Short-term Administration Research Articles

Potassium Nitrate in Heart Failure With Preserved Ejection Fraction: A Randomized Clinical Trial.

Nitric oxide deficiency may contribute to exercise intolerance in patients with heart failure with preserved ejection fraction (HFpEF). Prior pilot studies have shown improvements in exercise tolerance with single-dose and short-term inorganic nitrate administration. To assess the impact of chronic inorganic nitrate administration on exercise tolerance in a larger trial of participants with HFpEF. This multicenter randomized double-blinded crossover trial was conducted at the University of Pennsylvania, the Philadelphia Veterans Affairs Medical Center, and Northwestern University between October 2016 and July 2022. Participants included patients with symptomatic (New York Heart Association class II/III) HFpEF who had objective signs of elevated left ventricular filling pressures. Image quantification, physiological data modeling and biochemical measurements, unblinding, and statistical analyses were completed in 2024. Potassium nitrate (KNO3) (6 mmol 3 times daily) vs equimolar doses of potassium chloride (KCl) for 6 weeks, each with a 1-week washout in between. The coprimary end points included peak oxygen uptake and total work performed during a maximal effort incremental cardiopulmonary exercise test. Secondary end points included the exercise systemic vasodilatory reserve (ie, reduction in systemic vascular resistance with exercise) and quality of life assessed using the Kansas City Cardiomyopathy Questionnaire. Eighty-four participants were enrolled. Median age was 68 years and 58 participants were women (69.0%). Most participants had NYHA class II disease (69%) with a mean 6-minute walk distance of 335.5 (SD, 97.3) m. Seventy-seven participants received the KNO3 intervention and 74 received the KCl intervention. KNO3 increased trough levels of serum nitric oxide metabolites after 6 weeks (KNO3, 418.4 [SD, 26.9] uM vs KCl, 40.1 [SD, 28.3] uM; P < .001). KNO3 did not improve peak oxygen uptake (KNO3, 10.23 [SD, 0.43] mL/min/kg vs KCl, 10.17 [SD, 0.43] mL/min/kg; P = .73) or total work performed (KNO3, 25.9 [SD, 3.65] kilojoules vs KCl, 23.63 [SD, 3.63] kilojoules; P = .29). KNO3 nitrate did not improve the vasodilatory reserve or quality of life, though it was well-tolerated. In this study, potassium nitrate did not improve aerobic capacity, total work, or quality of life in participants with HFpEF. ClinicalTrials.gov Identifier: NCT02840799.

Short-term Administration of Naringin Improves Renal Function in Renal Ischemia-reperfusion by Increasing Aquaporin-1 and Aquaporin-2 Levels

Background: Since renal ischemia-reperfusion (I/R) can lead to a serious health problem, aquaporins have important roles in preventing negative changes in electrolyte-water balance. This study aimed to determine the effect of naringin treatment on renal function and AQP1 and AQP2 levels in the kidney cortex and medulla tissues in experimental renal I/R in rats. Materials and Methods: The study was carried out on 40 male Wistar-type rats, 8-12 weeks old. Experimental groups were formed as follows: 1) Control, 2) Sham+vehicle, 3) Renal (I/R)+vehicle, 4) Renal I/R+ Naringin (50mg/kg/day) (3 days of administration), and 5) Renal I/R+ Naringin( 100mg/kg/day) (3 days supplementation) group. First, the left kidney was removed by nephrectomy under general anesthesia, and then the right kidney was subjected to 45 minutes of ischemia and then 72 hours of reperfusion. Naringin was given to the experimental animals by an intraperitoneal route at the beginning of the reperfusion, after 24 and 48 hours. At the end of the experiments, first of all, blood samples were taken from the heart in animals under general anesthesia, and then the animals were killed by cervical dislocation, and kidney tissue samples were taken. Osmolarity in plasma and urine and plasma creatinine levels were evaluated. AQP1 and AQP2 levels were analyzed in the kidney cortex and medulla tissues by ELISA and PCR methods. Results: In kidney tissues, I/R led to a decrease in plasma and urinary osmolality, AQP1 and AQP2 levels in the cortex and medulla, and an increase in urea and creatinine levels (p &lt; 0.001). However, naringin supplementation corrected the deterioration to a certain extent. Conclusion: The results of the study show that naringin supplementation at different doses, such as 50 or 100 mg/kg, may have protective effects on the deterioration of renal function caused by unilateral nephrectomy and I/R in rats.

