Single Dose Research Articles

First-in-Human Evaluation of Safety, Pharmacokinetics and Muscle Glycogen Lowering of a Novel Glycogen Synthase 1 Inhibitor for the Treatment of Pompe Disease.

Pompe disease is a rare glycogen storage disease caused by mutations in the enzyme acid α-glucosidase (GAA) resulting in pathological accumulation of glycogen in muscle tissues leading to progressive weakness and respiratory dysfunction. Enzyme replacement therapy (ERT) with GAA is currently the sole treatment option for patients with Pompe disease. ERT burdens patients with frequent intravenous infusions while insufficiently halting disease progression due to incomplete ERT skeletal muscle distribution. Glycogen synthase 1 (GYS1) has been proposed as a substrate reduction therapy (SRT) target for Pompe disease. Here, we report results from the first-in-human study of the orally available GYS1 inhibitor MZE001 in healthy subjects. In 88 participants, MZE001 was well-tolerated up to a single dose of 480 mg BID and multiple doses of 720 mg BID for 10 days. Noncompartmental analysis determined that the half-life and Ctrough concentrations of MZE001 could provide efficacious exposures with once or twice daily oral dosing. Change from baseline of peripheral blood mononuclear cell (PBMC) glycogen, which correlated with muscle glycogen levels in preclinical models, was significantly reduced dose-dependently following 10 days of MZE001 treatment in healthy subjects. A muscle biopsy sub-study demonstrated that 10 days of MZE001 (480 mg BID) dosing safely and substantially lowered muscle glycogen stores in healthy adults. This correlated with the PBMC exposure response and supports the use of PBMC glycogen reduction as a surrogate for muscle response, and MZE001 potential for development as the first oral substrate reduction therapy for patients with Pompe disease.

The potential hepatoprotective effect of Erythropoietin against liver damage induced by Doxorubicin through modulation of PI3K/Akt/GSK3β and activation of Nrf2/HO-1 pathway

This study aims to evaluate the hepatoprotective effect of erythropoietin against doxorubicin-induced liver damage in a male rat model through PI3K/Akt/GSK3β axis modulation and activation of the Nrf2/HO-1 pathway. Doxorubicin, a chemotherapeutic antibiotic used to treat many types of cancer, has some considerable side effects that limit its clinical use, including hepatotoxicity. Erythropoietin is a glycoprotein hormone primarily recognized for its crucial function in promoting erythropoiesis. Recent studies have demonstrated the significant cytoprotective effects of erythropoietin in several organs. Thirty-six male Wistar rats were randomly separated into six groups: (Group 1) a negative control group; (Group 2) a doxorubicin induction group; (Groups 3, 4, and 5) three groups pre-treated with erythropoietin in three different doses (1000, 3000, and 6000 IU/kg); and (Group 6) a positive control group pre-treated with silymarin (100 mg/kg). On the 7th day, all groups (except group 1) were injected with a single dose of doxorubicin (20 mg/kg). On day 9 of the experiment, blood and liver samples were taken for subsequent analysis. The results showed that erythropoietin pre-treatment significantly reduced doxorubicin-induced hepatotoxicity by stimulating the PI3K/Akt and Nrf2/HO-1 pathways and suppressing GSK3β and caspase 3. In addition to that, erythropoietin pre-treatment also raised the levels of GSH, lowered the levels of MDA, and brought the levels of the liver enzymes ALT and AST back to normal compared to the induction group. In conclusion, via modulating PI3K/Akt/GSK3β and activating the Nrf2/HO-1 pathway, erythropoietin pre-treatment protected the liver against hepatotoxicity caused by doxorubicin in a dose-dependent manner.

Discovery and Synthesis of Heterobifunctional Degraders of Rearranged during Transfection (RET) Kinase.

We describe the design, synthesis, and structure-activity relationship (SAR) of heterobifunctional RET ligand-directed degraders (LDDs) derived from three different second-generation RET inhibitors. These LDDs are composed of a target binding motif (TBM) that binds to the RET protein, a linker, and a cereblon binding motif (CBM) as the E3 ligase recognition unit. This led to the identification of a series of pyrazolopyridine-based heterobifunctional LDDs, as exemplified by compound 39. LDD 39 demonstrated high in vitro inhibitory and degradation potency against both RET wild-type and the two representative mutants, V804M and G810R. Importantly, in PK/PD studies, 39 exhibited a differentiated and favorable in vivo profile compared to the corresponding tyrosine kinase inhibitor (TKI), compound 3. Robust and sustained degradation of total-RET (tRET) protein and inhibition of phospho-RET (pRET) signaling were observed in TPC-1 xenograft tumors driven by RET and the RET/G810R mutant following a single dose of LDD 39 at 15 and 75 mg/kg, respectively.

