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Posaconazole: SCH 56592.

Posaconazole [SCH 56592, SPRIAFIL, Noxafil] is an orally active triazole derivative that is in phase III trials with the Schering-Plough Research Institute (SPRI) in the US for the treatment of serious opportunistic fungal infections, including aspergillosis, candidiasis, coccidioidomycosis and fusariosis. This profile has been selected from R&D Insight, a pharmaceutical intelligence database produced by Adis International Ltd. Preclinical studies have also been conducted in Italy for the potential treatment of Cryptococcus neoformans infection (cryptococcosis).

Administration, Oral↗

Hydrogels: their future, Part I.

Hydrogels can be made from a wide variety of water-interactive or water-soluble polymers. They comprise a large family of materials with diverse properties, including some with "smart" responses to their environment. Part I of this two-part article will address the range of biomaterial syntheses, properties and applications that can be obtained from one ubiquitous and biocompatible structure: poly(ethylene oxide). Part II will discuss the applications of a novel class of intelligent materials.

Biocompatible Materials↗

The epidemiology of obsessive compulsive disorder.

The literature on the epidemiology and genetics of obsessive compulsive disorder (OCD) is reviewed. The application of recently developed diagnostic criteria, psychometric testing, and biologic markers to epidemiologic studies of OCD should provide important new data for increasing our understanding of the pathogenesis of the disorder. Identification of diagnostic subgroups will be important in reliably evaluating treatment response to current and new therapeutic agents. Directions for potential research in these areas are discussed.

Adolescent↗

A prospective neurocognitive evaluation of children treated with additional chemotherapy and craniospinal irradiation following isolated central nervous system relapse in acute lymphoblastic leukemia.

PURPOSE: A prospective assessment of neurocognitive performance was conducted in children with acute lymphoblastic leukemia (ALL) following isolated central nervous system (CNS) relapse to evaluate the impact of additional systemic/intrathecal (IT) chemotherapy and craniospinal irradiation (CSI) upon long-term intellectual function. METHODS AND MATERIALS: Twenty-one children with ALL manifesting an isolated CNS relapse between 1984 through 1989 underwent serial evaluations of intellectual function. Neurocognitive function was measured by the full-scale intelligence quotient (FSIQ) as determined by the age-appropriate Wechsler Intelligence Scale and by achievement in reading, math, and spelling as assessed by the Wide Range Achievement Test (WRAT). Intelligence testing was initiated following isolated CNS relapse after clearance of cerebrospinal fluid (CSF) cytology but prior to CSI and continued at annual intervals for a minimum of 4 years postmeningeal failure. Protocol treatment for isolated CNS relapse consisted of reinduction and maintenance systemic therapy, intrathecal (IT) triple-agent chemotherapy, and early CSI (cranium to 24 Gy and spine to 15 Gy at 1.5 Gy/fraction) as outlined on the institutional "Total XI" trial. RESULTS: All 21 children attained secondary CNS remission and underwent the planned additional systemic/IT chemotherapy and CSI. Fourteen of the 21 children remain in secondary continuous remission, while the remaining 7 experienced a second relapse and were removed from further neurocognitive assessment. For the eight female and six male long-term survivors, mean ages at original diagnosis and at CSI were 5.7 years (range = 0.6-16.2) and 7.0 years (range = 1.8-17.0), respectively. At a median follow-up interval of 4.6 years (ranges 1.7-6.8) post-CNS relapse, comparison of group mean initial to final FSIQs revealed no statistically significant difference between the two measures (94.5 vs. 95.9, respectively, n = 11, p = 0.52). None of the children are functioning in the mentally retarded range. Final FSIQ outcome directly correlated with initial FSIQ (p = 0.00005, n = 11), age at diagnosis (p = 0.009, n = 14), and age at CSI (p = 0.011, n = 14). In addition, change between initial and final FSIQ scores inversely correlated with age at diagnosis (p = 0.009) and age at CSI (p = 0.018) but not with baseline IQ score (p = 0.41). Initial FSIQ scores were not influenced by either age at diagnosis (p = 0.12) or age at CSI (p = 0.14). Final group mean (range) WRAT scores in reading, math, and spelling were measured to be 94.7 (68-132), 95.6 (69-126), and 93.7 (77-122), respectively (n = 13). Final reading and math scores directly correlated with both age at diagnosis (p = 0.01) and age at CSI (p = 0.009). Spelling outcome did not correlate with either age at diagnosis (p = 0.25) or age at CSI (p = 0.24). Nine children are placed in regular classrooms, while the remaining five require a mixed classroom environment. CONCLUSION: In our study, children with ALL experiencing an isolated CNS relapse tolerated additional systemic/IT chemotherapy and CSI without apparent deterioration of group serial intellectual scores. However, longitudinal analyses of group intellectual measures obscured the independent impact of initial FSIQ, age at original diagnosis, and age at CSI upon individual neurocognitive outcome. Early and more intensive psychoeducational stimulation may be needed in very young children presenting with low initial FSIQ scores who are treated with CSI and additional chemotherapy following isolated CNS relapse in ALL.

