroke has important clinical implications. The early assessment and timely diagnosis of post-stroke disorders is essential for influencing long-term outcomes. Localizing lesions and determining the underlying etiology is vital in targeting appropriate therapy. New and sudden onset of hemiparkinsonism with hemiparesis, rigidity, and tremor following an acute ischemic stroke is described here. This presentation was clinically diagnosed as acute post-stroke parkinsonism (APSP). The patient's level of impairment was significant enough to compromise his activities of daily living (ADL), physical therapy (PT), and occupational therapy (OT) in an inpatient rehabilitation center. In the inpatient rehabilitation center, the patient received a trial of levodopa for suspected APSP. After levodopa therapy was initiated, we observed an improvement of his parkinsonian features with a sustained response and reached the conclusion that the clinical recognition of post-stroke parkinsonism treated with a targeted trial with levodopa may improve the quality of life. Proper treatment of APSP has the potential to provide the best opportunity for recovery and positively influence the long-term outcomes in similar patients., Competing Interests: The authors have declared that no competing interests exist.

Linehan (1993) theorized that the experience of invalidating parenting interacts with emotional vulnerability in the development of borderline personality disorder (BPD). Parental psychological control is a type of invalidating parenting, defined as manipulation by parents of their offspring's psychological and emotional expression and experience (Barber, 1996). In a normative sample of adolescent females, adolescent-reported maternal psychological control was related to maternal borderline symptoms (Zalewski et al., 2014). The current study expanded on these findings to sample mothers with a diagnosis of BPD (n = 28) and normative comparisons (n = 28) with male and female adolescents aged 14-18. We assessed maternal and adolescent self-reported borderline features (affective instability, negative relationships, identity disturbance, and self-harm) and coded maternal psychological control from filmed problem-solving interactions. Controlling for current major depressive disorder and family income, mothers with BPD used more total psychological control with their adolescents in comparison with normative mothers. Further, maternal psychological control was positively associated with all mothers' borderline features and with adolescent affective instability. Finally, we found a significant indirect effect for maternal affective instability between maternal total psychological control and adolescent affective instability. We discuss adolescents' risk of developing BPD themselves and prevention and treatment implications. (PsycINFO Database Record, ((c) 2018 APA, all rights reserved).)

Background: EMPOWER-H (Engaging and Motivating Patients Online With Enhanced Resources-Hypertension) is a personalized-care model facilitating engagement in hypertension self-management utilizing an interactive Web-based disease management system integrated with the electronic health record. The model is designed to support timely patient-provider interaction by incorporating decision support technology to individualize care and provide personalized feedback for patients with chronic disease. Central to this process were patient-generated health data, including blood pressure (BP), weight, and lifestyle behaviors, which were uploaded using a smartphone., Objective: The aim of this study was to evaluate the program among patients within primary care already under management for hypertension and with uncontrolled BP., Methods: Using a 6-month pre-post design, outcome measures included office-measured and home-monitored BP, office-measured weight, intervention contacts, diet, physical activity, smoking, knowledge, and health-related quality of life., Results: At 6 months, 55.9% of participants (N=149) achieved office BP goals (<140/90 mm Hg; P<.001) and 86.0% achieved clinically meaningful reduction in office BP (reduction in systolic BP [SBP] ≥5 mm Hg or diastolic BP [DBP] ≥3 mm Hg). At baseline, 25.2% of participants met home BP goals (<135/85 mm Hg), and this percentage significantly increased to 71.4% (P<.001) at 6 months. EMPOWER-H also significantly reduced both office and home SBP and DBP, decreased office-measured weight and consumption of high-salt and high-fat foods (all P<.005), and increased intake of fruit and vegetables, minutes of aerobic exercise, and hypertension knowledge (all P<.05). Patients with higher home BP upload frequencies had significantly higher odds of achieving home BP goals. Patients receiving more total intervention, behavioral, pharmaceutical contacts had significantly lower odds of achieving home BP goals but higher improvements in office BP (all P<.05)., Conclusions: EMPOWER-H significantly improved participants' office-measured and home-monitored BP, weight, and lifestyle behaviors, suggesting that technologically enabled BP home-monitoring, with structured use of patient-generated health data and a personalized care-plan facilitating patient engagement, can support effective clinical management. The experience gained in this study provides support for the feasibility and value of using carefully managed patient-generated health data in the day-to-day clinical management of patients with chronic conditions. A large-scale, real-world study to evaluate sustained effectiveness, cost-effectiveness, and scalability is warranted., (©Nan Lv, Lan Xiao, Martha L Simmons, Lisa G Rosas, Albert Chan, Martin Entwistle. Originally published in the Journal of Medical Internet Research (http://www.jmir.org), 19.09.2017.)

