Endurance training-induced cardiac remodeling in a guinea pig athlete's heart model.

Besides the health benefits of regular exercise, high-level training-above an optimal level-may have adverse effects. In this study, we investigated the effects of long-term vigorous training and its potentially detrimental structural-functional changes in a small animal athlete's heart model. Thirty-eight 4-month-old male guinea pigs were randomized into sedentary and exercised groups. The latter underwent a 15-week-long endurance-training program. To investigate the effects of the intense long-term exercise, in vivo (echocardiography, electrocardiography), ex vivo, and in vitro (histopathology, patch-clamp) measurements were performed. Following the training protocol, the exercised animals exhibited structural left ventricular enlargement and a significantly higher degree of myocardial fibrosis. Furthermore, resting bradycardia accompanied by elevated heart rate variability occurred, representing increased parasympathetic activity in the exercised hearts. The observed prolonged QTc intervals and increased repolarization variability parameters may raise the risk of electrical instability in exercised animals. Complex arrhythmias did not occur in either group, and there were no differences between the groups in ex vivo or cellular electrophysiological experiments. Accordingly, the high parasympathetic activity may promote impaired repolarization in conscious exercised animals. The detected structural-functional changes share similarities with the human athlete's heart; therefore, this model might be useful for investigations on cardiac remodeling.

Development of predictive nomograms for clinical use to quantify the risk of isolating resistance prone organisms in patients with infected foot ulcers.

Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus (MRSA) have been considered prevalent pathogens in foot infections. However, whether empiric therapy directed against these organisms is necessary, and in whom to consider treatment, is rather unclear. The aim of this study was to develop predictive algorithms for forecasting the probability of isolating these organisms in the infected wounds of patients in a population where the prevalence of resistant pathogens is low. This was a retrospective study of regression model-based risk factor analysis that included 140 patients who presented with infected, culture positive foot ulcers to two urban hospitals. A total of 307 bacteria were identified, most frequently MRSA (11.1%). P. aeruginosa prevalence was 6.5%. In the multivariable analysis, amputation (odds ratio (OR) 5.75, 95% confidence interval (CI) 1.48-27.63), renal disease (OR 5.46, 95% CI 1.43-25.16) and gangrene (OR 2.78, 95% CI 0.82-9.59) were identified as risk factors associated with higher while diabetes (OR 0.07, 95% CI 0.01-0.34) and Infectious Diseases Society of America infection severity >3 (OR 0.18, 95% CI 0.03-0.65) were associated with lower odds of P. aeruginosa isolation (C statistic 0.81). Similar analysis for MRSA showed that amputation was associated with significantly lower (OR 0.29, 95% CI 0.09-0.79) risk, while history of MRSA infection (OR 5.63, 95% CI 1.56-20.63) and osteomyelitis (OR 2.523, 95% CI 1.00-6.79) was associated with higher odds of isolation (C statistic 0.69). We developed two predictive nomograms with reasonable to strong ability to discriminate between patients who were likely of being infected with P. aeruginosa or MRSA and those who were not. These analyses confirm the association of some, but also question the significance of other frequently described risk factors in predicting the isolation of these organisms.

Tailoring the hexagonal boron nitride nanomesh on Rh(111) with gold.

It is known that the hexagonal boron nitride (h-BN) monolayer has a periodically corrugated structure on Rh(111), termed "nanomesh", while the h-BN layer is planar on the close packed surfaces of coinage metals (Cu, Ag, Au) due the weak interactions. Our studies are aimed at understanding the metal-h-BN interaction, when both Rh and Au are present. On the one hand, the growth and thermal properties of gold deposited on h-BN nanomesh prepared on Rh(111) were studied. On the other hand, the formation of h-BN was examined on Au/Rh surface alloys prepared by the deposition of Au on Rh(111) and subsequent annealing at 1000 K. In each case, the h-BN was prepared by the decomposition of borazine at about 1000 K. Low energy ion scattering (LEIS), X-ray photoelectron spectroscopy (XPS) and scanning tunneling microscopy (STM) measurements revealed that the growth of Au on h-BN/Rh(111) at room temperature leads to the formation of mainly three dimensional (3D) gold nanoparticles, although at low coverages (<0.2 ML) 2D particles formed as well. Stepwise annealing to higher temperatures induces the intercalation of Au below the nanomesh, which was complete at around 1050 K. Some agglomeration and desorption of Au also took place. Interestingly, the nanomesh structure was observable after intercalation up to relatively large Au coverages. Measurements performed in the reverse order, namely exposing a Au/Rh(111) surface alloy to borazine, revealed that Rh atoms get covered by h-BN (or by its precursors) at significantly smaller borazine exposures than Au atoms. The nanomesh structure was essentially present up to a gold coverage of 0.9 ML, but with a smaller pore diameter, while it gradually disappeared at higher gold amounts. In this way the application of surface alloy supports provides a key for gradual tuning of the mesh morphology. Density functional theory calculations confirmed the decreased pore diameter of the BN layer upon the formation of a surface Rh-Au alloy layer.

