Ursachen und Diagnostik pharmakoresistenter fokaler Epilepsien

In den Originalarbeiten der vorliegenden Habilitationsschrift wurden die Mechanismen und Ursachen von Pharmakoresistenz bei Patient*innen mit fokalen strukturellen und autoimmunassoziierten Epilepsien untersucht. Dabei wurden Biomarker der Pharmakoresistenz von strukturellen Epilepsien und die Beteiligung des Multidrug-Efflux-Transporterproteins P-gp mit Hilfe von (R)-[11C]Verapamil-PET. Bei Patient*innen mit fokalen strukturellen Epilepsien aufgrund einer Hippocampussklerose oder zerebraler Entwicklungsstörungen konnte eine on P-gp im Vergleich zu anfallsfreien Patient*innen und gesunden Kontrollpersonen nachgewiesen werden. In Zukunft könnten Patient*innen hinsichtlich einer Überfunktion von P-gp mit (R)-[11C]Verapamil-PET untersucht und ihre ASM individuell angepasst werden, um die Pharmakoresistenz zu überwinden – beispielsweise mittles neu entwickelter Substanzen, die P-gp hemmen oder die dieses Multidrug-Efflux-Transporterprotein umgehen. In unserer Studie bei Patient*innen mit Autoimmunenzephalitiden konnten wir zeigen, dass sich bei Nachweis von GAD-Antikörpern häufig eine autoimmunassoziierte Epilepsie entwickelt. Oft wird eine Autoimmunenzephalitis aufgrund von GAD-Antikörpern jedoch zu spät erkannt und eine Therapie verzögert begonnen. Zusätzlich sprechen diese Antikörper generell schlecht auf Immunsuppressiva an. Im Vergleich dazu ist die Entstehung autoimmunassoziierter Epilepsien bei Autoimmunenzephalitiden aufgrund von neuronalen Oberflächenantikörpern nur sehr selten. Vielmehr treten hier die Anfälle nur in der Akutphase auf. Bei früher Diagnosestellung und rechtzeitiger Einleitung der immunsuppressiven Therapie kann ein Auftreten von wiederkehrenden, unprovozierten Anfällen vermieden werden. Eine langfristige Gabe von ASM ist daher nicht nötig. In der prächirurgischen Diagnostik findet die [18F]FDG-PET insbesondere bei unauffälligem cMRT ihre Anwendung. Mit unserer multizentrischen Studie an fast 1.000 Epilepsie-Patient*innen konnten wir die hohe Sensitivität von [18F]FDG-PET zur Lokalisation der Anfallsursprungszone gerade bei Patienten mit negativem MRT bestätigen. Andere Radiotracer wie der Perfusionstracer [15O]H2O-PET haben diesbezüglich auch vielversprechende Ergebnisse gezeigt

Status tanah yang dikuasai rakyat berdasarkan hukum adat dalam kaitannya dengan pemberian hak guna usaha (HGU) kepada pengusaha swasta nasional di Kabupaten Aceh Barat = The Status of Land Occupied by the People Under ..

This research aims to find out about how landholders acquire the rightful status of their landed property, the status of the right of exploitation granted to Karya Tanah Subur Inc. and the compensatory payments made to landholders, and the legal recognition of the people\u27s land right. This is important in. view of the purpose of the legitimation of land ownership, which is to increase the people\u27s income and improve their standard of living as a basis for the realization of a just and prosperous society. This research was conducted in nine villages in three subdistricts purposively selected. It involved 80 respondens who were randomly chosen from a population of 271, and 18 resource persons selected from government officials concerned. The research instruments used for the collection of data were questionnaires for the res-pondents and interviews with the resource persons. The results of the research are as follows : 1. Ownership of land is based on prevailing customs and traditions which continue to exist from generation to generation and is acknowledged by members of community at large. Landholders\u27 right of ownership are therefore legitimized by adat law2. The procedure adopted in the process of granting the right of exploitation is legally defective. This is partly evident in the implimentation of land survey which does not provide an accurate report and is not based on actual facts, and also in the legitimation of land ownership which does not comply with the Surat Keputusan Pemberian Hak (decision on the granting of right). Therefore, the right exploitation should be annulled and need to be reviewed3. The compensatory payments for the cultivated land within the exploitation area do not include compensation for the people\u27s right over their land. The payments only take into account the crops and cost of labour. The legitimacy of ownership of the people\u27s land right under adat law is not legally recognized because the officials of the National Agency for Land Management and the Local Government have incorrect perception and interpretation about the concept of land ownership. Keywords: Status of land occupied by the people - Adat law - Granting of the right of exploitatio

Atomic Resolution Structures of Human Bufaviruses Determined by Cryo-Electron Microscopy

