Assessment of the management of carcinomatous meningitis from breast cancer globally: a study by the Breast International Group Brain Metastasis Task Force.

BACKGROUND: Carcinomatous meningitis (CM) is a severe complication of breast cancer. The Breast International Group (BIG) carried out a survey to describe the approach to CM internationally. PATIENTS AND METHODS: A questionnaire on the management of CM was developed by the Brain Metastases Task Force of BIG and distributed to its groups, requesting one answer per group site. RESULTS: A total of 241 sites responded, 119 from Europe, 9 from North America, 39 from Central/South America, 58 from Asia, and 16 in Australia/New Zealand, with 24.5% being general hospitals with oncology units, 44.4% university hospitals, 22.4% oncology centers, and 8.7% private hospitals. About 56.0% of sites reported seeing <5 cases annually with 60.6% reporting no increase in the number of cases of CM recently. Nearly 63.1% of sites investigate for CM when a patient has symptoms or radiological evidence, while 33.2% investigate only for symptoms. For diagnosis, 71.8% of sites required a positive cerebrospinal fluid cytology, while magnetic resonance imaging findings were sufficient in 23.7% of sites. Roughly 97.1% of sites treat CM and 51.9% also refer patients to palliative care. Intrathecal therapy is used in 41.9% of sites, mainly with methotrexate (74.3%). As many as 20 centers have a national registry for patients with breast cancer with central nervous system metastases and of those 5 have one for CM. Most (90.9%) centers would be interested in participating in a registry as well as in studies for CM, the latter preferably (62.1%) breast cancer subtype specific. CONCLUSIONS: This is the first study to map out the approach to CM from breast cancer globally. Although guidelines with level 1 evidence are lacking, there is a high degree of homogeneity in the approach to CM globally and great interest for conducting studies in this area.

The Impact of the Renin-Angiotensin-Aldosterone System on Inflammation, Coagulation, and Atherothrombotic Complications, and to Aggravated COVID-19.

Atherosclerosis is considered a disease caused by a chronic inflammation, associated with endothelial dysfunction, and several mediators of inflammation are up-regulated in subjects with atherosclerotic disease. Healthy, intact endothelium exhibits an antithrombotic, protective surface between the vascular lumen and vascular smooth muscle cells in the vessel wall. Oxidative stress is an imbalance between anti- and prooxidants, with a subsequent increase of reactive oxygen species, leading to tissue damage. The renin-angiotensin-aldosterone system is of vital importance in the pathobiology of vascular disease. Convincing data indicate that angiotensin II accelerates hypertension and augments the production of reactive oxygen species. This leads to the generation of a proinflammatory phenotype in human endothelial and vascular smooth muscle cells by the up-regulation of adhesion molecules, chemokines and cytokines. In addition, angiotensin II also seems to increase thrombin generation, possibly via a direct impact on tissue factor. However, the mechanism of cross-talk between inflammation and haemostasis can also contribute to prothrombotic states in inflammatory environments. Thus, blocking of the renin-angiotensin-aldosterone system might be an approach to reduce both inflammatory and thrombotic complications in high-risk patients. During COVID-19, the renin-angiotensin-aldosterone system may be activated. The levels of angiotensin II could contribute to the ongoing inflammation, which might result in a cytokine storm, a complication that significantly impairs prognosis. At the outbreak of COVID-19 concerns were raised about the use of angiotensin converting enzyme inhibitors and angiotensin receptor blocker drugs in patients with COVID-19 and hypertension or other cardiovascular comorbidities. However, the present evidence is in favor of continuing to use of these drugs. Based on experimental evidence, blocking the renin-angiotensin-aldosterone system might even exert a potentially protective influence in the setting of COVID-19.

The role of magnetic order in VOCl.

