New Insights Into Pharmacology of GABAA Receptor Alpha Subunits-Selective Modulators.

BACKGROUND: Benzodiazepines have long held a leading position in medical therapeutics, known for their multiple common therapeutic properties and primarily being prescribed for anxiety and insomnia. However, their lack of specificity and various side effects have led to a reevaluation of their long-term use, resulting in a rapid growth in the literature focusing on targeted therapies. AREAS OF UNCERTAINTY: Despite many efforts, uncertainties persist and there are heterogeneous findings across studies regarding the pharmacological effects attributed to gamma-aminobutyric acid type A (GABAA) receptor subunits. Selective compounds targeting GABAA receptor alpha subunits are currently under active research and definitive conclusions have not been reached yet. Some compounds have not progressed to clinical trials, while others, if advanced, have been halted. These challenges emphasize the difficulty in translating preclinical findings into clinical use. DATA SOURCES: A literature review was conducted using the PubMed database, searching for articles discussing GABAA receptor subunits. The search was refined by including only selective compounds with potential anxiolytic and cognitive enhancement properties. RESULTS: Findings reveal compounds with promising anxiolytic and antidepressant effects with minimal sedation and absence of tolerance development. Moreover, some compounds show potential in alleviating cognitive dysfunction. There is a broad spectrum of potential therapeutic applications for selective compounds, ranging from neurological disorders such as epilepsy and neuropathic pain to cognitive dysfunction-related conditions. Currently, the leading selective compounds with the most promising results in ongoing clinical trials are basmisanil and darigabat. Basmisanil holds further exploration potential in the treatment of cognitive impairment and related conditions, while darigabat shows progress in the advancement of adjunctive therapy of focal onset seizures and for the treatment of panic disorder, respectively. CONCLUSIONS: Future drug discovery efforts are encouraged to focus on positive allosteric modulators that selectively target the α2, α3 subunits and negative/positive allosteric modulators that target the α5 subunit of the GABAA receptor. The pursuit of ligands possessing only anxiolytic effects or those enhancing cognition continues to be an important focus for future research, with promising advancements depicted in recent studies.

Latest Insights into the In Vivo Studies in Murine Regarding the Role of TRP Channels in Wound Healing-A Review.

Wound healing involves physical, chemical and immunological processes. Transient receptor potential (TRP) and other ion channels are implicated in epidermal re-epithelization. Ion movement across ion channels can induce transmembrane potential that leads to transepithelial potential (TEP) changes. TEP is present in epidermis surrounding the lesion decreases and induces an endogenous direct current generating an epithelial electric field (EF) that could be implicated in wound re-epithelialization. TRP channels are involved in the activation of immune cells during mainly the inflammatory phase of wound healing. The aim of the study was to review the mechanisms of ion channel involvement in wound healing in in vivo experiments in murine (mice, rats) and how can this process be influenced. This review used the latest results published in scientific journals over the last year and this year to date (1 January 2023-31 December 3000) in order to include the in-press articles. Some types of TRP channels, such as TRPV1, TRPV3 and TRPA1, are expressed in immune cells and can be activated by inflammatory mediators. The most beneficial effects in wound healing are produced using agonists of TRPV1, TRPV4 and TRPA1 channels or by inhibiting with antagonists, antisense oligonucleotides or knocking down TRPV3 and TRPM8 channels.

The Role of Programmed Cell Death 1/Programmed Death Ligand 1 (PD-1/PD-L1) Axis in Sepsis-Induced Apoptosis.