Effects of exogenous progesterone on the ovine serum progesterone profile during the non-breeding season

Exogenous progesterone (PRG) sources are used to induce ovine estrus during the non-breeding season. Intramuscular injection (IM) of PRG is an uncommon route for this purpose. This study investigated serum progesterone (P4) levels after IM administration of 50 mg of two different PRG products. Ten ewes were selected and received two consecutive PGF2α injections at 24-h intervals. Serum samples were collected (Time 0), followed by the injection of single doses of Fertigest® or Vetagesterone®. Serum P4 levels were assayed at times (T) 0, 30 min, 3,6,12,24,48,72,96, and 120 h after injection. A large variation in the serum P4 levels at T0 was detected. The serum P4 level at T0 was 4.3 ng/mL, which is considerable for anestrus ewes, following PGF2α administration. The mean time to reach maximum serum P4 concentration was 5.8 h, with a mean concentration of 22.5 ng/mL. Serum P4 levels returned to basal values (T0) after 48 h. An increased P4 production rate (PR) was detected following PRG administration, which continued for 24 h. A single injection of PRG reduced the variety of serum P4 levels from 24 h onward. The two different PRG generated different serum P4 concentrations. This study indicates an unusual change in serum P4 levels in anestrus ewes following PGF2α administration. 48 h after 50 mg PRG injection, the plasma levels of P4 reached basal levels in anestrus ewes.

Effect of furosemide on comprehensive renin-angiotensin-aldosterone system activity of Thoroughbred horses.

Furosemide, a commonly used diuretic, activates the renin-angiotensin-aldosterone system (RAAS) in other species. Little is known about RAAS peptide activation in horses. To evaluate equilibrium analysis as a practical method for RAAS quantification in horses and describe the RAAS response to a single dose of furosemide. We hypothesize that furosemide would cause transient increase in RAAS peptides in horses. 14 healthy adult thoroughbreds from a university teaching herd. Horses received either furosemide (1 mg/kg IV) or saline IV in a crossover study design. Protease-inhibited samples were compared with equilibrium analysis samples with Deming regression analysis. Renin-angiotensin-aldosterone system hormones were evaluated at 0, 0.25, 0.5, 4, and 24 hours postadministration, via equilibrium analysis. Values were compared with a mixed effects model. Correlation between protease inhibition and equilibrium analysis was high for angiotensin I peptide (AngI) and angiotensin II peptide (AngII) (r = .92 and .95, respectively). Baseline RAAS peptide concentrations were below the limit of detection except AngII (median, 7.5 [range, 3.5-14.0] pmol/L). Furosemide administration resulted in an increase in AngI (8.0 [0.5-15.5] pmol/L, P = .03), AngII (33.7 [9.6-57.9] pmol/L, P = .0008), angiotensin III peptide (AngIII) (2.9 [0.9-4.9] pmol/L, P = .0005), angiotensin IV peptide (AngIV) (2.0 [0.6-3.4] pmol/L, P = .0005), and angiotensin 1-5 peptide (Ang1-5) (5.6 [1.2-5.9] pmol/L, P = .003) at 4 hours. Differences are reported as difference in the mean (95% confidence interval [CI]). Furosemide produced an increase in hormones associated with both the classical and alternative RAAS pathways. Serum equilibrium analysis is practical for RAAS analysis in horses.

The contribution of neutrophils to bacteriophage clearance and pharmacokinetics in vivo.