VOCl and other transition metal oxychlorides are candidate materials for next-generation rechargeable batteries. We have investigated the influence of the underlying magnetic order on the crystallographic and electronic structure by means of density functional theory. Our study shows that antiferromagnetic ordering explains the observed low-temperature monoclinic distortion of the lattice, which leads to a decreased distance between antiferromagnetically coupled V-V nearest neighbors. We also show that the existence of a local magnetic moment removes the previously suggested degeneracy of the occupied levels, in agreement with experiments. To describe the electronic structure, it turns out crucial to take the correct magnetic ordering into account, especially at elevated temperature.

The most incompressible metal osmium at static pressures above 750 gigapascals.

Metallic osmium (Os) is one of the most exceptional elemental materials, having, at ambient pressure, the highest known density and one of the highest cohesive energies and melting temperatures. It is also very incompressible, but its high-pressure behaviour is not well understood because it has been studied so far only at pressures below 75 gigapascals. Here we report powder X-ray diffraction measurements on Os at multi-megabar pressures using both conventional and double-stage diamond anvil cells, with accurate pressure determination ensured by first obtaining self-consistent equations of state of gold, platinum, and tungsten in static experiments up to 500 gigapascals. These measurements allow us to show that Os retains its hexagonal close-packed structure upon compression to over 770 gigapascals. But although its molar volume monotonically decreases with pressure, the unit cell parameter ratio of Os exhibits anomalies at approximately 150 gigapascals and 440 gigapascals. Dynamical mean-field theory calculations suggest that the former anomaly is a signature of the topological change of the Fermi surface for valence electrons. However, the anomaly at 440 gigapascals might be related to an electronic transition associated with pressure-induced interactions between core electrons. The ability to affect the core electrons under static high-pressure experimental conditions, even for incompressible metals such as Os, opens up opportunities to search for new states of matter under extreme compression.

Hyperfine splitting and room-temperature ferromagnetism of Ni at multimegabar pressure.

Magnetic and elastic properties of Ni metal have been studied up to 260 GPa by nuclear forward scattering of synchrotron radiation with the 67.4 keV Mössbauer transition of 61Ni. The observed magnetic hyperfine splitting confirms the ferromagnetic state of Ni up to 260 GPa, the highest pressure where magnetism in any material has been observed so far. Ab initio calculations reveal that the pressure evolution of the hyperfine field, which features a maximum in the range of 100 to 225 GPa, is a relativistic effect. The Debye energy obtained from the Lamb-Mössbauer factor increases from 33 meV at ambient pressure to 60 meV at 100 GPa. The change of this energy over volume compression is well described by a Grüneisen parameter of 2.09.

Elastic properties of fcc Fe-Mn-X (X = Cr, Co, Ni, Cu) alloys studied by the combinatorial thin film approach and ab initio calculations.

The elastic properties of fcc Fe-Mn-X (X = Cr, Co, Ni, Cu) alloys with additions of up to 8 at.% X were studied by combinatorial thin film growth and characterization and by ab initio calculations using the disordered local moments (DLM) approach. The lattice parameter and Young's modulus values change only marginally with X. The calculations and experiments are in good agreement. We demonstrate that the elastic properties of transition metal alloyed Fe-Mn can be predicted by the DLM model.

Importance of correlation effects in hcp iron revealed by a pressure-induced electronic topological transition.

We discover that hcp phases of Fe and Fe(0.9)Ni(0.1) undergo an electronic topological transition at pressures of about 40 GPa. This topological change of the Fermi surface manifests itself through anomalous behavior of the Debye sound velocity, c/a lattice parameter ratio, and Mössbauer center shift observed in our experiments. First-principles simulations within the dynamic mean field approach demonstrate that the transition is induced by many-electron effects. It is absent in one-electron calculations and represents a clear signature of correlation effects in hcp Fe.

Effect of varying displays and room illuminance on caries diagnostic accuracy in digital dental radiographs.

