Gastrointestinal Motility Variation and Oral Drug Absorption.

Gastrointestinal (GI) motility is a physiological factor that affects oral drug absorption by controlling a drug's residence time in the GI tract. The development of an oral drug absorption model, the pulsatile emptying transit (PET) model, which takes into account variations in GI motility due to the migrating motor complex (MMC) is described. The absorption rate outputted by the PET model can be used as an input for pharmacokinetic models to estimate drug plasma concentration-time profiles. The effect of variations in GI motility on the drug plasma concentration-time profiles of high permeability and high solubility (BCS Class I) drugs was simulated. Simulations showed that increases in the maximum plasma concentration (Cmax) greater than 10% can occur when drugs that have an effective permeability greater than 0.04 cm/min and a high dissolution rate (85% of the dose dissolves within 15 minutes) are dosed during phase III of the MMC. Many explanations have been given for the appearance of double peaks in oral ranitidine plasma concentration-time curves. Using a discontinuous PET model with a 2-compartment pharmacokinetic model, parameter sensitivity analysis was done on the following parameters: dosing time relative to the MMC, dissolution rate, effective permeability in the duodenum and ileum, and intravenous pharmacokinetic parameters (k12, k21, kout, Vd). Simulations suggest that the variety of shapes for ranitidine plasma concentration-time profiles with double peaks is a result of differences in these parameter values between individuals. In addition, simulations showed that the dosing time relative to the MMC coupled with discontinuous absorption sites along the small intestine can explain the absence and presence of double peaks in oral ranitidine plasma concentration-time profiles. Cocrystals are non-covalently bonded crystal complexes with two or more components. The formation of cocrystals offers a means to alter the dissolution rate of a solid without changing covalent bonds. Dissolution experiments with CBZ:NCT cocrystal and CBZ(III) crystal in ethanol, 2-propanol and ethyl acetate were conducted and the relative dissolution rates were compared with estimated relative dissolution rates based on stoichiometric cocrystal solubility. Statistically significant differences in relative dissolution rates were not observed in all three solvents.Ph.D.PharmaceuticsUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/58439/1/jichung_1.pd

The Effects of Immobilization Stress on the Synthesis and the Catabolism of Dopamine and Norepinephrine in the Rat Hypothalamus

Immobilization stress was adopted as a prototype stress model for studying the effects of stress on dopaminergic and noradrenergic neuronal activity in the rat hypothalamus. Norepinephrine content was significantly increased after 4 hours of immobilization stress. Also, the turnover rates of both dopamine and norepinephrine were found to be significantly increased after the stress, providing the evidence of increased synthesis rates of both neurotransmitters. These findings were consistent with the increase in plasma corticosterone and catecholamine levels. The activities of tyrosine hydroxylase and dopamine-j1-hydroxylase, the synthesizing enzymes for catecholamines, were significantly increased after the stress, while that of monoamine oxidase, the catabolizing enzyme, did not change to a significant degree at all. Kinetic analysis of tyrosine hydroxylase, the rate-limiting step in catecholamine biosynthesis, revealed that Vmax was significantly increased after the stress without significant change of Km. These findings suggest that dopamine and norepinephrine may playa significant role in mediating stress responses by increasing their neuronal activities

Does Viral Anxiety Influence the Insomnia Severity Among Patients With Insomnia Disorder During COVID-19 Pandemic?

Background and Objective We aimed to investigate whether viral anxiety affects insomnia severity in patients with insomnia disorder during the coronavirus disease 2019 (COVID-19) pandemic. In addition, we examined whether viral anxiety mediates the influence of dysfunctional beliefs about sleep on insomnia severity. Methods The medical records of 111 patients who visit the sleep clinic from September 2021 to May 2022 were reviewed. Patients’ symptoms were rated with rating scales including Insomnia Severity Index (ISI), Stress and Anxiety to Viral Epidemics-6 items (SAVE-6), Dysfunctional Beliefs and Attitudes about Sleep-16 items (DBAS-16), Patient Health Questionnaire-9 items (PHQ-9), Epworth Sleepiness Scale, and discrepancy between desired time in bed and desired total sleep time (the DBST index). Results The SAVE-6 score was not significantly correlated with ISI score among insomnia patients. Linear regression analysis showed that the ISI score was expected by PHQ-9 (β = 0.21, p = 0.038) and DBAS-16 (β = 0.42, p < 0.001). Mediation analysis showed that viral anxiety did not mediate the influence of dysfunctional beliefs about sleep on insomnia severity. Conclusions We could not observe the mediating effect of viral anxiety on the association between dysfunctional beliefs about sleep on insomnia severity. Though COVID-somnia was one of big issues in this COVID-19 pandemic, the influence of virus on the severity of insomnia among insomnia patients needs to be interpreted cautiously

