Global transcriptional profiling demonstrates the combination of type I and type II interferon enhances antiviral and immune responses at clinically relevant doses.

A role for type II interferon (IFN-gamma) in resolving viral infection is suggested by the correlation of hepatitis C virus (HCV) clearance with enhancement of IFN-gamma-producing activated T cells in the resolution of acute HCV infection. Using vesicular stomatitis virus (VSV), a synergistic direct antiviral effect was documented using IFN-gamma1b and a potent, consensus type I IFN (IFN alfacon-1). Global expression profiling following EC50 exposure to IFN alfacon-1, IFN-gamma1b, or a cocktail of the two allowed the antiviral state to be correlated with induction of a subset of IFN-stimulated genes (ISGs). Genes identified through this analysis corresponded to classic antiviral components, ISGs more recently associated with direct antiviral functions, as well as expressed sequence tags (ESTs) and hypothetical proteins. The magnitude of these antiviral EC50-correlated expression events in human hepatoma (Huh7) cells exposed to clinically relevant doses of IFN alfacon-1, IFN-gamma1b, or a cocktail of the two was also probed because the standard of care for patients with chronic hepatitis C is type I IFN-containing regimens. Relative to type I IFNs used alone, the addition of type II IFN caused enhanced expression not only of many of the genes correlated with the direct antiviral state but also of genes involved in (1) antigen presentation to cytotoxic T lymphocytes (CTLs), (2) macrophage, natural killer (NK), and T helper 1 (Th1) cell recruitment and activation, (3) complement system function, (4) apoptosis, and (5) ISGs with unknown functions. As many of these processes are correlated clinically with resolution of chronic HCV infection, the combined use of these IFNs could display a beneficial effect on viral clearance in patients infected with HCV and other viruses through enhancement of one of these processes or of the direct antiviral state.     

Expanding Our Strategies to Study the Process of Change

The conceptual and methodological framework proposed by Doss (this issue) makes valuable suggestions for strategic choices in future research. This commentary addresses conceptual and terminological distinctions adopted by Doss, as well as his criticism of add-on/ dismantling studies. We also suggest research topics and methodological developments that could be integrated in Doss's framework to further expand understanding of therapeutic change.     

Patterns of abnormal motor cortex excitability in atypical parkinsonian syndromes.

OBJECTIVE: Multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and corticobasal-ganglionic degeneration (CBGD) are all clinically characterized by an akinetic-rigid syndrome together with a variety of additional signs. We hypothesised that these atypical parkinsonian syndromes (APS) will show distinctive patterns in their motor output upon transcranial magnetic stimulation (TMS) due to their different underlying anatomico-functional deficits. METHODS: We performed single and paired-pulse TMS and assessed inhibitory and excitatory response parameters from the first dorsal interosseus muscles in 13 patients with MSA, 18 with PSP, 13 with CBGD, 15 patients with Parkinson's disease and 17 healthy subjects. RESULTS: PSP and MSA patients had significantly enlarged response amplitudes at rest, reduced intracortical inhibition (ICI) and prolonged ipsi- and contralateral silent periods, whereas CBGD patients showed significantly increased motor thresholds, smaller response amplitudes at rest, shortened contralateral silent period, reduced transcallosal inhibition and a reduced ICI. In 22% of APS patients ipsilateral motor responses occurred in upper limb muscles irrespective of the underlying disease. CONCLUSIONS: Our results indicate that motor cortex disinhibition is predominant in patients with PSP and MSA. In CBGD more severe neuronal cell loss in the motor cortex itself may lead to hypoexcitability of corticospinal and transcallosal pathways.     

Vitamin a cost-effectiveness model

To assist in the selection of a preferable vitamin A deficiency control policy, a model has been developed to organize information on program costs and program-related effects. The model was designed to compare three approaches: (1) diet modification; (2) fortification of processed foods; and (3) periodic large doses. Health effects projected are rates of specific eye pathologies associated with vitamin A deficiency (xerophthalmia), and mortalities within age cohorts. Effectiveness is calculated as a function of coverage, biological efficacy, and incidence of vitamin A deficiency. The model was applied to data from the Province of West Java in Indonesia. The results of this application suggest that funding level considerations are an important factor in selecting a preferred control strategy. In addition to determining the relative resource requirements of alternative interventions aimed at reducing the morbidity and mortality effects of vitamin A deficiencies, the model, using marginal cost and marginal effectiveness information, can serve as a guide to the most efficient allocation of resources for each type of intervention.     

