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1.  Multicomponent reactions II 
doi:10.3762/bjoc.10.7
PMCID: PMC3896267  PMID: 24454563
multicomponent
2.  Enhanced Passive Bat Rabies Surveillance in Indigenous Bat Species from Germany - A Retrospective Study 
In Germany, rabies in bats is a notifiable zoonotic disease, which is caused by European bat lyssaviruses type 1 and 2 (EBLV-1 and 2), and the recently discovered new lyssavirus species Bokeloh bat lyssavirus (BBLV). As the understanding of bat rabies in insectivorous bat species is limited, in addition to routine bat rabies diagnosis, an enhanced passive surveillance study, i.e. the retrospective investigation of dead bats that had not been tested for rabies, was initiated in 1998 to study the distribution, abundance and epidemiology of lyssavirus infections in bats from Germany. A total number of 5478 individuals representing 21 bat species within two families were included in this study. The Noctule bat (Nyctalus noctula) and the Common pipistrelle (Pipistrellus pipistrellus) represented the most specimens submitted. Of all investigated bats, 1.17% tested positive for lyssaviruses using the fluorescent antibody test (FAT). The vast majority of positive cases was identified as EBLV-1, predominately associated with the Serotine bat (Eptesicus serotinus). However, rabies cases in other species, i.e. Nathusius' pipistrelle bat (Pipistrellus nathusii), P. pipistrellus and Brown long-eared bat (Plecotus auritus) were also characterized as EBLV-1. In contrast, EBLV-2 was isolated from three Daubenton's bats (Myotis daubentonii). These three cases contribute significantly to the understanding of EBLV-2 infections in Germany as only one case had been reported prior to this study. This enhanced passive surveillance indicated that besides known reservoir species, further bat species are affected by lyssavirus infections. Given the increasing diversity of lyssaviruses and bats as reservoir host species worldwide, lyssavirus positive specimens, i.e. both bat and virus need to be confirmed by molecular techniques.
Author Summary
According to the World Health Organization rabies is considered both a neglected zoonotic and a tropical disease. The causative agents are lyssaviruses which have their primary reservoir in bats. Although bat rabies is notifiable in Germany, the number of submitted bats during routine surveillance is rarely representative of the natural bat population. Therefore, the aim of this study was to include dead bats from various sources for enhanced bat rabies surveillance. The results show that a considerable number of additional bat rabies cases can be detected, thus improving the knowledge on the frequency, geographical distribution and reservoir-association of bat lyssavirus infections in Germany. The overall proportion of positives was lower than during routine surveillance in Germany. While the majority of cases were found in the Serotine bat and characterized as European bat lyssavirus type 1 (EBLV-1), three of the four EBLV-2 infections detected in Germany were found in Myotis daubentonii during this study.
doi:10.1371/journal.pntd.0002835
PMCID: PMC4006713  PMID: 24784117
3.  Prediction of mortality in adult patients with severe acute lung failure receiving veno-venous extracorporeal membrane oxygenation: a prospective observational study 
Critical Care  2014;18(2):R67.
Introduction
Veno-venous extracorporeal membrane oxygenation (vvECMO) can be a life-saving therapy in patients with severe acute lung failure refractory to conventional therapy. Nevertheless, vvECMO is a procedure associated with high costs and resource utilization. The aim of this study was to assess published models for prediction of mortality following vvECMO and optimize an alternative model.
Methods
Established mortality risk scores were validated to assess their usefulness in 304 adult patients undergoing vvECMO for refractory lung failure at the University Medical Center Regensburg from 2008 to 2013. A parsimonious prediction model was developed based on variables available before ECMO initiation using logistic regression modelling. We then assessed whether addition of variables available one day after ECMO implementation enhanced mortality prediction. Models were internally validated and calibrated by bootstrapping (400 runs). Predictive ability, goodness-of-fit and model discrimination were compared across the different models.
