Additive manufactured gyroid-based cell structures under compression: design, testing and simulation for biomedical applications.

The mechanical behaviour of a DMLS Ti-6Al-4V gyroid-based cellular structure (CS), with potential application in the fabrication of implants, was studied under compressive conditions. The influence of the CS volumetric fraction on the elastic modulus was experimentally evaluated in cubic and cylindrical samples. The experimental results showed that the selected parameters allowed approximating the mechanical behaviour of the CS to that of trabecular bone. Finite element analysis was employed to study the mechanical behaviour of the CS. The model presented a good approximation of the experimental results, being useful to predict the mechanical behaviour of the CS.

Foamy Cell Histiocytosis Is a Diagnostic Pitfall: A Case Report of Xanthomatosis Secondary to Sitosterolemia Mimicking Progressive Nodular Histiocytosis.

ABSTRACT: We report a noteworthy case of a 10-year-old girl who presented with papular and nodular lesions on the skin that were clinically and histologically mistaken for progressive nodular histiocytosis. During the clinical management of the patient, the high lipid levels raised the suspicion of lipid metabolism disease and helped us to make the correct diagnosis of sitosterolemia. In sitosterolemia, proper management such as restriction of plant sterol intake and administration of cholesterol absorption inhibitor can improve prognosis.

Characteristics and outcomes of patients infected with nCoV19 requiring invasive mechanical ventilation in Argentina. / Características y resultados de los pacientes infectados con nCoV19 con requerimiento de ventilación mecánica invasiva en la Argentina.

OBJECTIVE: A novel coronavirus emerged this year as a cause of viral pneumonia. The main characteristics of the virus are rapid transmission, high contagion capacity and potential severity. The objective of this case series study is to describe the clinical characteristics of patients with confirmed coronavirus disease (COVID-19) admitted to different intensive care units in Argentina for mechanical ventilation. METHODS: A descriptive, prospective, multicenter case series study was conducted between April 1 and May 8, 2020. Data from patients older than 18 years who were admitted to the intensive care unit for mechanical ventilation for acute respiratory failure with a positive diagnosis of COVID-19 were included. RESULTS: The variables for 47 patients from 31 intensive care units were recorded: 78.7% were men (median age of 61 years), with a SAPS II score of 43 and a Charlson index score of 3. The initial ventilatory mode was volume control - continuous mandatory ventilation with a tidal volume less than 8mL/kg in 100% of cases, with a median positive end-expiratory pressure of 10.5cmH2O. At the end of the study, 29 patients died, 8 were discharged, and 10 remained hospitalized. The SAPS II score was higher among patients who died (p = 0.046). Charlson comorbidity index was associated with higher mortality (OR = 2.27, 95% CI 1.13 - 4.55, p = 0.02). CONCLUSION: Patients with COVID-19 and on mechanical ventilation in this series presented clinical variables similar to those described to date in other international reports. Our findings provide data that may predict outcomes.

OBJETIVO: El coronavirus ha emergido este año como causa de neumonía viral. Una de las principales características es su rápida transmisión y su potencial severidad. El objetivo de este estudio de serie de casos es describir las características clínicas de los pacientes con confirmación de enfermedad por coronavirus (COVID-19) admitidos en diferentes unidades de cuidados intensivos de la Argentina con requerimiento de ventilación mecánica. MÉTODOS: Estudio de serie de casos, descriptivo-prospectivo, multicéntrico realizado entre el 01 de abril y el 08 de mayo de 2020. Se incluyeron los datos de los pacientes mayores a 18 años, que ingresaron a la unidad de cuidados intensivos con requerimiento de ventilación mecánica por falla respiratoria aguda con diagnóstico positivo de COVID-19. RESULTADOS: Se registraron las variables de 47 pacientes de 31 unidades cuidados intensivos, 78.7% hombres de una mediana de edad de 61 años, con un SAPS II de 43, un índice de Charlson de 3. El modo ventilatorio inicial fue volume control - continuous mandatory ventilation con volumen corriente menor a 8mL/kg en el 100% de los casos, con una mediana de presión positiva al final de la espiración de 10,5cmH2O. A la fecha de cierre del estudio, 29 pacientes fallecieron, 8 alcanzaron el alta, y 10 pacientes continúan internados al cierre del estudio. El SAPS II fue mayor entre los fallecidos (p = 0.046). El índice de Charlson se asoció con mayor mortalidad (OR = 2,27 IC95% 1,13 - 4,55; p = 0,02). CONCLUSIÓN: Los pacientes con COVID-19 y ventilación mecánica de esta serie presentan variables clínicas similares a las descriptas a la fecha en otros reportes internacionales. Nuestros hallazgos proporcionan datos que permitirían de alguna manera predecir los resultados.