A multicenter, phase II trial of triplet antiemetic therapy with palonosetron, aprepitant, and olanzapine for highly emetogenic chemotherapy in breast cancer (PATROL-II)

Dexamethasone is an antiemetic drug widely used to prevent nausea and vomiting caused by anticancer drugs. However, dexamethasone can cause several side effects even after short-term administration. Therefore, the development of dexamethasone-free antiemetic therapies has been recognized as an important challenge. The objective of this study was to investigate the efficacy and safety of palonosetron, aprepitant, and olanzapine. Patients who were chemotherapy-naïve and scheduled to receive highly emetogenic chemotherapy for breast cancer were enrolled and assessed for nausea and vomiting occurring within 120 h after the start of chemotherapy. The primary endpoint was the total control (TC) rate of overall phases. Secondary endpoints included the complete response (CR) rate, which was evaluated during the acute, delayed, and overall phases. A total of 88 patients were enrolled from eight centers in Japan, of whom 84 were included in the analysis. The proportion of patients achieving TC throughout the overall period was 17.1%. Similarly, CR and CC rates for the overall period were 43.4% and 39.5%, respectively. Frequently reported adverse events were loss of appetite and constipation, with rates of 52.4% and 50.0%, respectively. The primary endpoint was not achieved. Therefore, antiemetic therapy without dexamethasone shows an inadequate effect on nausea, and it is generally advisable to avoid omitting dexamethasone. However, in the overall period, both CR and CC were comparable to conventional three-drug combination therapy. Thus, in patients unable to use dexamethasone, replacing it with olanzapine could be an option.Trial registration number: UMIN 000038644, November 20, 2019. The date of first trial registration: 13/03/2020.

Effects of Short-Term Treatment with α-Lipoic Acid on Neuropathic Pain and Biomarkers of DNA Damage in Patients with Diabetes Mellitus.

Diabetes mellitus (DM) is a complex and heterogenous disease classified as a group of metabolic disorders characterized by chronic hyperglycemia resulting from defects in insulin secretion, insulin action, or both. It leads to various complications, some of which are macrovascular or microvascular complications, like diabetic polyneuropathy (DPN), having a profound impact on patients' quality of life. Oxidative stress (OS) is one of the significant mechanisms in the development and progression of DPN. Thus, targeting OS pathways by antioxidants, such as α-lipoic acid (ALA), could represent a promising therapeutic strategy for alleviating neuropathic symptoms. The aim of our study was to evaluate whether short-term (from 4 to 9 days) intravenous administration of ALA could cause any measurable improvement in subjects with DM. Sixteen subjects with DM (six type 1 and ten type 2) and sixteen nondiabetic subjects matched by sex and age were recruited to this study. Only subjects with DM received treatment with ALA (600 mg daily). Pain intensity and biomarkers of DNA damage including plasma concentration of 8-hydroxy-2'-deoxyguanosine (8-OHdG), frequency of micronucleated lymphocytes (MN), and frequency of sister-chromatid exchanges (SCEs), were measured before and after the treatment with ALA. Pain intensity and 8-OHdG levels were significantly lower in DM subjects after the ALA treatment than before the treatment. However, no changes in the frequency of SCEs and MN were observed. Our results show some evidence that even a short-term intravenous treatment with ALA could be beneficial for diabetic subjects, reducing pain intensity and concentration of 8-OHdG in blood plasma.

Anti-obesity effect of irreversible MAO-B inhibitors in patients with Parkinson’s disease

We read with great interest the report on the new anti-obesity potential in mice models of reversible monoamine oxidase B inhibitors by Moonsun et al., as opposed to the lack of such effects observed with irreversible MAO-B inhibitors (iMAO-Bi). Our research aimed to explore the potential anti-obesity effects of iMAO-Bi in patients with Parkinson’s disease (PD). This retrospective study included 37 PD in-patients from 2018 to 2023. Patients who took iMAO-Bi were assigned to the iMAO-Bi group, and those who never took iMAO-Bi were assigned to the control. The major outcomes were changes in body weight and body mass index (BMI) during follow-up. A subgroup analysis was conducted to compare the anti-obesity effect between the short-term and long-term administrations of the iMAO-Bi group. The results showed a slight yet insignificant trend of bodyweight loss among the iMAO-Bi group of PD patients. Subgroup analysis showed that short-term treatment of iMAO-Bi (less than six months) led to reductions in BMI and body weight, while the long-term treatment of iMAO-Bi displayed a slight increase in BMI and body weight. The results suggested that short-term administration of iMAO-Bi may have potential weight-loss effects. Further studies with larger sample sizes are needed to evaluate the weight-loss effect of iMAO-Bi.