Bicarbonate refractory QRS prolongation and left bundle-branch block following escitalopram and lamotrigine overdose: A case report and literature review of toxic left bundle-branch block.

WHAT IS KNOWN AND OBJECTIVE: Toxic prolongation of the QRS interval most often results from blockade of cardiac voltage-gated sodium channels and manifests on electrocardiogram with a right bundle-branch block-like morphology. Rarely, a left bundle-branch block (LBBB) morphology has been reported. CASE REPORT: We report a case of transient LBBB resultant from ingestion of lamotrigine and citalopram which was refractory to sodium bicarbonate therapy and eventually resolved spontaneously. WHAT IS NEW AND CONCLUSION: Cases of toxic LBBB are less likely to respond to bicarbonate therapy, suggesting that this finding is due to a mechanism other than sodium channel blockade.

Regulatory T Cells Promote Natural Killer Cell Education in Mixed Chimeras.

Therapeutic administration of regulatory T cells (Tregs) leads to engraftment of conventional doses of allogeneic bone marrow (BM) in nonirradiated recipient mice conditioned with costimulation blockade and mammalian target of rapamycin inhibition. The mode of action responsible for this Treg effect is poorly understood but may encompass the control of costimulation blockade-resistant natural killer (NK) cells. We show that transient NK cell depletion at the time of BM transplantation led to BM engraftment and persistent chimerism without Treg transfer but failed to induce skin graft tolerance. In contrast, the permanent absence of anti-donor NK reactivity in mice grafted with F1 BM was associated with both chimerism and tolerance comparable to Treg therapy, implying that NK cell tolerization is a critical mechanism of Treg therapy. Indeed, NK cells of Treg-treated BM recipients reshaped their receptor repertoire in the presence of donor MHC in a manner suggesting attenuated donor reactivity. These results indicate that adoptively transferred Tregs prevent BM rejection, at least in part, by suppressing NK cells and promote tolerance by regulating the appearance of NK cells expressing activating receptors to donor class I MHC.

Investigation of Deteriorated Dissolution of Amorphous Itraconazole: Description of Incompatibility with Magnesium Stearate and Possible Solutions.

Disadvantageous crystallization phenomenon of amorphous itraconazole (ITR) occurring in the course of dissolution process was investigated in this work. A perfectly amorphous form (solid dispersion) of the drug was generated by the electroblowing method (with vinylpyrrolidone-vinyl acetate copolymer), and the obtained fibers were formulated into tablets. Incomplete dissolution of the tablets was noticed under the circumstances of the standard dissolution test, after which a precipitated material could be filtered. The filtrate consisted of ITR and stearic acid since no magnesium content was detectable in it. In parallel with dissolution, ITR forms an insoluble associate, stabilized by hydrogen bonding, with stearic acid deriving from magnesium stearate. This is why dissolution curves do not have the plateaus at 100%. Two ways are viable to tackle this issue: change the lubricant (with sodium stearyl fumarate >95% dissolution can be accomplished) or alter the polymer in the solid dispersion to a type being able to form hydrogen bonds with ITR (e.g., hydroxypropyl methylcellulose). This work draws attention to one possible phenomenon that can lead to a deterioration of originally good dissolution of an amorphous solid dispersion.

The Immunosuppressive Effect of CTLA4 Immunoglobulin Is Dependent on Regulatory T Cells at Low But Not High Doses.

