Vitamin D and COVID-19: A review on the role of vitamin D in preventing and reducing the severity of COVID-19 infection.

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is a pathogenic coronavirus causing COVID-19 infection. The interaction between the SARS-CoV-2 spike protein and the human receptor angiotensin-converting enzyme 2, both of which contain several cysteine residues, is impacted by the disulfide-thiol balance in the host cell. The host cell redox status is affected by oxidative stress due to the imbalance between the reactive oxygen/nitrogen species and antioxidants. Recent studies have shown that Vitamin D supplementation could reduce oxidative stress. It has also been proposed that vitamin D at physiological concentration has preventive effects on many viral infections, including COVID-19. However, the molecular-level picture of the interplay of vitamin D deficiency, oxidative stress, and the severity of COVID-19 has remained unclear. Herein, we present a thorough review focusing on the possible molecular mechanism by which vitamin D could alter host cell redox status and block viral entry, thereby preventing COVID-19 infection or reducing the severity of the disease.

The use of vapour phase ultra-violet spectroscopy for the analysis of arson accelerants in fire scene debris.

A method has been developed for the analysis of arson accelerants in fire scene debris by vapour phase ultra-violet (UV) spectroscopy. The method is rapid, inexpensive, simple to use and is sufficiently sensitive and discriminating to be of use for the analysis of crime scene samples. Application to casework samples is described. On occasion, the method offers additional information to that which can be obtained by gas chromatography-flame ionisation detection (GC-FID) and gas chromatography-mass spectrometry (GC-MS) and represents a useful adjunct to these techniques. In addition, the method offers advantages where the use of GC-MS analysis of arson accelerants in fire scene debris is not a practical proposition.

AutoScan: an automated workstation for rapid determination of mass and tandem mass spectrometry conditions for quantitative bioanalytical mass spectrometry.

An automated flow injection analysis (FIA) mass spectrometry system (AutoScan) was developed to allow rapid unattended determination of optimal conditions during mass (ms) and tandem mass spectrometry (ms/ms) on new chemical entities (NCEs) arranged in 96-well plates. The 96-well plate is placed on the deck of a modified Gilson Multiprobe autosampler for injection into a PE Sciex API 2000 triple quadrupole mass spectrometer. A customized software interface is used to create the necessary scan experiments by associating each 96-well plate of NCEs to be scanned with an index file containing data on the identity of each analyte and its expected molecular weight. Analytes are injected four at a time into a custom injection manifold and conventional mass spectra are acquired in both polarities (+/-) using an alternating positive/negative Q1 scan function. The software determines the optimal polarity and definitive precursor ion for all analytes and uses the results to build the injection sequence for product ion scanning. The samples are automatically re-injected under MS/MS conditions, and product ion scans that loop among different collision energies are collected for each analyte. The resulting data are processed automatically and the optimal MS/MS transitions for each analyte are selected. A color-coded graphical interface facilitates data review. Any unusual ion transitions or transposition errors made during plate preparation are noted and corrected. Complete MS and MS/MS conditions are obtained for 96 compounds in about one hour and the resulting data are available for download as sample control injection sequence files.

Prolonged exposure to intermittent alcohol vapors blunts hypothalamic responsiveness to immune and non-immune signals.