Bufavirus strain 1 (BuV1), a member of the Protoparvovirus genus of the Parvoviridae, was first isolated from fecal samples of children with acute diarrhea in Burkina Faso. Since this initial discovery, BuVs have been isolated in several countries, including Finland, the Netherlands, and Bhutan, in pediatric patients exhibiting similar symptoms. Towards their characterization, the structures of virus-like particles of BuV1, BuV2, and BuV3, the current known genotypes, have been determined by cryo-electron microscopy and image reconstruction to 2.84, 3.79, and 3.25 angstrom, respectively. The BuVs, 65-73% identical in amino acid sequence, conserve the major viral protein, VP2, structure and general capsid surface features of parvoviruses. These include a core -barrel (B-I), -helix A, and large surface loops inserted between these elements in VP2. The capsid contains depressions at the icosahedral 2-fold and around the 5-fold axes, and has three separated protrusions surrounding the 3-fold axes. Structure comparison among the BuVs and to available parvovirus structures revealed capsid surface variations and capsid 3-fold protrusions that depart from the single pinwheel arrangement of the animal protoparvoviruses. These structures provide a platform to begin the molecular characterization of these potentially pathogenic viruses.Peer reviewe

Role of conventional and molecular techniques in soybean yield and quality improvement: A critical review

The soybean is one of the most significant legume crops around the globe and serves as a source of dietary components for humans and animals. It has a higher percentage of protein compared to any other crop. Soybean yield and quality have been affected by many environmental factors. The genetic mechanism of yield and quality is still not clearly understood. Hence there is still a need to investigate the major potent factors to shed light on the mechanism behind yield and quality traits in soybean. Recently, a lot of significant work, including novel QTL, genes, and CRISPR-based genome editing in soybeans, has been done, which opened new doors of hope. The current review has presented detailed work done previously. We have also discussed the role of different breeding techniques in the conventional way of soybean improvement. The genetic factors regulating yield, quality, and disease resistance could be further cloned and transferred into elite cultivars to attain higher output in the current situation of changing environment. The integrated use of several techniques, like CRISPR/Cas9, next-generation sequencing, omics approaches, would be a fruitful way to improve soybean yield and quality. Besides this, hybridization, mass selection, pure line selection, backcross breeding, and pedigree selection should be adopted to develop novel soybean cultivars. This review concluded that soybean yield and quality improvement could be enhanced by exploring its genetic mechanism using several molecular and conventional methods

CT analysis of subcutaneous and visceral adipose tissue in normal BMI subjects: association with level of physical activity and hypertension

Background: The distribution of adipose tissue, complex factors affecting it and its pathological consequences are among the hot topics in medical research nowadays. Most of the studies reported in the literature however describe the association of factors affecting the fat distribution in overweight and obese individuals. This particular study was however planned to find out the same in subjects having normal basal metabolic index (BMI). The objectives of the study were to analyze total adipose tissue (TAT), subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) in the abdomen volumetrically using CT, to establish the association of these to the levels of physical activity, presence or absence of hypertension and to compare these associations in both the genders.Methods: A prospective study was carried out on seventy five, normal BMI subjects aged between 20–50 years. CT imaging was used for volumetric measurement of TAT, SAT and VAT. Pearson’s correlation of these were then found out with age. Kruskal Wallis test was also performed to compare these in hypertensive and non-hypertensive subjects and in those with different physical activity levels (PAL).Results: Women showed significantly higher volumes of TAT and SAT. Men showed statistically significant correlations of TAT and VAT with age. SAT volumes had significant negative association with the PAL in both genders. Men showed higher responsiveness of fat deposition in all compartments to the presence of hypertension.Conclusion: In conclusion, factors such as gender, age, level of physical activity and hypertension affect the site specific deposition of fat even in those individuals who aren’t over-weight or obese.Keywords: Total Adipose Tissue (TAT); Subcutaneous Adipose Tissue (SAT); Visceral Adipose Tissue (VAT

Utility of 18F-fluorodeoxyglucose positron emission tomography in presurgical evaluation of patients with epilepsy: A multicenter study

OBJECTIVE: 18F-Fluorodeoxyglucose positron emission tomography (FDG-PET) is widely used in presurgical assessment in patients with drug-resistant focal epilepsy (DRE) if magnetic resonance imaging (MRI) and scalp electroencephalography (EEG) do not localize the seizure onset zone or are discordant. METHODS: In this multicenter, retrospective observational cohort study, we included consecutive patients with DRE who had undergone FDG-PET as part of their presurgical workup. We assessed the utility of FDG-PET, which was defined as contributing to the decision-making process to refer for resection or intracranial EEG (iEEG) or to conclude surgery was not feasible. RESULTS: We included 951 patients in this study; 479 had temporal lobe epilepsy (TLE), 219 extratemporal epilepsy (ETLE), and 253 epilepsy of uncertain lobar origin. FDG-PET showed a distinct hypometabolism in 62% and was concordant with ictal EEG in 74% in TLE and in 56% in ETLE (p < .001). FDG-PET was useful in presurgical decision-making in 396 patients (47%) and most beneficial in TLE compared to ETLE (58% vs. 44%, p = .001). Overall, FDG-PET contributed to recommending resection in 78 cases (20%) and iEEG in 187 cases (47%); in 131 patients (33%), FDG-PET resulted in a conclusion that resection was not feasible. In TLE, seizure-freedom 1 year after surgery did not differ significantly (p = .48) between patients with negative MRI and EEG-PET concordance (n = 30, 65%) and those with positive MRI and concordant EEG (n = 46, 68%). In ETLE, half of patients with negative MRI and EEG-PET concordance and three quarters with positive MRI and concordant EEG were seizure-free postsurgery (n = 5 vs. n = 6, p = .28). SIGNIFICANCE: This is the largest reported cohort of patients with DRE who received presurgical FDG-PET, showing that FDG-PET is a useful diagnostic tool. MRI-negative and MRI-positive cases with concordant FDG-PET results (with either EEG or MRI) had a comparable outcome after surgery. These findings confirm the significance of FDG-PET in presurgical epilepsy diagnostics