Background and Objectives: Sepsis involves a dysregulated host response, characterized by simultaneous immunosuppression and hyperinflammation. Initially, there is the release of pro-inflammatory factors and immune system dysfunction, followed by persistent immune paralysis leading to apoptosis. This study investigates sepsis-induced apoptosis and its pathways, by assessing changes in PD-1 and PD-L1 serum levels, CD4+ and CD8+ T cells, and Sequential Organ Failure Assessment (SOFA) and Acute Physiology and Chronic Health Evaluation (APACHE II) severity scores. Materials and Methods: This prospective, observational, single-centre study enrolled 87 sepsis patients admitted to the intensive care unit at the County Emergency Clinical Hospital in Târgu Mureș, Romania. We monitored the parameters on day 1 (the day sepsis or septic shock was diagnosed as per the Sepsis-3 Consensus) and day 5. Results: Our study found a statistically significant variation in the SOFA score for the entirety of the patients between the studied days (p = 0.001), as well as for the studied patient groups: sepsis, septic shock, survivors, and non-survivors (p = 0.001, p = 0.003, p = 0.01, p = 0.03). On day 1, we found statistically significant correlations between CD8+ cells and PD-1 (p = 0.02) and PD-L1 (p = 0.04), CD4+ and CD8+ cells (p < 0.0001), SOFA and APACHE II scores (p < 0.0001), and SOFA and APACHE II scores and PD-L1 (p = 0.001 and p = 0.01). On day 5, we found statistically significant correlations between CD4+ and CD8+ cells and PD-L1 (p = 0.03 and p = 0.0099), CD4+ and CD8+ cells (p < 0.0001), and SOFA and APACHE II scores (p < 0.0001). Conclusions: The reduction in Th CD4+ and Tc CD8+ lymphocyte subpopulations were evident from day 1, indicating that apoptosis is a crucial factor in the progression of sepsis and septic shock. The increased expression of the PD-1/PD-L1 axis impairs costimulatory signalling, leading to diminished T cell responses and lymphopenia, thereby increasing the susceptibility to nosocomial infections.

Roflumilast 0.3% Cream: a Phosphodiesterase 4 Inhibitor for the Treatment of Chronic Plaque Psoriasis.

BACKGROUND: Plaque psoriasis is a chronic dermatologic autoimmune disease that affects adults and children. Roflumilast 0.3% cream is currently the only topical phosphodiesterase 4 inhibitor indicated for the treatment of plaque psoriasis in patients 12 years or older. PHARMACODYNAMICS AND PHARMACOKINETICS: Roflumilast inhibits phosphodiesterase 4 inhibitor enzyme leading to the accumulation of cyclic adenosine monophosphate, which suppresses the inflammatory mediators interferon-γ and tumor necrosis factor-α. Roflumilast, applied once daily, reaches steady state by day 15 and has a half life of approximately 4 days in adults. Roflumilast undergoes extensive hepatic metabolism by cytochrome P450 enzymes and conjugation. Roflumilast is 99% bound to plasma proteins. CLINICAL TRIALS: Roflumilast efficacy and safety were evaluated in the DERMIS-1 and DERMIS-2 clinical trials. These identically designed, double-blind, vehicle-controlled phase 3 trials randomized 881 patients to roflumilast 0.3% cream or vehicle, applied once daily for 8 weeks. In DERMIS-1, the Investigator Global Assessment success rate was 42.4% with roflumilast 0.3% cream compared with 6.1% with the vehicle (32.3%-46.9%; P <0.001). Similarly, in DERMIS-2, the Investigator Global Assessment success rate was 37.5% with roflumilast 0.3% cream compared with 6.9% with the vehicle (20.8%-36.9%; P <0.001). Of 881 participants, 1% discontinued treatment with roflumilast cream due to adverse reactions compared with 1.3% treated with vehicle. Urticaria at the application site (0.3%) was the most common adverse reaction that led to discontinuation of roflumilast. THERAPEUTIC ADVANCE: To date, topical corticosteroids are the most commonly used agents to treat mild plaque psoriasis. Sensitive areas are often challenging to treat with existing topical therapy, including corticosteroids. Topical roflumilast has shown to be effective in treating sensitive areas, including skin folds, and may be an alternative to systemic therapy for some patients. The Food and Drug Administration approved topical roflumilast for the treatment of plaque psoriasis, including intertriginous areas, for patients 12 years or older.

A Systematic Review of Clinical Studies on the Effect of Psychoactive Cannabinoids in Psychiatric Conditions in Alzheimer Dementia.

