[Medical care data as the basis for evidence-based health care politics]. / Versorgungsdaten als Basis einer evidenzbasierten Berufspolitik.

The importance of data and statistics to support the political and tactical goals of the professional medical associations is constantly growing. Statements about the real medical care situation, including investments, operational expenses, use of labor and (medical) effectiveness, economic validity etc., should be reinforced by data and real-world evidence. More and more, in future arguments about the development of medical care, the party with the better data will prevail. That is why the umbrella organization of the medical specialists' professional associations SpiFa-Spitzenverband Fachärzte Deutschlands e. V.-has decided accept the challenge by founding DIFA-Deutsches Institut für Fachärztliche Versorgungsforschung (German institute for the pursuit of health economics and health care research). By collecting the regular data that the physicians generate in their daily medical practice and providing ways to analyze and evaluate these data statistically, DIFA is building an important foundation to strengthen the authority and power of the professional associations: pushing towards an evidence- (as opposed to 'eminence'-) based health care politics.

Oxidative stress-driven parvalbumin interneuron impairment as a common mechanism in models of schizophrenia.

Parvalbumin inhibitory interneurons (PVIs) are crucial for maintaining proper excitatory/inhibitory balance and high-frequency neuronal synchronization. Their activity supports critical developmental trajectories, sensory and cognitive processing, and social behavior. Despite heterogeneity in the etiology across schizophrenia and autism spectrum disorder, PVI circuits are altered in these psychiatric disorders. Identifying mechanism(s) underlying PVI deficits is essential to establish treatments targeting in particular cognition. On the basis of published and new data, we propose oxidative stress as a common pathological mechanism leading to PVI impairment in schizophrenia and some forms of autism. A series of animal models carrying genetic and/or environmental risks relevant to diverse etiological aspects of these disorders show PVI deficits to be all accompanied by oxidative stress in the anterior cingulate cortex. Specifically, oxidative stress is negatively correlated with the integrity of PVIs and the extracellular perineuronal net enwrapping these interneurons. Oxidative stress may result from dysregulation of systems typically affected in schizophrenia, including glutamatergic, dopaminergic, immune and antioxidant signaling. As convergent end point, redox dysregulation has successfully been targeted to protect PVIs with antioxidants/redox regulators across several animal models. This opens up new perspectives for the use of antioxidant treatments to be applied to at-risk individuals, in close temporal proximity to environmental impacts known to induce oxidative stress.

Functional monoclonal antibody acts as a biased agonist by inducing internalization of metabotropic glutamate receptor 7.

BACKGROUND AND PURPOSE: The mGlu(7) receptors are strategically located at the site of vesicle fusion where they modulate the release of the main excitatory and inhibitory neurotransmitters. Consequently, they are implicated in the underlying pathophysiology of CNS diseases such as epilepsy and stress-related psychiatric disorders. Here, we characterized a selective, potent and functional anti-mGlu(7) monoclonal antibody, MAB1/28, that triggers receptor internalization. EXPERIMENTAL APPROACH: MAB1/28's activity was investigated using Western blot and direct immunofluorescence on live cells, in vitro pharmacology by functional cAMP and [(35) S]-GTPγ binding assays, the kinetics of IgG-induced internalization by image analysis, and the activation of the ERK1/2 by elisa. KEY RESULTS: mGlu(7) /mGlu(6) chimeric studies located the MAB1/28 binding site at the extracellular amino-terminus of mGlu(7) . MAB1/28 potently antagonized both orthosteric and allosteric agonist-induced inhibition of cAMP accumulation. The potency of the antagonistic actions was similar to the potency in triggering receptor internalization. The internalization mechanism occurred via a pertussis toxin-insensitive pathway and did not require Gα(i) protein activation. MAB1/28 activated ERK1/2 with potency similar to that for receptor internalization. The requirement of a bivalent receptor binding mode for receptor internalizations suggests that MAB1/28 modulates mGlu(7) dimers. CONCLUSIONS AND IMPLICATIONS: We obtained evidence for an allosteric-biased agonist activity triggered by MAB1/28, which activates a novel IgG-mediated GPCR internalization pathway that is not utilized by small molecule, orthosteric or allosteric agonists. Thus, MAB1/28 provides an invaluable biological tool for probing mGlu(7) function and selective activation of its intracellular trafficking.

Salmeterol/fluticasone propionate (50/250 microg) combination is superior to double dose fluticasone (500 microg) for the treatment of symptomatic moderate asthma.