Objective: To determine the incidence with which a vancomycin dosing regimen of 15 mg/kg per dose every 6 hours achieves steady-state trough concentrations of 15 to 20 mg/L in pediatric patients with complicated infections., Methods: We performed a retrospective chart review for patients admitted to our children's hospital between July 1, 2009, and June 30, 2011. Patients were included if they were between 1 month and 18 years of age, had at least 1 steady-state vancomycin trough obtained, received an initial vancomycin dose of 15 mg/kg per dose every 6 hours, and were being treated for a diagnosis of meningitis, pneumonia, osteomyelitis, bacteremia/sepsis, or endocarditis., Results: Seventy-four patients were enrolled, mean age of 4.2±3.9 years and weight of 17.0±11.2 kg. Five (6.8%) patients obtained an initial trough of 15 to 20 mg/L. Patients between 1.0 and 5.9 years of age were significantly less likely to achieve an initial trough of 15 to 20 mg/L compared with other age groups evaluated (P=.041). Thirty-four patients with initial subtherapeutic troughs received a dose adjustment and a follow-up vancomycin trough. Of these patients, 15 (44.1%) achieved a trough between 15 and 20 mg/L. The median dose for patients achieving a therapeutic trough at any point during the study was 80 mg/kg per day., Conclusions: A vancomycin dosing regimen of 15 mg/kg per dose every 6 hours is not likely to achieve a trough concentration of 15 to 20 mg/L in pediatric patients with complicated infections. An initial regimen of 80 mg/kg per day for these patients may be more likely to result in therapeutic steady-state concentrations of vancomycin., (Copyright © 2015 by the American Academy of Pediatrics.)

With an overall mortality rate of 4.2%, sepsis is one of the most common causes of death in children worldwide. The Surviving Sepsis Campaign outlines rapid initiation of volume resuscitation with crystalloids and timely administration of broad-spectrum antibiotics as the backbone of sepsis treatment. Initial antibiotics should be broad enough to cover the most likely pathogens, but antibiotic therapy should be de-escalated when culture results become available. Therapy with a vasopressor and/or an inotrope is often necessary in patients with sepsis to improve blood pressure and cardiac output. Adjunctive therapy with hydrocortisone is sometimes beneficial in the setting of catecholamine resistance and/or adrenal insufficiency. Insulin may also be needed in some patients for the treatment of hyperglycemia. Current guidelines have improved the treatment of sepsis, but more research is needed. This article reviews sepsis pathophysiology, treatment, and supportive care specifically as they relate to pediatric patients.

Purpose: Recent studies have suggested relative radioresistance in glioblastoma multiforme (GM) tumors in older patients, consistent with their shorter survival. Two common molecular genetic abnormalities in GM are age related: epidermal growth factor receptor (EGFR) overexpression in older patients and p53 mutations in younger patients. We tested whether these abnormalities correlated with clinical heterogeneity in GM response to radiation treatment., Methods and Materials: Radiographically assessed radiation response (5-level scale) was correlated with EGFR immunoreactivity, p53 immunoreactivity, and p53 exon 5-8 mutation status in 170 GM patients treated using 2 prospective clinical protocols. Spearman rank correlation and proportional-odds ordinal regression were used for univariate and multivariate analysis., Results: Positive EGFR immunoreactivity predicted poor radiographically assessed radiation response (p = 0.046). Thirty-three percent of tumors with no EGFR immunoreactivity had good radiation responses (>50% reduction in tumor size by CT or MRI), compared to 18% of tumors with intermediate EGFR staining and 9% of tumors with strong staining. There was no significant relationship between p53 immunoreactivity or mutation status and radiation response. Significant relationships were noted between EGFR score and older age and between p53 score or mutation status and younger age., Conclusion: The observed relative radioresistance of some GMs is associated with overexpression of EGFR.

Glioblastoma multiforme (GBM) carries a dismal prognosis. However, a range of survival times exists, and parameters that define prognostic groups may help to optimize treatment. To identify such prognostic groups, we analyzed tumor tissue from 110 cases of newly diagnosed GBM from two clinical protocols. Similar to other studies, we found no association of epidermal growth factor receptor (EGFR) overexpression (as assessed by immunohistochemistry), p53 immunopositivity, or p53 mutation with survival in the entire sample. However, EGFR overexpression showed trends toward worse prognosis in patients younger than the median age, but better prognosis in patients older than the median age. This interaction of EGFR with age group was statistically significant and led us to focus our further analyses on the younger patients. In this group, a statistically significant association of EGFR overexpression with worse survival was identified in the p53-negative but not p53-positive tumors. We found a similar result after screening these cases for mutations in p53: EGFR overexpression was negatively associated with survival only in the p53 wild-type cases. To confirm this unexpected result, this finding was reproduced in a validation sample of an additional 42 tumors from younger patients on the same two clinical protocols. This complex relationship between EGFR and p53 in younger patients remained in a multivariate analysis that incorporated additional prognostic variables. The results suggest that analysis of prognostic markers in GBM is complex, and maximal information may require analysis of subgroups based on age and the status of specific markers such as p53. In addition, they suggest a specific group of patients on which to focus promising therapies targeting EGFR.