BACKGROUND: We have previously shown that long-term alcohol treatment blunts the ACTH response to alcohol itself, as well as to other stresses, and is accompanied by decreased pituitary responsiveness to vasopressin (VP), but not corticotropin-releasing factor (CRF). The present work aims to determine the relevance of changes in CRF and VP receptors in the pituitary gland and/or peptide stores of CRF neurons in the paraventricular nucleus (PVN) of the hypothalamus, the areas that are most directly involved in ACTH release. METHODS: Intact male rats were exposed to alcohol using a new vapor delivery system which enables individual rat housing in boxes. Alcohol treatment was delivered for 6 hr once daily (0700-1300), after which the rats were returned to their home cages where they had free access to food and water. Control rats were kept in similar boxes, but not exposed to alcohol. Total treatment time was 8 days. All animals were equipped with indwelling jugular cannulae that were used to monitor blood alcohol levels (BALs) as well as ACTH and corticosterone release throughout drug exposure. Due to the presence of a swivel, the animals' movements were not restricted or hindered by the presence of these cannulae. On the morning of day 9, the animals were decapitated under basal conditions or exposed to a neurogenic (mild electrofootshocks) or systemic [i.v. lipopolysaccharide (LPS)] stimulus. PVN neuronal responses, indicated by changes in mRNA concentrations of the immediate early genes (IEGs) c-fos and NGFI-B, and plasma ACTH levels were measured before and during endotoxemia or electrofootshocks. RESULTS: In the absence of alcohol, plasma ACTH and corticosterone remained at basal levels, indicating the absence of environment-induced stress. In rats exposed to alcohol, BALs were consistent and predictable, and we targeted peak values of about 200 mg%. At the end of the drug treatment period, there were no significant differences between CRF and VP receptor mRNA levels in the anterior pituitary of control and alcohol-treated rats. In contrast, alcohol treatment respectively decreased CRF and increased VP stores in the external zone of the median eminence. It also increased NGFI-B and c-fos transcripts in the magnocellular (m) portion of the PVN, but not the parvicellular (p) division of this nucleus under basal conditions (i.e., in the absence of shocks or LPS). After exposure to these stressors, on the other hand, all groups of rats showed significant increases in plasma ACTH levels as well as up-regulation of their PVN neuronal response, as indicated by changes in pPVN IEGs transcripts. However, these hormonal and neuronal responses were significantly blunted in animals pretreated with alcohol. CONCLUSIONS: Collectively, our results suggest that decreased PVN neuronal activation represents an important mechanism of the ability of long-term alcohol treatment to blunt the ACTH response to shocks or endotoxemia. In addition, the new system of alcohol delivery that we developed is practical and reliable, and has the significant advantage that it enables measurement of circulating hormone levels during drug exposure of the animals.

Requirement for the Candida albicans FAS2 gene for infection in a rat model of oropharyngeal candidiasis.

The virulence of Candida albicans strains deficient in fatty acid synthase activity by virtue of disruption/deletion of the FAS2 gene was examined in a rat model of oropharyngeal candidiasis. The FAS2 alleles of C. albicans CAI4 (delta ura3::imm434/delta ura3::imm434) were sequentially disrupted with a cassette that included a portion of FAS2 from which a 984 bp fragment containing the FAS condensing reaction domain was deleted and replaced with hisG-URA3-hisG sequences. Verification of fatty acid synthase inactivation was obtained from assays of enzyme activity. Strains in which a single allele was disrupted (CFD1 and CFD3) exhibited an approximately 20% reduction in activity, when compared to wild-type. In addition, fatty acid synthase activity was abolished in a FAS2 null mutant strain (CFD2), and growth of CFD2 occurred only when the growth medium was supplemented with Tween 40 and certain fatty acids. Strain CFD2 was avirulent in the rat model, indicating that fatty acid synthase activity is required for C. albicans oropharyngeal infection. Strains with a single FAS2 allele disruption colonized the oral cavity, but the number of cells recovered from infected animals was approximately fivefold less than for the parental strain. The results suggest that FAS may be exploited as a possible target for the development of new antifungal agents.

Unusual antimicrobial compounds from Aeollanthus buchnerianus.

Using bioassay guided isolation, three novel 12 carbon polyoxygenated fatty acids and a novel abietane diterpene have been isolated from the chloroform extract of aerial parts of Aeollanthus buchnerianus (Lamiaceae). Rigorous spectroscopic methods were used for compound identification. (Z,Z)-8zeta-acetoxy-5zeta-hydroxydodeca-2,6-dienoic acid and (Z,Z)-5zeta, 8zeta-dihydroxydodeca-2,6-dienoic acid inhibited the spore germination of Cladosporium cucumerinum (both with Minimum Inhibitory Dose (MID) values of 1 microgram) and Aspergillus niger (MID 5 and 25 microgram respectively). Further, they also reduced the hyphal growth of Pythium ultimum. (Z)-5zeta-hydroxy-6zeta,7zeta,8zeta-triacetox ydodeca-2-dienoic acid exhibited short term inhibition of the growth of Cladosporium cucumerinum. The novel abietane diterpenoid, (rel)-14alpha-acetoxyabiet-7-en-18-oic acid inhibited the growth of the gram positive bacteria Bacillus subtilis, Staphylococcus aureus and Streptomyces scabies (MIC values 80, 20 and 20 micrograms ml(-1) respectively).

An anti-murine CD3 monoclonal antibody with a low affinity for Fc gamma receptors suppresses transplantation responses while minimizing acute toxicity and immunogenicity.

