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BACKGROUND: Central histamine (HA) signaling modulates diverse cortical and subcortical circuits throughout the brain, including the nucleus accumbens (NAc). The NAc, a key striatal subregion directing reward-related behavior, expresses diverse HA receptor subtypes that elicit cellular and synaptic plasticity. However, the neuromodulatory capacity of HA within interneuron microcircuits in the NAc remains unknown. METHODS: We combined electrophysiology, pharmacology, voltammetry, and optogenetics in male transgenic reporter mice to determine how HA influences microcircuit motifs controlled by parvalbumin-expressing fast-spiking interneurons (PV-INs) and tonically active cholinergic interneurons (CINs) in the NAc shell. RESULTS: HA enhanced CIN output through an H(2) receptor (H(2)R)-dependent effector pathway requiring Ca(2+)-activated small-conductance K(1) channels, with a small but discernible contribution from H(1)Rs and synaptic H(3)Rs. While PV-IN excitability was unaffected by HA, presynaptic H(3)Rs decreased feedforward drive onto PV-INs via AC-cAMP-PKA (adenylyl cyclase-cyclic adenosine monophosphate-protein kinase A) signaling. H(3)R-dependent plasticity was differentially expressed at mediodorsal thalamus and prefrontal cortex synapses onto PV-INs, with mediodorsal thalamus synapses undergoing HA-induced long-term depression. These effects triggered downstream shifts in PV-IN- and CIN-controlled microcircuits, including near-complete collapse of mediodorsal thalamus-evoked feedforward inhibition and increased mesoaccumbens dopamine release. CONCLUSIONS: HA targets H-|R, H(2)R, and H(3)Rs in the NAc shell to engage synapse- and cell type-specific mechanisms that bidirectionally regulate PV-IN and CIN microcircuit activity. These findings extend the current conceptual framework of HA signaling and offer critical insight into the modulatory potential of HA in the brain.

The neuraminidase (NA) of influenza A and B viruses plays a distinct role in viral replication and has a highly conserved catalytic site. Numerous sialic (neuraminic) acid analogs that competitively bind to the NA active site and potently inhibit enzyme activity have been synthesized and tested. Four NA inhibitors are now licensed in various parts of the world (zanamivir, oseltamivir, peramivir, and laninamivir) to treat influenza A and B infections. NA changes, naturally occurring or acquired under selective pressure, have been shown to reduce drug binding, thereby affecting the effectiveness of NA inhibitors. Drug resistance and other drawbacks have prompted the search for the next-generation NA-targeting therapeutics. One of the promising approaches is the identification of monoclonal antibodies (mAbs) targeting the conserved NA epitopes. Anti-NA mAbs demonstrate Fab-based antiviral activity supplemented with Fc-mediated immune effector functions. Antiviral Fc-conjugates offer another cutting-edge strategy that is based on a multimodal mechanism of action. These novel antiviral agents are composed of a small-molecule NA inhibitor and an Fc-region that simultaneously engages the immune system. The significant advancements made in recent years further support the value of NA as an attractive target for the antiviral development.

The impact of antibiotics on growth, cocoon production was assessed in addition to isolation and characterization of bacteria associated with silkworm gut of infected larvae. Larval rearing was maintained at recommended conditions of temperature and humidity. Silkworm larvae showing abnormal symptoms were collected from the control group and dissected for gut collection. Bacteria were isolated from the gut content by spreading on agar plates and incubated at 37 °C for 48 hrs. Bacterial identification and phylogenetic analysis were carried out by 16S rRNA gene sequencing. The isolated bacteria were subjected to antimicrobial susceptibility test (disc diffusion methods) by using Penicillin (10 µg/mL), Tetracycline (30 µg/mL), Amoxicillin (25 µg/mL), Ampicillin (10 µg/mL), and Erythromycin (15 µg/mL). All isolated strains showed positive results for the catalase test. We isolated and identified bacterial strains (n = 06) from the gut of healthy and diseased silkworm larvae. Based on the 16S rRNA gene sequence, isolated bacteria showed close relation with Serratia, Bacillus, and Pseudomonas spp. Notably, 83.3% of strains were resistant to Penicillin, Tetracycline, Amoxicillin, Ampicillin, and Erythromycin but 16.6% showed antibiotic susceptibility to the above-mentioned commonly used antibiotics. Silkworm larvae fed on penicillin-treated leaves showed significant improvement in larval weight, larval length, and cocoon production. Significantly higher larval weight (6.88g), larval length (5.84cm), and cocoon weight (1.33g) were recorded for larvae fed on leaves treated with penicillin as compared to other antibiotics. Isolated bacterial strains showed close relation with Serratia spp., Bacillus spp. and Pseudomonas spp.

Myasthenia gravis (MG) is an autoimmune condition affecting the neuromuscular junction characterised by weakness and fatiguability, carrying a high morbidity if treatment is delayed. A clear association with thymoma has led to management with thymectomy as a common practice, but MG presenting post-thymectomy has rarely been reported. We present a case of an 82- year-old woman developing fatigue, ptosis and dysarthria 3 months after thymectomy. After a clinical diagnosis of MG was made, she responded well to prompt treatment with prednisolone and pyridostigmine. Her anti-acetylcholine receptor antibody (anti-AChR) subsequently came back positive. Our systematic review reveals that post-thymectomy MG can be categorised as early-onset or late-onset form with differing aetiology, and demonstrated correlation between preoperative anti-AChR titres and post-thymectomy MG. The postulated mechanisms for post-thymectomy MG centre around long-lasting peripheral autoantibodies. Clinicians should actively look for MG symptoms in thymoma patients and measure anti-AChR preoperatively to aid prognostication.

Chemotherapy can result in toxic side effects in the brain. Intake of marine-based omega-3 polyunsaturated fatty acids (n-3 PUFAs), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), alter brain fatty acids, potentially improving brain function. However, it is unclear if alpha-linolenic acid (ALA), the plant-based n-3, affects brain PUFAs during chemotherapy. The objective of this study was to examine the effects of dietary ALA, EPA and DHA, with high or low sucrose, on brain PUFAs in a mouse model of chemotherapy. Secondarily, the use of liver PUFAs as surrogate measures of brain PUFAs was examined. Lipid peroxidation (4-HNE) and neurotrophic markers (BDNF) were assessed. Female C57Bl/6 mice (n = 90) were randomized to 1 of 5 diets (high EPA + DHA/high or low sucrose, high ALA/high or low sucrose, or control with no EPA + DHA/low ALA/low sucrose) and injected with doxorubicin-based chemotherapy or saline. Brain EPA and DHA were greater (p < 0.0001) with high EPA + DHA diets, regardless of sucrose; there were no significant differences in brain PUFAs between high ALA diets and control. Chemotherapy-treated mice had higher brain and liver DHA (p < 0.05) and lower brain and liver linoleic acid (p < 0.0001). Brain n-3 and n-6 PUFAs were strongly correlated with liver n-3 (r = 0.8214, p < 0.0001) and n-6 PUFAs (r = 0.7568, p < 0.0001). BDNF was correlated with brain total PUFAs (r = 0.36; p < 0.05). In conclusion, dietary ALA in proportions approximately two times greater than consumed by humans did not appreciably increase brain n-3 PUFAs compared to low ALA intake. Liver PUFAs may be a useful surrogate marker of brain PUFAs in this mouse model.