Características y resultados de los pacientes infectados con nCoV19 con requerimiento de ventilación mecánica invasiva en la Argentina / Characteristics and outcomes of patients infected with nCoV19 requiring invasive mechanical ventilation in Argentina

RESUMEN Objetivo: El coronavirus ha emergido este año como causa de neumonía viral. Una de las principales características es su rápida transmisión y su potencial severidad. El objetivo de este estudio de serie de casos es describir las características clínicas de los pacientes con confirmación de enfermedad por coronavirus (COVID-19) admitidos en diferentes unidades de cuidados intensivos de la Argentina con requerimiento de ventilación mecánica. Métodos: Estudio de serie de casos, descriptivo-prospectivo, multicéntrico realizado entre el 01 de abril y el 08 de mayo de 2020. Se incluyeron los datos de los pacientes mayores a 18 años, que ingresaron a la unidad de cuidados intensivos con requerimiento de ventilación mecánica por falla respiratoria aguda con diagnóstico positivo de COVID-19 Resultados: Se registraron las variables de 47 pacientes de 31 unidades cuidados intensivos, 78.7% hombres de una mediana de edad de 61 años, con un SAPS II de 43, un índice de Charlson de 3. El modo ventilatorio inicial fue volume control - continuous mandatory ventilation con volumen corriente menor a 8mL/kg en el 100% de los casos, con una mediana de presión positiva al final de la espiración de 10,5cmH2O. A la fecha de cierre del estudio, 29 pacientes fallecieron, 8 alcanzaron el alta, y 10 pacientes continúan internados al cierre del estudio. El SAPS II fue mayor entre los fallecidos (p = 0.046). El índice de Charlson se asoció con mayor mortalidad (OR = 2,27 IC95% 1,13 - 4,55; p = 0,02). Conclusión: Los pacientes con COVID-19 y ventilación mecánica de esta serie presentan variables clínicas similares a las descriptas a la fecha en otros reportes internacionales. Nuestros hallazgos proporcionan datos que permitirían de alguna manera predecir los resultados.

Abstract Objective: A novel coronavirus emerged this year as a cause of viral pneumonia. The main characteristics of the virus are rapid transmission, high contagion capacity and potential severity. The objective of this case series study is to describe the clinical characteristics of patients with confirmed coronavirus disease (COVID-19) admitted to different intensive care units in Argentina for mechanical ventilation. Methods: A descriptive, prospective, multicenter case series study was conducted between April 1 and May 8, 2020. Data from patients older than 18 years who were admitted to the intensive care unit for mechanical ventilation for acute respiratory failure with a positive diagnosis of COVID-19 were included. Results: The variables for 47 patients from 31 intensive care units were recorded: 78.7% were men (median age of 61 years), with a SAPS II score of 43 and a Charlson index score of 3. The initial ventilatory mode was volume control - continuous mandatory ventilation with a tidal volume less than 8mL/kg in 100% of cases, with a median positive end-expiratory pressure of 10.5cmH2O. At the end of the study, 29 patients died, 8 were discharged, and 10 remained hospitalized. The SAPS II score was higher among patients who died (p = 0.046). Charlson comorbidity index was associated with higher mortality (OR = 2.27, 95% CI 1.13 - 4.55, p = 0.02). Conclusion: Patients with COVID-19 and on mechanical ventilation in this series presented clinical variables similar to those described to date in other international reports. Our findings provide data that may predict outcomes.

Self-Association of Rafoxanide in Aqueous Media and Its Application in Preparing Amorphous Solid Dispersions.

Our primary objective is to characterize the self-association of rafoxanide in alkaline media. The second objective is to illustrate the feasibility of using rafoxanide micellar solution as the feed solution to prepare amorphous solid dispersion via spray drying. Rafoxanide is a poorly water-soluble drug. It is a weak acid, and its poor aqueous solubility is due to its hydrophobicity. The surface-active property of rafoxanide has not been previously reported. It was discovered that the addition of a small percentage of organic solvents is required to elevate the solubility of rafoxanide above the critical micelle concentration to allow for the formation of micelles. Our fluorescence decay study confirms the self-association of rafoxanide in a cosolvent consisting of 70%, v/v, NaOH solution and 30%, v/v, acetone. The position of each functional group in the micellar structures using the 1H NMR technique was identified. The critical micelle concentration of rafoxanide in the cosolvent is determined to be 302 µg/mL using a surface tension method. The solubility of rafoxanide in 0.1 N NaOH solution is less than 11 µg/mL. Interestingly, the apparent solubility increased to 38,400 µg/mL in the presence of 30% acetone as the result of micelle formation. This unique solubility characteristic makes it feasible to prepare rafoxanide amorphous solid dispersions by spray drying a predominantly aqueous (70% 0.1 N NaOH solution and 30% acetone) based feed solution. Povidone and copovidone were both used as polymeric carriers. Based on solid-state characterization, including differential scanning calorimetry, X-ray powder diffraction, and hot-stage polarized light microscopy, our results indicate that rafoxanide solid dispersions prepared using this novel process are amorphous. Approximately 750-fold increase in the concentration of rafoxanide in aqueous media at pH 6.8 was achieved with the amorphous solid dispersions.