In clinical practice, digital radiographs taken for caries diagnostics are viewed on varying types of displays and usually in relatively high ambient lighting (room illuminance) conditions. Our purpose was to assess the effect of room illuminance and varying display types on caries diagnostic accuracy in digital dental radiographs. Previous studies have shown that the diagnostic accuracy of caries detection is significantly better in reduced lighting conditions. Our hypothesis was that higher display luminance could compensate for this in higher ambient lighting conditions. Extracted human teeth with approximal surfaces clinically ranging from sound to demineralized were radiographed and evaluated by 3 observers who detected carious lesions on 3 different types of displays in 3 different room illuminance settings ranging from low illumination, i.e. what is recommended for diagnostic viewing, to higher illumination levels corresponding to those found in an average dental office. Sectioning and microscopy of the teeth validated the presence or absence of a carious lesion. Sensitivity, specificity and accuracy were calculated for each modality and observer. Differences were estimated by analyzing the binary data assuming the added effects of observer and modality in a generalized linear model. The observers obtained higher sensitivities in lower illuminance settings than in higher illuminance settings. However, this was related to a reduction in specificity, which meant that there was no significant difference in overall accuracy. Contrary to our hypothesis, there were no significant differences between the accuracy of different display types. Therefore, different displays and room illuminance levels did not affect the overall accuracy of radiographic caries detection.

The influence of additions of Al and Si on the lattice stability of fcc and hcp Fe-Mn random alloys.

We have studied the influence of additions of Al and Si on the lattice stability of face-centred-cubic (fcc) versus hexagonal-closed-packed (hcp) Fe-Mn random alloys, considering the influence of magnetism below and above the fcc Néel temperature. Employing two different ab initio approaches with respect to basis sets and treatment of magnetic and chemical disorder, we are able to quantify the predictive power of the ab initio methods. We find that the addition of Al strongly stabilizes the fcc lattice independent of the regarded magnetic states. For Si a much stronger dependence on magnetism is observed. Compared to Al, almost no volume change is observed as Si is added to Fe-Mn, indicating that the electronic contributions are responsible for stabilization/destabilization of the fcc phase.

Influence of the magnetic state on the chemical order-disorder transition temperature in Fe-Ni permalloy.

In magnetic alloys, the effect of finite temperature magnetic excitations on phase stability below the Curie temperature is poorly investigated, although many systems undergo phase transitions in this temperature range. We consider random Ni-rich Fe-Ni alloys, which undergo chemical order-disorder transition approximately 100 K below their Curie temperature, to demonstrate from ab initio calculations that deviations of the global magnetic state from ideal ferromagnetic order due to temperature induced magnetization reduction have a crucial effect on the chemical transition temperature. We propose a scheme where the magnetic state is described by partially disordered local magnetic moments, which in combination with Heisenberg Monte Carlo simulations of the magnetization allows us to reproduce the transition temperature in good agreement with experimental data.

Rapid and easy semi-quantitative evaluation method for diacylglycerol and inositol-1,4,5-trisphosphate generation in orexin receptor signalling.

AIM: Fluorescent protein-based indicators have enabled measurement of intracellular signals previously nearly inaccessible for studies. However, indicators showing intracellular translocation upon response suffer from serious limitations, especially the very time-consuming data collection. We therefore set out in this study to evaluate whether fixing and counting cells showing translocation could mend this issue. METHODS: Altogether three different genetically encoded indicators for diacylglycerol and inositol-1,4,5-trisphosphate were transiently expressed in Chinese hamster ovary cells stably expressing human OX(1) orexin receptors. Upon stimulation with orexin-A, the cells were fixed with six different protocols. RESULTS: Different protocols showed clear differences in their ability to preserve the indicator's localization (i.e. translocation after stimulus) and its fluorescence, and the best results for each indicator were obtained with a different protocol. The concentration-response data obtained with cell counting are mostly comparable to the real-time translocation and biochemical data. CONCLUSION: The counting method, as used here, works at single time point and looses the single-cell-quantitative aspect. However, it also has some useful properties. First, it easily allows processing of a 100- to 1000-fold higher cell numbers than real-time imaging producing statistically consistent population-quantitative data much faster. Secondly, it does not require expensive real-time imaging equipment. Fluorescence in fixed cells can also be quantitated, though this analysis would be more time-consuming than cell counting. Thirdly, in addition to the quantitative data collection, the method could be applied for identifying responsive cells. This might be very useful in identification of e.g. orexin-responding neurones in a large population of non-responsive cells in primary cultures.