Adolescent↗

Neurologic, neurocognitive, and brain growth outcomes in human immunodeficiency virus-infected children receiving different nucleoside antiretroviral regimens. Pediatric AIDS Clinical Trials Group 152 Study Team.

OBJECTIVES: To compare the impact of three different nucleoside reverse transcriptase inhibitor regimens, zidovudine (ZDV) monotherapy, didanosine (ddI) monotherapy, and ZDV plus ddI combination therapy, on central nervous system (CNS) outcomes in symptomatic human immunodeficiency virus (HIV)-infected children. METHODS: Serial neurologic examinations, neurocognitive tests, and brain growth assessments (head circumference measurements and head computed tomography or magnetic resonance imaging studies) were performed in 831 infants and children who participated in a randomized double-blind clinical trial of nucleoside reverse transcriptase inhibitors. The Pediatric AIDS Clinical Trials Group study 152 conducted between 1991 and 1995 enrolled antiretroviral therapy-naive children. Subjects were stratified by age (3 to <30 months of age or 30 months to 18 years of age) and randomized in equal proportions to the three treatment groups. RESULTS: Combination ZDV and ddI therapy was superior to either ZDV or ddI monotherapy for most of the CNS outcomes evaluated. Treatment differences were observed within both age strata. ZDV monotherapy showed a modest statistically significant improvement in cognitive performance compared with ddI monotherapy during the initial 24 weeks, but for subsequent protection against CNS deterioration no clear difference was observed between the two monotherapy arms. CONCLUSIONS: Combination therapy with ZDV and ddI was more effective than either of the two monotherapies against CNS manifestations of human immunodeficiency virus disease. The results of this study did not indicate a long-term beneficial effect for ZDV monotherapy compared with ddI monotherapy.

Adolescent↗

Predicting HIV disease progression in children using measures of neuropsychological and neurological functioning. Pediatric AIDS clinical trials 152 study team.

BACKGROUND: Neuropsychological testing and 2 measures of neurological status, cortical atrophy, and motor dysfunction were assessed for their usefulness in predicting human immunodeficiency virus (HIV) disease progression in infants, children, and adolescents who participated in Pediatric AIDS Clinical Trials Group Protocol 152 (PACTG 152). METHODS: A cohort of 722 antiretroviral therapy-naive children with symptomatic HIV infection were assessed at study entry and at later intervals. Assessments included neurodevelopmental testing, neuroradiologic imaging, and neurological examination of motor function. CD4 cell count and plasma RNA viral load also were measured. RESULTS: Children with the lowest neuropsychological functioning (IQ < 70) at baseline had the highest risk for later HIV disease progression (56%), compared with those with borderline/low (IQ = 70-89) functioning (26%), or with average or above (IQ > 90) functioning (18%). This was also true of week 48 neuropsychological functioning. Motor dysfunction (especially reduced muscle mass) at entry also predicted disease progression. Furthermore, motor dysfunction and week 48 neuropsychological functioning provided predictive information beyond that obtainable from surrogate markers of HIV disease status (eg, CD4 count, HIV RNA level). Children with cortical atrophy also were at higher risk for later disease progression, but when CD4 count and RNA viral load were known, cortical atrophy information provided no additional predictive information. CONCLUSIONS: Measures of neuropsychological and motor function status provide unique information regarding pediatric HIV disease progression. As such, these findings have important implications for predicting long-term outcomes (eg, longevity) in pediatric patients.

AIDS Dementia Complex↗

A hybrid supervisory system to support WWTP operation: implementation and validation.