With the increasing prevalence of antimicrobial-resistant bacterial infections, there is interest in using bacteriophages (phages) to treat such infections. However, the factors that govern bacteriophage pharmacokinetics in vivo remain poorly understood. Here, we have examined the contribution of neutrophils, the most abundant phagocytes in the body, to the pharmacokinetics of i.v. administered bacteriophage in uninfected mice. A single dose of LPS-5, a bacteriophage recently used in human clinical trials to treat drug-resistant Pseudomonas aeruginosa, was administered i.v. to both immunocompetent BALB/c and neutropenic CD1 mice. Phage concentrations were assessed in peripheral blood and spleen at 0.25, 1, 2, 4, 8, 12, and 24 hours after administration by plaque assay and qPCR. We observed that the phage clearance was only minimally affected by neutropenia. Indeed, the half-lives of phages in blood in BALB/c and CD1 mice were 3.45 and 3.66 hours, respectively. These data suggest that neutrophil-mediated phagocytosis is not a major determinant of phage clearance. Conversely, we observed a substantial discrepancy in circulating phage levels over time when measured by qPCR versus plaque assay, suggesting that significant inactivation of circulating phages occurs over time. These data indicate that alternative factors, but not neutrophils, inactivate i.v. administered phages.

Helmet Continuous Positive Airway Pressure for Acute Bronchiolitis Respiratory Failure in a Pediatric Ward: Is It a Replicable Experience?

(1) Background: Helmet Continuous Positive Airway Pressure (H-CPAP) has primarily been used in intensive care settings to treat moderate-to-severe bronchiolitis in infants. We aim to report on the feasibility of H-CPAP for selected infants with bronchiolitis in a pediatric ward. (2) Methods: A retrospective, observational, consecutive case series was studied of 26 patients who received H-CPAP on the pediatric ward from October 2022 to February 2023, including a description of patient outcomes and costs. (3) Results: Of 130 infants with bronchiolitis admitted to Bambino Gesù Hospital in Rome, 34 were hospitalized for moderate to severe bronchiolitis, and 26 began H-CPAP on the ward. Among the 26 pediatric patients who received H-CPAP on the ward, 4 out of 26 (15%) required transfer to the PICU within the first hours of care due to clinical deterioration. No problems with the H-CPAP interface or side effects attributable to H-CPAP were reported. Pharmacological sedation with a single dose of dexmedetomidine was required for 15/26 patients (57%) following failure of non-pharmacological anxiety reduction strategies. After introducing H-CPAP in our pediatric ward, we achieved total cost savings of approximately EUR 147,120. (4) Conclusions: Treatment with H-CPAP for infants with bronchiolitis may be feasible in non-intensive care settings with trained staff, appropriate monitoring, and rapid access to pediatric intensive care.

Recovery after human bone marrow mesenchymal stem cells (hBM-MSCs)-derived extracellular vesicles (EVs) treatment in post-MCAO rats requires repeated handling.

Rehabilitation is the only current intervention that improves sensorimotor function in ischemic stroke patients, similar to task-specific intensive training in animal models of stroke. Bone marrow mesenchymal stem cells (BM-MSCs)-derived extracellular vesicles (EVs) are promising in restoring brain damage and function in stroke models. Additionally, the non-invasive intranasal route allows EVs to reach the brain and target specific ischemic regions. Yet unclear is how handling might enhance recovery or influence other therapies such as EVs after stroke. We used the transient middle cerebral artery occlusion (MCAO) model of stroke in rats to assess how intensive handling alone, in the form of sensorimotor behavioral tests, or in combination with an intranasal treatment of EVs restored neurological function and ischemic damage. Handled rats were exposed to a battery of sensorimotor tests, including the modified Neurological Severity Score (mNSS), beam balance, corner, grid walking, forelimb placement, and cylinder tests, together with Magnetic Resonance Imaging (MRI) at 2, 7, 14, 21, and 28 days post-stroke (dps). Handled MCAO rats were also exposed to an intranasal multidose or single dose of EVs. Non-handled rats were evaluated only by mNSS and MRI at 2, 28, and 56 dps and were treated with a single intranasal dose of EVs. Our results showed that handling animals after MCAO is necessary for EVs to work at the tested dose and frequency, and that a single cumulative dose of EVs further improves the neurological function recovered during handling. These results show the importance of rehabilitation in combination with other treatments such as EVs, and highlight how extensive behavioral testing might influence functional recovery after stroke.

Cardiorenal ketone metabolism in healthy humans assessed by 11C-acetoacetate PET: effect of D-β-hydroxybutyrate, a meal, and age.