Abstract 4121104: Fish Oil-Derived N-3 Very-Long-Chain Polyunsaturated Fatty Acids Improve Retinal Function in Aged Mice

Introduction: Epidemiological studies and clinical trials have revealed cardiometabolic benefits associated with dietary fish oil-derived omega-3 polyunsaturated fatty acids, particularly EPA and DHA. Omega-3 very-long-chain polyunsaturated fatty acids (VLCPUFA), synthesized in vivo by very-long-chain fatty acid elongase (ELOVL), e.g. ELOVL2 and 4, have recently garnered interest for their role in eye and cardiometabolic diseases. In our previous study, aging mice fed a VLCPUFA-rich diet for 8 weeks exhibited lowered plasma lipid levels, and repeated gavage of VLCPUFA in young mice resulted in improved retinal function. However, it is largely not known if VLCPUFA intake for a short term in aged mice would also improve retinal function and have beneficial effects in cardiometabolic risk factors. Hypothesis: We hypothesized that VLCPUFA may delay or rescue age-related vision loss by supplementing the products of ELOVL2, which decrease in quantity with age. We also hypothesize that short-term VLCPUFA intake may also confer favorable cardiometabolic benefits. Aims: We aimed to evaluate the effects of exogenous VLCPUFA on visual function and lipoprotein profiles in aged mice. Methods: Sixteen-month-old mice received a daily oral gavage of C24-28-rich VLCPUFA-oil (80 mg/kg BW) or an Intralipid vehicle for 15 consecutive days (n=8). The electroretinogram (ERG) instrument used was a UTAS E-3000 with gold corneal and stainless-steel scalp electrodes. Fast Protein Liquid Chromatography was performed using pooled plasma. Results: Consumption of VLCPUFA for 15 days increased scotopic a- (p &lt; 0.05 at −5, 0, 5, 10, and 15 dB) and b-wave (p &lt; 0.05 at 0 and 5 dB, p = 0.08 at 10 dB) amplitudes on ERG in both male and female mice compared with control. Although photopic ERG results did not exhibit statistically significant differences, likely due to low sample size, the overall results were consistent with those in our previous studies in young mice. We report no statistically significant difference in the composition of pro-atherogenic VLDL and LDL fractions due to VLCPUFA gavage. Increasing the duration and samples size in future gavage studies may be critical to determine the effects of VLCPUFA on eye and cardiovascular risk factors. Conclusions: This study revealed that a short-term oral administration of VLCPUFA was effective in improving ERG response overall, but not lipoprotein profiles.

Short-term Oral Nitrite Administration Decreases Arterial Stiffness in Both Trained and Sedentary Wistar Rats.

Nitric Oxide (NO) plays an important role in blood pressure (BP) regulation, acting directly on peripheral vascular resistance through vasodilation. Physical training (via eNOS/NO) and intake of nitrite have been considered major stimuli to increase NO. We examined the effects of oral nitrite administration and aerobic exercise training on BP and arterial stiffness in Wistar rats. Thirty-nine (39) young male Wistar rats were divided into the following groups (n = 9 or 10 per group): Sedentary-Control (SC), Sedentary-Nitrite (SN), Trained-Control (TC), and Trained-Nitrite (TN). They were submitted to aerobic physical training on treadmills for 8 weeks (50-60% of physical capacity, 1h/day, 5 days/week) or kept sedentary. In the last 6 days of training, oral nitrite was administered (15 mg/Kg by gavage). BP, arterial stiffness, and plasma and tissue nitrite concentrations were assessed after the training and oral nitrite administration period. The significant level was defined as p < 0.05. Oral administration of nitrite was effective in reducing arterial stiffness values (TN, -23%; and SN, -15%). Both groups that had only one type of intervention showed lower systolic BP compared with control (TC vs. SC, -14.23; and SN vs. SC, - 12.46). We conclude that short-term oral administration for 6 days and an aerobic physical training program promote several hemodynamic benefits in male Wistar rats, such as improvements in arterial stiffness and BP. These responses suggest that physical training and sodium nitrite supplementation can be alternatives for the prevention and treatment of hypertension.

