Impact of COVID­19 infection in patients with neurodegenerative diseases with particular focus on Alzheimer's and Parkinson's disease.

Neurodegenerative disorders (NDD) are chronic neurological diseases characterized by loss and/or damage to neurons along with the myelin sheath, and patients are at higher risk of severe infection with the SARS­CoV­2. A comprehensive literature search was performed using relevant terms and inclusion­exclusion criteria. Recent articles, subjects older than 50 years, and articles written in the English language were included, whereas letters to the editor and articles related to pregnant women were excluded from the review study. COVID­19 appears to damage angiotensin­II receptors which cause natural killer cells to lose the ability to clear virus­infected cells, owing to worse outcomes in patients with NDD. COVID­19 can worsen the symptoms of Alzheimer's disease. In addition, COVID­19 worsens drug­responsive motor symptoms in Parkinson's disease (PD) and other symptoms like fatigue and urinary complaints. Vitamin D is essential in decreasing pro­inflammatory and increasing anti­inflammatory cytokines in ongoing COVID­19 infections and reducing angiotensin receptors and, hence, decreasing COVID­19 infection severity. Telemedicine shows promise for patients with NDD but is yet to overcome legal issues and personal barriers. COVID­19 has a significant effect on neurodegenerative conditions, which appears partly to the nature of the NDD and the neuro­invasive capabilities of the SARS­CoV­2. The protective role of vitamin D in patients with NDD further supports this hypothesis. Modifications in current health care, like the telemedicine platform, are required to address the increased risk of serious infection in this population. Further studies will be required to clarify conflicting reports in many fields.

A Mycobacterial Systems Resource for the Research Community.

Functional characterization of bacterial proteins lags far behind the identification of new protein families. This is especially true for bacterial species that are more difficult to grow and genetically manipulate than model systems such as Escherichia coli and Bacillus subtilis To facilitate functional characterization of mycobacterial proteins, we have established a Mycobacterial Systems Resource (MSR) using the model organism Mycobacterium smegmatis This resource focuses specifically on 1,153 highly conserved core genes that are common to many mycobacterial species, including Mycobacterium tuberculosis, in order to provide the most relevant information and resources for the mycobacterial research community. The MSR includes both biological and bioinformatic resources. The biological resource includes (i) an expression plasmid library of 1,116 genes fused to a fluorescent protein for determining protein localization; (ii) a library of 569 precise deletions of nonessential genes; and (iii) a set of 843 CRISPR-interference (CRISPRi) plasmids specifically targeted to silence expression of essential core genes and genes for which a precise deletion was not obtained. The bioinformatic resource includes information about individual genes and a detailed assessment of protein localization. We anticipate that integration of these initial functional analyses and the availability of the biological resource will facilitate studies of these core proteins in many Mycobacterium species, including the less experimentally tractable pathogens M. abscessus, M. avium, M. kansasii, M. leprae, M. marinum, M. tuberculosis, and M. ulceransIMPORTANCE Diseases caused by mycobacterial species result in millions of deaths per year globally, and present a substantial health and economic burden, especially in immunocompromised patients. Difficulties inherent in working with mycobacterial pathogens have hampered the development and application of high-throughput genetics that can inform genome annotations and subsequent functional assays. To facilitate mycobacterial research, we have created a biological and bioinformatic resource (https://msrdb.org/) using Mycobacterium smegmatis as a model organism. The resource focuses specifically on 1,153 proteins that are highly conserved across the mycobacterial genus and, therefore, likely perform conserved mycobacterial core functions. Thus, functional insights from the MSR will apply to all mycobacterial species. We believe that the availability of this mycobacterial systems resource will accelerate research throughout the mycobacterial research community.

Evaluation of potential health effects associated with occupational and environmental exposure to styrene - an update.

