Prevalence and incidence of venous leg ulcers-a protocol for a systematic review.

BACKGROUND: Venous leg ulcers (VLUs) are chronic wounds characterized by slow healing and high recurrence. Information on prevalence and incidence is essential for ascertaining the burden of VLU on the health care system and to inform epidemiological research, priority setting, and health care planning. The objective of this protocol is to present a transparent process for how we plan to review the existing international literature on the prevalence and incidence of VLU as well as the characteristics of the population reported within these studies. METHODS: An exploratory search was performed using MEDLINE via PubMed and CINHAL via Ebsco to identify concepts, keywords, MeSH terms, and headings to identify study types looking at data of VLU prevalence and/or incidence and related patient characteristics. The findings of this exploratory search will determine the final search strategy. The titles and abstracts of the identified articles will be screened independently be two authors for relevance. Study which pass the quality assessment will be included. Data extraction will be performed independently by two authors and in accordance with a pre-designed data extraction form. If the data allows, a meta-analysis will be performed otherwise a descriptive summary of the findings will be conducted. DISCUSSION: The results of this review will contribute to the evidence base on VLU occurrence and may inform the decision making of healthcare professionals, policy-makers, and consumers. It will also inform future research in this area of VLU care. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42020205855.

Orbital hybridization-induced band offset phenomena in NixCd1-xO thin films.

Herein, we present the cationic impurity-assisted band offset phenomena in NixCd1-xO (x = 0, 0.02, 0.05, 0.1, 0.2, 0.4, 0.8, and 1) thin films and further discuss them based on orbital hybridization modification. The compositional and structural studies revealed that the cationic substitution of Cd2+ by Ni2+ ions leads to a monotonic shift in the (220) diffraction peak, indicating the suppression of lattice distortion, while the evolution of local strain with an increase in Ni concentration is mainly associated with the mismatch in the electronegativity of the Cd2+ and Ni2+ ions. In fact, Fermi level pinning towards the conduction band minimum takes place with an increase in the Ni concentration at the cost of electronically compensated oxygen vacancies, resulting in the modification of the distribution of carrier concentration, which eventually affects the band edge effective mass of the conduction band electrons and further endorses band gap renormalization. Besides, the appearance of a longitudinal optical (LO) mode at 477 cm-1, as manifested by Raman spectroscopy, also indicates the active involvement of electron-phonon scattering, whereas modification in the local coordination environment, particularly anti-crossing interaction in conjunction with the presence of satellite features and shake-up states with Ni doping, was confirmed by X-ray absorption near-edge and X-ray photoelectron spectroscopy studies. These results manifest the gradual reduction of orbital hybridization upon the incorporation of Ni, leading to a decrement in the band edge effective electron mass. Finally, the molecular dynamics simulation reflected a 13% reduction in the lattice parameter for the NiO thin film compared to the undoped film, while the projected density of states calculation further supports the experimental observation of reduced orbital hybridization with an increase in Ni concentration.

High temperature-mediated rocksalt to wurtzite phase transformation in cadmium oxide nanosheets and its theoretical evidence.

Herein, a high temperature-induced phase transformation (PT) in chemically grown CdO thin films is demonstrated, and its corresponding electronic origin further investigated by density functional theory. In particular, the cubic rocksalt to hexagonal wurtzite PT in the CdO thin film annealed at 900 °C was confirmed by X-ray diffraction (XRD), which was consistent with the high-resolution transmission electron microscopy (TEM) results. Moreover, atomic force microscopy and scanning electron microscopy clearly evidenced the morphological evolution via the formation of a nanosheet network in the wurtzite-phase CdO film. The high temperature treatment also led to a significant enhancement in the optical band gap from 2.2 to 3.2 eV, as manifested by UV-visible spectroscopy. The enhanced surface roughness of the nanosheet caused a deviation in the net dipole moment, which may break the polarizable bonds and help in reducing the average dielectric constant, resulting in a band gap opening for the transformed phase. Furthermore, X-ray absorption spectroscopy at the oxygen k-edge revealed a notable shift in the inflection point of the absorption edge, while the X-ray photoelectron spectroscopy (XPS) Cd 3d and O 1s spectra suggested a gradual reduction in the CdO2 phase with an increase in annealing temperature. In addition, different complementary techniques including Rutherford backscattering and Raman spectroscopy were exploited to understand the aforementioned PT and its structural correlation. Finally, molecular dynamics simulation together with density functional theory calculation suggested that the symmetry modification at the Brillouin zone boundary provides a succinct signature for the PT in the CdO thin film.

