[Interdisciplinary COVID board for patients with SARS-CoV-2-triggered hyperferritinemic Inflammation]. / Interdisziplinäres COVID-Board bei SARS-CoV-2-getriggerter hyperferritinämischer Inflammation.

BACKGROUND: Patients with severe COVID-19 develop hyperferritinemic inflammation, a rare sepsis-like immune dysregulation syndrome. METHODS: Stratified treatment decisions in a cross-location telemedical interdisciplinary case conference were assessed in this retrospective cohort study. A standardized treatment algorithm including continuous positive airway pressure and noninvasive ventilation was implemented. A locally developed COVID inflammation score (CIS) defined patients at risk for severe disease. Patients with life-threatening inflammation were offered off-label treatment with the immune modulator ruxolitinib. RESULTS: Between 4 March 2020 and 26 June 2020 COVID-19 patients (n = 196) were treated. Median patient age (70 years) and comorbidity were high in interstudy comparison. Mortality in all patients was 17.3%. However, advance care planning statements and physician directives limited treatment intensity in 50% of the deceased patients. CIS monitoring of ruxolitinib-treated high-risk patients (n = 20) on days 5, 7, and15 resulted in suppression of inflammation by 42% (15-70), 54% (15-77) and 60% (15-80). Here, mortality was 20% (4/20). Adjusted for patients with a maximum care directive including ICU, total mortality was 8.7% (17/196). CONCLUSION: Severe COVID-19 pneumonia with hyperferritinemic inflammation is related to macrophage activation syndrome-like sepsis. An interdisciplinary intensive care teleconference as a quality tool for ICUs is proposed to detect patients with rare sepsis-like syndromes.

The Janus kinase 1/2 inhibitor ruxolitinib in COVID-19 with severe systemic hyperinflammation.

A subgroup of patients with severe COVID-19 suffers from progression to acute respiratory distress syndrome and multiorgan failure. These patients present with progressive hyperinflammation governed by proinflammatory cytokines. An interdisciplinary COVID-19 work flow was established to detect patients with imminent or full blown hyperinflammation. Using a newly developed COVID-19 Inflammation Score (CIS), patients were prospectively stratified for targeted inhibition of cytokine signalling by the Janus Kinase 1/2 inhibitor ruxolitinib (Rux). Patients were treated with efficacy/toxicity guided step up dosing up to 14 days. Retrospective analysis of CIS reduction and clinical outcome was performed. Out of 105 patients treated between March 30th and April 15th, 2020, 14 patients with a CIS ≥ 10 out of 16 points received Rux over a median of 9 days with a median cumulative dose of 135 mg. A total of 12/14 patients achieved significant reduction of CIS by ≥25% on day 7 with sustained clinical improvement in 11/14 patients without short term red flag warnings of Rux-induced toxicity. Rux treatment for COVID-19 in patients with hyperinflammation is shown to be safe with signals of efficacy in this pilot case series for CRS-intervention to prevent or overcome multiorgan failure. A multicenter phase-II clinical trial has been initiated (NCT04338958).

Prevalence of Risk Factors for the Refeeding Syndrome in Older Hospitalized Patients.

OBJECTIVES: The incidence of refeeding syndrome (RFS) in older patients is not well-known. The aim of the study was to determine the prevalence of known risk factors for RFS in older individuals during hospitalization at geriatric hospital departments. DESIGN AND SETTING: 342 consecutive older participants (222 females) who admitted at acute geriatric hospital wards were included in a cross-sectional study. We applied the National Institute for Health and Clinical Excellence (NICE) criteria for determining patients at risk of RFS. In addition, Mini Nutritional Assessment Short Form (MNA®-SF) was used to identify patients at risk of malnutrition. Weight and height were assessed. The degree of weight loss was obtained by interview. Serum phosphate, magnesium, potassium, sodium, calcium, creatinine and urea were analyzed according to standard procedures. RESULTS: Of 342 older participants included in the study (mean age 83.1 ± 6.8, BMI range of 14.7-43.6 kg/m2), 239 (69.9%) were considered to be at risk of RFS, in which 43.5% and 11.7% were at risk of malnutrition and malnourished, respectively, according to MNA-SF. Patients in the risk group had significantly higher weight loss, lower phosphate and magnesium levels. In a multivariate logistic regression analysis, low levels of phosphate and magnesium followed by weight loss were the major risk factors for fulfilling the NICE criteria. CONCLUSION: The incidence of risk factors for RFS was relatively high in older individuals acutely admitted in geriatric hospital units, suggesting that, RFS maybe more frequent among older persons than we are aware of. Patients with low serum levels of phosphate and magnesium and higher weight loss are at increased risk of RFS. The clinical characteristics of the older participants at risk of RFS indicate that these patients had a relatively poor nutritional status which can help us better understand the potential scale of RFS on admission or during the hospital stay.