The potential chronic health risks of occupational and environmental exposure to styrene were evaluated to update health hazard and exposure information developed since the Harvard Center for Risk Analysis risk assessment for styrene was performed in 2002. The updated hazard assessment of styrene's health effects indicates human cancers and ototoxicity remain potential concerns. However, mechanistic research on mouse lung tumors demonstrates these tumors are mouse-specific and of low relevance to human cancer risk. The updated toxicity database supports toxicity reference levels of 20 ppm (equates to 400 mg urinary metabolites mandelic acid + phenylglyoxylic acid/g creatinine) for worker inhalation exposure and 3.7 ppm and 2.5 mg/kg bw/day, respectively, for general population inhalation and oral exposure. No cancer risk value estimates are proposed given the established lack of relevance of mouse lung tumors and inconsistent epidemiology evidence. The updated exposure assessment supports inhalation and ingestion routes as important. The updated risk assessment found estimated risks within acceptable ranges for all age groups of the general population and workers with occupational exposures in non-fiber-reinforced polymer composites industries and fiber-reinforced polymer composites (FRP) workers using closed-mold operations or open-mold operations with respiratory protection. Only FRP workers using open-mold operations not using respiratory protection have risk exceedances for styrene and should be considered for risk management measures. In addition, given the reported interaction of styrene exposure with noise, noise reduction to sustain levels below 85 dB(A) needs be in place.

Heparanase promotes lymphangiogenesis and tumor invasion in pancreatic neuroendocrine tumors.

Heparan sulfate proteoglycans are an important and abundant component of the extracellular matrix, which undergo substantial remodeling throughout tumorigenesis via the enzymatic activity of heparanase. Heparanase has been shown to be upregulated in many human cancers; however, its specific functions in human pancreatic neuroendocrine tumors (PanNETs) and spontaneous mouse models of cancer have not been evaluated. Here, we investigated the role of heparanase in PanNETs using patient samples and the RIP1-Tag2 (RT2) PanNET-transgenic mouse model. High heparanase expression significantly correlated with more advanced tumor stage, higher tumor grade and the presence of distant metastasis in PanNET patients. We genetically manipulated heparanase levels in the RT2 model using heparanase-transgenic mice, which constitutively overexpress heparanase, and heparanase-knockout mice. Heparanase was found to have a critical role in promoting tumor invasion, through both macrophage and cancer cell sources in the tumor microenvironment. In addition, elevated heparanase levels significantly increased peritumoral lymphangiogenesis in vivo and promoted the trans-differentiation of macrophages into lymphatic endothelial cell-like structures in culture. Conversely, we found that heparanase deletion led to increased angiogenesis and pericyte coverage. Together, these data identify important roles for heparanase in regulating several critical aspects of tumorigenesis, demonstrating that heparanase represents a potential therapeutic target for PanNET patients.

Discovery of novel p-arylthio cinnamides as antagonists of leukocyte function-associated antigen-1/intercellular adhesion molecule-1 interaction. 4. Structure-activity relationship of substituents on the benzene ring of the cinnamide.

We have shown that p-arylthio cinnamides can inhibit the interaction of LFA-1 and ICAM-1, which is involved in cell adhesion and the inflammatory process. We now show that 2,3-disubstitution on the aryl portion of the cinnamide results in enhanced activity over mono substitution on the ring. The best 2,3-substituents were chlorine and trifluoromethyl groups. Compounds 39 and 40 which contain two CF3 groups have IC(50) values of 0.5 and 0.1 nM, respectively, in inhibiting JY8 cells expressing LFA-1 on their surface, from adhering to ICAM-1. The structure-activity relationship (SAR) was examined using an NMR based model of the LFA-1 I domain/compound 31 complex. One of our compounds (38) was able to reduce cell migration in two different in vivo experiments.

A nationwide study of decisions to forego life-prolonging treatment in Dutch medical practice.

