Serotonergic agents in the treatment of acute neuroleptic-induced akathisia: open-label study of buspirone and mianserin

It has been suggested that dopamine/serotonin (5-HT) imbalance, with relative enhancement of serotonergic activity, might be one of the possible pathophysiological mechanisms underlying neuroleptic-induced akathisia. On the basis of preclinical data, which imply that the partial 5-HT1A agonist buspirone possesses anti-5-HT activity, in the present open-label study we examined the putative antiakathitic effect of buspirone in 10 neuroleptic-treated patients with acute neuroleptic-induced akathisia. Buspirone (up to 30 mg/day in divided doses) was administered for a trial period of 4 days (first part of the study). No significant changes in neuroleptic-induced akathisia as rated using the Barnes Akathisia Scale were detected during buspirone treatment. Buspirone was effective in only two neuroleptic-induced akathisia patients and caused worsening of akathisia in the other two patients. According to the study design, eight buspirone non-responders were switched to the 5-HT2A/2C antagonist mianserin (15 mg/day) for the other 4 days of treatment (second part of the study). Seven mianserin-treated patients improved and five revealed complete disappearance of neuroleptic-induced akathisia. It seems that the 5-HT1A partial agonist buspirone is of limited value in the treatment of acute neuroleptic-induced akathisia. It contrast, it appears that low-dose mianserin is therapeutically effective in acute neuroleptic-induced akathisia.     

Akathisia in adults with mental retardation: development of the Akathisia Ratings of Movement Scale (ARMS)

We developed an akathisia rating scale for use with persons who have mental retardation and screened for the occurrence of akathisia in three samples: 66 adults receiving maintenance neuroleptic treatment, 20 adults not receiving neuroleptics, and 8 adults undergoing neuroleptic dose reduction. The scale had an acceptable level of interrater reliability and validly measured group differences related to neuroleptic treatment status. Using an empirically derived cut-off-score, we estimated the prevalence rate for akathisia to be 5% in neuroleptic-free subjects, 17% in neuroleptic-maintenance subjects, and 25% in neuroleptic-reduction subjects. Akathisia, dyskinesia, and stereotypy manifested as qualitatively different movement topograhies. The occurrence of dyskinesia stereotyped movement disorder was associated significantly with an increased occurrence of akathisia.     

Subjective experiences of patients with acute neuroleptic-induced akathisia

Neuroleptic-induced akathisia is a clinically important neuropsychiatric syndrome with mainly subjectively experienced psychic symptoms on the one hand and well-observable motor signs on the other. There is no general consensus of opinion on the relative importance of these two aspects for diagnosing akathisia. Hence, differential diagnosis is difficult and in the absence of a biological marker it depends crucially on clinical judgement. Systematic investigation of 27 in-patients via a semistructural interview, a self-assessment scale (20 in-patients) and established akathisia rating scales (Hillside, Barnes, Prince Henry Hospital and Chouinard) revealed four characteristics of subjective experience in acute neuroleptic-induced akathisia: 1. perception of a foreign but nevertheless inner compulsion to move; 2. lack of control over motor behaviour; 3. feeling of inhibition of purposeful actions and 4. subjectively close or inseparable relationship between inner restlessness and restless movements. These features are strongly interrelated and correlate with severity of akathisia. They could be useful in differentiating akathisia from other states of restlessness. The results of this study are discussed in context of the literature on clinical phenomenology of akathisia. We propose a symptom-severity model of akathisia emphasizing psychodynamic aspects with considerable consequences for diagnosis and quantification of the disorder. The model points to the relevance of patient exploration for optimizing diagnostic reliability and should be taken into account when developing new and valid akathisia rating instruments.     

Akathisia

The syndrome of akathisia typically consists of a subjective component, e.g. inner restlessness and an urge to move, and observable symptoms such as restless legs and inability to sit still. In most cases akathisia is caused by neuroleptics. There are several subtypes of akathisia according to the time of onset in the course of neuroleptic treatment. In clinical routine extrapyramidal motor disturbances are often underestimated or misinterpreted. As far as akathisia is concerned, differential diagnosis of restlessness or of repetitive movement patterns may be problematic. Non-compliance and impulsive behaviour are regarded as possible complications of akathisia, but systematic investigations are lacking. The pathophysiology of akathisia is not clear, but it probably differs from other pharmacologically induced motor disturbances. If warrantable, the first step in akathisia treatment is dose-reduction of the causing agent. Anticholinergic drugs, benzodiazepines, and beta-receptor blockers may be effective. Clinical assessment and survey of the patient's behaviour, e.g. during occupational therapy and group therapy is important for an early diagnosis of akathisia so that complications may be minimised.     

Introducing evidence-based medicine into a community family medicine residency

In this article we discuss how we are introducing the concept of evidence-based medicine (EBM) into our Family Practice Residency Program. We review the basic concepts of EBM., show how these have been incorporated in the curriculum, and how they are applied to patient care. We identify the need for further work to evaluate our efforts and improve them.     