Background: The optimal vasopressor management for septic patients with left ventricular (LV) dysfunction has not been well established, and current evidence is conflicting regarding the optimal vasopressor discontinuation order. Objective: The objective was to evaluate the impact of LV dysfunction on the hemodynamic management of septic shock by assessing the incidence of clinically significant hypotension after vasopressor discontinuation. Methods: In this single-center, retrospective cohort study, adult patients were included if they met the Sepsis-3 definition of septic shock, had LV dysfunction (defined as an ejection fraction ≤40%), and received norepinephrine and vasopressin as the last vasopressors discontinued. The primary outcome was the incidence of clinically significant hypotension following discontinuation of vasopressin or norepinephrine. Clinically significant hypotension was defined as a MAP less than 60 mmHg and the need for either: 1) the reinstitution of the previously discontinued agent at any dosage, 2) the receipt of at least 500 mL of a crystalloid at a rate of at least 500 mL/hour, 3) or the receipt of at least 25 grams of albumin 5% at a rate of at least 25 gram/hour. Secondary outcomes included intensive care unit (ICU) and hospital lengths of stay, and ICU and hospital mortality. Results: A total of 78 patients met inclusion criteria, with 37 patients having vasopressin discontinued first and 41 having norepinephrine discontinued first. Clinically significant hypotension occurred in 28 patients (76%) following the discontinuation of vasopressin, compared to 28 patients (81%) following the discontinuation of norepinephrine (p = 0.61). ICU length of stay was 9 days in the vasopressin discontinued first cohort, compared to 15 days in the norepinephrine discontinued first cohort (p = 0.01). There was no statistically significant difference in mortality observed. Conclusion: The discontinuation order of norepinephrine and vasopressin did not impact the incidence of clinically significant hypotension in patients with septic shock and LV dysfunction, but may influence ICU length of stay, although other factors may have impacted this finding.

Nephrogenic syndrome of inappropriate antidiuresis (NSIAD) is an X-linked disease caused by activating mutations in the arginine vasopressin (AVP) receptor-2 (AVPR2) gene. Affected patients excrete concentrated urine despite very low levels of AVP, and consequently develop euvolemic hyponatremia. Due to its low frequency, patients may be misdiagnosed and treated incorrectly. We report two related male infants with NSIAD that was initially confused with hyporeninemic hypoaldosteronism (HH). First, a 2-month-old male presented with hyponatremia, low plasma osmolality, relatively high urine osmolality, and low plasma renin-aldosterone levels. These clinical and laboratory findings were compatible with syndrome of inappropriate antidiuretic hormone secretion without apparent cause. Consequently,fludrocortisone was initiated with a presumptive diagnosis of HH While correction of hyponatremia, fludrocortisone treatment led to hypertension and discontinued in a short time. The second patient at age of 1 year was admitted with a history of oligohydramnios, four times hospitalizations due to hyponatremia since birth, and a diagnosis of epilepsy. Similarly, the second infant had clinical and laboratory findings compatible with syndrome of inappropriate antidiuretic hormone secretion with no apparent cause. Fluid restriction normalized his serum sodium despite plasma AVP level was undetectable. In both infants, AVPR2 gene analysis revealed a known mutation (c.409C>T; p.R137C) and confirmed the diagnosis of NSIAD. In conclusion, NSIAD should be considered in all patients with unexplained euvolemic hyponatremia despite high urine osmolality. In case of unawareness from NSIAD, plasma renin-aldosterone profile can be confused with HH, especially in the infants. 34645113

Variants of the melanocortin-4 receptor (MC4R) gene are the most common cause of monogenic obesity. In this situation; while obesity cannot be controlled with diet and exercise, it was shown that Glucagon-like-peptide-1 receptor agonists (GLP-1 RA) provide weight loss in short term. In this paper, we present our experience with Liraglutide treatment in an adolescent patient carrying MC4R gene variant. A female patient had admitted first at the age of 12.5 years with a complaint of progressive weight gain. She had a marked excess of appetite since infancy. In the physical examination of the pubertal female patient with a body mass index (BMI) of 36.1kg/m2 (3.48 SDS), there was no pathological finding except diffuse acanthosis nigricans. Laboratory examinations revealed only insulin resistance. Weight loss couldn't be achieved with lifestyle changes, metformin and orlistat treatments In genetic examination, a sporadic heterozygous c.206T>G(p.I69R) variant (reported previously) was found in the MC4R gene. GLP-1 RA Liraglutide treatment was initiated and a loss of 19.2% reduction was achieved in the patient's body weight and BMI at the end of 32 weeks. However, the patient, whose treatment compliance was disrupted due to significant gastrointestinal complaints, returned to her former weight within a few months after treatment was stopped. In our case carrying a pathogenic variant in the MC4R gene, decrease of appetite and weight loss were achieved with Liraglutide treatment, but this situation could not be maintained. In such cases, there is a need for effective and tolerable treatment options.

Prolyl endopeptidase-like (PREPL) deficiency (MIM#616224) is a rare congenital disorder characterised by neonatal hypotonia and feeding difficulties, growth hormone (GH) deficiency and hypergonadotropic hypogonadism. This syndrome is an autosomal recessive disease resulting from mutations in the PREPL gene (MIM#609557). Herein we report a 7-year-old female patient with biallelic mutations in PREPL (c.1528C>T in one allele and a whole gene deletion in the other) with early growth impairment in infancy. Growth hormone deficiency was confirmed at 20 months of life. Recombinant growth hormone treatment was introduced with a good response. Her clinical features were similar to those of previously reported cases. The description of new patients with PREPL deficiency syndrome is essential to better delineate the phenotypic and genotypic spectrum of the disease.

INTRODUCTION Advances in the treatment of myasthenia gravis (MG) have improved quality of life and prognosis for the majority of patients. However, 10%-20% of patients present refractory MG, with frequent relapses and significant functional limitations. PATIENTS AND METHODS Patients with refractory MG were selected from a cohort of patients diagnosed with MG between January 2008 and June 2019. Refractory MG was defined as lack of response to treatment with prednisone and at least 2 immunosuppressants, inability to withdraw treatment without relapse in the last 12 months, or intolerance to treatment with severe adverse reactions. RESULTS We identified 84 patients with MG, 11 of whom (13%) met criteria for refractory MG. Mean (standard deviation) age was 47 (18) years; 64% of patients with refractory MG had early-onset generalised myasthenia (as compared to 22% in the group of patients with MG; P

DRESS is a potentially life-threatening severe cutaneous adverse reaction (SCAR). Historically, it was most frequently linked with phenytoin and was initially described as phenytoin hypersensitivity syndrome; however, it was later found to be caused by various other medications, with the commonest been aromatic anticonvulsants, allopurinol and sulfonamides. The severity of this entity is related to systemic involvement, which can result in multiorgan failure and death. The diagnosis of DRESS, especially in the early stages, remains challenging and elusive due to its heterogeneous clinical presentation and the complex course of the disease with different patterns depending on the causal drug. The most important step in the management of DRESS is early diagnosis and immediate cessation of the suspected offending drug along with oral steroids or immunosuppressants to control the disease. We describe the varying presentation and management of six adults with DRESS from a tertiary care hospital, observed over a two-year period with a brief review of the literature.

Classic Toxic Epidermal Necrolysis (TEN) in Lupus Erythematosus (LE) is rare and that caused by oxcarbazepine is even rarer. It can be triggered/induced by various insults, the most prominent being drugs. Herein, we describe a young female, a diagnosed case of LE with lupus nephritis, with recent-onset central nervous system vasculitis (incidentally detected on neuroimaging while she was being evaluated for a recent-onset behavioural change), who within a month of exposure to the drug developed an extensive exfoliating skin rash with mucosal lesions, which on histopathological evaluation showed TEN in LE, triggered by Oxcarbazepine, which was commenced for seizure prophylaxis. She was managed with pulse methylprednisolone, followed by intravenous immunoglobulin (IVIg), after which she made a satisfactory recovery. It is highlighted that TEN in LE patterns must be recognized in an emergency and Acute Syndrome of Apoptotic Panepidermolysis (ASAP) concept applied promptly without awaiting diagnoses. Further, many common drugs possibly trigger this pathology making the rara-avis not rare anymore!