Integrated operation of Wastewater Treatment Plants is still far from being solved. A reasonable proposal should link advanced and robust control algorithms to some knowledge-based techniques, allocating the detailed engineering to numerical computations, while delegating the logical analysis and reasoning to supervisory intelligent systems. This paper describes the development and implementation of a knowledge-based Hybrid Supervisory System to support the operation of a real Wastewater Treatment Plant. The system integrates different reasoning modules, overcoming the limitations in the use of each single technique, while providing an agent based architecture with additional modularity and independence. It is structured into three separated levels: data gathering, diagnosis, and decision support. The different tasks of the system are performed in a seven-step cycle: data gathering and update, diagnosis, supervision, prediction, communication, actuation, and evaluation phase. In spite of certain reservations of the scientific community about the use of these techniques, the system is successfully performing real-time support to the operation of the Granollers facility since September 1999. Results of the first four-month validation period are shown and discussed. An example of the system behavior is also shown in the paper. The conclusions indicate the key steps which are necessary to transfer the system to another facility.

Algorithms↗

Contraceptive management for female adolescents with mental retardation and handicapping disabilities.

Adolescent girls with mental retardation and handicapping disabilities have a need for sexual counseling and contraceptive management. Societal attitudes have changed, allowing these patients to experience normal and satisfying sexuality. The reproductive health concerns of these patients are extensive. Contraceptive selection varies with regard to the mental and physical capabilities of individual patients. The use of barrier methods, intrauterine devices, oral contraceptives, intramuscular medroxyprogesterone acetate, and sterilization has been discussed thoroughly in the past. No formal studies have been performed to evaluate the use of subdermal levonorgestrel implants in patients with mental retardation and physical disabilities.

Adolescent↗

New approaches to catheter navigation for interventional radiology simulation.

For over 20 years, interventional methods have improved the outcomes of patients with cardiovascular disease. However, these procedures require an intricate combination of visual and tactile feedback and extensive training periods. In this paper, we describe a series of novel approaches that have lead to the development of a high-fidelity simulation system for interventional neuroradiology. In particular we focus on a new approach for real-time deformation of devices such as catheters and guidewires during navigation inside complex vascular networks. This approach combines a real-time incremental Finite Element Model, an optimization strategy based on substructure decomposition, and a new method for handling collision response in situations where the number of contacts points is very large. We also briefly describe other aspects of the simulation system, from patient-specific segmentation to the simulation of contrast agent propagation and fast volume rendering techniques for generating synthetic X-ray images in real-time.

Algorithms↗

Mémoire: A framework for semantic interoperability of case-based reasoning systems in biology and medicine.

OBJECTIVE: Mémoire is a framework for sharing and distributing case bases and case-based reasoning (CBR) systems in biology and medicine. METHODS AND MATERIAL: This paper first introduces the semantic Web approach to build a better Web where search engines, knowledge sources and servers, applications and services can live, work, and learn in cooperation. This semantic approach is particularly well suited for biomedical domains because significant ontologies have been developed there and constitute a sound basis for the standardization effort required for the semantic Web. Case-based reasoning systems in biomedicine have also benefited from these biomedical ontologies and models. RESULTS: This article demonstrates for three such systems how a semantics infused approach in CBR gives better, more accurate results in CBR. From this previous work on a semantic approach in CBR in biomedicine, the Mémoire framework has evolved. CONCLUSION: Mémoire proposes a unified OWL-based representation language for cases and case-based ontologies in biomedicine, where a Web Ontology Language (OWL) is a language to represent ontologies on the Web. Mémoire provides a set of tools for building case-based reasoning systems compliant with its language. Mémoire is extensible and can be adapted to different types of biomedical application domains, tasks, and environments. Mémoire will permit bridging the gap within the multiple case-based reasoning systems dedicated to a single domain, and make available to agents and Web services the case-based competency of the CBR systems adopting its interchange language. The approach could be extended to other application domains of CBR.

Artificial Intelligence↗

Nipah virus in the era of global connectivity: molecular evolution, transmission risk, and preparedness strategies.

