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Hepatocellular carcinoma (HCC) has been known as the second common leading cancer worldwide, as it responds poorly to both chemotherapy and medication. Triptolide (TP), a diterpenoid triepoxide, is a promising treatment agent for its effective anticancer effect on multiple cancers including HCC. However, its clinical application has been limited owing to its severe systemic toxicities, low solubility, and fast elimination in the body. Therefore, to overcome the above obstacles, photo-activatable liposomes (LP) integrated with both photosensitizer Ce6 and chemotherapeutic drug TP (TP/Ce6-LP) was designed in the pursuit of controlled drug release and synergetic photodynamic therapy in HCC therapy. The TP encapsulated in liposomes accumulated to the tumor site due to the enhanced permeability and retention (EPR) effect. Under laser irradiation, the photosensitizer Ce6 generated reactive oxygen species (ROS) and further oxidized the unsaturated phospholipids. In this way, the liposomes were destroyed to release TP. TP/Ce6-LP with NIR laser irradiation (TP/Ce6-LP+L) showed the best anti-tumor effect both in vitro and in vivo on a patient derived tumor xenograft of HCC (PDXHCC). TP/Ce6-LP significantly reduced the side effects of TP. Furthermore, TP/Ce6-LP+L induced apoptosis through a caspase-3/PARP signaling pathway. Overall, TP/Ce6-LP+L is a novel potential treatment option in halting HCC progression with attenuated toxicity., Graphical abstract Photo-activatable liposomes incorporating Ce6 and triptolide (TP/Ce6-LP) for hepatocellular carcinoma (HCC) therapy were designed. Photodynamic therapy (PDT) and TP possibly induced cell apoptosis via a caspase-3/PARP signaling pathway in PDXHCC model.Image 1

A 47-year-old woman presented with atypical chest pain and a troponin level of 30.15 ng/dl. A detailed diagnostic work-up did not detect an acute myocardial infarction but revealed the presence of heterophile antibodies. Laboratory values need to be interpreted in the context of the clinical picture when test results do not correspond to clinical findings. (Level of Difficulty: Beginner.), Graphical abstract, A 47-year-old woman presented with atypical chest pain and a troponin level of 30.15 ng/dl. A detailed diagnostic work-up did not detect an acute…

A young man presented with syncope. He was diagnosed with triglyceride deposit cardiomyovasculopathy and skeletal myopathy secondary to adipose triglyceride lipase (ATGL) deficiency. Despite optimal medical therapy, he required heart transplantation to treat his heart failure. Five years post-transplant, the graft function was normal with no evidence of triglyceride deposits. (Level of Difficulty: Intermediate.), Graphical abstract, A young man presented with syncope. He was diagnosed with triglyceride deposit cardiomyovasculopathy and skeletal myopathy secondary to adipose…

Graphical abstract, Highlights • Ursolic acid was administered at a dose of 100, 300 or 1000 mg/kg/day. • No Ursolic acid related effects were found after administrating orally for 90 days. • The no observed adverse effect level is likely to be higher than 1000 mg/kg/day., Background Ursolic acid (UA) has been used in alternative medicine for decades, and there has been a great interest in its medicinal properties. Despite this increased interest, a detailed long-term toxicity study has not been performed. The objective of this study was to determine the long-term toxic effect of UA on clinical chemistry, haematology, coagulation, pathology/morphology, behaviour and motor skills in rats. Methods A solution was made by dissolving UA in a mixture of 0.1% Tween 80 and 0.5% hydroxypropyl methylcellulose in Milli-Q Water. The control group received the vehicle, and the test groups received a dose up to 1000 mg/kg/day via oral gavage. The solution was administered to both male and female (Han-Wistar) rats for 90 consecutive days. Results UA did not cause any deaths, abnormal body weights or abnormal pathology at all test doses. In addition to that, no toxicological changes were observed in behaviour, neurotoxicity, coagulation, haematology or clinical chemistry that are related to the administration of UA. Conclusion This study indicates that oral dosing of UA for 90 consecutive days does not lead to toxic effects at any of the doses. Therefore, the NOAEL for UA is likely to be higher than 1000 mg/kg/day.

