[Ability to drive with cerebrovascular diseases : Position paper of the German societies DGNB, DGN, DGNC, DGNR, DSG and GNP]. / Fahreignung bei Hirngefäßerkrankungen : Positionspapier der DGNB, DGN, DGNC, DGNR, DSG und GNP.

The regulations for ability to drive with cerebrovascular diseases in the German Driving License Regulations (Fahrerlaubnisverordnung, FeV) and German Guidelines for the Evaluation of Driving Ability of the Federal Highway Research Institute (BASt) are not up to date with the current medical knowledge and are not consistent with comparable regulations regarding cardiovascular diseases. This is particularly true for the assessment of future risks for a sudden loss of control during driving. The present position paper of six medical and neuropsychological societies in Germany presents the current conditions for the assessment of driving ability of patients a cerebrovascular diesease and recommends an estimation of the ability to drive founded on the current state of scientific knowledge. It addresses the following: 1. Physical and mental functional limitations and the possibilities for compensation, which if necessary enable a fitness to drive under conditions or within limits, including the importance of behavioral or personality changes and cognitive deficiencies that interfere with safety. 2. The potential danger due to a sudden loss of control as a result of a transient ischemic attack (TIA) new stroke event, or another cardiovascular event while driving. A summary in the form of a table provides physicians and expert assessors with assistance for the most important cerebrovascular diseases.

[Guideline "Legal evaluation after closed brain injury in adulthood"]. / Leitlinie "Begutachtung nach gedecktem Schädel-Hirntrauma im Erwachsenenalter".

In 2005 and 2013, the "Deutsche Gesellschaft für Neurowissenschaftliche Begutachtung" (German Society for Neuroscientific Evaluation) together with other societies developed and consented guidelines fort the legal evaluation of patients with closed head injuries and published them trough the National Working Group of Scientific Medical Societies and in this journal. Five years later, a revision was necessary, this was developed on the higher S2 k level of consent through a Delphi conference.

Optimization of PCR for quantification of simian immunodeficiency virus genomic RNA in plasma of rhesus macaques (Macaca mulatta) using armored RNA.

INTRODUCTION: Quantification of plasma viral load (PVL) is used to monitor disease progression in SIV-infected macaques. This study was aimed at optimizing of performance characteristics of the quantitative PCR (qPCR) PVL assay. METHODS: The PVL quantification procedure was optimized by inclusion of an exogenous control hepatitis C virus armored RNA (aRNA), a plasma concentration step, extended digestion with proteinase K, and a second RNA elution step. Efficiency of viral RNA (vRNA) extraction was compared using several commercial vRNA extraction kits. Various parameters of qPCR targeting the gag region of SIVmac239, SIVsmE660, and the LTR region of SIVagmSAB were also optimized. RESULTS: Modifications of the SIV PVL qPCR procedure increased vRNA recovery, reduced inhibition and improved analytical sensitivity. The PVL values determined by this SIV PVL qPCR correlated with quantification results of SIV RNA in the same samples using the 'industry standard' method of branched-DNA (bDNA) signal amplification. CONCLUSIONS: Quantification of SIV genomic RNA in plasma of rhesus macaques using this optimized SIV PVL qPCR is equivalent to the bDNA signal amplification method, less costly and more versatile. Use of heterologous aRNA as an internal control is useful for optimizing performance characteristics of PVL qPCRs.

[Driving ability with cerebral perfusion disorders]. / Fahreignungsbeurteilung bei Hirndurchblutungsstörungen.

In Germany expert testimony on driving ability requires knowledge of the corresponding legislation, the guidelines for expertises on driver aptitude and a qualification in traffic medicine. The testimony should clearly identify handicaps with regard to driving, give estimates on the risks of a sudden loss of the driving capability by stroke recurrence or epileptic seizures, and also consider personal attitudes, such as inadequate behaviour and lack of insight. Physical handicaps can often be compensated for by restraints, such as vehicle modifications and restrictions, such as daylight driving only.The testimony must also give estimates on the risks of a sudden loss of the driving capability by stroke recurrence or epileptic seizures. Two models are proposed by which an estimate of harmful traffic accidents due to stroke recurrence can be made.

