Plasma protein haptoglobin modulates renal iron loading

Haptoglobin is the plasma protein with the highest binding affinity for hemoglobin. The strength of hemoglobin binding and the existence of a specific receptor for the haptoglobin-hemoglobin complex in the monocyte/macrophage system clearly suggest that haptoglobin may have a crucial role in heme-iron recovery. We used haptoglobin-null mice to evaluate the impact of haptoglobin gene inactivation on iron metabolism. Haptoglobin deficiency led to increased deposition of hemoglobin in proximal tubules of the kidney instead of the liver and the spleen as occurred in wild-type mice. This difference in organ distribution of hemoglobin in haptoglobin-deficient mice resulted in abnormal iron deposits in proximal tubules during aging. Moreover, iron also accumulated in proximal tubules after renal ischemia-reperfusion injury or after an acute plasma heme-protein overload caused by muscle injury, without affecting morphological and functional parameters of renal damage. These data demonstrate that haptoglobin crucially prevents glomerular filtration of hemoglobin and, consequently, renal iron loading during aging and following acute plasma heme-protein overload.     

Proanthocyanidins and Flavan-3-ols in the Prevention and Treatment of Periodontitis—Immunomodulatory Effects,Animal and Clinical Studies

This paper continues the systematic review on proanthocyanidins and flavan-3-ols in the prevention and treatment of periodontal disease and covers the immunomodulatory effects, and animal- and clinical studies, while the other part discussed the direct antibacterial properties. Inflammation as a major response of the periodontal tissues attacked by pathogenic microbes can significantly exacerbate the condition. However, the bidirectional activity of phytochemicals that simultaneously inhibit bacterial proliferation and proinflammatory signaling can provide a substantial alleviation of both cause and symptoms. The modulatory effects on various aspects of inflammatory and overall immune response are covered, including confirmed and postulated mechanisms of action, structure activity relationships and molecular targets. Further, the clinical relevance of flavan-3-ols and available outcomes from clinical studies is analyzed and discussed. Among the numerous natural sources of flavan-3-ols and proanthocyanidins the most promising are, similarly to antibacterial properties, constituents of various foods, such as fruits of Vaccinium species, tea leaves, grape seeds, and tannin-rich medicinal herbs. Despite a vast amount of in vitro and cell-based evidence of immunomodulatory there are still only a few animal and clinical studies. Most of the reports, regardless of the used model, indicated the efficiency of these phytochemicals from cranberries and other Vaccinium species and tea extracts (green or black). Other sources such as grape seeds and traditional medicinal plants, were seldom. In conclusion, the potential of flavan-3-ols and their derivatives in prevention and alleviation of periodontal disease is remarkable but clinical evidence is urgently needed for issuing credible dietary recommendation and complementary treatments.     

The economics of alternative payment models for pharmaceuticals

The European Journal of Health Economics - Pharmaceuticals are priced uniformly by convention, but vary in their degree of effectiveness for different disease indications. As more high-cost...     

Interleukin 12-based immunotherapy improves the antitumor effectiveness of a low-dose 5-Aza-2'-deoxycitidine treatment in L1210 leukemia and B16F10 melanoma models in mice.

PURPOSE: Recent findings indicating that many genes related to cancer development are silenced by an aberrant DNA methylation suggest that inhibitors of this process may be effective cancer therapeutics. In this study we investigated the efficacy of low-dose 5-aza-2'-deoxycitydine (DAC), a methylation inhibitor, with interleukin (IL) 12, one of the most potent cytokines with antitumor activity. Experimental Design: Mice inoculated with L1210 leukemia cells or with B16F10 melanoma cells were treated with 7 daily injections of low-dose DAC (0.2 mg/kg) and/or 7 daily doses of IL-12 (100 ng/dose). Scid/scid mice as well as monoclonal antibodies against CD4, CD8, and NK1.1 were used to investigate the mechanisms of the antitumor effects of the combination treatment. The activity of murine lymphocytes was measured with enzyme-linked immunospot and (51)Cr release assays. RESULTS: Treatment with DAC or IL-12 given alone produced moderate antitumor effects. In both tumor models combined treatment resulted in potentiated antitumor effects and produced 70% long-term survivors among mice inoculated with L1210 cells. The antitumor efficacy of combined treatment was abrogated in scid/scid mice, and after depletion of CD4(+) and CD8(+) T cells. Mice inoculated with B16F10 melanoma cells had significantly delayed tumor growth after combined treatment with DAC and IL-12. Strong antitumor effect correlated with a significant activation of lymph node-derived CD8(+) and CD4(+) cells. Transient neutropenia was observed in mice under treatment of DAC alone, but remarkably this effect was not potentiated by IL-12. CONCLUSIONS: This study provides the first evidence that antitumor effects of DAC can be strongly potentiated by IL-12 and could be beneficial in an effective low-dose-based antitumor therapy.     

Inhibition of cyclooxygenase-2 indirectly potentiates antitumor effects of photodynamic therapy in mice.

