Elucidating an amorphous form stabilization mechanism of tenapanor hydrochloride: crystal structure analysis using Xray diffraction, NMR crystallography and molecular modelling

By the combined use of powder and single crystal X-ray diffraction, solid-state NMR, and molecular modelling, the crystal structures of two systems containing the unusually large tenapanor drug molecule have been determined: the free form, ANHY and a dihydrochloride salt form, 2HCl. Dynamic nuclear polarization (DNP) assisted solid-state NMR (SSNMR) crystallography investigations were found essential for the final assignment, and were used to validate the crystal structure of ANHY. From the structural informatics analysis of ANHY and 2HCl, conformational ring differences in one part of the molecule were observed which influences the relative orientation of a methyl group on a ring nitrogen and thereby impacts the crystallizability of the dihydrochloride salt. From quantum chemistry calculations, the dynamics between different ring conformations in tenapanor is predicted to be fast. Addition of HCl to tenapanor results in general in a mixture of protonated ring conformers and hence a statistical mix of diastereoisomers which builds up the amorphous form, a-2HCl. This was qualitatively verified by 13C CP/MAS NMR investigations of the amorphous form. Thus, to form any significant amount of the crystalline material 2HCl, which originates from the minor (i.e., energetically less stable) ring conformations, one needs to involve nitrogen deprotonation to allow exchange between minor and major conformations of ANHY in solution. Thus, by controlling the solution pH value to well below the pKa of ANHY, the equilibrium between ANHY and 2HCl can be controlled and by this mechanism the crystallization of 2HCl can be avoided and the amorphous form of the dichloride salt can therefore be stabilized

Do we know more about hypertension in Poland after the May Measurement Month 2017?-Europe

Elevated blood pressure (BP) is a worldwide burden, leading to over 10 million deaths yearly. May Measurement Month (MMM) is a global initiative organized by the International Society of Hypertension aimed at raising awareness of hypertension and the need for BP screening. An opportunistic cross-sectional survey of volunteers aged ≥18 was carried out in May 2017. BP measurement, the definition of hypertension and statistical analysis followed the globally approved MMM17 Study Protocol. In Poland 5834 (98.9%, Caucasian) individuals were screened. After multiple imputation, 2601 (35.3%) had hypertension. Of individuals not receiving anti-hypertensive medication, 976 (20.6%) were hypertensive. Of individuals receiving anti-hypertensive medication, 532 (49.1%) had uncontrolled BP. In the crude screened group, 81.4% declared to not receive any anti-hypertensive treatment, while the remaining 18.6% were on such medications. In overweight and obese patients both systolic and diastolic BP were significantly higher than in normal weight and underweight subjects. In addition, BP measured on Sundays was significantly lower than on Mondays. MMM17 was one of the largest recent BP screening campaigns in Poland. We found that over 1/3 of participants were hypertensive. Almost half of the treated subjects had uncontrolled BP. These results suggest that opportunistic screening can identify substantial numbers with raised BP

Development of a Chemiresistor Sensor Based on Polymers-Dye Blend for Detection of Ethanol Vapor

The conductive blend of the poly (3,4-ethylene dioxythiophene) and polystyrene sulfonated acid (PEDOT-PSS) polymers were doped with Methyl Red (MR) dye in the acid form and were used as the basis for a chemiresistor sensor for detection of ethanol vapor. This Au | Polymers-dye blend | Au device was manufactured by chemical vapor deposition and spin-coating, the first for deposition of the metal electrodes onto a glass substrate, and the second for preparation of the organic thin film forming ∼1.0 mm2 of active area. The results obtained are the following: (i) electrical resistance dependence with atmospheres containing ethanol vapor carried by nitrogen gas and humidity; (ii) sensitivity at 1.15 for limit detection of 26.25 ppm analyte and an operating temperature of 25 °C; and (iii) the sensing process is quickly reversible and shows very a low power consumption of 20 μW. The thin film morphology of ∼200 nm thickness was analyzed by Atomic Force Microscopy (AFM), where it was observed to have a peculiarly granulometric surface favorable to adsorption. This work indicates that PEDOT-PSS doped with MR dye to compose blend film shows good performance like resistive sensor

