Motor-cortex excitability and response variability following paired-associative stimulation: a proof-of-concept study comparing individualized and fixed inter-stimulus intervals.

While diverging efficacy and inter-individual response variability have repeatedly been reported for paired-associative stimulation (PAS), approaches to overcome these issues are yet lacking. Hence, the aim of the present study was to determine whether response variability could be reduced through the application of an individualized PAS paradigm. Changes of transcranial magnetic stimulation (TMS) elicited motor-evoked potentials (MEP) following different PAS paradigms were assessed in three experimental conditions. According to a within-subjects design, 21 participants received three consecutive PAS paradigms differing with respect to the applied inter-stimulus intervals (ISI) between peripheral nerve stimulation (PNS) and TMS. Based on foregoing considerations, we compared fixed ISI of 25 ms (PAS 25) and 22 ms (PAS 22) to an individualized PAS paradigm accounting for conduction time differences on the single subject level (iPAS). Overall, we did not observe significantly increased post-stimulation MEP magnitudes in any of the three experimental paradigms. Explorative analyses revealed increased inter-individual response variability in case of PAS 25 and PAS 22 compared to higher rates of expected MEP magnitude increases in case of our iPAS paradigm. The findings of our proof-of-concept study points towards a potential association of decreased inter-individual variability with individually selected ISI that account for differences in conduction time. However, as our findings did not reach the significance threshold, our study highlights the issue of intra-individual variability in PAS paradigms. Further replication studies with larger sample sizes and repetitive designs are needed to confirm our findings.

Beneficial effects of anodal transcranial direct current stimulation (tDCS) on spatial working memory in patients with schizophrenia.

Schizophrenia is a severe and often detrimental psychiatric disorder. The individual patients' level of functioning is essentially determined by cognitive, particularly working memory (WM), deficits that are critically linked to dysfunctional activity of the dorsolateral prefrontal cortex (dlPFC). Transcranial direct current stimulation (tDCS) can transiently modulate activity of the dlPFC and remote areas and has been shown to improve WM functions. It may therefore provide a new, targeted treatment option. For this aim, the present study investigated the effect of anodal tDCS of different intensities on spatial WM in patients with schizophrenia. In two experiments, 32 patients performed a spatial n-back task with increasing WM load (1-, 2-, and 3-back) at baseline and in two sessions with anodal or sham tDCS (EXP I [n = 16]: 1 mA; EXP II [n = 16]: 2 mA) to the right dlPFC (cathode: left m. deltoideus). With 1 mA anodal tDCS, no effect on WM performance could be detected. However, 2 mA anodal tDCS increased accuracy (measured by d') of the task with the highest WM load (3-back). This effect was larger in patients with a lower level of general neurocognitive functioning. These results demonstrate a beneficial effect of 2 mA anodal tDCS on deficient WM accuracy in patients with schizophrenia particularly under challenging conditions and in subjects with higher cognitive impairments. This data will inform future clinical trials on tDCS-enhanced cognitive training to improve treatment of schizophrenia.

[Non-invasive brain stimulation for treatment of schizophrenic psychoses]. / Hirnstimulationsverfahren zur Behandlung schizophrener Psychosen.

Despite many different available pharmacological and psychosocial treatment options, an optimal control of symptoms is only partly possible for most schizophrenia patients. Especially, persistent auditory hallucinations, negative symptoms and cognitive impairment are difficult to treat symptoms. Several non-invasive brain stimulation techniques are increasingly being considered as new therapeutic add on options for the management of schizophrenia, targeting these symptom domains. The technique which has been available for the longest time and that is best established in clinical care is electroconvulsive therapy (ECT). New stimulation techniques, such as repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) allow a more pathophysiological-based approach. This review article introduces various non-invasive brain stimulation techniques and discusses recent treatment studies on schizophrenia. In total, the novel brain stimulation techniques discussed here can be considered relevant add on therapeutic approaches for schizophrenia. In this context, the best evidence is available for the application of rTMS for the treatment of negative symptoms and persistent auditory hallucinations; however, negative studies have also been published for both indications. Studies using other non-invasive brain stimulation techniques showed promising results but further research is needed to establish the clinical efficacy. Based on a growing pathophysiological knowledge, non-invasive brain stimulation techniques provide new treatment perspectives for patients with schizophrenia.