Novel ß-carboline-quinazolinone hybrids disrupt Leishmania donovani redox homeostasis and show promising antileishmanial activity.

Visceral Leishmaniasis is a deadly parasitic disease caused by Leishmania donovani. Paucity exists in the discovery of novel chemotherapeutics against Leishmaniasis. In this study, we synthesized a natural product inspired Diversity Oriented Synthesis library of L. donovani Trypanothione reductase (LdTR) inhibitor ß-carboline-quinazolinone hybrids, which are different in stereochemical architecture and diverse in the bioactive chemical space. It is noteworthy that chirality affects drug-to-protein binding affinity since proteins in any living system are present only in one of the chiral forms. Upon evaluation of the hybrids, one of the chiral forms i.e. Compound 1 showed profound cytotoxic effect in micromolar range as compared to its other chiral form i.e. Compound 2. In-silico docking studies confirmed high binding efficiency of Compound 1 with the catalytic pocket of LdTR. Treatment of L. donovani parasites with Compound 1 inhibits LdTR activity, induces imbalance in redox homeostasis by enhancing ROS, disrupts the mitochondrial membrane potential, modifies actin polymerization and alters the surface topology and architecture. All these cellular modifications eventually led to apoptosis-like death of promastigotes. Furthermore, we synthesized the analogues of Compound 1 and found that these compounds show profound antileishmanial activity in the nanomolar range both in promastigotes and intracellular amastigotes. The enhanced inhibitory potential of these compounds was further supported by in-silico analysis of protein-ligand interactions which revealed high binding efficiency towards the catalytic pocket of LdTR. Taken together, this study reports the serendipitous discovery of ß-carboline-quinazolinone hybrids with enhanced antileishmanial activity along with the in-depth structure-activity relationships and mechanism of action of these analogues.

Effect of removal of phenolic compounds on structural and thermal properties of sunflower protein isolate.

The present study evaluated the effect of removal of polyphenols on the structural properties of protein isolates extracted from sunflower seed and kernel. The structural and thermal changes in protein upon phenolic interaction were studied using circular dichroism, differential scanning calorimetry, thermal gravimetric analysis, X-ray diffraction, sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE), and Fourier Transform Infrared (FT-IR) spectroscopy. Presence of phenolic compounds in proteins decreased the ordered structure content with parallel increase in unordered structure content. Denaturation temperature was higher for protein isolates with phenolic compounds while, enthalpy decreased upon phenolic interaction. In the presence of phenolic compounds, higher mass loss was observed upon heating. Crystalinity and crystal size got increased after removal of phenolic compounds. Protein isolates from kernels had higher percentage of crystalinity and crystal size as compared to seed protein isolates. Higher molecular weights were observed for protein isolates with phenolic compounds. Presence of polyphenols reduced the hydrophobicity as well the sulfhydryl content and increased the particle size of proteins.

A functional circadian clock is required for proper insulin secretion by human pancreatic islet cells.

