Fabrication and tunable reinforcement of net-shaped aluminum matrix composite parts via 3D printing.

Advanced materials, such as metal matrix composites (MMCs), are important for innovation, national security, and addressing climate change. MMCs are used in military, aerospace, and automotive applications because of their exceptional mechanical and thermal properties, however adoption has been slow due to costly and onerous manufacturing processes. A new process using fused filament fabrication 3D printing has been developed to make net shape MMCs without tooling or machining. The process involves printing an alumina preform and then using pressure-less infiltration with a molten aluminum alloy to form the composite. Arbitrary shapes can be formed in this process-a brake lever and a flange are demonstrated-and the properties can be tuned by varying the ceramic infill geometric pattern and ceramic loading. By using 35 vol% continuous fiber reinforcement over 800 MPa strength and 140 GPa modulus are achieved for the aluminum composite, 3.4 × and 2 × the matrix aluminum properties.

[Escalation and de-escalation concept for intensive care beds in hospitals reserved for COVID-19]. / Eskalations­/Deeskalationskonzept zur COVID-19-bedingten Freihaltung von Intensivkapazitäten an Kliniken.

BACKGROUND: Since the spread of Severe Acute Respiratory Syndrom Corona Virus 2 (SARS-CoV­2) in Germany, intensive care beds have been kept free for patients suffering from Corona Virus Disease (COVID-19). Also, after the number of infections had declined, intensive care beds were kept free prophylactically; however, the percentage of beds reserved for COVID-19 differ in the individual federal states in Germany. The aim of this article is to define a necessary clearance quota of intensive beds for COVID-19 patients in Germany. An escalation and de-escalation scheme was created for rising and falling numbers of infected patients. METHODS: Data from the COVID-19 resource board of the state of Baden-Württemberg, the daily situation report of the Robert Koch Institute (RKI), the register of COVID-19 intensive care beds of the German Interdisciplinary Association for Intensive Care and Emergency Medicine (DIVI) as well as the daily report of COVID-19 Baden-Württemberg from April to November 2020 were used for the calculation. RESULTS: At the end of November 2020 approximately 13.5% of intensive care beds in Germany were used by COVID-19 patients. Of all persons tested positive for SARS-CoV­2, 1.5% were admitted to an intensive care unit. The hospitalization rate was 6% and the mean age of infected persons was 43 years. Based on these numbers hospitals are recommended to keep 10% of intensive care beds available for COVID-19 patients in the case of less than 35 new infections/100,000 in the catchment area, 20% should be kept free in case of an advanced warning level of 35 new infections/100,000 inhabitants and 30% for a critical limit of 50 new infections/100,000 inhabitants. Further internal hospital triggers, such as the occupancy of the intensive care beds with COVID-19 patients, should be considered. CONCLUSION: If the number of infections is low a general nationwide retention rate of more than 10% of intensive care beds for COVID-19 patients is not justified. Locally increasing numbers of infections require a local dynamic approach. If the number of infections increases, the free holding capacity should be increased according to a step by step concept in close coordination with the local health authorities and other internal hospital triggers. In order not to overwhelm hospital capacities in the event of local outbreaks, a corresponding relocation concept should be considered at an early stage.

Characterization of Botrytis cinerea From Commercial Cut Flower Roses.

Botrytis cinerea Pers. infects cut flower roses (Rosa × hybrida L.) during greenhouse production and gray mold symptoms are often expressed in the postharvest environment, resulting in significant economic losses. Disease management is based on cultural practices and preventative chemical treatments; however, gray mold outbreaks continue to occur. Rose tissues from six commercial shipments from two greenhouses in Colombia were evaluated to determine the Botrytis species composition as well as identify other pathogens present, gray mold incidence and severity, and fungicide resistance profiles. Botrytis isolates (49 total) were grouped into six morphological phenotypes, and all were identified to be B. cinerea sensu stricto. Disease incidence was higher in the petals than in the stem, stamen, ovary, sepal, or leaf tissues. Other fungi were isolated infrequently and included Alternaria alternata, Cladosporium cladosporioides, Epicoccum nigrum, Penicillium citrinum, Aspergillus brasiliensis, and Diplodia sp. Fungicide resistance profiles were determined using previously established discriminatory doses. Isolates resistant to thiophanate-methyl, iprodione, boscalid, and cyprodinil were found frequently in all shipments and in both greenhouses. The frequency of resistance to penthiopyrad, fenhexamid, fluopyram, isofetamid, and fludioxonil varied between shipments and greenhouses. No resistance to pydiflumetofen was observed at the discriminatory doses tested. Isolates with resistance to multiple chemical classes were commonly found. These results indicate that fungicide resistance management practices may improve preharvest and postharvest gray mold control of cut flower roses.