Ab initio lattice stability of fcc and hcp Fe-Mn random alloys.

We have studied the lattice stability of face centred cubic (fcc) versus hexagonal close packed (hcp) Fe-Mn random alloys using ab initio calculations. In the calculations we considered the antiferromagnetic order of local moments, which for fcc alloys models the magnetic configuration of this phase at room temperature (below its Néel temperature) as well as their complete disorder, corresponding to paramagnetic fcc and hcp alloys. For both cases, the results are consistent with our thermodynamic calculations, obtained within the Calphad approach. For the room temperature magnetic configuration, the cross-over of the total energies of the hcp phase and the fcc phase of Fe-Mn alloys is at the expected Mn content, whereas for the magnetic configuration above the fcc Néel temperature, the hcp lattice is more stable within the whole composition range studied. The increase of the total energy difference between hcp and antiferromagnetic fcc due to additions of Mn as well as the stabilizing effect of antiferromagnetic ordering on the fcc phase are well displayed. These results are of relevance for understanding the deformation mechanisms of these random alloys.

Angiotensin II infusion in man is proinflammatory but has no short-term effects on thrombin generation in vivo.

BACKGROUND: Angiotensin (Ang) II may be involved in the development of cardiovascular disease. We examined the potential proinflammatory and prothrombotic effects of Ang II in 16 healthy subjects and in 16 subjects with familial combined hyperlipidemia (FCHL), a condition associated with an increased risk of cardiovascular complications. METHODS: We studied the effects of a three hour intravenous infusion of Ang II (10 ng/kg/min) on plasma concentrations of interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-alpha), circulating leukocyte count, tissue plasminogen activator/plasminogen activator inhibitor-1 (t-PA/PAI-1) complexes, prothrombin fragment 1+2 (F1+2), and thrombin-antithrombin (TAT) complexes. Blood was collected before, during and 1 h after Ang II infusion. RESULTS: IL-6 was higher in subjects with FCHL at rest (P < 0.05) and increased (P < 0.001) similarly in both groups by Ang II infusion. Also leukocyte count was higher in subjects with FCHL at rest (P < 0.001) and increased (P < 0.001) similarly in both groups by Ang II infusion. T-PA/PAI-1 complexes were higher in subjects with FCHL at rest (P < 0.001) and decreased (P < 0.001) similarly in both groups during Ang II infusion. TNF-alpha, F1+2 and TAT complexes were similar in the two groups at rest and did not change during or after the Ang II infusion. CONCLUSIONS: A three hour Ang II infusion increases inflammation and may enhance fibrinolysis but does not affect short term thrombin generation. Subjects with FCHL have signs of increased inflammation and impaired fibrinolysis.

Multiple phospholipase activation by OX(1) orexin/hypocretin receptors.

We investigated coupling of OX(1) receptors to phospholipase activation and diacylglycerol generation in Chinese hamster ovary (CHO) cells using both biochemical and fluorescence "real-time" methods. The results indicate that at lowest orexin-A concentrations (highest potency), diacylglycerol generated results from phospholipase D activity. At 10-100-fold higher orexin-A concentrations, phospholipase C is activated, likely hydrolyzing phosphatidylinositol (PI) or phosphatidylinositol monophosphate (PIP) but not phosphatidylinositol bisphosphate (PIP(2)). At further 7-fold higher orexin-A concentrations, PIP(2) is hydrolyzed, releasing both diacylglycerol and inositol-1,4,5-trisphosphate. Thus, OX(1) orexin receptors connect to multiple phospholipase activities, apparently composed of at least one phospholipase D and two different phospholipase C activities. At low agonist concentrations, diacylglycerol and phosphatidic acid are the preferred products, and interestingly, it seems that even the primarily activated phospholipase C mainly works to increase diacylglycerol and not inositol-1,4,5-trisphosphate.

