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Biomedical subjects

J Monahan

Publications and source records attributed to J Monahan.

At least 19 recordsLinked to original sources
PubMed2004

Biochemical and immunological properties of cytokines conjugated to dendritic polymers.

Here we describe a post-translational modification of SC-63032, a variant of the species restricted, multi-lineage hematopoeitic factor human interleukin-3 (hIL-3). We have made two new dendritic polymer (polyamidoamine or PAMAM dendrimers, generation 5)-SC-63032 bioconjugates. Using two distinct chemistries (one of which is novel to this work), we achieved site-specific conjugation with respect to the amino acid in the proteins ligated to the dendrimers. In both bioconjugates, conjugated cytokine maintains its ability to bind the hIL-3 alpha receptor subunit, but is significantly (about 10-fold) less potent in inducing hIL-3 dependent in vitro cell proliferation than is the free cytokine. In vivo data indicates that conjugation decreases the immunogenicity of the conjugated cytokine modestly. In the absence of pharmacokinetic or biodistribution effects associated with the bioconjugates that increase their potency in vivo (which can only be tested in a higher primate, due to the species restriction of hIL-3 and its derivatives), these immune mitigation effects may be too small to be therapeutically significant. Though unmodified PAMAM dendrimers fail to elicit an antibody response in mice, protein conjugation to dendrimers haptenizes them, and a dendrimer-specific antibody response is produced. In toto, the principal limitation of the dendrimer-cytokine bioconjugates herein is in their reduced receptor affinity and potency in vitro. Were the in vivo potency of the bioconjugates to parallel the in vitro potency of the conjugates reported here, it is likely that particular dendrimer bioconjugates could not justify their higher costs of goods relative to the parent SC-63032 molecule, though retention of SC-63032 biological activities in conjugates suggests that other cytokine-dendrimer bioconjugates may be bioactive. This is good news to the nanotechnology community, in as much as PAMAM dendrimers are among the monodisperse polymeric nanomaterials available, and these results show that they can be used successfully in conjugates to bioactive proteins.

Animals↗
PubMed2001

A method for filling complex polymeric microfluidic devices and arrays.

This paper describes an improved method for filling microfluidic structures with aqueous solutions. The method, channel outgas technique (COT), is based on a filling procedure carried out at reduced pressures. This procedure is compared with previously reported methods in which microfluidic channels are filled either by using capillary forces or by applying a pressure gradient at one or more empty reservoirs. The technique has proven to be > 90% effective in eliminating the formation of bubbles within microfluidic networks. It can be applied to many devices, including those containing PDMS-terminated channel features, a single channel inlet, and three-dimensional arrays.

Journal Article↗
PubMed2001

A novel recombinant adeno-associated virus vaccine induces a long-term humoral immune response to human immunodeficiency virus.

Recombinant adeno-associated virus (AAV) has attracted tremendous interest as a promising vector for gene delivery. In this study we have developed an HIV-1 vaccine, using an AAV vector expressing HIV-1 env, tat, and rev genes (AAV-HIV vector). A single injection of the AAV-HIV vector induced strong production of HIV-1-specific serum IgG and fecal secretory IgA antibodies as well as MHC class I-restricted CTL activity in BALB/c mice. The titer of HIV-1-specific serum IgG remained stable for 10 months. When AAV-HIV vector was coadministered with AAV-IL2 vector, the HIV-specific cell-mediated immunity (CMI) was significantly enhanced. Boosting with AAV-HIV vector strongly enhanced the humoral response. Furthermore, the mouse antisera neutralized an HIV-1 homologous strain, and BALB/c mice immunized via the intranasal route with an AAV vector expressing the influenza virus hemagglutinin (HA) gene showed protective immunity against homologous influenza virus challenge. These results demonstrate that AAV-HIV vector immunization may provide a novel and promising HIV vaccination strategy.

AIDS Vaccines↗
PubMed2001

Adeno-associated virus-mediated transfer of endothelial nitric oxide synthase gene inhibits protein synthesis of rat ventricular cardiomyocytes.

We investigated whether nitric oxide (NO) synthase gene transfer could attenuate growth of cultured cardiac myocytes. First, we investigated the effects of exogenous NO and cGMP analog on protein synthesis of cultured neonatal rat cardiac myocytes. The NO donor 3-morpholino-sydnonimine-hydrochloride (SIN-1) and 8-bromo-cGMP caused concentration-dependent decreases in phenylephrine-stimulated incorporation of 3H-leucine into cardiac myocytes. We then transferred endothelial constitutive NO synthase (ecNOS) gene into cultured neonatal rat cardiac myocytes using adeno-associated virus (AAV) vectors. ecNOS gene transfer into cardiac myocytes induced 140 kD ecNOS protein expression and significantly increased cGMP contents of myocytes compared with control cells. ecNOS gene transfer inhibited 3H-leucine incorporation into cardiac myocytes in response to phenylephrine, which was significantly recovered in the presence of the NOS inhibitor N(G)-monomethyl-L-arginine acetate. These results indicate that endogenously generated NO by ecNOS gene transfer using AAV vectors inhibits the alpha-adrenergic agonist-induced cardiac protein synthesis at least partially via cGMP production.