Refractive errors and corrections for OCT images in an inflated lung phantom.

Visualization and correct assessment of alveolar volume via intact lung imaging is important to study and assess respiratory mechanics. Optical Coherence Tomography (OCT), a real-time imaging technique based on near-infrared interferometry, can image several layers of distal alveoli in intact, ex vivo lung tissue. However optical effects associated with heterogeneity of lung tissue, including the refraction caused by air-tissue interfaces along alveoli and duct walls, and changes in speed of light as it travels through the tissue, result in inaccurate measurement of alveolar volume. Experimentally such errors have been difficult to analyze because of lack of 'ground truth,' as the lung has a unique microstructure of liquid-coated thin walls surrounding relatively large airspaces, which is difficult to model with cellular foams. In addition, both lung and foams contain airspaces of highly irregular shape, further complicating quantitative measurement of optical artifacts and correction. To address this we have adapted the Bragg-Nye bubble raft, a crystalline two-dimensional arrangement of elements similar in geometry to alveoli (up to several hundred µm in diameter with thin walls) as an inflated lung phantom in order to understand, analyze and correct these errors. By applying exact optical ray tracing on OCT images of the bubble raft, the errors are predicted and corrected. The results are validated by imaging the bubble raft with OCT from one edge and with a charged coupled device (CCD) camera in transillumination from top, providing ground truth for the OCT.

Biofilm formation and composition on different implant materials in vivo.

Biofilm formation was evaluated on the following titanium and zirconia implants in vivo: machined titanium (Ti-m), modified titanium (TiUnite), modified zirconia (ZiUnite), machined alumina-toughened zirconia (ATZ-m), sandblasted alumina-toughened zirconia (ATZ-s), and machined zirconia (TZP-A-m). Bovine enamel slabs were used as controls. Surface morphologies were examined by atomic force (AFM) and scanning electron microscopy (SEM). The surface wettability was also determined. Twelve healthy volunteers wore a splint system with the tested materials. After 3 and 5 days the materials were examined by fluorescence in situ hybridization (FISH) and confocal laser scanning microscopy (CLSM). The levels of Streptococcus spp., Veillonella spp., Fusobacteriaum nucleatum, and Actinomyces naeslundii were quantitatively determined. The biofilm thickness was found to be between 19.78 and 36.73 µm after 3 days and between 26.11 and 32.43 µm after 5 days. With the exception of Ti-m the biofilm thickness after 3 days was correlated with surface roughness. In addition to Streptococcus spp. as the main component of the biofilm (11.23-25.30%), F. nucleatum, A. naeslundii, and Veillonella spp. were also detected. No significant differences in biofilm composition on the implant surfaces could be observed. In total, the influence of roughness and material on biofilm formation was compensated by biofilm maturation.

Paclitaxel-based chemoradiotherapy in localized gastric carcinoma: degree of pathologic response and not clinical parameters dictated patient outcome.

PURPOSE: Preoperative chemoradiotherapy may increase the R0 (curative) resection rate, overall survival (OS) duration, and disease-free survival (DFS) duration. We evaluated paclitaxel-based induction chemotherapy and chemoradiotherapy in patients with localized gastric or gastroesophageal adenocarcinoma to determine its feasibility, impact on the R0 resection rate, type of pathologic response, OS, and DFS. PATIENTS AND METHODS: Patients with operable, localized gastric, or gastroesophageal adenocarcinoma were eligible. Staging included endoscopic ultrasonography (EUS) and laparoscopy. Patients received two 28-day cycles of induction chemotherapy of fluorouracil, paclitaxel, and cisplatin followed by 45 Gy of radiation and concurrent fluorouracil plus paclitaxel. The cancer was restaged and surgery was attempted. Postsurgery pathologic findings and R0 resection were correlated with OS and DFS. RESULTS: Forty-one patients were enrolled. Most carcinomas were proximal (83%) and pretreatment stage EUST3 (85%). Forty patients (98%) underwent surgery, and 78% had an R0 resection. We observed a pathologic complete response (pathCR) rate of 20% and a pathologic partial response (pathPR) rate of 15% (< 10% residual cancer cells in the resected specimen). No pretreatment parameter (sex, cancer location, baseline T stage, or baseline N stage) predicted the type of postsurgery pathologic response, OS, or DFS. However, pathCR (P = .02), pathCR + pathPR (P = .006), R0 resection (P < .001), and postsurgery T and N stages (P = .01 and P < .001, respectively) were associated with OS. Same parameters were significantly correlated with DFS. Toxicity was manageable. CONCLUSION: The type of pathologic response but not pretreatment parameters was associated with OS and DFS. Efforts to increase the rate of pathologic response and better systemic cancer control are warranted.