Coronavirus disease 2019 (COVID-19) is associated with considerable morbidity and mortality. The number of confirmed cases of infection with SARS-CoV-2, the virus causing COVID-19 continues to escalate with over 70 million confirmed cases and over 1.6 million confirmed deaths. Severe-to-critical COVID-19 is associated with a dysregulated host immune response to the virus, which is thought to lead to pathogenic immune dysregulation and end-organ damage. Presently few effective treatment options are available to treat COVID-19. Leronlimab is a humanized IgG4, kappa monoclonal antibody that blocks C–C chemokine receptor type 5 (CCR5). It has been shown that in patients with severe COVID-19 treatment with leronlimab reduces elevated plasma IL-6 and chemokine ligand 5 (CCL5), and normalized CD4/CD8 ratios. We administered leronlimab to 4 critically ill COVID-19 patients in intensive care. All 4 of these patients improved clinically as measured by vasopressor support, and discontinuation of hemodialysis and mechanical ventilation. Following administration of leronlimab there was a statistically significant decrease in IL-6 observed in patient A (p=0.034) from day 0–7 and patient D (p=0.027) from day 0–14. This corresponds to restoration of the immune function as measured by CD4+/CD8+ T cell ratio. Although two of the patients went on to survive the other two subsequently died of surgical complications after an initial recovery from SARS-CoV-2 infection., Highlights • Leronlimab is a monoclonal antibody in clinical trials to treat the cytokine storm. • Critically ill patients received leronlimab through compassionate use and had remarkable recoveries measured objectively. • The CCR5 receptor is important in recruiting inflammatory cells mainly T cells and macrophages. • Leronlimab disrupted this signal and may have been responsible for restoration of the immune system, improved survival and decrease in IL-6.

Hypervirulent Klebsiella pneumoniae (hvKP) with a high mucus phenotype, can cause liver abscess and extrahepatic invasive infection. The morbidity of hvKP infections has increased recently. Here we describe a case report of septicemia caused by hvKP due to the term septic arthritis of right knee joint in a 29-year-old male. The patient was persistent fever with a peak temperature at 40.6 °C. However, based on the drug sensitivity, the treatment failed frequently. The patient did not improve clinically on susceptible monotherapy antimicrobial. Combination therapy with meropenem and rifampicin (RFP) lead to clinical improvement and discharge.

Introduction Mitochondrial fatty acid oxidation disorders (FAODs) are a heterogeneous group of hereditary autosomal recessive diseases included in newborn screening (NBS) program in Italy. The aim of this study was to analyse FAODs cases, identified either clinically or by NBS,for clinical and genetic characterization and to evaluate a five years' experience of NBS, in the attempt to figure out the complexity of genotype-phenotype correlation and to confirm the clinical impact of NBS in our centre experience. Materials and methods We analysed FAODs patients diagnosed either by NBS or clinically, followed since February 2014 to April 2019 at the Regional Screening Centre and Inherited Metabolic Diseases Unit of Verona. Diagnosis was confirmed by plasma acylcarnitines, urinary organic acids, enzymatic and genetic testing. For not clear genotypes due to the presence of variants of uncertain significance, in silico predictive tools have been used as well as enzymatic activity assays. Patients underwent clinical, nutritional and biochemical follow up. Results We diagnosed 30 patients with FAODs. 20 by NBS: 3 CUD, 6 SCADD, 5 MCADD, 4 VLCADD, 2 MADD. Overall incidence of FAODs diagnosed by NBS was 1:4316 newborns. No one reported complications during the follow up period. 10 patients were diagnosed clinically: 2 CUD, 2 CPT2D, 1 VLCADD, 5 MADD. Mean age at diagnosis was 29.3 years. Within this group, complications or symptoms were reported at diagnosis, but not during follow-up. 12 mutations not previously reported in literature were found, all predicted as pathogenic or likely pathogenic. Discussion and conclusions Our study highlighted the great phenotypic variability and molecular heterogeneity of FAODs and confirmed the importance of a tailored follow up and treatment. Despite the short duration of follow up, early identification by NBS prevented diseases related complications and resulted in normal growth and psycho-motor development as well., Highlights • Early identification by newborn screening prevents disease related complications. • Newborn screening is changing prevalence clinical and molecular heterogeneity of FAODs. • Genotype-phenotype correlation helps to achieve personalized follow-up and treatment. • Enzymatic assay may be pivotal in predicting phenotype and symptoms severity. • Diagnosis on clinical grounds is anyway important to change disease course.

