Successful treatment of immune checkpoint inhibitor-related periaortitis.

We report a 64-year-old patient with melanoma receiving ipilimumab and nivolumab therapy who presented with a periaortic soft tissue mass around the abdominal aorta on restaging fluorodeoxyglucose positron emission tomography/computed tomography imaging. Clinical, laboratory, and radiologic findings resulted in a diagnosis of immune checkpoint inhibitor-related periaortitis. Periaortitis is a rare disease presenting with fibro-inflammatory tissue around the aorta and may lead to serious complications. Immune checkpoint inhibitors were discontinued, and the patient was treated with glucocorticoids, leading to a complete resolution of the periaortitis. To our knowledge, this is only the third reported case of immune checkpoint inhibitor-related periaortitis.

How drug onset rate and duration of action affect drug forgiveness.

Medication nonadherence is one of the largest problems in healthcare today, particularly for patients undergoing long-term pharmacotherapy. To combat nonadherence, it is often recommended to prescribe so-called "forgiving" drugs, which maintain their effect despite lapses in patient adherence. Nevertheless, drug forgiveness is difficult to quantify and compare between different drugs. In this paper, we construct and analyze a stochastic pharmacokinetic/pharmacodynamic (PK/PD) model to quantify and understand drug forgiveness. The model parameterizes a medication merely by an effective rate of onset of effect when the medication is taken (on-rate) and an effective rate of loss of effect when a dose is missed (off-rate). Patient dosing is modeled by a stochastic process that allows for correlations in missed doses. We analyze this "on/off" model and derive explicit formulas that show how treatment efficacy depends on drug parameters and patient adherence. As a case study, we compare the effects of nonadherence on the efficacy of various antihypertensive medications. Our analysis shows how different drugs can have identical efficacies under perfect adherence, but vastly different efficacies for adherence patterns typical of actual patients. We further demonstrate that complex PK/PD models can indeed be parameterized in terms of effective on-rates and off-rates. Finally, we have created an online app to allow pharmacometricians to explore the implications of our model and analysis.

Synthesis of the Indolizidine Core of Virosinine A via a Microwave-Promoted Cascade Cyclization Involving Iminyl Radicals.

The indolizidine core of virosinine A was synthesized by means of a microwave-promoted cascade reaction featuring 5-exo-trig iminyl radical cyclization, thiyl radical elimination, and intramolecular imine alkylation. The resulting bicyclic iminium ion underwent stereoselective reduction by Red-Al to deliver the target compound. DFT calculations suggested that both the radical cyclization and thiyl radical elimination steps are reversible at high reaction temperatures.

Effect of print orientation, storage conditions, and storage time on intaglio surface accuracy of implant surgical guides fabricated by using a stereolithography technology.

STATEMENT OF PROBLEM: The accuracy of printed implant surgical guides can be affected by different factors that negatively impact the planned implant position. How print orientation, storage time, and conditions influence manufacturing accuracy remains uncertain. PURPOSE: The purpose of this in vitro study was to evaluate the influence of print orientation, storage conditions, and storage time on the intaglio surface accuracy of implant surgical guides manufactured by using a stereolithography (SLA) printer. MATERIAL AND METHODS: A tooth-supported maxillary implant surgical guide design (control file) was used to fabricate the specimens (N=40, n=10). Four groups were created based on the print orientation used: 0 (Group 0), 45 (Group 45), 70 (Group 70), and 90 degrees (Group 90). The specimens were fabricated using an SLA printer (Form 3B+) and a biocompatible dental resin (Surgical Guide Resin V1) following the manufacturer's recommended protocol. Each group was divided into 2 subgroups based on the storage conditions: light (L subgroup) and dark (D subgroup) settings. Each specimen was digitized by using a desktop scanner (Medit T710) at days 0, 1, 7, and 14. The control file and each digitized specimen were superimposed by using the best-fit technique with a metrology program (Geomagic Control X). The root mean square (RMS) error was used to calculate the discrepancies between the control files and specimen files. Three-way ANOVA and pairwise comparison Tukey tests were used to analyze trueness. The Levene test was used to assess precision (α=.05). RESULTS: Significant trueness discrepancies were found among the groups tested (P<.001), but no significant differences were found among the subgroups (P=.100) and the storage times analyzed (P=.609). Additionally, the Tukey test showed significant RMS error mean value discrepancies between Group 0 and Group 45 (P<.001), Group 0 and Group 90 (P<.001), Group 45 and Group 70 (P<.001), and Group 70 and Group 90 (P<.001). The Levene test revealed significant SD discrepancies among the groups tested (P<.05). CONCLUSIONS: The trueness and precision of the intaglio surface of the implant surgical guides manufactured by using the printer and material tested were affected by the print orientation. However, storage conditions over a 14-day period did not impact the intaglio accuracy of the specimens.

