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Over the past two decades, our understanding of Parkinson's disease (PD) has been gleaned from the discoveries made in familial and/or sporadic forms of PD in the Caucasian population. The transferability and the clinical utility of genetic discoveries to other ethnically diverse populations are unknown. The Indian population has been under-represented in PD research. The Genetic Architecture of PD in India (GAP-India) project aims to develop one of the largest clinical/genomic bio-bank for PD in India. Specifically, GAP-India project aims to: (1) develop a pan-Indian deeply phenotyped clinical repository of Indian PD patients; (2) perform whole-genome sequencing in 500 PD samples to catalog Indian genetic variability and to develop an Indian PD map for the scientific community; (3) perform a genome-wide association study to identify novel loci for PD and (4) develop a user-friendly web-portal to disseminate results for the scientific community. Our “hub-spoke” model follows an integrative approach to develop a pan-Indian outreach to develop a comprehensive cohort for PD research in India. The alignment of standard operating procedures for recruiting patients and collecting biospecimens with international standards ensures harmonization of data/bio-specimen collection at the beginning and also ensures stringent quality control parameters for sample processing. Data sharing and protection policies follow the guidelines established by local and national authorities.We are currently in the recruitment phase targeting recruitment of 10,200 PD patients and 10,200 healthy volunteers by the end of 2020. GAP-India project after its completion will fill a critical gap that exists in PD research and will contribute a comprehensive genetic catalog of the Indian PD population to identify novel targets for PD.
Denervation-induced changes in excitatory synaptic strength were studied following entorhinal deafferentation of hippocampal granule cells in mature (≥3 weeks old) mouse organotypic entorhino-hippocampal slice cultures. Whole-cell patch-clamp recordings revealed an increase in excitatory synaptic strength in response to denervation during the first week after denervation. By the end of the second week synaptic strength had returned to baseline. Because these adaptations occurred in response to the loss of excitatory afferents, they appeared to be in line with a homeostatic adjustment of excitatory synaptic strength. To test whether denervation-induced changes in synaptic strength exploit similar mechanisms as homeostatic synaptic scaling following pharmacological activity blockade, we treated denervated cultures at 2 days post lesion for 2 days with tetrodotoxin. In these cultures, the effects of denervation and activity blockade were not additive, suggesting that similar mechanisms are involved. Finally, we investigated whether entorhinal denervation, which removes afferents from the distal dendrites of granule cells while leaving the associational afferents to the proximal dendrites of granule cells intact, results in a global or a local up-scaling of granule cell synapses. By using computational modeling and local electrical stimulations in Strontium (Sr2+)-containing bath solution, we found evidence for a lamina-specific increase in excitatory synaptic strength in the denervated outer molecular layer at 3–4 days post lesion. Taken together, our data show that entorhinal denervation results in homeostatic functional changes of excitatory postsynapses of denervated dentate granule cells in vitro.
Background: H5N1 influenza vaccines, including live intranasal, appear to be relatively less immunogenic compared to seasonal analogs. The main influenza virus surface glycoprotein hemagglutinin (HA) of highly pathogenic avian influenza viruses (HPAIV) was shown to be more susceptible to acidic pH treatment than that of human or low pathogenic avian influenza viruses. The acidification machinery of the human nasal passageway in response to different irritation factors starts to release protons acidifying the mucosal surface (down to pH of 5.2). We hypothesized that the sensitivity of H5 HA to the acidic environment might be the reason for the low infectivity and immunogenicity of intranasal H5N1 vaccines for mammals. Methodology/Principal Findings: We demonstrate that original human influenza viruses infect primary human nasal epithelial cells at acidic pH (down to 5.4), whereas H5N1 HPAIVs lose infectivity at pH <= 5.6. The HA of A/Vietnam/1203/04 was modified by introducing the single substitution HA2 58K -> I, decreasing the pH of the HA conformational change. The H5N1 reassortants containing the indicated mutation displayed an increased resistance to acidic pH and high temperature treatment compared to those lacking modification. The mutation ensured a higher viral uptake as shown by immunohistochemistry in the respiratory tract of mice and 25 times lower mouse infectious dose50. Moreover, the reassortants keeping 58K -> I mutation designed as a live attenuated vaccine candidate lacking an NS1 gene induced superior systemic and local antibody response after the intranasal immunization of mice. Conclusion/Significance: Our finding suggests that an efficient intranasal vaccination with a live attenuated H5N1 virus may require a certain level of pH and temperature stability of HA in order to achieve an optimal virus uptake by the nasal epithelial cells and induce a sufficient immune response. The pH of the activation of the H5 HA protein may play a substantial role in the infectivity of HPAIVs for mammals.