Summary Objectives The understanding of vocal fold hydration state, including dehydrated, euhydrated, rehydrated tissue, and how hydration affects vocal fold biomechanical properties is still evolving. Although clinical observations support the benefits of increasing vocal fold hydration after dehydrating events, more mechanistic information on the effects of vocal fold dehydration and the beneficial effects of rehydration are needed. Alterations to hyaluronic acid (HA), an important component of the vocal fold extracellular matrix, are likely to influence the biomechanical properties of vocal folds. In this study, we investigated the influence of hydration state and HA on vocal fold tissue stiffness via biomechanical testing. Study design Prospective, ex vivo study design. Methods Fresh porcine vocal folds (N = 18) were examined following sequential immersion in hypertonic (dehydration) and isotonic solutions (rehydration). In a separate experiment, vocal folds were incubated in hyaluronidase (Hyal) to remove HA. Control tissues were not exposed to any challenges. A custom micromechanical system with a microforce sensing probe was used to measure the force-displacement response. Optical strain was calculated, and ultrasound imaging was used to measure tissue cross-sectional area to obtain stress-strain curves. Results Significant increases (P ≤ 0.05) were found in tangent moduli between dehydrated and rehydrated vocal folds at strains of e = 0.15. The tangent moduli of Hyal-digested tissues significantly increased at both e = 0.15 and 0.3 (P ≤ 0.05). Conclusion Vocal fold dehydration increased tissue stiffness and rehydration reduced the stiffness. Loss of HA increased vocal fold stiffness, suggesting a potential mechanical role for HA in euhydrated vocal folds.

In five patient undergoing surgery for proximal humerus fracture we investigated into postoperative analgesia provided by continuous costoclavicular block using continuous stimulating catheter. The postoperative pain scores were less than 4 in all patients except in two patients who required intravenous tramadol 50 mg as a rescue analgesic. The radiocontrast dye study executed in two patients revealed contiguous contrast spread through the brachial plexus sheath with the catheter tip in the interscalene space. We propose that a continuous costoclavicular block with a retrograde stimulating catheter is a feasible alternative regional anesthesia technique for postoperative analgesia in shoulder surgery.

Background: Current guidelines recommend electrical cardioversion (ECV) in patients with atrial fibrillation (AF) after at least 3 weeks of adequate non-vitamin K antagonist oral anticoagulant (NOAC) treatment without prior transesophageal echocardiography (TEE). However, in clinical practice in some centres, TEE is performed before ECV in patients with AF. The aim of the study was to evaluate prevalence of thromboembolic and hemorrhagic complications in patients with AF treated with NOACs and undergoing ECV without prior TEE. Methods: This observational, multicentre study included consecutive patients with AF treated with NOACs who were admitted for ECV without prior TEE. Thromboembolic events and major bleeding complications were investigated during a 30-day follow-up. Results: In the study group there were 611 patients, mean age was 66.3 ± 9.2 years, 40% were women. 52 (8.5%) patients had a low thromboembolic risk, 148 (24.2%) patients had an intermediate thromboembolic risk and 411 (67.2%) patients had a high thromboembolic risk. In the study group 253 (41.4%) patients were treated with rivaroxaban, 252 (41.2%) patients were treated with dabigatran and 106 (17.3%) patients were treated with apixaban. Reduced doses of NOACs were administered to 113 (18.9%) patients. In the entire study group, there were no thromboembolic events or major bleeding complications during the in-hospital stay and the 30-day follow-up. Conclusions: In this “real-world” study of AF patients treated with NOACs, it was proved that ECV is safe without a preceding TEE, regardless of the risk of thromboembolic complications and of the type of NOAC used.

Purpose Hydralazine, doxazosin, and verapamil are currently recommended by the Endocrine Society as acceptable bridging treatment in those in whom full cessation of antihypertensive medication is infeasible during screening for primary aldosteronism (PA). This is under the assumption that they cause minimal to no effect on the aldosterone-to-renin ratio, the most widely used screening test for PA. However, limited evidence is available regarding the effects of these particular drugs on said ratio. Methods In the present study, we retrospectively assessed the changes in aldosterone, renin, and aldosterone-to-renin values in essential hypertensive participants before and after treatment with either hydralazine (n = 26) or doxazosin (n = 20) or verapamil (n = 15). All samples were taken under highly standardized conditions. Results Hydralazine resulted in a borderline significant rise in active plasma renin concentration (19 vs 25 mIU/L, p = 0.067) and a significant fall in the aldosterone-to-renin ratio (38 vs 24, p = 0.017). Doxazosin caused declines in both plasma aldosterone concentration (470 vs 330 pmol/L, p = 0.028) and the aldosterone-to-renin ratio (30 vs 20, p = 0.020). With respect to verapamil, we found no statistically significant effect on any of these outcome variables. Conclusion We conclude that the assumption that these drugs can be used with little consequence to the aldosterone-to-renin cannot be substantiated. While it is possible that they are indeed the best option when full antihypertensive drug cessation is infeasible, the potential effects of these drugs must still be taken into account when interpreting the aldosterone-to-renin ratio.

A plethora of paraneoplastic syndromes have been reported as remote effects of colorectal carcinoma (CRC). However, there is a dearth of data pertaining to the association of this cancer with demyelinating neuropathies. Herein, we describe the case of a young woman diagnosed with chronic inflammatory demyelinating polyneuropathy (CIDP). Treatment with intravenous immunoglobulins and prednisone did not improve her condition, and her neurological symptoms worsened. Subsequently, she was readmitted with exertional dyspnea, lightheadedness, malaise, and black stools. Colonoscopy revealed a necrotic mass in the ascending colon, which directly invaded the second part of the duodenum. Pathologic results confirmed the diagnosis of locally advanced CRC. Upon surgical resection of the cancer, her CIDP showed dramatic resolution without any additional therapy. Patients with CRC may develop CIDP as a type of paraneoplastic syndrome. Clinicians should remain cognizant of this potential association, as it is of paramount importance for the necessary holistic clinical management.

This study was carried out to examine the effect of combining factors for immersion technique on masculinization of red tilapia (Oreochromis spp.). Three selected doses (1000, 1,500, and 2000 μg/L) of 17α-methyltestosterone (17 MT) immersion, 2 exposure times (3 and 6 h) once or twice a week, and interaction of these factors were tested. A total of 12 treatment combinations under 3 × 2 × 2 factorial experiments in randomized complete block design were conducted to compare with the negative control group (no 17 MT-treated) and positive control group (17 MT-treated feed administration). One hundred red tilapia larvae (14 days post-hatch) were randomly allocated in each treatment and were operated in a 10-L glass jar for 21 days. At the end of the treatment regime, the survival rate was determined. Then, fish were raised in a 150-L glass tank using normal commercial feed for 2 months and sex ratios were determined via the gonad squash technique. None of the immersion treatments tested resulted in a statistically significant (p > 0.05) decrease in survival rate. All 17 MT-treated groups produced progenies with a significantly higher (p

Objectives This study aimed to compare the effects of N-acetylcysteine and benfotiamine in protection of ovarian tissue from ischemia caused by slow neovascularization injury due to intraperitoneal ovarian autotransplant in rats. Materials and methods Twenty-eight female rats were divided into 4 groups, each containing 7 rats. Group 1 only had the abdomen opened and closed, group 2 was the transplant-only group, group 3 received benfotiamine for 3 weeks starting 1 day before the transplant procedure, and group 4 received N-acetylcysteine for 3 weeks starting 1 day before the transplant procedure. At the end of the experimental period, malondialdehyde levels in ovarian tissues together with the apoptosis and fibrosis, proliferating cell nuclear antigen and vascular endothelial growth factor immunoreactivity, and ovarian reserves were investigated. Results Apoptosis was significantly increased in group 2 animals. Primordial follicle count was higher in groups 3 and 4 than in group 2. Vascular endothelial growth factor immunoreactivity was decreased in groups 3 and 4 compared with group 2. Proliferating cell nuclear antigen immunoreactivity was reduced in the secondary follicles in all transplant groups. Conclusions In autologous intraperitoneal ovarian transplant, both benfotiamine and N-acetylcysteine are equal and effective agents in protection of ovarian tissue against ischemic injury.