AIM: To determine the impact of a functional human islet clock on insulin secretion and gene transcription. METHODS: Efficient circadian clock disruption was achieved in human pancreatic islet cells by small interfering RNA-mediated knockdown of CLOCK. Human islet secretory function was assessed in the presence or absence of a functional circadian clock by stimulated insulin secretion assays, and by continuous around-the-clock monitoring of basal insulin secretion. Large-scale transcription analysis was accomplished by RNA sequencing, followed by quantitative RT-PCR analysis of selected targets. RESULTS: Circadian clock disruption resulted in a significant decrease in both acute and chronic glucose-stimulated insulin secretion. Moreover, basal insulin secretion by human islet cells synchronized in vitro exhibited a circadian pattern, which was perturbed upon clock disruption. RNA sequencing analysis suggested alterations in 352 transcript levels upon circadian clock disruption. Among them, key regulators of the insulin secretion pathway (GNAQ, ATP1A1, ATP5G2, KCNJ11) and transcripts required for granule maturation and release (VAMP3, STX6, SLC30A8) were affected. CONCLUSIONS: Using our newly developed experimental approach for efficient clock disruption in human pancreatic islet cells, we show for the first time that a functional ß-cell clock is required for proper basal and stimulated insulin secretion. Moreover, clock disruption has a profound impact on the human islet transcriptome, in particular, on the genes involved in insulin secretion.

The systemic control of circadian gene expression.

The mammalian circadian timing system consists of a central pacemaker in the brain's suprachiasmatic nucleus (SCN) and subsidiary oscillators in nearly all body cells. The SCN clock, which is adjusted to geophysical time by the photoperiod, synchronizes peripheral clocks through a wide variety of systemic cues. The latter include signals depending on feeding cycles, glucocorticoid hormones, rhythmic blood-borne signals eliciting daily changes in actin dynamics and serum response factor (SRF) activity, and sensors of body temperature rhythms, such as heat shock transcription factors and the cold-inducible RNA-binding protein CIRP. To study these systemic signalling pathways, we designed and engineered a novel, highly photosensitive apparatus, dubbed RT-Biolumicorder. This device enables us to record circadian luciferase reporter gene expression in the liver and other organs of freely moving mice over months in real time. Owing to the multitude of systemic signalling pathway involved in the phase resetting of peripheral clocks the disruption of any particular one has only minor effects on the steady state phase of circadian gene expression in organs such as the liver. Nonetheless, the implication of specific pathways in the synchronization of clock gene expression can readily be assessed by monitoring the phase-shifting kinetics using the RT-Biolumicorder.

The mammalian circadian timing system: synchronization of peripheral clocks.

Mammalian physiology has to adapt to daily alternating periods during which animals either forage and feed or sleep and fast. The adaptation of physiology to these oscillations is controlled by a circadian timekeeping system, in which a master pacemaker in the suprachiasmatic nucleus (SCN) synchronizes slave clocks in peripheral organs. Because the temporal coordination of metabolism is a major purpose of clocks in many tissues, it is important that metabolic and circadian cycles are tightly coordinated. Recent studies have revealed a multitude of signaling components that possibly link metabolism to circadian gene expression. Owing to this redundancy, the implication of any single signaling pathway in the synchronization of peripheral oscillators cannot be assessed by determining the steady-state phase, but instead requires the monitoring of phase-shifting kinetics at a high temporal resolution.

Regulation of circadian gene expression in liver by systemic signals and hepatocyte oscillators.

The mammalian circadian timing system has a hierarchical structure, in that a master pacemaker located in the suprachiasmatic nuclei (SCN) coordinates slave oscillators present in virtually all body cells. In both the SCN and peripheral organs, the rhythm-generating oscillators are self-sustained and cell-autonomous, and it is likely that the molecular makeup of master and slave oscillators is nearly identical. However, due to variations in period length, the phase coherence between peripheral oscillators in intact animals must be established by daily signals emanating directly or indirectly from the SCN master clock. The synchronization of individual cellular clocks in peripheral organs is probably accomplished by immediate-early genes that interpret the cyclic systemic signals and convey this phase information to core clock components. This model predicts that circadian gene expression in peripheral organs can be influenced either by systemic signals emanating from the SCN master clock, local oscillators, or both. We developed a transgenic mouse strain in which hepatocyte clocks are only operative when the tetracycline analog doxycycline is added to the food or drinking water. The genome-wide mapping of genes whose cyclic expression in liver does not depend on functional hepatocyte oscillators unveiled putative signaling pathways that may participate in the phase entrainment of peripheral clocks.