kappa opioid receptor activation inhibits granule cell-mediated excitatory neurotransmission in the hippocampal formation via a decrease in glutamate release from both perforant path and mossy fiber terminals. We now report a third, anatomically and pharmacologically distinct site of such kappa opioid inhibition within the hippocampus. Granule cell population responses to selective stimulation of an excitatory hilar pathway were decreased by the kappa(1) opioid receptor agonist U69,593, an effect blocked by the kappa(1) antagonist norbinaltorphimine. U69,593 also inhibited hilar path induced long-term potentiation (LTP) of granule cell responses. LTP in this pathway was also blocked by the NMDA receptor antagonist d-2-amino-5-phosphonovalerate, unlike granule cell mossy fiber LTP in CA3. The kappa opioid peptide dynorphin is present in hilar mossy fiber collaterals. Ultrastructural analysis of these collaterals demonstrated dynorphin-containing vesicles in asymmetric synapses formed between axon terminals and granule cell dendrites, suggesting direct granule cell-granule cell connections. Evoked release of endogenous dynorphin within the hilus was effective in reducing hilar excitation of granule cells, although this release, in contrast to the release of dynorphin in the dentate molecular layer, was not dependent on L-type calcium channels. No hilar path excitation was observed in the absence of bicuculline, suggesting a strong GABA(A)-mediated inhibition of this pathway. However, hilar path activity could be seen after LTP, with or without bicuculline. Thus, kappa opioids can inhibit granule cell recurrent excitation, likely via effects on excitatory mossy fiber collaterals. Such collaterals are thought to be important in mediating temporal lobe epilepsy.

Background: Valid and reliable diagnoses of disease are key both to meaningful epidemiologic and clinical investigations and to decision-making about appropriate treatment. One previous study highlighted the lack of precision in diagnosing primary brain tumors in a neuropathology referral practice. The current study explores diagnostic discrepancies in a population-based adult glioma series by hospital of origin, specialty training of the original diagnosing pathologist, and clinical significance., Methods: To confirm patients' eligibility for the San Francisco Adult Glioma Study, the authors obtained participants' pathology specimens and conducted a uniform secondary neuropathology review. Eligible patients were all adults age 20 years or older newly diagnosed with glioma between August 1, 1991, and March 31, 1994, who resided in 1 of 6 San Francisco Bay Area counties., Results: Overall, the original and secondary diagnoses were the same (concordant) for 352 (77%) of the 457 cases available for study. Twenty-six percent of the cases from community hospitals were discordant, compared with 12% of the cases from academic hospitals P= 0.004. Of the 105 discordant diagnoses, 17 (16%) were determined to be clinically significant, defined as a difference that could significantly alter patient management and/or prognosis. Sixteen of these 17 cases originated at community hospitals, and only 1 originated at a hospital with a neuropathologist. Based on the distribution of review diagnoses, subjects presenting at nonacademic hospitals were more likely than those presenting at academic hospitals to have glioblastoma (61% vs. 52%; P = 0.07)., Conclusions: The percentage of cases with discrepant original and review diagnoses was higher among those originally diagnosed at community hospitals without a neuropathologist than among those originally diagnosed at an academic hospital with a neuropathologist. Clinically significant discrepancies were much more likely to have originated at a community hospital without a neuropathologist. These data highlight the importance of review of brain tumors by a neuropathologist prior to decision-making regarding treatment. A separate implication of this study is that glioma cases selected exclusively from academic or nonacademic institutions in a particular geographic area are unlikely to be representative of all cases occurring in that area.

A 59-year-old man with severe neck extensor weakness had findings diagnostic of nemaline myopathy on muscle biopsy. Review of the literature shows that dropped head occurs in nearly half of the patients with adult-onset nemaline myopathy. Other leading causes of dropped head syndrome are amyotrophic lateral sclerosis, myasthenia gravis, and isolated neck extensor myopathy., (Copyright 1999 John Wiley & Sons, Inc.)

