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Sonstige beteiligte Institutionen
- Department of Hematology and Oncology, Sana Hospital Hof, Hof, Germany (1)
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- Department of Medicine A, University Hospital of Münster, Münster, Germany (1)
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- Interdisciplinary Center for Clinical Research (1)
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- University of Bari Medical School, Bari, Italy (1)
Bacterial meningitis is a serious life threatening infection of the CNS. To cause meningitis, blood–borne bacteria need to interact with and penetrate brain endothelial cells (BECs) that comprise the blood–brain barrier. BECs help maintain brain homeostasis and they possess an array of efflux transporters, such as P-glycoprotein (P-gp), that function to efflux potentially harmful compounds from the CNS back into the circulation. Oftentimes, efflux also serves to limit the brain uptake of therapeutic drugs, representing a major hurdle for CNS drug delivery. During meningitis, BEC barrier integrity is compromised; however, little is known about efflux transport perturbations during infection. Thus, understanding the impact of bacterial infection on P-gp function would be important for potential routes of therapeutic intervention. To this end, the meningeal bacterial pathogen, Streptococcus agalactiae, was found to inhibit P-gp activity in human induced pluripotent stem cell-derived BECs, and live bacteria were required for the observed inhibition. This observation was correlated to decreased P-gp expression both in vitro and during infection in vivo using a mouse model of bacterial meningitis. Given the impact of bacterial interactions on P-gp function, it will be important to incorporate these findings into analyses of drug delivery paradigms for bacterial infections of the CNS.
Objective
The aim of this study was to determine the prevalence of Neisseria meningitidis, Haemophilus influenzae, Streptococcus pneumoniae, group A Streptococcus (GAS), and Staphylococcus aureus in asymptomatic elderly people and to unravel risk factors leading to colonization.
Methods
A multi-centre cross-sectional study was conducted including 677 asymptomatic adults aged 65 years or more, living at home or in nursing homes. Study areas were Greater Aachen (North-Rhine-Westphalia) and Wuerzburg (Bavaria), both regions with medium to high population density. Nasal and oropharyngeal swabs as well as questionnaires were collected from October 2012 to May 2013. Statistical analysis included multiple logistic regression models.
Results
The carriage rate was 1.9% ([95%CI: 1.0–3.3%]; 13/677) for H. influenzae, 0.3% ([95%CI: 0–1.1%]; 2/677) for N. meningitidis and 0% ([95% CI: 0–0.5%]; 0/677) for S. pneumoniae and GAS. Staphylococcus aureus was harboured by 28.5% of the individuals ([95% CI: 25.1–32.1%]; 193/677) and 0.7% ([95% CI: 0.2–1.7%]; 5/677) were positive for methicillin-resistant S. aureus. Among elderly community-dwellers colonization with S. aureus was significantly associated with higher educational level (adjusted OR: 1.905 [95% CI: 1.248–2.908]; p = 0.003). Among nursing home residents colonization was associated with being married (adjusted OR: 3.367 [1.502–7.546]; p = 0.003).
Conclusion
The prevalence of N. meningitidis, H. influenzae, S. pneumoniae and GAS was low among older people in Germany. The S. aureus rate was expectedly high, while MRSA was found in less than 1% of the individuals.
Background
Immune checkpoint inhibition and in particular anti-PD-1 immunotherapy have revolutionized the treatment of advanced melanoma. In this regard, higher tumoral PD-L1 protein (gene name: CD274) expression is associated with better clinical response and increased survival to anti-PD-1 therapy. Moreover, there is increasing evidence that tumor suppressor proteins are involved in immune regulation and are capable of modulating the expression of immune checkpoint proteins. Here, we determined the role of p53 protein (gene name: TP53) in the regulation of PD-L1 expression in melanoma.
Methods
We analyzed publicly available mRNA and protein expression data from the cancer genome/proteome atlas and performed immunohistochemistry on tumors with known TP53 status. Constitutive and IFN-ɣ-induced PD-L1 expression upon p53 knockdown in wildtype, TP53-mutated or JAK2-overexpressing melanoma cells or in cells, in which p53 was rendered transcriptionally inactive by CRISPR/Cas9, was determined by immunoblot or flow cytometry. Similarly, PD-L1 expression was investigated after overexpression of a transcriptionally-impaired p53 (L22Q, W23S) in TP53-wt or a TP53-knockout melanoma cell line. Immunoblot was applied to analyze the IFN-ɣ signaling pathway.