QUESTIONS UNDER STUDY: if patients with asthma remain symptomatic in spite of chronic treatment with inhaled corticosteroids (ICS), increasing the ICS dosage or adding another drug to the treatment regimen are possible therapeutic alternatives. We compared the efficacy and safety of combined salmeterol fluticasone therapy (SFC, 50/250 microg twice daily) with twice the dose of fluticasone propionate (FP, 500 microg b.i.d.) in symptomatic asthmatics. METHODS: this prospective, double-blind study was conducted in 76 study centres. 365 symptomatic patients with moderate asthma aged >18 years and receiving ICS in a dose equivalent to 1000 microg beclomethasone propionate per day were randomly assigned to receive either salmeterol xinafoate (50 microg) and fluticasone propionate (250 microg) in a single dry powder inhaler (Diskus) or 500 microg FP twice daily. The primary efficacy endpoint was morning peak expiratory flow rate (PEFR). Secondary measurements included forced expiratory volume in 1 second (FEV1), asthma symptom scores, and use of rescue medication. RESULTS: combined salmeterol fluticasone therapy resulted in significantly greater improvements in PEFR and symptom control than doubling the dose of FP. At week 12, morning PEFR had increased by 52 L/min from baseline in patients on SFC and by 36 L/min in subjects receiving FP. The adjusted difference between groups was 16.6 L/min (95% confidence interval, 1.1 to 32.0 L/min). In the SFC group, the percentage of symptom-free days increased from baseline by 49% of days as compared with 38% of days after FP (adjusted difference: 12.6% of days, 95% CI 4.0 to 20.7). Quality of life improved to a greater degree after SFC therapy, and patients regarded study drugs as superior to their previous asthma medication. Adverse event profiles were similar between groups. CONCLUSIONS: the combination of salmeterol 50 microg and fluticasone 250 microg in a single dry powder inhaler was superior to twice the dose of FP (500 microg). It seems justified to add salmeterol rather than increasing the ICS dose if symptomatic asthmatics require supplementary therapy.

Prenatal diagnosis of congenital cytomegalovirus infection in 189 pregnancies with known outcome.

Prenatal diagnosis (PD) of fetal cytomegalovirus (CMV) infection was performed in 242 pregnancies, with known outcome in 189 cases. In 141/189 pregnancies, PD was carried out on account of suspicious maternal CMV serology up to gestational week (WG) 23, and in 48 cases on account of abnormal ultrasonic findings detected between WG 18 and 39. Chorionic villus samples (n = 6), amniotic fluid (AF, n = 176) and/or fetal blood specimens (n = 80) were investigated for detection of virus by cell culture, shell vial assay, PCR and/or CMV-specific IgM antibodies. Of 189 fetuses correctly evaluated by CMV detection either in fetal tissue following therapeutic abortion/stillbirth (n = 24) or in urine of neonates within the first 2 weeks of life (n = 33), 57 were congenitally infected. In women with proven or suspected primary infection, the intrauterine transmission rates were 20.6% (7/34) and 24.4% (10/41), respectively. Of the congenitally infected live-born infants, 57.6% (19/33) had symptoms of varying degree. The overall sensitivity of PD in the serologic and ultrasound risk groups was 89.5% (51/57). A sensitivity of 100% was achieved by combining detection of CMV-DNA and CMV-specific IgM in fetal blood or by combined testing of AF and fetal blood for CMV-DNA or IgM antibodies. There was no instance of intrauterine death following the invasive procedure. The predictive value of PD for fetal infection was 95.7% (132/138) for negative results and 100% (51/51) for positive results. Correct results for congenital CMV infection by testing AF samples can be expected with samples obtained after WG 21 and after a time interval of at least 6 weeks between first diagnosis of maternal infection and PD. In case of negative findings in AF or fetal blood and the absence of ultrasound abnormalities at WG 22-23, fetal infection and neonatal disease could be excluded with high confidence. Positive findings for CMV infection in AF and/or fetal blood in combination with CMV suspicious ultrasound abnormalities predicted a high risk of cytomegalic inclusion disease (CID). Furthermore, detection of specific IgM antibodies in fetal blood was significantly correlated with severe outcome for the fetus or the newborn (p = 0.0224). However, normal ultrasound of infected fetuses at WG 22-23 can neither completely exclude an abnormal ultrasound at a later WG and the birth of a severely damaged child nor the birth of neonates which are afflicted by single manifestations at birth or later and of the kind which are not detectable by currently available ultrasonographic techniques.

SAF-B protein couples transcription and pre-mRNA splicing to SAR/MAR elements.