Adenoviridae↗
PubMed2001

Gamma-rays enhance rAAV-mediated transgene expression and cytocidal effect of AAV-HSVtk/ganciclovir on cancer cells.

Adeno-associated virus (AAV) vector has several unique properties suited for gene therapy applications. However, relatively low efficiency of transgene expression, which is mainly due to a limited second-strand synthesis from the single-stranded AAV genome, can be a problem in some applications that require potent gene expression such as antitumor applications. Recently, gamma-ray irradiation has been reported to enhance the second-strand synthesis of the AAV genome, and consequently transgene expression. We demonstrate here that an AAV vector harboring the herpes simplex virus type-1 thymidine kinase (HSVtk) is able to kill cancer cells more efficiently when used in combination with gamma-ray irradiation. A human maxillary sinus cancer cell line, NKO-1, was efficiently killed in combination with HSVtk transduction and ganciclovir (GCV), as expected. More importantly, gamma-ray irradiation of practical dosages augmented the cytocidal effect of the HSVtk/GCV system. Southern analysis indicated that gamma-rays enhanced the double-strand synthesis of the rAAV genome in NKO-1 cells. These findings suggest that the combination of rAAVtk/GCV suicide gene therapy with radiotherapy has synergistic effects in the treatment of cancers and may lead to a reduction of the potential toxicity of both rAAVtk/GCV and gamma-ray irradiation.

Antiviral Agents↗
PubMed2001

Mandated community treatment: beyond outpatient commitment.

Outpatient commitment, although often viewed as merely an extension of inpatient commitment, is only one of a growing array of legal tools used to mandate treatment adherence. The authors describe various forms of mandated community treatment. People with severe and chronic mental disorders often depend on goods and services provided by the social welfare system. Benefits disbursed by representative payees and the provision of subsidized housing have both been used as leverage to ensure treatment adherence. Many discharged patients are arrested for criminal offenses. Favorable disposition of their cases by a mental health court may be tied to participation in treatment. Under outpatient commitment statutes, judges can order committed patients to comply with prescribed treatment. Patients may attempt to maximize their control over treatment in the event of later deterioration by executing an advance directive. The ideological posturing that currently characterizes the field must be replaced by an evidence-based approach.

Advance Directives↗
PubMed2000

Triple transduction with adeno-associated virus vectors expressing tyrosine hydroxylase, aromatic-L-amino-acid decarboxylase, and GTP cyclohydrolase I for gene therapy of Parkinson's disease.

Parkinson's disease (PD), a neurological disease suited to gene therapy, is biochemically characterized by a severe decrease in the dopamine content of the striatum. One current strategy for gene therapy of PD involves local production of dopamine in the striatum achieved by inducing the expression of enzymes involved in the biosynthetic pathway for dopamine. We previously showed that the coexpression of tyrosine hydroxylase (TH) and aromatic-L-amino-acid decarboxylase (AADC), using two separate adeno-associated virus (AAV) vectors, resulted in more effective dopamine production and more remarkable behavioral recovery in 6-hydroxydopamine-lesioned parkinsonian rats, compared with the expression of TH alone. Not only levels of TH and AADC but also levels of tetrahydrobiopterin (BH4), a cofactor of TH, and GTP cyclohydrolase I (GCH), a rate-limiting enzymes for BH4 biosynthesis, are reduced in parkinsonian striatum. In the present study, we investigated whether transduction with separate AAV vectors expressing TH, AADC, and GCH was effective for gene therapy of PD. In vitro experiments showed that triple transduction with AAV-TH, AAV-AADC, and AAV-GCH resulted in greater dopamine production than double transduction with AAV-TH and AAV-AADC in 293 cells. Furthermore, triple transduction enhanced BH4 and dopamine production in denervated striatum of parkinsonian rats and improved the rotational behavior of the rats more efficiently than did double transduction. Behavioral recovery persisted for at least 12 months after stereotaxic intrastriatal injection. These results suggest that GCH, in addition to TH and AADC, is important for effective gene therapy of PD.

Animals↗
PubMed2000

A classification tree approach to the development of actuarial violence risk assessment tools.