There is scarce clinical experience with etelcalcetide in patients with secondary hyperparathyroidism uncontrolled with cinacalcet. The effect of etelcalcetide on serum sclerostin levels remains to be clarified.Prospective cohort study in prevalent hemodialysis patients with uncontrolled sHPT under cinacalcet for at least 3 months, mean parathyroid hormone (PTH)800pg/mL and calcium (Ca)8.3mg/dL. Etelcalcetide 5mg IV/HD was initiated after cinacalcet washout. Levels of PTH, Ca, and phosphorus (Pi) followed monthly for 6 months. Plasma sclerostin levels measured before etelcalcetide treatment and after 6 months.Thirty-four patients were enrolled, 19 (55.9%) male gender. Mean age 60.7 (± 12.3) years; median time on HD 82.5 (7-296) months and median cinacalcet dose was 180mg/week (Interquartile Range: 180-270). Serum Ca, Pi and PTH levels showed a significant reduction after etelcalcetide treatment from 8.8mg/dL, 5.4mg/dL and 1005pg/mL to 8.1mg/dL (p=0.08), 4.9mg/dL (p=0.01) and 702pg/mL (p0.001), respectively. Median etelcalcetide dose remained at 5mg/HD. Plasma sclerostin concentration increased from 35.66pmol/L (IQR11.94-54.58) to 71.05pmol/L (IQR54.43-84.91) (p0.0001).Etelcalcetide improved sHPT control in this group of patients, previously under cinacalcet treatment, and significantly increased plasma sclerostin concentration. The impact of etelcalcetide treatment on sclerostin levels is a novel finding.

RE-containing magnesium alloys were prepared via molten-salt-mediated magnesiothermic reduction by using RE2O3 (RE=Y, Nd and Gd) and Mg metal as raw materials. The thermomechanical analysis of the magnesiothermic reduction reactions in molten salt was investigated. Then the molten-salt-mediated magnesiothermic reduction process was studied from three different perspectives. After that, the RE-containing magnesium alloy was characterized by using chemical analysis, XRD analysis and SEM analysis. The magnesiothermic reduction was a liquid-liquid reaction with relatively weak driving force. During the melting process and the magnesiothermic reduction process, magnesium metal and the obtained alloy went up and down as a whole in molten salt, which improved the process safety without introducing chloride inclusions. Meanwhile, the hydrolysis of the RECl3-containing molten salt occurred at elevated temperature, which severely impeded the magnesiothermic reduction process. After the magnesiothermic reduction at 750 °C for 2.0 h, the content of RE and the common impurity elements in the obtained RE-containing alloy met the both requirements of the commercial WE43A and WE43B.

Periodontitis is an oral chronic inflammatory disease. Inhibiting tissue destruction and promoting tissue regeneration are important means for the treatment of periodontitis. Metformin not only has hypoglycemic effect but also has anti-inflammatory effect. Metformin has been shown to inhibit oxidative stress and activate autophagy through AMPK/mTOR pathway. High mobility group box 1 (HMGB1) has been implicated in the pathogenesis of many inflammatory diseases including periodontitis, it can participate in the induction of oxidative stress. HMGB1 is an autophagy regulator under oxidative stress, which can activate mTOR pathway. However, it is not clear whether metformin is related to HMGB1 and its mechanism in the process of periodontitis. Cell viability and expression of inflammatory cytokines were clarified by Cell Counting Kit-8, real-time PCR and enzyme-linked immunosorbent assay. Western blot and immunofluorescence were conducted to determine HMGB1 intracellular localization and expression of autophagy-associated proteins in vitro. Experimental periodontitis mice model was induced by administering a ligature. Immunohistochemistry was performed to detect the expression and localization of HMGB1 in vivo. The results of CCK-8, real-time PCR, enzyme-linked immunosorbent assay, Western blot and immunofluorescence showed lipopolysaccharide (LPS) treatment inhibited cell viability, and increased HMGB1 expression at a dose-independent manner. Metformin can reduce the effect of LPS. It also improves autophagy pathway inhibited by LPS and down-regulates mTOR expression. In addition, metformin attenuated alveolar bone resorption induced by ligation. This study provides new evidence for that metformin is a potential drug for the treatment of periodontitis and HMGB1 may be a potential target for periodontal intervention.

Radiation-induced sarcoma (RIS) of the central nervous system is an uncommon late complication of radiation therapy. We report a case of a 47-year-old male patient who underwent surgery followed by irradiation and chemotherapy with temozolomide for a frontal lobe gliosarcoma and presented 43 months later with a recurrent tumor in the same location with interval growth in the size of the lesion. Histology from surgical resection of the recurrent tumor revealed embryonal rhabdomyosarcoma (RMS). Adjacent brain parenchyma showed radiation-induced changes. There was no evidence of gliosarcoma at recurrence. In addition to the rarity of sarcomas arising following irradiation for glial tumors, this case represents one of the first reports of an intracerebral RMS arising in this setting.

ObjectivesDetermine the role of apolipoprotein M (ApoM) in anthracycline (Dox) cardiotoxicity.BackgroundApoM binds the cardioprotective sphingolipid sphingosine-1-phosphate (S1P). Circulating ApoM is inversely associated with mortality in human heart failure (HF).MethodsIn the Penn HF Study (PHFS), we tested the relationship between ApoM and mortality in a subset with anthracycline-induced cardiomyopathy. We measured ApoM in humans and mice treated with Dox and utilized hepatic ApoM transgenic (ApomTG), ApoM knockout (ApomKO), ApoM knock-in mice with impaired S1P binding, and S1P receptor 3 (S1PR3) knockout mice in Dox cardiotoxicity. We assayed autophagy in left ventricular tissue from anthracycline-induced HF patients versus donor controls.ResultsApoM was inversely associated with mortality in PHFS, and Dox reduced circulating ApoM in mice and breast cancer patients.ApomTGmice were protected from Dox-induced cardiac dysfunction and loss of left ventricular mass.ApomTGattenuated Dox-induced impairment in autophagic flux in vivo and accumulation of insoluble p62, which was also observed in the myocardium of patients with anthracycline-induced HF. In vehicle-treated mice, ApoM negatively regulated transcription factor EB (TFEB), a master regulator of autophagy and lysosomal biogenesis. The effect of ApoM on TFEB required both S1P binding and S1PR3. In the presence of Dox, ApoM preserved TFEB and cardiomyocyte lysosomal abundance assessed as lysosomal associated membrane protein 1 positive structures in vivo, while S1P mimetic pretreatment of cardiomyocytes prevented Dox-induced changes in lysosomal pH.ConclusionsApoM attenuates Dox cardiotoxicity via the autophagy-lysosome pathway. The association between ApoM and reduced mortality may be explained by its role in sustaining autophagy.HighlightsCirculating ApoM is inversely associated with survival in human anthracycline-induced cardiomyopathyAnthracycline treatment reduces circulating ApoM in humans and miceIncreasing ApoM attenuates doxorubicin cardiotoxicity, lysosomal injury and preserves myocardial autophagic flux, but does not impact doxorubicin anti-neoplastic efficacyAutophagic impairment is characteristic of human anthracycline cardiomyopathy