[The German guideline "legal evaluation after closed head injury"]. / Die leitlinie "begutachtung nach gedecktem schädel-hirntrauma".

In 2005, the "Deutsche Gesellschaft für Neurowissenschaftliche Begutachtung" (German Society for Neuroscientific Legal Evaluation) together with other Societies published a guideline for the legal evaluation of patients with closed head injuries. Meanwhile, not only scientific progress in imaging techniques but also in other fields such as neuropsychology has necessitated a revision, which is presented here. In the mean time, the handling of guidelines has been systematised in Germany so that a registration with the Cooperation of German Medical Learned Societies is applied for and publication in the German Guideline Registry is expected.

Progesterone implants enhance SIV vaginal transmission and early virus load.

Simian immunodeficiency virus (SIV) can cross the intact vaginal epithelium to establish a systemic infection in macaques (mac). Using this SIVmac model, we found that subcutaneous progesterone implants, which could mimic hormonally based contraceptives, thinned the vaginal epithelium and enhanced SIV vaginal transmission 7.7-fold over that observed in macaques treated with placebo implants and exposed to SIV in the follicular phase of the menstrual cycle. Progesterone treatment also increased the number of SIV DNA-positive cells in the vaginal lamina propria as detected by in situ polymerase chain reaction analysis. Moreover, plasma viral RNA was elevated for the first three months in macaques with progesterone implants, and three of the progesterone-treated macaques developed relatively rapid disease courses. This study shows that SIV genital infection and disease course are enhanced by subcutaneous implants containing progesterone when compared with the rate of vaginal transmission in the follicular phase.

[Assessment of whiplash and cervical spine injury]. / Begutachtung von Beschleunigungsverletzungen der Halswirbelsäule.

Formulating an expert opinion on whiplash injuries requires that consideration be given to biomechanical, orthopedic, neurological, psychiatric and medicolegal aspects. The greatest difficulties are encountered in cases of mild whiplash where patients complain of constant pain without any physical correlative. Diverse assessments and principles for approving a claim are reflected in the fact that the prevalence of chronic spine pain after whiplash injuries (late whiplash syndrome) varies between 16% and 71% in different countries, and the proportion of whiplash injuries involved in petitions for compensation differs greatly across Europe (UK 75%, Germany 47%, Finland 8.5% and France 3% of all personal injuries).Important biomechanical, orthopedic, neurological, psychiatric and medicolegal aspects of expert testimony on whiplash associated disorders (WAD) are delineated.

Antigenic modulation of Friend virus erythroleukemic cells in vitro by serum from mice with dormant erythroleukemia.

Friend leukemia virus (FLV) erythroleukemic cells cultured in medium containing FLV-immune serum from dormant FLV-infected mice undergo modulation of FLV cell surface antigens. Modulation was determined by an increased resistance to FLV antibody-mediated complement-dependent lysis and was associated temporally with the capping of FLV-immune complexes at the cell surface. Modulated cells regained their susceptibility to FLV antibody-mediated complement-dependent lysis when transferred to medium containing normal mouse serum. After 48 h of culture in FLV-immune serum, 26% of the FLV erythroleukemic cells were devoid of FLV cell surface antigens as demonstrated by immunofluoresence. Antigenic modulation occurred to a greater extent in cells maintained in logarithmic growth than in cells in GO or resting phase. FLV-antigenic modulation is discussed as a possible mechanism by which antibody induces and maintains FLV-transformed cells in a dormant state.

Cellular targets of infection and route of viral dissemination after an intravaginal inoculation of simian immunodeficiency virus into rhesus macaques.

We used the simian immunodeficiency virus (SIV)/rhesus macaque model to study events that underlie sexual transmission of human immunodeficiency virus type 1 (HIV-1). Four female rhesus macaques were inoculated intravaginally with SIVmac251, and then killed 2, 5, 7, and 9 d later. A technique that detected polymerase chain reaction-amplified SIV in situ showed that the first cellular targets for SIV were in the lamina propria of the cervicovaginal mucosa, immediately subjacent to the epithelium. Phenotypic and localization studies demonstrated that many of the infected cells were likely to be dendritic cells. Within 2 d of inoculation, infected cells were identified in the paracortex and subcapsular sinus of the draining internal iliac lymph nodes. Subsequently, systemic dissemination of SIV was rapid, since culturable virus was detectable in the blood by day 5. From these results, we present a model for mucosal transmission of SIV and HIV-1.