Neuroimaging glutamatergic mechanisms differentiating antipsychotic treatment-response.

Glutamatergic dysfunction is associated with failure to respond to antipsychotic medication in individuals with schizophrenia. Our objective was to combine neurochemical and functional brain imaging methods to investigate glutamatergic dysfunction and reward processing in such individuals compared with those with treatment responsive schizophrenia, and healthy controls. 60 participants played a trust task, while undergoing functional magnetic resonance imaging: 21 classified as having treatment-resistant schizophrenia, 21 patients with treatment-responsive schizophrenia, and 18 healthy controls. Proton magnetic resonance spectroscopy was also acquired to measure glutamate in the anterior cingulate cortex. Compared to controls, treatment responsive and treatment-resistant participants showed reduced investments during the trust task. For treatment-resistant individuals, glutamate levels in the anterior cingulate cortex were associated with signal decreases in the right dorsolateral prefrontal cortex when compared to those treatment-responsive, and with bilateral dorsolateral prefrontal cortex and left parietal association cortex when compared to controls. Treatment-responsive participants showed significant signal decreases in the anterior caudate compared to the other two groups. Our results provide evidence that glutamatergic differences differentiate treatment resistant and responsive schizophrenia. The differentiation of cortical and sub-cortical reward learning substrates has potential diagnostic value. Future novel interventions might therapeutically target neurotransmitters affecting the cortical substrates of the reward network.

Species selection determines carbon allocation and turnover in Miscanthus crops: Implications for biomass production and C sequestration.

Growing Miscanthus species and hybrids has received strong scientific and commercial support, with the majority of the carbon (C) modelling predictions having focused on the high-yield, sterile and noninvasive hybrid Miscanthus × giganteus. However, the potential of other species with contrasting phenotypic and physiological traits has been seldom explored. To better understand the mechanisms underlying C allocation dynamics in these bioenergy crops, we pulse-labelled (13CO2) intact plant-soil systems of Miscanthus × giganteus (GIG), Miscanthus sinensis (SIN) and Miscanthus lutarioriparius (LUT) and regularly analysed soil respiration, leaves, stems, rhizomes, roots and soils for up to 190 days until leaf senescence. A rapid isotopic enrichment of all three species was observed after 4 h, with the amount of 13C fixed into plant biomass being inversely related to their respective standing biomass prior to pulse-labelling (i.e., GIG < SIN < LUT). However, both GIG and LUT allocated more photoassimilates in the aboveground biomass (leaves+stems = 78 % and 74 %, respectively) than SIN, which transferred 30% of fixed 13C in its belowground biomass (rhizomes+roots). Although less fixed 13C was recovered from the soils (<1 %), both rhizospheric and bulk soils were signficantly more enriched under SIN and LUT than under GIG. Importantly, the soils under SIN emitted less CO2, which suggests it could be the best choice for reaching C neutrality. These results from this unique large-scale study indicate that careful species selection may hold the success for reaching net GHG mitigation.

Effect of Salivary Flow on Bleached Enamel Roughness and Mineral Content: an In Situ and In Vitro Study.