PURPOSE: The aim of the present study was to potentiate the antitumor effectiveness of photodynamic therapy (PDT). A cDNA microarray analysis was used to evaluate the gene expression pattern after Photofrin-mediated PDT to find more effective combination treatment with PDT and inhibitor(s) of the identified gene product(s) overexpressed in tumor cells. EXPERIMENTAL DESIGN: Atlas Mouse Stress Array was used to compare the expression profile of control and PDT-treated C-26 cells. The microarray results have been confirmed using Western blotting. Cytostatic/cytotoxic in vitro assay as well as in vivo tumor models were used to investigate the antitumor effectiveness of PDT in combination with cyclooxygenase (COX) 2 inhibitors. RESULTS: PDT induced the expression of 5 of 140 stress-related genes. One of these genes encodes for COX-2, an enzyme important in the tumor progression. Inhibition of COX-2 in vitro with NS-398, rofecoxib, or nimesulide, or before PDT with nimesulide did not influence the therapeutic efficacy of the treatment. Administration of a selective COX-2 inhibitor after PDT produced potentiated antitumor effects leading to complete responses in the majority of treated animals. CONCLUSIONS: COX-2 inhibitors do not sensitize tumor cells to PDT-mediated killing. However, these drugs can be used to potentiate the antitumor effectiveness of this treatment regimen when administered after tumor illumination.     

Ankle fracture classification using deep learning: automating detailed AO Foundation/Orthopedic Trauma Association (AO/OTA) 2018 malleolar fracture identification reaches a high degree of correct classification

Background and purpose — Classification of ankle fractures is crucial for guiding treatment but advanced classifications such as the AO Foundation/Orthopedic Trauma Association (AO/OTA) are often too complex for human observers to learn and use. We have therefore investigated whether an automated algorithm that uses deep learning can learn to classify radiographs according to the new AO/OTA 2018 standards.Method — We trained a neural network based on the ResNet architecture on 4,941 radiographic ankle examinations. All images were classified according to the AO/OTA 2018 classification. A senior orthopedic surgeon (MG) then re-evaluated all images with fractures. We evaluated the network against a test set of 400 patients reviewed by 2 expert observers (MG, AS) independently.Results — In the training dataset, about half of the examinations contained fractures. The majority of the fractures were malleolar, of which the type B injuries represented almost 60% of the cases. Average area under the area under the receiver operating characteristic curve (AUC) was 0.90 (95% CI 0.82–0.94) for correctly classifying AO/OTA class where the most common major fractures, the malleolar type B fractures, reached an AUC of 0.93 (CI 0.90–0.95). The poorest performing type was malleolar A fractures, which included avulsions of the fibular tip.Interpretation — We found that a neural network could attain the required performance to aid with a detailed ankle fracture classification. This approach could be scaled up to other body parts. As the type of fracture is an important part of orthopedic decision-making, this is an important step toward computer-assisted decision-making.

Ankle fractures are recognized among the most common fractures, with peak incidence between 15 and 29 years (67 per 100,000 person-years) and elderly women ≥ 60 years (174 per 100,000 person-years) (Westerman and Porter 2007, Thur et al. 2012). Efforts to classify ankle fractures in clinically relevant entities have a long history, ending in 3 classic systems, i.e., the Lauge-Hansen (Hansen 1942), Danis–Weber, and the AO/OTA classifications (Association Committee for Coding and Classification 1996; Budny and Young 2008), where the Danis–Weber with its A, B, and C classes is probably the most used in everyday practice.The most recent update for the AO/OTA classification system was published in 2018 (Meinberg et al. 2018). The AO/OTA system contains classifications for the entire body. The ankle is divided into (1) malleolar, (2) distal tibia, and (3) fibular fractures. For malleolar fractures, the subcategories correspond to the Danis–Weber ABC classification (Hughes et al. 1979) with the addition of a suffix of 2 digits (range 1–3), e.g., the common intra-syndesmotic B-injury without widening of the mortise corresponds to the B1.1 class. The numbers correspond roughly to the severity of each fracture.The complexity of this classification makes it difficult to learn and apply, limiting inter-observer reliability and reproducibility (Fonseca et al. 2017). This has hindered its use in an everyday clinical setting, suggesting the need for better aid during the classification.During recent years, the resurgence of neural networks, a form of artificial intelligence (AI), has proven highly successful for image classification. In some medical image classification applications neural networks attain (Olczak et al. 2017, Kim and MacKinnon 2018, Gan et al. 2019), and surpass, human expert performance (Esteva et al. 2017, Lee et al. 2017, Chung et al. 2018, Urakawa et al. 2019). Machine learning and neural networks are also becoming more commonplace research tools in orthopedics. They hold great potential, as the diagnostic underpinning and intervention decision relies heavily on medical imaging (Cabitza et al. 2018). The strength of these learning algorithms is their ability to review a vast number of examinations and examples, and the speed and consistency with which they can review each examination and at the same time remember thousands of categories without issue.We therefore hypothesized that a neural network can learn to classify ankle fractures according to the AO/OTA 2018 classification from radiographs.     

Effect of Transmural Extent of the Simulated Infarction in a Left Ventricular Model on Displacement and Strain Distribution Estimated from Synthetic Ultrasonic Data

The identification of a sub-endocardial infarction is of major interest in cardiology. This study evaluates the sensitivity of selected measures to the thickness of such an infarction. Synthetic ultrasonic data (long-axis view) of left ventricular models with inclusions were generated using Field II and meshes obtained from finite-element simulations, which also provided the reference for the estimates obtained from ultrasonic data. The displacements, the first and second component of the principal strain (ε₁ and ε₂), and several measures derived from these quantities were estimated. All estimates, except for the poorly estimated ε₂, exhibited sensitivity to the presence and transmurality of the inclusion. The most sensitive was the gradient of the averaged transmural profiles of ε₁, and ε₁ averaged over the area corresponding to the transmural inclusion. The inflection point of the ε₁ profile shifted toward the outer wall with increasing thickness of the non-transmural inclusion.