[Forced sterilisation based on the Law for the Prevention of Hereditarily Diseased Offspring. The role of the Heil- und Pflegeanstalt (State Hospital) Günzburg]. / Zwangssterilisationen nach dem Gesetz zur Verhütung erbkranken Nachwuchses. Die Rolle der Heil- und Pflegeanstalt Günzburg.

OBJECTIVE: From 1934 to 1945, 350,000-400,000 human beings were sterilised by force in the German Reich. Forced sterilisation was based on the Gesetz zur Verhütung erbkranken Nachwuchses (Law for the Prevention of Hereditarily Diseased Offspring). The Heil- und Pflegeanstalt (State Hospital) Günzburg was one of the institutions where compulsory sterilisation was practised. METHODS: Data evaluation was based on patient documents and annual reports of the archives of today's district hospital at Günzburg. Patient records were analysed with respect to predefined criteria. The municipal archives of Günzburg provided further historical sources and data. RESULTS: Between 1934 and 1943, 366 patients were sterilised in the Heil- und Pflegeanstalt (State Hospital) Günzburg. Age, sex and diagnosis were found to be criteria relevant for selection of patients for sterilisation. CONCLUSIONS: The study was able to show the active involvement of the Heil- und Pflegeanstalt (State Hospital) Günzburg in the compulsory sterilisation programme.

[Neuropathological research on organs of patients of the "Heil- und pflegeanstalt" (state hospital) Günzburg]. / Neuropathologische Forschung an Organen von Patienten der Heil- und Pflegeanstalt Günzburg.

BACKGROUND: The two Kaiser Wilhelm-Institutes (KWI) in Berlin (1914, new building 1931) and in Munich (1917, new building 1926-28), specialized on pathologic anatomical as well as psychiatric genetic research, were set up before times of National Socialism. METHODS: Data evaluation is based on patient documents and annual reports of the archive of today's district hospital Günzburg and on patient documents (copies) of the historical archive of today's Max-Planck Institute of Psychiatry. RESULTS: The KWI in Munich was indirectly provided with brain material by Bavarian "Heil- und Pflegeanstalten" (state hospitals) including the state hospital Günzburg. CONCLUSIONS: During National Socialism patients' organs were sent from the "Heil- und Pflegeanstalt" (state hospital) Günzburg to the KWI in Munich for the purpose of conducting research. Commemorating patients' fates and clarifying what happened defines a place of remembrance.

[The "Aktion T4". In remembrance of victims of the healing and nursing institution in Günzburg]. / Die "Aktion-T4". Erinnerung an Patientenopfer aus der Heil- und Pflegeanstalt Günzburg.

OBJECTIVE: The aim of this article was to achieve a commemoration of patients of the Healing and Nursing Institute in Günzburg who were victims of "Aktion T4". METHODS: On the basis of pre-defined criteria several individual patient documents were selected for this study and analyzed historically. Most items of information concerning patient histories and diagnoses were obtained from the stock R 179 of the branch office of the federal archives in Berlin Lichterfelde. Further supplementary information was extracted from administrative documents and patient charts of the archives of the psychiatric department at the regional hospital Günzburg. RESULTS: The historical reconstruction of three individual life histories contributes to a literary memorial for the victims. CONCLUSIONS: It is a historical responsibility to remember the victims of the "Aktion T4" by contributing to a reconstruction of their life histories.

Poxvirus-induced immunostimulating effects on porcine leukocytes.

The prophylactic application of inactivated parapox ovis viruses (Baypamun; Bayer AG, Leverkusen, Germany) has been shown to reduce efficiently the outbreak of stress-mediated diseases in different species. However, little is known about the basic mechanism behind this observed stimulatory property. We therefore tested eight inactivated poxvirus strains belonging to three different genera (Orthopoxvirus, Avipoxvirus, and Parapoxvirus) for their capacity to activate cells of the porcine innate and specific immune systems in vitro. The results indicated that poxviruses failed to induce increased phagocytosis, oxidative burst, or natural killer cell activity in swine. In contrast, enhanced release of interleukin-2, alpha interferon, and gamma interferon, as well as strong proliferation, could be measured. Flow cytometric analyses and cell sorting experiments identified T-helper cells as the main target responding to inactivated poxviruses: the activated cells had a CD4(high) CD25(+) major histocompatibility complex type II-positive phenotype and were the major source of secreted cytokines. Together, the results demonstrated that all tested poxviruses possessed immunostimulating capacity. These in vitro poxvirus-induced effects may be responsible at least in part for the in vivo immunostimulating capacity of inactivated poxviruses.

