Simultaneous Administration Research Articles

Hypophagia induced by intracerebroventricular injection of apelin-13 is mediated via CRF1/CRF2 and MC3/MC4 receptors in neonatal broiler chicken

Previous studies have shown the role of apelin and its receptors in the regulation of food intake. In the present study, we investigate the mediating role of melanocortin, corticotropin, and neuropeptide Y systems in apelin-13- induced food intake in broilers. Eight trials were run in the current investigation to ascertain the relationships between the aforementioned systems and apelin-13 on food intake and behavioral changes after apelin-13 administration. In experiment 1, hens were given an intracerebroventricular administration of a solution for control in addition to apelin-13 (0.25, 0.5, and 1 µg). Astressin-B (a CRF1/CRF2 receptor antagonist, 30 µg), apelin-13 (1 µg), and administration of astressin-B and apelin-13 concurrently, were all injected into the birds in experiment 2. Experiments 3 through 8 were quite similar to experiment 2, with the exception of astressin2-B (CRF2 receptor antagonist, 30 µg), SHU9119 (MC3/MC4 receptor antagonist, 0.5 nmol), MCL0020 (MC4 receptor antagonist, 0.5 nmol), BIBP-3226 (NPY1 receptor antagonist, 1.25 nmol), BIIE 0246 (NPY2 receptor antagonist, 1.25 nmol), and CGP71683A (NPY5 receptor antagonist, 1.25 nmol) were injected instead of astressin-B. After then, total food consumption was monitored for 6 h. Apelin-13 injections of 0.5 and 1 µg decreased feeding (P < 0.05). The hypophagic effects of apelin were attenuated following the simultaneous administration of Astressin-B and Astressin2-B with apelin-13 (P > 0.05). Co-infusion of SHU9119 and apelin-13 reduced the appetite-decreasing effects of apelin-13 (P > 0.05). When MCL0020 and apelin-13 were injected at the same time, the hypophagia that apelin-13 induced was eliminated (P > 0.05). BIBP-3226, BIIE 0246, and CGP71683A had no effect on the hypophagia brought on by apelin-13 (P > 0.05). Also, apelin-13 significantly increased number of steps, jumps, exploratory food, pecks and standing time while decreased siting time (P < 0.05). These findings suggest that apelin-13-induced hypophagia in hens may involve the CRF1/CRF2 and MC3/MC4 receptors.

Diagnosis and Prevention of Scabies in Low Mobility Patients with Cognitive Impairment

Scabies is an infectious skin disease caused by the human-specific ectoparasite Sarcoptes scabiei var. hominis. Despite the comprehensive study of scabies, the problem of its timely diagnosis in low-mobility patients with neurological and cognitive impairments remains relevant all over the world. Simultaneous administration of a large number of medications to patients with limited mobility may mask the clinical manifestations of scabies and mistakenly attribute itching to manifestations of skin allergic reactions or other dermatoses. The authors observed patient K., who was admitted in FCBRN of FMBA of Russia from 14.11.2022 to 15.11.2022. Clinical diagnosis upon admission: I69.3. The consequences of a stroke. Early recovery period of ischemic stroke in the basin of the left middle cerebral artery from 09.08.2022, atherothrombotic subtype according to TOAST criteria. Right-sided hemiparesis. Gross aphasia. Violation of the pelvic organs function. RMS 5. Comorbid diseases: arterial hypertension, controlled, the risk of CVE 4 (very high). The target blood pressure is less than 135/85 mmHg. Occlusion of the left anterior cerebral artery, middle cerebral artery. Toxic-allergic dermatitis (medicinal) in the acute phase. Based on a set of clinical data and laboratory detection of the pathogen, patient K. was diagnosed with B86 — scabies. Even though the patient was under medical supervision at the ambulatory step, scabies was not diagnosed timely. Late diagnosis of scabies leads to the spread of the disease and an unfavorable epidemiological situation.

Comparative effect of resveratrol, carnosic acid and hernandulcin on target enzymes and biochemical markers linked to carbohydrate and lipid metabolism in mice