Twenty-five percent human albumin solution in clinical practice: indications, risks and monitoring protocols.

Human albumin solution is a commonly used therapeutic agent because of its ability to expand plasma volume and improve oncotic pressure in various clinical settings, such as in patients with cirrhosis and sepsis, whose management is a major challenge. Despite the lack of evidence for the superiority of human albumin solutions compared with crystalloids in improving major outcomes, short-term administration of human albumin solution appears to be more effective than both saline and plasmalyte in recovering systemic hemodynamics and achieving a lower daily net fluid balance in patients with cirrhosis and sepsis-induced hypotension. The use of 25% human albumin solution could also effectively manage ascites in patients with cirrhosis, reducing the volume of fluids administered and allowing a faster achievement of the plasma target concentration. This article aims to comprehensively review the indications for the use of human albumin solutions, examine the associated risks, and outline best practices for monitoring patients receiving this treatment, ensuring optimal patient outcomes while minimizing adverse effects.

Oral low-dose rapamycin treatment prevents aortic aneurysms in marfan mice

Abstract Background/Introduction Marfan syndrome (MFS) is a hereditary connective tissue disorder caused by fibrillin-1 (FBN1) gene mutations. Life-threatening complications are cardiovascular, e.g. thoracic aortic aneurysms and dissections. The pathophysiological cause is the increased release of transforming growth factor β-1 (TGF-β1) from the FBN1-deficient extracellular matrix (ECM) and structural disintegrity. Overactivation of the mechanistic target of rapamycin (mTOR) pathway has been demonstrated in the murine mgR/mgR model of MFS. Short-term administration of rapamycin significantly reduced aortic aneurysm formation and increased the life span in these mice. Purpose To assess the effect of an early continuous oral low-dose rapamycin treatment on the aortic aneurysm formation in the FBN1 hypomorphic mgR/mgR mouse model. Methods Male and female 3-4 week-old mgR/mgR mice were orally administered vehicle or rapamycin through diet (8mg/kg/KG) and sacrificed after 11 weeks. Rapamycin concentration was measured by liquid chromatography-mass spectrometry in whole blood. Aortic diameter was studied using echocardiography. Histopathological and immunofluorescence analyses were performed using aortic tissue sections and techniques. Results Blood rapamycin concentration following oral administration remained below detection level. Rapamycin normalized the aortic wall thickness and the diameter in female mgR/mgR mice to levels of the littermate control mice but not in male mgR/mgR mice. The circumferentially distributed elastin fibres remained significantly intact in sections of the ascending aorta of female mice. Echocardiography revealed that rapamycin-treated female mice stayed below a cut-off value for aortic aneurysms of 2 mm inner aortic diameter eight weeks after starting therapy. In contrast, vehicle-treated female animals already exceeded this value after five weeks. In female but not in male mice, the abundance of the mTOR downstream target phosphorylated ribosomal protein S6 was effectively suppressed by low-dose rapamycin up to levels detected in control animals. At the same time, extracellular matrix proteins like the proteoglycan aggrecan (ACAN) and the related chondroitin sulfate were significantly decreased in female mice. The abundance of ADAMTS5 transglutaminase-2 and xylosyltransferase-1, key enzymes involved in the turnover of proteoglycans and biosynthesis of glycosaminoglycan chains, was improved by the rapamycin treatment in female mice. No decrease in mTOR activity could be detected in male mgR/mgR animals. Here, the ACAN and chondroitin sulphate levels also remained at the level of the vehicle-treated animals. Conclusions Chronic low-dose rapamycin treatment reduced aneurysm formation only in female mgR/mgR mice, since the dose was too low for male mgR/mgR mice, by affecting the composition and organization of key ECM components essential for maintaining aortic homeostasis and mechanical properties.

Short-term Outpatient Parenteral Antimicrobial Therapy Administration in the Pediatric Emergency Department: Feasibility, Safety, and Outcome.