Genomic (5'UTR) and serological differences among German BVDV field isolates.

Isolates of bovine viral diarrhoea virus (BVDV) collected in Germany were examined for their genomic heterogeneity in sequences from the 5'untranslated region (UTR) of the viral genome. Polymerase chain reaction (PCR) tests based on the 5'UTR and the region coding for the NS2-3/4A polypeptide were used to differentiate between BVDV I and BVDV II genotypes. Eleven out of 96 BVDV-isolates were identified as BVDV II. Virus neutralization tests with BVDV I- or II-specific antisera raised in cattle were done. The mean titers were reduced by 7.2-fold (BVDV I-antiserum versus type II-isolates) or 35-fold (BVDV II-antiserum versus type I-isolates) when using the respective heterologous virus.

A gE deleted infectious bovine rhinotracheitis marker vaccine for use in improved bovine herpesvirus 1 control programs.

Based on a glycoprotein E (gE) deleted bovine herpesvirus 1 (BHV1) strain (Kaashoek et al., 1994) a killed virus as well as a modified live virus marker vaccine have been developed that allow differentiation between immunized and BHV1 infected cattle. Safety and efficacy of both vaccines were tested extensively following the current European Union (EU) requirements for the development of bovine vaccines. The minimum vaccine dose, vaccination regimen, route of administration and duration of immunity were evaluated for both vaccines in comprehensive vaccination/challenge trials in cattle. The most potent adjuvant formulation for the killed virus vaccine was also selected by experimental challenge infections. For the modified live virus marker vaccine it could be demonstrated that maternally derived BHV1 specific antibodies did not interfere with vaccination. Safety could be demonstrated for both the killed virus and the modified live virus vaccine in all target animal categories including veal calves, beef cattle, bulls, heifers and dairy cattle, including pregnant animals.

Safety aspects in the development of an infectious bovine rhinotracheitis marker vaccine.

Clinical trials in cattle demonstrated that the IBR marker modified live vaccine based on the gE-deleted IBR strain Difivac is immunogenic and safe for bovines of all ages. Potential effects of the vaccine virus have also been tested in swine and sheep and proved safe for these species as well. For evaluation of other environmental aspects, the spread of the vaccine virus after immunisation was investigated. The data indicated that the vaccine virus may be shed by immunised animals but that it has a limited ability to pass from animal to animal. It was also demonstrated that the attenuated Difivac strain does not revert to virulence during calf passage. Preliminary results indicated that the gE-deleted vaccine virus of the IBR marker vaccine cannot be reactivated after dexamethasone treatment, an important advantage for a vaccine strain. Furthermore, immunisation with the Difivac strain reduced the ability of a superinfecting challenge virus to become latent or to be reactivated.

[Recent information about the etiopathogenesis of paretic-paralytic forms of herpesvirus infection in horses]. / Neuere Erkenntnisse zur Atiopathogenese der paretisch-paralytischen Verlaufsform der Herpesvirusinfektion des Pferdes.

From spring 1990 to summer 1991 we investigated 21 horses with clinical symptoms of EHV-infection by means of serological and virological methods including DNA-hybridization to identify the causative agents. The results indicated that, as already reported by us, EHV4 may also cause the paralytic form of the infection. The possibility of double infection with EHV4 and EHV1 cannot be excluded. In 3 out of 21 affected horses we could investigate brain tissue and/or spinal fluid by Dotblot hybridization with EHV1 and EHV4-DNA. The investigated samples of all three horses showed hybridization with EHV4-DNA, without or with less pronounced reaction with EHV1-DNA. The results were confirmed by serological investigation. Brain tissue and cerebrospinal fluid from two horses with paretic or paralytic disorders (1979 and 1980) was also investigated by DNA hybridization. In the liquor of one horse--a 5-month-old foal with neonatal ataxia--we detected EHV1-DNA. The other horse showed a strong reaction with EHV1 and a weaker reaction with EHV4 in its brain material and no hybridisation in the cerebrospinal fluid. The results are discussed.

[Effect of a paramunity inducer on the incidence of diseases and the plasma cortisol content in Thoroughbred foals before and after weaning]. / Einfluss eines Paramunitätsinducers auf die Inzidenz von Erkrankungen und die Plasmakortisolgehalte bei Vollblutfohlen vor und nach dem Absetzen.