Resveratrol (RV), carnosic acid (CA) and hernandulcin (HE; a non-caloric sweetener) are envisioned as promising nutraceuticals to designnew functional foods for improving lipid and carbohydrate metabolism. This study aimed to investigate the in vitro inhibitory effectof these molecules on specific enzyme targets and their capacity to improve distinctive markers associated to carbohydrate and lipidmetabolism in murine model. The enzymes explored were alpha-amylase, alpha-glucosidase, and pancreatic lipase whereas ICR malemice were used for in vivo testing. Saturation curves (10-200 µM mL-1) and Lineweaver-Burk regressions suggested that RV, CA andHE exerts non-competitive inhibition on pancreatic lipase, alpha-glucosidase and alpha-amylase but, CA produced a strong competitiveactivity on alpha-amylase. RV was more effective to inhibit alpha-glucosidase (IC50, 22.1 µM) whereas CA was the most effective toinhibit both alpha-amylase (IC50, 11.7 µM) and pancreatic lipase (IC50, 31.5 µM). The effects of the oral administration of RV (300 mg/kg) HE (100 mg/kg) and CA (100 mg/kg) as well as the simultaneous administration of the three compounds at the same concentration was also explored in normoglycemic and diabetic mice. In addition, the prolonged administration of these substances combined with hypercaloric/atherogenic diet for 30 days was performed. Our results revealed a clear modulatory activity in both postprandial glucose and triglyceride levels as well an improvement in biochemical markers of mice treated with hypercaloric/atherogenic diet. The administration of HE produced a notable change (p &lt; 0.01) in postprandial glucose assimilation at 60 min post-treatment in diabetic mice, whereas the other two compounds exerted a stronger depletion of glucose levels from 30 to 120 min post-treatment. A similar trend was recorded by RV and CA in postprandial triglyceride content, however, the latter compound was more effective (p &lt; 0.05) at lower doses than RV. The simultaneous administration of the three compounds produced a significant improvement (p &lt; 0.01) in biochemical parameters associated to carbohydrate (insulin and glucose) and lipid metabolism (total cholesterol, LDL-c, HDL-c, triglycerides, leptin, and adiponectin).Outstandingly, the mixture of the three compounds was more effective (p &lt; 0.01) than the administration of sole compounds to amelioratethe side effects of the hypercaloric/atherogenic diet. Finally, the body weight of treated mice significantly decreased (from 5 to 20%; p &lt; 0.05) in comparison with mice only fed with hypercaloric/atherogenic diet. Our results suggest that mixtures of RV, HE and CA may work better than their sole administration in mice and part of their biological activity could be associated with their inhibitory properties on the enzyme targets evaluated in this investigation.&#x0D; Keywords: Carnosic acid; Hernandulcin; Resveratrol; Hypoglycemic; Hypolipidemic; Murine model; Target enzymes

Interactions between complementary medicines and drugs used in primary care and oral COVID-19 antiviral drugs.

Patient harm resulting from drug interactions between conventional and traditional or complementary medicines (CM) are avoidable. To provide a clinical overview of a selection of CM interactions with drugs commonly used in Australian general practice or in the management of COVID-19. Many herb constituents are substrates for cytochrome P450 enzymes, and inducers and/or inhibitors of transporters such as P-glycoprotein. Hypericum perforatum (St John's Wort), Hydrastis canadensis (golden seal), Ginkgo biloba (ginkgo) and Allium sativum (garlic) are reported to interact with many drugs. Simultaneous administration of certain anti-viral drugs with zinc compounds and several herbs should also be avoided. Preventing and identifying unwanted CM-drug interactions in primary care requires vigilance, access toCM-drug interaction checkers and excellent communication skills. Potential risks from interactions should be balanced against the potential benefits of continuing the drug and/or CM and involve shared decision making.

The Effect of the Microbiota Metabolite – Butyric Acid on Motor Coordination, Muscle Strength and the Level of Oxidative Stress in Skeletal Muscles in Mice with Dysbiosis

According to modern concepts, the composition and diversity of the intestinal microbiota play an essential role in maintaining immunity, homeostasis, and, in general, the physiological functions of the host organism. Recently the positive role of the microbiota and its metabolites especially short-chain fatty acids, in the metabolism and functional activity of skeletal muscles was reported. The aim of our work was to analyze muscle strength and motor coordination in mice after injection of broad–spectrum antibiotics with simultaneous administration of a microbiota metabolite – one of the representatives of short-chain fatty acids – butyric acid. In addition, we determined the level of malondialdehyde, the concentration of total glutathione and the activity of glutathione peroxidases in the muscles of the hind limbs in mice with administration of antibiotics and butyric acid. The administration of antibiotics to adolescent mice for two weeks induced higher mortality and decrease of weight, and also caused significant changes in motor behavior, including an increase in horizontal motor activity, decrease in vertical motor activity, muscle strength, and motor coordination. A higher level of oxidative stress was found in the muscle tissues of the hind limbs of mice treated with antibiotics. At the same time, oral administration of butyric acid prevented the observed changes and improved not only behavioral disorders, but also partially reduced the level of oxidative stress. In conclusion, metabolite of normal microbiota has a positive effect on the functional and biochemical parameters of skeletal muscles in dysbiosis, which can be used to prevent loss of muscle function in various pathological conditions.