Inhaled antibiotics are commonly used to treat persistent airway infection with Pseudomonas aeruginosa that contributes to lung damage in people with cystic fibrosis. Current guidelines recommend inhaled tobramycin for individuals with cystic fibrosis and persistent Pseudomonas aeruginosa infection who are aged six years or older. The aim is to reduce bacterial load in the lungs so as to reduce inflammation and deterioration of lung function. This is an update of a previously published review.To evaluate the effects of long-term inhaled antibiotic therapy in people with cystic fibrosis on clinical outcomes (lung function, frequency of exacerbations and nutrition), quality of life and adverse events (including drug-sensitivity reactions and survival).We searched the Cochrane Cystic Fibrosis Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. We also searched ongoing trials registries. Date of last search: 28 June 2022.We selected trials where people with cystic fibrosis received inhaled anti-pseudomonal antibiotic treatment for at least three months, treatment allocation was randomised or quasi-randomised, and there was a control group (either placebo, no placebo or another inhaled antibiotic).Two authors independently selected trials, judged the risk of bias, extracted data from these trials and judged the certainty of the evidence using the GRADE system.The searches identified 410 citations to 125 trials; 18 trials (3042 participants aged between five and 45 years) met the inclusion criteria. Limited data were available for meta-analyses due to the variability of trial design and reporting of results. A total of 11 trials (1130 participants) compared an inhaled antibiotic to placebo or usual treatment for a duration between three and 33 months. Five trials (1255 participants) compared different antibiotics, two trials (585 participants) compared different regimens of tobramycin and one trial (90 participants) compared intermittent tobramycin with continuous tobramycin alternating with aztreonam. One trial (18 participants) compared an antibiotic to placebo and also to a different antibiotic and so fell into both groups. The most commonly studied antibiotic was tobramycin which was studied in 12 trials. Inhaled antibiotics compared to placebo We found that inhaled antibiotics may improve lung function measured in a variety of ways (4 trials, 814 participants). Compared to placebo, inhaled antibiotics may also reduce the frequency of exacerbations (risk ratio (RR) 0.66, 95% confidence interval (CI) 0.47 to 0.93; 3 trials, 946 participants; low-certainty evidence). Inhaled antibiotics may lead to fewer days off school or work (quality of life measure) (mean difference (MD) -5.30 days, 95% CI -8.59 to -2.01; 1 trial, 245 participants; low-certainty evidence). There were insufficient data for us to be able to report an effect on nutritional outcomes and there was no effect on survival. There was no effect on antibiotic resistance seen in the two trials that were included in meta-analyses. We are uncertain of the effect of the intervention on adverse events (very low-certainty evidence), but tinnitus and voice alteration were the only events occurring more often in the inhaled antibiotics group. The overall certainty of evidence was deemed to be low for most outcomes due to risk of bias within the trials and imprecision due to low event rates. Different antibiotics or regimens compared Of the eight trials comparing different inhaled antibiotics or different antibiotic regimens, there was only one trial for each unique comparison. We found no differences between groups for any outcomes except for the following. Aztreonam lysine for inhalation probably improved forced expiratory volume at one second (FEVsub1/sub) % predicted compared to tobramycin (MD -3.40%, 95% CI -6.63 to -0.17; 1 trial, 273 participants; moderate-certainty evidence). However, the method of defining the endpoint was different to the remaining trials and the participants were exposed to tobramycin for a long period making interpretation of the results problematic. We found no differences in any measure of lung function in the remaining comparisons. Trials measured pulmonary exacerbations in different ways and showed no differences between groups except for aztreonam lysine probably leading to fewer people needing treatment with additional antibiotics than with tobramycin (RR 0.66, 95% CI 0.51 to 0.86; 1 trial, 273 participants; moderate-certainty evidence); and there were fewer hospitalisations due to respiratory exacerbations with levofloxacin compared to tobramycin (RR 0.62, 95% CI 0.40 to 0.98; 1 trial, 282 participants; high-certainty evidence). Important treatment-related adverse events were not very common across comparisons, but were reported less often in the tobramycin group compared to both aztreonam lysine and colistimethate. We found the certainty of evidence for these comparisons to be directly related to the risk of bias within the individual trials and varied from low to high.Long-term treatment with inhaled anti-pseudomonal antibiotics probably improves lung function and reduces exacerbation rates, but pooled estimates of the level of benefit were very limited. The best evidence available is for inhaled tobramycin. More evidence from trials measuring similar outcomes in the same way is needed to determine a better measure of benefit. Longer-term trials are needed to look at the effect of inhaled antibiotics on quality of life, survival and nutritional outcomes.

Gambierdiscus spp. are epi-benthic dinoflagellates that have been associated with ciguatera poisoning. These microalgae can have complex secondary metabolite profiles including ciguatoxins, maitotoxins, and gambierones, with varying compositions and toxicities across species and strains. Given this chemical diversity there is a need to develop selective and sensitive methods for secondary metabolite profiling. In this study, we used a cultured Caribbean strain of Gambierdiscus silvae to develop sample preparation and analysis strategies for characterizing vic-diol containing secondary metabolites. A pooled cellular extract was first screened by liquid chromatography–high–resolution mass spectrometry (LC–HRMS) for ciguatoxin-related compounds, which resulted in the confirmation of gambierone (1) and tentative identification of 29-methylgambierone (3). Treatment of the extract with periodate confirmed that the gambierones each contained one reactive vic-diol, which was exploited for the development of a selective extraction procedure using m-aminophenylboronic acid gel and the non-aqueous binding solvent chloroform. Using this non-traditional boronate affinity procedure, LC-HRMS also revealed the presence of additional sulfated polycyclic ethers in the gambierone-containing vic-diol fraction, while pigments and other contaminants were removed. The developed tools could be applied to screen collections of Gambierdiscus and other benthic algae to provide additional chemical characterization of gambierone-related compounds. The selective extraction procedure may also prove useful as a step in the isolation of these sulfated polyethers for structural, toxicological and biotransformation studies.

Tamoxifen exposure is a recognised risk for primary endometrial cancer. This case serves as a reminder to meticulously check the past medical history and inform patients of the risk-benefit of treatment as part of a shared-decision making process.

Introduction: Phytocannabinoids have emerged as a potential alternative treatment option for individuals experiencing persistent pain. However, evidence-based research regarding their clinical utility in both males and females remains incomplete. In addition, it is unknown whether combining readily available cannabinoids with opioids has a synergistic or subadditive effect on pain modulation. To begin to fill this knowledge gap, we investigated the antinociceptive effects of the phytocannabinoid, CBD, either alone or in combination with opioids in male and female C57BL/6J mice. Results: Using the formalin test, our results show that CBD (10 mg/kg, i.p.) treatment evoked antinociception in phase I, but not in phase II, of the formalin test in male mice. However, in female mice, CBD showed no significant antinociceptive effect. In addition, a direct sex comparison showed that CBD evoked a significant increase in nociceptive behaviors in female versus male mice during phase I of the formalin test. Furthermore, we show that CBD (10 mg/kg, i.p.) in combination with low-dose morphine (1 mg/kg, i.p.) was ineffective at eliciting a synergistic antinociceptive response in both male and female mice. Lastly, consistent with previous literature, we showed that females treated with a relatively higher dose of morphine (10 mg/kg, i.p.) displayed a significant increase in the variability of nociceptive behaviors compared to morphine-treated male mice. Conclusion: Overall, our results suggest that CBD treatment may have beneficial antinociceptive effects during the acute phase of persistent pain, but these effects are more beneficial to males than females. We provide further pre-clinical support that treatments geared toward reducing nociceptive behaviors differentially affect males and females.