The heart and kidney have a high energy requirement, but relatively little is known about their utilization of ketones as a potential energy source. We assessed the metabolism of the ketone tracer, carbon-11 acetoacetate (11C-AcAc), by the left and right ventricles of the heart and by the kidney using positron emission tomography (PET) in n = 10 healthy adults under four experimental conditions: a 4-h fast (fasted) ± a single 12g oral dose of D-beta-hydroxybutyrate (D-BHB), and a single complete, liquid replacement meal (hereafter referred to as the "fed" condition) ± a single 12g oral dose of D-BHB. Under these experimental conditions, the kinetics of 11C-AcAc metabolism fitted a two-compartment model in the heart and a three-compartment model in the kidney. Plasma ketones were about 10-fold higher with the oral dose of D-BHB. During the four conditions, tracer kinetics were broadly similar in the myocardium and kidney cortex. 11C-AcAc metabolism by the kidney pelvis was similar in three of the four study conditions but, later, peaked significantly higher than that in the cortex; the exception was that the tracer uptake was significantly lower in the fed condition without D-BHB. 11C-AcAc uptake was significantly inversely correlated with age in the kidney cortex, and its oxidative metabolism was significantly positively correlated with age in the left ventricle. D-BHB blunted the insulin, gastric inhibitory peptide, and C-peptide response to the meal. This PET methodology and these acute metabolic perturbations would be suitable for future studies assessing cardiorenal ketone metabolism in conditions in which heart and kidney functions are experimentally modified or compromised by disease.

Study on bioequivalence and influence of obesity-related indicators on pharmacokinetics and pharmacodynamics for insulin degludec in healthy subjects

This study aimed to evaluate the bioequivalence between test and reference insulin degludec (IDeg) and the effects of body composition on pharmacokinetics and pharmacodynamics of IDeg in Chinese healthy volunteers. In this randomized, open-label, crossover trial, 30 healthy Chinese males were assigned to receive a single subcutaneous dose (0.4 IU/kg) of each formulation under 24-h euglycemic hyperinsulinaemic clamp. Body compositions were analysed prior to administration and blood samples were collected at specific times. The 90% of primary pharmacokinetic parameters and 95% of primary pharmacodynamic parameters confidence intervals for the ratio of the least-squares geometric means were all in the range of 80–125%. As the fat content level increases, Cmax, AUC0−12 and GIR-AUC0−24 decreased whereas AUC24−96 increased sequentially. Therefore, the equivalence was demonstrated between test and reference, and in healthy Chinese volunteers, higher levels of adiposity are associated with slower rates of insulin absorption and distribution and the poorer glucose-lowering effect.

Proton dose calculation with LSTM networks in presence of a magnetic field

Objective.To present a long short-term memory (LSTM) network-based dose calculation method for magnetic resonance (MR)-guided proton therapy.Approach.35 planning computed tomography (CT) images of prostate cancer patients were collected for Monte Carlo (MC) dose calculation under a perpendicular 1.5 T magnetic field. Proton pencil beams (PB) at three energies (150, 175, and 200 MeV) were simulated (7560 PBs at each energy). A 3D relative stopping power cuboid covering the extent of the PB dose was extracted and given as input to the LSTM model, yielding a 3D predicted PB dose. Three single-energy (SE) LSTM models were trained separately on the corresponding 150/175/200 MeV datasets and a multi-energy (ME) LSTM model with an energy embedding layer was trained on either the combined dataset with three energies or a continuous energy (CE) dataset with 1 MeV steps ranging from 125 to 200 MeV. For each model, training and validation involved 25 patients and 10 patients were for testing. Two single field uniform dose prostate treatment plans were optimized and recalculated with MC and the CE model.Results.Test results of all PBs from the three SE models showed a mean gamma passing rate (2%/2 mm, 10% dose cutoff) above 99.9% with an average center-of-mass (COM) discrepancy below 0.4 mm between predicted and simulated trajectories. The ME model showed a mean gamma passing rate exceeding 99.8% and a COM discrepancy of less than 0.5 mm at the three energies. Treatment plan recalculation by the CE model yielded gamma passing rates of 99.6% and 97.9%. The inference time of the models was 9-10 ms per PB.Significance.LSTM models for proton dose calculation in a magnetic field were developed and showed promising accuracy and efficiency for prostate cancer patients.