Structural Characterization of Cuta- and Tusavirus: Insight into Protoparvoviruses Capsid Morphology

Several members of the Protoparvovirus genus, capable of infecting humans, have been recently discovered, including cutavirus (CuV) and tusavirus (TuV). To begin the characterization of these viruses, we have used cryo-electron microscopy and image reconstruction to determine their capsid structures to ~2.9 Å resolution, and glycan array and cell-based assays to identify glycans utilized for cellular entry. Structural comparisons show that the CuV and TuV capsids share common features with other parvoviruses, including an eight-stranded anti-parallel β-barrel, depressions at the icosahedral 2-fold and surrounding the 5-fold axes, and a channel at the 5-fold axes. However, the viruses exhibit significant topological differences in their viral protein surface loops. These result in three separated 3-fold protrusions, similar to the bufaviruses also infecting humans, suggesting a host-driven structure evolution. The surface loops contain residues involved in receptor binding, cellular trafficking, and antigenic reactivity in other parvoviruses. In addition, terminal sialic acid was identified as the glycan potentially utilized by both CuV and TuV for cellular entry, with TuV showing additional recognition of poly-sialic acid and sialylated Lewis X (sLeXLeXLeX) motifs reported to be upregulated in neurotropic and cancer cells, respectively. These structures provide a platform for annotating the cellular interactions of these human pathogens

Structural Characterization of Cuta- and Tusavirus: Insight into Protoparvoviruses Capsid Morphology

Several members of the Protoparvovirus genus, capable of infecting humans, have been recently discovered, including cutavirus (CuV) and tusavirus (TuV). To begin the characterization of these viruses, we have used cryo-electron microscopy and image reconstruction to determine their capsid structures to ~2.9 Å resolution, and glycan array and cell-based assays to identify glycans utilized for cellular entry. Structural comparisons show that the CuV and TuV capsids share common features with other parvoviruses, including an eight-stranded anti-parallel β-barrel, depressions at the icosahedral 2-fold and surrounding the 5-fold axes, and a channel at the 5-fold axes. However, the viruses exhibit significant topological differences in their viral protein surface loops. These result in three separated 3-fold protrusions, similar to the bufaviruses also infecting humans, suggesting a host-driven structure evolution. The surface loops contain residues involved in receptor binding, cellular trafficking, and antigenic reactivity in other parvoviruses. In addition, terminal sialic acid was identified as the glycan potentially utilized by both CuV and TuV for cellular entry, with TuV showing additional recognition of poly-sialic acid and sialylated Lewis X (sLeXLeXLeX) motifs reported to be upregulated in neurotropic and cancer cells, respectively. These structures provide a platform for annotating the cellular interactions of these human pathogens

Can trained field community workers identify stroke using a stroke symptom questionnaire as well as neurologists? Adaptation and validation of a community worker administered stroke symptom questionnaire in a peri-urban Pakistani community.

Background: Stroke is a leading cause of morbidity and mortality worldwide. There is a paucity of data from South Asia where stroke is highly prevalent. Validated tools administrable by Community Health Workers (CHWs) are required to identify stroke in the community in a resource strapped region such as this. Methods: The study was conducted in a transitional slum in Karachi, Pakistan. Questionnaire for Verifying Stroke-Free Status (QVSFS) was adapted and translated into Urdu. Two CHWs, trained by a neurologist, selected 322 community dwelling subjects using purposive sampling. Each CHW collected data independently which was validated by a vascular neurologist who directly examined each participant. To assess the effect of audit and feedback, data from the final 10% of the subjects was collected following a second training session for the CHWs. Sensitivity, specificity and Cohen’s kappa was determined for the CHW administered questionnaire against neurovascular assessment. Results: Mean age of participants was 56.5 years with 71% of participants being women. The sensitivity and specificity of the questionnaire of detecting stroke was 77.1% (CI: 64.1%–86.9%) and 85.8% (CI: 83.5%–87.5%). The chance corrected agreement using the Cohen’s Kappa statistic was 0.51 (CI: 0.38–0.60). Kappa ranged from 0.37 to 0.58 for each of the seven stroke symptoms. Hemianesthesia (72.9%) and hemiplegia (64.6%) were the most sensitive symptoms. The performance and agreement improved from moderate to substantial after audit and feedback. Conclusion: We found a reasonable sensitivity and specificity and moderate agreement between CHW administered QVSFS and assessment by a vascular neurologist