BACKGROUND: The systematic reviews and meta-analyses performed until now did not provide the adequate picture of actual knowledge in the field of neuropsychiatric symptoms treatment using psychotropic cannabinoids in patients with Alzheimer disease (AD). THE STUDY QUESTION: Which is the level of evidence, from quantitative and qualitative point of view, concerning the efficacy and safety of the treatment with psychotropic cannabinoids of neuropsychiatric symptoms in AD? STUDY DESIGN: PubMed, EMBASE, Cochrane Database of Systematic Reviews, Google Scholar Data, and Clinicaltrials.gov were searched for randomized clinical trials with cannabinoids in Alzheimer dementia agitation and aggression. MEASURES AND OUTCOMES: The rationale, the objectives, and the methods used for searching the trials have been established according to PRISMA Criteria 2009. RESULTS: The total number of patients in the 9 publications evaluated in this study, which included data from 6 clinical trials, was 422 patients-treatments, where treatment was a psychoactive cannabinoid or placebo, some of them obtained by multiplying selected patients with the number of cannabinoid treatments in the crossover studies. There are multiple sources of bias in the analyzed studies; 2 elements have prevented conclusive results. One element was polypragmazia, a major role being played by the use of psychotropic drugs other than cannabinoids, in an effort to reduce agitation and aggressive behavior. The second one was the large number of concomitant symptoms, for example, pain (commonly causing anxiety and agitation). CONCLUSIONS: No clear conclusion can be drawn on the effectiveness of psychoactive cannabinoids in the treatment of psychiatric manifestations, in particular agitation and aggression, in AD. In the future, large randomized controlled trial with adequate designs, without crossover and for longer duration, adapted to cannabinoid pharmacokinetics, is required to establish the real efficacy and safety of these drugs in aggressive and/or agitated patients with AD.

The Complex Role of Botulinum Toxin in Enhancing Goal Achievement for Post-Stroke Patients.

INTRODUCTION: The rehabilitation medical team is responsible for the therapeutic management of post-stroke patients and, therefore, for the complex therapeutic approach of spasticity. Considering the generous arsenal at our disposal in terms of both pharmacological treatment, through the possibility of administering botulinum toxin to combat spasticity, and in terms of accurate assessment through developed functional scales such as the GAS (Goal Attainment Scale), one of our purposes is to monitor the parameters that influence the achievement of functional goals set by patients together with the medical team in order to render the patients as close as possible to achieving their proposed functional goals, thus enhancing their quality of life. By assessing and establishing statistical and clinical correlations between the GAS and quantifiable parameters related to the affected post-stroke upper limb, namely degree of spasticity, motor control, pain level and evolution of pain under treatment with BoNT-A (abobotulinum toxin A), and patients' overall response to BoNT-A treatment, we aim to quantify the improvement of the therapeutic management of post-stroke patients with spasticity and develop a more personalized and effective approach to their disability and impairment. RESULTS AND DISCUSSIONS: The analysis concluded that there were two independent predictors of the Achieved GAS-T score (the study's endpoint parameter) motor control at any level of the upper limb and number of prior BoNT-A injections. The number of prior BoNT-A injections was an independent predictor of Achieved GAS-T score improvement but had no significant influence over Baseline GAS-T score. Enhancement in proximal and intermediate motor control showed a GAS score improvement of 3.3 points and a 0.93-point GAS score improvement for wrist motor control progress. From a separate viewpoint, patients with motor deficit on the left side have shown significantly greater improvement in Changed GAS-T scores by 2.5 points compared to patients with deficits on the right side; however, we note as a study limitation the fact that there was no statistical analysis over the dominant cerebral hemisphere of each patient. CONCLUSIONS: Improvement in the Achieved GAS-T score means better achievement of patients' goals. Thus, after the BoNT- A intervention, at follow-up evaluation, GAS was found to be directly correlated with improvement in motor control of the affected upper limb. Mobility of the corresponding limb was enhanced by pain decrease during p-ROM (passive range of motion) and by amelioration of spasticity. MATERIALS AND METHODS: We conducted an observational, non-randomized clinical study on 52 stroke patients, a representative sample of patients with post-stroke spasticity and disability from our neurological rehabilitation clinic, who have been treated and undergone a specific rehabilitation program in our tertiary diagnostic and treatment medical center, including BoNT-A focal treatment for spasticity in the affected upper limb. The primary objective of the study was to assess the influence of abobotulinum toxin A treatment on the Goal Attainment Scale. Secondary objectives of the study included the assessment of BoNT-A treatment efficacy on spasticity with the MAS (Modified Ashworth Scale), pain with the NRS (Numerical Rating Scale), and joint passive range of motion (p-ROM), identifying demographic, clinical, and pharmacological factors that influence the response to BoNT-A treatment, as well as to conduct a descriptive and exploratory analysis of the studied variables.