0556 Simultaneous comparison of unedited and manually edited HSAT with level 1 PSG in persons with hospitalized TBI

Abstract Introduction Previous studies have shown automatic scoring of portable level 3 sleep study provides similar findings when compared to polysomnography (PSG), establishing home sleep apnea tests (HSAT) as an adequate screening tool for OSA. Accuracy of level 3 studies with Nox T3 portable sleep studies (Noxturna Inc., Atlanta GA) may improve with manual editing to include total sleep time (TST). No other studies have compared unedited versus manually edited HSAT with level 1 in-lab PSG performed simultaneously. This study evaluates if added manual editing optimizes the diagnostic accuracy of HSAT in classifying the severity of OSA, using both AASM and CMS criteria. Methods Secondary analysis of six-center (n=206) sleep apnea diagnostic comparative effectiveness trial. Participants underwent simultaneous administration of level 1 PSG (Philips Alice 6 LDx Diagnostic Sleep system) and Nox T3 portable sleep study with centralized scoring using AASM and CMS criteria. All HSAT were autoscored and then edited by the registered polysomnographic technician. Editing entailed establishing start and stop recording times based on accompanying actigraphy data (reduction in movement) in the portable device and elimination of recording artifact. Results Using AASM criteria, poor sensitivity OSA (AHI≥5) was observed using unedited vs PSG (p=.01) compared to manually edited HSAT vs. PSG (p=.06). No statistically significant difference was observed using AHI≥15 or via categorization across four levels of OSA (none, mild, moderate, or severe). In contrast, CMS criteria comparisons to PSG showed poor specificity of OSA (AHI≥5) for unedited (p=.003) compared to edited (p=.372) HSAT studies. As expected, total sleep time was overestimated using T3 actigraphy devices compared to the criterion standard across both edited and unedited studies (p=.001, .001 respectively). Conclusion Improvements in sensitivity and specificity of OSA were noted using edited versus unedited T3 HSAT when compared to Level 1 PSG using both AASM and CMS criteria. Results support need for manualized editing of HSAT in persons with hospitalized TBI. Support (if any) PCORI (CER-1511-33005), GDHS (W91YTZ-13-C-0015)

5-aminolevulinic acid, fluorescein sodium, and indocyanine green for glioma margin detection: analysis of operating wide-field and confocal microscopy in glioma models of various grades.

Surgical resection remains the first-line treatment for gliomas. Several fluorescent dyes are currently in use to augment intraoperative tumor visualization, but information on their comparative effectiveness is lacking. We performed systematic assessment of fluorescein sodium (FNa), 5-aminolevulinic acid (5-ALA)-induced protoporphyrin IX (PpIX), and indocyanine green (ICG) fluorescence in various glioma models using advanced fluorescence imaging techniques. Four glioma models were used: GL261 (high-grade model), GB3 (low-grade model), and an in utero electroporation model with and without red fluorescence protein (IUE +RFP and IUE -RFP, respectively) (intermediate-to-low-grade model). Animals underwent 5-ALA, FNa, and ICG injections and craniectomy. Brain tissue samples underwent fluorescent imaging using a wide-field operative microscope and a benchtop confocal microscope and were submitted for histologic analysis. Our systematic analysis showed that wide-field imaging of highly malignant gliomas is equally efficient with 5-ALA, FNa, and ICG, although FNa is associated with more false-positive staining of the normal brain. In low-grade gliomas, wide-field imaging cannot detect ICG staining, can detect FNa in only 50% of specimens, and is not sensitive enough for PpIX detection. With confocal imaging of low-intermediate grade glioma models, PpIX outperformed FNa. Overall, compared to wide-field imaging, confocal microscopy significantly improved diagnostic accuracy and was better at detecting low concentrations of PpIX and FNa, resulting in improved tumor delineation. Neither PpIX, FNa, nor ICG delineated all tumor boundaries in studied tumor models, which emphasizes the need for novel visualization technologies and molecular probes to guide glioma resection. Simultaneous administration of 5-ALA and FNa with use of cellular-resolution imaging modalities may provide additional information for margin detection and may facilitate maximal glioma resection.

Distinct signatures on d-galactose-induced aging and preventive/protective potency of two low-dose vitamin D supplementation regimens on working memory, muscular damage, cardiac and cerebral oxidative stress, and SIRT1 and calstabin2 downregulation.