Psychometric properties of the Stress and Anxiety to Viral Epidemics-9 scale among frontline nursing professionals working in the COVID-19 inpatients ward

This study examined the reliability and validity of the Stress and Anxiety to Viral Epidemics-9 (SAVE-9) scale among nursing professionals working in a COVID-19 inpatient ward. An anonymous, online survey was conducted among working frontline nursing professionals between April 7 and 18, 2022. We collected information about the participants' age, sex, years of employment, shift work, and marital status. In addition, the participants were asked whether they had dealt with infected patients recently, and whether they had been quarantined, infected, or vaccinated. SAVE-9, Generalized Anxiety Disorder-7 (GAD-7), and Patient Health Questionnaire-9 (PHQ-9) were used to evaluate symptoms. We used the Confirmatory Factor Analysis (CFA) to determine the validity of the two-factor model of the SAVE-9 scale. We also tested reliability and convergent validity using the PHQ-9 and GAD-7 scales. A total of 136 responses was analyzed, and CFA for two-factors model of the SAVE-9 scale showed a good model fit among frontline nursing professionals (CFI = 1.000, TLI = 1.040, RMSEA = 0.000, RSMR = 0.060). Multi-group CFAs revealed that the SAVE-9 scale can measure work-related stress and viral anxiety in the same way across sex, having depression, or having generalized anxiety. The internal consistency was shown to be good, and the SAVE-9 scale was significantly correlated with the GAD-7 (r = 0.328, p &lt; 0.001) and PHQ-9 score (r = 0.361, p &lt; 0.001). The two-factor model of the SAVE-9 is a valid and reliable scale for frontline nursing professionals

Impairment of Instrumental Activities of Daily Living in Patients with Mild Cognitive Impairment

ObjectiveaaThis study was conducted to examine the following: whether patients with mild cognitive impairment (MCI) show impairments in instrumental activities of daily living (IADL) as compared to controls; to identify the functional sub-domains of instrumental activities of daily living (IADL) that are affected in MCI and, finally, to identify the Seoul-Instrumental Activities of Daily Living (S-IADL) scale cut-off score that best differentiated between MCI and controls. MethodsaaThis study was carried out at the geropsychiatry clinic, university hospital. The study participants included 66 patients with MCI and 61 normal elderly. The S-IADL and Seoul-Activities of Daily Living (S-ADL) scales were administered to the main caregivers of all participants in order to assess everyday functioning. ResultsaaThe total S-IADL score was significantly higher in the patients with MCI [mean (SD) score=4.47 (2.06)] than in the controls [mean (SD) score=1.44 (1.65)] (p&lt;0.001). The patients with MCI performed significantly worse on IADLs, such as the ability to use the telephone, prepare meals, take medication, manage belongings, keep appointments, talk about recent events, and perform leisure activities/hobbies (p&lt;0.05). The S-IADL scal