Regulation of OX1 orexin/hypocretin receptor-coupling to phospholipase C by Ca2+ influx.

BACKGROUND AND PURPOSE: Orexin (OX) receptors induce Ca2+ elevations via both receptor-operated Ca2+ channels (ROCs) and the "conventional" phospholipase C (PLC)-Ca2+ release-store-operated Ca2+ channel (SOC) pathways. In this study we assessed the ability of these different Ca2+ influx pathways to amplify OX1 receptor signalling to PLC in response to stimulation with the physiological ligand orexin-A. EXPERIMENTAL APPROACH: PLC activity was assessed in CHO cells stably expressing human OX1 receptors. KEY RESULTS: Inhibition of total Ca2+ influx by reduction of the extracellular [Ca2+] to 1 microM effectively inhibited the receptor-stimulated PLC activity at low orexin-A concentrations (by 93% at 1 nM), and this effect was gradually reduced by higher orexin-A concentrations. A similar but weaker inhibitory effect (84% at 1 nM) was obtained on depolarization to approximately 0 mV, which disrupts most of the driving force for Ca2+ entry. The inhibitor of the OX1 receptor-activated ROCs, tetraethylammonium chloride (TEA), was somewhat less effective than the reduction in extracellular [Ca2+] at inhibiting PLC activation, probably because it only partially blocks ROCs. The partial inhibitor of both ROCs and SOCs, Mg2+, and the SOC inhibitors, dextromethorphan, SKF-96365 (1-[beta-(3-(4-methoxyphenyl)propoxy)-4-methoxyphenethyl]-1H-imidazole HCL) and 2-APB (2-aminoethoxydiphenyl borate), inhibited PLC activity at low concentrations of orexin-A, but were not as effective as TEA. CONCLUSIONS AND IMPLICATIONS: Both ROCs and SOCs markedly amplify the OX(1) receptor-induced PLC response, but ROCs are more central for this response. These data indicate the crucial role of ROCs in orexin receptor signalling.

A histological and immunohistochemical study of tissue reactions to solid poly(ortho ester) in rabbits.

In many cases only the temporary presence of a biomaterial is needed in tissue support, augmentation or replacement. In such cases biodegradable materials are better alternatives than biostable ones. At present, biodegradable polymers are widely used in the field of maxillofacial surgery as sutures, fracture fixation devices and as absorbable membranes. The most often used polymers are aliphatic polyesters, such as polyglycolic acid (PGA) and polylactic acid (PLA). Poly(ortho ester) is a surface eroding polymer, which has been under development since 1970, but is used mostly in drug delivery systems in semisolid form. The aim of this study was to evaluate the tissue reactions of solid poly(ortho ester) (POE), histologically and immunohistochemically. Resorption times and the effect of 2 different sterilization methods (gamma radiation and ethylene oxide) upon resorption were also evaluated. Material was implanted into the tibia and subcutaneously into the mandibular ramus area of 24 rabbits. Follow-up times were 1-10, 14 and 24 weeks. Histological studies showed that POE induces a moderate inflammation in soft tissue and in bone. At 24 week follow-up, inflammation was mild in soft tissue and moderate in bone. In immunohistochemical studies, no highly fluorescent layer of tenascin or fibronectin was found adjacent to the implant. Resorption of gamma-sterilized rods was faster than ethylene oxide-sterilized rods. The total resorption time was more than 24 weeks in both groups. Clinically the healing was uneventful and the implants the well tolerated by the living tissue. This encourages these authors to continue studies with this interesting new material to search for the ideal material for bone filling and fracture fixation.

The copolymer of epsilon-caprolactone-lactide and tricalcium phosphate does not enhance bone growth in mandibular defect of sheep.