Mitochondrial trifunctional protein (TFP) deficiency is a rare inherited metabolic disorder caused by defects in fatty acid β-oxidation (FAO) of long-chain fatty acids, leading to impaired energy production. Fasting avoidance, fatty acid-restricted diets, and supplementation with medium-chain triglycerides are recommended as a treatment, but there are no pharmaceutical treatments available with strong evidence of efficacy. Bezafibrate, which enhances the transcription of FAO enzymes, is a promising therapeutic option for FAO disorders (FAODs). The effectiveness of bezafibrate for FAODs has been reported in some clinical trials, but few clinical studies have investigated its in vivo efficacy toward TFP deficiency. Herein, we describe two Japanese patients with TFP deficiency. Patient 1 presented with recurrent myalgia since the age of 5 years. Laboratory findings showed increased serum levels of long-chain fatty acids and reduced expression of TFPα and TFPβ in his skin fibroblasts. Based on these findings, he was diagnosed with the myopathic type of TFP deficiency. Patient 2 suddenly exhibited cardiopulmonary arrest one day after birth. Elevated levels of creatine kinase and long-chain acylcarnitines were observed. Genetic analysis identified compound heterozygous variants in HADHB (c.1175C>T/c.1364T>G). He was diagnosed with the lethal type of TFP deficiency. Although both patients were treated with dietary therapy and l -carnitine supplementation, they experienced frequent myopathic attacks associated with respiratory infections and exercise. After the initiation of bezafibrate, their myopathic manifestations were markedly reduced, leading to an improvement in quality of life without any side effects. Our clinical findings indicate that bezafibrate combined with other treatments such as dietary therapy may be effective in improving myopathic manifestations in TFP deficiency.

Nemaline myopathy is a heterogeneous disorder of skeletal muscle, and histologically characterized by the presence of nemaline bodies in muscle fibers. Patients with typical congenital form of nemaline myopathy initially present with proximal but later also distal muscle weakness, mostly involving facial and respiratory muscle. Cardiac involvement has been rarely observed especially in nebulin-related nemaline myopathy and there have been only two reports about nebulin-related nemaline myopathy patients with cardiac involvement. We present here the case of a 65-year-old woman manifesting slowly progressive distal myopathy with respiratory and heart failure. She harbored two variants in the nebulin gene, c.20131C > T (p.Arg6711Trp) and c.674C > T (p.Pro225Leu), and one of them, c.674C > T, was a novel variant. In this report, we discuss the pathogenicity of the novel variant and its association with clinical phenotypes including cardiac involvement., Highlights • A NEB-related nemaline myopathy patient developed distal myopathy, respiratory and heart failure. • Two variants in NEB were noted and one of them was a novel variant. • The novel variant might be associated with the clinical symptoms including heart failure.

Dermatomyositis, one of the subtypes of idiopathic inflammatory myopathies, presents with a prominent skin rash in up to 80% of patients with or without proximal muscle weakness.1 Dermatomyositis treatment can be very challenging. In particular, cutaneous disease is usually refractory and impacts the quality of life in patients with dermatomyositis.2 Systemic steroids are still considered first-line treatment; however, their chronic use should be limited.3 Many steroid-sparing agents have been used with variable outcomes.3 Currently used immunomodulators include antimalarials, azathioprine, methotrexate, mycophenolate mofetil, intravenous immunoglobulin, rituximab, and oral calcineurin inhibitors.4Apremilast is a phosphodiesterase-4 (PDE-4) inhibitor recently used in the treatment of several inflammatory diseases including psoriasis, psoriatic arthritis, and Behcet disease.5, 6 Apremilast was not previously reported in the treatment of patients with dermatomyositis. We report the efficacy of off-label use of apremilast in the treatment of 3 patients with recalcitrant dermatomyositis.