Results
In the present study population, existing mortality prediction tools for vvECMO patients showed suboptimal performance. Evaluated before vvECMO initiation, a logistic prediction model comprising age, immunocompromised state, artificial minute ventilation, pre-ECMO serum lactate and hemoglobin concentrations showed best mortality prediction in our patients (area under curve, AUC: 0.75). Additional information about norepinephrine dosage, fraction of inspired oxygen, C-reactive protein and fibrinogen concentrations the first day following ECMO initiation further improved discrimination (AUC: 0.79, P = 0.03) and predictive ability (likelihood ratio test, P < 0.001). When classifying patients as lower (<40%) or higher (>80%) risk based on their predicted mortality, the pre-ECMO and day1-on-ECMO models had negative/positive predictive values of 76%/82% and 82%/81%, respectively.
Conclusions
While pre-ECMO mortality prediction remains a challenge due to large patient heterogeneity, evaluation one day after ECMO initiation may improve the ability to separate lower- and higher-risk patients. Our findings support the clinical perception that chronic health condition, high comorbidity and reduced functional reserves are strongly related to survival during and following ECMO support. Renewed evaluation the first day after ECMO initiation may provide enhanced guidance for further handling of ECMO patients. Despite the usefulness of prediction models, thorough clinical evaluation should always represent the cornerstone in decision for ECMO.
doi:10.1186/cc13824
PMCID: PMC4057201  PMID: 24716510
4.  Tolcapone addition improves Parkinson’s disease associated nonmotor symptoms 
Background:
Addition of catechol-O-methyltransferase inhibitors to a conventional levodopa/dopadecarboxylase inhibitor regimen improves motor symptoms in patients with Parkinson’s disease. Optimizing dopamine substitution is also beneficial for nonmotor features.
Objectives:
To investigate the efficacy of supplemental tolcapone intake on nonmotor symptoms.
Design/methods:
A total of 125 levodopa-treated patients additionally took tolcapone in this observational trial. Initially and following 4 weeks of tolcapone intake, the neurologist scored with Unified Parkinson’s Disease Rating Scale parts I, II, IV, the nonmotor symptoms scale for Parkinson’s disease and recorded the off time. The patients rated themselves with the EuroQuol, its visual analogue scale and the nonmotor screening questionnaire. Caregivers reported the daily duration of care giving.
Results:
All scores improved except for Unified Parkinson’s Disease Rating Scale part IV and domains 4, 5 and 8 of the nonmotor symptoms scale for Parkinson’s disease.
Conclusion:
This trial demonstrates that tolcapone addition may improve nonmotor features.
doi:10.1177/1756285613512392
PMCID: PMC3932768  PMID: 24587824
nonmotor symptoms; Parkinson’s disease; tolcapone
5.  FemZone trial: a randomized phase II trial comparing neoadjuvant letrozole and zoledronic acid with letrozole in primary breast cancer patients 
BMC Cancer  2014;14:66.
Background
The objective of this prospectively randomized phase II trial (Trial registration: EUCTR2004-004007-37-DE) was to compare the clinical response of primary breast cancer patients to neoadjuvant therapy with letrozole alone (LET) or letrozole and zoledronic acid (LET + ZOL).
Methods
Patients were randomly assigned to receive either LET 2.5 mg/day (n = 79) or the combination of LET 2.5 mg/day and a total of seven infusions of ZOL 4 mg every 4 weeks (n = 89) for 6 months. Primary endpoint was clinical response rate as assessed by mammogram readings. The study was terminated prematurely due to insufficient recruitment. We report here on an exploratory analysis of this data.
Results
Central assessment of tumor sizes during the treatment period was available for 131 patients (66 LET, 65 LET + ZOL). Clinical responses (complete or partial) were seen in 54.5% (95% CI: 41.8-66.9) of the patients in the LET arm and 69.2% (95% CI: 56.6-80.1) of those in the LET + ZOL arm (P = 0.106). A multivariate model showed an OR of 1.72 (95% CI: 0.83-3.59) for the experimental arm.