The practice of administration of intravenous (IV) antimicrobial therapy in outpatient settings (OPAT) is a low-cost alternative to in-patient admission and treatment. There is, however, limited evidence supporting OPAT management protocols for children. The primary objective of this study was to describe the use of pediatric emergency-based OPAT, as well as the safety of this practice. The study was a prospective, observational study conducted in pediatric emergency department of a tertiary care hospital. Children younger than 14 years who required pediatric emergency department-based OPAT were included in the study. Three hundred and ninety-two children were included in the study. The mean duration of OPAT was 3.5 days. Ceftriaxone was the most frequently used antimicrobial. Chest infection was the commonest indication, followed by sickle cell disease with fever and soft tissue infections. There were no major intravenous line-related complications over course of treatment. Most of the patients (89.5%) completed the OPAT course successfully. Only 10.4% patients required subsequent hospital admission, with failure to improve on the OPAT protocol being the main reason patients for admission. None of the admitted patients required intensive care settings or faced unexpected morbidity. Our results affirm that pediatric emergency-based OPAT is a safe yet effective practice in children with good clinical outcome. We believe that a reduction in admissions translates to better hospital resource utilization.

Pharmacological management of osteoarthritis: judicious use of nonsteroidal anti-inflammatory drugs

Background: Osteoarthritis (OA) is a chronic disease characterized by persistent pain and joint deformation. Effective pain management in patients with OA necessitates accurate diagnosis and appropriate treatment planning, considering the prolonged therapy required for OA. Although non-steroidal anti-inflammatory drugs (NSAIDs) are widely used for pain management in patients with OA, their long-term use can lead to various adverse effects that warrant careful consideration.Current Concepts: NSAIDs inhibit cyclo-oxygenase (COX) enzymes and produce an anti-inflammatory and analgesic effect. However, this mechanism of action can produce adverse gastrointestinal, cardiovascular, and renal effects. The relative risk of gastrointestinal and cardiovascular adverse events depends on the COX selectivity of NSAIDs. Consequently, selective COX-2 inhibitor or concomitant proton pump inhibitor administration is recommended in patients at a high risk of gastrointestinal complications. Minimizing NSAID use is advised in patients at a high risk of cardiovascular adverse events; however, if this is unavoidable, short-term administration of naproxen or low-dose celecoxib should be considered. COX selectivity is not associated with adverse renal events. Therefore, acetaminophen is preferred in patients with impaired renal function, and short-term use of NSAID patches or topical formulations may be useful.Discussion and Conclusion: The choice of NSAIDs for OA should be tailored to patients’ needs, considering their risk factors, potential drug interactions, and other relevant factors. Additionally, incorporation of nonpharmacological interventions can minimize the NSAID dosage and reduce the risk of adverse effects, and regular monitoring is essential to identify adverse effects.

Short-Term Metformin Therapy in Clomiphene Citrate Resistant PCOS Patients Improves Fertility Outcome by Regulating Follicular Fluid Redox Balance: A Case-Controlled Study.

To determine the effect of short-term metformin administration on follicular fluid (FF) total oxidant status (TOS), total antioxidant status (TAS), oxidative stress index (OSI) and nuclear factor kappa B (NF-kB) in women with clomiphene citrate-resistant polycystic ovary syndrome (PCOS). Fifty-eight patients aged 23-34 who were planned to have intracytoplasmic sperm injection due to clomiphene citrate-resistant PCOS were included in the study. Participants were divided into two groups according to whether they used metformin or not. While 30 of 58 PCOS patients were using short-term metformin in combination with controlled ovarian stimulation, 28 PCOS patients were not using metformin. Metformin was started in the mid-luteal period and continued until the day before oocyte retrieval at 850 mg twice daily. To determine FF-NF-kB, TAS, TOS and OSI values, a dominant follicle ≥17-18 mm in diameter was selected for aspiration. The number of mature follicles and fertilization rates of the metformin group were significantly higher than those not taking metformin. FF-TOS and OSI of the metformin group were significantly lower than those of the group not receiving metformin. Patients receiving metformin had higher FF-TAS than the group not receiving metformin. FF-NF-kB levels of the metformin group were significantly lower than the group not receiving metformin. Insulin resistance, FF-NF-kB and FF-TOS were negatively correlated with the number of mature oocytes. FF-TAS was positively correlated with the number of oocytes. Short-term metformin treatment in clomiphene-resistant PCOS improves the number of mature follicles and fertilization rates by regulating the intra-follicle redox balance.