B7.1/2-targeted costimulation blockade (CTLA4 immunoglobulin [CTLA4-Ig]) is available for immunosuppression after kidney transplantation, but its potentially detrimental impact on regulatory T cells (Tregs) is of concern. We investigated the effects of CTLA4-Ig monotherapy in a fully mismatched heart transplant model (BALB/c onto C57BL/6). CTLA4-Ig was injected chronically (on days 0, 4, 14, and 28 and every 4 weeks thereafter) in dosing regimens paralleling clinical use, shown per mouse: low dose (LD), 0.25 mg (≈10 mg/kg body weight); high dose (HD), 1.25 mg (≈50 mg/kg body weight); and very high dose (VHD), 6.25 mg (≈250 mg/kg body weight). Chronic CTLA4-Ig therapy showed dose-dependent efficacy, with the LD regimen prolonging graft survival and with the HD and VHD regimens leading to >95% long-term graft survival and preserved histology. CTLA4-Ig's effect was immunosuppressive rather than tolerogenic because treatment cessation after ≈3 mo led to rejection. FoxP3-positive Tregs were reduced in naïve mice to a similar degree, independent of the CTLA4-Ig dose, but recovered to normal values in heart recipients under chronic CTLA4-Ig therapy. Treg depletion (anti-CD25) resulted in an impaired outcome under LD therapy but had no detectable effect under HD therapy. Consequently, the immunosuppressive effect of partially effective LD CTLA4-Ig therapy is impaired when Tregs are removed, whereas CTLA4-Ig monotherapy at higher doses effectively maintains graft survival independent of Tregs.

Seasonal and size-related variation of subcellular biomarkers in quagga mussels (Dreissena bugensis) inhabiting sites affected by moderate contamination with complex mixtures of pollutants.

The size-related differences in subcellular biomarker responses were assessed in Dreissena bugensis mussels inhabiting harbours moderately affected by pollution with complex mixtures of heavy metals and polycyclic aromatic hydrocarbons (PAHs). Adult D. bugensis samples were collected from three harbours of Lake Balaton (Hungary) characterized by moderate shipping activity, and as reference site, from a highly protected remote area of the lake. Biomarkers of exposure (metallothioneins (MTs), ethoxyresorufin-o-deethylase (EROD)), oxidative stress (lipid peroxidation (LPO), DNA strand breaks (DNAsb)) and possible endocrine disruption (vitellogenin-like proteins (VTG)) were analysed in whole-tissue homogenates of differently sized groups of mussels in relation to environmental parameters and priority pollutants (heavy metals and polycyclic aromatic hydrocarbons). Integrated biomarker response (IBR) indices were calculated for biomarker responses gained through in situ measurements to signalize critical sites and to better distinguish natural tendencies from biological effects of contaminants. Biomarker responses showed close positive correlation in case of MT, EROD, LPO, and DNAsb and negative correlation with VTG levels with mussel shell length in autumn, when higher levels of biomarkers appeared, possibly due to natural lifecycle changes of animals.

Pharmacological studies confirm neurotoxic metabolite(s) produced by the bloom-forming Cylindrospermopsis raciborskii in Hungary.

A rapid cyanobacterial bloom of Cylindrospermopsis raciborskii (3.2 × 10(4) filaments/mL) was detected early November, 2012, in the Fancsika pond (East Hungary). The strong discoloration of water was accompanied by a substantial fish mortality (even dead cats were seen on the site), raising the possibility of some toxic metabolites in the water produced by the bloom-forming cyanobacteria (C. raciborskii). The potential neuronal targets of the toxic substances in the bloom sample were studied on identified neurons (RPas) in the central nervous system of Helix pomatia. The effects of the crude aqueous extracts of the Fancsika bloom sample (FBS) and the laboratory isolate of C. raciborskii from the pond (FLI) were compared with reference samples: C. raciborskii ACT 9505 (isolated in 1995 from Lake Balaton, Hungary), the cylindrospermopsin producer AQS, and the neurotoxin (anatoxin-a, homoanatoxin-a) producer Oscillatoria sp. (PCC 6506) strains. Electrophysiological tests showed that both FBS and FLI samples as well the ACT 9505 extracts modulate the acetylcholine receptors (AChRs) of the neurons, evoking ACh agonist effects, then inhibiting the ACh-evoked neuronal responses. Dose-response data suggested about the same range of toxicity of FBS and FLI samples (EC50 = 0.397 mg/mL and 0.917 mg/mL, respectively) and ACT 9505 extracts (EC50 = 0.734 mg/mL). The extract of the neurotoxin-producing PCC 6506 strain, however, proved to be the strongest inhibitor of the ACh responses on the same neurons (EC50 = 0.073 mg/mL). The presented results demonstrated an anatoxin-a-like cholinergic inhibitory effects of cyanobacterial extracts (both the environmental FBS sample, and the laboratory isolate, FLI) by some (yet unidentified) toxic components in the matrix of secondary metabolites. Previous pharmacological studies of cyanobacterial samples collected in other locations (Balaton, West Hungary) resulted in similar conclusions; therefore, we cannot exclude that this chemotype of C. raciborskii which produce anatoxin-a like neuroactive substances is more widely distributed in this region.