Compostos fenólicos da casca de Handroanthus heptaphyllus (Mart. ) Mattos e efeitos do extrato aquoso no perfil lipídico, glicêmico e na lipoperoxidação em ratos diabéticos / Phenolic compounds from Handroanthus heptaphyllus (Mart. ) Mattos bark and effects of aqueous extract on lipid profile, glucose, and lipid peroxidation in diabetic rats

RESUMO A preocupação com o tratamento do Diabetes mellitus (DM) leva a uma crescente busca por terapias alternativas, como o uso de plantas medicinais, entre as quais, destaca-se o uso de Handroanthus heptaphyllus (Mart.) Mattos (popular Ipê roxo). Neste estudo realizamos a investigação química da presença de compostos fenólicos em H. heptaphyllus e o efeito do tratamento com o extrato aquoso da casca desta planta em parâmetros bioquímicos e nos níveis de lipoperoxidação tecidual e plasmática em animais diabéticos. Metodologia: Ratos Wistar machos foram submetidos ao desenvolvimento do quadro de DM por meio da administração intraperitoneal (IP) de Aloxano monohidrato (150 mg/Kg IP). Após a confirmação de hiperglicemia (>200 mg dL-1), os animais foram distribuídos nos grupos Diabético (D; n=6) e Diabético Tratado (DT; n=6). O tratamento consistiu na administração diária do extrato aquoso da casca de H. heptaphyllus via oral (v.o.) (150mg/Kg v.o.) por quatro semanas. O extrato aquoso foi analisado qualitativamente por cromatografia de camada delgada. Resultados: A análise qualitativa do extrato aquoso da casca indicou a presença de compostos fenólicos da subclasse flavonoides. O tratamento com o extrato aquoso reduziu a glicemia de jejum a partir da 3ª semana de tratamento, melhorou a resposta glicêmica à sobrecarga de glicose, diminuiu os níveis de triglicerídeos e índice LDL (Triglicerídeos/HDL). Estes resultados sugerem o uso terapêutico do extrato aquoso das cascas de H. heptaphyllus no tratamento do DM.

ABSTRACT Alternative medicine for diabetes mellitus (DM) treatment represents a growing research area on the use of medicinal plants, of which Handroanthus heptaphyllus (mart.) Mattos (popularly known as purple ipe) is most prominent. In this study, we investigated the presence of phenolic compounds and the effects of treatment with aqueous extract of in H. heptaphyllus in biochemical profile in plasma and the levels of lipid peroxidation in tissues and plasma in diabetic animals. Male Wistar rats were induced to develop DM through intraperitoneal (IP) administration of alloxan monohydrate (150 mg/kg IP). Once hyperglycemia (>200 mg dL-1) was confirmed, the animals were divided into the Diabetic (D; n=6) and Treated Diabetic (TD; n=6) groups. The TD group received daily administration (150 mg/kg v.o.) of aqueous extract of H. heptaphyllus for four weeks. The aqueous extract was also analyzed qualitatively by layer chromatography. Qualitative analysis of the aqueous extract of the bark indicated the presence of phenolic compounds from the flavonoid subclass. The treatment with the aqueous extract reduced fasting blood glucose levels from the third week of treatment on, improved the glycemic response to the glucose tolerance test, and lowered the levels of triglycerides and the LDL index (triglycerides/HDL). These findings suggest therapeutic use of the aqueous extract of H. heptaphyllus bark in treating DM.

Development of nanocomposite membranes with photocatalytic surfaces.