Adverse physiological effects can often interfere with the use of nitric oxide (NO) as a therapeutic agent, especially when it is systemically generated from prodrugs. NO which is generated and delivered site-specifically by transdermal donors may be useful in the treatment of parasitic, bacterial or viral skin infections without causing systemic side effects. Three diazeniumdiolates (formerly "NONOate"), including two water soluble compounds, (Z)-1-[N-2-aminoethyl)-N-(2-ammonioethyl)amino]-diazen-1- ium-1,2-diolate (DETA-NO) and (Z)-1-[N-(3-aminopropyl)-N-(3-ammoniopropyl)amino] diazen-1-ium-1,2-diolate (DPTA-NO), and one insoluble compound, DPTA-NO grafted to dextran microspheres (DPTA-NO-g-dextran) were used to transdermally deliver NO to rats. Dextran microspheres were obtained by simultaneously grafting DPTA-NO to dextran and cross-linking dextran with CNBr in an oil-water emulsion. Suspended in hydrogel, DETA-NO, DPTA-NO, and DPTA-NO-g-dextran were applied three times to depilated rats at 4 day intervals. Results show that metabolic urinary nitrate levels increase with time (24-48 h), reach a maximum, and return to baseline by the fourth day. DPTA-NO applications produced an average maximum nitrate level of 94.2 mumol/day +/- 34.2 mumol S.D. compared to the average maximum nitrate level of 39.8 mumol/day +/- 8.6 mumol S.D. obtained from treatment with DETA-NO. These results suggest that DPTA-NO delivered NO more efficiently than DETA-NO. When DPTA-NO-g-dextran microspheres were used as the NO donor, results comparable to DPTA-NO were observed with an average maximum nitrate level of 14.9 mumol/day +/- 3.0 mumol S.D. These and other conclusive data indicate that, via these diazeniumdiolates, NO can be delivered effectively through rat skin.

A 36-year-old patient with acquired immunodeficiency syndrome sought care because of an upper eyelid lesion that dramatically increased in size. The histopathologic examination revealed a high-grade diffuse large cell non-Hodgkin lymphoma in continuity with a Kaposi sarcoma. In situ hybridization revealed Epstein-Barr virus in the large cell lymphoma and Kaposi sarcoma-associated herpesvirus in the Kaposi sarcoma lesion. This collision tumor is an unusual presentation of 2 malignant neoplasms in a patient with acquired immunodeficiency syndrome, with in situ hybridization evidence of Epstein-Barr virus and Kaposi sarcoma-associated herpesvirus in the lesion.

Temporal lobe epilepsy is associated with a characteristic pattern of synaptic reorganization in the hippocampal formation, consisting of neuronal loss and aberrant growth of mossy fiber collaterals into the dentate gyrus inner molecular layer. We have used the rat pilocarpine model of temporal lobe epilepsy to study the functional consequences of mossy fiber sprouting on excitatory activity and kappa-opioid receptor-mediated inhibition. Using the whole cell voltage-clamp technique, we found that abnormal excitatory activity was evident in granule cells of the dentate gyrus from pilocarpine-treated rats. The frequency of spontaneous excitatory postsynaptic currents (EPSCs) was increased greatly in cells from tissue in which significant mossy fiber sprouting had developed. In the presence of bicuculline, giant spontaneous EPSCs, with large amplitudes and long durations, were seen only in association with mossy fiber sprouting. Giant EPSCs also could be evoked by low-intensity stimulation of the perforant path. Mossy fibers release not only excitatory amino acids, but also opioid peptides. kappa-Opioid receptor-mediated inhibition in normal Sprague-Dawley rats was seen only in hippocampal sections from the ventral pole. In pilocarpine-treated rats, however, kappa receptor-mediated effects were seen in both ventral and more dorsal sections. Thus in this model of temporal lobe epilepsy, several types of abnormal excitatory activity were observed, thereby supporting the idea that mossy fiber sprouting leads to recurrent excitatory connections. At the same time, inhibition of excitatory activity by kappa-opioid receptors was increased, perhaps representing an endogenous anticonvulsant mechanism.

Solitary fibrous tumors are spindle-cell neoplasms that originally were described in the pleura but that can occur in a large variety of sites. We report a well-circumscribed tumor, apparently involving the renal capsule, clinically thought to be a renal-cell carcinoma or oncocytoma. It was composed of bland spindle-shaped cells with a patchy lymphoplasmacytic infiltrate, suggesting sarcomatoid renal-cell carcinoma, inflammatory myofibroblastic tumor, or solitary fibrous tumor; however, immunohistochemical stains were negative for keratin, alpha-smooth-muscle actin, and desmin but strongly positive for CD34. Ultrastructural examination revealed fibroblast-like cells without myofibroblastic or epithelial differentiation. The combined findings favor a diagnosis of a solitary fibrous tumor involving the renal capsule. To our knowledge, this lesion has not been reported in this location.