Immune profile of patients­a new approach in management of sepsis and septic shock?

The present study was a prospective observational single center study, enrolling 102 patients with sepsis, admitted in the Intensive Care Unit of the County Emergency Clinical Hospital in Târgu Mureș (Mureș, Romania). The main goal of the present study was to compare the changes of the following parameters on day 1 compared with day 5, in sepsis compared with septic shock, as well as in survivors compared with non-survivors: Cell blood count parameters, neutrophil-lymphocyte ratio, platelet-lymphocyte ratio and systemic inflammation index, C reactive protein (CRP), ferritin, procalcitonin (PCT), CD 3+ T cells, CD4+ T cells, CD8+ T cells, CD16+CD56+/CD3-NK cells and CD19+ B cells. The relationship between the subcategories of lymphocytes with the inflammatory markers was evaluated. The serum concentration of CRP and PCT was significantly lower on day 5 compared with day 1 and serum ferritin was significantly higher in patients with septic shock. The percentage of cytotoxic T lymphocytes was significantly decreased and the percentage of NK lymphocytes was significantly increased in patients who developed septic shock. The results indicated a negative significant correlation between the proportion of T lymphocytes and PCT concentration and a positive significant correlation between the proportion of B lymphocytes and PCT concentration.

Is Carboxyhaemoglobin an Effective Bedside Prognostic Tool for Sepsis and Septic Shock Patients?

Introduction: Proper management of sepsis poses a challenge even today, with early diagnosis and targeted treatment being the most important steps. Easy, cost-effective bedside tools are needed in order to pinpoint towards the outcome of sepsis or septic shock. Aim of study: This study aims to find a correlation between Sequential Organ Failure Assessment (SOFA), Acute Physiology and Chronic Health Evaluation II (APACHE II) and Simplified Acute Physiology Score II (SAPS II) severity scores, the Neutrophil-Lymphocytes Ratio (NLR) and carboxyhaemoglobin (COHb) levels in septic or septic shock patients with the scope of establishing a bed side cost-effective prognostic tool. Materials and methods: A pilot, prospective, observational, and ongoing study was conducted on 61 patients admitted with sepsis or septic shock according to the SEPSIS 3 Consensus definition. We followed clinical and paraclinical parameters on day 1 (D1) and day 5 (D5) after meeting the inclusion criteria. Results: On D1 we found a statistically significant positive correlation between each severity score (p <0.0001), r = 0.7287 for SOFA vs. APACHE II with CI: 0.5841-0.8285, r = 0.6862 for SOFA vs. SAPS II with CI: 0.5251-0.7998 and r = 0.8534 for APACHE II vs. SAPS II with CI: 0.7663 to 0.9097. On D5 we observed similar results: a significant positive correlation between each severity score (p <0.0001), with r = 0.7877 for SOFA vs. APACHE II with CI: 0.6283 to 0.8836, r = 0.8210 for SOFA vs. SAPS II with CI: 0.6822 to 0.9027 and r = 0.8880 for APACHE II vs. SAPS II., CI: 0.7952 to 0.9401. Nil correlation was found between the severity scores, NLR and COHb on D1 and D5. Conclusion: Cost-effective bedside tools to pinpoint towards the outcome of sepsis are yet to be found, however the positive correlation between the severity scores point out to a combination of such tools for prognosis prediction of septic or septic shock patients.

Antidiabetic Molecule Efficacy in Patients with Type 2 Diabetes Mellitus-A Real-Life Clinical Practice Study.