Since the 1970s, a wide body of research has suggested that the accuracy of clinical risk assessments of violence might be increased if clinicians used actuarial tools. Despite considerable progress in recent years in the development of such tools for violence risk assessment, they remain primarily research instruments, largely ignored in daily clinical practice. We argue that because most existing actuarial tools are based on a main effects regression approach, they do not adequately reflect the contingent nature of the clinical assessment processes. To enhance the use of actuarial violence risk assessment tools, we propose a classification tree rather than a main effects regression approach. In addition, we suggest that by employing two decision thresholds for identifying high- and low-risk cases--instead of the standard single threshold--the use of actuarial tools to make dichotomous risk classification decisions may be further enhanced. These claims are supported with empirical data from the MacArthur Violence Risk Assessment Study.

Actuarial Analysis↗
PubMed2000

Violence risk assessment and risk communication: the effects of using actual cases, providing instruction, and employing probability versus frequency formats.

This article describes studies designed to inform policy makers and practitioners about factors influencing the validity of violence risk assessment and risk communication. Forensic psychologists and psychiatrists were shown case summaries of patients hospitalized with mental disorder and were asked to judge the likelihood that the patient would harm someone within six months after discharge from the hospital. They also judged whether the patient posed a high risk, medium risk, or low risk of harming someone after discharge. Studies 1 and 2 replicated, with real case summaries as stimuli, the response-scale effects found by Slovic and Monahan (1995). Providing clinicians with response scales allowing more discriminability among smaller probabilities led patients to be judged as posing lower probabilities of committing harmful acts. This format effect was not eliminated by having clinicians judge relative frequencies rather than probabilities or by providing them with instruction in how to make these types of judgments. In addition, frequency scales led to lower mean likelihood judgments than did probability scales, but, at any given level of likelihood, a patient was judged as posing higher risk if that likelihood was derived from a frequency scale (e.g., 10 out of 100) than if it was derived from a probability scale (e.g., 10%). Similarly, communicating a patient's dangerousness as a relative frequency (e.g., 2 out of 10) led to much higher perceived risk than did communicating a comparable probability (e.g., 20%). The different reactions to probability and frequency formats appear to be attributable to the more frightening images evoked by frequencies. Implications for risk assessment and risk communication are discussed.

Adult↗
PubMed2000

Sources of coercive behaviours in psychiatric admissions.

OBJECTIVE: Coercion during psychiatric admissions has been a topic of debate for many years. Although there has been considerable research on patients' perceptions of coercion, there has been no work on who places pressures on patients to be admitted. METHOD: This article integrates interview data from interviews with patients, admitting staff and family and friends to describe the pressures brought to bear on patients to be admitted. RESULTS: Health-care professionals appear to be the most important source of pressures on patients, and to have the most impact on patients' perceptions of coercion. However, there are differences in type of pressure, and the pressures used by family and friends appear to have the most longstanding impact. CONCLUSION: Legal and clinical efforts to reduce the level of coercive pressures on patients need to recognize the importance of mental-health professionals, including especially those who are not legally mandated to participate in the admission process.

Adolescent↗
PubMed2000

Adeno-associated virus vector-mediated bcl-2 gene transfer into post-ischemic gerbil brain in vivo: prospects for gene therapy of ischemia-induced neuronal death.

The proto-oncogene bcl-2 is known as an anti-apoptotic gene that confers the ability to block neuronal cell death after transient ischemia. In order to examine whether the bcl-2 gene can be used for protection of ischemic brain injury, we generated adeno-associated virus (AAV) vectors capable of expressing human bcl-2. Replication-defective AAV vectors were found effectively to transfer and express bcl-2 gene in the gerbil hippocampal neurons. Transduction with AAV bcl-2 5 days before forebrain ischemia prevented the DNA fragmentation in the CA1 neurons that is commonly associated with ischemia-induced cell death. Furthermore, the application of AAV bcl-2 as late as 1 h following an ischemic insult also prevented DNA fragmentation in CA1 neurons. These results suggest that the bcl-2 protein has neuroprotective functions that inhibit ischemic cell death and demonstrate the potential of AAV bcl-2 for use in post-ischemic gene therapy in the brain. Gene Therapy (2000) 7, 1244-1249.

Adenoviridae↗
PubMed2000

Adeno-associated virus-mediated vascular endothelial growth factor gene transfer into cardiac myocytes.