Evaluation of multixenobiotic resistance in dreissenid mussels as a screening tool for toxicity in freshwater sediments.

The multixenobiotic defense mechanism (MXR) in aquatic organisms was recognized as a first-line defense system, and its potential use as an early biomarker of exposure to environmental stress has raised attention in the last two decades. To evaluate the relevance of this biomarker in the freshwater mussel Dreissena polymorpha, we studied its responsiveness within laboratory exposures to contaminants sequestered in freshwater sediments affected by moderate anthropogenic impact. The effectiveness of this biomarker was assessed by comparing the MXR-transporter activities determined in bivalves first with toxicity scores recorded with the D. rerio embryo developmental assay. Both bioassays were applied in the sediment contact test format. As a second evaluation approach, MXR activities determined in exposed mussels were compared with sediment-contamination data integrated into toxic units on the basis of acute toxicity to Daphnia magna. In D. polymorpha subjected to acute exposure with moderately polluted sediments, we detected limited (22-33 %) but statistically significant induction of MXR activity. Mean MXR activities significantly correlated with TU values computed for test sediments. MXR activities in mussels showed strong positive correlation with the metal load of sediments and proved to be unrelated to the contamination with polycyclic aromatic compounds. MXR activity in laboratory-exposed mussels showed low variability within treatments and thus reliably reflected even low contaminant differences between the negative reference and moderately polluted harbor sediments. The strong correlation found in this study between the MXR-transporter activity in exposed mussels and environmentally realistic sediment contamination underscores the fairly good sensitivity of this biomarker in laboratory testing conditions to signal the bioavailability of sediment bound contaminants, and it may also anticipate even the incidence of toxicity to biota.

Large shallow lake response to anthropogenic stressors and climate change: Missing macroinvertebrate recovery after oligotrophication (Lake Balaton, East-Central Europe).

East-Central Europe's largest shallow lake, Balaton, experienced strong eutrophication in the 1970-80s, followed by water quality improvement and oligotrophication by 2010 CE. Recently however, repeated cyanobacterial blooms occurred and warned that internal P-recycling can act similarly to external P load, therefore we need a better understanding of past water level (WL) and trophic changes in the lake. In this study we discuss the last 500-yr trophic, WL and habitat changes of the lake using paleoecological (chironomids, pollen) and geochemical (sediment chlorophyll, TOC, TS, TN, C/H ratio, major and trace element) methods. We demonstrate that the most intensive and irreversible change in the macroinvertebrate fauna occurred during the period of economic boom between the First and Second World War (∼1925-1940 CE), when large-scale built-in and leisure use of the lake has intensified. At that time, the Procladius-Microchironomus-Stempellina dominated community transformed to Procladius-Chironomus plumosus-type-Microchironomus community that coincided with land use changes, intensified erosion and water-level regulation in the lake with the maintenance of year-round high WL. This was followed by the impoverishment and population size decrease of the chironomid fauna and Procladius dominance since 1940 CE, without any recovery after 1994 CE despite the ongoing oligotrophication. Accelerated rate of change and turnover of the fauna was connected to an increase in the benthivorous fish biomass and eutrophication. The basin lost almost completely its once characteristic Stempellina species between 1927 and 1940 CE due to trophic level increase and seasonal anoxia in the Szemes Basin. Reference conditions for ecosystem improvement were assigned to 1740-1900 CE. We conclude that in spite of the ongoing oligotrophication, the re-establishment of the Procladius-Microchironomus-Stempellina assemblage is hampered, and requires fish population regulation.

