Lattice zonotopes of degree 2

The Ehrhart polynomial $ehr_P (n)$ of a lattice polytope $P$ gives the number of integer lattice points in the $n$-th dilate of $P$ for all integers $n\geq 0$. The degree of $P$ is defined as the degree of its $h^\ast$-polynomial, a particular transformation of the Ehrhart polynomial with many useful properties which serves as an important tool for classification questions in Ehrhart theory. A zonotope is the Minkowski (pointwise) sum of line segments. We classify all Ehrhart polynomials of lattice zonotopes of degree $2$ thereby complementing results of Scott (1976), Treutlein (2010), and Henk-Tagami (2009). Our proof is constructive: by considering solid-angles and the lattice width, we provide a characterization of all $3$-dimensional zonotopes of degree $2$.Comment: 12 pages, 1 figure; v2: minor revision

Einfluss der Lungenfunktion auf die gesundheitsbezogene Lebensqualität bei langzeitüberlebenden Patienten nach akutem Lungenversagen (ARDS)

In der vorliegenden Arbeit wurde eine Querschnittsanalyse der Lungenfunktion und der gesundheitsbezogenen Lebensqualität bei insgesamt 50 Langzeitüberlebenden nach ARDS untersucht (im Median 5,5 Jahre nach Extubation). Das untersuchte Patientenkollektiv rekrutierte sich aus einer 1995 retrospektiv identifizierten Kohorte von 80 ehemaligen ARDS-Patienten, die zwischen Januar 1985 und Januar 1995 an der Klinik für Anaesthesiologie der Ludwig-Maximilians-Universität München behandelt wurden. Anhand der erhobenen Daten konnte gezeigt werden: 1. Bei der Mehrzahl der ehemaligen ARDS-Patienten persistieren pathologische Lungenfunktionswerte auch noch nach Jahren, wobei sich als häufigste Störung eine Reduktion des exspiratorischen Flows im Sinne einer während des ARDS erworbenen „small airway disease“ bei 32 % aller Patienten zeigte. 2. Es konnte zwischen Schwere der initialen Lungenschädigung und dem späteren Grad der Einschränkung der Lungenfunktion keine direkte Beziehung nachgewiesen werden. 3. Es besteht ein signifikanter Zusammenhang zwischen gesundheitsbezogener Lebensqualität und Zahl der eingeschränkten Lungenfunktionsparameter. 4. Bei den meisten Patienten war die gesundheitsbezogene Lebensqualität in allen Bereichen des SF-36-Scores im Vergleich zu einer alters- und geschlechtsspezifisch identischen Kontrollgruppe reduziert. Hierbei war die größte Reduktion im Bereich der auf somatischer Ebene erfassten Kategorien festzustellen, eine geringere Reduktion zeigte sich bei psychosozialen Kategorien. Erkennbar war durch Heranziehung des SF-36-Scores der Voruntersuchung ein signifikanter Trend der Besserung bei beiden Komplexen im Langzeitverlauf. 5. Lediglich bezüglich der Diffusionskapazität DLCO besteht eine positive Korrelation zwischen Normalisierung dieses Parameters der Lungenfunktion und der gleichzeitigen Verbesserung der HRQL. 6. Leichte somatische und psychosoziale Einschränkungen bei Langzeitüberlebenden nach ARDS sind häufig nach Jahren noch nachweisbar und vermutlich von bleibender Natur. 7. Der Großteil der Patienten erreicht wieder eine generelle körperliche Erholung, einen ausreichenden HRQL- Wert und war wieder in der Lage einer Erwerbstätigkeit nachzugehen. 8. Patienten, die multiple Einschränkungen ihrer Lungenfunktion nach ARDS aufweisen, sind gefährdet eine dauerhafte, schwere Beeinträchtigung ihrer körperlichen und geistigen gesundheitsbezogenen Lebensqualität zu erleiden und benötigen daher eine gründliche körperliche und psychologische Evaluierung

Solidarity for all? Europe's unequal treatment of refugees

The willingness of European states and societies to welcome refugees varies, and not only due to differences between the host countries. Developments since the Spring 2022 escalation of the war in Ukraine reveal that the origin of refugees also influences what kind of help they can expect to receive. In liberal societies, solidarities that are guided by perceived similarity are in need of corrective measures. This is the only way to fulfil the universalist claim of refugee law, which applies to everyone affected by war and persecution

Drug-induced endocrine blood pressure elevation

Patients with uncontrolled hypertension are at risk for cardiovascular complications. The majority of them suffers from unidentified forms of hypertension and a fraction has so-called secondary hypertension with an identifiable cause. The patient's medications, its use of certain herbal supplements and over-the-counter agents represent potential causal factors for secondary hypertension that are often overlooked. The current review focuses on drugs that are likely to elevate blood pressure by affecting the human endocrine system at the level of steroid synthesis or metabolism, mineralocorticoid receptor activity, or by affecting the catecholaminergic system. Drugs with known adverse effects but where benefits outweigh their risks, drug candidates and market withdrawals are reviewed. Finally, potential therapeutic strategies are discussed