Meningioma surgery in patients ≥70 years of age: clinical outcome and validation of the SKALE score
(2021)
Along with increasing average life expectancy, the number of elderly meningioma patients has grown proportionally. Our aim was to evaluate whether these specific patients benefit from surgery and to investigate a previously published score for decision-making in meningioma patients (SKALE). Of 421 patients who underwent primary intracranial meningioma resection between 2009 and 2015, 71 patients were ≥70 years of age. We compared clinical data including World Health Organization (WHO) grade, MIB-1 proliferation index, Karnofsky Performance Status Scale (KPS), progression free survival (PFS) and mortality rate between elderly and all other meningioma patients. Preoperative SKALE scores (Sex, KPS, ASA score, location and edema) were determined for elderly patients. SKALE ≥8 was set for dichotomization to determine any association with outcome parameters. In 71 elderly patients (male/female 37/34) all data were available. Postoperative KPS was significantly lower in elderly patients (p < 0.0001). Pulmonary complications including pneumonia (10% vs. 3.2%; p = 0.0202) and pulmonary embolism (12.7% vs. 6%; p = 0.0209) occurred more frequently in our elderly cohort. Analyses of the Kaplan Meier curves revealed differences in three-month (5.6% vs. 0.3%; p = 0.0033), six-month (7% vs. 0.3%; p = 0.0006) and one-year mortality (8.5% vs. 0.3%; p < 0.0001) for elderly patients. Statistical analysis showed significant survival benefit in terms of one-year mortality for elderly patients with SKALE scores ≥8 (5.1 vs. 25%; p = 0.0479). According to our data, elderly meningioma patients face higher postoperative morbidity and mortality than younger patients. However, resection is reasonable for selected patients, particularly when reaching a SKALE score ≥ 8.
Debattieren wir in der Rechtsgeschichte zu wenig über Grundsätzliches und über Methodenfragen – oder lässt sich im Gegenteil eine gewisse Ermüdung feststellen, weil die Vielzahl übergreifender Diskussionen nur von der Quellenlektüre und der inhaltlichen Arbeit ablenkt? Die Antwort fällt schwer. Im Anschluss an einige Gespräche auf dem Rechtshistorikertag in Tübingen haben wir uns entschlossen, in Rechtsgeschichte – Legal History den Raum für genau diese Erörterung zur Verfügung zu stellen. Um die Debatte anzustoßen, haben wir den einleitenden Beitrag über Normengeschichte, Wissenschaftsgeschichte und Praxisgeschichte an knapp 30 Kolleginnen und Kollegen versandt und sie eingeladen, ihre Sicht der Dinge knapp und zugespitzt darzulegen. ...
Background: The focus of this study is to identify particular microRNA (miRNA) signatures in exosomes derived from plasma of 435 human epidermal growth factor receptor 2 (HER2)-positive and triple-negative (TN) subtypes of breast cancer (BC).
Methods: First, miRNA expression profiles were determined in exosomes derived from the plasma of 15 TNBC patients before neoadjuvant therapy using a quantitative TaqMan real-time PCR-based microRNA array card containing 384 different miRNAs. Forty-five miRNAs associated with different clinical parameters were then selected and mounted on microRNA array cards that served for the quantification of exosomal miRNAs in 435 BC patients before therapy and 20 healthy women. Confocal microscopy, Western blot, and ELISA were used for exosome characterization.
Results: Quantification of 45 exosomal miRNAs showed that compared with healthy women, 10 miRNAs in the entire cohort of BC patients, 13 in the subgroup of 211 HER2-positive BC, and 17 in the subgroup of 224 TNBC were significantly deregulated. Plasma levels of 18 exosomal miRNAs differed between HER2-positive and TNBC subtypes, and 9 miRNAs of them also differed from healthy women. Exosomal miRNAs were significantly associated with the clinicopathological and risk factors. In uni- and multivariate models, miR-155 (p = 0.002, p = 0.003, respectively) and miR-301 (p = 0.002, p = 0.001, respectively) best predicted pathological complete response (pCR).
Conclusion: Our findings show a network of deregulated exosomal miRNAs with specific expression patterns in exosomes of HER2-positive and TNBC patients that are also associated with clinicopathological parameters and pCR within each BC subtype.
Hereditary angioedema (HAE) in children and adolescents : a consensus on therapeutic strategies
(2012)
Hereditary angioedema due to C1 inhibitor (C1 esterase inhibitor) deficiency (types I and II HAE-C1-INH) is a rare disease that usually presents during childhood or adolescence with intermittent episodes of potentially life-threatening angioedema. Diagnosis as early as possible is important to avoid ineffective therapies and to properly treat swelling attacks. At a consensus meeting in June 2011, pediatricians and dermatologists from Germany, Austria, and Switzerland reviewed the currently available literature, including published international consensus recommendations for HAE therapy across all age groups. Published recommendations cannot be unconditionally adopted for pediatric patients in German-speaking countries given the current approval status of HAE drugs. This article provides an overview and discusses drugs available for HAE therapy, their approval status, and study results obtained in adult and pediatric patients. Recommendations for developing appropriate treatment strategies in the management of HAE in pediatric patients in German-speaking countries are provided.Conclusion Currently, plasma-derived C1 inhibitor concentrate is considered the best available option for the treatment of acute HAE-C1-INH attacks in pediatric patients in German-speaking countries, as well as for short-term and long-term prophylaxis.