Chronic administration of d-galactose (d-gal) in rodents reproduces the overproduction of reactive oxygen species of physiological aging. The present research shows for the first time distinct signatures on d-gal-induced aging (500 mg/kg, 6 weeks) and the preventive and protective potential of two vitamin D (50 IU) supplementation regimens (pre-induction and simultaneous, respectively) in two vital organs (heart and brain). d-gal-induced notorious alterations in working memory, a strong increase in brain malondialdehyde (MDA) oxidative levels, and strong downregulation of sirtuin 1 (SIRT1) in the heart and hippocampus and of calstabin2 in the heart. Cardiac and brain superoxide dismutase (SOD) and glutathione peroxidase (GPx) enzymatic antioxidant capacities were damaged, brain calstabin2 was downregulated, and neuropathology was observed. Heart damage also included a moderate increase in MDA levels, serologic lactate dehydrogenase (LDH), total creatine kinase (CK) activities, and histopathological alterations. The used dose of vitamin D was enough to prevent cognitive impairment, avoid muscular damage, hamper cardiac and cerebral oxidative stress, and SIRT1 and calstabin2 downregulation. Most importantly, the potencies of the two preventive schedules depended on the tissue and level of study. The pre-induction schedule prevented d-gal-induced aging by 1 order of magnitude higher than simultaneous administration in all the variables studied except for SIRT1, whose strong downregulation induced by d-gal was equally prevented by both schedules. The benefits of vitamin D for oxidative stress were stronger in the brain than in the heart. Brain MDA levels were more sensitive to damage, while SOD and GPx antioxidant enzymatic activities were in the heart. In this order, the magnitude of SOD, MDA, and GPx oxidative stress markers was sensitive to prevention. In summary, the results unveiled distinct aging induction, preventive signatures, and sensitivity of markers depending on different levels of study and tissues, which are relevant from a mechanistic view and in the design of targeted interventions.

Inhalation exposure to crude oil vapor induces behavioural deficits by increasing oxidative stress and histopathological changes in rat hippocampus: Quercetin therapeutic approach

ObjectiveInhalation exposure to crude oil vapor (COV) and petroleum products is considered responsible for neurobehavioral toxicity in human and animal models. The antioxidant activity of quercetin (Que) and its derivatives are promising for protecting the hippocampus. This study aimed to evaluate the neuroprotective role of Que against COV-induced behavioral alterations and hippocampus damage. MethodsEighteen adult male Wistar rats were randomly divided into the following three groups (n = 6): the control, the COV, and the COV + Que group. The inhalation method was used to expose the rats to crude oil vapors for 5 h daily, and Que (50 mg/kg) was administered orally. After 30 days of treatment, the spatial working memory and anxiety levels were evaluated using the cross-arm maze and elevated plus maze (EPM), respectively. TUNEL assay and hematoxylin-eosin (H&E) staining were used to identify the necrosis, normal and apoptotic cells in the hippocampus. Moreover, the levels of oxidative stress biomarkers including malondialdehyde (MDA), glutathione peroxidase (GPx), superoxide dismutase (SOD), catalase (CAT), and total antioxidant capacity (TAC) were investigated in the hippocampus tissue. ResultsThe results indicated that exposure to COV was associated with a significant decrease in spatial working memory and activity of CAT, TAC, SOD, and GPx enzymes compared to the control (P < 0.05). Moreover, COV significantly increased the level of anxiety, MDA, and hippocampal apoptosis (P < 0.05). The simultaneous administration of quercetin along with exposure to COV improved the behavioral alterations, activity of antioxidant enzymes, and hippocampal apoptosis. ConclusionsThese findings suggest that quercetin prevents COV-induced hippocampal damage by enhancing the antioxidant system and preventing cell apoptosis.

Systematic Review of Piperacillin-Tazobactam and Vancomycin Y-Site Compatibility: Consideration of Concentration and Solution Variability.

Simultaneous administration of vancomycin and piperacillin-tazobactam (VPT) poses significant challenges related to physical and chemical compatibility, as well as clinical practice. A systematic review of available literature related to VPT Y-site compatibility was performed. Data was collected from primary and tertiary sources. Seven articles were included in addition to one internal assessment and one review article and information from tertiary drug databases. The literature supports the simultaneous administration via Y-site of piperacillin-tazobactam 33.75 mg/mL in normal saline (NS) and vancomycin 4 to 8 mg/mL in NS. The same drug products at differing concentrations, diluents, storage conditions, or preparations outside of this recommendation should be considered incompatible.