Approaches to sample pretreatment in the determination of perchlorate in real world samples.

Perchlorate can be determined by the tandem technique of ion chromatography (IC) coupled to electrospray ionization mass spectrometry (ESI-MS). However, detection by ESI-MS can be compromised by the coelution of matrix components that can suppress the analyte signal. In addition, the presence of surface-active and other types of matrix components can cause fouling of the electrospray inlet, reducing overall signal and requiring frequent maintenance. The influences of matrix components can be minimized by using analytical columns with different selectivities, in-line diversion of separated matrix components, and off-line selective removal of matrix components via ion exchange or adsorption. This paper will discuss these sample preparation approaches for samples containing anionic species including surfactants and inorganic ions that elute in the vicinity of perchlorate.

Determination of inorganic anions in environmental waters with a hydroxide-selective column.

US Environmental Protection Agency Method 300.0 specifies the use of an IonPac AS4A anion-exchange column with a carbonate-hydrogencarbonate eluent and suppressed conductivity detection for the determination of inorganic anions in environmental waters by ion chromatography. Hydroxide eluents have not typically been used for the routine analysis of common inorganic anions due to the lack of an appropriate hydroxide selective column and the difficulty in preparing contaminant free hydroxide eluents. The use of ion chromatography with a hydroxide-selective IonPac AS17 column, automated eluent generation and potassium hydroxide gradient represents a new approach to the routine determination of inorganic anions in environmental waters. This new approach, which is a modification of Method 300.0, allows equivalent method performance with improved linearity, precision, and method detection limits. The AS17 column provides superior retention of fluoride from the column void volume and improved resolution from small organic acids, such as formate and acetate, compared to the AS4A column. Quantitative recoveries were obtained for all the common inorganic anions spiked into typical environmental waters using this new approach, and the Performance Based Measurement System Tier 1 method validation quality control acceptance criteria are well within the acceptable ranges defined by Method 300.0. In addition, the EG40 eluent generator eliminates the need to manually prepare eluents, increasing the level of automation and ease-of-use of the ion chromatography system.

Synthesis and chemical properties of ibopamine and of related esters of N-substituted dopamines--synthesis of ibopamine metabolites.

The therapeutic usefulness of intravenously infused dopamine in congestive heart failure and in shock prompted us to synthesize a wide series of 3,4-O-diesters of dopamine and N-substituted derivatives to obtain an orally active dopamine-like prodrug having adequate absorption and duration of action. The pharmacological results and in particular, the hemodynamic studies in the dog led to the selection of ibopamine, i.e. the 3,4-diisobutyryl ester of N-methyldopamine and to its development as a useful drug for the chronic treatment of congestive heart failure. The choice of ibopamine from among several analogs was also influenced by other favourable properties such as good chemical stability in pharmaceutical formulations and in the biopharmaceutical phases of the absorption, and fast enzymatic activation of the prodrug by plasma and peripheral tissue esterases; the latter property appeared desirable to avoid any accumulation in the central nervous system and consequent undesired side effects. The isomeric mixture of 3-O- and 4-O-isobutyrates of N-methyldopamine as well as the main conjugated metabolites, i.e. the 3-O- and 4-O-sulphate and 4-O-beta-glucuronide of N-methyldopamine were synthesized as analytical references in metabolic studies and for the investigation on their pharmacokinetic and pharmacological properties. Dopamine O-sulphates were also prepared using the methods developed for the corresponding N-methyl derivatives.