145-2C11, a hamster mAb directed against the mouse CD3 complex, is a potent immunosuppressive agent. Upon initial treatment, 145-2C11 triggers a systemic release of multiple cytokines that is responsible for the acute toxicity of the mAb. This cellular activation is a consequence of the cross-linking between T lymphocytes and Fc gamma R-bearing cells, mediated by the high affinity of the hamster mAb for murine Fc gamma Rs. Repeated mAb injections result in the onset of a neutralizing humoral response. Therefore, there has been an increased interest in developing nonmitogenic forms of anti-CD3 mAbs, although it is not clear whether these Abs will retain immunosuppressive properties. To determine whether the initial cytokine production is necessary for the immunosuppressive properties and the immunogenicity of anti-CD3 mAbs in vivo, we have generated chimeric (hamster 145-2C11 F(ab')2 region/mouse Fc gamma portion) mAbs using murine isotypes with different affinities for Fc gamma Rs. The 145-2C11 and a chimeric IgG2a isotype, both of which bind murine Fc gamma Rs avidly, had similar activating, immunogenic, and immunosuppressive properties in mice. The administration of a chimeric IgG3 isotype with a very low affinity for murine Fc gamma Rs did not result in cytokine production, a humoral response against the mAb, or TCR desensitization. Nevertheless, prolongation of skin graft survival was similar in the IgG3, IgG2a, and 145-2C11-treated mice, indicating that Fc gamma R nonbinding anti-CD3 mAbs retain potent immunosuppressive properties in vivo while not being immunogenic. This enhanced therapeutic to toxic profile may be beneficial in clinical transplantation.

Etoposide pharmacokinetics in children: the development and prospective validation of a dosing equation.

Pharmacokinetic studies of etoposide administered at 100-200 mg/m2 to 33 children are described. Twenty-seven studies were performed in children aged < 10 years. Repeat studies were performed in 11 patients. Median pharmacokinetic parameters were as follows: plasma clearance, 26 ml/min/m2; volume of distribution, 4.9 liters/m2; area under the etoposide plasma concentration-time curve (AUC), 3.9 mg/ml x min per 100 mg/m2. Interindividual variability in pharmacokinetic parameters was large (coefficient of variation (CV) = 30, 28, and 27%, respectively) in comparison with intraindividual variability (CV = 12, 14, and 12%, respectively). Variability in AUC was much greater in those patients treated with 150-200 mg/m2 etoposide than with 100 mg/m2 (CV, 35 versus 13%) and was related to variability in renal function and prior exposure to cisplatin. Data from the first 20 studies were used to develop pharmacokinetic monitoring equations which were validated in a further 13 patients. The most accurate equation relies upon the elimination constant of 51Cr-EDTA and a single blood specimen taken at the end of the etoposide infusion. [formula: see text] where K = 51Cr-EDTA elimination rate constant. This equation showed no significant bias, and the predictive error was small with respect to AUC calculated according to a two-compartment model. Predictive error did not increase with increasing AUC, whereas a marked increase in predictive error was seen for dosing according to body surface area. Dosing according to body surface area alone led to marked over- or underexposure to etoposide in 8 patients. Pharmacokinetic monitoring using the equation described would have identified these patients and permitted dose modification. This approach provides an accurate means of monitoring etoposide AUC for administration times of 1-4 h without the need for detailed pharmacokinetic sampling. It will allow a significant reduction in the variability of exposure seen with surface area-based dosing.

Thalamic amnesia: Korsakoff syndrome due to left thalamic infarction.

In order to support the concept that a lesion of the thalamus is sufficient to cause a Korsakoff syndrome, we are presenting 5 patients, all of whom developed the syndrome after sustaining a left (dominant) thalamic infarction. Two patients had pure thalamic strokes followed by a permanent Korsakoff syndrome. One of these patients was studied with neuropsychometric testing, as well as with a modern MRI scan. In 2 other patients, clinical and imaging data indicate that infarction was not limited to the thalamus. Another patient had bilateral thalamic infarcts but only a temporary Korsakoff syndrome. Neuropathological data are needed to elucidate the exact anatomical substrate of dominant thalamic Korsakoff syndrome.

Gasoline explosions, gasoline sniffing: an epidemic in young adolescents.