Experimental design for the optimization and robustness testing of a liquid chromatography tandem mass spectrometry method for the trace analysis of the potentially genotoxic 1,3-diisopropylurea.

This paper discusses a design of experiments (DoE) assisted optimization and robustness testing of a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method development for the trace analysis of the potentially genotoxic 1,3-diisopropylurea (IPU) impurity in mometasone furoate glucocorticosteroid. Compared to the conventional trial-and-error method development, DoE is a cost-effective and systematic approach to system optimization by which the effects of multiple parameters and parameter interactions on a given response are considered. The LC and MS factors were studied simultaneously: flow (F), gradient (G), injection volume (Vinj), cone voltage (E(con)), and collision energy (E(col)). The optimization was carried out with respect to four responses: separation of peaks (Sep), peak area (A(p)), length of the analysis (T), and the signal-to-noise ratio (S/N). An optimization central composite face (CCF) DoE was conducted leading to the early discovery of carry-over effect which was further investigated in order to establish the maximum injectable sample load. A second DoE was conducted in order to obtain the optimal LC-MS/MS method. As part of the validation of the obtained method, its robustness was determined by conducting a fractional factorial of resolution III DoE, wherein column temperature and quadrupole resolution were considered as additional factors. The method utilizes a common Phenomenex Gemini NX C-18 HPLC analytical column with electrospray ionization and a triple quadrupole mass detector in multiple reaction monitoring (MRM) mode, resulting in short analyses with a 10-min runtime. The high sensitivity and low limit of quantification (LOQ) was achieved by (1) MRM mode (instead of single ion monitoring) and (2) avoiding the drawbacks of derivatization (incomplete reaction and time-consuming sample preparation). Quantitatively, the DoE method development strategy resulted in the robust trace analysis of IPU at 1.25 ng/mL absolute concentration corresponding to 0.25 ppm LOQ in 5 g/l mometasone furoate glucocorticosteroid. Validation was carried out in a linear range of 0.25-10 ppm and presented a relative standard deviation (RSD) of 1.08% for system precision. Regarding IPU recovery in mometasone furoate, spiked samples produced recoveries between 96 and 109 % in the range of 0.25 to 2 ppm.

Combined chelation of bi-functional bis-hydroxypiridinone and mono-hydroxypiridinone: synthesis, solution and in vivo evaluation.

3-Hydroxy-4-pyridinones (3,4-HP) are well known iron-chelators with applications in medicinal chemistry, mainly associated with their high affinity towards trivalent hard metal ions (e.g. M(3+), M=Fe, Al, Ga) and use as decorporating agents in situations of metal accumulation. The polydenticity and the extra-functionality of 3,4-HP derivatives have been explored, aimed at improving the chelating efficacy and the selectivity of the interaction with specific biological receptors. However, the ideal conjugation of both features in one molecular unity usually leads to high molecular weight compounds which can have crossing-membrane limitations. Herein, a different approach is used combining a arylpiperazine-containing bis-hydroxypyridone (H(2)L(1)) with a biomimetic mono-hydroxypyridinone, ornithine-derivative (HL(2)), to assess the potential coadjuvating effect that could result from the administration of both compounds for the decorporation of hard metal ions. This work reports the results of solution and in vivo studies on their chelating efficacy either as a simple binary or a ternary system (H(2)L(1):HL(2):M(3+)), using potentiometric and spectrophotometric methods. The solution complexation studies with Fe(III) indicate that the solubility of the complexes is considerably increased in the ternary system, an important feature for the metal complex excretion, upon the metal sequestration. The results of the in vivo studies with (67)Ga-injected mice show differences on the biodistribution profiles of the radiotracer, upon the administration of each chelating agent, that are mainly ascribed to the differences of their extra-functional groups and lipo/hydrophilic character. However, administration of both chelating agents leads to a more steady metal mobilization, which may be attributed to an improved access to different cellular compartments.