In this paper, we aim to evaluate the efficacy of antidiabetic cardioprotective molecules such as Sodium-Glucose Cotransporter-2 Inhibitors (SGLT-2i) and Glucagon-like Peptide 1 Receptor Agonists (GLP-1 RAs) when used with other glucose-lowering drugs, lipid-lowering, and blood pressure (BP)-lowering drugs in a real-life setting. A retrospective, observational study on 477 patients admitted consecutively in 2019 to the outpatient clinic of a tertiary care unit for Diabetes Mellitus was conducted. Body mass index (BMI), blood pressure (BP) (both systolic and diastolic), and metabolic parameters, as well as A1c hemoglobin, fasting glycaemia and lipid profile, including total cholesterol (C), HDL-C, LDL-C and triglycerides), were evaluated at baseline and two follow-up visits were scheduled (6 months and 12 months) in order to assess the antidiabetic medication efficacy. Both SGLT-2i and GLP-1 RAs were efficient in terms of weight control reflected by BMI; metabolic control suggested by fasting glycaemia and A1c; and the diastolic component of BP control when comparing the data from the 6 and 12-month visits to the baseline, and when comparing the 12-month visit to the 6-month visit. Moreover, when comparing SGLT-2i and GLP-1 RAs with metformin, there are efficacy data for SGLT-2i at baseline in terms of BMI, fasting glycaemia, and HbA1c. In this retrospective study, both classes of cardioprotective molecules, when used in conjunction with other glucose-lowering, antihypertensive, and lipid-lowering medications, appeared to be efficient in a real-life setting for the management of T2DM.

Survey on Anxiety and Post-Traumatic Stress Disorder in Intensive Care Personnel during the COVID-19 Pandemic in a Medically Under-Resourced Country.

The COVID-19 pandemic has increased the need for intensive care personnel. Romania has a low number of physicians per inhabitant. The stress of pandemics upon an already weak medical health system triggered some psychological effects upon burnt-out personnel. The main objective is to provide an insight into the psychological status of Romanian ICU personnel by evaluating their level of anxiety. The secondary objectives aim to identify the level of post-traumatic stress disorder and anxiety in different groups and to identify the personnel most affected psychologically. This study enrolled adult responders from the ICU of Târgu Mureș Emergency Clinical County Hospital, Romania, participating voluntarily. The evaluation tests were the State-Trait Anxiety Inventory and Post-Traumatic Stress Test. Out of the 126 eligible participants, 87 adult employees were enrolled-with a 69% response rate. The study comprised three groups: doctors, nurses, and auxiliary personnel. All three groups scored for moderate anxiety symptoms. COVID-19-related anxiety was strongly correlated with age and number of working years in all groups. Increased PTSD scores were observed in doctors and nurses. All ICU personnel who dealt with COVID-19 patients presented with moderate anxiety and post-traumatic stress disorder symptoms. The years of ICU experience had a positive impact on anxiety symptoms.

The Effect of Topical Celecoxib as an Anti-Psoriasis Agent.

Our previous research showed that, in a mice tail model for psoriasis, topical celecoxib might have an antipsoriatic effect in vivo by increasing granular layer development. The aim of the present study is to assess the effect of three celecoxib concentrations using a mice model for psoriasis. Topical application of celecoxib (2%, 4% and 8%), with two negative controls (untreated and white soft paraffin as ointment base) and one positive control (tretinoin 0.05%), was performed for two weeks. The effect on granular layer development and epidermal thickness was measured on hematoxylin-eosin staining. The morphometric assessment was made by using mean orthokeratosis degree and mean epidermal thickness as main parameters. All celecoxib concentrations have significantly increased the mean orthokeratosis degree as a marker of an anti-psoriatic effect. Celecoxib 8% and 4% lead to a statistically significant increase in orthokeratosis degree when compared with celecoxib 2% and tretinoin 0.05%. Along with cyclo-oxygenase inhibition, other mechanisms of action of celecoxib are discussed. This study offers valuable information for future clinical trials with celecoxib as a topical anti-psoriasis agent.

Endogenous Carboxyhemoglobin Level Variation in COVID-19 and Bacterial Sepsis: A Novel Approach?

BACKGROUND: The increased production of carbon monoxide (CO) in sepsis has been proven, but the blood level variations of carboxyhemoglobin (COHb) as a potential evolutionary parameter of COVID-19 and sepsis/septic shock have yet to be determined. This study aims to evaluate the serum level variation of COHb as a potential evolutionary parameter in COVID-19 critically ill patients and in bacterial sepsis. MATERIALS AND METHOD: A prospective and observational study was conducted on two groups of patients: the bacterial sepsis group (n = 52) and the COVID-19 group (n = 52). We followed paraclinical parameters on Day 1 (D1) and Day 5 (D5) of sepsis/ICU admission for COVID-19 patients. RESULTS: D1 of sepsis: statistically significant positive correlations between: COHb values and serum lactate (p = 0.024, r = 0.316), and total bilirubin (p = 0.01, r = 0.359). In D5 of sepsis: a statistically significant positive correlations between: COHb values and procalcitonin (PCT) (p = 0.038, r = 0.402), and total bilirubin (p = 0.023, r = 0.319). D1 of COVID-19 group: COHb levels were statistically significantly positively correlated with C-reactive protein CRP values (p = 0.003, r = 0.407) and with PCT values (p = 0.022, r = 0.324) and statistically significantly negatively correlated with serum lactate values (p = 0.038, r = -0.285). CONCLUSION: COHb variation could provide rapid information about the outcome of bacterial sepsis/septic shock, having the advantages of a favorable cost-effectiveness ratio, and availability as a point-of-care test.