Nipah virus (NiV) is a highly pathogenic zoonotic RNA virus belonging to the genus Henipavirus within the family Paramyxoviridae, representing a continuing global health concern due to its high case fatality rate and potential for epidemic expansion in the era of increasing international connectivity. The virus demonstrates strong evolutionary adaptability driven by the absence of proofreading mechanisms during RNA replication, enabling genetic diversification that may influence host range, virulence, and transmission dynamics. Molecular pathogenesis of NiV is primarily mediated through interaction of viral glycoproteins with ephrin-B2 and ephrin-B3 receptors, facilitating host cell entry, endothelial damage, and neuroinvasion. Immune evasion facilitated by the action of accessory proteins encoded by the P gene (P, V, W, and C) acts to suppress innate antiviral immunity through the inhibition of interferon induction and JAK/STAT signaling. Human-to-human transmission of Nipah virus remains limited, with epidemiological evidence indicating basic reproduction numbers generally below unity; however, respiratory involvement and healthcare-associated exposure may enhance cluster outbreaks. Global travel, ecological disruption, and fragmented surveillance systems contribute to spillover risk, particularly in South and Southeast Asia where fruit bats of the genus Pteropus serve as natural reservoirs. Despite advances in vaccine technology, including subunit, viral vector, mRNA-based platforms, and monoclonal antibody therapies, no licensed prophylactic or therapeutic agent is currently available for human use. Global preparedness remains challenged by the scarcity of high-containment biosafety facilities, limited research funding, and absence of integrated One Health surveillance networks. Ethical considerations surrounding wildlife population control further complicate disease mitigation strategies. Emerging genomic surveillance, artificial intelligence-assisted predictive modeling, and regional data-sharing frameworks are essential for early detection and response. Strengthening molecular research on viral-host interactions and transmission determinants will be critical for preventing future Nipah virus outbreaks in an increasingly interconnected world.

Genomic surveillance↗

Theory of networked minority games based on strategy pattern dynamics.

We formulate a theory of agent-based models in which agents compete to be in a winning group. The agents may be part of a network or not, and the winning group may be a minority group or not. An important feature of the present formalism is its focus on the dynamical pattern of strategy rankings, and its careful treatment of the strategy ties which arise during the system's temporal evolution. We apply it to the minority game with connected populations. Expressions for the mean success rate among the agents and for the mean success rate for agents with k neighbors are derived. We also use the theory to estimate the value of connectivity p above which the binary-agent-resource system with high resource levels makes the transition into the high-connectivity state.

Adaptation, Physiological↗

Physiologic and pathophysiologic role of cyclo-oxygenase metabolites of arachidonic acid in circulatory disease states.

The overall assessment of eicosanoids in ischemia and shock is complex. Certain prostaglandins, notably PGI2, actually improved survival in shock and ischemic states; however, some, including TxA2, act as mediators, significantly contributing to the pathophysiology of vasospasm and ischemia. This makes the intelligent use of eicosanoid-related drugs very difficult. Broad-based inhibitors (for example, cyclo-oxygenase inhibitors) are not likely to exert significant protective effects because they inhibit beneficial as well as detrimental eicosanoids. More appropriately, the therapy of ischemic disorders should be designed to employ specific agents (for example, TxSI and TxRA) rather than broad-based agents. Preliminary studies already suggest the success of such an approach. Future investigations will focus on the application of potent synthetic modulators or analogues of specific eicosanoids in an attempt to prevent the deleterious effects of eicosanoid mediators of ischemic disorders and to potentiate and prolong the beneficial actions of therapeutic eicosanoids.

Animals↗

Inhibition of dopamine synthesis in chronic schizophrenia. Clinical ineffectiveness of metyrosine.

According to the dopamine (DA) hypothesis of schizophrenia, there is a functional excess of dopaminergic activity within unspecified areas of the brain in schizophrenic patients. As a clinical test of this hypothesis, we administered metyrosine for three weeks to symptomatic chronic male schizophrenic patients who were maintained on suboptimal doses of neuroleptic agents. Metyrosine inhibits tyrosine hydroxylase, the rate-limiting enzymatic step in the synthesis of DA. No clinical improvement was observed, using the National Institute of Mental Health Inpatient Behavioral Rating Scale or the Brief Psychiatric Rating Scale. Central inhibition of DA synthesis by metyrosine was suggested, however, by (1) the development of extrapyramidal side effects and (2) a significant increase in plasma prolactin concentrations. Plasma chlorpromazine concentrations remained unchanged during metyrosine treatment. There was, nevertheless, a significant improvement on the scores of the Wechsler Adult Intelligence Scale Comprehension subtest, which measures judgment and common sense. This finding suggests that DA may be involved in the regulation of subtle psychological processes. The results are discussed in light of the DA hypothesis of schizophrenia and previous reports suggesting that metyrosine potentiates the antipsychotic effect of neuroleptics in schizophrenia.

Adult↗

A hypermedia system for parasite identification.

In this paper a hypermedia system for parasite identification is described. The knowledge base is relative to the class of the Trematoda parasites and reports agent, vector, disease, related category of the International Classification of Diseases and geographic area. A graphic user-friendly human-machine interface has been realized for this system.

Animals↗