Conclusion
No increase in the clinical response rate was observed with the addition of ZOL to a neoadjuvant treatment regimen with LET. However a trend towards a better reponse in the LET + ZOL arm could be observed. This trend is consistent with previous studies that have investigated the addition of ZOL to chemotherapy, and it may support the evidence for a direct antitumor action of zoledronic acid.
doi:10.1186/1471-2407-14-66
PMCID: PMC3937056  PMID: 24499441
Zoledronic acid; Neoadjuvant treatment; Breast cancer; Letrozole; Aromatase inhibitors; Bisphosphonates
6.  Synthesis and biological activity of N-substituted-tetrahydro-γ-carbolines containing peptide residues 
Summary
The synthesis of novel peptide conjugates of N-substituted-tetrahydro-γ-carbolines has been performed using the sequence of the Ugi multicomponent reaction and Cu(I)-catalyzed click chemistry. The effect of obtained γ-carboline–peptide conjugates on the rat liver mitochondria was evaluated. It was found that all compounds in the concentration of 30 µM did onot induce depolarization of mitochondria but possessed some inhibitory effect on the mitochondria permeability transition. The original N-substituted-tetrahydro-γ-carbolines containing an terminal alkyne group demonstrated a high prooxidant activity, whereas their conjugates with peptide fragments slightly inhibited both autooxidation and the t-BHP-induced lipid peroxidation.
doi:10.3762/bjoc.10.13
PMCID: PMC3896248  PMID: 24454569
mitochondrial membrane potential; mitochondrial permeability transition; multicomponent; peptides; tetrahydro-γ-carbolines; Ugi multicomponent reaction
7.  One-pot synthesis of cyanohydrin derivatives from alkyl bromides via incorporation of two one-carbon components by consecutive radical/ionic reactions 
Summary
The consecutive radical/ionic reaction consisting of radical formylation of alkyl bromides and nucleophilic addition of a cyanide ion was investigated, which gave moderate to good yields of cyanohydrin derivatives in one-pot.
doi:10.3762/bjoc.10.12
PMCID: PMC3896227  PMID: 24454568
alkyl bromide; carbon monoxide; cyanohydrin; ethyl cyanoformate; multicomponent; radical reaction
8.  Organobase-catalyzed three-component reactions for the synthesis of 4H-2-aminopyrans, condensed pyrans and polysubstituted benzenes 
Summary
Novel routes for the preparation of 2-amino-4H-pyran-3-carbonitrile 9, amino-arylbenzoic acid ester derivatives 13a,b, 2-aminotetrahydro-4H-chromene-3-carbonitrile 18, 3-amino-4-cyanotetrahydronaphthalene-2-carboxylic acid ester 26 and 4-amino-3,5-dicyanophthalic acid ester derivatives 37a–c were developed. The synthetic methods utilize one-pot reactions of acetylene carboxylic acid esters, α,β-unsaturated nitriles and/or active methylenenitriles in the presence of L-proline or DABCO. Plausible mechanisms are suggested for the formation of the products. Finally, these compounds were used for the efficient synthesis of 6-amino-5-cyanonicotinic acid ester derivatives 31a,b, ethyl 4-amino-5H-pyrano[2,3-d]pyrimidine-6-carboxylates 33a,b, 4-amino-6H-pyrrolo[3,4-g]quinazoline-9-carbonitrile 39, and 1,7-diamino-6-(N'-hydroxycarbamimidoyl)-3-oxo-5-phenyl-3H-isoindole-4-carboxylate (40).
doi:10.3762/bjoc.10.11
PMCID: PMC3896230  PMID: 24454567
aminopyranes; arylbenzoic acid; DABCO; L-proline; multicomponent; tetrahydronaphthalene; three-component reaction
9.  The regioselective synthesis of spirooxindolo pyrrolidines and pyrrolizidines via three-component reactions of acrylamides and aroylacrylic acids with isatins and α-amino acids 
Summary
The regioselective three-component condensation of azomethine ylides derived from isatins and α-amino acids with acrylamides or aroylacrylic acids as dipolarophiles has been realized through a one-pot 1,3-dipolar cycloaddition protocol. Decarboxylation of 2'-aroyl-2-oxo-1,1',2,2',5',6',7',7a'-octahydrospiro[indole-3,3'-pyrrolizine]-1'-carboxylic acids is accompanied by cyclative rearrangement with formation of dihydropyrrolizinyl indolones.