Combination of Metabolomics, Lipidomics, and Molecular Biology for the Investigation of the Metabolic Disturbance of Short-Term Administration of Emodin.

Emodin, a natural anthraquinone derivative, is an active ingredient in many Chinese traditional herbs. Interestingly, although it is generally considered to possess hepatoprotective activity, some studies have also reported that it has a certain degree of hepatotoxicity. Additionally, the underlying metabolic regulation of emodin remains uncertain. Therefore, we conducted a nontargeted metabolomic study based on UHPLC/Q-Orbitrap-MS and NMR. Data are available via ProteomeXchange with the identifier PXD055000. The results indicated a close association between the short-term administration of emodin and lipid metabolism. Moreover, a lipidomics investigation utilizing QTRAP 6500+ UHPLC-MS/MS was conducted, with a focus on determining the position of C═C double bonds in unsaturated lipids based on Paternò-Büchi (PB) reaction to discover the metabolic disturbance more precisely. Specifically, lipidomics revealed elevated levels of free fatty acids (FFA) alongside notable reductions in sphingomyelin (SM) and triacylglycerol (TAG) levels. Furthermore, the combination of PB reaction and molecular biology results indicated that short-term administration of emodin may lead to the accumulation of n-6 polyunsaturated fatty acids by up-regulating the expression of FASN, stearyl CoA desaturase 1 (SCD1), and cytosolic phospholipase A 2 (cPLA2). Simultaneously, up-regulation of cyclooxygenase-2 (Cox-2) expression was observed, potentially fostering the production of prostaglandin E2 (PGE2) and subsequent inflammation.

Atrial fibrillation in combination with severe mitral regurgitation : Which should be treated first, the atrial fibrillation or the mitral valve?

The primary therapeutic approach for severe secondary mitral regurgitation (MR) in combination with atrial fibrillation is often not clear. To create atherapeutic guideline for daily clinical practice based on acase report as well as basic literature. If afunctional component is suspected, restoration of sinus rhythm may lead to asignificant improvement in MR. The extent of the improvement and the time required to achieve this improvement are often difficult to predict. The involvement of an electrophysiologist is recommended in order to assess the likelihood of successful long-term rhythm control aimed at improving MR. In unclear cases, cardioversion combined with short-term administration of antiarrhythmic medication may be useful to demonstrate potential improvement of MR in sinus rhythm.

ω-3 PUFAs Ameliorated the Maternal High-Fructose Diet-Induced Early-Onset Retinopathy in Offspring via Inhibiting NLRP3-Associated Neuroinflammation.

Maternal high fructose diet (HFD) during pregnancy and lactation can initiate retinal dysfunction. However, the underlying mechanism remains largely unknown. By using the rodent model of maternal HFD in this study, the results from electroretinography (ERG) indicate that b-wave amplitude, an index of inner retinal function, is significantly reduced as early as 3 months old and the deteriorated effect can be detected at 15 months old. Further, the protein expressions of CD11b (a marker of active microglia), p40phox subunit of NADPH oxidase, GFAP (a marker of active astrocytes), and NLPR3 examined by western blot and immunofluorescence are significantly increased in the retina of the male HFD offspring at 3 months old. Treatment with omega-3 polyunsaturated fatty acids (ω-3 PUFAs) for 2 weeks (from 2.5 to 3 months old) effectively reverses the aforementioned changes. Together, these results indicate that the early onset and extensive retinal dysfunction may be a result of glial activation which is induced by maternal HFD to initiate an inflammatory microenvironment leading to a long-term progression of retinopathy. Short-term administration of ω-3 PUFA at a young age may be a feasible strategy to intervene in the maternal HFD-programmed retinal impairment in male offspring.

Characterization of intestine-specific TRPM6 knockout C57BL/6J mice: effects of short-term omeprazole treatment.