Interpersonal distress as a mediator between avoidance goals and goal satisfaction in psychotherapy inpatients

Interpersonal behavior is assumed to be motivated by personal goals that an individual develops ontogenetically to satisfy and protect psychological needs. Interpersonal problems are hypothesized to (1) occur as a consequence of strong avoidance goals and (2) lead to decreased satisfaction of the person's approach goals. The hypotheses are tested using the self‐report data of 284 subjects with predominantly anxiety, affective and eating disorders who applied for treatment in a clinic offering inpatient cognitive–behavioral psychotherapy. Results indicate that interpersonal problems mediate the relationship between avoidance goals and the satisfaction of approach goals. Additional analyses explore specific associations between avoidance goals and certain kinds of interpersonal problem. Avoidance goals are then located within the interpersonal circle structure. Copyright © 2006 John Wiley & Sons, Ltd.     

Endokrine Therapie solider Tumoren

Zum Thema Medikamente, die in hormonelle Regelkreise eingreifen, werden wegen ihrer hohen Wirksamkeit und guten Vertr?glichkeit bei hormonsensitiven Tumoren wie Mamma-, Prostata- und dem Endometriumkarzinom eingesetzt. Ziel aller hormonellen Behandlungsma?nahmen ist die Ausschaltung der hormonbedingten Wachstumsstimulation durch Blockade der Hormonproduktion oder Hemmung der Hormonwirkung auf zellul?rer Ebene. Dies erfolgt bei postmenopausalen Frauen mit Brustkrebs durch Aromatasehemmstoffe, bei pr?menopausalen, ebenso wie bei Patienten mit Prostatakarzinom durch GnRH-Analoga. Eine neue Generation von Aromatasehemmstoffen zur Behandlung des Brustkrebses weist nicht nur bessere Vertr?glichkeit und Wirksamkeit auf, sondern bedeutet auch einen überlebensvorteil für die Patientinnen. Anti?strogene sind bei pr?- und insbesondere bei postmenopausalen Patientinnen sowohl in der adjuvanten, als auch in der palliativen Behandlungssituation wirksam. Aufgrund ihrer guten Vertr?glichkeit wurden sie bei Frauen mit erh?htem Brustkrebsrisiko mit Erfolg zur Pr?vention eingesetzt. Bei Patienten mit Prostatakarzinom hat die sog. komplette Androgenblockade (chirurgische oder medikament?se Ausschaltung der Testesfunktion und gleichzeitige Antiandrogengabe) die Hoffnung auf bessere Krankheitskontrolle nicht erfüllen k?nnen.     

THz radiation from free electron lasers and its potential for cell and tissue studies

Free electron lasers (FELs) allow the generation of electromagnetic radiation (EM) in a wide field of frequencies (respectively wavelengths) through the proper adjustment of the energy of an electron beam and the field configuration of a magnetic undulator passed by this beam. Terahertz (THz) radiation covers the region of the electromagnetic spectrum between approximately 0.3 and 30 THz and thus can be considered a continuation of the optical spectrum beyond the far infrared (IR). The very interesting results obtained from various studies of the interaction between IR radiation and biomolecules or tissue have stimulated increasing interest in the study of biological systems using THz radiation. This paper points out what role modern FELs can play in this research.     

Autoimmunity and inflammation due to a gain-of-function mutation in phospholipase C gamma 2 that specifically increases external Ca2+ entry

The identification of specific genetic loci that contribute to inflammatory and autoimmune diseases has proved difficult due to the contribution of multiple interacting genes, the inherent genetic heterogeneity present in human populations, and a lack of new mouse mutants. By using N-ethyl-N-nitrosourea (ENU) mutagenesis to discover new immune regulators, we identified a point mutation in the murine phospholipase Cg2 (Plcg2) gene that leads to severe spontaneous inflammation and autoimmunity. The disease is composed of an autoimmune component mediated by autoantibody immune complexes and B and T cell independent inflammation. The underlying mechanism is a gain-of-function mutation in Plcg2, which leads to hyperreactive external calcium entry in B cells and expansion of innate inflammatory cells. This mutant identifies Plcg2 as a key regulator in an autoimmune and inflammatory disease mediated by B cells and non-B, non-T haematopoietic cells and emphasizes that by distinct genetic modulation, a single point mutation can lead to a complex immunological phenotype.     

Myosin VIIA gene: heterogeneity of the mutations responsible for Usher syndrome type IB

Usher syndrome is recognized as the most frequent cause of hereditary deaf-blindness. Usher syndrome type I (USH1), the most severe form of the disease, is characterized by profound congenital sensorineural deafness, constant vestibular dysfunction, and retinitis pigmentosa of prepubertal onset. This form is genetically heterogeneous and five loci (USH1A-E) have been mapped thusfar. However, only the gene responsible for USH1 B (which accounts for approximately 75% of USH1 cases) has been characterized. It encodes a long-tailed unconventional myosin, myosin VIIA, with a predicted 2215 amino acid sequence. Primers covering the complete myosin VIIA coding sequence as well as the 3' non coding sequence were designed, allowing direct sequence analysis of each of the 48 coding exons and flanking splice sites in seven patients affected by USH1. Four novel mutations were thereby identified. The possibility should now be considered of a sequence-based prenatal diagnosis in some of the families affected by this very severe form of Usher syndrome.