doi:10.3762/bjoc.10.8
PMCID: PMC3896290  PMID: 24454564
acrylamides; aroylacrylic acids; azomethine ylide; cyclative rearrangement; cycloaddition; multicomponent; spirooxindoles
10.  Studies on the interaction of isocyanides with imines: reaction scope and mechanistic variations 
Summary
The interaction of imines with isocyanides has been studied. The main product results from a sequential process involving the attack of two units of isocyanide, under Lewis acid catalysis, upon the carbon–nitrogen double bond of the imine to form the 4-membered ring system. The scope of the reaction regarding the imine and isocyanide ranges has been determined, and also some mechanistic variations and structural features have been described.
doi:10.3762/bjoc.10.3
PMCID: PMC3896293  PMID: 24454559
azetidines; heterocycles; imines; isocyanides; multicomponent reactions
11.  Four-component reaction of cyclic amines, 2-aminobenzothiazole, aromatic aldehydes and acetylenedicarboxylate 
Summary
The four-component reaction of 2-aminobenzothiazole, aromatic aldehydes, acetylenedicarboxylate and piperidine or pyrrolidine in ethanol afforded the functionalized 2-pyrrolidinones containing both benzothiazolyl and piperidinyl (or pyrrolidinyl) units in good yields. On the other hand, the similar four-component reactions resulted in the functionalized morpholinium or piperidinium 2-pyrrolidinon-3-olates in the presence of p-toluenesulfonic acid.
doi:10.3762/bjoc.9.330
PMCID: PMC3896266  PMID: 24454573
benzothiazole; domino reaction; electron-deficient alkyne; multicomponent reaction; pyrrolidinone
12.  Ventral striatum gray matter density reduction in patients with schizophrenia and psychotic emotional dysregulation☆ 
NeuroImage : Clinical  2013;4:232-239.
Introduction
Substantial heterogeneity remains across studies investigating changes in gray matter in schizophrenia. Differences in methodology, heterogeneous symptom patterns and symptom trajectories may contribute to inconsistent findings. To address this problem, we recently proposed to group patients by symptom dimensions, which map on the language, the limbic and the motor systems. The aim of the present study was to investigate whether patients with prevalent symptoms of emotional dysregulation would show structural neuronal abnormalities in the limbic system.
Method
43 right-handed medicated patients with schizophrenia were assessed with the Bern Psychopathology Scale (BPS). The patients and a control group of 34 healthy individuals underwent structural imaging at a 3T MRI scanner. Whole brain voxel-based morphometry (VBM) was compared between patient subgroups with different severity of emotional dysregulation. Group comparisons (comparison between patients with severe emotional dysregulation, patients with mild emotional dysregulation, patients with no emotional dysregulation and healthy controls) were performed using a one way ANOVA and ANCOVA respectively.
Results
Patients with severe emotional dysregulation had significantly decreased gray matter density in a large cluster including the right ventral striatum and the head of the caudate compared to patients without emotional dysregulation. Comparing patients with severe emotional dysregulation and healthy controls, several clusters of significant decreased GM density were detected in patients, including the right ventral striatum, head of the caudate, left hippocampus, bilateral thalamus, dorsolateral prefrontal and orbitofrontal cortex. The significant effect in the ventral striatum was lost when patients with and without emotional dysregulation were pooled and compared with controls.
Discussion
Decreased gray matter density in a large cluster including the right ventral striatum was associated with severe symptoms of emotional dysregulation in patients with schizophrenia. The ventral striatum is an important part of the limbic system, and was indicated to be involved in the generation of incentive salience and psychotic symptoms. Only patients with severe emotional dysregulation had decreased gray matter in several brain structures associated with emotion and reward processing compared to healthy controls. The results support the hypothesis that grouping patients according to specific clinical symptoms matched to the limbic system allows identifying patient subgroups with structural abnormalities in the limbic network.
Highlights
•We examined whole brain VBM in schizophrenia patients and healthy controls.•We compared patients with different severity of emotional dysregulation (ED).•Symptoms of ED were associated with GM density in the ventral striatum.•Grouping patients according to symptoms identified specific GM abnormalities.
doi:10.1016/j.nicl.2013.12.007
PMCID: PMC3895617  PMID: 24455473
Dimensions; Emotional dysregulation; Limbic system; Brain circuits; Psychopathology
13.  Multimorbidity in Adult Asylum Seekers: A First Overview 
PLoS ONE  2013;8(12):e82671.