Anti-Psoriasis Effect of Diclofenac and Celecoxib Using the Tail Model for Psoriasis.

Non-steroidal anti-inflammatory drugs (NSAIDs) showed effects in some hyperproliferative dermatologic pathologies. The aim of the study is the assessment of anti-psoriasis effect of diclofenac and celecoxib using a mice tail model. The topical application of substances on the proximal mice tails was performed for two weeks. The effects on the epidermal granular layer and mean epidermal thickness (excluding the stratum corneum) were evaluated using hematoxylin-eosin staining. Orthokeratosis degree and percentual drug activity were calculated. A positive control group treated with tretinoin and two negative controls (white soft paraffin and untreated mice) were used. Orthokeratosis degree significantly increased in all the NSAIDs groups (celecoxib 1%, 2% and diclofenac 1%, 2%) and in the tretinoin 0.05% group, versus negative controls. Celecoxib 1% and 2%, tretinoin 0.05% and white soft paraffin significantly increased mean epidermal thickness, versus untreated mice. The values obtained in the case of celecoxib 2% ointment regarding the orthokeratosis degree and percentual drug activity are providing premises for further investigations regarding this effect and the mechanisms of action involved. Celecoxib 2% had the greatest percentual drug activity and is a promising substance for the anti-psoriasis topical treatment. Along with the COX-2 inhibition, celecoxib might have an anti-psoriasis effect by other independent mechanisms.

Studies Regarding the Antimicrobial Behavior of Clotrimazole and Limonene.

The paper presents the results of the studies performed to establish the effect of the mixtures between limonene and clotrimazole against microbial pathogens involved in dermatological diseases, such as Candida albicans, Staphyloccocus aureus, and Escherichia coli. Preliminary data obtained from the studies performed in microplates revealed a possible synergism between the mixture of clotrimazole and limonene for Staphylococcus aureus. Studies performed "in silico" with programs such as CLC Drug Discovery Workbench and MOLEGRO Virtual Docker, gave favorable scores for docking each compound on a specific binding site for each microorganism. The tests performed for validation, with the clotrimazole (0.1%) and different sources of limonene (1.9% citrus essential oils), showed a synergistic effect on Staphylococcus aureus in the case of the mixtures between clotrimazole and the essential oils of Citrus reticulata or Citrus paradisi. The studies performed on Staphylococcus aureus MRSA showed a synergistic effect between clotrimazole and the essential oils obtained from Citrus bergamia, Citrus aurantium, or Citrus paradisi. In the case of Pseudomonas aeruginosa, essential oils and clotrimazole used alone did not exhibit antimicrobial activities, but the mixtures between clotrimazole and the essential oils of Citrus bergamia or Citrus sinensis exhibited a synergistic antimicrobial effect.

Non-Insulin Novel Antidiabetic Drugs Mechanisms in the Pathogenesis of COVID-19.

The present study aimed to analyse the published data and to realize an update about the use and pathogenesis of the novel antidiabetic drugs, respectively, dipeptidyl peptidase-4 inhibitors (DPP-4i), glucagon-like peptide-1 receptor agonists (GLP-1 Ra), and sodium-glucose co-transporter-2 inhibitors (SGLT-2i), in patients with type 2 diabetes mellitus (T2DM) and coronavirus disease (COVID-19). Literature research in the PubMed and Web of Science database was performed in order to identify relevant published clinical trials and meta-analyses that include information about the treatment with novel antidiabetic agents in patients with T2DM and COVID-19. A total of seven articles were included, and their primary and secondary outcomes were reported and analysed. DPP-4i has mixed results on mortality in T2DM patients with COVID-19 but with an overall slightly favourable or neutral effect, whereas GLP-1 Ra seems to have a rather beneficial impact, while SGLT-2i may be useful in acute illness. Even if there are limited data, they seem to have favourable efficacy and safety profiles. The available evidence is heterogenous and insufficient to evaluate if the benefits of non-insulin novel antidiabetic drugs in COVID-19 treatment are due to the improvement of glycaemic control or to their intrinsic anti-inflammatory effects but highlights their beneficial effects in the pathogenesis and evolution of the disease.