PITX1 is a regulator of TERT expression in prostate cancer with prognostic power

Simple Summary Most prostate cancer is of an indolent form and is curable. However, some prostate cancer belongs to rather aggressive subtypes leading to metastasis and death, and immediate therapy is mandatory. However, for these, the therapeutic options are highly invasive, such as radical prostatectomy, radiation or brachytherapy. Hence, a precise diagnosis of these tumor subtypes is needed, and the thus far applied diagnostic means are insufficient for this. Besides this, for their endless cell divisions, prostate cancer cells need the enzyme telomerase to elongate their telomeres (chromatin endings). In this study, we developed a gene regulatory model based on large data from transcription profiles from prostate cancer and chromatin-immuno-precipitation studies. We identified the developmental regulator PITX1 regulating telomerase. Besides observing experimental evidence of PITX1′s functional role in telomerase regulation, we also found PITX1 serving as a prognostic marker, as concluded from an analysis of more than 15,000 prostate cancer samples. Abstract The current risk stratification in prostate cancer (PCa) is frequently insufficient to adequately predict disease development and outcome. One hallmark of cancer is telomere maintenance. For telomere maintenance, PCa cells exclusively employ telomerase, making it essential for this cancer entity. However, TERT, the catalytic protein component of the reverse transcriptase telomerase, itself does not suit as a prognostic marker for prostate cancer as it is rather low expressed. We investigated if, instead of TERT , transcription factors regulating TERT may suit as prognostic markers. To identify transcription factors regulating TERT , we developed and applied a new gene regulatory modeling strategy to a comprehensive transcriptome dataset of 445 primary PCa. Six transcription factors were predicted as TERT regulators, and most prominently, the developmental morphogenic factor PITX1. PITX1 expression positively correlated with telomere staining intensity in PCa tumor samples. Functional assays and chromatin immune-precipitation showed that PITX1 activates TERT expression in PCa cells. Clinically, we observed that PITX1 is an excellent prognostic marker, as concluded from an analysis of more than 15,000 PCa samples. PITX1 expression in tumor samples associated with (i) increased Ki67 expression indicating increased tumor growth, (ii) a worse prognosis, and (iii) correlated with telomere length

Liver X receptor is a therapeutic target for photoaging and chronological skin aging

Liver X receptors (LXRalpha and -beta) are liposensors that exert their metabolic effects by orchestrating the expression of macrophage genes involved in lipid metabolism and inflammation. LXRs are also expressed in other tissues, including skin, where their natural oxysterol ligands induce keratinocyte differentiation and improve epidermal barrier function. To extend the potential use of LXR ligands to dermatological indications, we explored the possibility of using LXR as a target for skin aging. We demonstrate that LXR signaling is down-regulated in cell-based models of photoaging, i.e. UV-activated keratinocytes and TNFalpha-activated dermal fibroblasts. We show that a synthetic LXR ligand inhibits the expression of cytokines and metalloproteinases in these in vitro models, thus indicating its potential in decreasing cutaneous inflammation associated with the etiology of photoaging. Furthermore, a synthetic LXR ligand induces the expression of differentiation markers, ceramide biosynthesis enzymes, and lipid synthesis and transport genes in keratinocytes. Remarkably, LXRbeta-null mouse skin showed some of the molecular defects that are observed in chronologically aged human skin. Finally, we demonstrate that a synthetic LXR agonist inhibits UV-induced photodamage and skin wrinkle formation in a murine model of photoaging. Therefore, the ability of an LXR ligand to modulate multiple pathways underlying the etiology of skin aging suggests that LXR is a novel target for developing potential therapeutics for photoaging and chronological skin aging indications

Thermodynamically Stable Synthesis of Large-Scale and Highly Crystalline Transition Metal Dichalcogenide Monolayers and their Unipolar n-n Heterojunction Devices.

Transition metal dichalcogenide (TMDC) monolayers are considered to be potential materials for atomically thin electronics due to their unique electronic and optical properties. However, large-area and uniform growth of TMDC monolayers with large grain sizes is still a considerable challenge. This report presents a simple but effective approach for large-scale and highly crystalline molybdenum disulfide monolayers using a solution-processed precursor deposition. The low supersaturation level, triggered by the evaporation of an extremely thin precursor layer, reduces the nucleation density dramatically under a thermodynamically stable environment, yielding uniform and clean monolayer films and large crystal sizes up to 500 µm. As a result, the photoluminescence exhibits only a small full-width-half-maximum of 48 meV, comparable to that of exfoliated and suspended monolayer crystals. It is confirmed that this growth procedure can be extended to the synthesis of other TMDC monolayers, and robust MoS2 /WS2 heterojunction devices are easily prepared using this synthetic procedure due to the large-sized crystals. The heterojunction device shows a fast response time (≈45 ms) and a significantly high photoresponsivity (≈40 AW-1 ) because of the built-in potential and the majority-carrier transport at the n-n junction. These findings indicate an efficient pathway for the fabrication of high-performance 2D optoelectronic devices.European Research Council under the the European Union's Seventh Framework Programme (FP/2007-2013)/Grant Agreement no. 340538 (Project ‘UniQDS’) European Union under H2020 programme Grant Agreement no. 685758 (Project ‘1D-NEON’)