In the field of craniomaxillofacial and orthopaedic surgery there is a constant need for bone or bone substitute. At the present, the most effective way to enhance bone healing clinically is to use autogenous bone grafts. The problems associated with the use of these autografts are donor site morbidity, limited supply and need for a second operative site. Currently there are several different synthetic products commercially available in the market; nevertheless, none of them is ideal for filling bone defects. Therefore, search for new synthetic materials for bone replacement is necessary. A mixture of tricalcium phosphate (TCP) and epsilon-caprolactone-lactide copolymer P(epsilon -CL/DL-LA) was prepared and implanted in critical size mandibular bone defects in twelve sheep. Contralateral side was used as a control. Follow-up times for histological and radiological studies were 9, 14, 24 and 52 weeks. We found that the implanted material did not enhance bone formation compared to control site. We also confirmed that defect size was of critical size, since there was no complete healing of the control site either. The results do not encourage us to continue our studies with the mixture of TCP and P(epsilon-CL/DL-LA) as a filling material for bone defects. Therefore the search for the ideal material is still ongoing.

Histological study of tissue reactions to epsilon-caprolactone-lactide copolymer in paste form.

In previous studies, epsilon-caprolactone-lactide copolymer in solid form has been used in experimental animals as suture material, and as a biodegradable nerve guide. The aim of the study reported here was to assess tissue reactions to epsilon-caprolactone-lactide copolymer in paste form, histologically, and to compare bone healing at the sites of implantation versus that at control sites. The other purpose of the study was to evaluate the properties of the implanted material as a filling material for bone defects. Resorption time and intensity of inflammatory reaction were also evaluated. Material was implanted into the abdominal walls and femurs of 34 rats. Follow-up times were from 2 weeks to 1 year. The results showed that epsilon-caprolactone-lactide copolymer in paste form induces a severe inflammatory reaction when placed in muscle, and moderate inflammation when implanted into bone. The resorption time was more than 1 year. Bone healing at sites of implantation was slower than at control sites.

Mixture of epsilon-caprolactone-lactide copolymer and tricalcium phosphate: a histological and immunohistochemical study of tissue reactions.

In cranio-maxillofacial surgery, bone transplantation is needed for treatment of bony defects. An autograft, allograft or biomaterial can be used. Autogenous bone grafts are considered to be the best materials available, but there are some disadvantages in their use including donorsite morbidity, need for a second operative site and limited graft supply. A search for new bone-graft materials therefore remains necessary. We prepared a mixture of tricalcium phosphate (TCP), which is a resorbable, non-toxic, osteoconductive ceramic material and epsilon-caprolactone-lactide copolymer P(epsilon-CL/DL-LA), a resorbable polymer, and placed it in the dermis and in mandibular bone defects in 13 rabbits. Follow-up times were two, three, seven, eight, 12, 15 and 18 weeks, tissue reactions were assessed, histologically and immunohistochemically. Times of resorption of the material from tissues were reported. We found that the mixture caused a mild inflammatory reaction when placed in bone and severe inflammation when placed in dermis. No highly fluorescent layer of tenascin or fibronectin was found surrounding the implant area. The mixture was excellent to handle and very easy to place into bone defects. The results are promising and have led us to continue development of the mixture.

Biocompatibility of solid poly (ortho ester).

In previous studies poly (ortho ester) (POE) has shown promise as a resorbable device, a hemostatic sealant and as a carrier for drugs in bone surgery. The aim of this study was to evaluate the tissue reactions of solid poly (ortho ester) implanted into both tibiae of 17 rabbits. One half of the rods were sterilized by gamma radiation and the other half by ethylene oxide. The follow-up times were from 1 week to 21 weeks, after which the animals were killed and the bony specimens examined histologically. The connective tissue samples were examined immunohistochemically in order to study the occurrences of two extracellular matrix glycoproteins, tenascin and fibronectin. The results showed that solid poly (ortho ester)s induce a moderate inflammatory reaction for 9 weeks. Tenascin and fibronectin were present in samples from 1 week up to 4 weeks. It was also found that gamma sterilized POE was resorbed at week 7 and ethylene oxide sterilized POE at week 13.