Interphase chromatin is arranged into topologically separated domains comprising gene expression and replication units through genomic sequence elements, so-called MAR or SAR regions (for matrix- or scaffold-associating regions). S/MAR regions are located near the boundaries of actively transcribed genes and were shown to influence their activity. We show that scaffold attachment factor B (SAF-B), which specifically binds to S/MAR regions, interacts with RNA polymerase II (RNA pol II) and a subset of serine-/arginine-rich RNA processing factors (SR proteins). SAF-B localized to the nucleus in a speckled pattern that coincided with the distribution of the SR protein SC35. Furthermore, we show that overexpressed SAF-B induced an increase of the 10S splice product using an E1A reporter gene and repressed the activity of an S/MAR flanked CAT reporter gene construct in vivo . This indicates an association of SAF-B with SR proteins and components of the transcription machinery. Our results describe the coupling of a chromatin organizing S/MAR element with transcription and pre-mRNA processing components and we propose that SAF-B serves as a molecular base to assemble a 'transcriptosome complex' in the vicinity of actively transcribed genes.

[Hearing in a geriatric perspective]. / Hørelse i geriatrisk perspektiv.

To assess whether hearing rehabilitation of older people can be improved by co-operation between the audiology and geriatric departments and the home service, 139 old and frail audiological patients were allocated to three groups with three different fitting procedures: 1) conventional fitting including verification of acoustical gain in the patient's ear; 2) home-fitting by hearing therapists, and 3) home-fitting by a specially trained geriatric nursing assistant, the home help also being present. Outcome was assessed by the ordinary questionnaire mailed to hearing aids users three to four months after fitting and by a geriatric evaluation procedure. The response rate in the conventionally fitted group was highly unsatisfactory (36%) and too small for further data-analysis. In the educational group a tendency was found towards better manipulation skills and significantly higher hearing aid use. However, the response rate was lower than in the geriatric group (71% compared to 81%), and no knowledge of hearing aid use was registered in the home service by this procedure. In the geriatric group a correlation was found between practical ability and use and satisfaction with the hearing aid. However, two thirds of the group were dependent on lasting help for the handling of the aid. Most patients in this group were already known by the hospital and home service, and the individual home help showed an interest in learning about hearing aid use. Home fitting by a joint audiological and geriatric effort in collaboration with the home help has proven feasible and valuable to both patient and home help. Extended co-operation is recommended between the health care and the social sector concerning hearing aid use.

The use and benefit of in-the-ear hearing aids. A four-year follow-up examination.

The present investigation was performed in order to evaluate the use and benefit of in-the-ear hearing aids (ITE-HAs) after a 4-year observation period, and to examine the validity of this type of hearing aid. A sample of 537 subjects still in possession of ITE-HAs, fitted in 1985, responded to a postal questionnaire in 1989, including questions identical to the first follow-up in 1985. The 537 persons correspond to 60% of the originally fitted sample of 894 subjects. The investigation indicated that no change in the use of or benefit from ITE-HAs has taken place during a 4-year period, and in addition the manipulative skills of the hearing aid users did not improve. However, the overall frequency of handling problems is low, though with a tendency to increase in the age group above 75 years. It is concluded that the use of and benefit obtained with ITE-HAs remains unchanged over a 4-year period; that the use and benefit is similar in the age groups below and above 75 years of age; that the ITE-HAs seem to be fairly stable during a 4-year period.

[Rubella immunization with HPV77DE5 and RA 27/3 vaccines of 11 to 16-year-old girls: studies of antibody formation and antibody resistance after 4 and 8 years]. / Die Rötelnschutzimpfung mit HPV77DE5- und RA 27/3-Impfstoffen von 11-16 Jahre alten Mädchen: Untersuchungen zur Antikörperentwicklung und Antikörperpersistenz nach 4 und 8 Jahren.