Multiple primary choledocholithiasis in sickle cell disease.

Choledocholithiasis can be caused by either primary or secondary bile duct stones. Although patients with sickle cell disease (SCD) are at high risk of development of pigmented gallstones due to chronic hemolysis, primary choledocholithiasis in SCD is very uncommon. The delay in the diagnosis of biliary tract pathology can occur in patients who had a prior cholecystectomy. There is a possible relationship between prior cholecystectomy and the subsequent occurrence of primary common bile duct stones, due to the higher probability of infection of the biliary system. Here, we report an unusual and severe case of multiple primary choledocholithiasis, associated with pancreatitis, in a patient with SCD, fourteen years after cholecystectomy.

Biologically relevant O,S-donor compounds. Synthesis, molybdenum complexation and xanthine oxidase inhibition.

Two O,S-donor ligands, hydroxythiopyrone and hydroxythiopyridinone derivatives, were developed and studied, as well as the corresponding O,O-derivatives, with a view to their potential pharmacological applications as xanthine oxidase (XO) inhibitors. The biological assays revealed that the O,S-ligands present high inhibitory activity towards XO (nanomolar order, close to that of the pharmaceutical drug allopurinol), in contrast to the corresponding O,O-analogues. Due to the biomedical relevance of this molybdenum-containing enzyme, the corresponding Mo(VI) complexes were studied both in solution and in the solid state, aimed at identifying the source of the biological properties. The solution studies showed that, in comparison with the O,O-analogues, the Mo(VI) complexes with the O,S-ligands present some stabilization, which is even more pronounced for the reduced Mo(IV) species. The crystal structures of the Mo(VI) complexes with the hydroxythiopyrone revealed good flexibility of the coordination modes, with two structural isomers and two polymorphic forms for a mononuclear and a binuclear species, respectively. These results give some support to mechanistic proposals for the XO inhibition involving the interaction of the thione group with the molybdenum cofactor, thus indicating a role of the sulfur atom in the XO inhibition.

A new approach for potential combined chelation therapy using mono- and bis-hydroxypyridinones.

Iron (Fe) overload diseases, such as beta-thalassemia (thal) major and hemochromatosis, have been treated for several decades by chelating therapy with desferrioxamine (DFO). However, drawbacks associated with that drug led to the development of new chelating drugs. The 3-hydroxy-4-pyridinones emerged as highly effective Fe chelators, and deferiprone (L1) has been approved as a Fe chelating drug. The most recent strategy for Fe overload problems is based on the replacement of monotherapies by a combination therapy with both chelators. Following a similar chelating strategy, we present herein the results of animal tests with a combination of two different hydroxypyridinone-based chelators. Both are of the 3-hydroxy-4-pyridinone (HP) type, but with one and two HP chelating units, and extra functional groups to account for differentiation in their physicochemical and biological properties, namely chelating efficacy and bioavailability. Animal studies have shown that the simultaneous administration of this pair of HP chelators, under appropriate proportion, to metal-loaded mice, could speed up metal excretion. This may be rationalized by adjuvant and eventual synergistic effects, due to complementary accessibility of each chelator to different cellular compartments.

Bifunctional 3-hydroxy-4-pyridinone derivatives as potential pharmaceuticals: synthesis, complexation with Fe(III), Al(III) and Ga(III) and in vivo evaluation with 67Ga.

A series of extra-functionalized 3-hydroxy-4-pyridinone chelators of hard metal ions, containing different side-chains with peptidomimetic groups, was studied to assess the effect of those groups on the physico-chemical properties, the metal-chelating affinity and the in vivo behaviour of the compounds, in view of their potential pharmaceutical applications. Besides the synthesis of the chelators, the study of their properties in aqueous solution alone and in the presence of M (3+) (M = Fe, Ga and Al) was performed by potentiometric/spectroscopic techniques. The octanol/water partition coefficient values of these hydroxypyridinone derivatives cover ca. 3 orders of magnitude (1.1 > log P > -2). They all form very stable tris-chelated M(III) complexes, the pFe and pGa values ranging up to five orders of magnitude. The in vivo studies showed the effect of the ligands on the biodistribution of (67)Ga citrate and also of (67)Ga-complexes in mice, in view of the potential use of the ligands or complexes as metal decorporating or as imaging agents, respectively. Although almost all these peptidomimetic hydroxypyridinone derivatives present very rapid clearance rate from most organs, the L-ornithine derivative (H(2)L(9)) shows to be superior to the others and as good as Deferiprone as metal decontaminant of Ga. Concerning the (67)Ga complexes, the benzyl-propylamine (H(2)L(3)) shows considerable bone retention, thus suggesting its potential application as imaging agent.