Second-hand smoke and chronic bronchitis in Taiwanese women: a health-care based study

<p>Abstract</p> <p>Background</p> <p>Cigarette smoking cannot fully explain the epidemiologic characteristics of chronic obstructive pulmonary disease (COPD) in women, particularly for those who rarely smoke, but COPD risk is not less than men. The aim of our study is to investigate the relationship between second-hand smoke (SHS) exposure and chronic bronchitis in Taiwanese women.</p> <p>Methods</p> <p>We used Taiwan's National Health Insurance Bureau claims data in 1999, and cross-checked using criteria set by the American Thoracic Society; there were 33 women with chronic bronchitis, 182 with probable chronic bronchitis, and 205 with no chronic bronchitis during our interview time between 2000 and 2005. We measured second-hand smoke (SHS) exposure by self-reported measures (household users and duration of exposure), and validated this by measuring urinary cotinine levels of a subset subjects. Classification of chronic bronchitis was also based on spirometry defined according to the GOLD guidelines to get the severity of COPD.</p> <p>Results</p> <p>Women who smoked and women who had been exposed to a lifetime of SHS were 24.81-fold (95% CI: 5.78-106.38) and 3.65-fold (95% CI: 1.19-11.26) more likely to have chronic bronchitis, respectively, than those who had not been exposed to SHS. In addition, there was a significant increasing trend between the severity of COPD and exposure years of SHS (<it>p </it>< 0.01). The population attributable risk percentages of chronic bronchitis for smokers and those exposed to SHS were 23.2 and 47.3% respectively.</p> <p>Conclusions</p> <p>These findings indicate that, besides cigarette smoking, exposure to SHS is a major risk factor for chronic bronchitis in Taiwanese women.</p

Geogenic and atmospheric sources for volatile organic compounds in fumarolic emissions from Mt. Etna and Vulcano Island (Sicily, Italy)

In this paper, fluid source(s) and processes controlling the chemical composition of volatile organic compounds (VOCs) in gas discharges from Mt. Etna and Vulcano Island(Sicily, Italy) were investigated. The main composition of the Etnean and Volcano gas emissions is produced by mixing, to various degrees, of magmatic and hydrothermal components. VOCs are dominated by alkanes, alkenes and aromatics, with minor, though significant, concentrations of O-, S- and Cl(F)-substituted compounds. The main mechanism for the production of alkanes is likely related to pyrolysis of organic-matterbearing sediments that interact with the ascending magmatic fluids. Alkanes are then converted to alkene and aromatic compounds via catalytic reactions (dehydrogenation and dehydroaromatization, respectively). Nevertheless, an abiogenic origin for the light hydrocarbons cannot be ruled out. Oxidative processes of hydrocarbons at relatively high temperatures and oxidizing conditions, typical of these volcanic-hydrothermal fluids, may explain the production of alcohols, esters, aldehydes, as well as O- and S-bearing heterocycles. By comparing the concentrations of hydrochlorofluorocarbons (HCFCs) in the fumarolic discharges with respect to those of background air, it is possible to highlight that they have a geogenic origin likely due to halogenation of both methane and alkenes. Finally, chlorofluorocarbon (CFC) abundances appear to be consistent with background air, although the strong air contamination that affects the Mt. Etna fumaroles may mask a possible geogenic contribution for these compounds. On the other hand, no CFCs were detected in the Vulcano gases, which are characterized by low air contribution. Nevertheless, a geogenic source for these compounds cannot be excluded on the basis of the present data