TRH: Pathophysiologic and clinical implications

Thyrotropin releasing hormone is thought to be a tonic stimulator of the pituitary TSH secretion regulating the setpoint of the thyrotrophs to the suppressive effect of thyroid hormones. The peptide stimulates the release of normal and elevated prolactin. ACTH and GH may increase in response to exogenous TRH in pituitary ACTH and GH hypersecretion syndromes and in some extrapituitary diseases. The pathophysiological implications of extrahypothalamic TRH in humans are essentially unknown. The TSH response to TRH is nowadays widely used as a diganostic amplifier in thyroid diseases being suppressed in borderline and overt hyperthyroid states and increased in primary thyroid failure. In hypothyroid states of hypothalamic origin, TSH increases in response to exogenous TRH often with a delayed and/or exaggerated time course. But in patients with pituitary tumors and suprasellar extension TSH may also respond to TRH despite secondary hypothyroidism. This TSH increase may indicate a suprasellar cause for the secondary hypothyroidism, probably due to portal vessel occlusion. The TSH released in these cases is shown to be biologically inactive

Survival of Chondrocytes in Rabbit Septal Cartilage After Electromechanical Reshaping

Electromechanical reshaping (EMR) has been recently described as an alternative method for reshaping facial cartilage without the need for incisions or sutures. This study focuses on determining the short- and long-term viability of chondrocytes following EMR in cartilage grafts maintained in tissue culture. Flat rabbit nasal septal cartilage specimens were bent into semi-cylindrical shapes by an aluminum jig while a constant electric voltage was applied across the concave and convex surfaces. After EMR, specimens were maintained in culture media for 64 days. Over this time period, specimens were serially biopsied and then stained with a fluorescent live–dead assay system and imaged using laser scanning confocal microscopy. In addition, the fraction of viable chondrocytes was measured, correlated with voltage, voltage application time, electric field configuration, and examined serially. The fraction of viable chondrocytes decreased with voltage and application time. High local electric field intensity and proximity to the positive electrode also focally reduced chondrocyte viability. The density of viable chondrocytes decreased over time and reached a steady state after 2–4 weeks. Viable cells were concentrated within the central region of the specimen. Approximately 20% of original chondrocytes remained viable after reshaping with optimal voltage and application time parameters and compared favorably with conventional surgical shape change techniques such as morselization

A Review of "STRIPS: A New Approach to the Application of Theorem Proving to Problem Solving by R.E. Fikes, N.J. Nillson, 1971"

this paper will also discuss about theorem proving (as an example of reasoning, or logical inference), which is another problem-solving method. It is important to distinguish between the original STRIPS planner, and the STRIPS representation language. Due to its power of representation, the language developed for describing STRIPS' operators and world models was since then used, with minor modifications, in a large number of traditional (but more advanced than STRIPS) planners, Planning was historically motivated by the need of robotics. Indeed, STRIPS was designed to act as the planner for another pioneering project: "Shakey the robot", developed at SRI International. Shakey was supposed to wander in his world (see figure 1), push boxes around, and turn light switches on/off (the former action also required to climb on top of a box, since the robot was short and the switches were high on the wall). It is important to note that this environment was quite idealized compared to a real one, given the primitive sensors and effectors available at that time. STRIPS represents world models as a collection of first order predicate calculus formulas. In this context, "problem solving" means finding a sequence of operators in the space of world models that will transform an initial model into another model in which a given formula (goal) can be proven to be true. Two main techniques are used in the problem solving: means-end analysis for the goal search, and a resolution theorem prover that answers questions about a given world model. Room 4 Room 3 Room 2 Room 1 Door 1 Door 2 Door 3 Door 4 Box1 Box2 Box3 Shakey Ls1 Ls2 Ls3 Ls4 Box4 Corridor Figure 1: "Shakey the robot" 's world (from [7]). Each room has a door and a light switch. Since Shakey was rather short, he had to climb ..