Alcohol, liver, systemic inflammation and skin: a focus on patients with psoriasis.

Emerging evidence suggests that excessive alcohol consumption is associated with psoriasis. In alcoholics, antipsoriatic treatments are less efficient, but more toxic and an additional challenge is poor therapeutic compliance. There is a correlation between excess alcohol intake and increased risk of infections, but on the other hand alcohol and its metabolites can trigger a persistent systemic inflammation, mediated by pro-inflammatory cytokines released from activated Kupffer cells in the liver and from monocytes in the circulation. Ethanol and its metabolites can also enhance lymphocyte and keratinocyte activation and proliferation and can increase the mRNA levels of genes characteristic for proliferating keratinocytes. In this review, we discuss the mechanisms by which alcohol contributes to psoriasis development focusing on liver, systemic inflammation and skin.

Feasibility of individualised patient modelling for continuous vancomycin infusions in outpatient antimicrobial therapy, a retrospective study.

BACKGROUND: The area under the curve (AUC) to minimum inhibitory concentration (MIC) ratio is proposed as a therapeutic drug-monitoring parameter for dosing vancomycin continuous infusion in methicillin-resistant Staphylococcus aureus (MRSA) infection. Individualised pharmacokinetic-pharmacodynamic (PK/PD) calculation of AUC24 may better represent therapeutic dosing than current Therapeutic Drug Monitoring (TDM) practices, targeting a Steady State Concentration of 15-25 mg/L. AIM: To compare real world TDM practice to theoretical, individualised, PK/PD target parameters utilising Bayesian predictions to steady state concentrations (Css) for outpatients on continuous vancomycin infusions. METHOD: A retrospective single centre study was conducted at a tertiary hospital on adult patients, enrolled in an outpatient parenteral antimicrobial therapy (OPAT) program, receiving vancomycin infusions for MRSA infection. Retrospective Bayesian dosing was modelled to target PK/PD parameters and compared to real world data. RESULTS: Fifteen patients were evaluated with 53% (8/15) achieved target CSS during hospitalisation, and 83% (13/15) as outpatient. Median Bayesian AUC/MIC was 613 mg.h/L with CSS 25 mg/L. Patients suffering an Acute Kidney Injury (33%) had higher AUC0-24/MIC values. Retrospective Bayesian modelling demonstrated on median 250 mg/24 h lower doses than that administered was required (R2 = 0.81) which achieved AUC24/MIC median 444.8 (range 405-460) mg.h/L and CSS 18.8 (range 16.8-20.4) mg/L. CONCLUSION: Bayesian modelling could assist in obtaining more timely target parameters at lower doses for patients receiving continuous vancomycin infusion as part of an OPAT program, which may beget fewer adverse effects. Utilisation of personalised predictive modelling may optimise vancomycin prescribing, achieving earlier target concentrations as compared to empiric dosing regimens.

Size distribution and relationship of airborne SARS-CoV-2 RNA to indoor aerosol in hospital ward environments.

Aerosol particles proved to play a key role in airborne transmission of SARS-CoV-2 viruses. Therefore, their size-fractionated collection and analysis is invaluable. However, aerosol sampling in COVID departments is not straightforward, especially in the sub-500-nm size range. In this study, particle number concentrations were measured with high temporal resolution using an optical particle counter, and several 8 h daytime sample sets were collected simultaneously on gelatin filters with cascade impactors in two different hospital wards during both alpha and delta variants of concern periods. Due to the large number (152) of size-fractionated samples, SARS-CoV-2 RNA copies could be statistically analyzed over a wide range of aerosol particle diameters (70-10 µm). Our results revealed that SARS-CoV-2 RNA is most likely to exist in particles with 0.5-4 µm aerodynamic diameter, but also in ultrafine particles. Correlation analysis of particulate matter (PM) and RNA copies highlighted the importance of indoor medical activity. It was found that the daily maximum increment of PM mass concentration correlated the most with the number concentration of SARS-CoV-2 RNA in the corresponding size fractions. Our results suggest that particle resuspension from surrounding surfaces is an important source of SARS-CoV-2 RNA present in the air of hospital rooms.