This study aimed to evaluate the effect of human saliva in vitro and salivary flow in situ on the roughness and mineral content of bleached enamel. Dental specimens were divided into five groups (n=15): not bleached (NB); bleached (35% hydrogen peroxide) and exposed to distilled water (DW); human saliva in vitro (IV); normal salivary flow in situ (NSF); and low salivary flow (LSF) in situ. Enamel roughness (Ra, Rz) and calcium/phosphorus contents were evaluated with laser profilometry and energy-dispersive spectroscopy, respectively, at baseline (T1), after bleaching (T2), and after seven days (T3). Salivary pH and buffer capacity were evaluated with colorimetric strips and salivary calcium and phosphorus with absorbance spectrophotometry. Data were analyzed with non-parametric tests and linear regression (α=0.05). After contact with saliva, Ra and Rz of LSF=DW>IV=NSF=NB was found. For DW and LSF, the roughness of T1

Evaluating the impact of a cemetery on groundwater by multivariate analysis.

Water analyses in conjunction with hydrological and geotechnical investigations were carried out to assess the potential for groundwater contamination from the decomposition of buried human bodies. Water samples were collected from 2007 to 2018 in three monitoring wells built within the cemetery area. Water quality was evaluated based on the determination of 25 analytical parameters (20 physical-chemical and 5 microbiological). Laboratory data reported by the local sewage water company for water collected in household cisterns located outside the cemetery area were also evaluated. Multivariate analysis showed a similar pattern between iron content, turbidity, and rainfall data collected at the rainfall station closest to the study area. This behavior is a direct consequence of soil leaching (oxisol). The physical characterization of the soil of the unsaturated area above the aquifer indicates that the absorption of body waste by the soil is favored, preventing surface contaminants from reaching the aquifer. This work also found that the water samples collected outside the cemetery area do not comply with the Brazilian limits for drinking water. In conclusion, water samples collected from monitoring wells located within the cemetery area have little to none impact on both subsurface and underground contamination.

Mobility-resolved broadband dissociation and parallel reaction monitoring for laser desorption/ionization-mass spectrometry - Tattoo pigment identification supported by trapped ion mobility spectrometry.

In this work, trapped ion mobility spectrometry (TIMS) was introduced to facilitate tandem mass spectrometry (MS2) experiments for laser desorption/ionization-mass spectrometry (LDI-MS) as mobility-resolved fragmentation. The mobility separation of desorbed ions was followed by subsequent fragmentation using data-independent broadband collision-induced dissociation (bbCID) or targeted fragmentation through a prototypic version of parallel reaction monitoring-parallel accumulation serial fragmentation (prm-PASEF) for LDI. Both mobility-resolved fragmentation options, TIMS-bbCID and prm-PASEF, were applied to LDI point measurements to identify organic pigments in tattoo inks. Furthermore, the prototypic prm-PASEF algorithm was used in imaging applications to increase confidence in annotating organic tattoo pigments in skin samples with adverse reactions. Due to less complex spectra in matrix-free LDI, both fragmentation methods yielded fast and reliable MS2 identification workflows. TIMS-bbCID was especially beneficial for the rapid acquisition of multiple fragment spectra. For the targeted prm-PASEF approach, analytes' mobilities needed to be collected prior to simplified fragmentation. Therefore, a reference list for 14 pigments was created. The possible number of experiments per thin section and the associated savings in analysis time compared to conventional MS2 were particularly suitable for the imaging application. Furthermore, the mobility dimension enabled a new orthogonal identification parameter, increasing the annotation confidence of tattoo pigments through compound specific mobilities.

Rosai-Dorfman Disease of the Rectum: Newly Identified Genetic Point Mutations and Robotic Resection.

Rosai-Dorfman disease (RDD) is a rare disease characterized by histiocytic proliferation which typically presents as massive, painless, cervical lymphadenopathy in children or young adults. GI involvement is exceedingly rare with only 20 documented cases to date. Of those 20 cases, only 3 cases have involved the rectum. Here, we present 2 cases of rectal RDD with attention paid to the diagnostic and technical challenges presented by this disease. When presenting as a perirectal mass, RDD can be mistaken for other lesions to include malignancy, leading to surgical removal. We present a video of a robotic low-anterior resection with intracorporeal anastomosis in order to remove a pelvic mass involving the rectum, initially considered to be a stromal tumor. In addition, we describe a copy number variation in AKT and 3 point mutations detected by next generation sequencing, which had not been previously reported in association with this disease.