Results
For TP53-mutated tumors, an increased CD274 mRNA expression and a higher frequency of PD-L1 positivity was observed. Interestingly, positive correlations of IFNG mRNA and PD-L1 protein in both TP53-wt and -mutated samples and of p53 and PD-L1 protein suggest a non-transcriptional mode of action of p53. Indeed, cell line experiments revealed a diminished IFN-ɣ-induced PD-L1 expression upon p53 knockdown in both wildtype and TP53-mutated melanoma cells, which was not the case when p53 wildtype protein was rendered transcriptionally inactive or by ectopic expression of p53\(^{L22Q,W23S}\), a transcriptionally-impaired variant, in TP53-wt cells. Accordingly, expression of p53\(^{L22Q,W23S}\) in a TP53-knockout melanoma cell line boosted IFN-ɣ-induced PD-L1 expression. The impaired PD-L1-inducibility after p53 knockdown was associated with a reduced JAK2 expression in the cells and was almost abrogated by JAK2 overexpression.
Conclusions
While having only a small impact on basal PD-L1 expression, both wildtype and mutated p53 play an important positive role for IFN-ɣ-induced PD-L1 expression in melanoma cells by supporting JAK2 expression. Future studies should address, whether p53 expression levels might influence response to anti-PD-1 immunotherapy.
Background
Early inflammatory processes may play an important role in the development of early brain injury (EBI) after subarachnoid hemorrhage (SAH). Experimental studies suggest that anti-inflammatory and membrane-stabilizing drugs might have beneficial effects, although the underlying mechanisms are not fully understood. The aim of this study was to investigate the effect of early treatment with methylprednisolone and minocycline on cerebral perfusion and EBI after experimental SAH.
Methods
Male Sprague-Dawley rats were subjected to SAH using the endovascular filament model. 30 minutes after SAH, they were randomly assigned to receive an intravenous injection of methylprednisolone (16mg/kg body weight, n=10), minocycline (45mg/kg body weight, n=10) or saline (n=11). Mean arterial blood pressure (MABP), intracranial pressure (ICP) and local cerebral blood flow (LCBF) over both hemispheres were recorded continuously for three hours following SAH. Neurological assessment was performed after 24 hours. Hippocampal damage was analyzed by immunohistochemical staining (caspase 3).
Results
Treatment with methylprednisolone or minocycline did not result in a significant improvement of MABP, ICP or LCBF. Animals of both treatment groups showed a non-significant trend to better neurological recovery compared to animals of the control group. Mortality was reduced and hippocampal damage significantly attenuated in both methylprednisolone and minocycline treated animals.
Conclusion
The results of this study suggest that inflammatory processes may play an important role in the pathophysiology of EBI after SAH. Early treatment with the anti-inflammatory drugs methylprednisolone or minocycline in the acute phase of SAH has the potential to reduce brain damage and exert a neuroprotective effect.
Models of eye-movement control distinguish between different control levels, ranging from automatic (bottom-up, stimulus-driven selection) and automatized (based on well-learned routines) to voluntary (top-down, goal-driven selection, e.g., based on instructions). However, one type of voluntary control has yet only been examined in the manual and not in the oculomotor domain, namely free-choice selection among arbitrary targets, that is, targets that are of equal interest from both a bottom-up and top-down processing perspective. Here, we ask which features of targets (identity- or location-related) are used to determine such oculomotor free-choice behavior. In two experiments, participants executed a saccade to one of four peripheral targets in three different choice conditions: unconstrained free choice, constrained free choice based on target identity (color), and constrained free choice based on target location. The analysis of choice frequencies revealed that unconstrained free-choice selection closely resembled constrained choice based on target location. The results suggest that free-choice oculomotor control is mainly guided by spatial (location-based) target characteristics. We explain these results by assuming that participants tend to avoid less parsimonious recoding of target-identity representations into spatial codes, the latter being a necessary prerequisite to configure oculomotor commands.