P331 ANALYSIS OF THE CLINICAL AND THERAPEUTIC CHARACTERISTICS OF PATIENTS ADMITTED TO THE HEART FAILURE CLINIC IN THE PERIOD APRIL–SEPTEMBER 2022. ORGANIZED BY THE ANMCO AREA CARDIO RENO METABOLICA

Abstract In recent years, the pharmacological treatment of HFrEF has undergone considerable development. Two pharmacological classes in particular have been shown to significantly reduce cardiovascular events and hospitalizations: ARNI and SGLT2i. The objective of this observational study was to provide "real word" data on the effective use of these drugs, the efficacy, safety and tolerability of their simultaneous administration. We analyzed 82 patients admitted to our clinic over a period of 6 months and reported their clinical characteristics and the effective therapies administered. The data of 82 patients, 64% male, with an average age of 70.5 years were analysed. 49% with ischemic heart disease, 54% hypertension and 31% type 2 diabetes mellitus. Of these, 47.5% with HFrEF, 21% with HFmrEF, and the remaining 30% with HFpEF. At the time of visit, 19.5% of patients had a GFR &amp;lt;59 mL/min/1.73m2. 31% of the patients were in NYHA Class III. We then analyzed the drug therapies provided. Assuming that a very high percentage of patients were taking beta blockers and MRA (91% and 79% respectively), we found that about 72% of patients were on concomitant therapy with a renin angiotensin system inhibitor (51% ARNI, 21% ACEI/ARBs). Among the 51% of patients in ARNI, as many as 32% took the minimum dose of the drug (24/26mg bid), 11% the intermediate dose (49/51mg bid) and only the 8% the maximum recommended dosage (97/103 mg bid). In the group of patients with HFrEF, 10% were not on ARNI therapy or this drug had been discontinued during the follow–up (92% for hypotension, 8% for ARF on IRC). As for gliflozines, 46% of the patients analyzed were on SGLT2i therapy (and of these, approximately 70% had HFrEF). 30% of the total patients were in concomitant therapy with ARNi and SGLT2i (62% of patients affected by HFrEF). Conclusions most of our outpatients are affected by HFrEF, they benefit from the best pharmacological strategy recommended by the most recent international guidelines . The simultaneous administration of ARNI and SGLT2i is not burdened by significant adverse events. None of our patients discontinued SGLT2i therapy since there were no adverse effects related to drug administration.

The protective role of curcumin nanoparticles on the submandibular salivary gland toxicity induced by methotrexate in male rats

ObjectiveTo evaluate the protective role of nanocurcumin on the toxicity induced by methotrexate in the submandibular glands of rats. DesignTwenty- four healthy male Wistar albino rats were randomly distributed into 3 groups, 8 rats each. Group I-control: rats received a single intraperitoneal injection of saline; Group II-methotrexate (MTX): rats received methotrexate 20 mg/ kg day 1 of the experiment; Group III-methotrexate and nanocurcumin (MTX+NCU): rats received methotrexate 20 mg/ kg on day 1 of the experimental period in addition to nanocurcumin 100 mg/kg/day for 7 days. After euthanasia, the submandibular salivary glands of all rats were collected and prepared for histological, histomorphometric, and immunohistochemical examination (Caspase 3, Bcl2), in addition to transmission electron microscopy. ResultsHistological and ultrastructural assessment revealed less salivary gland damage in the nanocurcumin group in comparison to the methotrexate group, and the percentage of acinar vacuolization showed significantly lower values in the nanocurcumin group. Group III (MTX+NCU) showed lower immunoexpression of caspase 3 than group II (MTX), while Bcl2 immunoreactivity was higher in the MTX group than in the MTX+NCU group. ConclusionsOur results suggest that simultaneous administration of nanocurcumin reduces apoptosis in salivary glands subjected to methotrexate.

The Protective Effects of Pyridoxine on Linezolid-Induced Hematological Toxicity, Hepatotoxicity, and Oxidative Stress in Rats.

Linezolid is often used to treat antibacterial-resistant infections. Linezolid can cause side effects. To date, the effectiveness of the simultaneous administration of pyridoxine and linezolid is unclear. Here we investigate the protective effect of pyridoxine on linezolid-induced hematological toxicity, hepatotoxicity, and oxidative stress in rats. The 40 male pediatric Spraque-Dawley rats were separated into 4 groups: control, linezolid, pyridoxine, and linezolid-pyridoxine. A complete blood count, liver function test, and measurements of antioxidant enzyme activities for superoxide dismutase, glutathione peroxidase, catalase, and lipid peroxidation were performed in blood before treatment and 2 weeks after administration of the treatment. White blood cell and hemoglobin counts for the linezolid group decreased, and the alanine aminotransferase level in the linezolid group increased compared to their respective baseline values. Post-treatment white blood cell decreased in the linezolid and linezolid- pyridoxine groups compared to those in the control group (P < .001). Alanine aminotransferase levels increased in the linezolid and linezolid-pyridoxine groups compared to those in the control group (P < .001 and P < .05, respectively). The activity of superoxide dismutase, catalase, glutathione peroxidase, and malondialdehyde levels increased in the linezolid group compared to the control group (P < .001, P < .05, P < .001, and P < .001, respectively). Linezolid plus pyridoxine treatment caused a significant decrease in malondialdehyde levels and superoxide dismutase, catalase, and glutathione peroxidase enzyme activities compared to the linezolid group (P < .001, P < .01, P < .001, and P < .01, respectively). Pyridoxine may be an effective adjuvant agent for the prevention of linezolid toxicity in rat models.

