Short-course subcutaneous treatment with PQ Grass strongly improves symptom and medication scores in grass allergy.

BACKGROUND: A modified grass allergen subcutaneous immunotherapy (SCIT) product with MicroCrystalline Tyrosine and monophosphoryl lipid-A as an adjuvant system (Grass MATA MPL [PQ Grass]) is being developed as short-course treatment of grass-pollen allergic rhinitis (SAR) and/or rhinoconjunctivitis. We sought to evaluate the combined symptom and medication score (CSMS) of the optimized cumulative dose of 27,600 standardized units (SU) PQ Grass in a field setting prior to embarking on a pivotal Phase III trial. METHODS: In this exploratory, randomized, double-blind, placebo-controlled trial subjects were enrolled across 14 sites (Germany and the United States of America). Six pre-seasonal subcutaneous injections of PQ Grass (using conventional or extended regimens) or placebo were administered to 119 subjects (aged 18-65 years) with moderate-to-severe SAR with or without asthma that was well-controlled. The primary efficacy endpoint was CSMS during peak grass pollen season (GPS). Secondary endpoints included Rhinoconjunctivitis Quality of Life Questionnaire standardized (RQLQ-S) and allergen-specific IgG4 response. RESULTS: The mean CSMS compared to placebo was 33.1% (p = .0325) and 39.5% (p = .0112) for the conventional and extended regimens, respectively. An increase in IgG4 was shown for both regimens (p < .01) as well as an improvement in total RQLQ-S for the extended regimen (mean change -0.72, p = .02). Both regimens were well-tolerated. CONCLUSIONS: This trial demonstrated a clinically relevant and statistically significant efficacy response to PQ Grass. Unprecedented effect sizes were reached for grass allergy of up to ≈40% compared to placebo for CSMS after only six PQ Grass injections. Both PQ Grass regimens were considered equally safe and well-tolerated. Based on enhanced efficacy profile extended regime will be progressed to the pivotal Phase III trial.

Bronchodilator Reversibility in the GAN Severe Asthma Cohort.

BACKGROUND AND OBJECTIVE: Positive bronchodilator reversibility (BDR) is a diagnostic criterion for asthma. However, patients with asthma may exhibit a negative BDR response. Aim: To describe the frequency of positive and Negative BDR response in patients with severe asthma and study associations with phenotypic characteristics. METHODS: A positive BDR response was defined as an increase in FEV1 >200 mL and >12% upon testing with a short-acting ß-agonist. RESULTS: BDR data were available for 793 of the 2013 patients included in the German Asthma Net (GAN) severe asthma registry. Of these, 250 (31.5%) had a positive BDR response and 543 (68.5%) a egative BDR response. Comorbidities significantly associated with a negative response were gastroesophageal reflux disease (GERD) (28.0% vs 40.0%, P<.01) and eosinophilic granulomatosis with polyangiitis (0.4% vs 3.0%; P<.05), while smoking history (active: 2.8% vs 2.2%; ex: 40.0% vs 41.7%) and comorbid chronic obstructive pulmonary disease (COPD) (5.2% vs 7.2%) were similar in both groups. Patients with a positive BDR response had worse asthma control (median Asthma Control Questionnaire 5 score, 3.4 vs 3.0, P<.05), more frequently reported dyspnea at rest (26.8% vs 16.4%, P<.001) and chest tightness (36.4% vs 26.2%, P<.001), and had more severe airway obstruction at baseline (FEV1% predicted, 56 vs 64, P<.001) and higher fractional exhaled nitric oxide (FeNO) levels (41 vs 33 ppb, P<0.05). There were no differences in diffusion capacity of the lung for carbon monoxide, single breath (% pred, 70% vs 71%). Multivariate linear regression analysis identified an association between positive BDR response and lower baseline FEV1% (P<.001) and chest tightness (P<.05) and a negative association between BDR and GERD (P<.05). CONCLUSION: In this real-life setting, most patients with severe asthma had a negative BDR response. Interestingly, this was not associated with smoking history or COPD, but with lower FeNO and presence of GERD.