In the first prepubertal study 292 girls aged 11-15 years from 5 secondary schools were immunized with HPV77DE5 with the normal dose and 1/10 of it. The seronegative rate was 30.4%. HAI-antibody conversion occurred in 98.2 to 100%. The mean antibody titer in the two groups with 1:80 and 1:84 were 2 titer steps below the mean HAI-titer of the prevaccinal seropositive girls. The booster effect on the pre-existing titers was minimal. In the second prepubertal study with 625 girls aged 11-16 years from 3 gymnasiums 50.4% were seronegative. Of 312 seronegative girls, 56 had been immunized with HPV77DE5 s.c., 151 with RA 27/3 s.c. and 105 with RA 27/3 i.n. HAI-antibody conversion was observed in 98.2%, 100% and 100% respectively. The mean HAI-antibody titer following HPV77DE5 was +/- 2 titer steps, following RA 27/3 s.c. and RA 27/3 i.n. only 0.6 titer steps lower than the mean titer of the prevaccinal seropositive group. The individuals with a low prevaccinal antibody titer showed a significant but transient antibody booster response. Antibody titer controls 4 years post vaccination in 213 of the girls (160 prevaccinal seronegative, 53 prevaccinal seropositive) showed that all prevaccinal seronegatives had remained antibody-positive. The mean HAI-titer following HPV77DE5 was only slightly lower (1: 97) than 8-12 weeks post vaccination (1: 104) wereas the mean titers following RA 27/3 s.c. and i.n. showed a decline from 1: 158 to 1: 119 and from 1: 181 to 1: 111. The comparison of negative, low and higher HAI-antibody titers with neutralisation antibody titers in sera taken before, 8-12 weeks and 4 years after vaccination gave a perfect correlation between negative and positive results in both tests. Also 8 years post vaccination all vaccinees had remained seropositive. In comparison to the 4-year value, the geometric mean HAI antibody titer had dropped to somewhat lower levels of 1: 64, 1: 74 and 1: 64 respectively in the prevaccinal seronegative vaccinees so that no titer differences existed 8 years following vaccination in the different vaccine groups. Low positive HAI titers of 1: 16 were found in 3 of 23 (13%) in the HPV77DE5 group and in 2 of 76 (2.6%) in the RA 27/3 s.c. group but in none of 54 in the RA 27/3 i.n. group. The low positive HAI titer of 1: 16 could be confirmed in the HiG and ELISA IgG tests.(ABSTRACT TRUNCATED AT 400 WORDS)

[Mucociliary clearance. Results in smokers, nonsmokers and patients with with respiratory tract diseases]. / Mukoziliäre Klärfunktion. Ergebnisse bei Rauchern, Nichtrauchern und Patienten mit Atemwegskrankheiten.

Using the modified radiographic teflon particle method the tracheal mucociliary clearance velocity (TCV) was found to be 13.5 +/- 4.5 mm/min in 36 normal probands. In 18 "normal" smokers there was a statistically slightly significant diminution when compared with 18 age-matched non-smokers (12.1 +/- 5.7 vs 15.0 +/- 4.2 mm/min; P less than 0.1). Some smokers with values below 7 mm/min could be "potential chronic bronchitis". Acute exposure to cigarette smoke led to a decrease of TCV from 19 to 8 in healthy smokers, and from 20 to 5 mm/min in nonsmokers. Whereas TCV was equally diminished to values between 0 and 5 mm/min in chronic bronchitis (n = 42), bronchial carcinoma (n = 8) and advanced bronchial asthma (n = 8), patients with bronchiectasis (n = 8) showed marked negative tracheal clearance of up to -25 mm/min.

[Effect of salicylic acid and finely divided sulfur on the bioavailability of corticosteroids in the skin in external therapy]. / Uber den Einfluss von Salicylsäure und feinverteiltem Schwefel auf die Bioverfügbarkeit von Corticosteroiden in der Haut bei externer Therapie.

Investigation on 60 volunteers are reported in whom the influence of salicylic acid and finely divided sulfur on the blanching effect of ointments with and without steroid was analysed. The higher the concentration of salicylic acid the greater is the decrease in the blanching effect of the steroid free ointment. At low concentrations finely divided sulfur also reduces the blanching effect of the steroid is reduced by salicylic acid as well as by sulfur. This effect is at least partly produced by the decrease of the blanching effect due to the base. An increase in the bioavailability of corticosteroids in the skin after local application cannot be achieved by addition of salicylic acid or sulfur under the conditions chosen.

[Age-dependent changes of stress-related immunosuppression]. / Altersabhängige Veränderungen stressbedingter Immunsuppression.

The present investigations on the influence of physical stress and physical training and on the influence of aging on 19-S-antibody producing spleen cells showed: 1. Physical stress causes a failing of immunity in mice, which had no training. The immune response can be diminished by physical stress before and after sensitization. The immunosuppressive effect of stress is greater, if it was placed after sensitization. There is a strict correlation between the immunosuppressive effect of physical stress and the time of maximum production of 19-S-antibodies. 2. The immunosuppressive effect of physical stress increases with increasing age. The protecting effect of physical training is lower in adult and old animals than in young mice. 3. There is an increase of antibody loaded spleen cells until an age of eight months. In elder mice the number of immunocytes decreases significantly. 4. The mortality rate is greater in stressed and trained young mice than in the adult and old animals. Supposing a better adaptation in young mice it is to be considered that the biologically better developed animals survived by selections.