Principals
Over the last two decades, the total annual number of applications for asylum in the countries of the European Union has increased from 15,000 to more than 300,000 people. The aim of this study was to give a first overview on multimorbidity of adult asylum seekers.
Methods
Our retrospective Swiss single center data analysis examined multimorbidity of adult asylums seekers admitted to our ED between 1 January 2000 and 31 December 2012.
Results
A total of 3170 patients were eligible for the study; they were predominantly male (2392 male, 75.5% versus 778 female, 24.5). The median age of the patients was 28 years (range 28–82). The most common region of origin was Africa (1544, 48.7%), followed by the Middle East (736, 23.6%). 2144 (67.6%) of all patients were not multimorbid. A total of 1183 (37.7%) of our patients were multimorbid. The mean Charlson comorbidity index was 0.25 (SD 1.1, range 0–12). 634 (20%) of all patients sufferem from psychiatric diseases, followed by chronic medical conditions (12.6%, 399) and infectious diseases (4.7%, 150). Overall, 11% (349) of our patients presented as a direct consequence of prior violence. Patients from Sri Lanka/India most often suffered from addictions problems (50/240, 20.8%, p<0.0001). Infectious diseases were most frequent in patients from Africa (6.6%), followed by the Balkans and Eastern Europe/Russia (each 3.8%).
Conclusion
The health care problems of asylum seekers are manifold. More than 60% of the study population assessed in our study did not suffer from more than one disease. Nevertheless a significant percentage of asylum seekers is multimorbid and exhibits underlying psychiatric, infectious or chronic medical conditions despite their young age.
doi:10.1371/journal.pone.0082671
PMCID: PMC3869724  PMID: 24376565
14.  Efficient synthesis of dihydropyrimidinones via a three-component Biginelli-type reaction of urea, alkylaldehyde and arylaldehyde 
Summary
A one-pot three-component synthesis of dihydropyrimidinones via a molecular iodine-catalyzed tandem reaction of simple readily available mono-substituted urea, alkylaldehyde, and arylaldehyde has been developed. The reaction proceeds with high chemo- and regioselectivity to give highly diverse dihydropyrimidinones in reasonable yields under mild reaction conditions. Moreover, the first catalytic enantioselective version of this reaction was also realized by using chiral spirocyclic SPINOL-phosphoric acids.
doi:10.3762/bjoc.9.320
PMCID: PMC3869270  PMID: 24367449
Biginelli-type reaction; chiral phosphoric acid; dihydropyrimidinone; iodine; multicomponent reaction
15.  New syntheses of 5,6- and 7,8-diaminoquinolines 
Summary
The synthesis of 5,6- and 7,8-diaminoquinoline derivatives starting from angularly annelated selenadiazoloquinolones is presented. Simple chlorination of the pyridone ring followed by reductive deselenation of the 1,2,5-selenadiazole ring afforded novel 4-chloro-o-diaminoquinolines. Dechlorination of 4-chloro-7,8-diaminoquinoline gave 7,8-diaminoquinoline hydrochloride which was successfully employed as starting material in the synthesis of condensed nitrogen heterocycles.
doi:10.3762/bjoc.9.302
PMCID: PMC3869217  PMID: 24367431
chlorination; deselenation; nitrogen heterocycles; o-diaminoquinolines; selenadiazoloquinolones
16.  Neuropsychological effects of deep brain stimulation for Parkinson's disease 
Surgical Neurology International  2013;4(Suppl 6):S443-S447.
Background:
Putative changes of cognition after deep brain stimulation (DBS) in patients with Parkinson's disease (PD) are a matter of debate. The aim of this study was to assess cognitive abilities before and following bilateral subthalamic nucleus (STN) DBS and to review the available literature.
Methods:
Twenty patients underwent bilateral DBS of the STN. Cognitive skills were assessed in a standardized fashion before and at least at 12 months after the surgical intervention.
Results:
There was a significant decline of both semantic and phonematic verbal fluency and a mild trend for a deterioration of verbal memory after DBS. Mood, general cognitive screening, and visospatial abilities remained unchanged.