Bronchodilator Reversibility in the GAN Severe Asthma Cohort

Background: Positive bronchodilator reversibility (BDR) is a diagnostic criterion for asthma. However, patients with asthma may exhibit a negative BDR response. Aim: To describe the frequency of positive and negative BDR response in patients with severe asthma and study associations with phenotypic characteristics. Methods: A positive BDR response was defined as an increase in FEV1 >200 mL and >12% upon testing with a short-acting ß-agonist. Results: BDR data were available for 793 of the 2013 patients included in the German Asthma Net (GAN) severe asthma registry. Of these, 250 (31.5%) had a positive BDR response and 543 (68.5%) a negative BDR response. Comorbidities significantly associated with a negative response were gastroesophageal reflux disease (GERD) (28.0% vs 40.0%, P<.01) and eosinophilic granulomatosis with polyangiitis (0.4% vs 3.0%; P<.05), while smoking history (active: 2.8% vs 2.2%; ex: 40.0% vs 41.7%) and comorbid chronic obstructive pulmonary disease (COPD) (5.2% vs 7.2%) were similar in both groups. Patients with a positive BDR response had worse asthma control (median Asthma Control Questionnaire 5 score, 3.4 vs 3.0, P<.05), more frequently reported dyspnea at rest (26.8% vs 16.4%, P<.001) and chest tightness (36.4% vs 26.2%, P<.001), and had more severe airway obstruction at baseline (FEV1% predicted, 56 vs 64, P<.001) and higher fractional exhaled nitric oxide (FeNO) levels (41 vs 33 ppb, P<0.05). There were no differences in diffusion capacity of the lung for carbon monoxide, single breath (% pred, 70% vs 71%). Multivariate linear regression analysis identified an association between positive BDR response and lower baseline FEV1% (P<.001) and chest tightness (P<.05) and a negative association between BDR and GERD (P<.05). Conclusion: In this real-life setting, most patients with severe asthma had a negative BDR response. Interestingly, this was not associated with smoking history or COPD, but with lower FeNO and presence of GERD. (AU)

Antecedentes: La reversibilidad broncodilatadora (RB) positiva es un criterio diagnóstico para el asma. Sin embargo, los pacientes con asma pueden presentar una prueba RB negativa. Objetivos: Describir la frecuencia de RB positivas y negativas en pacientes con asma grave y sus asociaciones con características fenotípicas. Métodos: La RB positiva se definió como un aumento del FEV1 > 200 ml y > 12% tras la inhalación de un agonista beta de acción corta (SABA). Resultados: De 2013 pacientes incluidos en el registro de asma grave del German Asthma Net (GAN), 793 tenían datos sobre RB. De estos, 250 (31,5%) tuvieron una prueba RB positiva y 543 (68,5%) negativa. Las comorbilidades significativamente asociadas con RB negativa fueron el reflujo gastroesofágico (ERGE) (28,0% frente a 40,0%, p<0,01) y EGPA (0,4% frente a 3,0%; p<0,05), mientras que el antecedente de tabaquismo (activo: 2,8% frente a 2,2%; exfumador: 40,0% vs. 41,7%) y la comorbilidad de la EPOC (5,2% vs. 7,2%) fueron similares en ambos grupos. Los pacientes con RB positiva tenían peor control del asma (mediana ACQ-5 3,4 vs. 3,0, p<0,05), más disnea en reposo (26,8% vs. 16,4%, p<0,001) y mayor opresión torácica (36,4% vs. 26,2%, p<0,001), además presentaban una obstrucción de las vías respiratorias más grave al inicio del estudio (FEV1% pred: 56 frente a 64, p<0,001) y niveles más altos de FeNO (41 frente a 33 ppb, p<0,05), mientras que la capacidad de difusión fue similar (DLCO-SB% pred. 70% vs. 71%). El análisis de regresión lineal multivariable identificó una asociación de FEV1% basal inferior (p<0,001) y opresión torácica (p<0,05) con RB positiva y ERGE (p<0,05) con RB negativa. Conclusión: En este entorno en vida real, la mayoría de los pacientes con asma grave tuvieron una RB negativa. Curiosamente, esto no se asoció con antecedentes de tabaquismo o EPOC, sino con FeNO más bajo y presencia de ERGE. (AU)

Electrodermal hyporeactivity as a trait marker for suicidal propensity in uni- and bipolar depression.

BACKGROUND: A meta-analysis of studies investigating electrodermal activity in depressed patients, suggested that electrodermal hyporeactivity is sensitive and specific for suicide. AIMS: To confirm this finding and to study electrodermal hyporeactivity relative to type and severity of depression, trait anxiety, its stability and independence of depressive state. METHOD: Depressed inpatients (n = 783) were tested for habituation of electrodermal responses and clinically assessed using the Beck Depression Inventory (BDI) and the STAI-Trait scale for trait anxiety. RESULTS: The high sensitivity and raw specificity of electrodermal hyporeactivity for suicide were confirmed. Its prevalence was highest in bipolar disorders and was independent of severity of depression, trait anxiety, gender and age. Hyporeactivity was stable, while reactivity changed into hyporeactivity in a later depressive episode. CONCLUSIONS: The findings support the hypothesis that electrodermal hyporeactivity is a trait marker for suicidal propensity in depression.

Differential expression of ABC transporters (MDR1, MRP1, BCRP) in developing human embryos.