BACKGROUND: Decisions to withhold or withdraw life-prolonging treatment in terminally ill patients are common in some areas of medical practice. Information about the frequency and background of these decisions is generally limited to specific clinical settings. This article describes the practice of withholding or withdrawing life-prolonging treatment in the Netherlands. METHODS: Questionnaires were sent to the attending physicians of a stratified sample of 6060 of all 43002 cases of death in the Netherlands from August 1 through November 30, 1995. The questions concerned the treatments foregone, the patient characteristics, and the decision-making process. The response rate was 77%. RESULTS: A nontreatment decision was made in 30% (95% confidence interval, 28%-31%) of all deaths in the Netherlands in 1995; this is an increase compared with 28% (95% confidence interval, 26%-29%) in 1990; in 20% of all deaths, this decision was the most important end-of-life decision. Artificial nutrition or hydration and antibiotics were the treatments most frequently foregone, each accounting for 25% of cases in which a nontreatment decision was made. Nursing-home physicians withheld or withdrew treatment more often than clinical specialists or general practitioners in 52%, 35%, and 17% of all deaths they were involved with, respectively. Of the patients in whom a nontreatment decision was the most important end-of-life decision, 26% were competent; of those, 93% were involved in the decision making. In 17% of patients, the nontreatment decision was made without being discussed with the patient or the patient's relatives and without knowledge of the patient's wishes. Life was shortened by an estimated 24 hours or less in 42% and 1 month or more in 8% of patients. CONCLUSIONS: Decisions to forego life-prolonging treatment are frequently made end-of-life decisions in the Netherlands and may be increasing. Most of these decisions do not involve high-technology treatments, and the consequences, in terms of shortening of life, are relatively small.

Olestra formulation and the gastrointestinal tract.

Olestra is a mixture of compounds comprising sucrose esterified with 6-8 long-chain fatty acids. It is not hydrolyzed by pancreatic lipase and as a result is not absorbed from the small intestine. Olestra in general has physical properties similar to those of a triacylglycerol with the same fatty acid composition. Foods made with olestra are virtually identical in taste and texture to those made with typical triacylglycerols. Olestra consumption does not generate hydrolytic products in the small intestine and, therefore, does not generate some of the signals that alter motility in the gastrointestinal tract. A reduction in gastroesophageal reflux with olestra, in contrast to triacylglycerols, is consistent with a lack of effect on stomach emptying. Unlike triacylglycerols that are absorbed in the proximal small intestine, olestra is distributed throughout the small intestine during transit and passes into the colon. In the colon, olestra's effects depend on its physical properties. Liquid nondigestible lipids result in separation of oil from the fecal matrix. Olestra formulations made with specific fatty acid compositions, particularly those containing a solid sucrose polyester component including behenic acid, possess appropriate rheology to hinder separation of oil from the rest of the fecal matrix, thereby reducing gastrointestinal symptoms.

Medical end-of-life decisions made for neonates and infants in the Netherlands.

BACKGROUND: Advances in neonatal intensive care have lowered the neonatal death rate. There are still some severely ill neonates and infants, however, for whom the application of all possible life-prolonging treatment modalities may be questioned. METHODS: We did two studies in the Netherlands. In the first we sent questionnaires to physicians who had attended 338 consecutive deaths (August-November, 1995) within the first year of life (death-certificate study), and in the second we interviewed 31 neonatologists or paediatric intensive-care specialists and 35 general paediatricians. The response rates were 88% and 99%, respectively. FINDINGS: In the death-certificate study, 57% of all deaths had been preceded by a decision to forgo life-sustaining treatment; this decision was accompanied by the administration of potentially life-shortening drugs to alleviate pain or other symptoms in 23%, and by the administration of drugs with the explicit aim of hastening death in 8%. A drug was given explicitly to hasten death to neonates not dependent on life-sustaining treatment in 1% of all death cases. No chance of survival was the main motive in 76% of all end-of-life decisions, and a poor prognosis was the main motive in 18%. The interview study showed that parents had been involved in making 79% of decisions. The physicians consulted colleagues about 88% of decisions. Most paediatricians favoured formal review of medical decisions by colleagues together with ethical or legal experts. INTERPRETATION: Death among neonates and infants is commonly preceded by medical end-of-life decisions. Most Dutch paediatricians seem to find prospects for survival and prognostic factors relevant in such decisions. Public control by a committee of physicians, paediatricians, ethicists, and legal experts is widely endorsed by paediatricians.

[Frequency of decisions to forgo (artificial) administration of food and fluids at life's end]. / Frequentie van het afzien van (kunstmatige) toediening van voeding en vocht aan het levenseinde.