Activation of kappa-opioid receptors on mossy fiber terminals in the hippocampus inhibits excitatory amino acid release. The mechanism of presynaptic inhibition at the mossy fiber synapse was investigated through whole-cell voltage-clamp of CA3 pyramidal cells. The application of a kappa-opioid agonist, U69593, reduced the amplitude of the excitatory postsynaptic current response, and this effect was reversed with a k receptor antagonist. Presynaptic potassium channels were blocked by bath application of channel toxins, and the effect of kappa receptor activation was tested. The inhibition caused by U69593 was blocked by low doses of 4-aminopyridine (30 microM) and the selective peptide toxins dendrotoxin and mast cell degranulating peptide. The inhibition was not blocked by low doses of tetraethylammonium chloride (1 mM), barium, or glibenclamide. Thus, we conclude that presynaptic kappa-opioid receptors are coupled to a Shaker-type voltage-dependent potassium channel that is sensitive to dendrotoxin and mast cell degranulating peptide. An increase in presynaptic potassium conductance would enhance the rate of repolarization after action potential invasion, thereby limiting calcium influx and neurotransmitter release. This is the first physiological demonstration of the involvement of a dendrotoxin-sensitive potassium current in presynaptic inhibition mediated by a G protein-coupled receptor.

Physiological and pharmacological studies have suggested that kappa opioid receptors (KORs) may be located presynaptically in the guinea pig hippocampal formation. In the present study, KOR-like immunoreactivity (-LI) was examined by using a rabbit antibody raised against a synthetic peptide from the carboxyl terminus of a cloned rat kappa receptor (KT). The specificity of affinity-purified KT antibody was confirmed by Western blotting, enzyme-linked immunosorbent assay, immunolabeling of KORs expressed in Xenopus oocytes, and immunocytochemical preadsorption controls. Specificity also was demonstrated by the light microscopic distribution of KT-LI in sections through the forebrain and the pons, which was largely consistent with the distribution of KORs previously reported, and resembled that of immunoreactivity for dynorphin B, an endogenous ligand for KORs. Detailed analysis of the hippocampal formation revealed that KT-LI was located predominantly in thin processes in the granule cell and inner molecular layers of the dentate gyrus. A few KT-labeled processes were also present in stratum lacunosum-moleculare of the CA1 region and all layers of the CA3 region of the hippocampus. By electron microscopy, KT-LI was restricted to unmyelinated axons and axon terminals, and was associated with plasma membranes, large dense-core vesicles, and cytoplasmic surfaces of small vesicles. In the dentate gyrus, immunolabeled terminals formed asymmetric synapses with granule cell perikarya and large unlabeled dendrites. In the CA3 region of hippocampus, KT-LI was present in small unmyelinated axons. The results of this study 1) demonstrate the specificity of the KT antibody, 2) show that the distribution of KT labeling corresponds well with previous KOR and dynorphin localization in many regions, and 3) provide ultrastructural evidence that KORs are located presynaptically in the guinea pig hippocampal formation.

Ions of structure X[N(O)NO]- display broad-spectrum pharmacological activity that correlates with the rate and extent of their spontaneous, first-order decomposition to nitric oxide when dissolved. We report incorporation of this functional group into polymeric matrices that can be used for altering the time course of nitric oxide release and/or targeting it to tissues with which the polymers are in physical contact. Structural types prepared include those in which the [N(O)NO]- group is attached to heteroatoms in low molecular weight species that are noncovalently distributed throughout the polymeric matrix, in groupings pendant to the polymer backbone, and in the polymer backbone itself. They range in physical form from films that can be coated onto other surfaces to microspheres, gels, powders, and moldable resins. Chemiluminescence measurements confirm that polymers to which the [N(O)NO]- group is attached can serve as localized sources of nitric oxide, with one prototype providing sustained NO release for 5 weeks in pH 7.4 buffer at 37 degrees C. The latter composition, a cross-linked poly-(ethylenimine) that had been exposed to NO, inhibited the in vitro proliferation of rat aorta smooth muscle cells when added as a powder to the culture medium and showed potent antiplatelet activity when coated on a normally thrombogenic vascular graft situated in an arteriovenous shunt in a baboon's circulatory system. The results suggest that polymers containing the [N(O)NO]- functional group may hold considerable promise for a variety of biomedical applications in which local delivery of NO is desired.

Endogenous opioid peptides modulate neural transmission in the hippocampus. Procnkephalin-derived peptides have been demonstrated to act at mu and delta opioid receptors to inhibit GABA release from inhibitory interneurons, resulting in increased excitability of hippocampal pyramidal cells and dentate gyrus granule cells. Prodynorphin-derived peptides primarily act at presynaptic kappa opioid receptors to inhibit excitatory amino acid release from perforant path and mossy fiber terminals. Opioid receptors reduce membrane excitability by modulating ion conductances, and in this way they may decrease voltage-dependent calcium influx and transmitter release. Synaptic plasticity in the hippocampus also is modulated by endogenous opioids. Enkephalins facilitate long-term potentiation, whereas dynorphins inhibit the induction of this type of neuroplasticity. Further, opioids may play important roles in hippocampal epilepsy. Recurrent seizures induce changes in the expression of opioid peptides and receptors. Also, enkephalins have proconvulsant effects in the epileptic hippocampus, whereas dynorphins may function as endogenous anticonvulsants.