Conclusion:
STN DBS in the treatment of PD has resulted in a significant reduction of motor symptoms and improved independence and quality of life in appropriately selected patients. However, it may have isolatable effects on verbal fluency and related function. Case series in the literature reported similar findings. Potential candidates for DBS should be counseled about the risk of mild cognitive declines.
doi:10.4103/2152-7806.121637
PMCID: PMC3858804  PMID: 24349868
Cognitive decline; deep brain stimulation; memory; Parkinson's disease; subthalamic nucleus; verbal fluency
17.  Diversity and Epidemiology of Mokola Virus 
Mokola virus (MOKV) appears to be exclusive to Africa. Although the first isolates were from Nigeria and other Congo basin countries, all reports over the past 20 years have been from southern Africa. Previous phylogenetic studies analyzed few isolates or used partial gene sequence for analysis since limited sequence information is available for MOKV and the isolates were distributed among various laboratories. The complete nucleoprotein, phosphoprotein, matrix and glycoprotein genes of 18 MOKV isolates in various laboratories were sequenced either using partial or full genome sequencing using pyrosequencing and a phylogenetic analysis was undertaken. The results indicated that MOKV isolates from the Republic of South Africa, Zimbabwe, Central African Republic and Nigeria clustered according to geographic origin irrespective of the genes used for phylogenetic analysis, similar to that observed with Lagos bat virus. A Bayesian Markov-Chain-Monte-Carlo- (MCMC) analysis revealed the age of the most recent common ancestor (MRCA) of MOKV to be between 279 and 2034 years depending on the genes used. Generally, all MOKV isolates showed a similar pattern at the amino acid sites considered influential for viral properties.
Author Summary
According to the World Health Organization, rabies is considered both a neglected zoonotic and tropical disease. Among all the lyssavirus species known to exist today, Mokola virus is unique and appears to be exclusive to Africa. In contrast to all other known virus species in the genus Lyssavirus of the family Rhabdoviridae, its reservoir host has not been identified yet. As only limited sequence information is available, this study significantly contributes to the understanding of the genetic diversity and relatedness of Mokola viruses. In a collective approach, the complete nucleoprotein, phosphoprotein, matrix, and glycoprotein genes of all Mokola viruses isolated to date were sequenced in various rabies laboratories across the world. A phylogenetic analysis was undertaken and the most recent common ancestor was determined. Subsequently, results were linked to epidemiological background data. We also conducted a comparative study of distinct antigenic sites considered influential for viral properties within those genes.
doi:10.1371/journal.pntd.0002511
PMCID: PMC3812115  PMID: 24205423
18.  Post-Ugi gold-catalyzed diastereoselective domino cyclization for the synthesis of diversely substituted spiroindolines 
Summary
An Ugi four-component reaction of propargylamine with 3-formylindole and various acids and isonitriles produces adducts which are subjected to a cationic gold-catalyzed diastereoselective domino cyclization to furnish diversely substituted spiroindolines. All the reactions run via an exo-dig attack in the hydroarylation step followed by an intramolecular diastereoselective trapping of the imminium ion. The whole sequence is atom economic and the application of a multicomponent reaction assures diversity.
doi:10.3762/bjoc.9.246
PMCID: PMC3817510  PMID: 24204421
alkynes; gold; indoles; multicomponent; spiroindolines; Ugi
19.  MHC Universal Cells Survive in an Allogeneic Environment after Incompatible Transplantation 
BioMed Research International  2013;2013:796046.
Cell, tissue, and organ transplants are commonly performed for the treatment of different diseases. However, major histocompatibility complex (MHC) diversity often prevents complete donor-recipient matching, resulting in graft rejection. This study evaluates in a preclinical model the capacity of MHC class I-silenced cells to engraft and grow upon allogeneic transplantation. Short hairpin RNA targeting β2-microglobulin (RN_shβ2m) was delivered into fibroblasts derived from LEW/Ztm (RT1l) (RT1-Al) rats using a lentiviral-based vector. MHC class I (RT1-A-) expressing and -silenced cells were injected subcutaneously in LEW rats (RT1l) and MHC-congenic LEW.1W rats (RT1u), respectively. Cell engraftment and the status of the immune response were monitored for eight weeks after transplantation. In contrast to RT1-A-expressing cells, RT1-A-silenced fibroblasts became engrafted and were still detectable eight weeks after allogeneic transplantation. Plasma levels of proinflammatory cytokines IL-1α, IL-1β, IL-6, TNF-α, and IFN-γ were significantly higher in animals transplanted with RT1-A-expressing cells than in those receiving RT1-A-silenced cells. Furthermore, alloantigen-specific T-cell proliferation rates derived from rats receiving RT1-A-expressing cells were higher than those in rats transplanted with RT1-A-silenced cells. These data suggest that silencing MHC class I expression might overcome the histocompatibility barrier, potentially opening up new avenues in the field of cell transplantation and regenerative medicine.