Small molecule-protein interactions exemplified on short-chain dehydrogenases/reductases

The short-chain dehydrogenase/reductase (SDRs) family represents one of the largest enzyme superfamilies, with over 80 members in the human genome. Even though the human genome project has sequenced and mapped the entire human genome, the physiological functions of more than 70% of all SDRs are currently unexplored or insufficiently characterized. To start to fill this gap, the present thesis aimed to employ a combination of molecular modeling approaches and biological assessments for the identification and characterization of novel inhibitors and/or potential substrates of different SDRs. Due to their involvement in steroid biosynthesis and metabolism, SDRs are potential targets of endocrine disrupting chemicals (EDCs). To test the use of pharmacophore-based virtual screening (VS) applications and subsequent in vitro evaluation of virtual hits for the identification and characterization of potential inhibitors, 11β-hydroxysteroid dehydrogenase 2 (11β-HSD2) was selected as an example. 11β-HSD2 has an important role in the placenta by inactivating cortisol and protecting the fetus from high maternal glucocorticoid levels. An impaired placental 11β-HSD2 function has been associated with altered fetal growth and angiogenesis as well as a higher risk for cardio-metabolic diseases in later life. Despite this vital function, 11β-HSD2 is not covered in common off-target screening approaches. Several azole fungicides were identified as 11β-HSD inhibitors amongst approved drugs by testing selected virtually retrieved hits for inhibition of cortisol to cortisone conversion in cell lysates expressing recombinant human 11β-HSD2. Moreover, a significant structure-activity relationship between azole scaffold size, 11β-HSD enzyme selectivity and potency was observed. The most potent 11β-HSD2 inhibition was obtained for itraconazole (IC50 139 ± 14 nM), for its active metabolite hydroxyitraconazole (IC50 223 ± 31 nM), and for posaconazole (IC50 460 ± 98 nM). Interestingly, substantially lower inhibitory 11β-HSD2 activity of these compounds was detected using mouse and rat kidney homogenate preparations, indicating species-specific differences. Impaired placental 11β-HSD2 function exerted by these compounds might, in addition to the known inhibition of P-glycoprotein efflux transport and cytochrome P450 enzymes, lead to locally elevated cortisol levels and thereby could affect fetal programming. Successful employment of pharmacophore-based VS applications requires suitable and reliable in vitro validation strategies. Therefore, the following study addressed the re-evaluation of a potential EDC, the widely used flame retardant tetrabromobisphenol A (TBBPA), on glucocorticoid receptor (GR) and androgen receptor (AR) function. TBBPA was reported earlier in yeast-based reporter assays to potently interfere with GR and moderately with AR function. Human HEK-293 cell-based reporter assays and cell-free receptor binding assays did not show any activity of TBBPA on GR function, which was supported by molecular docking calculations. The antiandrogenic effect, however, could be confirmed, although less pronounced than in the HEK-293 cell system. Nevertheless, the evaluation of the relevant concentrations of an EDC found in the human body is crucial for an appropriate safety assessment. Considering the rapid metabolism of TBBPA and the low concentrations observed in the human body, it is questionable whether relevant concentrations can be reached to cause harmful effects. Thus, it is vital to take the limitations of each testing system including the distinct sensitivities and specificities into account to avoid false positive or false negative results. To extend the applications of in silico tools with demonstrated proof-of-concept, they were further employed to investigate novel substrate specificities for three different SDR members: the two multi-functional enzymes, 11β-HSD1 and carbonyl reductase (CBR) 1 as well as the orphan enzyme DHRS7. A role for 11β-HSD1 in oxysterol metabolism by metabolizing 7-ketocholesterol (7kC) has already been described. However, in contrast to the known receptors for 7α,25-dihydroxycholesterol (7α25OHC), i.e. Epstein-Barr virus-induced gene 2 (EBI2), or 7β,27-dihydroxycholesterol (7β27OHC), i.e. retinoic acid related orphan receptor (ROR)γ, no endogenous receptor has been identified so far for 7kC or its metabolite 7β-hydroxycholesterol. To explore the underlying biosynthetic pathways of such dihydroxylated oxysterols, the role of 11β-HSD1 in the generation of dihydroxylated oxysterols was investigated. For the first time, the stereospecific and seemingly irreversible oxoreduction of 7-keto,25-hydroxycholesterol (7k25OHC) and 7-keto,27-hydroxycholesterol (7k27OHC) to their corresponding 7β-hydroxylated metabolites 7β25OHC and 7β27OHC by recombinant human 11β-HSD1 could be demonstrated in vitro in intact HEK-293 cells. Furthermore, 7k25OHC and 7k27OHC were found to be potently inhibited the 11β-HSD1-dependent oxoreduction of cortisone to cortisol. Molecular modeling experiments confirmed these results and suggested competition of 7k25OHC and 7k27OHC with cortisone in the enzyme binding pocket. For a more detailed enzyme characterization, 11β-HSD1 pharmacophore models were generated and employed for VS of the human metabolome database and the lipidmaps structure database. The VS yielded several hundred virtual hits, including the successful filtering of known substrates such as endogenous 11-ketoglucocorticoids, synthetic glucocorticoids, 7kC, and several bile acids known to inhibit the enzyme. Further hits comprised several eicosanoids including prostaglandins, leukotrienes, cyclopentenone isoprostanes, levuglandins or hydroxyeicosatetraenoic acids (HETEs) and compounds of the kynurenine pathway. The important role of these compounds as well as 11β-HSD1 in inflammation emphasizes a potential association. However, further biological validation is of utmost necessity to explore a potential link. The closest relative of 11β-HSD1 is the orphan enzyme DHRS7, which has been suggested to act as tumor suppressor. Among others, cortisone and 5α-dihydrotestosterone have been identified as substrates of DHRS7, although effects in functional assays could only be observed at high concentrations that may not be of physiological relevance. Hence, the existence of other yet unexplored substrates of DHRS7 can be assumed, and the generation of homology models to study the structural features of the substrate binding site of DHRS7 was employed. The predictivity of the constructed models is currently limited, due to a highly variable region comprising a part of the ligand binding site but particularly the entry of the binding pocket, and requires further optimizations. Nevertheless, the models generally displayed a cone-shaped binding site with a rather hydrophobic core. This may suggest larger metabolites to be converted by DHRS7. Moreover, the flexible loops surrounding the binding pocket may lead to the induction of an induced fit upon ligand binding. However, further studies are crucial to confirm these findings. CBR1 is well-known for its role in phase I metabolism of a variety of carbonyl containing xenobiotic compounds. Several endogenous substrates of CBR1 have been reported such as prostaglandins, S-nitrosoglutathione or lipid aldehydes. The physiological relevance of these endogenous substrates, however, is not fully understood. Thus, the physiological roles of CBR1 was further explored by identifying a novel function for CBR1 in the metabolism glucocorticoids. CBR1 was found to catalyze the conversion of cortisol into 20β-dihydrocortisol (20β-DHF), which was in turn detected as the major route of cortisol metabolism in horses and elevated in adipose tissue derived from obese horses, humans and mice. Additionally, 20β-DHF was demonstrated as weak endogenous agonist of the GR, suggesting a novel pathway to modulate GR activation by CBR1-depenent protection against excessive GR activation in obesity. In conclusion, this thesis emphasized the employment of molecular modeling approaches as an initial filter to identify toxicological relevant compound classes for the identification of potential EDCs and, moreover, as valuable tools to identify novel substrates of multifunctional SDRs and to unravel novel functions for the large majority of yet unexplored orphan SDR members, while carefully considering the limitations of this strategy