Abstract #1402115: A Case of Starvation Ketoacidosis in Pregnancy Secondary to Perforated Appendicitis

Starvation ketoacidosis in pregnant patients is a rare but life-threatening condition. There are few case reports in the literature of starvation ketoacidosis of pregnancy with no consensus on treatment. We present a case of starvation ketoacidosis in pregnancy that was successfully treated with dextrose and insulin infusion. A 35-year-old pregnant woman with a history of prior gestational diabetes diagnosed in a previous but not current pregnancy presented at 33 weeks of gestation with severe abdominal and poor oral intake for 3 days prior to admission. On evaluation, the patient was found to have a perforated appendix with peritonitis and was taken to the operating room for open laparotomy. During surgery, she was noted to have an anion gap metabolic acidosis. Arterial blood gas revealed pH of 7.06 (range 7.35-7.45), pCO2 of 43mmHg (range 32-35 mmHg), pO2 of 120 mmHg (range 83-108 mmHg), and bicarbonate of 12 mmol/L (range 22-26 mmol/L). Further blood work demonstrated serum bicarbonate of 14 mmol/L (range 21-30 mmol/L), and an anion gap of 18 (4-16). Beta-hydroxybutyrate was elevated at 58.5 mg/dL (range 0-3 mg/dL), with serum glucose of 134 mg/dL (range 70-99 mg/dL) and normal lactate of 1.3 mmol/L (range 0.5-2.2 mmol/L). Urinalysis demonstrated 2+ ketones (range negative). She was started on a dextrose 5% infusion with insulin infusion at a fixed rate to overcome any inherent insulin resistance and suppress lipolysis. Metabolic parameters were corrected in 12 hours and the patient was extubated in 24 hours. At 48 hours, insulin and dextrose infusions were discontinued. She then underwent cesarian section 1.5 weeks later due to development of pelvic abscess requiring surgical intervention. She delivered a healthy baby girl. Women in late pregnancy are at increased risk for ketosis during even brief periods of fasting. This is due to increased relative insulin resistance and enhanced lipolysis, a protective mechanism to ensure adequate glucose supply to the growing fetus. Prompt recognition of ketosis and timely management are essential to prevent profound acidosis and avoid maternal-fetal mortality. Although there is no consensus on management of starvation ketoacidosis in pregnancy, most case reports suggest carbohydrate administration is the cornerstone of treatment, although insulin administration can be considered if there is concern for marginal insulin reserve or there is treatment failure with carbohydrate administration alone. In our case, given the profound degree of acidosis, simultaneous administration of carbohydrate and insulin was pursued with rapid resolution of the patient’s metabolic derangements.

Double-lumen catheter is a risk factor for complications of peripherally inserted central venous catheters in children

BackgroundAlthough peripherally inserted central venous catheters (PICCs) are useful for children because of the high burden of vascular puncture, no guidelines exist for PICC in terms of insertion site, blood vessel, and type of catheter. We investigated the risk factors of complications during PICC placement in pediatric patients. MethodsWe analyzed the medical records of children who were admitted to the Tokyo Medical and Dental University Hospital and had PICCs inserted between January 2016 and December 2020. A total of 92 patients with 141 PICCs (age at insertion: 0–18 years, average PICC per patient: 1.48) were analyzed. The median duration of indwelling catheter use was 49 days (interquartile range: 24–80 days). Exposures are patient characteristics (age, weight, primary disease) and variables that the surgeons have choices for during the clinical procedure, such as inserted vessel, inserted part, catheter diameter, catheter lumen, and catheter type (open or closed end). Multilevel logistic regression, considering the correlation among multiple PICCS within a patient, was performed. ResultsForty-four PICCs (31%) were removed because of catheter-related complications (18 suspected infections, 9 occlusions, 7 breakages, 6 dislodgements, and 4 phlebitis). Double-lumen catheters were significantly positively associated with complications (odds ratio: 3.91; 95% confidence interval: 1.03, 14.9) after adjusting for all covariates. The other factors were not significantly associated with the occurrence of complications. ConclusionsDouble-lumen PICCs were associated with complications. The double lumen is useful for the simultaneous administration of multiple drugs, but cases should be carefully monitored.