No medications are approved for cannabis use disorder (CUD), though a small clinical trial demonstrated that the voltage-dependent calcium channel (VDCC) ligand gabapentin reduced cannabis use in treatment seekers. VDCCs are modulated by cannabinoid (CB) ligands, and there are shared effects between CB agonists and VDCC ligands. This overlapping neuropharmacology and the initial clinical results supported the evaluation of pregabalin, a "next-generation" VDCC ligand, as a CUD medication. Two separate placebo-controlled, double-blind, counterbalanced, within-subjects human laboratory studies tested placebo and 300 (N = 2 females, 11 males; Experiment [EXP] 1) or 450 (N = 3 females, 11 males; EXP 2) mg/day pregabalin in cannabis users who were not seeking treatment or trying to reduce/quit their cannabis use. The protocol consisted of two outpatient maintenance phases (11 days in EXP 1 and 15 days in EXP 2) that concluded with four experimental sessions within each phase. During experimental sessions, maintenance continued, and participants completed two 2-day blocks of sampling and self-administration sessions to determine the reinforcing effects of smoked cannabis (0% and 5.9% delta⁹-tetrahydrocannabinol [THC]), as well as subjective, attentional bias, performance, and physiological responses. In addition, naturalistic cannabis use, side effects, sleep quality, craving, and other self-reported substance use were measured during pregabalin maintenance. Cannabis was self-administered and produced prototypical effects, but pregabalin generally did not impact the effects of cannabis or alter naturalistic use. These human laboratory results in cannabis users not trying to reduce/quit their use do not support the efficacy of pregabalin as a stand-alone pharmacotherapy for CUD. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Background and Purpose Cochlear vascular micro-thrombosis has been hypothesized as one of the pathogenic mechanisms for sudden sensorineural hearing loss (SSNHL) refractory to regular management. This study aimed to evaluate the feasibility and safety of intra-arterial pulsed-injection urokinase (IAPU) as a salvage therapy for SSNHL after the failure of conventional therapy. Methods We retrospectively reviewed our patient database to identify refractory SSNHL patients between November 2017 and July 2020. Study outcomes before and after the IAPU therapy were compared between IAPU and conventional therapy groups. Results Sixty-seven moderate-profound SSNHL patients (29 in IAUP group, 38 in control group) were included in this study. Compared to the control group, patients in the IAPU group showed more significant improvement in pure tone average (PTA) (34.2 ± 23.5 vs. 10.7 ± 13.1, p < 0.001) and degree of hearing recovery (total: 20.7% vs. 5.3%, partial: 24.1% vs. 10.5%, mild: 27.6% vs. 13.2% and non: 27.6% vs. 71.1%) 2 weeks after admission. In the IAPU group, a significant improvement of PTA (86.6 ± 11.5 vs. 54.6 ± 20.1 dB, p < 0.005) was observed on the first day after IAPU treatment. Conclusion In carefully selected SSNHL cases with a highly suspected vascular origin, IAPU is a safe and effective therapy when conventional treatments have failed. Despite the encouraging findings of our work, large studies are needed to better investigate the strengths and limitations of this salvage therapy.

Substance use in young adulthood and polysubstance users (PSU), in particular, pose unique risks for adverse consequences. Prior research on young adult PSU has identified multiple classes of users, but most work has focused on college students. We examined PSU patterns by age and college attendance during young adulthood in two nationally representative samples. Using National Epidemiological Survey on Alcohol and Related Conditions (NESARC) Wave 1 and NESARC-III data sets, multigroup latent class analysis (MG-LCA) was employed to examine PSU patterns based on age (18-24 vs. 25-34) and determine whether solutions were similar (i.e., statistically invariant) by college attendance/graduation. Classes were estimated by binary past-year use of sedatives, tranquilizers, opioids/painkillers, heroin, amphetamines/stimulants, cocaine, hallucinogens, club drugs, and inhalants, and past-year frequency of alcohol, cigarette, and cannabis use. PSU patterns are largely replicated across waves. Model fit supported 3-class solutions in each MG-LCA: Low frequency-limited-range PSU (alcohol, cigarettes, and cannabis only), medium-to-high frequency limited-range PSU (alcohol, cigarettes, and cannabis only), and extended-range PSU (ER PSU; all substances). Apart from one model, MG-LCA solutions were not invariant by college attendance/graduation, suggesting important differences between these groups. Except for alcohol, cannabis, and cigarette use frequency, results showed that probabilities of illicit and prescription drug use declined in the older age group. Findings also supported examining college and noncollege youth separately when studying PSU. ER PSU may be uniquely vulnerable to coingesting substances, particularly for nongraduates, warranting future research to classify patterns of simultaneous PSU and identify predictors and consequences of high-risk combinations (e.g., alcohol and opioids). (PsycInfo Database Record (c) 2021 APA, all rights reserved).

COVID-19 is the disease caused by SARS-CoV-2 which has led to 2,643,000 deaths worldwide, a number which is rapidly increasing. Urgent studies to identify new antiviral drugs, repurpose existing drugs, or identify drugs that can target the overactive immune response are ongoing. Antiretroviral drugs (ARVs) have been tested in past human coronavirus infections, and also against SARS-CoV-2, but a trial of lopinavir and ritonavir failed to show any clinical benefit in COVID-19. However, there is limited data as to the course of COVID-19 in people living with HIV, with some studies showing a decreased mortality for those taking certain ARV regimens. We hypothesized that ARVs other than lopinavir and ritonavir might be responsible for some protection against the progression of COVID-19. Here, we used chemoinformatic analyses to predict which ARVs would bind and potentially inhibit the SARS-CoV-2 main protease (Mpro) or RNA-dependent-RNA-polymerase (RdRp) enzymes in silico. The drugs predicted to bind the SARS-CoV-2 Mpro included the protease inhibitors atazanavir and indinavir. The ARVs predicted to bind the catalytic site of the RdRp included Nucleoside Reverse Transcriptase Inhibitors, abacavir, emtricitabine, zidovudine, and tenofovir. Existing or new combinations of antiretroviral drugs could potentially prevent or ameliorate the course of COVID-19 if shown to inhibit SARS-CoV-2 in vitro and in clinical trials. Further studies are needed to establish the activity of ARVs for treatment or prevention of SARS-CoV-2 infection . Communicated by Ramaswamy H. Sarma

Neuroinflammation is implicated in the development and maintenance of alcohol use disorder (AUD) and neuroimmune therapeutics show promise in treating AUD. Proinflammatory signaling contributes to progressive elevations in the dysfunction of mood and alcohol craving. The current study sought to examine potential biobehavioral mechanisms of neuroimmune modulation in AUD under experimental conditions. In a community sample of individuals with AUD who completed a placebo-controlled crossover trial of ibudilast, we tested the effect of ibudilast on the relationship between mood states and alcohol craving. Multilevel modeling analyses tested the hypothesis that ibudilast would moderate the effect of positive and negative mood states on alcohol craving during stress and cue exposures. Results revealed that after stress-induction, participants' feelings of depression and happiness were more strongly predictive of their craving for alcohol while taking ibudilast as compared with placebo (

Background Allergic bronchopulmonary aspergillosis (ABPA) is an allergic reaction to colonisation of the lungs with the fungus Aspergillus fumigatus and affects around 10% of people with cystic fibrosis. ABPA is associated with an accelerated decline in lung function. High doses of corticosteroids are the main treatment for ABPA; although the long-term benefits are not clear, their many side effects are well-documented. A group of compounds, the azoles, have activity against Aspergillus fumigatus and have been proposed as an alternative treatment for ABPA. Of this group, itraconazole is the most active. A separate antifungal compound, amphotericin B, has been employed in aerosolised form to treat invasive infection with Aspergillus fumigatus, and may have potential for the treatment of ABPA. Antifungal therapy for ABPA in cystic fibrosis needs to be evaluated. This is an update of a previously published review. Objectives The review aimed to test the hypotheses that antifungal interventions for the treatment of ABPA in cystic fibrosis: 1. improve clinical status compared to placebo or standard therapy (no placebo); 2. do not have unacceptable adverse effects. If benefit was demonstrated, we aimed to assess the optimal type, duration and dose of antifungal therapy. Search methods We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register which comprises references identified from comprehensive electronic database searches, handsearches of relevant journals and abstract books of conference proceedings. In addition, pharmaceutical companies were approached. Date of the most recent search of the Group's Trials Register: 29 September 2016. Selection criteria Published or unpublished randomised controlled trials, where antifungal treatments have been compared to either placebo or no treatment, or where different doses of the same treatment have been used in the treatment of ABPA in people with cystic fibrosis. Data collection and analysis Four trials were identified by the searches; none of which was judged eligible for inclusion in the review. Main results No completed randomised controlled trials were included. Authors' conclusions At present, there are no randomised controlled trials to evaluate the use of antifungal therapies for the treatment of ABPA in people with cystic fibrosis, although trials in people who do not have cystic fibrosis have shown clinical and serological evidence of improvement and a reduction in the use of corticosteroids with no increase in adverse effects. Trials with clear outcome measures are needed to properly evaluate this potentially useful treatment for cystic fibrosis.