Opportunistic pathogens and faecal indicators in drinking water associated biofilms in Cluj, Romania.

Biofouling occurs without exception in all water systems, with undesirable effects such as biocorrosion and deterioration of water quality. Drinking water associated biofilms represent a potential risk to human health by harbouring pathogenic or toxin-releasing microorganisms. This is the first study investigating the attached microbiota, with potential threat to human health, in a public water system in Romania. The presence and the seasonal variation of viable faecal indicators and opportunistic pathogens were investigated within naturally developed biofilms in a drinking water treatment plant. Bacterial frequencies were correlated with microbial loads in biofilms as well as with physical and chemical characteristics of biofilms and raw water. The biofilms assessed in the current study proved to be extremely active microbial consortia. High bacterial numbers were recovered by cultivation, including Pseudomonas aeruginosa, Escherichia coli, Aeromonas hydrophila, intestinal enterococci and Clostridium perfringens. There were no Legionella spp. detected in any biofilm sample. Emergence of opportunistic pathogens in biofilms was not significantly affected by the surface material, but by the treatment process. Implementation of a water safety plan encompassing measures to prevent microbial contamination and to control biofouling would be appropriate.

Interferon-α in the generation of monocyte-derived dendritic cells: recent advances and implications for dermatology.

Dendritic cells (DCs) have a critical role in antiviral responses, in autoimmune disease pathogenesis and in initiating and maintaining inflammatory skin disorders, and are candidates for cell-based immunotherapeutic approaches for tumours. Recent studies have shown the important role of type I interferons (IFNs) in DC differentiation and activation. In the presence of IFN-α and granulocyte/macrophage colony-stimulating factor monocytes differentiate into DCs referred to as IFN-DCs. In vitro generated IFN-DCs show a partially mature phenotype, are effective in taking up antigens, share features of myeloid DCs, plasmacytoid DCs and natural killer cells, exhibit an enhanced chemotactic response and are capable of migrating to the lymph nodes. IFN-DCs produce several chemokines and cytokines, including T-helper 1 (Th1) mediators belonging to the interleukin-12 family. IFN-DCs stimulate T- and B-cell responses and the production of IFN-γ in mixed lymphocyte reactions and have a capacity to produce IFN-γ themselves. IFN-DCs express several toll-like receptor (TLR) subtypes and TLR ligand stimulation improves their costimulatory molecule expression, increases their Th1 cytokine production and enhances their capacity to stimulate naive T-cell proliferation. Here we review the interaction of IFN-α and monocytes and the role of IFN-DCs in infections, in autoimmunity, in inflammation and in cancer immunotherapy focusing on dermatological conditions.

Real-life measurement of size-fractionated aerosol concentration in a plethysmography box during the COVID-19 pandemic and estimation of the associated viral load.

INTRODUCTION: There are concerns about pulmonary function tests (PFTs) being associated with aerosol generation and enhanced virus transmission. As a consequence, the number of PFTs was reduced significantly during the coronavirus disease 2019 pandemic. However, there are no robust data supporting this fear. OBJECTIVES: To perform real-life measurement of aerosol concentrations in a PFT laboratory to monitor the concentration of particles near the patient, and to model the associated potential viral load. METHODS: Two optical particle counters were used to sample the background concentration and the concentration of particles near the patient's mouth in a whole-body plethysmography box. Statistical evaluation of the measured particle concentration time series was completed. The particle exhalation rate was assessed based on the measured particle concentration data by applying the near-field/far-field theory. The number of exhaled viruses by an infected patient during the test was compared with the emission of viruses during quiet breathing and speaking. RESULTS: Twenty-five patients were included in the study. Eighteen patients showed a significant increase in aerosol concentration [mean 1910 (standard deviation 593) particles/L]. Submicron particles dominated the number size distribution of the generated particles, but large particles represented a higher volume fraction in the generated particles compared with background. An average gene exhalation rate of 0.2/min was estimated from this data. This is one order of magnitude higher than the release rate for the same infected person during quiet breathing, and of the same order of magnitude as the release rate during normal speaking. CONCLUSIONS: This study demonstrated that PFTs are aerosol-generating procedures. Based on these results, the moderate increase in viral load does not underpin stopping such examinations.