Artemisin and human endometrial-derived stem cells improve cognitive function and synaptic plasticity in a rat model of Alzheimer disease and diabetes.

Alzheimer disease (AD) is a common form of dementia associated with loss of memory and disruption of synaptic plasticity. There is a strong correlation between the pathophysiological features of AD and diabetes, including induction of oxidative stress, inflammation, and abnormality in blood vessels. Considering the brain's limited capacity to repair damage and the potential of stem cell-derived neural cells in the repair of neurodegenerative disease, we investigated the effects of artemisinin and TSP‑1‑human endometrial-derived-derived stem cells (TSP‑1‑hEDSCs) on the cognitive function and synaptic plasticity in AD-diabetes rats. The authors previously showed that artemisinin and TSP‑1‑hEDSCs suppressed oxidative stress and inflammation in AD-diabetes rats. Thrombospondins-1 (TSPs-1) is a glycoprotein that inhibits angiogenesis. AD and diabetes were induced using streptozotocin. Synaptic plasticity and learning and memory function were studied using the Morris water maze and electrophysiological test, respectively. Streptozotocin increased traveled swimming distance and escape latency in the morris water maze test, decreased the percent time spent in the target quadrant, inhibited the long-term potentiation (LTP), and increased the blood glucose levels. Simultaneous or separate administration of artemisinin and TSP‑1‑hEDSCs decreased the blood levels of glucose and improved cognitive tasks and synaptic plasticity by considerably reducing traveled swimming distance and escape latency, increasing the percent time spent in the target quadrant, and retrieval of the LTP; therefore, they could be utilized as an adjunct treatment for AD treatment. These results may be due to a decrease in oxidative stress and inflammation.

Pediococcus acidilactici pA1c® Improves the Beneficial Effects of Metformin Treatment in Type 2 Diabetes by Controlling Glycaemia and Modulating Intestinal Microbiota.

Type 2 diabetes (T2D) is a complex metabolic disease, which involves maintained hyperglycemia, mainly due to the development of an insulin resistance process. Metformin administration is the most prescribed treatment for diabetic patients. In a previously published study, we demonstrated that Pediococcus acidilactici pA1c® (pA1c) protects from insulin resistance and body weight gain in HFD-induced diabetic mice. The present work aimed to evaluate the possible beneficial impact of a 16-week administration of pA1c, metformin, or the combination of pA1c and metformin in a T2D HFD-induced mice model. We found that the simultaneous administration of both products attenuated hyperglycemia, increased high-intensity insulin-positive areas in the pancreas and HOMA-β, decreased HOMA-IR and also provided more beneficial effects than metformin treatment (regarding HOMA-IR, serum C-peptide level, liver steatosis or hepatic Fasn expression), and pA1c treatment (regarding body weight or hepatic G6pase expression). The three treatments had a significant impact on fecal microbiota and led to differential composition of commensal bacterial populations. In conclusion, our findings suggest that P. acidilactici pA1c® administration improved metformin beneficial effects as a T2D treatment, and it would be a valuable therapeutic strategy to treat T2D.

Abstract 4099: Dual targeting of tumor cells and cancer associated fibroblasts enhances CAR T efficacy in solid tumors