We analyze the processing of cereals and its role at Early Neolithic Göbekli Tepe, southeastern Anatolia (10th / 9th millennium BC), a site that has aroused much debate in archaeological discourse. To date, only zooarchaeological evidence has been discussed in regard to the subsistence of its builders. Göbekli Tepe consists of monumental round to oval buildings, erected in an earlier phase, and smaller rectangular buildings, built around them in a partially contemporaneous and later phase. The monumental buildings are best known as they were in the focus of research. They are around 20 m in diameter and have stone pillars that are up to 5.5 m high and often richly decorated. The rectangular buildings are smaller and–in some cases–have up to 2 m high, mostly undecorated, pillars. Especially striking is the number of tools related to food processing, including grinding slabs/bowls, handstones, pestles, and mortars, which have not been studied before. We analyzed more than 7000 artifacts for the present contribution. The high frequency of artifacts is unusual for contemporary sites in the region. Using an integrated approach of formal, experimental, and macro- / microscopical use-wear analyses we show that Neolithic people at Göbekli Tepe have produced standardized and efficient grinding tools, most of which have been used for the processing of cereals. Additional phytolith analysis confirms the massive presence of cereals at the site, filling the gap left by the weakly preserved charred macro-rests. The organization of work and food supply has always been a central question of research into Göbekli Tepe, as the construction and maintenance of the monumental architecture would have necessitated a considerable work force. Contextual analyses of the distribution of the elements of the grinding kit on site highlight a clear link between plant food preparation and the rectangular buildings and indicate clear delimitations of working areas for food production on the terraces the structures lie on, surrounding the circular buildings. There is evidence for extensive plant food processing and archaeozoological data hint at large-scale hunting of gazelle between midsummer and autumn. As no large storage facilities have been identified, we argue for a production of food for immediate use and interpret these seasonal peaks in activity at the site as evidence for the organization of large work feasts.
Spread and clinical severity of respiratory syncytial virus A genotype ON1 in Germany, 2011–2017
(2019)
Background
The Respiratory Syncytial Virus (RSV) A genotype ON1, which was first detected in Ontario (Canada) in 2010/11, appeared in Germany in 2011/12. Preliminary observations suggested a higher clinical severity in children infected with this new genotype. We investigated spread and disease severity of RSV-A ON1 in pediatric in- and outpatient settings.
Methods
During 2010/11 to 2016/17, clinical characteristics and respiratory samples from children with acute respiratory tract infections (RTI) were obtained from ongoing surveillance studies in 33 pediatric practices (PP), one pediatric hospital ward (PW) and 23 pediatric intensive care units (PICU) in Germany. RSV was detected in the respiratory samples by PCR; genotypes were identified by sequencing. Within each setting, clinical severity markers were compared between RSV-A ON1 and RSV-A non-ON1 genotypes.
Results
A total of 603 children with RSV-RTI were included (132 children in PP, 288 in PW, and 183 in PICU). Of these children, 341 (56.6%) were infected with RSV-A, 235 (39.0%) with RSV-B, and one child (0.2%) with both RSV-A and RSV-B; in 26 (4.3%) children, the subtype could not be identified. In the 341 RSV-A positive samples, genotype ON1 was detected in 247 (72.4%), NA1 in 92 (26.9%), and GA5 in 2 children (0.6%). RSV-A ON1, rarely observed in 2011/12, was the predominant RSV-A genotype in all settings by 2012/13 and remained predominant until 2016/17. Children in PP or PW infected with RSV-A ON1 did not show a more severe clinical course of disease compared with RSV-A non-ON1 infections. In the PICU group, hospital stay was one day longer (median 8 days, inter-quartile range (IQR) 7–12 vs. 7 days, IQR 5–9; p = 0.02) and duration of oxygen treatment two days longer (median 6 days, IQR 4–9 vs. 4 days, IQR 2–6; p = 0.03) for children infected with RSV-A ON1.
Conclusions
In children, RSV-A ON1 largely replaced RSV-A non-ON1 genotypes within two seasons and remained the predominant RSV-A genotype in Germany during subsequent seasons. A higher clinical severity of RSV-A ON1 was observed within the group of children receiving PICU treatment, whereas in other settings clinical severity of RSV-A ON1 and non-ON1 genotypes was largely similar.