Association between Liver Cirrhosis and Diabetes Mellitus: A Review on Hepatic Outcomes.

BACKGROUND: Liver cirrhosis (LC) is largely associated with diabetes mellitus (DM). More than 80% of patients with LC manifest glucose intolerance and about 30% have type 2 DM. A particular and yet unrecognized entity is hepatogenous diabetes (HD), defined as impaired glucose regulation caused by altered liver function following LC. Numerous studies have shown that DM could negatively influence liver-related outcomes. AIM: We aimed to investigate whether patients with LC and DM are at higher risk for hepatic encephalopathy (HE), variceal hemorrhage (VH), infections and hepatocellular carcinoma (HCC). The impact of DM on liver transplant (LT) outcomes was also addressed. METHODS: Literature search was performed in PubMed, Ovid, and Elsevier databases. Population-based observational studies reporting liver outcomes in patients with LC were included. RESULTS: Diabetics are at higher risk for HE, including post-transjugular intrahepatic portosystemic shunt HE. DM also increases the risk of VH and contributes to elevated portal pressure and variceal re-bleeding, while uncontrolled DM is associated with increased risk of bacterial infections. DM also increases the risk of HCC and contributes to adverse LT outcomes. CONCLUSIONS: Patients with DM and LC may benefit from close follow-up in order to reduce readmissions and mortality. Due to the heterogeneity of available research, prospective multicenter clinical trials are needed to further validate these findings.

Experimental research in topical psoriasis therapy (Review).

Psoriasis, one of the most prevalent inflammatory diseases in dermatologic pathology, remains a challenge in regards to the therapeutic approach. Topical therapy for psoriasis is a current trending subject as it implies good compliance for the patient, few adverse systemic reactions and a targeted effect. Numerous substances are now being tested, from natural to synthetic compounds and already known substances in improved formulas such as vesicular systems. The aim of this article was to conduct a literature review regarding the topical therapy of psoriasis in animal models, between June, 27, 2019 and July 9, 2020. For this article, the authors conducted extensive research in PubMed with the following keywords: Psoriasis AND (topical OR local) and (therapy OR treatment) AND (mice OR rats). The main new studied substances included lycopene, sodium butyrate, salvianolic acid B, small interfering RNAs (siRNAs) in ionic liquids, albendazole, phosphodiesterase inhibitors, biomimetic reconstituted high-density lipoprotein nanocarrier gel containing microRNA (miRNA)-210 antisense, thymoquinone in ethosomal vesicle, Sea buckthorn oil (Hippophae rhamnoides), nitidine chloride, Melissa officinalis spp. Altissima extract and [1-(4-chloro-3-nitrobenzenesulfonyl)-1H-indol-3-yl]-methanol (CIM). New formulas of already known anti-psoriasis substances such as: Cyclosporine, methotrexate, calcipotriol, tazarotene, protein kinase p38 and integrin α5ß1 as a target, are also reviewed. Recent research in topical psoriasis underlines the importance of animal experimental research in dermatology, providing a starting point for developing new therapeutic approaches in one of the most frequently diagnosed chronic dermatologic diseases. Vesicular systems are now providing the best vehicle for topical therapy, thus easing the action of the active substances at their target sites.

VEGF-induced corneal neovascularisation in a rabbit experimental model.