In 2030, 47% of the world population will be living in areas of high water stress (UN World Water Development Report 3, 2009). The global water shortage results in an emerging need for novel, more efficient and cost saving water purification methods. Membrane technology with its very low use of chemical substances and secure retention of contaminants represents a promising water cleaning method. The approach presented focuses on the application of nanocoating procedures to membrane processes which aims at reducing the fouling potential of membranes and destroying water contaminants. Photocatalytic titanium dioxide nanoparticles are applied. Novel suitable microsieves including a homogeneous pore size distribution and high robustness were developed from metallic material. An appropriate multilayer coating system was developed and applied on a new nanocomposite filter resulting in high photocatalytic activities with maximum photon efficiencies of 0.0733. The coating layer do not have a negative influence on the permeate flux. The effectiveness of the nanocomposite filter was proven in a 12 days biofouling experiment with activated sludge suspensions.

Wnt/ß-catenin/LEF-1 signaling in chronic lymphocytic leukemia (CLL): a target for current and potential therapeutic options.

There is a growing body of evidence that Wnt signaling, which is already known to play a critical role in various types of cancer, also has a vital function in B cell neoplasias, particularly in chronic lymphocytic leukemia (CLL). It is known that Wnt proteins are overexpressed in primary CLL cells and several physiological inhibitors are partly inactivated in this disease. Furthermore, ß-catenin is upregulated upon Wnt stimulation and cooperates with the transcription factor lymphoid enhancer binding factor-1 (LEF-1). LEF-1 is excessively overexpressed in CLL cells by more than 3,000-fold compared to normal B cells. Moreover, LEF-1 could be identified as an important regulator of pathophysiologically relevant genes in CLL, and several Wnt/ß-catenin signaling components substantially influence CLL cell survival. In this review we summarize the current state of knowledge about Wnt/ß-catenin/LEF-1 signaling in CLL. Following a short overview of current treatment concepts in CLL, we briefly describe Wnt signaling in human cancers. We then discuss recent progress in understanding regulation of the Wnt/ß-catenin/LEF-1 signaling pathway in this disease. Based on the present scientific evidence we highlight which components of this important signaling pathway could serve as therapeutic targets in CLL. We then present previous results gained from experimental approaches to target different parts of the Wnt/ß-catenin/LEF-1 cascade. Together with potentially promising approaches we also critically reflect on the kind of difficulties and problems that may arise using such strategies.

Meso-portal bypass in children with portal vein thrombosis: rapid increase of the intrahepatic portal venous flow after direct portal hepatic reperfusion.

BACKGROUND/PURPOSE: In children with portal vein (PV) thrombosis, hepatopetal portal flow can be restored by an innovative surgical procedure, the meso-portal-bypass (MPB), if the umbilical portion of the intrahepatic left PV and the superior mesenteric vein are patent. This is associated with resolution of symptoms related to extrahepatic portal hypertension (EHPH). However, no data are available yet on intrahepatic hemodynamic changes after MPB. The aim of this study was to evaluate morphologic adaptation and flow characteristics of the intrahepatic PV branches (ihPVb) after MPB. METHODS: Prospective follow-up Doppler scans of the ihPVb were performed at 0.5 to 1, 3 to 6 and 12 months after MPB in 13 consecutive patients (2000-2002) and compared with preoperative findings. RESULTS: Only small ihPVb were detected preoperatively on Doppler in 8 of 13 cases. Postoperatively (median follow up 12; range, 6 to 24 months), all 13 patients had patent MPB with hepatopetal flow, and ihPVb were easy to detect with satisfactory vessel diameters and flow velocities. CONCLUSIONS: The preoperatively small ihPVb increase rapidly in diameter and hepatopetal flow velocity in patients benefiting from MPB. This correlates well with progressive resolution of their symptoms related to EHPH and reflects rapid adaptation of ihPVb.

Biliary atresia--bile acids and prostaglandin E2 in cell cultures of bile duct epithelia.

In a cell culture model of bile duct epithelial cells, the effect of prostaglandin E2, lithocholic acid and deoxycholic acid was studied. Bile acids and prostaglandin are administered postoperatively in biliary atresia empirically as choleretics. Prostaglandin E2 and the bile acids all had inhibitory effects on bile duct epithelial cells in culture. There is no clinical study proving the efficacy of either bile acids or prostaglandin E2 in biliary atresia. The negative results with these substances in cell cultures warrants reserve in their routine clinical use in biliary atresia.

Is the bronchus-associated lymphoid tissue (BALT) an integral structure of the lung in normal mammals, including humans?