[Fabry's disease, glomerulonephritis with crescentic and granulomatous interstitial nephritis. Case of one family]. / Morbus Fabry, Glomerulonephritis mit Halbmondbildung und granulomatöse interstitielle NephritisBericht über eine Familie.

A 26-year-old female patient was admitted to the hospital because of fever of unknown origin and renal failure. Diagnosis of Fabry's disease, extracapillary proliferative (crescentic) glomerulonephritis and granulomatous interstitial nephritis was made by histological, immunohistochemical and electron microscopical diagnosis in a kidney biopsy and confirmed by further investigations. Years ago the brother of the patient had a kidney biopsy diagnosed as metabolic disease. The re-evaluation of this biopsy confirmed Fabry's disease while in this patient an association with tubulointerstitial nephritis occurred. To our knowledge this is the first family with two members having Fabry's disease combined with further kidney diseases.

The very elderly dialysis patient: indication and discontinuation of dialysis.

1. When the current available data in the literature is summarized it becomes evident that the majority of it supports the position that it is, at least for medical reasons, not advisable to exclude patients over the age of 80 years from chronic dialysis. 2. It is correct to say that the refusal of dialysis therapy for elderly dialysis patients would lead to a not insignificant cutting of costs, although elderly patients are not as 'expensive' as younger dialysis patients. 3. The decision to exclude patients over 80 from dialysis treatment is difficult, in our opinion, to support ethically. 4. The refusal of therapy by a dialysis patient--independent of his age--can only occur with his/her consent, as long as the patient is clearly conscious of the decision. 5. Should the patient no longer be in the condition to exercise his/her autonomy, and there is no AD, the Surrogate's Court must be consulted. 6. AD can be seen as helpful, since they not only make the decisions for physicians easier, but also because they can be seen as an act of care for family members. 7. Whenever dialysis therapy is discontinued the problematic nature of so-called essential care should be carefully considered, especially if no clear position has been taken in an AD.

Comparing the efficacy of staff versus housestaff instruction in an intervention to improve hypertension management.

PURPOSE: To determine whether a resident physician can be as effective as a faculty opinion leader in changing physicians' compliance with a hypertension practice guideline. METHOD: At a general internal medicine clinic associated with an internal medicine residency program, sequential charts were reviewed for patients with uncontrolled or new-onset hypertension who were seen routinely during a two-week period. Subsequently, 23 providers were randomly assigned to an academic intervention to implement a hypertension practice guideline led by a single second-year resident instructor (RI), and 21 providers were assigned to the same intervention led by a single staff internist (SI) with an interest in hypertension. The intervention involved academic detailing, chart audit with feedback, and behavior reinforcement. Six weeks later, the chart audit was repeated to assess the change in practice patterns among providers taught by the RI compared with those taught by the SI. RESULTS: Overall, management consistent with the practice guideline improved from 32% (51/157) to 45% (56/123) (p < .01) after the intervention. This change was due to improvement in the care provided by providers from the SI-led intervention: 28% (17/60) to 57% (26/46) (p < .003). Providers from the RI-led intervention showed no improvement: 35% (34/97) to 39% (30/77) (p = NS). CONCLUSIONS: This intervention was effective in improving providers' compliance with a hypertension practice guideline, but only when led by a faculty opinion leader. A resident instructor using the same format was unable to change the providers' behaviors.

Targeting dipeptidyl peptidase IV (CD26) suppresses autoimmune encephalomyelitis and up-regulates TGF-beta 1 secretion in vivo.