Three ABC transporters (MDR1, MRP1, BCRP), belonging to the family of multidrug resistance (MDR) proteins, play a crucial role in the protection mechanisms during embryogenesis and mediate drug resistance in cancer cells. The distribution of these transporters in the series of human embryonal/fetal intestine, liver and kidneys of various stages of intrauterine development (IUD) by indirect two-step immunohistochemical method was investigated. The organ- and age-specific expression patterns of these transporters were depicted and compared with the expression in adult organs. The evaluation of intestine and liver samples demonstrate differences in expression pattern of ABC transporters during IUD. On the contrary, in kidneys the age-specific localization was not observed. However, the increasing positivity from the kidney surface towards deeper, more differentiated parts was found. Hopefully, our study may contribute to elucidation of the role of multidrug resistance (MDR) pathways during IUD in man.

[Epileptic seizures during treatment with antidepressants and neuroleptics]. / Epileptische Anfälle unter der Behandlung mit Antidepressiva und Neuroleptika.

Epileptic seizures are observed during treatment with antidepressants and neuroleptics more frequently than is the case for other neuroactive substances. Evidence from experimental and observational studies is mixed, suggesting an increased incidence of seizures for certain drugs, whilst other drugs such as SSRIs appear to have a protective effect. There is robust evidence for an elevated seizure incidence (up to 4.5 % of treated patients) associated with clozapine treatment, but with other neuroleptics the effect is moderate (2-fold). The evaluation of data from FDA approval reports reveals lower standardised incidence rates associated with antidepressants vs. placebo except for clomipramine and bupropione. Psychiatric disorders such as schizophrenia, depression, and obsessive-compulsive disorder are associated with a considerably increased incidence of seizures. Therefore, in clinical practice, taking into account ictogenic properties of substances is required only in patients with a history of seizures.

[The use of repetitive transcranial magnetic stimulation (rTMS) in auditory verbal hallucinations (AVH)]. / Die Anwendung der repetitiven transkraniellen Magnetstimulation (rTMS) bei akustischen Halluzinationen.

Up to one-third of all schizophrenic patients suffer from auditory verbal hallucinations (AVH) that are resistant to antipsychotics. The use of repetitive transcranial magnetic stimulation (rTMS) is a therapeutic option that may disrupt or attenuate treatment resistant (TR) AVHs. This article reviews the available literature on the use of rTMS to treat AVHs, particularly focusing on randomised controlled trials, which have introduced new definitions ("refractory AVHs"), and techniques (active comparator strategies and imaging-guided rTMS). A number of meta-analyses are considered, which support a range of positive effect sizes for AVH attenuation in response to rTMS. Larger maintenance and follow-up studies with clearer clinical definitions of TR AVH are required. The underlying mechanism of action of rTMS on language networks needs further clarification and future trials should focus on methods for assessing AVH changes, time courses of response, and the development of response markers.

Changes in negative symptoms and EEG in schizophrenic patients after repetitive transcranial magnetic stimulation (rTMS): an open-label pilot study.

The effects of repetitive transcranial magnetic stimulation (rTMS) on schizophrenic negative symptoms (NS) and EEG topography were investigated in this pilot study. 10 patients with predominant NS were treated with 10 Hz rTMS over the left dorsolateral prefrontal cortex for 5 days. For NS ratings, the Scale for the Assessment of Negative Symptoms (SANS) was used. Both ratings and EEG recordings were obtained pre- and post-rTMS. Electrical activity changes were computed by Low Resolution Brain Electromagnetic Tomography. SANS showed an improvement after rTMS, from 49.0 (SD: 10.7) to 44.7 (SD: 11.8) (means). EEG frequency bands were changed fronto-temporally (right) and were mainly decreases in delta- and beta- and increases in alpha1-activity, as well as decreases in beta-activity in the temporal and parieto-occipital regions (left). Although we are aware of the limitations of this study, we assume a slight improvement in NS. The EEG findings refer to a possible neurophysiologic correlate of their improvement after rTMS.

The experimental combination of rTMS and fMRI reveals the functional relevance of parietal cortex for visuospatial functions.

We combined repetitive transcranial magnetic stimulation (rTMS) and functional magnetic resonance imaging (fMRI) to investigate the functional relevance of parietal cortex activation during the performance of visuospatial tasks. fMRI provides information about local transient changes in neuronal activation during behavioural or cognitive tasks. Information on the functional relevance of this activation was obtained by using rTMS to induce temporary regional deactivations. We thereby turned the physiological parameter of brain activity into an independent variable controlled and manipulated by the experimenter and investigated its effect on the performance of the cognitive tasks within a controlled experimental design. We investigated cognitive tasks that were performed on the same visual material but differed in the demand on visuospatial functions. For the visuospatial tasks we found a selective enhancement of fMRI signal in the superior parietal lobule (SPL) and a selective impairment of performance after rTMS to this region in comparison to a control group. We could thus show that the parietal cortex is functionally important for the execution of spatial judgements on visually presented material and that TMS as an experimental tool has the potential to interfere with higher cognitive functions such as visuospatial information processing.