Senolytics To slOw Progression of Sepsis (STOP-Sepsis) in elderly patients: Study protocol for a multicenter, randomized, adaptive allocation clinical trial

BackgroundSenescent immune cells exhibit altered gene expression and resistance to apoptosis. The prevalence of these cells increases with age and emerging data implicate senescence-associated maladaptive signaling as a potential contributor to sepsis and septic shock. The senolytic drug fisetin promotes clearance of senescent cells and is hypothesized to mitigate septic responses to infection.MethodsWe are conducting a multi-center, randomized, double-blinded, adaptive allocation phase 2 clinical trial to assess the efficacy of the senolytic drug fisetin in preventing clinical deterioration of elderly patients diagnosed with sepsis. We intend to enroll and randomize 220 elderly patients (age > 65) with the clinical diagnosis of sepsis to receive either fisetin as a single oral dose of 20 mg/kg, fisetin in two oral doses of 20 mg/kg each spaced 1 day apart, or placebo. The primary outcome will be changed in the composite of cardiovascular, respiratory, and renal sequential organ failure assessment scores at 7 days from enrollment. Secondary outcomes include quantification of senescent CD3 + cells at 7 days, and 28-day assessments of organ failure-free days, days in an intensive care unit, and all-cause mortality.DiscussionThis multi-center, randomized, double-blinded trial will assess the efficacy of fisetin in preventing clinical deterioration in elderly patients with sepsis and measure the effects of this drug on the prevalence of senescent immune cells. We intend that the results of this phase 2 trial will inform the design of a larger phase 3 study.Trial registrationThis trial is registered to ClinicalTrials.gov under identifier NCT05758246, first posted on March 7, 2023.

The proliferation and viability of human periodontal ligament stem cells cultured on polymeric scaffolds can be improved by low-level laser irradiation.

This study assessed the impact of low-level laser irradiation on the viability and proliferation of human periodontal ligament stem cells (hPDLSCs) cultivated on polylactic acid (PLA) scaffolds. hPDLSCs were obtained, characterized, and grown on the surface of PLA films produced via the solvent casting technique. The study involved two groups: the control group, which was not exposed to radiation, and the laser group, which was irradiated with a diode laser (InGaAIP) with a power of 30 mW, a wavelength of 660 nm, and a single dose of 1 J/cm² emitted continuously. Cell viability was assessed 24 and 48 hours after irradiation using the Alamar blue and Live/Dead assays. Flow cytometry was used to assess cell cycle events, and scanning electron microscopy (SEM) was used to evaluate the interaction between cells and the biomaterial. The results revealed a statistically significant increase in cell metabolic activity in the laser group compared with the control group at 24 hours (p <0.05) and 48 hours (p <0.001), as indicated by the Alamar blue assay. The Live/Dead assay also revealed a greater density of viable cells in the laser group. The cell cycle analysis revealed a significant increase in the number of cells in the proliferative phase (G2/M) in the laser group compared with the control group (p <0.001). The SEM images demonstrated that the irradiated group had a greater concentration of cells while still maintaining their cell shape and projections. This study demonstrated that photobiomodulation can increase the viability and proliferation of periodontal stem cells cultured on PLA scaffolds, suggesting the potential of this protocol for future studies on periodontal tissue engineering.

A surface lipoprotein on Pasteurella multocida binds complement factor I to promote immune evasion.

Pasteurella multocida is the leading cause of wound infections in humans following animals' bites or scratches. This bacterium is also commonly found in the respiratory tract of many mammals and can cause serious diseases resulting in the brutal rapid death of infected animals, especially cattle. To prevent these infections in cattle, a subunit-based vaccine utilizing the surface lipoprotein PmSLP was developed and showed remarkable protection with a single dose administration. Here, we report that PmSLP binds host complement factor I (FI) and facilitates cleavage of complement components C3b and C4b independently of any cofactors (e.g FH, C4BP), thereby allowing the pathogen to evade host defence. Cryo-EM structure of PmSLP bound to FI reveals that PmSLP stimulates FI enzymatic activity by stabilizing the catalytic domain. This is the first time that a bacterial protein has been shown to directly activate FI independent of complement cofactors and target all arms of the complement cascade.

What is the risk of meningitis, utilising a single agent, single dose perioperative antibiotic following endonasal endoscopic repair of a CSF leak?

What is the risk of meningitis, utilising a single agent, single dose perioperative antibiotic following endonasal endoscopic repair of a CSF leak?

Npbwr1 signaling mediates fast antidepressant action.