Comparing Symmetric Dimethylarginine and Amyloid-ß42 as Predictors of Alzheimer's Disease Development.

Background: Physicians may soon be able to diagnose Alzheimer's disease (AD) in its early stages using fluid biomarkers like amyloid. However, it is acknowledged that additional biomarkers need to be characterized which would facilitate earlier monitoring of AD pathogenesis. Objective: To determine if a potential novel inflammation biomarker for AD, symmetric dimethylarginine, has utility as a baseline serum biomarker for discriminating prodromal AD from cognitively unimpaired controls in comparison to cerebrospinal fluid amyloid-ß42 (Aß42). Methods: Data including demographics, magnetic resonance imaging and fluorodeoxyglucose-positron emission tomography scans, Mini-Mental State Examination and Functional Activities Questionnaire scores, and biomarker concentrations were obtained from the Alzheimer's Disease Neuroimaging Initiative for a total of 146 prodromal AD participants and 108 cognitively unimpaired controls. Results: Aß42 (p = 0.65) and symmetric dimethylarginine (p = 0.45) were unable to predict age-matched cognitively unimpaired controls and prodromal AD participants. Aß42 was negatively associated with regional brain atrophy and hypometabolism as well as cognitive and functional decline in cognitively unimpaired control participants (p < 0.05) that generally decreased in time. There were no significant associations between Aß42 and symmetric dimethylarginine with imaging or neurocognitive biomarkers in prodromal AD patients. Conclusions: Correlations were smaller between Aß42 and neuropathological biomarkers over time and were absent in prodromal AD participants, suggesting a plateau effect dependent on age and disease stage. Evidence supporting symmetric dimethylarginine as a novel biomarker for AD as a single measurement was not found.

Splenic red pulp macrophages provide a niche for CML stem cells and induce therapy resistance.

Disease progression and relapse of chronic myeloid leukemia (CML) are caused by therapy resistant leukemia stem cells (LSCs), and cure relies on their eradication. The microenvironment in the bone marrow (BM) is known to contribute to LSC maintenance and resistance. Although leukemic infiltration of the spleen is a hallmark of CML, it is unknown whether spleen cells form a niche that maintains LSCs. Here, we demonstrate that LSCs preferentially accumulate in the spleen and contribute to disease progression. Spleen LSCs were located in the red pulp close to red pulp macrophages (RPM) in CML patients and in a murine CML model. Pharmacologic and genetic depletion of RPM reduced LSCs and decreased their cell cycling activity in the spleen. Gene expression analysis revealed enriched stemness and decreased myeloid lineage differentiation in spleen leukemic stem and progenitor cells (LSPCs). These results demonstrate that splenic RPM form a niche that maintains CML LSCs in a quiescent state, resulting in disease progression and resistance to therapy.

Neuroimaging oxytocin modulation of social reward learning in schizophrenia.

BACKGROUND: Conventional pharmacological approaches have limited effectiveness for schizophrenia. There is interest in the application of oxytocin, which is involved in social cognition. Clinical trials have yielded mixed results, with a gap in understanding neural mechanisms. AIMS: To evaluate the behavioural impact of oxytocin administration on a social learning task in individuals with schizophrenia, and elucidate any differential neural activity produced. METHOD: We recruited 20 clinically stable right-handed men diagnosed with schizophrenia or schizoaffective disorder. In a double-blind cross-over randomised controlled study, 40 IU of oxytocin or placebo were administered before functional magnetic resonance imaging of participants playing a multi-round economic exchange game of trust. Participants had the role of investors (investment trials) receiving repayment on their investments (repayment trials), playing one session against a computer and a second against a player believed to be human. RESULTS: During investment trials, oxytocin increased neural signalling in the right lateral parietal cortex for both human and computer player trials, and attenuated signalling in the right insula for human player trials. For repayment trials, oxytocin elicited signal increases in left insula and left ventral caudate, and a signal decrease in right amygdala during the human player trials; conversely it resulted in right dorsal caudate activation during the computer player trials. We did not find a significant change in behavioural performance associated with oxytocin administration, or any associations with symptoms. CONCLUSIONS: During a social learning task oxytocin modulates cortical and limbic substrates of the reward-processing network. These perturbations can be putatively linked to the pathoaetiology of schizophrenia.