Effects of in vivo CD8(+) T cell depletion on virus replication in rhesus macaques immunized with a live, attenuated simian immunodeficiency virus vaccine.

The role of CD8(+) T lymphocytes in controlling replication of live, attenuated simian immunodeficiency virus (SIV) was investigated as part of a vaccine study to examine the correlates of protection in the SIV/rhesus macaque model. Rhesus macaques immunized for >2 yr with nef-deleted SIV (SIVmac239Deltanef) and protected from challenge with pathogenic SIVmac251 were treated with anti-CD8 antibody (OKT8F) to deplete CD8(+) T cells in vivo. The effects of CD8 depletion on viral load were measured using a novel quantitative assay based on real-time polymerase chain reaction using molecular beacons. This assay allows simultaneous detection of both the vaccine strain and the challenge virus in the same sample, enabling direct quantification of changes in each viral population. Our results show that CD8(+) T cells were depleted within 1 h after administration of OKT8F, and were reduced by as much as 99% in the peripheral blood. CD8(+) T cell depletion was associated with a 1-2 log increase in SIVmac239Deltanef plasma viremia. Control of SIVmac239Deltanef replication was temporally associated with the recovery of CD8(+) T cells between days 8 and 10. The challenge virus, SIVmac251, was not detectable in either the plasma or lymph nodes after depletion of CD8(+) T cells. Overall, our results indicate that CD8(+) T cells play an important role in controlling replication of live, attenuated SIV in vivo.

Natural infection of a homozygous delta24 CCR5 red-capped mangabey with an R2b-tropic simian immunodeficiency virus.

A homozygous 24-bp deletion (Delta24) was found in the CC chemokine receptor 5 (CCR5) of 11 out of 15 red-capped mangabeys (RCMs), Cercocebus torquatus torquatus, both in Africa and in an American zoo. The CCR5 Delta24 defect encompassed eight amino acids in frame in the fourth transmembrane region. Unexpectedly, RCM-009, one of 11 homozygotes (Delta24CCR5/ Delta24CCR5), was found to be naturally infected with a divergent simian immunodeficiency virus (SIV) strain, which was not R5-tropic, but used CCR2b (R2b) as its major coreceptor. SIVrcmGab1 was the only R2b-tropic SIV among other divergent SIVs tested. Cells transfected with the Delta24 CCR5 did not support entry of R5-tropic SIVmac, SIVcpz, SIVmne, HIV-2, or HIV-1, and were also inactive in signal transduction mediated by beta-chemokines. At 86.6%, the Delta24 allelic frequency was significantly higher than that of the 32-bp deletion found in humans. The Delta24 frequency was 4.1% in 34 sooty mangabeys (SMs), a geographically isolated subspecies that was naturally infected with R5-tropic SIV. Finding identical deletions in two mangabey subspecies separated for 10,000 years or more dates the Delta24 CCR5 deletion as ancient. However, the source of the selective pressure for the high rate of CCR5 deletion in RCMs remains to be determined. The high allelic frequency of the Delta24 CCR5 in RCMs, in comparison to that of SMs, suggests that R2b-tropism may have been acquired by SIVrcm, as an adaptation to CCR5 genetic defects appeared in its host.

Control of downy mildew (Pseudoperonospora cubensis) of greenhouse grown cucumbers with alternative biological agents.