The transient receptor potential melastatin type 6 (TRPM6) is a divalent cation channel pivotal for gatekeeping Mg2+ balance. Disturbance in Mg2+ balance has been associated with the chronic use of proton pump inhibitors (PPIs) such as omeprazole. In this study, we investigated if TRPM6 plays a role in mediating the effects of short-term (4days) omeprazole treatment on intestinal Mg2+ malabsorption using intestine-specific TRPM6 knockout (Vill1-TRPM6-/-) mice. To do this, forty-eight adult male C57BL/6J mice (50% TRPM6fl/fl and 50% Vill1-TRPM6-/-) were characterized, and the distal colon of these mice was subjected to RNA sequencing. Moreover, these mice were exposed to 20mg/kg bodyweight omeprazole or placebo for 4days. Vill1-TRPM6-/- mice had a significantly lower 25Mg2+ absorption compared to control TRPM6fl/fl mice, accompanied by lower Mg2+ serum levels, and urinary Mg2+ excretion. Furthermore, renal Slc41a3, Trpm6, and Trpm7 gene expressions were higher in these animals, indicating a compensatory mechanism via the kidney. RNA sequencing of the distal colon revealed a downregulation of the Mn2+ transporter Slc30a10. However, no changes in Mn2+ serum, urine, and feces levels were observed. Moreover, 4days omeprazole treatment did not affect Mg2+ homeostasis as no changes in serum 25Mg2+ and total Mg2+ were seen. In conclusion, we demonstrate here for the first time that Vill1-TRPM6-/- mice have a lower Mg2+ absorption in the intestines. Moreover, short-term omeprazole treatment does not alter Mg2+ absorption in both Vill1-TRPM6-/- and TRPM6fl/fl mice. This suggests that TRPM6-mediated Mg2+ absorption in the intestines is not affected by short-term PPI administration.

Residual Depressive Symptoms in Treatment-Resistant Bipolar Depression Following Short-Term Ketamine Administration.

Residual symptoms are frequently observed in a significant number of patients with depression, indicating an unmet need for effective management strategies to achieve functional recovery. This observational study aimed to evaluate the impact of ketamine infusions on depressive symptoms in patients with bipolar disorder who continued their baseline psychotropic and chronic somatic treatments. Datasets of the two consecutive real-world registries (NCT04226963 for 2019-2022; NCT05565352 from 2023 onward) for the tertiary reference center for psychiatry at the Medical University of Gdańsk (Poland) for the safety and tolerability of ketamine use in mood and anxiety disorders were retrospectively analyzed. Depressive symptoms were assessed using the Inventory of Depressive Symptomatology Self-Report 30 (IDS-SR30). Residual symptoms were identified in patients who achieved a treatment response, defined as a 50% or greater reduction in Montgomery-Åsberg Depression Rating Scale (MADRS) scores from baseline to the seventh infusion. Overall, 14 out of 22 patients met the criteria for response. The most commonly persistent depressive symptoms included sad mood (85.7%), view of my future (78.6%), difficulty falling asleep, and leaden paralysis/physical energy (both 71.4%), with the most severe being difficulty falling asleep (64.3%) and sad mood (42.9%). This observational post hoc analysis indicates that the most frequently observed residual depressive symptoms were low mood, altered view of future, sleep disturbances, and low energy levels. This study should be treated with caution as causality does not apply, however, it reports on a real-world population of subjects with treatment-resistant bipolar depression. Establishing standardized definitions for residual symptoms could enhance the quality and comparability of future research in this area.

Bio-spectroscopic investigation linking changes of retinal structure with short-term administration of Amiodarone and revealing the ameliorative effect of vitamin E supplementation

Long term use of Amiodarone (AMIO) is associated with the development of ocular adverse effects. This study investigates the short term effects, and the ameliorative consequence of vitamin E on retinal changes that were associated with administration of AMIO. This is accomplished by investigating both retinal structural and conformational characteristics using Fourier transform infrared spectroscopy (FTIR) and Fundus examination. Three groups of healthy rabbits of both sexes were used; the first group served as control. The second group was orally treated with AMIO (160 mg /kg body weight) in a daily basis for two weeks. The last group orally received AMIO as the second group for two weeks then, oral administration of vitamin E (100 mg/kg body weight) for another two weeks as well. FTIR results revealed significant structural and conformational changes in retinal tissue constituents that include lipids and proteins due to AMIO administration. AMIO treatment was associated with fluctuated changes (increased/decreased) in the band position and bandwidth of NH, OH, and CH bonds. This was concomitant with changes in the percentage of retinal protein constituents in particularly α-helix and Turns. AMIO facilitates the formation of intra-molecular hydrogen bonding and turned retinal lipids to be more disordered structure. In conclusion, the obtained FTIR data together with principal component analysis provide evidence that administration of vitamin E following the treatment with AMIO can ameliorate these retinal changes and, these biophysical changes are too early to be detected by Fundus examination.