CD26 or dipeptidyl peptidase IV (DP IV) is expressed on various cell types, including T cells. Although T cells can receive activating signals via CD26, the physiological role of CD26/DP IV is largely unknown. We used the reversible DP IV inhibitor Lys[Z(NO(2))]-pyrrolidide (I40) to dissect the role of DP IV in experimental autoimmune encephalomyelitis (EAE) and to explore the therapeutic potential of DP IV inhibition for autoimmunity. I40 administration in vivo decreased and delayed clinical and neuropathological signs of adoptive transfer EAE. I40 blocked DP IV activity in vivo and increased the secretion of the immunosuppressive cytokine TGF-beta1 in spinal cord tissue and plasma during acute EAE. In vitro, while suppressing autoreactive T cell proliferation and TNF-alpha production, I40 consistently up-regulated TGF-beta1 secretion. A neutralizing anti-TGF-beta1 Ab blocked the inhibitory effect of I40 on T cell proliferation to myelin Ag. DP IV inhibition in vivo was not generally immunosuppressive, neither eliminating encephalitogenic T cells nor inhibiting T cell priming. These data suggest that DP IV inhibition represents a novel and specific therapeutic approach protecting from autoimmune disease by a mechanism that includes an active TGF-beta1-mediated antiinflammatory effect at the site of pathology.

[Epithelioid hemangioendothelioma of the spine]. / Epithelioides Hämangioendotheliom der Wirbelsäule.

BACKGROUND: Epithelioid hemangioendotheliomas are rare vascular tumors, mostly originating from soft tissue, lungs or liver. CASE REPORT: A 58-year-old woman was admitted to hospital because of upper congestion, Horner's syndrome and segmental sensory disturbance. MRI of the spine showed a spinal mass, reaching from the seventh cervical vertebra to the fourth chest vertebra. Because of worsening of upper congestion and progressive neurological impairment, the patient had to be operated twice. Unfortunately a surgical excision of the infiltrating tumor in sano was not possible and the patient died 4 weeks after the second operation. Histologic examination revealed the diagnosis of infiltrating epithelioid hemangioendothelioma, originating from the first chest vertebra. CONCLUSION: Prognosis of epithelioid hemangioendothelioma is mainly determinated by its location. In advanced stages of disease or lack of surgical cure epithelioid hemangioendotheliomas may be fatal. Therefore epithelioid hemangioendotheliomas should be considered early in the differential diagnosis of patients with uncertain bone lesions.

Down-regulation of T cell activation following inhibition of dipeptidyl peptidase IV/CD26 by the N-terminal part of the thromboxane A2 receptor.

Using synthetic inhibitors, it has been shown that the ectopeptidase dipeptidyl peptidase IV (DP IV) (CD26) plays an important role in the activation and proliferation of T lymphocytes. The human immunodeficiency virus-1 Tat protein, as well as the N-terminal nonapeptide Tat(1-9) and other peptides containing the N-terminal sequence XXP, also inhibit DP IV and therefore T cell activation. Studying the effect of amino acid exchanges in the N-terminal three positions of the Tat(1-9) sequence, we found that tryptophan in position 2 strongly improves DP IV inhibition. NMR spectroscopy and molecular modeling show that the effect of Trp(2)-Tat(1-9) could not be explained by significant alterations in the backbone structure and suggest that tryptophan enters favorable interactions with DP IV. Data base searches revealed the thromboxane A2 receptor (TXA2-R) as a membrane protein extracellularly exposing N-terminal MWP. TXA2-R is expressed within the immune system on antigen-presenting cells, namely monocytes. The N-terminal nonapeptide of TXA2-R, TXA2-R(1-9), inhibits DP IV and DNA synthesis and IL-2 production of tetanus toxoid-stimulated peripheral blood mononuclear cells. Moreover, TXA2-R(1-9) induces the production of the immunosuppressive cytokine transforming growth factor-beta1. These data suggest that the N-terminal part of TXA2-R is an endogenous inhibitory ligand of DP IV and may modulate T cell activation via DP IV/CD26 inhibition.

Dipeptidyl peptidase IV (DP IV/CD26) mRNA expression in PWM-stimulated T-cells is suppressed by specific DP IV inhibition, an effect mediated by TGF-beta(1).