Background: Ulcerative colitis (UC), belongs to inflammatory bowel diseases (IBD), frequently induces liver inflammation and injury. Previous studies have proved that bone marrow-derived mesenchymal stem cells (BMSCs) can suppress inflammation and improve intestinal mucosal injury in colitis, however, the effects of BMSCs on colitis-induced liver injury and the underlying molecular mechanisms remain unclear. Here, we investigated the effects and mechanisms of BMSCs in acute ulcerative colitis Balb/C mice, which were induced by 4 % dextran sodium sulphate (DSS). Methods: In this study, BMSCs derived from Balb/C mice were administrated by single intravenous injection with a dose of 5*10^7 cells/kg. And then, the effects and underlying molecular mechanisms were investigated. Firstly, degree of liver injury in colitis mice was evaluated by hepatic ALT, AST, ALP and TBIL levels, which were measured by specific determination kits, the levels of TNF-α, IL-6, IFNγ and LPS were examined by ELISA. Secondly, as the indicator of intestinal-liver barrier disorder, tight junction proteins were analyzed by western blot. Thirdly, the pathological changes in colon and liver were detected by H&E staining. At last, homing of BMSCs to lesion tissues was investigated by Immunofluorescence. Results: The results indicated that histopathological changes in model mice had been greatly alleviated, BMSCs infusion remarkably decreased the serum ALT, AST, ALP and TBIL level, and meanwhile reduced pro-inflammatory cytokines in liver tissues. Furthermore, homing of BMSCs was observed in colon and liver, and the disorder of intestinal-liver barrier was declined significantly. Conclusions: In conclusion, BMSCs alleviate liver injury induced by ulcerative colitis via repairing the intestinal-liver barrier and activating hepatocyte growth factor, it has potential application prospects in the treatment of liver injury induced by ulcerative colitis.

Propofol is widely used to sedate agitated patients in intensive care units. However, it can cause a rare but fatal complication, propofol-related infusion syndrome (PRIS). The pathophysiology of PRIS is not clear, and there is no definitive diagnosis and treatment. We report a successfully treated case of PRIS in a critically ill patient receiving low-dose propofol infusion. A 59-year-old male patient complaining of sudden chest pain repeatedly collapsed in an ambulance and the emergency room, and veno-arterial extracorporeal membrane oxygenation was delivered. He was diagnosed with a total occluded left anterior descending coronary artery in coronary angiography. On day 20, he showed arrhythmia, increased creatinine kinase (CK), and increased CK-MB and troponin I, accompanied by unstable hemodynamic status despite high-dose vasopressors. He was administered propofol for 20 days at an average dose of 1.3 mg/kg/hr owing to issues with agitation and ventilator synchrony. We strongly suspected PRIS and immediately discontinued propofol infusion, and he was successfully treated with aggressive supportive care. PRIS can occur in patients administered propofol for a prolonged period at low doses. Thus, clinicians should use propofol with caution for PRIS and change to alternative sedatives for long-term sedation.

Coexistence of congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency and Turner Syndrome (TS) is rare. We report a 6-year-old Portuguese girl with mosaic TS [45,XO(39)/47,XXX(21)] presented with premature pubarche at the age of 5 years. Laboratory findings showed elevated 17-hydroxyprogesterone, dehydroepiandrosterone sulfate, androstenedione and total testosterone, and sex-determining region Y (SRY) was negative. CYP21A2 gene analysis revealed two mutations (c.[844G>T]; [CYP21A2del]), consistent with the non-classical form of CAH. Complete deletion of CYP21A2 allele occurred de novo. At 6 years and 4 months, she presented accelerated growth velocity and hydrocortisone at the dose of 5 mg/m2/day was initiated. This case highlights the need to perform global examinations looking for virilization signs in TS patients follow-up. It also supports the reported genetic combination of TS and CAH. Therefore, CAH should be kept in mind in TS patients with SRY negative and virilization signs, even in the absence of short stature.

Using the combined application of L-arginine with HMG-Co-A reductase inhibitors simvastatin, atorvastatin, rosuvastatin and nanoparticulated rosuvastatin on the background of modeling of sepsis-induced disease through the introduction of strain 603 Staphylococcus aureus shows endotelio- and cardioprotective effects, manifesting itself in preventing the proliferation of endothelial dysfunction coefficient (CED), adrenoreactivity, maintenance of myocardial reserve and the normalization of biochemical markers values (Total NO, eNOS expression, C-reactive protein, IL-6, TNF). In this case, the combined therapy was so effective that the values obtained thereunder did not differ from those obtained from control animals.

The Ru-catalyzed carbonylation of alkenes with CO2 as a C1 surrogate and imidazole chlorides as the promotor is investigated by a combination of computational and experimental study. The conversion rate of CO2 to CO is positively correlated with the efficiency of both hydroesterification and hydroformylation, which is found facilitated in the presence of chloride additives with a decreasing order of BmimCl ∼ B3MimCl > BmmimCl ∼ LiCl. Taking the hydroesterification with MeOH as a representative example, BmimCl bearing C–H functionality at the C2 site of the cation assists the reduction of CO2 to CO as a hydrogen donor medium, with the anion and cation acting in a synergistic fashion. Subsequent insertion of CO2 into the formed Ru–H bond with the assistance of chloride anion produces the Ru–COOH species, which ultimately accelerates the activation of CO2.

Background: Methadone maintenance treatment (MMT) is an effective treatment for opioid use disorder. However, subtherapeutic dosing may lead to continued opioid use by failing to suppress opioid withdrawal and craving. Preclinical and pilot experimental research suggests that cannabinoids may reduce opioid withdrawal and craving. We sought to test whether the association between low methadone dose and illicit opioid use differs according to concurrent cannabis use patterns. Methods: Data for this study were derived from two community-recruited cohorts of people (≥18 years old) who use illicit drugs in Vancouver, Canada. We used generalized estimating equations to estimate the adjusted association between lower daily MMT dose (

Introduction: A recent law (DCTO-2020-883-APN-PTE-Law No. 27,350. Regulation) passed in Argentina put an end to the ban imposed for the last 60 years on cannabis cultivation within the country. The law permits restricted access to cannabis derivatives for medicinal, therapeutic, and palliative use by individuals and communities, allowing self- and community-based cannabis production. This is cause for concern in view of the lack of quality controls for cannabis derivatives. The several varieties of cannabis grown in Argentina have different chemical profiles and are processed in a variety of ways-mostly by alcohol extraction or maceration at different temperatures and for different amounts of times-making the cannabinoid content of these preparations highly variable. Determining the characteristics of home- and community-grown cannabis products will facilitate the implementation of public policies conducive to their safety and improvement. Objective: The aim of this study was to determine the cannabinoid chemotypes used for therapeutic purposes in Argentina and evaluate whether the cannabinoids present in homemade derivatives are comparable to those in commercially available products. Materials and Methods: High performance liquid chromatography with ultraviolet and diode array detector (HPLC/UV-DAD) analysis of 436 samples (oils, resins, and inflorescences) was carried out to determine the identity and concentration of five cannabinoids: tetrahydrocannabinolic acid (THCA), tetrahydrocannabinol (THC), cannabidiolic acid (CBDA), cannabidiol (CBD), and cannabinol (CBN). From three different sources, the samples represent the type of medical cannabis preparations to which patients have access. Results: The results indicate that the medium-to-low cannabinoid concentration in a significant number of homemade oil samples is similar to that found in commercial products. Most of the samples have a THC/CBD ratio >1 or only contain THC. Acidic cannabinoids were detected in homemade preparations, but were not reported in package inserts of commercial products. Conclusions: Our results indicate that despite their considerable variability, homemade preparations as a whole show cannabinoid levels and profiles equivalent to the commercially available products commonly used for medicinal, therapeutic, and palliative purposes in Argentina.