Integrated twin-screw wet granulation, continuous vibrational fluid drying and milling: A fully continuous powder to granule line.

Highly homogeneous low-dose (50 µg) tablets were produced incorporating perfectly free-flowing granules prepared by a fully integrated Continuous Manufacturing (CM) line. The adopted CM equipment consisted of a Twin-Screw Wet Granulator (TSWG), a Continuous Fluid Bed Dryer (CFBD) and a Continuous Sieving (CS) unit. Throughout the experiments a pre-blend of lactose-monohydrate and corn starch was gravimetrically dosed with 1 kg/h into the TSWG, where they were successfully granulated with the drug containing water-based PVPK30 solution. The wet mass was subsequently dried in the CFBD on a vibratory conveyor belt and finally sieved in the milling unit. Granule production efficiency was maximized by determining the minimal Liquid-to-Solid (L/S) ratio (0.11). Design of Experiments (DoE) were carried out in order to evaluate the influence of the drying process parameters of the CFBD on the Loss-on-Drying (LOD) results. The manufactured granules were compressed into tablets by an industrial tablet rotary press with excellent API homogeneity (RSD < 3%). Significant scale-up was realized with the CM line by increasing the throughput rate to 10 kg/h. The manufactured granules yielded very similar results to the previous small-scale granulation runs. API homogeneity was demonstrated (RSD < 2%) with Blend Uniformity Analysis (BUA). The efficiency of TSWG granulation was compared to High-Shear Granulation (HSG) with the same L/S ratio. The final results have demonstrated that both the liquid distribution and more importantly API homogeneity was better in case of the TSWG granulation (RSD 1.3% vs. 4.5%).

Airway obstruction can be better predicted using Global Lung Function Initiative spirometry reference equations in Marfan syndrome.

Marfan syndrome is a genetic disorder of the connective tissue, including involvement of the lungs.Pulmonary function test was performed in 32 asymptomatic adult Marfan patients using European Community for Coal and Steel (ECCS) and Global Lung Function Initiative (GLI) reference values.Using GLI equations for reference, significantly lower lung function values were noted for forced vital capacity (FVC) (87.0 ± 16.6% vs. 97.1 ± 16.9%; P < 0.01) and forced expiratory volume in the first second (FEV1) (79.6 ± 18.9% vs. 88.0 ± 19.1%; P < 0.01) predicted compared to ECCS. Obstructive ventilatory pattern was present in 25% of the cases when calculating with GLI lower limit of normal (LLN), and it was significantly more common in men as compared to women (n = 6, 50% vs. n = 2, 10%; P = 0.03).GLI is more suitable to detect early ventilatory changes including airway obstruction in young patients with special anatomic features, and should be used as a standard way of evaluation in asymptomatic Marfan population.

Psoriasis and alcohol: is cutaneous ethanol one of the missing links?

Many exogenous factors including excessive alcohol consumption have been associated with psoriasis, but the underlying mechanisms still remain elusive. Drinking worsens therapeutic compliance, and decreases the efficacy and increases the toxicity of systemic antipsoriatic treatments. Excess alcohol intake results in compromised immunity and increased risk of infections, but alcohol can induce proinflammatory cytokine production in various cell types and can increase mitogen-derived lymphocyte proliferation and lymphocyte activation. As we have previously reported, alcohol and one of its metabolites, acetone, induce keratinocyte proliferation and increase the mRNA levels of genes characteristic for proliferating keratinocytes, such as alpha5 integrin, cyclin D1 and keratinocyte growth factor receptor. Recently the correlation between blood and skin ethanol levels in humans was determined by a transdermal alcohol monitoring device, against the 'gold standard' breath alcohol readings. Based on transdermal alcohol measurements it can be concluded that cutaneous alcohol concentrations can reach levels that induce proinflammatory cytokine production and lymphocyte and keratinocyte proliferation in vitro. It is expected that the development of methodologies measuring transdermal ethanol will provide additional tools to evaluate how alcohol influences skin physiology and different dermatological conditions including psoriasis. Our review focuses on the possible link between alcohol misuse and psoriasis, particularly on the possible role of cutaneous ethanol in precipitating the disease.