In situ hybridization: a possible diagnostic aid in leptomeningeal metastasis

In this review we discuss the clinical features and pathophysiology of leptomeningeal metastasis (LM), and elaborate on diagnostic tools for the detection of this serious complication of cancer. Because of the low sensitivity of the cytologic examination, new diagnostic approaches have been developed. The in situ hybridization technique may prove to be a reliable and early test for the detection of LM.     

Muscle-based gene therapy: realistic possibilities for the future

The past five years have witnessed tremendous growth in the field of gene therapy, with pre-clinical and clinical gene therapy trials for diseases as diverse as cancer, AIDS and atherosclerosis. These studies have utilized many different vectors and target organs in order to achieve therapeutic effects. In this review, we examine the rationale for using skeletal muscle as a target tissue for gene therapy, discuss the wide array of vectors that have been used for muscle-based gene therapy, summarize the disease-targets that have been approached using these techniques, and discuss some of the obstacles that remain to be overcome en route to successful muscle-based human gene therapy.     

SSRI-induced extrapyramidal side-effects and akathisia: implications for treatment

The selective serotonin reuptake inhibitors (SSRIs) may occasionally induce extrapyramidal side-effects (EPS) and/or akathisia. This may be a consequence of serotonergically-mediated inhibition of the dopaminergic system. Manifestations of these effects in patients may depend on predisposing factors such as the presence of psychomotor disturbance, a previous history of drug-induced akathisia and/or EPS, concurrent antidopaminergic and/or serotonergic therapy, recent monoamine oxidase inhibitor discontinuation, comorbid Parkinson's disease and possibly deficient cytochrome P450 (CYP) isoenzyme status. There is increasing awareness that there may be a distinct form of melancholic or endogenous depression with neurobiological underpinnings similar to those of disorders of the basal ganglia such as Parkinson's disease. Thus, it is not surprising that some individuals with depressive disorders appear to be susceptible to developing drug-induced EPS and/or akathisia. In addition, the propensity for the SSRIs to induce these effects in individual patients may vary within the drug class depending, for example, on their selectivity for serotonin relative to other monoamines, affinity for the 5-HT2C receptor, pharmacokinetic drug interaction potential with concomitantly administered neuroleptics and potential for accumulation due to a long half-life. The relative risk of EPS and akathisia associated with SSRIs have yet to be clearly established. The potential risks may be reduced by avoiding rapid and unnecessary dose titration. Furthermore, early recognition and appropriate management of EPS and/or akathisia is required to prevent the impact of these effects on patient compliance and subjective well-being. It is important that the rare occurrence of EPS in patients receiving SSRIs does not preclude their use in Parkinson's disease where their potentially significant role requires more systematic evaluation.     

One-sided invasion events in homologous recombination at double-strand breaks

Two classes of homologous recombination mechanism for repair of double-strand breaks (DSBs) have been described in eukaryotes so far. One is conservative and has been explained by the double-strand break repair model (Szostak et al., 1983), whereas the other one is non-conservative and has been explained by the single-strand annealing model (Lin et al., 1984). Here, we will review data supporting the existence of another homologous recombination mechanism for double-strand break repair. We will present the one-sided invasion model that we have proposed to explain this mechanism and discuss its potential implication in various homologous recombination events.     

The regulation of AMPA receptor-binding sites

A wide variety of mechanisms have been identified that can regulate the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA)-receptor complex. Modulation has been shown to occur at the nucleic acid level via RNA editing and alternative splicing. At the posttranslational level, processes such as phosphorylation, glycosylation, chemical modification of reactive groups on the receptor proteins, interaction with a putative receptor-associated modulatory protein, and changes in the lipid environment have been reported to regulate receptor binding and function. In this review, we discuss general aspects of the cell biology, pharmacology, and function of AMPA receptors. In particular, we focus on some factors shown to modulate agonist binding and discuss possible molecular mechanisms underlying the regulation observed.     

Angiogenesis and cancer

Tumor invasion and dissemination is tightly controlled by angiogenesis. In recent years, a number of angiogenic factors and inhibitors have been identified. However, the molecular mechanisms leading to this phenomenon are still incompletely understood. In this review, we focus on recent developments in the angiogenesis field. We will summarize our present knowledge about the molecular mechanisms involved in angiogenesis and about the factors that control this phenomenon. We will then shortly discuss the pharmacological modulation and the therapeutic and clinical implications for cancer biology.     

Autografting in chronic myeloid leukemia: an overview

Autografting could become a promising treatment for patients with chronic myeloid leukemia (CML) who cannot undergo allogeneic bone marrow transplantation or failed to respond to recombinant alpha-interferon (IFN). In this review, we analyze the results which have been published for patients transplanted in chronic phase and which suggest that autografting could prolong survival, at least in some patients. We also discuss the different methods of purging whose clinical efficacy remains to be assessed.     