Candida glabrata - basic characteristics, virulence, treatment, and resistance.

Fungal infections are currently a serious health concern. Life-threatening conditions that occur mainly in immunocompromised patients are largely caused by representatives of the genus Candida. The most common causative agent is the yeast Candida albicans, but in recent years there has been a significant shift towards Candida glabrata and other so-called non-albicans Candida yeasts (e.g. Candida tropicalis or Candida parapsilosis). Invasive infections caused by the multidrug-resistant yeast Candida auris are associated with high mortality. There are several differences between C. glabrata and other causative agents of candidiasis in biological characteristics and virulence factors. The innate increased resistance to azoles along with the ability to rapidly acquire resistance to other groups of antifungal agents is a dangerous combination which makes it difficult to manage Candida infections. A better understanding of the virulence factors and mechanisms of resistance to antifungal agents can benefit the management of Candida infections. Equally important is the search for new target sites for antifungal therapy. The present work briefly summarizes the existing knowledge in this area.

Occlusal features of 5-year-old Greek children: a cross-sectional national study.

BACKGROUND: Occlusal characteristics of the primary dentition are crucial in predicting and determining permanent tooth alignment and occlusion. The aim of our study was to determine the occlusal characteristics of the primary dentition of 5-year-old children in Greece through a national pathfinder survey. METHODS: A stratified cluster sample of 1222 5-year-old children was selected according to the WHO guidelines for national pathfinder surveys. Five occlusal traits were registered clinically in centric occlusion, separately for the left and right sides: sagittal relationships of the second primary molars and primary canines, overjet, overbite, crossbite, and maxillary and mandibular spacing. RESULTS: Most children showed a flush terminal plane of primary second molars (44.8%), a class I primary canine relationship (52.2%) and normal overjet (46.4%), but a high prevalence of Class II canine relationship (25.6%) and overjet (37.8%) were also observed. A normal overbite was found in 40% of the children and 40% had a deep overbite. Spacing was apparent in both maxilla (71.1% of children) and mandible (56.4%). The prevalence of open bite and distal step molar relationship significantly rose in children with non-nutritive sucking habits. CONCLUSIONS: Νon-nutritive habits were associated to altered occlusal features. No sex significant differences were found in either the sagittal relationships of second primary molars and primary canines, or overjet, overbite, crossbite and spacing.

Cosolvent Sites-Based Discovery of Mycobacterium Tuberculosis Protein Kinase G Inhibitors.

Computer-aided drug discovery methods play a major role in the development of therapeutically important small molecules, but their performance needs to be improved. Molecular dynamics simulations in mixed solvents are useful in understanding protein-ligand recognition and improving molecular docking predictions. In this work, we used ethanol as a cosolvent to find relevant interactions for ligands toward protein kinase G, an essential protein of Mycobacterium tuberculosis (Mtb). We validated the hot spots by screening a database of fragment-like compounds and another one of known kinase inhibitors. Next, we performed a pharmacophore-guided docking simulation and found three low micromolar inhibitors, including one with a novel chemical scaffold that we expanded to four derivative compounds. Binding affinities were characterized by intrinsic fluorescence quenching assays, isothermal titration calorimetry, and the analysis of melting curves. The predicted binding mode was confirmed by X-ray crystallography. Finally, the compounds significantly inhibited the viability of Mtb in infected THP-1 macrophages.

Should patients skip late doses of medication? A pharmacokinetic perspective.