INTRODUCTION AND PURPOSE: Various conditions may cause vascularization of the normally avascular cornea. The aim of the present study was to create a reproducible experimental model that could enable the investigation of the phenomena leading to corneal vascularization. This involved creating a software to record the experimental data, enabling a subsequent digital analysis based on the growth models. The VEGF-induced pattern of neovascularization was also investigated. MATERIAL AND METHODS: Twenty-seven rabbits divided in groups were used for the purposes of the present study. Some of them underwent intracorneal implants with or without vascular endothelial growth factor (VEGF) pellets, using an original microsurgical technique. Central and peripheral corneal burns were induced to other groups of animals in order to mimic the neovascularization process induced by inflammation. Finally, Dexamethasone (Maxidex) was given intraocularly, on days 1 and 3 after the onset of neovascularisation, in rabbit groups with both corneal burns and VEGF-implants. Video recording and data analysis of the corneal vascularization were made with an advanced biomicroscope, a computerized imaging system and a special software. A histochemical study of the animals' eyes was also carried out. RESULTS AND DISCUSSION: The recorded data showed the simplicity and reproducibility of the present experimental model. The results showed the importance of VEGF as an initiator and promoter of corneal vascularization through a non-inflammatory mechanism, quite different from the inflammation illustrated by the corneal burn. At the same time, Dexamethasone therapy proved its effectiveness in corneal angiogenesis induced by thermal burn, but not by VEGF-implant.

Antimicrobial peptides as an argument for the involvement of innate immunity in psoriasis (Review).

Antimicrobial peptides (AMPs) are a group of oligopeptides found in most multicellular organisms with a capacity for rapid and nonspecific destruction of pathogens. The action of destroying pathogens is associated with a strong proinflammatory activity, stimulating the secretion of cytokines, chemokines, growth factors but also chemotaxis, the activation of dendritic cells and involving adaptive immunity also. The action of AMPs fits perfectly into the characteristics of innate immunity which makes these peptides candidates to be considered as an important element of this type of immunity. It has been shown that AMPs are involved in a number of cellular processes such as: differentiation, proliferation, maturation, thus widening the degree of involvement of these peptides in the pathogenesis of chronic inflammatory diseases. In psoriasis, AMPs act both as a pro-inflammatory and chemotaxis factor and through the cathelicidin (LL-37)/dc DNA complex as a possible autoantigen for T cells, triggering an autoimmune response, activating the Th17/IL23 axis and maintaining the inflammatory process. Thus, many arguments are accumulated to consider that innate immunity through AMPs is an important link in the pathogenesis of psoriasis. Moreover, the action of antimicrobial peptides in psoriasis is almost entirely characteristic for the general mode of action of innate immunity.

The Diagnostic and Prognostic Role of Vascular Endothelial Growth Factor C in Sepsis and Septic Shock.

INTRODUCTION: Variations in the expression of vascular endothelial growth factor (VEGF) could be used as a biomarker in critically ill patients with sepsis and septic shock. Inflammation potently upregulates VEGF-C expression via macrophages with an unpredictable response. This study aimed to assess one of the newer biomarkers (VEGF-C) in patients with sepsis or septic shock and its clinical value as a diagnostic and prognostic tool. MATERIAL AND METHODS: The study involved 142 persons divided into three groups. Group A consisted of fifty-eight patients with sepsis; Group B consisted of forty-nine patients diagnosed as having septic shock according to the Sepsis -3 criteria. A control group of thirty-five healthy volunteers comprised Group C. Severity scores, prognostic score and organ dysfunction score, were recorded at the time of enrolment in the study. The analysis included specificity and sensitivity of plasma VEGF-C for diagnosis of septic shock. Circulating plasma VEGF-C levels were correlated with the APACHE II, MODS and severity scores and mortality. RESULTS: The mean (SD) plasma VEGF-C levels in septic shock patients (1374(789) pg./m), on vasopressors at the time of admission to the ICU, were significantly higher 1374(789)pg./mL, compared the mean (SD) plasma VEGF-C levels in sepsis patients (934(468) pg./mL); (p = 0.0005, Student's t-test.) Plasma VEGF-C levels in groups A and B were shown to be significantly correlated with the APACHE II (r = 0.21, p = 0.02; r = 0.45, p = 0.0009) and MODS score (r = 0.29, p = 0.03; r = 0.4, p = 0.003). There was no association between plasma VEGF-C levels and mortality [p = 0.1]. The cut-off value for septic shock was 1010 pg./ml. CONCLUSIONS: VEGF-C may be used as a prognostic marker in sepsis and septic shock due to its correlation with APACHE II values and as an early marker to determine the likelihood of developing MODS. It could be used as an early biomarker for diagnosing patients with septic shock.