Chronic stress is a major risk factor for depression, a leading cause of disability and suicide. Because current antidepressants work slowly, have common side effects, and are only effective in a minority of patients, there is an unmet need to identify the underlying molecular mechanisms. Here, we identify the receptor for neuropeptides B and W, Npbwr1, as a key regulator of depressive-like symptoms. Npbwr1 is increased in the nucleus accumbens of chronically stressed mice and postmortem in patients diagnosed with depression. Using viral-mediated gene transfer, we demonstrate a causal link between Npbwr1, dendritic spine morphology, the biomarker Bdnf, and depressive-like behaviors. Importantly, microinjection of the synthetic antagonist of Npbwr1, CYM50769, rapidly ameliorates depressive-like behavioral symptoms and alters Bdnf levels. CYM50769 is selective, well tolerated, and shows effects up to 7 days after administration of a single dose. In summary, these findings advance our understanding of mood and chronic stress and warrant further investigation of CYM50769 as a potential fast-acting antidepressant.

Effect of Gonadotropin-Releasing Hormone Treatment on Superovulation Response and Embryo Recovery in Holstein Heifers: A Field Trial at Zagros Milk and Meat Company, Iran

Background: Superovulation is a crucial component of assisted reproductive technology. Inducing superovulation with Gonadotropin-releasing hormone (GnRH) can lead to ovarian hyperstimulation, potentially affecting reproductive outcomes. Objectives: This study aimed to examine the effects of GnRH treatment on superovulation response and embryo recovery in Holstein heifers. Methods: Twenty-one Holstein heifers (age: 135.15 months; weight: 361.05 kg) were selected based on their general health status and ovarian function. All heifers received two consecutive doses of prostaglandin F2α and underwent superovulation. The heifers were inseminated twice: Once at the onset of standing estrus and again 12 hours later. In the treatment group (13 heifers), a single dose of GnRH was administered simultaneously with the second insemination. The superovulation response was evaluated based on the number of corpus luteum (CL), unovulated follicles (UoF), total recovered embryos/ova, and the number of transferable embryos, using logistic regression with the GENMOD procedure in SAS. Results: The mean number of CL was not significantly greater in the control group (13.6) compared to the GnRH group (11.4). The average number of UoF was similar between the two groups (P = 0.1853). However, the control group had a significantly higher average total number of recovered embryos/ova (7.7) compared to the GnRH group (2.1). Additionally, the control group produced more transferable embryos, with an average of 2.5, while the GnRH group averaged 0.7 (P &lt; 0.0062). Conclusions: Gonadotropin-releasing hormone likely deactivated the oviduct by disrupting the balance of estradiol and estrogen, leading to a reduction in both the total number of embryos and the number of transferable embryos in heifers.

Hand dynamometer and clinical tests to evaluate the recovery of neuromuscular conductance in atracurium versus rocuronium in patients undergoing laparoscopic surgery

Background. Postoperative muscle weakness is not unusual and may be related to postoperative complications in patients after general anesthesia. However, the clinical practice of neuromuscular conductance monitoring is uncommon among anesthesiologists.The objective was to evaluate the rate of neuromuscular recovery after atracurium and rocuronium and to determine the numerical value of grip strength using a hand dynamometer, indicating the safety of transferring a patient from the postoperative ward.study design. A prospective, observational, clinical comparison study.Materials and Methods. Upon proper authorization and approval from the local ethics committee, patients referred for laparoscopic surgery, 120 patients of the American Society of Anesthesiology (ASA) physical status I &amp;II between ages 20–49 years were randomly assigned into 2 groups of 60 each. Group I received a single atracurium dose of 0.5mg/kg of ideal body weight and Group II patients received a single rocuronium dose of 0.6mg/kg of ideal body weight. Parameters such as modified Alderete score (MAS), grip strength, and sustained head and leg lift for five seconds were compared in both groups 50 minutes after giving the reversal agent at 10-minute intervals.Results. Postoperative muscle recovery (grip strength) was faster in the atracurium group than the rocuronium group, with a p-value of 0.042 at 20 minutes, and 0.0000 for 30, 40, and 50 minutes after giving the reversal agent. The time to obtain a modified Alderete score (MAS) &gt; 8 scores was statistically insignificant with a p-value of 0.335. Positive clinical test for sustained head lift for 5 seconds was statistically insignificant within a majority of the time, except in the 20 minutes, most of the cases in the atracurium group were able to sustain head elevation for 5 seconds with a p-value of 0.021. In the 10 &amp;20 minutes, most cases in the atracurium group could sustain leg elevation for 5 seconds with a p-value of 0.015 and 0.014 respectively. However, most cases in both groups could sustain head and leg elevation for 5 seconds in the 30 minutes after giving a reversal agent.Conclusion. Compared to rocuronium, atracurium has been associated with faster muscle recovery after a single tracheal intubation dose for a short surgery. This was determined by utilizing an electronic hand dynamometer to measure grip strength. 42% grip strength from baseline might be applicable for safe discharge from the recovery room. A hand dynamometer assessment revealed more post-operative muscle weakening than a clinical evaluation.