Missed doses, late doses, and other dosing irregularities are major barriers to effective pharmacotherapy, especially for the treatment of chronic conditions. What should a patient do if they did not take their last dose at the prescribed time? Should they take it late or skip it? In this paper, we investigate the pharmacokinetic effects of taking a late dose. We consider a single compartment model with linear absorption and elimination for a patient instructed to take doses at regular time intervals. We suppose that the patient forgets to take a dose and then realizes some time later and must decide what remedial steps to take. Using mathematical analysis, we derive several metrics which quantify the effects of taking the dose late. The metrics involve the difference between the drug concentration time courses for the case that the dose is taken late and the case that the dose is taken on time. In particular, the metrics are the integral of the absolute difference over all time, the maximum of the difference, and the maximum of the integral of the difference over any single dosing interval. We apply these general mathematical formulas to levothyroxine, atorvastatin, and immediate release and extended release formulations of lamotrigine. We further show how population variability can be immediately incorporated into these results. Finally, we use this analysis to propose general principles and strategies for dealing with dosing irregularities.

Early life stress influences basal ganglia dopamine receptors and novel object recognition of adolescent and adult rats.

Environmental stimuli in early life are recognized to affect brain development and behavior. Mother-pup interaction constitutes a determinant stimulus during this critical period. It is known that the dopaminergic system undergoes significant reorganization during adolescence and that dopamine receptors are involved in recognition memory. Based on the above, we examined the effects of brief and prolonged maternal separation during the neonatal period (15 or 180 min daily) on basal ganglia dopamine receptors and on the behavior in the novel object recognition task of adolescent and adult male rats. Using the NOR task, we observed that the discrimination index (DI) was decreased in rats with brief maternal separations independent of age. Using receptor autoradiography, we observed that brief maternal separation induced decreases in D1, D2 and D4 receptor binding levels in adult basal ganglia nuclei, while prolonged maternal separation induced increases in D1 receptor binding levels in caudate - putamen (CPu) of adolescent rats. With immunoblotting experiments, we found decreases in D1 and increases in D2 total protein levels in CPu of adult rats with prolonged maternal separations. Α positive correlation was observed between DI and D1 binding levels in CPu, internal globus pallidus and substantia nigra, and D2 binding levels in nucleus accumbens core in adult rats, using the Pearson correlation coefficient. Our results indicate that the long-lasting effects of neonatal mother-offspring separation on dopamine receptors depend on the duration of maternal separation and age and that this early life experience impairs recognition memory in adolescent and adult rats. Furthermore, the present results suggest that modulation of striatal dopamine receptors might underlie the reduced recognition memory of adult rats with brief neonatal maternal separations.

Specificity and Reactivity of Mycobacterium tuberculosis Serine/Threonine Kinases PknG and PknB.

Mycobacterium tuberculosis (Mtb), the causative agent of Tuberculosis, has 11 eukaryotic-like serine/threonine protein kinases, which play essential roles in cell growth, signal transduction, and pathogenesis. Protein kinase G (PknG) regulates the carbon and nitrogen metabolism by phosphorylation of the glycogen accumulation regulator (GarA) protein at Thr21. Protein kinase B (PknB) is involved in cell wall synthesis and cell shape, as well as phosphorylates GarA but at Thr22. While PknG seems to be constitutively activated and recognition of GarA requires phosphorylation in its unstructured tail, PknB activation is triggered by phosphorylation of its activation loop, which allows binding of the forkhead-associated domain of GarA. In the present work, we used molecular dynamics and quantum-mechanics/molecular mechanics simulations of the catalytically competent complex and kinase activity assays to understand PknG/PknB specificity and reactivity toward GarA. Two hydrophobic residues in GarA, Val24 and Phe25, seem essential for PknG binding and allow specificity for Thr21 phosphorylation. On the other hand, phosphorylated residues in PknB bind Arg26 in GarA and regulate its specificity for Thr22. We also provide a detailed analysis of the free energy profile for the phospho-transfer reaction and show why PknG has a constitutively active conformation not requiring priming phosphorylation in contrast to PknB. Our results provide new insights into these two key enzymes relevant for Mtb and the mechanisms of serine/threonine phosphorylation in bacteria.