Granule cells in the guinea pig dentate gyrus release kappa opioid neuropeptides, dynorphins, from dendrites as well as from axon terminals. We have found that both L- and N-type calcium channel antagonists inhibited dendritic dynorphin release. In contrast, N-type but not L-type calcium channel antagonists inhibited axonal dynorphin release. Neither L- nor N-type channel antagonists directly altered the effects of kappa opioid receptor activation. By inhibiting dynorphin release, L-type channel antagonists also facilitated the induction of long-term potentiation of the perforant path-granule cell synapse. These studies establish that a single cell type can release a transmitter from two different cellular domains and provide new distinction between axonal and dendritic transmitter release mechanisms.

The murine Ca(2+)-stimulated adenylyl cyclase (type I) (EC 4.6.1.1), which is expressed predominantly in brain, was inactivated by targeted mutagenesis. Ca(2+)-stimulated adenylyl cyclase activity was reduced 40-60% in the hippocampus, neocortex, and cerebellum. Long-term potentiation in the CA1 region of the hippocampus from mutants was perturbed relative to controls. Both the initial slope and maximum extent of changes in synaptic response were reduced. Although mutant mice learned to find a hidden platform in the Morris water task normally, they did not display a preference for the region where the platform had been when it was removed. These results indicate that disruption of the gene for the type I adenylyl cyclase produces changes in behavior and that the cAMP signal transduction pathway may play an important role in synaptic plasticity.

1. Activation of kappa 1-opioid receptors inhibits excitatory transmission in the hippocampal dentate gyrus of the guinea pig. The present studies used both anatomic and physiological approaches to distinguish between a pre- and postsynaptic localization of these receptors. 2. The entorhinal cortex was lesioned unilaterally to cause degeneration of perforant path afferents to the dentate molecular layer, and kappa 1-opioid binding sites were measured by labeling with the selective agonist, [3H]-U69593. Binding density was reduced significantly in the dentate gyrus molecular layer ipsilateral to the lesion compared with the contralateral molecular layer and with sham-lesioned controls. 3. Paired-pulse facilitation is a neurophysiologic paradigm that has been used to differentiate pre- and postsynaptic sites of action for agents that inhibit excitatory neurotransmission. U69593 reduced the amplitude of single population spikes and increased the degree of paired pulse facilitation. The potentiation of paired-pulse facilitation was maintained when the stimulation intensity was increased to compensate for the inhibition of excitatory transmission. These effects of kappa 1-receptor activation were similar to those seen after presynaptic inhibition of excitatory neurotransmitter release and support the hypothesis that U69593 presynaptically inhibits excitatory amino acid release in the dentate gyrus. 4. Local application of glutamate by pressure ejection in the dentate molecular layer evoked field excitatory postsynaptic potentials that mimicked those evoked by electrical stimulation of the perforant path. Both responses were sensitive to the non-N-methyl-D-aspartate glutamate receptor antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione. U69593 inhibited responses evoked by perforant path stimulation but had no effect on responses evoked by glutamate application.(ABSTRACT TRUNCATED AT 250 WORDS)

Lipopolysaccharide (LPS) or a combination of interferon (IFN)-gamma and interleukin (IL)-1 beta can induce a calcium-independent nitric oxide synthase (iNOS) in astrocyte cultures (Simmons and Murphy: J Neurochem 59:897, 1992; Eur J Neurosci 5:825, 1993; Galea et al: Proc Natl Acad Sci USA 89:10945, 1992). This induction can be measured by assaying cyclic GMP levels in the cultures, which correlates with, but is more sensitive than, measurement of nitrite accumulation. To study potential second-messenger systems involved in the induction of iNOS, phorbol 12-myristate 13-acetate (PMA), a protein kinase C (PKC) activator, and various protein kinase inhibitors were employed. PMA induced a time-, dose-, and L-arginine-dependent increase in cyclic GMP, which could be inhibited by dexamethasone or actinomycin D. This induction could be dramatically increased by concurrent treatment with IFN-gamma. The presence of iNOS mRNA could be demonstrated by hybridization with a specific cDNA probe. H7 (a non-specific serine/threonine kinase inhibitor) but not H89 (a more specific PKA inhibitor) prevented induction by all agents. However, downregulation of PKC or pretreatment with the PKC inhibitor calphostin C did not prevent the induction by LPS or cytokines, suggesting that PKC is not necessary for iNOS induction by these mediators. Additionally, genistein (a nonspecific tyrosine kinase inhibitor) could prevent induction by all agents, but the more specific inhibitor, tyrphostin, attenuated only NOS induction by LPS. These results suggest that activation of PKC can lead to, but is not necessary for, the induction of NOS in astrocytes and that there is a potential role for tyrosine kinases in NOS induction by LPS.(ABSTRACT TRUNCATED AT 250 WORDS)