Abstract CAR T cell therapies have demonstrated considerable potency in treating hematologic cancers, but only limited efficacy in eliminating solid tumors. One reason for this discrepancy may derive from the immunologic and physical barriers created by infiltration of cancer associated fibroblasts (CAFs) into solid tumors. These CAFs, which can comprise 15-85% of the stromal cells in a tumor mass, are correlated with poor patient survival and can reduce CAR T cell efficacies by secreting immunosuppressive cytokines, stimulating tumor cell proliferation, and depositing fibrotic barriers to CAR T cell penetration. Here, we are pursuing a method to suppress or eliminate CAF activities in the tumor microenvironment (TME). A potential CAR T cell target that is uniquely expressed on CAF surfaces is fibroblast activation protein (FAP). In this study, we have employed a novel, highly specific FAP targeting small molecule to direct our universal CAR T cells to CAFs. For this purpose, we have designed a CAR that contains an otherwise classical CAR except the extracellular scFv specifically binds fluorescein. Upon addition of a bispecific adaptor comprised of fluorescein linked via a short spacer to our FAP ligand, a bridge is formed between the anti-fluorescein CAR on the T cell and FAP on the CAF, resulting in formation of an immunologic synapse between the CAR T cell and CAF that triggers CAF destruction and CAR T cell proliferation. Importantly, this CAR T cell design also permits simultaneous administration of a second bispecific adaptor (i.e. fluorescein linked via a short spacer to a cancer-specific ligand) that can enable the same CAR T cell to concurrently kill adjacent cancer cells. To test whether this universal CAR T cell can eliminate both cancer cells and CAFs, we have implanted KB cells (i.e. a cell line that creates an immunologically “cold” folate receptor (FR) expressing solid tumor) into NSG mice and quantitated the CAR T cell’s toxicity in the presence of one or both bispecific adapters. While administration of the universal CAR T cells followed by intravenous injection of an FR-targeting bispecific adaptor achieved significant anti-tumor efficacy, co-injection of a FAP-targeted bispecific adaptor enhanced this efficacy without apparent toxicity. Analyses of tumor masses from the therapy further revealed that co-administration of the FAP-targeted bispecific adaptor not only promoted CAF elimination but also enhanced CAR T infiltration and activation. Importantly, a similar improvement in anti-tumor efficacy could be readily demonstrated in a second immunologically “cold” PSMA-expressing solid tumor model. Taken together, we conclude that the bispecific adaptor/universal CAR T approach offers a unique opportunity to concurrently eradicate cancer cells and tumor-supporting CAFs in a manner that can improve the overall performance of the CAR T cells in solid tumors. Citation Format: Bo Huang, Suilan Zheng, Haiyan Chu, Ramesh Mukkamala, Suresh K. Bowroju, Yashapal Singh, Sudarsan R. Kasireddy, Md Sazzadul Bari, Madduri Srinivasarao, Laurie Beitz, Byoung Ryu, Michael Jensen, Andrew M. Scharenberg, Philip S. Low. Dual targeting of tumor cells and cancer associated fibroblasts enhances CAR T efficacy in solid tumors. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4099.

Capsazepine-Induced Altered Colonic Mucosal Health Limits Isomalto-oligosaccharide Action in High-Fat Diet-Fed C57BL/6J Mice.

The present study sought to understand the effects of a combination of altered colonic mucosal health (intrarectal capsazepine administration) and high-fat diet (HFD) administration in mice. Furthermore, we also studied whether this combination prevents protective actions of dietary prebiotic, isomaltooligosaccharides. We studied the alterations in intestinal permeability, histological and transcriptional changes, short-chain fatty acid (SCFA) concentrations, and gut microbial abundance. Capsazepine (CPZ) was administered rectally twice a day along with HFD feeding. Following confirmation of CPZ action (loss of TRPA1 and TRPV1-associated nocifensive behavior), the intrarectal dose of CPZ was reduced to once in 2 days up to 8 weeks. Simultaneous intrarectal administration of CPZ exacerbated the HFD (8 weeks feeding)-induced damage to mucosal lining, intestinal permeability, tight junction protein expression, SCFA levels, and gut bacterial abundances. This higher degree of mucosal damage and pathological alteration in colonic mucosa prevented the previously reported protective actions of isomaltooligosaccharides as a prebiotic in HFD-fed mice. Overall, we present evidence that colonic precondition (gut permeability and mucosal lining) is an important factor in determination of HFD-induced changes in the colon, and success of diet-associated interventions (dietary fibers, pre/probiotics, etc.) is dependent on it.

Flurbiprofen: Determination of safety profile, analgesic effect, and interaction with lipoic acid in murine

our study aimed study aimed to detect and investigate the safety profile of flurbiprofen and evaluate the analgesic effects of the tail immersion and writhing tests, as well as its interaction with lipoic acid as an analgesic for visceral pain in mice. The up-and-down manner described by Dixon was utilized to determine the median lethal dose (LD50) and the median analgesic dose (ED50), the safety criteria were calculated, mathematical equations were applied, and the interaction between flurbiprofen and alpha-lipoic acid was evaluated using the writhing test. The LD50 of oral flurbiprofen was 1147.4 mg/kg, and the ED50 of oral flurbiprofen was 8.6 mg/kg using the tail immersion test. The therapeutic index was 133, and the standard safety margin was 35%. The highest analgesia time was one h after dosing, which faded after 24 h. Administration of flurbiprofen 10, 20, and 40 mg/kg had an analgesic effect in a dose-dependent manner. Flurbiprofen relieved visceral pain when dosed at 20, 40, and 80 mg/kg, with analgesic efficacies of 53, 56, and 65%, respectively. The simultaneous administration of flurbiprofen and alpha-lipoic acid had a synergistic analgesic effect on visceral pain. From our results, we conclude that flurbiprofen has a wide range of safety and is an effective analgesic for peripheral and visceral pain. The synergistic effect between flurbiprofen and alpha-lipoic acid may have clinical benefits, including reducing the dose of flurbiprofen when used together.