Objective Enzyme replacement therapy (ERT), the only approved therapy for infantile-onset Pompe disease (IOPD), had heterogeneous clinical effects due to factors such as severity, age at first treatment, dosage, and dosing regimens. We report the clinical and biochemical outcomes of a cohort of IOPD patients identified through newborn screening, and evaluating the dosage effect. Study design A retrospective observational study was designed to describe the long-term clinical and biochemical outcomes of a uniform cohort of IOPD patients who have been treated with high-dosage of ERT. Results Twenty-eight patients received alglucosidase alpha at either the labeled dosage followed by a high dosage (n = 23) or a high dosage exclusively (n = 5). At a median age of 8.3 years (0.8–17.3), 15 patients were walkers, 8 were weak walkers, and 5 were nonwalkers. The three groups exhibited a significant difference in the age of gross motor decline (p, Highlights • CK and uGlc4 levels were correlated with favorable response to ERT in IOPD patients. • Once these biomarkers rose, they never returned to normal. • High-dose ERT instituted immediately at newborn screening seems to give the best outcome.

Reperfusion of ischemic myocardium is crucial for salvaging myocardial cells from ischemic cell death. However, reperfusion itself induces various deleterious effects on the ischemic myocardium. These effects, known collectively as reperfusion injury, comprise stunned myocardium, reperfusion-induced arrhythmia, microvascular reperfusion injury, and lethal reperfusion injury. No approach has proven successful in preventing any of these injuries in the clinical setting. My colleagues and I recently proposed a new postconditioning protocol, postconditioning with lactate-enriched blood (PCLeB), for the prevention of reperfusion injury. This new approach consists of intermittent reperfusion and timely coronary injections of lactated Ringer's solution, aiming to achieve controlled reperfusion with cellular oxygenation and minimal lactate washout from the cells. This approach appeared to be effective in preventing all types of reperfusion injury in patients with ST-segment elevation myocardial infarction (STEMI), and we have already reported excellent in-hospital outcomes of patients with STEMI treated using PCLeB. In this review article, I discuss a possible mechanism of reperfusion injury, which we believe to be valid and which we targeted using this new approach, and I report how the approach worked in preventing each type of reperfusion injury., Highlights • Postconditioning with lactate-enriched blood (PCLeB) targets hypercontracture. • PCLeB employs lactate as an inherent contractile activity blocker. • PCLeB appears to be effective in preventing all four types of reperfusion injury. • PCLeB may also suppress early inflammation after myocardial infarction. • PCLeB may improve outcomes of patients with acute myocardial infarction.

Background Early initiation of enzyme replacement therapy (ERT) with recombinant human acid alpha-glucosidase is an effective treatment for patients with infantile-onset Pompe disease (IOPD) but cannot prevent a slow progression of myopathy. Albuterol has been shown to be helpful in adult patients with Pompe disease, and therefore, we administered an open-label adjunctive therapy with albuterol in IOPD patients undergoing ERT. Methods Fourteen patients, aged 2 to 12 years, were enrolled in this study; all of them had a disease onset before 12 months of life, and 13 of them were ambulatory because of early initiation of ERT. All patients received albuterol (also referred to as salbutamol) 12 mg daily for 26 weeks. The outcome measurements included a 6-minute walk test, four-stair climb test (SCT), the standing/walking/running/jumping domains of Gross Motor Function Measure-88, speech quality, serum creatine kinase, and urinary glucose tetrasaccharide. Outcome and safety measurements were evaluated at baseline, and at 1, 3, and 6 months (26 weeks) after entering the trial. Results After a period of 26 weeks, among the 12 patients who were able to complete the SCT, the median time needed decreased by 22% (p = 0.034). Other parameters inconsistently improved in a variety of individuals. Eleven adverse events, including nausea, urinary frequency, and tachycardia, were potentially related to the study drug, but all were mild and disappeared after a brief drug withdrawal. One patient was actively withdrawn from the trial because of poor compliance. Conclusions The results of our study suggest that albuterol showed a good safety profile as an adjunctive treatment in our IOPD cohort, although the benefits are limited., Highlights • Albuterol may benefit some children with infantile-onset Pompe disease. • Albuterol is safe as an adjunctive treatment to enzyme replacement therapy in children with Pompe disease. • Adverse events associated with albuterol are usually manageable.