The effect of the prophylactic application of the paramunity inducer Baypamun on the incidence of diseases among foals (n = 63) in four Thoroughbred studs was evaluated. In a blind study, 38 of the foals received 2 ml of Baypamun intramuscularly while 25 of the foals received a placebo at six and four days before weaning and on the fifth day post-weaning. During the observation period of three weeks, beginning with the first and ending ten days after the last application, 7.9% of the foals treated with Baypamun (3 out of 38) suffered from respiratory infections compared to 24% of the foals treated with placebo (6 out of 25). The blood plasma cortisol concentrations were also measured in 53 of the foals of three studs before and 24 hours after weaning. The cortisol concentration increased in all the foals. However, the increase was significant only for the Baypamun treated foals of one stud while it was significant for the placebo treated foals of all studs (p < 0.01).

[The effectiveness of the paramunity inducer Baypamun (PIND-ORF) for the prevention and metaphylaxis of an experimental infection with the infectious bovine rhinotracheitis virus in cattle]. / Wirksamkeit des Paramunitätsinducers Baypamun (PIND-ORF) zur Prophylaxe und Metaphylaxe einer experimentellen Infektion mit Virus der Infektiösen Bovinen Rhinotracheitis beim Rind.

Efficacy of the paramunity inducer Baypamun (PIND-ORF) was evaluated by an IBR challenge trial in cattle, as one model for infectious diseases in bovine. Prophylactic treatment with Baypamun protected cattle against manifestation of clinical symptoms after experimental IBR infection. The degree of protection depended on the time between paramunization and challenge infection. Even in metaphylactically paramunized cattle Baypamun reduced the IBR symptoms. In correlation to the reduction of clinical symptoms paramunization also reduced virus excretion by more than 99% in treated cattle compared to non paramunized animals. The induction of interferon following IBR infection was investigated in paramunized cattle. Application of Baypamun enabled treated animals to react faster with interferon synthesis following IBR infection than control animals did. The demonstration of the status of paramunity following Baypamun application in cattle provides a concept in the prevention of infectious disease in the practice.

Vinculin and 36 kDa protein are not tyrosine-phosphorylated in Rous sarcoma virus infected cells which have been treated with interferon.

The expression of membrane-associated transformation-specific parameters was analyzed in de novo Rous sarcoma virus (strain SR-RSV-D) infected chicken embryo fibroblasts pretreated with homologous interferon. Cellular morphology, hexose transport, microfilament organization, and tyrosine-phosphate content of two primary substrates of the transformation-generating viral kinase, pp60src, were found indistinguishable from non-infected controls. These observations support the hypothesis that vinculin and possibly 36 kDa protein are involved in microfilament organization and that tyrosine-phosphorylation of these structural proteins is a prerequisite for the rearrangement of microfilaments during transformation. In de novo infection, interferon pretreatment reduces viral protein synthesis and pp60src activity as compared to non-treated, SR-RSV-D infected cells. However, the phosphotyrosine content of total cellular proteins as measured under steady state conditions is as high in interferon-pretreated as in nontreated transformed cells.

Interferon inhibits establishment of fibroblast infection with avian retroviruses.

Pretreatment of chick embryo fibroblasts (CEF) with low doses of homologous interferon (16 u/ml) drastically inhibits cell transformation by, and replication of Rous sarcoma virus (RSV). Treatment of chick cells with 16 u/ml of interferon before de novo infection with a transformation defective (td) mutant-RSV, also resulted in a reduction of extracellular virus particles. This was determined by infectivity titrations, virus associated reverse transcriptase (RT) activity and measurement of metabolically radioactively labelled virus particles. The viral proteins pr 180, pr 76, p 27, p 19 and p 12 were still synthesized in interferon-treated cells in an unaltered form, although at slightly reduced levels. No difference in the pattern of structural proteins could be detected between virus particles harvested from cells treated with interferon and from control cells. In contrast to de novo infected cells, concentrations of interferon as high as 200 u/ml had no influence on the reversible transformation of cloned fibroblasts infected with a temperature sensitive mutant of RSV. In addition, fibroblasts infected with td-SR-RSV-D before addition of interferon showed only a marginal effect on formation of infectious virus even after treatment with 200-500 u/ml of interferon. This was not caused by interferon-resistance of the td-SR-RSV-D infected cells since viral protein synthesis by superinfecting Vesicular stomatitis virus (VSV) was as sensitive to interferon as in cells not preinfected with retrovirus. Our results support the notion that exogenous infection of fibroblasts with avian retrovirus is inhibited by interferon during an early phase of the replication cycle.