In organic cucumber production infection with downy mildew (Pseudoperonospora cubensis) is a major problem. Plant extracts from Glycyrrhiza glabra L. (licorice), a plant belonging to the family Fabaceae, and Salvia officinalis (sage) as well as cultures of the bacterium Aneurinibacillus migulanus were investigated for efficacy of disease control under commercial growing conditions. Contrary to bioassays, where sage extract and the microorganism showed highest activity, in the trials of 2008 G. glabra extract was more effective than sage extract or A. migulanus against P. cubensis. Parameters such as concentrations of the preparations or application intervals could have been the reason for this. In the following year's trial (2009) the concentration of these agents was therefore increased somewhat and plants were either treated in seven day application intervals or in ten day application intervals. In the semi-commercial trials of 2009 all alternative biological agents showed good efficacies up to around 80% against infection with downy mildew. The application interval seemed to have a marginal effect only. Again, the licorice extract tended to be the best agent.

Nucleotide sequence of SRV-1, a type D simian acquired immune deficiency syndrome retrovirus.

Simian acquired immune deficiency syndrome (SAIDS) in the macaque genus of monkeys at the California Primate Research Center is apparently caused by infection by a type D retrovirus. The complete nucleotide sequence (8173 base pairs) of a molecular clone of the prototype SAIDS virus isolate, SRV-1, reveals a typical retrovirus structure with long terminal repeats (346 base pairs) and open reading frames for the gag (663 codons), pol (867 codons), and env (605 codons) genes. SRV-1 also has a separate open reading frame of 314 codons between the gag and pol genes that defines the viral protease gene (prt) and a short open reading frame of unknown significance downstream from the env gene. The SRV-1 protease region shows a high degree of homology to its counterpart in the hamster intracisternal A-type particle genome; both these protease genes are about twice as long as the analogous region of other retroviruses. SRV-1 has no notable similarity in either genetic organization or sequence to the human AIDS retroviruses.

Protection against vaginal SIV transmission with microencapsulated vaccine.

Although protection in animal models against intravenous challenges with simian immunodeficiency virus (SIV) has been reported, no previous vaccines have protected against a heterosexual route of infection. In this study, five of six macaques were protected against vaginal challenge when immunized with formalin-treated SIV in biodegradable microspheres by the intramuscular plus oral or plus intratracheal route. Oral immunization alone did not protect. After a second vaginal challenge, three of four intramuscularly primed and mucosally boosted macaques remained protected. The data suggest that protection against human immunodeficiency virus vaginal transmission could be provided by microsphere-based booster vaccines when used to immunize women who are systemically primed.

Transmission of simian acquired immunodeficiency syndrome (SAIDS) with blood or filtered plasma.

Simian acquired immunodeficiency syndrome (SAIDS), a disease clinically and pathologically similar to acquired immunodeficiency syndrome in humans, was transmitted from diseased rhesus monkeys (Macaca mulatta) to normal monkeys by inoculation with heparinized whole blood or plasma that had been passed through filters of 0.45 micrometer pore size. This suggests that the causative agent is small and most probably a virus. No viruses, however, were isolated by standard cell culture techniques from the blood or filtered plasma which caused SAIDS. Both cellular and humoral immunity were markedly depressed in animals with advanced SAIDS.

Simian AIDS: isolation of a type D retrovirus and transmission of the disease.

A type D retrovirus related to but distinct from Mason-Pfizer monkey virus was isolated in vitro from the blood of two rhesus monkeys (Macaca mulatta) with simian acquired immunodeficiency syndrome (SAIDS). Three juvenile rhesus monkeys that were injected intravenously with tissue culture fluids containing this virus developed SAIDS after 2 to 4 weeks.

[Manipulative treatment of the cervical spine and stroke]. / Manipulationsbehandlung der HWS und Schlaganfall.

Manipulative therapy of the cervical spine is associated with a considerable risk of stroke. We evaluated all cases with the diagnosis of arterial dissection submitted between 1996 and 2005 to the Schlichtungsstelle für Arzthaftpflichtfragen der Norddeutschen Arztekammern for assessment of the accusations brought against the therapists who conducted the manipulation. Neither in the 7 carotid nor in the 9 vertebral artery cases could a causal link be made between the dissection and the manipulation. However, in 5 of the 7 carotid and 7 of the 9 vertebral artery dissections there was clear evidence or high probability that the dissection was present prior to the manipulation, and had caused neck pain, segmental dysfunction and, in some cases, even neurological symptoms. Stroke after manipulative therapy was due to embolisation of thrombotic material from the dissected artery. As both cervical arterial dissection and cervical spine disorder usually cause similar signs and symptoms physicians must differentiate between these two entities prior to any manipulative therapy. Clinical indicators of pre-existent dissection and the medicolegal implications are discussed in this paper.