Terbinafine is a common antifungal medication taken orally to treat onychomycosis. This drug is considered a first-line agent for this disease and has a better cure rate than other antifungal drugs.1 Terbinafine functions as an allylamine agent, which inhibits squalene epoxidase, a key enzyme of ergosterol biosynthesis. The increase in concentration of extracellular squalene is thought to result in toxic levels that kill fungal cells.2 Side effects of terbinafine include gastrointestinal disturbances, dysgeusia, headache, and rash.1 Hepatotoxicity is a less frequent adverse effect of terbinafine that has an incidence of 2.5 cases/100,000.3 Because of the potential for this feared adverse event, some physicians have chosen to monitor liver enzymes during the course of terbinafine treatment. Rhabdomyolysis is another rare side effect that has been associated with terbinafine use. Many occurrences have been reported by physicians in adverse drug reaction reporting databases; however, there have been few published cases of this association.4, 5 Because rhabdomyolysis is not a well-known side effect of terbinafine, patients might not readily discuss symptoms of weakness, myalgia, or darkened urine. Elevated liver enzymes found on routine monitoring might also mistakenly be attributed to terbinafine-induced hepatotoxicity. As a result, it is important to have rhabdomyolysis as a differential diagnosis when monitoring patients on terbinafine.

Polymyositis (PM) and dermatomyositis (DM) are different disease subtypes of idiopathic inflammatory myopathies (IIMs). The main clinical features of PM and DM include progressive symmetric, predominantly proximal muscle weakness. Laboratory findings include elevated creatine kinase (CK), autoantibodies in serum, and inflammatory infiltrates in muscle biopsy. Dermatomyositis can also involve a characteristic skin rash. Both polymyositis and dermatomyositis can present with extramuscular involvement. The causative factor is agnogenic activation of immune system, leading to immunologic attacks on muscle fibers and endomysial capillaries. The treatment of choice is immunosuppression. PM and DM can be distinguished from other IIMs and myopathies by thorough history, physical examinations and laboratory evaluation and adherence to specific and up-to-date diagnosis criteria and classification standards. Treatment is based on correct diagnosis of these conditions., High lights • Challenges of diagnosis and management influences the clinical research and practice of Polymyositis and dermatomyositis. • Diagnostic criteria have been updated and novel therapies have been developed in PM/DM. • Pathogenesis investigation and diagnosis precision improvement may help to guide future treatment strategies.

Very long-chain acyl-coenzyme A dehydrogenase deficiency (VLCADD, OMIM 201475) is a congenital fatty acid oxidation disorder. Individuals with VLCADD should avoid catabolic states, including strenuous exercise and long-term fasting; however, such conditions are required when undergoing surgery. The perioperative management of VLCADD in infants has rarely been reported and details regarding the transition of serum biomarkers reflecting catabolic status have not been disclosed. Herein, we present the perioperative clinical and biological data of cryptorchidism in a 1.5-year-old boy with VLCADD. The patient was diagnosed through newborn screening and his clinical course was very stable. Genetic testing of ACADVL revealed compound heterozygous variants c.506 T > C (p.Met169Thr) and c.606-609delC (p.L216*). The enzyme activity of the patient with VLCAD was only 20% compared to that of healthy control. Left orchiopexy for the pediatric cryptorchidism was planned and performed at 1 and a half year of age. Induction anesthesia involved thiopental, fentanyl and rocuronium. The glucose infusion rate was maintained above 6.6 mg/kg/min starting the day before surgery until the operation was completed. Anesthesia was maintained with sevoflurane at approximately 2%. The serum concentration of tetradecenoylcarnitine were stable during the operation, ranging between 0.08 and 0.19 μM (cutoff, Highlights • Catabolic biomarker status details during surgery in infants with VLCADD is lacking. • We performed uneventful surgical intervention in a 1.5-year-old patient with VLCADD. • Serum levels of tetradecenoyl carnitine remained stable during the operation. • Serum biomarkers creatine kinase, 3-hydroxybutyrate, and free fatty acid remained similarly unchanged. • These findings will be beneficial in the management of VLCADD.