Vascular endothelial growth factor (VEGF) is an angiogenic growth factor that stimulates endothelial cell proliferation, increases endothelial permeability, and promotes collateral vessel formation. We transferred human VEGF gene into rat cardiac myocytes using adeno-associated virus (AAV) vectors and investigated whether VEGF secreted from the transduced cardiac myocytes promoted proliferation of endothelial cells. We produced VEGF-expressing AAV vectors (AAV-VEGF) by the adenovirus-free method. Immunoblotting revealed VEGF protein expression in AAV-VEGF-transduced rat cardiac myocytes. More than 60% of cardiac myocytes were stained positively on immunohistochemical staining using anti-VEGF antibody. Concentration of VEGF in the culture medium of AAV-VEGF-transduced myocytes was increased in a vector dose-dependent manner, and VEGF secretion from the transduced myocytes persisted for > or = 14 days. Thymidine incorporation into human vascular endothelial cells was significantly increased by incubation with the conditioned medium from AAV-VEGF-transduced myocytes. This increased thymidine uptake was significantly inhibited by anti-VEGF antibody. We demonstrated here that AAV-mediated VEGF gene transfer into cardiac myocytes induces the secretion of functional VEGF.

Animals↗
PubMed2000

Violence and delusions: data from the MacArthur Violence Risk Assessment Study.

OBJECTIVE: Previous work has suggested that delusions are associated with a higher risk of violence, particularly delusions in which patients believe that people are seeking to harm them or that outside forces are controlling their minds (denoted as "threat/control override" delusions). This study explores the relationship between delusions and violence among patients recently discharged from acute psychiatric hospitalization. METHOD: Data were drawn from the MacArthur Violence Risk Assessment Study, a study of violence in the community that followed 1,136 recently discharged psychiatric patients for 1 year. Interviews at discharge and at five 10-week intervals gathered clinical, historical, situational, and dispositional information, including the presence and nature of delusional thoughts. Violence was ascertained from reports of subjects, collateral informants, and official records. RESULTS: Neither delusions in general nor threat/control override delusions in particular were associated with a higher risk of violent behavior. Comparisons with prior studies suggest that reliance on subject self-reports of delusional symptoms may result in mislabeling as delusions other phenomena that can contribute to violence. CONCLUSIONS: Although delusions can precipitate violence in individual cases, these data suggest that they do not increase the overall risk of violence in persons with mental illness in the year after discharge from hospitalization.

Adolescent↗
PubMed2000

Developing a clinically useful actuarial tool for assessing violence risk.

BACKGROUND: A new actuarial method for violence risk assessment--the Iterative Classification Tree (ICT)--has become available. It has a high degree of accuracy but can be time and resource intensive to administer. AIMS: To increase the clinical utility of the ICT method by restricting the risk factors used to generate the actuarial tool to those commonly available in hospital records or capable of being routinely assessed in clinical practice. METHOD: A total of 939 male and female civil psychiatric patients between 18 and 40 years old were assessed on 106 risk factors in the hospital and monitored for violence to others during the first 20 weeks after discharge. RESULTS: The ICT classified 72.6% of the sample as either low risk (less than half of the sample's base rate of violence) or high risk (more than twice the sample's base rate of violence). CONCLUSIONS: A clinically useful actuarial method exists to assist in violence risk assessment.

Actuarial Analysis↗
PubMed2000

Violent thoughts and violent behavior following hospitalization for mental disorder.

Using a standardized schedule of questions, this study examined (a) the prevalence of self-report of violent thoughts by patients hospitalized for mental disorders compared with nonpatients, (b) the persistence of violent thoughts after discharge, and (c) the relation between patients' violent thoughts while hospitalized and violent acts within 20 weeks after hospital discharge. About 1/3 of the patients reported thoughts of violence while hospitalized, more than twice the proportion found among nonpatients. Reporting violent thoughts in hospital was significantly related to engaging in violent acts within 20 weeks after discharge for non-White patients, patients without major mental disorder but with substance abuse diagnoses, patients with high symptom severity, and patients whose reports of violent thoughts persisted after discharge. Reporting violent thoughts was significantly related to measures of psychopathy, anger, and impulsiveness.

Adult↗
PubMed1999

Assessing violence risk among discharged psychiatric patients: toward an ecological approach.

This paper draws upon data from the Pittsburgh site of the MacArthur Foundation's Risk Assessment Study, a large-scale study of violence risk among persons discharged from psychiatric hospitals, to examine the effect of the neighborhood context on risk of violence. This paper has two purposes: (1) to assess the extent to which the inclusion of neighborhood characteristics enhances violence prediction models-models that traditionally only include individual-level characteristics; and (2) to assess the consistency of individual level risk factors across different neighborhood contexts. Results indicate that neighborhood poverty has an impact over and above the effects of individual characteristics in identifying cases with violence. These findings support efforts to include neighborhood context in the assessment and management of violence risk among discharged psychiatric patients.

Adult↗