Hibernoma is a rare benign lipomatous tumor showing differentiation of brown fatty tissue. To the author’s best knowledge, there is no known case of malignant transformation or metastasis. Due to their slow, noninfiltrating growth hibernomas are often an incidental finding in the third or fourth decade of life. The vast majority are located in the thigh, neck, and periscapular region. A diagnostic workup includes ultrasound and contrast-enhanced MRI. Differential diagnosis is benign lipoma, well-differentiated liposarcoma, and rhabdomyoma. An incisional biopsy followed by marginal resection of the tumor is the standard of care, and recurrence after complete resection is not reported. The current paper presents diagnostic and intraoperative findings of a hibernoma of the upper arm and reviews similar reports in the current literature.
A unique series of six biaryl natural products displaying four different coupling types (5,10 , 7,10 , 7,80 , and 5,80) were isolated from the roots of the West African liana Ancistrocladus abbreviatus (Ancistrocladaceae). Although at first sight structurally diverse, these secondary metabolites all have in common that they belong to the rare group of naphthylisoquinoline alkaloids with a fully dehydrogenated isoquinoline portion. Among the African Ancistrocladus species, A. abbreviatus is so far only the second one that was found to produce compounds with such a molecular entity. Here, we report on four new representatives, named ancistrobreveines A–D (12–14, and 6). They were identified along with the two known alkaloids 6-O-methylhamateine (4) and entdioncophylleine A (10). The two latter naphthylisoquinolines had so far only been detected in Ancistrocladus species from Southeast Asia. All of these fully dehydrogenated alkaloids have in common being optically active despite the absence of stereogenic centers, due to the presence of the rotationally hindered biaryl axis as the only element of chirality. Except for ent-dioncophylleine A (10), which lacks an oxygen function at C-6, the ancistrobreveines A–D (12–14, and 6) and 6-O-methylhamateine (4) are 6-oxygenated alkaloids, and are, thus, typical ‘Ancistrocladaceae-type’ compounds. Ancistrobreveine C (14), is the first – and so far only – example of a 7,80-linked fully dehydrogenated naphthylisoquinoline discovered in nature that is configurationally stable at the biaryl axis. The stereostructures of the new alkaloids were established by spectroscopic (in particular HRESIMS, 1D and 2D NMR) and chiroptical (electronic circular dichroism) methods. Ancistrobreveine C (14) and 6-O-methylhamateine (4) exhibited strong antiproliferative activities against drug-sensitive acute lymphoblastic CCRF-CEM leukemia cells and their multidrugresistant subline, CEM/ADR5000.
Background:
Flap reconstruction of the distal lower extremity is challenging. Especially, the concept of perforator surgery has increased available surgical options. Although results are generally judged in terms of objective facts, patients-perceived quality of life has largely remained unexamined. The aim of the study was to compare quality of life after lower extremity reconstruction with pedicled and free flaps.
Methods:
Patients were evaluated retrospectively after reconstruction of defects of the distal lower extremity either with distally based adipofascial sural flap (pedicled reverse sural flap) or an anterior lateral thigh (ALT) flap. A specific questionnaire was developed to measure the patient’s quality of life, based on short form health survey-12, Dresden Body Image Score-35, Patient Health Questionnaire-4, and XSMFA questionnaires with additional specific questions. Furthermore, results, secondary surgeries, and complications were analyzed.
Results:
Thirty-seven patients with reconstruction of lower limb defects treated with a pedicled reverse sural flap and 34 patients treated with an ALT flap were included in the study. There was no statistical significant difference in the overall satisfaction with the procedure in the long-term follow-up between both groups, but patients with ALT showed a higher satisfaction with the treatment in the initial postoperative period. Both groups demonstrated approximately similar results in the long term for self-acceptance and vitality.
Conclusions:
Although anatomic situation may dictate flap choice coverage with free flaps, a less-complicated flap is by no means regarded as an inferior treatment option in patient’s estimation. Despite the intuitive speculation that patients with more advanced reconstruction methods should have better function and subsequently higher quality of life, this assumption was clearly not supported by data in this study.