Heat adaptation measures in private households: an application and adaptation of the protective action decision model

Extreme heatwaves will occur more frequently and with higher intensity in future. Their consequences for human health can be fatal if adaptation measures will not be taken. This study analyses factors related to heat adaptation measures in private households in Germany. During the summer months of 2019, indoor temperatures were measured in over 500 private households in the City of Augsburg, Germany, accompanied by a survey to find out about heat perception and adaptation measures. Hypotheses deducted from the Protective Action Decision Model were tested using one-way ANOVAs, regression analysis and in the end a multiple hierarchical regression model. The results of the hypotheses tested imply an influence of knowledge and heat risk perception of heat adaptation behaviour and an influence of age on heat risk perception. The results of the regression model show an influence of the efficacy-related attribute, of age, indoor temperature, subjective heat stress and health implications to heat adaptation behaviour. In the end, this study proposes adjustments to the PADM according to the results of the hierarchical regression analysis

Posaconazole-Induced Hypertension Due to Inhibition of 11β-Hydroxylase and 11β-Hydroxysteroid Dehydrogenase 2

We describe two cases of hypertension and hypokalemia due to mineralocorticoid excess caused by posaconazole treatment of coccidioidomycosis and rhinocerebral mucormycosis infections, respectively. Clinical laboratory evaluations, including a comprehensive analysis of blood and urine steroid profiles, revealed low renin and aldosterone and indicated as the underlying mechanism primarily a block of 11β-hydroxylase activity in patient 1, whereas patient 2 displayed weaker 11β-hydroxylase but more pronounced 11β-hydroxysteroid dehydrogenase 2 inhibition. The results show that both previously suggested mechanisms must be considered and emphasize significant interindividual differences in the contribution of each enzyme to the observed mineralocorticoid excess phenotype. The mineralocorticoid symptoms of patient 1 resolved after replacement of posaconazole therapy by isavoconazole, and posaconazole dosage de-escalation ameliorated the effects in patient 2. By providing a thorough analysis of the patients' blood and urine steroid metabolites, this report adds further evidence for two individually pronounced mechanisms of posaconazole-induced hypertension and hypokalemia. The elucidation of the factors responsible for the individual phenotype warrants further research

Smooth Centrally Symmetric Polytopes in Dimension 3 are IDP

In 1997 Oda conjectured that every smooth lattice polytope has the integer decomposition property. We prove Oda’s conjecture for centrally symmetric 3-dimensional polytopes, by showing they are covered by lattice parallelepipeds and unimodular simplices