doi:10.1155/2013/796046
PMCID: PMC3856147  PMID: 24350288
20.  Alterations of White Matter Integrity Related to the Season of Birth in Schizophrenia: A DTI Study 
PLoS ONE  2013;8(9):e75508.
In schizophrenia there is a consistent epidemiological finding of a birth excess in winter and spring. Season of birth is thought to act as a proxy indicator for harmful environmental factors during foetal maturation. There is evidence that prenatal exposure to harmful environmental factors may trigger pathologic processes in the neurodevelopment, which subsequently increase the risk of schizophrenia. Since brain white matter alterations have repeatedly been found in schizophrenia, the objective of this study was to investigate whether white matter integrity was related to the season of birth in patients with schizophrenia. Thirty-four patients with schizophrenia and 33 healthy controls underwent diffusion tensor imaging. Differences in the fractional anisotropy maps of schizophrenia patients and healthy controls born in different seasons were analysed with tract-based spatial statistics. A significant main effect of season of birth and an interaction of group and season of birth showed that patients born in summer had significantly lower fractional anisotropy in widespread white matter regions than those born in the remainder of the year. Additionally, later age of schizophrenia onset was found in patients born in winter months. The current findings indicate a relationship of season of birth and white matter alterations in schizophrenia and consequently support the neurodevelopmental hypothesis of early pathological mechanisms in schizophrenia.
doi:10.1371/journal.pone.0075508
PMCID: PMC3785501  PMID: 24086548
21.  Cyclization of substitued 2-(2-fluorophenylazo)azines to azino[1,2-c]benzo[d][1,2,4]triazinium derivatives 
Summary
Light-induced cyclization of several substituted 2-(2-fluorophenylazo)azines in the presence of Ca2+ ions to the corresponding triazinium derivatives is investigated experimentally and computationally. The azo derivatives of 4-methylpyridine 4 undergo facile cyclization to the corresponding triazinium 1, and the rate of cyclization increases with increasing number of fluorine atoms at the benzene ring. No triazinium ions were obtained from azo derivatives of 4-cyanopyridine, pyrazine and pyrimidine, presumably due to their instability under the reaction conditions. The experimental results and mechanism are discussed with the aid of DFT computational results.
doi:10.3762/bjoc.9.219
PMCID: PMC3778383  PMID: 24062855
DFT; heterocycles; mechanism; synthesis
22.  Oral and dental health in Huntington‘s disease - an observational study 
BMC Neurology  2013;13:114.
Background
Only a few case reports and case series dealing with oral and dental health care are available in literature until now. The aim of the present pilot study was to determine the status of dental health in comparison to matched controls and to heighten the neurologists’ and dentists’ awareness of the oral aspects of the disease.
Methods
42 Huntington’s disease (HD) participants were scored according to the Unified Huntington’s Disease Rating Scale. The dental status was assessed by using the well established score for decayed, missing, and filled teeth (DMFT) and the dental plaque score (Silness-Loe plaque index).
Results
Compared to controls HD participants showed significantly more decayed teeth and more plaques in both plaque indices. A higher motor impairment and a lower functional status of the patients lead to a worsening in dental status.
Conclusion
Possible reasons for our findings are discussed. Apart from local oral complications general complications may also occur. Thus, as a consequence, we would encourage patients, caregivers, neurologists, and the dentists to ensure regular preventive dental examinations and dental treatments of individuals with Huntington’s disease even in the premanifest stage of this disease.
doi:10.1186/1471-2377-13-114
PMCID: PMC3766132  PMID: 24138900
23.  X-ray analysis of residual stress gradients in TiN coatings by a Laplace space approach and cross-sectional nanodiffraction: a critical comparison 
Journal of Applied Crystallography  2013;46(Pt 5):1378-1385.