Dorsal root ganglion (DRG) neurons express receptors for bradykinin and capsaicin, both algesic substances. Administration of bradykinin or capsaicin to neurons cultured from embryonic rat DRG stimulated the production of cyclic GMP but did not affect the production of cyclic GMP in nonneuronal DRG cultures. Bradykinin-evoked cyclic GMP production was mediated by B2 receptors and was unaltered by indomethacin. Both bradykinin- and capsaicin-stimulated cyclic GMP production required Ca2+ and was inhibited by methylene blue. Furthermore, methylene blue attenuated basal cyclic GMP production in DRG neurons, suggesting tonic cyclic GMP production in these cells. L-NG-monomethyl arginine inhibited both bradykinin- and capsaicin-stimulated cyclic GMP production as well as basal cyclic GMP production. These findings suggest the involvement of a nitrosyl compound in bradykinin- and capsaicin-stimulated cyclic GMP production and in tonic cyclic GMP production in DRG neurons.

Attention has focused on particular neurons as the source of nitric oxide (NO) within the parenchyma of the CNS. In contrast, glial cells have been viewed mainly as potential reservoirs of L-arginine, the substrate for nitric oxide synthase (NOS), and as likely targets for neuronally derived NO because of their proximity and their expression of soluble guanylyl cyclase (sGC). However, it is becoming evident that astrocytes display both constitutive and inducible NOS activity under various conditions, and that activated microglia express an inducible NOS. The NO-producing capacity of oligodendrocytes is not yet known. Glial-derived NO has significant implications for CNS pathophysiology, given the anatomical location and abundance of these cells, and the wide variety of potential interactions that NO can have with cellular biochemistry. Our intention here is to evaluate the evidence for NO production from non-neuronal CNS sources and thus prompt discussion about potential 'nitrinergic' roles for glial cells.

We have previously demonstrated that primary astrocyte cultures from neonatal rat cortex and C6 glioma cells express a calcium-independent nitric oxide synthase (NOS) on induction with bacterial endotoxin (lipopolysaccharide, LPS). One hypothesis regarding the mechanism of the LPS induction is that it causes release of cytokines from these cells which then induce the enzyme directly. Such cytokine induction of NOS has been demonstrated in many extraneural cell types. L-Arginine-dependent increases in cyclic GMP correlate with smaller increases in accumulation of nitrite, the major oxidation product of nitric oxide, and hence can serve as a more sensitive measure of nitric oxide production. Here we provide evidence that interferon-gamma (IFN-gamma), interleukin (IL)-1 beta and tumour necrosis factor-alpha induce L-arginine-dependent cyclic GMP synthesis in C6 cells and that a combination of IFN-gamma and IL-1 beta induce L-arginine-dependent cyclic GMP synthesis in astrocyte cultures, indicating that these cytokines induce NOS. In both cell types the induction by cytokines was less sensitive to inhibition by dexamethasone, IL-10 and IL-4 than was induction by LPS. These data suggest that cytokines can also induce a NOS in glial cells and that the mechanism of this induction may be more direct than that of LPS, since it is less sensitive to modulation by immunosuppressors. Due to the close associations of astrocytes with neurons and microvasculature, cytokine-induced NOS could have potentially important pathophysiological effects in the central nervous system.

Primary astrocyte cultures, C6 glioma cells, and N18 neuroblastoma cells were assayed for nitric oxide synthase (NOS) activity with a bioassay of cyclic GMP production in RFL-6 fibroblasts. Treatment of astrocyte cultures for 16-18 h with lipopolysaccharide (LPS) induced NOS-like activity that was L-arginine and NADPH dependent, Ca2+ independent, and potentiated by superoxide dismutase. Induction was evident after 4 h, was dependent on the dose of LPS, and required protein synthesis. Treatment of astrocyte cultures with leucine methyl ester reduced microglial cell contamination from 7 to 1%, with a loss of 44% of NOS-like activity. C6 cells treated with LPS also showed Ca(2+)-independent and L-arginine-dependent NOS-like activity. N18 cells demonstrated constitutive Ca(2+)-dependent NOS-like activity that was not enhanced by LPS induction. These data indicate that NOS-like activity can be induced in microglia, astrocytes, and a related glioma cell line as it can in numerous other cell types, but not in neuron-like N18 cells.

Release of endogenous norepinephrine was detected in guinea pig hippocampal slices using a radioligand displacement assay. Focal electrical stimulation released endogenous norepinephrine and caused a calcium-dependent reduction in specific [3H]propranolol binding at beta-adrenergic receptors in the brain slice. The mu-opioid agonist PL017 decreased norepinephrine release, and the inhibition by PL017 could be blocked by the opioid antagonist naloxone. Endogenous opioid peptides concomitantly released by tissue stimulation also decreased norepinephrine release in a naloxone-sensitive manner. These results support the hypothesis that endogenous opioids can regulate excitability in the hippocampus by presynaptic modulation of norepinephrine release.