One hundred twenty-two patients between the ages of 10 and 15 were admitted to the Shriners Burns Institute between July 1981 and November 1984. Seventy-five of the 122 patients sustained burns as a direct result of liquid gasoline explosions. Thirty patients had thrown gasoline on a fire and 17 others admitted to having ignited gasoline with a match. During admission interviews, none of the patients admitted to gasoline sniffing; however, 19 patients were subsequently found to have been sniffing gasoline at the time of the accident. All of the patients with gasoline burns sustained much larger burns, had longer hospitalizations, and required more surgery than did patients burned by other means. Similarly, the 19 patients who had been sniffing gasoline had larger burns, had longer hospital stays, and required more surgery than did those injured by gasoline in other accidents. The most common cause of thermal injury in the ten-to-15 year age group is a gasoline-related accident. The histories of a large number of these adolescents may be compatible with explosions related to gasoline sniffing. Educational efforts relating to the explosive nature of the substance and the dangers of gasoline sniffing are warranted.

Pharmacokinetics and bioavailability of theophylline following enema and suppository administration in man.

The pharmacokinetics and bioavailability of theophylline from a commercial oral elixir of theophylline, a rectal suppository of aminophylline, and a rectal enema of theophylline monoethanolamine was compared in six normal subjects. Using a complete crossover design, the fasted subjects received a single dose of each dosage form. Blood and saliva samples were collected at frequent time intervals for 24 h, and the plasma assayed for theophylline by a specific thin-layer chromatography densitometric method. No statistically significant differences existed among the three dosage forms with respect to Cmax and AUC corrected for the elimination rate constant and the dose (mg kg-1). However, tmax was significantly larger for the suppository. While the rate of absorption was significantly slower for the suppository, no differences in the extent of absorption existed among the three dosage forms. A one-compartment open model with apparent first-order absorption adequately described the plasma concentration-time data for the elixir and enema, whereas the suppository data were best fitted by a one-compartment open model with apparent zero-order absorption and a lag time. A rate-limiting, concentration-independent release of drug from the base most likely accounts for the slow absorption of theophylline from the suppository. While the saliva:plasma ratio remained fairly constant for most of the study period, the large variability found during the absorption phase following drug administration limits the usefulness of this parameter as a monitor of theophylline plasma concentrations.

'Beta-lactams' as beta-lactamase inhibitors.

The application of inhibitors to block the beta-lactamase destruction of penicillins and cephalosporins by resistant bacteria is a potentially useful way of improving the efficacy of established compounds. Certain semi-synthetic penicillins and cephalosporins have been found to be competitive inhibitors of selected beta-lactamases but an examination of streptomycete culture fluids has revealed two new types of beta-lactam compound: clavulanic acid, which is a progressive inactivator of a wide range of beta-lactamases, and the olivanic acids, which are both broad-spectrum antibiotics and potent beta-lactamase inhibitors. Penicillanic acid sulphone and 6-beta-bromopenicillanic acid have been shown to be significant inhibitors of beta-lactamase. The chemotherapeutic application of these compounds is discussed.

An anti-A1 lectin in the seeds of Amphicarpaea bracteata.

An anti-A1 lectin has been isolated from the extract of Amphicarpaea bracteata seeds by affinity chromatography on Epoxy-activated Sepharose 6B coupled to N-acetyl-D-galactosamine. The yield of the purified lectin was 86 microgram/g of seeds. The purified lectin shows one main band on electrophoresis in sodium dodecyl sulfate-polyacrylamide. The amino acid and neutral sugar composition indicate that this lectin is an acidic glycoprotein with a neutral sugar content of approx. 2%. The composition of the lectin is different from that of the Dolichos biflorus lectin but the two lectins have some common characteristics. The most powerful inhibitors of the agglutination of A1 red blood cells by the A. bracteata lectin is N-acetyl-D-galactosamine. Much weaker inhibitors of the agglutination are alpha-lactose, D-fucose, and five other sugars.

Effect of sodium phytate on the chemical and microbial composition of dental plaque in the monkey (Macaca fascicularis)

The incorporation of 1 or 3% sodium phytate in confectioners sugar produced minimal changes in the physical,chemical, and microbial composition of dental plaque in tube-fed monkeys during a two-week period. Only a reduction in yeasts and lactobacilli could be ascribed to the presence of phytate. Other changes were attributable to the transition from conventional feeding to tube-feeding, irrespective of the presence of absence of phytate.