Adoptive immunotherapy for Epstein-Barr virus-related lymphoma

Epstein-Barr virus (EBV) causes opportunistic B cell lymphomas in patients whose cellular immunity is compromised. We have been investigating whether infusions of donor-derived, EBV-specific cytotoxic T cells can prevent and/or treat EBV-related lymphoproliferative disease in children receiving T cell-depleted bone marrow from HLA-matched, unrelated or HLA-mismatched, related donors. In this review, we discuss the rationale for this therapeutic approach, describe our experiences with the regimen thus far, and consider some future directions in immunotherapy.     

Transporters Contributing to Iron Trafficking in Plants

T This review will discuss recent progress in understanding the many roles of transporters in the whole-plant physiological processes that maintain iron (Fe) homeostasis. These processes include uptake from the soil via roots, control of transport from roots to above-ground parts of the plant, unloading of Fe from the xylem in above-ground parts, loading of Fe into mitochondria and plastids, transport of Fe to reproductive parts of the plant, and Fe mobilization during seed germination. In addition, we will discuss the mechanisms that plants use to cope with an apparently unintended consequence of Fe acquisition: the uptake of toxic heavy metals via Fe transporters. Rapid progress has been made in understanding the transport processes involved in each of these areas in the last 5 years and this review will focus on this recent progress. We will also highlight the key questions regarding transport steps that remain to be elucidated.     

Social competence and head injury: a practical approach

Social competence assessment and training has long focused on specific skills within the clinical setting. In addition, emphasis has been placed on identifying deficits relative to an arbitrary, often idiosyncratic metric. In this article, we discuss the importance of the principles that underlie communication and which are reflected in the range of behaviours described as 'social competence'. We review methods we have found productive in the training of these principles with persons who have suffered traumatic brain injuries.     

Seven Things We Think We Know about Auxin Transport

T Polar transport of the phytohormone auxin and the establishment of localized auxin maxima regulate embryonic development, stem cell maintenance, root and shoot architecture, and tropic growth responses. The past decade has been marked by dramatic progress in efforts to elucidate the complex mechanisms by which auxin transport regulates plant growth. As the understanding of auxin transport regulation has been increasingly elaborated, it has become clear that this process is involved in almost all plant growth and environmental responses in some way. However, we still lack information about some basic aspects of this fundamental regulatory mechanism. In this review, we present what we know (or what we think we know) and what we do not know about seven auxin-regulated processes. We discuss the role of auxin transport in gravitropism in primary and lateral roots, phototropism, shoot branching, leaf expansion, and venation. We also discuss the auxin reflux/fountain model at the root tip, flavonoid modulation of auxin transport processes, and outstanding aspects of post-translational regulation of auxin transporters. This discussion is not meant to be exhaustive, but highlights areas in which generally held assumptions require more substantive validation.     

Mammalian iron transport: an unexpected link between metal homeostasis and host defense

Iron deficiency and iron overload disorders are common in clinical practice. Both can result from perturbations in the flux of iron across the absorptive intestinal enterocyte. Until recently iron transport has been poorly understood. In 1997 two independent cloning strategies identified Nramp2 (DCT1) as the first mammalian transmembrane iron transporter. In this review we discuss evidence that Nramp-related proteins play essential roles in metal homeostasis and host defense.     

Getting the glycosylation right: implications for the biotechnology industry

Glycosylation is the most extensive of all the posttranslational modifications, and has important functions in the secretion, antigenicity and clearance of glycoproteins. In recent years major advances have been made in the cloning of glycosyltransferase enzymes, in understanding the varied biological functions of carbohydrates, and in the accurate analysis of glycoprotein heterogeneity. In this review we discuss the impact of these advances on the choice of a recombinant host cell line, in optimizing cell culture processes, and in choosing the appropriate level of glycosylation analysis for each stage of product development.     

Etiology and treatment of the psychological side effects associated with cancer chemotherapy: A critical review and discussion.

Cancer patients receiving chemotherapeutic treatments routinely experience a wide range of distressing side effects, including nausea, vomiting, and dysphoria. Such symptoms often compromise patients' quality of life and may lead to the decision to postpone or even reject future, potentially life-saving, treatments. In this article, we discuss the hypotheses that have been offered to explain the development of such symptoms. We also review, in greater detail, the research evidence for the efficacy of five treatments for such symptoms: hypnosis, progressive muscle relaxation training with guided imagery, systematic desensitization, attentional diversion or redirection, and biofeedback. We discuss the implications of this treatment research, paying particular attention to factors associated with treatment outcome, mechanisms of treatment effectiveness, and issues associated with clinical application. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Immunoreactivation of Epstein-Barr virus due to cytomegalovirus primary infection

Interleukin (IL)-6 plays a major role in the control of the survival and proliferation of myeloma cell lines and primary myeloma cells. The genes of the receptors of IL-6 have been cloned, and the major signaling pathways involved in gp130 IL-6 transducer activation have been identified. In addition, another five cytokines that activate the gp130 IL-6 transducer have been identified. We review the recent data on gp130 cytokines and gp130-mediated signal transduction, their involvement in myeloma cell biology, and we discuss the possible therapeutic applications of this knowledge.