Stimulation of human T-cells by pokeweed mitogen (PWM) results in a significant increase of IL-2, IFN-gamma, and DP IV mRNA expression as analyzed by quantitative RT-PCR. Here we show for the first time that the changes observed in cytokine mRNA expression are dose-dependently suppressed by the specific dipeptidyl peptidase IV inhibitor Lys[Z(NO(2))]-thiazolidide. Most interestingly, the inhibition of DP IV activity leads to a decrease in mRNA expression of the enzyme itself. Furthermore, evidence is provided that this suppression is mediated by TGF-beta(1). The presented data fit into the hypothesis that inhibition of DP IV leads to the induction of TGF-beta(1), which in turn provokes an arrest of cell cycle in late G(1).

A new type of fluorogenic substrates for determination of cellular dipeptidyl peptidase IV (DP IV/CD26) activity.

The stability of cell associated fluorescence is an essential requirement for measurements of cellular enzymatic activity via enzyme catalyzed liberation of fluorophores. Rhodamine 110 (R110), a highly fluorescent xanthene dye, was used to synthesize nonfluorescent dipeptidyl peptidase IV (DP IV) substrates Xaa-Pro-R110-Y allowing the stable covalent binding of the enzymatically released fluorescent R110-Y on cells. All compounds have been characterized as substrates of isolated DP IV with kcat/Km values of about 10(6) M-1.s-1. The hydrophobicity of the residue Y affects the affinity of the substrate to the catalytic site of DP IV. The compounds are characterized as sensitive substrates of cell surface associated DP IV of DP IV rich U-937 cells. The binding of the enzymatically released R110-Y on cells results in a stable cellular fluorescence. This way, the quantitative determination of cell surface associated DP IV activity is possible.

Potent inhibitors of dipeptidyl peptidase IV and their mechanisms of inhibition.

Dipeptidyl peptidase IV (DP IV) is a proline specific serine protease which cleaves Xaa-Pro-dipeptides from the N-terminus of longer peptides. A series of product analogous amino acid amides containing different structure modifications like substitution of a ring atom, variation of the ring size and/or the introduction of a thioxo amide bond, phosphono amide bond or reduced amide bond were done to characterize these compounds as inhibitors of DP IV. These compounds are mostly classical reversible inhibitors of DP IV. In contrast amino acyl-2-cyanopyrrolidides inhibit DP IV according to a slow-binding mechanism with inhibition constants in the nanomolare range. On the other hand, diaryl dipeptide phosphonates inhibit irreversibly. In conclusion, this work shows, that the mechanism of inhibition of DP IV depends on the structure of the investigated compounds.

N-terminal HIV-1 Tat nonapeptides as inhibitors of dipeptidyl peptidase IV. Conformational characterization.

Compared to the N-terminal nonapeptide of the HIV-1 Tat protein as inhibitor of activity of DP IV which is supposed to mediate the immunosuppressive effects of HIV-1 Tat, the Ile5 and Leu6 analogues showed strongly reduced inhibitory activity. Interestingly, replacement of Asp2 with Gly or Lys led to compounds with considerably enhanced inhibition. Therefore, we have applied 1H NMR spectroscopy and restrained molecular dynamics calculations to elucidate the molecular conformation of a series of Tat nonapeptides. Conformational backbone differences of these peptides as well as the nature and the arrangement of the side chains per se at significant positions preventing effective binding to DP IV might explain their different inhibitory activity on DP IV.

Signal transduction events induced or affected by inhibition of the catalytic activity of dipeptidyl peptidase IV (DP IV, CD26).

DP IV (CD26) represents an accessory surface molecule playing an important role in the process of activation and proliferation of human lymphocytes. The molecular events mediated by this ectoenzyme are only partly established and the necessity of DP IV enzymatic activity for its signalling capacity has been discussed controversial. Focusing on the putative role of the catalytic domain of this peptidase, it could be shown that inhibition of the catalytic activity can provoke many cellular effects, including induction of tyrosine phosphorylations and p38 MAP kinase activation as well as suppression of DNA synthesis and reduced production of various cytokines. TGF-beta 1, the production and secretion of which is increased after DP IV inhibition, supposedly mediates the observed suppressive effects by maintaining p27kip expression levels which leads to a cell cycle arrest in G1. Moreover, anti-CD3-induced signalling pathways, including Ca2+ mobilisation, MEK1-, Erk1/2- and PKB-activation, can be strongly affected by DP IV inhibition. Thus, the enzymatic activity or at least the interaction of effectors with the catalytic domain of CD26 seems to be important for crucial functions of this cell surface antigen.