Residual stresses in as-deposited and blasted TiN coatings are characterized using a Laplace approach and using the novel cross-sectional X-ray nanodiffraction technique. A comparison of real and Laplace space techniques demonstrates the advantages of the nanodiffraction method, with a possibility to analyse local gradients of stress, texture, crystallite size and phase in thin films and coatings.
Novel scanning synchrotron cross-sectional nanobeam and conventional laboratory as well as synchrotron Laplace X-ray diffraction methods are used to characterize residual stresses in exemplary 11.5 µm-thick TiN coatings. Both real and Laplace space approaches reveal a homogeneous tensile stress state and a very pronounced compressive stress gradient in as-deposited and blasted coatings, respectively. The unique capabilities of the cross-sectional approach operating with a beam size of 100 nm in diameter allow the analysis of stress variation with sub-micrometre resolution at arbitrary depths and the correlation of the stress evolution with the local coating microstructure. Finally, advantages and disadvantages of both approaches are extensively discussed.
doi:10.1107/S0021889813019535
PMCID: PMC3778322  PMID: 24068842
residual stress; TiN coatings; Laplace methods; X-ray diffraction; cross-sectional nanodiffraction
24.  The elimination of fox rabies from Europe: determinants of success and lessons for the future 
Despite perceived challenges to controlling an infectious disease in wildlife, oral rabies vaccination (ORV) of foxes has proved a remarkably successful tool and a prime example of a sophisticated strategy to eliminate disease from wildlife reservoirs. During the past three decades, the implementation of ORV programmes in 24 countries has led to the elimination of fox-mediated rabies from vast areas of Western and Central Europe. In this study, we evaluated the efficiency of 22 European ORV programmes between 1978 and 2010. During this period an area of almost 1.9 million km² was targeted at least once with vaccine baits, with control taking between 5 and 26 years depending upon the country. We examined factors influencing effort required both to control and eliminate fox rabies as well as cost-related issues of these programmes. The proportion of land area ever affected by rabies and an index capturing the size and overlap of successive ORV campaigns were identified as factors having statistically significant effects on the number of campaigns required to both control and eliminate rabies. Repeat comprehensive campaigns that are wholly overlapping much more rapidly eliminate infection and are less costly in the long term. Disproportionally greater effort is required in the final phase of an ORV programme, with a median of 11 additional campaigns required to eliminate disease once incidence has been reduced by 90 per cent. If successive ORV campaigns span the entire affected area, rabies will be eliminated more rapidly than if campaigns are implemented in a less comprehensive manner, therefore reducing ORV expenditure in the longer term. These findings should help improve the planning and implementation of ORV programmes, and facilitate future decision-making by veterinary authorities and policy-makers.
doi:10.1098/rstb.2012.0142
PMCID: PMC3720040  PMID: 23798690
fox rabies; oral rabies vaccination; elimination; influencing factors; efforts/expenses; endgame
25.  Coordination Chemistry of Disilylated Germylenes with Group 4 Metallocenes 
Organometallics  2013;32(11):3300-3308.
Reaction of the PEt3 adduct of a disilylated five-membered cyclic germylene with group 4 metallocene dichlorides in the presence of magnesium led to the formation of the respective germylene metallocene phosphine complexes of titanium, zirconium, and hafnium. Attempts to react the related NHC adduct of a disilylated four-membered cyclic germylene under the same conditions with Cp2TiCl2 did not give the expected germylene NHC titanocene complex. This complex was, however, obtained in the reaction of Cp2Ti(btmsa) with the NHC germylene adduct. A computational analysis of the structure of the group 4 metallocene germylene complexes revealed the multiple-bond character of the M–Ge(II) linkage, which can be rationalized with the classical σ-donor/π-acceptor interaction. The strength of the M–Ge(II) bond increases descending group 4.
doi:10.1021/om400215v
PMCID: PMC3714165  PMID: 23874053

Results 1-25 (94)