N-Arylamine derivatives of 3-hydroxy-4-pyridinones: solution studies and bioevaluation in view of Al-detoxification roles.

A study of a series of bifunctional 3-hydroxy-4-pyridinone derivatives, containing side-chains with various alkyl-aryl-amine-amides as extra-functional groups, was conducted to assess the relevance of those groups to the Al-chelating affinity, the lipo-hydrophilic balance of the compounds, and 67Ga biodistribution in mice, in view of their potential use as Al-decorporating agents; the results were compared with those for the drug Deferriprone. Their acid-base properties and Al-chelating affinity in aqueous solution were studied by potentiometric techniques. These ligands form very stable tris-chelated Al complexes and the non-chelating extra-groups are only responsible for small differences in the complex stability (DeltapAl< or =1.2). At physiological pH the major ligand/complex species have different charges, because of the different extent of protonation of the ligands. The introduction of the different groups induces a well-balanced stepwise-like lipo-hydrophilic character (-0.2 < log D(oct./water) < +1.1). The effect of each ligand on the biodistribution of 67Ga in overloaded mice is rapid blood clearance for all of them, but with different biodistribution patterns, namely excretion pathways and brain uptake/clearance, thus suggesting potential different clinical use.

Protease inhibitors: synthesis of bacterial collagenase and matrix metalloproteinase inhibitors incorporating succinyl hydroxamate and iminodiacetic acid hydroxamate moieties.

A series of succinyl hydroxamates/bishydroxamates as well as a new structural type of matrix metalloproteinase (MMP)/bacterial protease (BP) inhibitors, incorporating iminodiacetic (IDA) hydroxamate/bishydroxamate moieties, has been synthesized and tested for interaction with four vertebrate proteases, MMP-1, MMP-2, MMP-8 and MMP-9, and a BP, the collagenase isolated from Clostridium histolyticum (ChC). The new derivatives generally showed inhibition constants in the range of 8-62 nM against the five proteases mentioned above.

Alkylaryl-amino derivatives of 3-hydroxy-4-pyridinones as aluminium chelating agents with potential clinical application.

The neurotoxicity of aluminium is well established and so strategies for suitable aluminium chelating therapies, aimed at the treatment and/or amelioration of some neurological disorders, are of current interest. The present work describes a set of new bifunctional compounds containing a 3-hydroxy-4-pyridinone (3,4-HP) unit, as the aluminium chelating moiety, which is extra-functionalised with different alkyl-arylamine molecular segments, to account for the improvement on the biodistribution specificity of the chelating agents or the corresponding complexes. Besides the synthetic scheme, studies are performed to assess the properties of these compounds, namely in terms of lipophilicity, Al-chelating ability, speciation and in vivo 67Ga biodistribution. These studies show that the extrafunctional groups fortunately have small effects on the high Al chelating affinity of the 3,4-HP units, over a wide range of pH, but they lead to favourable changes on the lipo-hydrophilic balance of the ligands and on the complex speciation. Differences found in the biodistribution, namely the decrease of the blood-clearance rate and increase of the bone retention or the hepatobiliary excretion, seem to be mostly rationalized in terms of the increasing lipophilic character of the ligands.

N-Carboxyalkyl derivatives of 3-hydroxy-4-pyridinones: synthesis, complexation with Fe(III), Al(III) and Ga(III) and in vivo evaluation.

A set of three N-carboxyalkyl 3-hydroxy-4-pyridinones has been studied as bidentate M(III) chelators (M=Fe, Al, Ga), with potential for oral administration. After preparation of the ligands, their protonation constants (log K(i)) and the stability constants of their metal complexes have been determined. The distribution coefficients of these compounds, between 1-octanol and Tris buffer pH 7.4, were measured. The effect of these compounds on the biodistribution of 67Ga-citrate loaded rats was investigated and compared with that of the administered 67Ga-complexes. Results indicated that, among these chelating agents, the N-carboxyethyl derivative has the highest affinity towards this set of metal ions, irrespective of the metal, and that it could even compete with transferrin, the main Fe-plasma protein. The binding affinity and the hydrophilic character decrease with the increase in the size of the alkylic chain. The biological assays indicate that the complex formation in vivo is characterized by a high kinetics and thermodynamic stability, suggesting a competition with the transferrin. All the ligands were found to enhance the excretion of the gallium. Noteworthy is the observed Ga bone fixation, mostly with the ethyl derivative, thus suggesting the potential use of the complex as a bone seeking agent.