In the respiratory tract, lymphoid aggregates with a specialized epithelium have been called bronchus-associated lymphoid tissue (BALT) and compared to the organized lymphoid tissue of the gut (GALT), e.g., Peyer's patches. BALT might play a central role in antigen uptake, initiating immune responses and disseminating primed lymphoid cells in the respiratory tract. In the present study, lungs of mice, rats, guinea pigs, rabbits, pigs, cats, and humans have been studied with respect to the presence and number of BALT and the dependence of BALT on age and microbial stimulation. BALT is not a constitutive structure in all these species. Its frequency varies widely, from 100% in rabbits and rats, 50% in guinea pigs, 33% in pigs, to its absence in cats and all normal human lungs. BALT seems to be a lymphoid structure which is not present in all the species studied but can develop in the lung after stimulation. This is in contrast to lymphoid organs, such as lymph nodes or Peyer's patches, which can always be found. These species differences are of major importance in interpreting the clinical relevance of experiments in animal models on the lung immune system, e.g., antigen uptake, immunostimulation, or lung transplantation.

The epithelium overlying rabbit bronchus-associated lymphoid tissue does not express the secretory component of immunoglobulin A.

The epithelium associated with lymphoid aggregates in the bronchial tract (BALT) was studied in rabbits by immunohistochemistry using monoclonal antibodies against the secretory component (SC) of IgA. The normal bronchus epithelium was intensely labelled. In contrast, epithelium overlying the central parts of the follicles was negative. This specialized epithelium cannot participate in the SC-mediated transport of IgA, which might be a basis for the adherence and transport of microorganisms into the lymphoid tissue, thus initiating immune responses of the BALT.

[Bronchoalveolar lavage in the pig--comparison of normal, pathogen-free and pneumonic animals]. / Die bronchoalveoläre Lavage (BAL) beim Schwein--Vergleich normaler, keimfreier und pneumonischer Tiere.

The cells found in the BAL fluid of the pig were characterised morphologically and immunocytologically with monoclonal antibodies. The percentage of macrophages was found to be 80%, and that of lymphocytes, 20%. Granulocytes are characteristic when pneumonia is presenting. B-cells are rarely observed in germ-free animals, account for 5-8% in the normal animal, and are elevated in pneumonia. The percentage of T-helper cells is not changed by germ-free breeding or in the presence of pneumonia. In germ-free animals, the percentage of T-suppressor cells is reduced, but remains unchanged in pneumonia.

Cell composition and lymphocyte subsets in the bronchoalveolar lavage of normal pigs of different ages in comparison with germfree and pneumonic pigs.

For studies of lymphocyte kinetics in the different compartments of the lung, basic data on the cellular composition and lymphocyte subsets of porcine bronchoalveolar lavage (BAL) are essential. Therefore BAL was performed in pigs, and cytologic findings were studied using cytologic staining, enzyme cytochemistry, and immunologic labeling techniques. Four groups of normal pigs at different ages and of different breeds, 1 group with bacterial pneumonia, and 1 group of germfree animals were used. The total cell recovery was 10 x 10(6) in germfree pigs, in normal pigs it was 1.2-4 times higher, and in pneumonic pigs 23 times higher. The main cell type was macrophages, approximately 80% in normal and germfree and 50% in pneumonic pigs. The BAL contained 20% lymphocytes. Granulocytes were absent in normal BAL, but formed 30% of pneumonic BAL. Here the total number of macrophages was 3-9 times higher than normal, the total number of lymphocytes was 11-23 times higher. The proportion of surface immunoglobulin positive (sIg+) cells was 4.5% in the young and 8.5% in the older pigs, and of T cells it was 6% in the young and 14.9% in the older pigs. The BAL of germfree pigs contained few sIg+ cells and half of the normal number of T cells. In pneumonic animals the BAL contained twice the number of sIg+ and a normal percentage of T cells. The percentage of T-helper lymphocytes was approximately 2% without marked differences between the groups, whereas the percentage of T-suppressor lymphocytes varied significantly from 0.8% in germfree to 4% in young normal and 8% in the older pigs. In this respect the pneumonic pigs did not differ from the normal groups. The study shows that the pig is a suitable animal model for further investigation of the cellular immune system of the lung.