Clinical and angiographic risk factors for stroke and death within 30 days after carotid endarterectomy and stent-protected angioplasty: a subanalysis of the SPACE study.

BACKGROUND: Carotid endarterectomy (CEA) and carotid artery stenting (CAS) are used to prevent ischaemic stroke in patients with stenosis of the internal carotid artery. Better knowledge of risk factors could improve assignment of patients to these procedures and reduce overall risk. We aimed to assess the risk of stroke or death associated with CEA and CAS in patients with different risk factors. METHODS: We analysed data from 1196 patients randomised to CAS or CEA in the Stent-Protected Angioplasty versus Carotid Endarterectomy in Symptomatic Patients (SPACE) trial. The primary outcome event was death or ipsilateral stroke (ischaemic or haemorrhagic) with symptoms that lasted more than 24 h between randomisation and 30 days after therapy. Six predefined variables were assessed as potential risk factors for this outcome: age, sex, type of qualifying event, side of intervention, degree of stenosis, and presence of high-grade contralateral stenosis or occlusion. The SPACE trial is registered at Current Controlled Trials, with the international standard randomised controlled trial number ISRCTN57874028. FINDINGS: Risk of ipsilateral stroke or death increased significantly with age in the CAS group (p=0.001) but not in the CEA group (p=0.534). Classification and regression tree analysis showed that the age that gave the greatest separation between high-risk and low-risk populations who had CAS was 68 years: the rate of primary outcome events was 2.7% (8/293) in patients who were 68 years old or younger and 10.8% (34/314) in older patients. Other variables did not differ between the CEA and CAS groups. INTERPRETATION: Of the predefined covariates, only age was significantly associated with the risk of stroke and death. The lower risk after CAS versus CEA in patients up to 68 years of age was not detectable in older patients. This finding should be interpreted with caution because of the drawbacks of post-hoc analyses.

Development of sandwich-type ELISAs for the quantification of rat and murine thrombin activatable fibrinolysis inhibitor in plasma.

BACKGROUND: Altered plasma levels of thrombin activatable fibrinolysis inhibitor (TAFI) are associated with a large number of pathologies. Rat and murine models are frequently used to study the pathophysiological role of TAFI in vivo but immunological tools to quantify rat and murine TAFI are lacking. OBJECTIVE: The production of monoclonal antibodies (mAb) towards rat TAFI and the development of an ELISA for the quantification of rat and murine TAFI in plasma. METHODS AND RESULTS: Monoclonal antibodies were raised in TAFI-deficient mice towards (activated) recombinant rat TAFI. Pair-wise testing of the mAb revealed three suitable ELISA combinations, namely RT36A3F5/RT30D8-HRP, RT36A3F5/RT82F12-HRP and RT82F12/RT36A3F5-HRP. All three ELISAs are highly specific for rat and murine TAFI. TAFI concentrations in the lower ng mL(-1) range can be determined in plasma samples with a high reproducibility. Comparing TAFI antigen levels measured by these ELISAs with TAFIa activity values determined by activity based assays revealed excellent correlations (R(2) > 0.98). The average antigen levels of 20 individual rat plasma samples were 16 +/- 2 microg mL(-1) using the RT36A3F5-RT30D8-HRP, 12 +/- 2 microg mL(-1) using the RT36A3F5-RT82F12-HRP and 21 +/- 2 microg mL(-1) using the RT82F12-RT36A3F5-HRP ELISA. The determined antigen levels in rat plasma are similar to the levels reported for human plasma. CONCLUSIONS: We developed three highly specific and extremely sensitive sandwich-type ELISAs for the quantification of rat and murine TAFI in plasma. The described ELISAs will facilitate in vivo investigation on the pathophysiological role of TAFI.