Recent success in training artificial agents and robots derives from a combination of direct learning of behavioural policies and indirect learning through value functions1–3. Policy learning and value learning use distinct algorithms that optimize behavioural performance and reward prediction, respectively. In animals, behavioural learning and the role of mesolimbic dopamine signalling have been extensively evaluated with respect to reward prediction4; however, so far there has been little consideration of how direct policy learning might inform our understanding5. Here we used a comprehensive dataset of orofacial and body movements to understand how behavioural policies evolved as naive, head-restrained mice learned a trace conditioning paradigm. Individual differences in initial dopaminergic reward responses correlated with the emergence of learned behavioural policy, but not the emergence of putative value encoding for a predictive cue. Likewise, physiologically calibrated manipulations of mesolimbic dopamine produced several effects inconsistent with value learning but predicted by a neural-network-based model that used dopamine signals to set an adaptive rate, not an error signal, for behavioural policy learning. This work provides strong evidence that phasic dopamine activity can regulate direct learning of behavioural policies, expanding the explanatory power of reinforcement learning models for animal learning6.

Background: Immune checkpoint inhibitors (ICIs) have been widely implemented in the treatment of solid tumors. Although epithelial ovarian carcinoma is considered as scarcely immunogenic, the presence of tumor-infiltrating T lymphocytes (TILs) in the ovarian tumor microenvironment (TME) could increase sensitivity to immune checkpoint inhibitors (ICIs). Combinations of ICIs with chemotherapy, anti-VEGF compounds and PARP inhibitors are under evaluation in ovarian cancer. Recently, a Phase II study evaluated the efficacy of Pembrolizumab in Combination with bevacizumab and oral cyclophosphamide in patients with recurrent platinum-sensitive, platinum-resistant, or refractory epithelial ovarian cancer.Methods: Herein, we present a retrospective study of all patients who received pembrolizumab in combination with bevacizumab and oral cyclophosphamide for recurrent platinum-resistant heavily pretreated ovarian cancer in the Oncology Unit of Alexandra University Hospital.Results: Median age at diagnosis was 54.5 years (SD; 8.9; range: 44–72). All patients were diagnosed with high-grade serous ovarian carcinoma (HGSC). Initial disease stage was FIGO IIIC (8/10; 80%), IIIB (1/10; 10%) and IIC (1/10; 10%)). Patients were heavily pretreated with a median of 6 (range: 4–9) prior lines of systemic therapy. All patients have experienced disease progression on first-line platinum-based chemotherapy and median PFS to first-line treatment was 20.1 months (95%CI; 11.4 – 28.7). Patients received a median of 4 cycles of pembrolizumab in combination with cyclophosphamide and bevacizumab (range 2-11). ORR was 20% (2/10) with two patients achieving partial response (PR) and two patients achieving stable disease (SD) while disease control rate (DCR) was 40% (4/10). Median PFS was 2.7 months (95%; 0.6 – 4.8) and 6-month PFS rate 20%. Conclusions: Though our data reflect a small population, we here demonstrate that the combination of pembrolizumab with bevacizumab and oral cyclophosphamide is an effective alternative in platinum-resistant recurrent ovarian carcinoma. This novel combination provides a promising alternative in heavily pretreated patients that have otherwise limited treatment options.

Background There has been a growing interest in the use of ketamine following orthopedic surgeries. We hypothesized that low dose intravenous ketamine during surgery would help in mobilization following total knee replacement (TKR) in oncology patients as assessed by the timed to up and go (TUG) test at 72 hours post-surgery. Our secondary objectives were to compare the opioid requirement at the end of 72 hours, pain scores, satisfaction with pain management, adverse effects, range of joint movement achieved in the post-operative period and the functional recovery at the end of 1 month. Methods After the ethics commitee approval, registration of the trial with the Clinical Trial Registry - India (CTRI), and informed consent, this double-blinded trial was conducted. Using computer generated randomization chart, an independent team randomized the patients into ketamine group which received at induction, a ketamine bolus dose of 0.5 mg.kg-1 before the incision followed by 10 µg.kg-1min-1 infusion which was maintained intraoperatively till skin closure and the saline group received an equivalent volume of saline. Postoperatively, patient controlled morphine pumps were attached and the pain score with morphine usage were recorded for 72 hours. The TUG tests and range of motion were assessed by the physiotherapists until 72 hours. Results Fifty-two patients were enrolled in the trial. Demographics were comparable. No significant intraoperative hemodynamic changes and post-operative adverse events were noted between the groups. A decrease in the TUG test, along with decreased opioid usage with a better range of movements was noted in the ketamine group, but this was not statistically significant. Day of discharge, patient satisfaction score, and functional recovery assessed by Oxford Knee Score (OKS) were comparable between the groups. Conclusion In conclusion, low dose intraoperative ketamine infusion does not provide clinical benefit in perioperative pain management and postoperative rehabilitation following total knee endoprosthetic replacement in oncology.

Background We aimed to describe the thiamine status in hospitalized hypervolemic heart failure (HF) and/or renal failure (RF) patients treated with furosemide and to investigate whether there was a difference in furosemide-related thiamine deficiency between patients with RF and HF. Methods Patients who were diagnosed as hypervolemia and treated with intravenous furosemide (at least 40 mg/day) were included in this prospective observational study. Whole blood thiamine concentrations were measured 3 times during hospital follow-up of patients. Results We evaluated 61 hospitalized hypervolemic patients, of which 22 (36%) were men and 39 (64%) were women, with a mean age of 69.00 ± 10.39 (45–90) years. The baseline and post–hospital admission days 2 and 4 mean thiamine levels were 51.71 ± 20.66 ng/ml, 47.64 ± 15.43 ng/ml and 43.78 ± 16.20 ng/ml, respectively. Thiamine levels of the hypervolemic patients decreased significantly during the hospital stay while furosemide treatment was continuing (p = 0.029). There was a significant decrease in thiamine levels in patients who had HF (p = 0.026) and also, thiamine was significantly lower in HF patients who had previously used oral furosemide before hospitalization. However, these findings were not present in patients with RF. Conclusions Thiamine substantially decreases in most hypervolemic patients receiving intravenous furosemide treatment during the hospital stay. Thiamine levels were significantly decreased with furosemide treatment in especially HF patients, but the decrease in thiamine levels did not detected at the same rate in RF patients. Diuretic-induced thiamine loss may be less likely in RF patients, probably due to a reduction in excretion.

Introduction Cancer-associated thrombosis is a leading cause of morbidity and mortality in malignancy patients. Prophylactic anticoagulation is under-utilized and the cost of low-molecular-weight heparin (LMWH) and direct oral anticoagulants is a major barrier in developing countries. Material and methods A retrospective analysis was performed of all cancer-associated thrombosis patients attending the thrombosis clinic at a tertiary-level referral hospital based in North India between 2011 and 2015. Patient demographics and disease-related parameters were collected and analyzed. Results A total of 771 patients attended the thrombosis clinic during study period, of which 64 cases were malignancy-associated. Of these, 56% of the patients were female and 20% were bedridden. The median age was 48.5 years, adenocarcinoma (48%) being the most common histological subtype. Gynecological malignancies (30%) were the most common malignancies, followed by genitourinary (11%) malignancies. Most of the cases occurred during first year of diagnosis (51%), and only 14% occurred after 3 years. Most of the patients were on combined treatment. Almost 40% of the patients developed thrombosis within 30 days of surgical treatment. Lower limb thrombosis was the most commonly seen type (56%), while abdominal and pulmonary thrombosis were both seen in 5%. Patients were managed with LMWH and vitamin K antagonists (84.3%) and only 6.25% with LMWH alone. Direct oral anticoagulants were not commonly used during the study period. Discussion At the hospital studied, most of the cases occurred early in the disease course. Postoperative prophylaxis could have contributed towards reducing thrombosis in the peri-operative period. Early suspicion and prompt treatment can improve quality of life in such patients.