OBJECTIVE: To determine the frequency and characteristics of decisions to forgo (artificial) feeding and hydration with hastening of death as a possible result. DESIGN: Retrospective, descriptive study. SETTING: The Netherlands. METHODS: Data were collected from questionnaires mailed to physicians attending 6060 deaths identified from death certificates dating from August through November 1995 (response rate: 77%). RESULTS: Decisions to forgo feeding and hydration preceded 8% of all deaths studied; for deaths attended by nursing home physicians this percentage was 23%, for deaths attended by general practitioners and specialists it was 4%. In 68% of all these death cases, the patients had been 80 years of age or over, and 76% of them had been partly or completely incompetent. The non-treatment decision had been discussed with relatives in 82% of all cases, and in 89% of the death cases attended by nursing home physicians. These patients had had (possibly) life-shortening medication less frequently than other patients for whom a medical decision concerning the end of life had been made. CONCLUSION: Decisions to forgo (artificial) feeding and hydration were made relatively often by nursing home physicians, and rarely by general practitioners and specialists. These decisions were usually but not always made after discussion with relatives. There were no indications that these decisions entailed a great deal of suffering for the patients.

Euthanasia, physician-assisted suicide, and other medical practices involving the end of life in the Netherlands, 1990-1995.

BACKGROUND: In 1991 a new procedure for reporting physician-assisted deaths was introduced in the Netherlands that led to a tripling in the number of reported cases. In 1995, as part of an evaluation of this procedure, a nationwide study of euthanasia and other medical practices concerning the end of life was begun that was identical to a study conducted in 1990. METHODS: We conducted two studies, the first involving interviews with 405 physicians (general practitioners, nursing home physicians, and clinical specialists) and the second involving questionnaires mailed to the physicians attending 6060 deaths that were identified from death certificates. The response rates were 89 percent and 77 percent, respectively. RESULTS: Among the deaths studied, 2.3 percent of those in the interview study and 2.4 percent of those in the death-certificate study were estimated to have resulted from euthanasia, and 0.4 percent and 0.2 percent, respectively, resulted from physician-assisted suicide. In 0.7 percent of cases, life was ended without the explicit, concurrent request of the patient. Pain and symptoms were alleviated with doses of opioids that may have shortened life in 14.7 to 19.1 percent of cases, and decisions to withhold or withdraw life-prolonging treatment were made in 20.2 percent. Euthanasia seems to have increased in incidence since 1990, and ending of life without the patient's explicit request to have decreased slightly. For each type of medical decision except those in which life-prolonging treatment was withheld or withdrawn, cancer was the most frequently reported diagnosis. CONCLUSIONS: Since the notification procedure was introduced, end-of-life decision making in the Netherlands has changed only slightly, in an anticipated direction. Close monitoring of such decisions is possible, and we found no signs of an unacceptable increase in the number of decisions or of less careful decision making.

2,4-Diarylpyrrolidine-3-carboxylic acids--potent ETA selective endothelin receptor antagonists. 1. Discovery of A-127722.

We have discovered a novel class of endothelin (ET) receptor antagonists through pharmacophore analysis of the existing non-peptide ET antagonists. On the basis of this analysis, we determined that a pyrrolidine ring might replace the indian ring in SB 209670. The resultant compounds were readily prepared and amenable to extensive SAR studies. Thus a series of N-substituted trans,trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)pyrroli din e-3- carboxylic acids (8) have been synthesized and evaluated for binding at ET(A) and ET(B) receptors. Compounds with N-acyl and simple N-alkyl substituents had weak activity. Compounds with N-alkyl substituents containing ethers, sulfoxides, or sulfones showed increased activity. Much improved activity resulted from compounds where the N-substituents were acetamides. Compound 17u (A-127722) with the N,N-dibutylacetamide substituent is the best of the series. It has an IC(50)=0.36 nM for inhibition of ET-1 radioligand binding at the ET(A) receptor, with a 1000-fold selectivity for the ET(A) vs the ET(B) receptor. It is also a potent inhibitor (IC(50)=0.16 nM) of phosphoinositol hydrolysis stimulated by ET-1, and it antagonized the ET-1-induced contraction of the rabbit aorta with a pA(2)=9.20. The compound has 70% oral bioavailability in rats.

Azole endothelin antagonists. 1. A receptor model explains an unusual structure-activity profile.