Activation of Heschl's gyrus during auditory hallucinations.

Apart from being a common feature of mental illness, auditory hallucinations provide an intriguing model for the study of internally generated sensory perceptions that are attributed to external sources. Until now, the knowledge about the cortical network that supports such hallucinations has been restricted by methodological limitations. Here, we describe an experiment with paranoid schizophrenic patients whose on- and offset of auditory hallucinations could be monitored within one functional magnetic resonance imaging (fMRI) session. We demonstrate an increase of the blood oxygen level-dependent (BOLD) signal in Heschl's gyrus during the patients' hallucinations. Our results provide direct evidence of the involvement of primary auditory areas in auditory verbal hallucinations and establish novel constraints for psychopathological models.

Is migration supply--or demand--determined? Some remarks on the ideological use of economic language.

The author briefly discusses debate on the question of "whether international migration is essentially 'supply-determined' or 'demand-determined'.... In general, the supply school holds that there are any number of migrants willing to move (usually from poor to rich countries) irrespective of demand conditions in their destination countries, whereas the demand school claims that migration actually emerges out of specific demand conditions in prospective immigration countries.... By explicitly applying economic concepts of supply and demand to migration analysis--restricting attention to the situation in receiving countries--migration can rarely be called supply--or demand--determined alone, but will usually depend on the interaction of these forces." (SUMMARY IN FRE AND SPA)

Acute and chronic effects of nitrendipine in patients with precapillary pulmonary hypertension due to pulmonary fibrosis.

Eleven patients with histologically confirmed fibrosis of the lung were investigated for the effects of the dihydropyridine calcium antagonist nitrendipine on pulmonary hemodynamics. After 5 mg of acute sublingual nitrendipine, mean pulmonary artery pressure was significantly lowered (p less than or equal to 0.05) from 32 +/- 3 to 29 +/- 3 mmHg at rest, and significantly lowered (p less than or equal to 0.05) during exercise from 55 +/- 4 to 49 +/- 4 mmHg. Short-term oxygen application at rest significantly reduced this parameter to 28 +/- 3 mmHg (p less than or equal to 0.001). Nitrendipine lowered total pulmonary vascular resistance during both rest (from 412 +/- 50 to 351 +/- 49 dyn.s.cm-5; p less than or equal to 0.05), although it did not affect pulmonary arteriolar resistance. Also, oxygen treatment at rest influenced only total pulmonary vascular resistance (reduction from 412 +/- 50 to 373 +/- 48 dyn.s.cm-5; p less than or equal to 0.01), but not pulmonary arteriolar resistance. Pressure-flow curves, which were derived from cardiac output at rest and during exercise and from the corresponding gradient between mean pulmonary artery pressure and pulmonary capillary wedge pressure, remained unchanged by acute medication. Since a change in arterial oxygen partial pressure was not noticed after nitrendipine, arteriovenous shunting or a worsening of ventilation perfusion relationships can be excluded. Long-term (3 weeks) treatment (double-blind parallel design) with 10 mg of nitrendipine (4 patients) once daily showed no advantage in comparison to placebo (6 patients).(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of 5 mg sublingual nitrendipine in patients with precapillary pulmonary hypertension due to pulmonary fibrosis.

In 10 patients with precapillary pulmonary hypertension due to pulmonary fibrosis, the arterial blood pressure, right heart hemodynamics, cardiac output, and arterial oxygen partial pressure were measured to evaluate the benefits of acute sublingual (5 mg) nitrendipine. Additionally, the effect of oxygen enriched air was compared to control. At rest, nitrendipine significantly diminished arterial blood pressure [102 +/- 3 to 93 +/- 3 mm Hg (mean +/- SEM)], right atrial pressure (5.7 +/- 0.9 to 3.4 +/- 0.8 mm Hg), mean pulmonary artery pressure (33.4 +/- 3.5 to 29.8 +/- 3.3 mm Hg), and pulmonary artery wedge pressure (13.0 +/- 2.0 to 6.8 +/- 0.8 mm Hg). During exercise, nitrendipine reduced mean pulmonary artery pressure (54.5 +/- 4.8 to 49.3 +/- 4.7 mm Hg) and right atrial pressure (9.3 +/- 1.3 to 6.8 +/- 1.4 mm Hg). A diminuation of arterial partial oxygen pressure did not occur at rest (63.2 +/- 3.8 mm Hg) or during exercise (50.9 +/- 5.1 mm Hg). Thus, nitrendipine causes a slight but significant improvement of right heart hemodynamics. The occurrence of arteriovenous intrapulmonary shunting due to vasodilatating effects of nitrendipine can be excluded. Also, nitrendipine can safely be used in combined arterial hypertension and pulmonary fibrosis.