Movement of organisms is one of the key mechanisms shaping biodiversity, e.g. the distribution of genes, individuals and species in space and time. Recent technological and conceptual advances have improved our ability to assess the causes and consequences of individual movement, and led to the emergence of the new field of ‘movement ecology’. Here, we outline how movement ecology can contribute to the broad field of biodiversity research, i.e. the study of processes and patterns of life among and across different scales, from genes to ecosystems, and we propose a conceptual framework linking these hitherto largely separated fields of research. Our framework builds on the concept of movement ecology for individuals, and demonstrates its importance for linking individual organismal movement with biodiversity. First, organismal movements can provide ‘mobile links’ between habitats or ecosystems, thereby connecting resources, genes, and processes among otherwise separate locations. Understanding these mobile links and their impact on biodiversity will be facilitated by movement ecology, because mobile links can be created by different modes of movement (i.e., foraging, dispersal, migration) that relate to different spatiotemporal scales and have differential effects on biodiversity. Second, organismal movements can also mediate coexistence in communities, through ‘equalizing’ and ‘stabilizing’ mechanisms. This novel integrated framework provides a conceptual starting point for a better understanding of biodiversity dynamics in light of individual movement and space-use behavior across spatiotemporal scales. By illustrating this framework with examples, we argue that the integration of movement ecology and biodiversity research will also enhance our ability to conserve diversity at the genetic, species, and ecosystem levels.
Response to upfront azacitidine in juvenile myelomonocytic leukemia in the AZA-JMML-001 trial
(2021)
Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative therapy for most children with juvenile myelomonocytic leukemia (JMML). Novel therapies controlling the disorder prior to HSCT are needed. We conducted a phase 2, multicenter, open-label study to evaluate the safety and antileukemic activity of azacitidine monotherapy prior to HSCT in newly diagnosed JMML patients. Eighteen patients enrolled from September 2015 to November 2017 were treated with azacitidine (75 mg/m2) administered IV once daily on days 1 to 7 of a 28-day cycle. The primary end point was the number of patients with clinical complete remission (cCR) or clinical partial remission (cPR) after 3 cycles of therapy. Pharmacokinetics, genome-wide DNA-methylation levels, and variant allele frequencies of leukemia-specific index mutations were also analyzed. Sixteen patients completed 3 cycles and 5 patients completed 6 cycles. After 3 cycles, 11 patients (61%) were in cPR and 7 (39%) had progressive disease. Six of 16 patients (38%) who needed platelet transfusions were transfusion-free after 3 cycles. All 7 patients with intermediate- or low-methylation signatures in genome-wide DNA-methylation studies achieved cPR. Seventeen patients received HSCT; 14 (82%) were leukemia-free at a median follow-up of 23.8 months (range, 7.0-39.3 months) after HSCT. Azacitidine was well tolerated and plasma concentration-–time profiles were similar to observed profiles in adults. In conclusion, azacitidine monotherapy is a suitable option for children with newly diagnosed JMML. Although long-term safety and efficacy remain to be fully elucidated in this population, these data demonstrate that azacitidine provides valuable clinical benefit to JMML patients prior to HSCT. This trial was registered at www.clinicaltrials.gov as #NCT02447666.
Extensive black shale deposits formed in the Early Cretaceous South Atlantic, supporting the notion that this emerging ocean basin was a globally important site of organic carbon burial. The magnitude of organic carbon burial in marine basins is known to be controlled by various tectonic, oceanographic, hydrological, and climatic processes acting on different temporal and spatial scales, the nature and relative importance of which are poorly understood for the young South Atlantic. Here we present new bulk and molecular geochemical data from an Aptian–Albian sediment record recovered from the deep Cape Basin at Deep Sea Drilling Project (DSDP) Site 361, which we combine with general circulation model results to identify driving mechanisms of organic carbon burial. A multimillion-year decrease (i.e., Early Aptian–Albian) in organic carbon burial, reflected in a lithological succession of black shale, gray shale, and red beds, was caused by increasing bottom water oxygenation due to abating hydrographic restriction via South Atlantic–Southern Ocean gateways. These results emphasize basin evolution and ocean gateway development as a decisive primary control on enhanced organic carbon preservation in the Cape Basin at geological timescales (> 1 Myr). The Early Aptian black shale sequence comprises alternations of shales with high (> 6 %) and relatively low (∼ 3.5 %) organic carbon content of marine sources, the former being deposited during the global Oceanic Anoxic Event (OAE) 1a, as well as during repetitive intervals before and after OAE 1a. In all cases, these short-term intervals of enhanced organic carbon burial coincided with strong influxes of sediments derived from the proximal African continent, indicating closely coupled climate–land–ocean interactions. Supported by our model results, we show that fluctuations in weathering-derived nutrient input from the southern African continent, linked to changes in orbitally driven humidity and aridity, were the underlying drivers of repetitive episodes of enhanced organic carbon burial in the deep Cape Basin. These results suggest that deep marine environments of emerging ocean basins responded sensitively and directly to short-term fluctuations in riverine nutrient fluxes. We explain this relationship using the lack of wide and mature continental shelf seas that could have acted as a barrier or filter for nutrient transfer from the continent into the deep ocean.