The pseudotetrapeptide FR-139317 is a potent and highly selective antagonist of the endothelin-A (ET(A)) receptor; however, its peptidic nature leads to poor oral absorption characteristics which make it an unlikely drug candidate. In an attempt to improve these properties, we have replaced a portion of the amide bond framework of FR-139317 with a heterocyclic surrogate. The resultant analogs are also ET(A)-selective antagonists, but show a structure-activity profile substantially different from that of the peptidic series, particularly with regard to the requirements for the side chain group that has been incorporated into the heterocycle. The nature of the heterocycle itself also has profound effects on the activity of the compounds. Both of these surprising results can be rationalized through examination of a 3D model of ET ligand--receptor binding that has previously been developed in our laboratories.

Azole endothelin antagonists. 2. Structure-activity studies.

Structure-activity studies have been performed in an attempt to improve the potency of a novel series of azole-based endothelin-A (ET(A)) selective antagonists. Modifications of the hydrophobic group on the terminal urea produced substantial effects on receptor affinity; in particular, the choice of cyclohexyl- or arylureas led to substantial improvements in activity. Conformational restriction of these groups provides an additional benefit. N-Methylation of the indole moiety which is part of the heterocyclic dipeptide surrogate also improves potency. The effects of these two modifications appear to be synergistic, with the best of the resultant doubly modified analogs (e.g. 14q, 15y, and 15ff) exhibiting an 80-200-fold improvement over the original leads.

Azole endothelin antagonists. 3. Using delta log P as a tool to improve absorption.

The oral absorption profile of a family of azole-based ET(A)-selective antagonists has been improved through a rational series of structural modifications which were suggested by analysis of the physicochemical parameter delta log P. Comparison of urea 2 with a series of well-absorbed compounds using delta log P analysis suggested that 2 has an excess capacity for forming hydrogen bonds with solvent. A series of urea modifications were explored as a means of reducing H-bonding capacity while maintaining affinity for the ET(A)-receptor. The correlation between delta log P values and absorption in an intraduodenal (id) bioavailability model was good; this strategy uncovered replacements for each of the urea NH groups which simultaneously improve both potency and drug absorption. A combination of these optimized modifications produces carbamate 16h, a highly-selective ET(A) antagonist with a potency/bioavailability profile consistent with an oral route of administration.

Planar geometry thin-film all-optical programmable switch.

We describe an all-optical programmable switch that can perform logic gate functions. This switch consists of a planar geometry germanium-doped silica waveguide, a Q-switched and mode-locked Nd:YAG laser, and the means of coupling laser light into different waveguiding modes of the thin film at the fundamental and second-harmonic frequencies. By the application of the appropriate optical programming sequence, the film-generated second-harmonic light can be made to perform the functionalities of various gates. In particular, a single waveguide was optically programmed to perform the Or function and was then made to perform the And function with little change to the experimental arrangement.

The significance of coumarin anticoagulation in laser assisted percutaneous transluminal angioplasty of femoropopliteal arterial obstructions.

The optimal regime of drugs to prevent thrombocyte aggregation leading to reocclusion after percutaneous transluminal angioplasty (PTA) of peripheral vessels is not established. Both antiplatelet and antithrombotic drugs are prescribed. Prospective observations of two different anticoagulation regimes were made during an ongoing multicenter study of laser-assisted PTA (PTLA) of the femoropopliteal artery. Group I (129 patients) received coumarin at least during the first month, Group II (n = 71) did not get oral anticoagulation. Seventy-eight patients (61%) in Group I and 29 patients (47%) in Group II received platelet inhibitors. Groups I and II did not differ in baseline characteristics and PTLA complications (20.9 vs. 18.2%). Ankle brachial indices at 1, 3, 6 and 12 months were similar in both groups. This observational study does not provide evidence for superiority of oral anticoagulation in the management of patients undergoing PTLA of the femoropopliteal tract.

Cholinergic agents: effect of methyl substitution in a series of arecoline derivatives on binding to muscarinic acetylcholine receptors.

Arecoline, arecaidine, and a series of derivatives, differing by the presence or absence of methyl groups at positions on the periphery of the molecule, were prepared, and their binding to muscarinic acetylcholine receptors was tested. On the basis of this study, muscarinic agonism for arecoline series is governed by strict structure-activity relationships, as previously observed for other agonist series. Only minor changes in nitrogen substitution were tolerated in the present series of arecoline derivatives.