Neuronal cultures from rat cerebellum consisting of approximately 90% glutamatergic granule neurons, 5-7% GABAergic inhibitory interneurons, and 3-5% glial cells, were treated for four days with 50 microM kainic acid (KA) to determine the cellular origin of released endogenous neuroactive substances. KA, known to be selectively toxic to GABAergic neurons, caused an estimated 80% decrease in glutamic acid decarboxylase (GAD) immunofluorescence. Furthermore, K(+)-stimulated release of GABA decreased to 20% of control values, and did not return to control levels in cultures "recovered" two days in KA-free media, suggesting the loss of inhibitory interneurons. Similarly, adenosine and taurine showed decreased K(+)-stimulated release, which was unrecoverable when KA was removed from the medium. K(+)-stimulated release of glutamate and aspartate also decreased by 50% and 70%, respectively, after chronic KA treatment. In contrast, however, this release returned to control levels in recovered cultures. All decreases in K(+)-stimulated release were prevented by concurrent treatment with KA and the KA antagonist 6-cyano-6-nitroquinoxaline-2,3-dione (CNQX), indicating that a receptor-mediated mechanism was involved. We conclude that, in these cultures, most of the K(+)-stimulated release of adenosine and taurine originates from the GABAergic interneurons, the basket and stellate cells, which are selectively killed by the KA treatment. The data also strongly suggest that glutamate and aspartate, the levels of which recover after KA treatment, originate mainly from the granule neurons.

The evidence presented, together with the lack of solid evidence for a specific receptor site, strongly suggests that taurine does not act as a traditional neurotransmitter in the CNS. In fact, the properties seen to be governing its efflux from both glial cells and neurons argue strongly in favor of a primary role in volume regulation. However, subsequent to its release into the extracellular space, it is possible that the inherent neuroactive properties (e.g., inhibitory neuromodulation and Ca(2+)-level modulation) may be important at the synapse, at the cell plasma membrane, and intracellularly in further directing the level of neuronal activity. Whether or not the levels of released taurine are great enough to sustain these effects has still to be determined.

N-Acetyl-aspartate is found in high concentrations in all areas of the brain, but is undetectable in non-neuronal tissue. In order to characterize the cellular localization of N-acetyl-aspartate in brain, highly specific monoclonal antibodies against N-acetyl-aspartate were produced by fusing spleen lymphocytes obtained from mice immunized with N-acetyl-aspartate conjugated to thyroglobulin by carbodiimide with P3/x63-Ag8.653 mouse myeloma cells. Clones were selected which secrete IgG2a(k) antibodies highly specific for conjugated N-acetyl-aspartate. Only 3-6% cross-reactivity with conjugated N-acetyl-aspartate-glutamate was observed at high antibody concentrations, whereas no cross-reactivity (less than 1%) was observed with conjugated N-acetyl-glutamate or aspartate. Preincubation of the antibodies with 0.5 mg/ml conjugated N-acetyl-aspartate blocked immunoreactivity more than 90%, while preincubation with conjugated N-acetyl-aspartate-glutamate and free N-acetyl-aspartate had no effect. Immunocytochemical staining has shown that N-acetyl-aspartate-like immunoreactivity is localized in neurons, which are widely distributed throughout the brain. The immunoreactive neurons exhibited intense staining of the perikarya, proximal dendrites and axons. No consistent pattern of distribution of immunoreactivity was observed with regard to primary neurotransmitter characteristics of stained neurons although neurons with long projections or extensive arbors, such as pyramidal cells in cortex, locus coeruleus, motor neurons and Purkinje cells, stained much more intensively than local circuit neurons.

N-Acetylated alpha-linked acidic dipeptidase (NAALA dipeptidase) is a membrane-bound metallopeptidase that cleaves glutamate from the endogenous neuropeptide N-acetyl-L-aspartyl-L-glutamate. In this report, we have solubilized NAALA dipeptidase activity from synaptosomal membranes with Triton X-100 and purified it to apparent homogeneity by sequential column chromatography on DEAE-Sepharose, CM-Sepharose, and lentil lectin-Sepharose. This procedure resulted in a 720-fold purification with 1.6% yield. The purified ezyme migrated as a single silver-stained band on a sodium dodecyl sulfate gel with an apparent molecular weight of 94 kDa. Using an enzymatic stain to visualize NAALA dipeptidase activity within a gel matrix, we have confirmed that the 94-kDa band is, indeed, NAALA dipeptidase. The purified enzyme was characterized and found to be pharmacologically similar to NAALA dipeptidase activity described previously in synaptosomal membrane extracts. Using the purified NAALA dipeptidase as antigen, we have raised specific and high titer polyclonal antibodies in guinea pig. Immunocytochemical studies show intense NAALA dipeptidase immunoreactivity in the cerebellar and renal cortices.