Angiotensin-(1–7) infusion in COVID-19 patients admitted to the ICU: a seamless phase 1–2 randomized clinical trial

BackgroundThe coronavirus-related disease (COVID-19) is mainly characterized by a respiratory involvement. The renin-angiotensin system (RAS) has a relevant role in the pathogenesis of COVID-19, as the virus enters host’s cells via the angiotensin-converting enzyme 2 (ACE2).MethodsThis investigator-initiated, seamless phase 1–2 randomized clinical trial was conceived to test the safety and efficacy of continuous short-term (up to 7 days) intravenous administration of Angiotensin-(1–7) in COVID-19 patients admitted to two intensive care units (ICU). In addition to standard of care, intravenous administration of Angiotensin-(1–7) was started at 5 mcg/Kg day and increased to 10 mcg/Kg day after 24 h (Phase 1; open label trial) or given at 10 mcg/Kg day and continued for a maximum of 7 days or until ICU discharge (Phase 2; double-blind randomized controlled trial). The rate of serious adverse events (SAEs) served as the primary outcome of the study for Phase 1, and the number of oxygen free days (OFDs) by day 28 for Phase 2.ResultsBetween August 2020 and July 2021, when the study was prematurely stopped due to low recruitment rate, 28 patients were included in Phase 1 and 79 patients in Phase 2. Of those, 78 were included in the intention to treat analysis, and the primary outcome was available for 77 patients. During Phase 1, one SAE (i.e., bradycardia) was considered possibly related to the infusion, justifying its discontinuation. In Phase 2, OFDs did not differ between groups (median 19 [0–21] vs. 14 [0–18] days; p = 0.15). When patients from both phases were analyzed in a pooled intention to treat approach (Phase 1–2 trial), OFDs were significantly higher in treated patients, when compared to controls (19 [0–21] vs. 14 [0–18] days; absolute difference −5 days, 95% CI [0–7] p = 0.04).ConclusionsThe main findings of our study indicate that continuous intravenous infusion of Angiotensin-(1–7) at 10 mcg/Kg day in COVID-19 patients admitted to the ICU with severe pneumonia is safe. In Phase II intention to treat analysis, there was no significant difference in OFD between groups.Trial Registration ClinicalTrials.gov Identifier: NCT04633772—Registro Brasileiro de Ensaios Clínicos, UTN number: U1111-1255-7167.

Adverse effects of graft congestion and ameliorative effects of hepatocyte growth factor after liver transplantation in rats.

Living donor liver transplantation (LT) and deceased donor split-LT often result in congestion within liver grafts. The regenerative process and function of congested areas, especially graft congestion associated with LT, are not well understood. Therefore, we created new rat models with congested areas in partially resected livers and orthotopically transplanted these livers into syngeneic rats to observe liver regeneration and function in congested areas. This study aimed to compare liver regeneration and the function of congested areas after liver resection and LT, and to explore a new approach to ameliorate the adverse effects of graft congestion. Although the congested areas after liver resection regenerated normally on postoperative day 7, the congested areas after LT had poor regeneration with abscess development on postoperative day 7. Necrotic areas in congested areas were larger after LT than after liver resection on postoperative days 1, 3, and 7 (p < 0.05, p < 0.05, and p < 0.01, respectively). Although congested areas after liver resection did not affect survival, in the LT model, the survival of rats with congested areas was significantly poorer even with larger grafts than that of rats with smaller noncongested grafts (p = 0.04). hepatocyte growth factor administration improved the survival rate of rats with congested grafts from 41.7% to 100%, improved the regeneration of congested areas, and significantly reduced the size of necrotic areas (p < 0.05). Thus, congested areas in liver grafts may negatively impact recipients. Short-term administration of hepatocyte growth factor may improve postoperative outcomes of recipients with graft congestion and contribute to more effective use of liver grafts (approval number: MedKyo-23137, Institutional Ethics Committee/Kyoto University).