Second-harmonic generation in planar waveguides of doped silica.

Second-harmonic generation was produced in germanium-doped silica planar waveguides prepared by simulfaneous illumination with 1064- and 532-nm laser light. During preparation using prism coupling to specific waveguiding modes, the film-generated second-harmonic intensity grew as a function of preparation time until it saturated. The growth rate and saturation level for p-polarized second-harmonic intensity was an order of magnitude greater than that observed for the s polarization. The efficiency for a 2-cm waveguide length was at least 0.5%. The comparison of experimental results indicates a mechanism for this planar geometry that is similar to that producing harmonic effects in optical fibers.

Resistance of lipid films to transmission of water vapor and oxygen.

Various lipids, present as thin films on polar filter paper supports, were evaluated for resistance to the transmission of water vapor (rH2O) and oxygen (rO2). Beeswax exhibited the largest r(H2O), followed in order by fully-hydrogenated soy-rapeseed oil, stearyl alcohol, acetylated monoglycerides, hexatriacontane, tristearin, and stearic acid. Most of the lipids exhibited negative activation energies, E, for resistance to transmission of water vapor and positive Es for resistance to transmission of oxygen. The type of lipid support (hydrophobic or hydrophilic) also influenced E for resistance to water vapor transmission. Differences in r(H2O) for the various lipids, comparative r(H2O) and r(O2) values, and the temperature dependence of these values can be explained, in part, by the degree of hydrophilicity of the lipid molecule. Tempering at 48 degrees C of stearyl alcohol caused a substantial decrease in its permeability to oxygen and water vapor. The polymorphic form of a blend of fully-hydrogenated soybean and rapeseed oil had a moderate influence on its permeability to oxygen and water vapor. This information will be useful for formulating lipid-containing films with controlled barrier properties to the passage of water vapor and oxygen.

Effects of SH-modifying reagents on the rat hepatic Ah receptor: inhibition of ligand binding and transformation, and disruption of the ligand-receptor complex.

The importance of sulfhydryl (SH) groups in maintenance of physicochemical properties of the rat hepatic Ah receptor was demonstrated using a variety of sulfhydryl (SH)-modifying reagents. Inhibition of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) specific binding was approximately equivalent by 5,5'-dithiobis(2-nitrobenzoate), mersalyl, N-ethylmaleimide, and p-chloromercuriphenylsulfonate, whose inhibition curves were steep in the concentration range close to that of nonprotein SH groups in cytosol (ED50 values 50-200 microM or 13-48 nmol/mg cytosolic protein). Inhibition by p-hydroxymercuribenzoate (PHMB), although exhibiting a lower ED50, was more gradual over this range; iodoacetamide was an order of magnitude less potent. The ability of dithiothreitol to reverse binding inhibition induced by 150 microM (approximately 60 nmol/mg protein) mersalyl diminished with time; it decreased more rapidly in the simultaneous presence of TCDD and mersalyl than when mersalyl was present alone, consistent with increased accessibility of key SH group(s) due to conformational changes attending TCDD-receptor complex formation. Brief exposure of unoccupied receptor to mersalyl prior to TCDD binding caused slower sedimentation of the complex in 0-KCl sucrose gradients and alterations in its elution profiles on DEAE- and DNA-Sepharose suggestive of some impairment of the transformation process. When reagents were added to the transformed TCDD-receptor complex, loss of binding was observed only at concentrations which were an order of magnitude higher than those inhibiting TCDD binding. Loss of binding by each reagent was biphasic, and except for that caused by mersalyl, was not complete even after 6-8 h. Dithiothreitol was able to reverse the effects of mersalyl or PHMB only partially and only if added during the early phase (10-30 min) of binding loss. Mersalyl was much more potent in disrupting the untransformed than the transformed TCDD receptor complex. Physical alteration of the mersalyl-treated TCDD-receptor complex was evident from gel filtration, sucrose gradients, and DNA- and DEAE-Sepharose chromatography. Our results are in striking contrast to the effects of these reagents on steroid receptors, whose bound steroid hormone ligand is rapidly and reversibly displaced by lower concentrations of reagent.(ABSTRACT TRUNCATED AT 400 WORDS)