Anogenital Lesions in Children: A Critical Alert for Pediatricians.

A 7-y-old girl presented to the pediatric department with a two-week history of a skin lesion in the anogenital region. She appeared well-nourished, quiet, afebrile; vitals and her systemic examination was normal. Examination revealed a greyish white wart-like perianal lesion, unusual for her age. Further history revealed the child had become withdrawn, avoiding play recently, and had oral and vaginal ulcers a month earlier without treatment. These findings raised suspicion of sexual abuse. Investigations confirmed positive VDRL (1:64 titres), positive TPHA, and negative results for her parents' TPHA and HIV. A medicolegal case was registered, involving child welfare services and police. A psychiatrist diagnosed post-traumatic stress disorder and recommended counselling. Treatment with a single dose of intramuscular Benzathine penicillin led to improvement, with VDRL titres decreasing to 1:8 and complete resolution of the lesion after 3 months. Pediatricians are pivotal in identifying and managing child sexual abuse cases promptly.

Gardenia jasminoides extract mitigates acetaminophen-induced liver damage in mice

BackgroundAcetaminophen (APAP)-induced hepatotoxicity is a potentially life-threatening condition. Gardenia jasminoides fruit extract (GJE), which contains geniposide (Gen) as its major active constituent, possesses anti-inflammatory and antioxidant properties and may help address the underlying pathogenesis of APAP-induced hepatotoxicity. This study aimed to evaluate the effects of GJE in a mouse model of APAP-induced hepatotoxicity.MethodsTwenty-four male ICR mice were divided into 4 groups (n = 6/group): [1] Control group, mice were given distilled water; [2] APAP group, mice received a single dose of 600 mg/kg APAP; [3] APAP + low-dose GJE group, mice received APAP followed 30 min later by 2 doses of low-dose GJE (0.44 g/kg/dose, containing Gen 100 mg/kg/dose) 8 h apart; [4] APAP + high-dose GJE group, mice received APAP followed by 2 doses of high-dose GJE (0.88 g/kg/dose, containing Gen 200 mg/kg/dose). All mice were euthanized 24 h after APAP administration. Liver tissue was used for histological examination and to measure glutathione (GSH) and malondialdehyde (MDA) levels. Serum was used to determine levels of ALT and inflammatory cytokines (tumor necrosis factor- α (TNF-α) and interleukin-6 (IL-6)).ResultsLiver histopathology showed moderate to severe hepatic necroinflammation in the APAP group, whereas only mild necroinflammation was observed in both treatment groups. Serum ALT levels were significantly elevated in the APAP group compared to the control group but were significantly reduced after low- and high-dose GJE treatment. Serum TNF- α levels were significantly higher in the APAP group than in the control group and were significantly lower after high-dose GJE treatment (135.5 ± 477.2 vs. 35.5 ± 25.8 vs. 74.7 ± 47.2 vs. 41.4 ± 50.8 pg/mL, respectively). Serum IL-6 followed a similar pattern. Hepatic GSH levels were significantly lower in the APAP group compared to the control group but significantly increased after both low- and high-dose GJE treatment (19.9 ± 4.5 vs. 81.5 ± 12.4 vs. 71.4 ± 7.8 vs. 82.6 ± 6.6 nmol/mg protein, respectively). Conversely, hepatic MDA levels were significantly elevated in the APAP group compared with the control group but significantly decreased after high-dose GJE treatment (108.6 ± 201.5 vs. 40.5 ± 18.0 vs. 40.5 ± 16.8 nmol/mg protein, respectively).ConclusionsTreatment with G. jasminoides fruit extract can alleviate APAP-induced hepatotoxicity, likely through its anti-inflammatory and antioxidant properties.