A generalist-specialist trade-off between switchgrass cytotypes impacts climate adaptation and geographic range.

Polyploidy results from whole-genome duplication and is a unique form of heritable variation with pronounced evolutionary implications. Different ploidy levels, or cytotypes, can exist within a single species, and such systems provide an opportunity to assess how ploidy variation alters phenotypic novelty, adaptability, and fitness, which can, in turn, drive the development of unique ecological niches that promote the coexistence of multiple cytotypes. Switchgrass, Panicum virgatum, is a widespread, perennial C4 grass in North America with multiple naturally occurring cytotypes, primarily tetraploids (4×) and octoploids (8×). Using a combination of genomic, quantitative genetic, landscape, and niche modeling approaches, we detect divergent levels of genetic admixture, evidence of niche differentiation, and differential environmental sensitivity between switchgrass cytotypes. Taken together, these findings support a generalist (8×)­specialist (4×) trade-off. Our results indicate that the 8× represent a unique combination of genetic variation that has allowed the expansion of switchgrass' ecological niche and thus putatively represents a valuable breeding resource.

Urticaria Pigmentosa Without Pruritus.

Mastocytosis is a group of disorders characterized by the pathologic accumulation of mast cells in various tissues. One example of mastocytosis is urticaria pigmentosa, which presents with mastocytomas that can cause hives and, when irritated, pruritus. To our knowledge, we are describing the first case of urticaria pigmentosa without pruritus. The patient had a positive Darier's sign, stated that they never felt itchy, and denied ever using a topical steroid or antihistamine. Although our patient declined additional testing, patients like this may benefit from a detailed evaluation of their sensory system through both quantitative sensory testing and genetic analysis. J Drugs Dermatol. 2024;23(3):     doi:10.36849/JDD.7558e.

Risks of occupational mental disorders in Korean civil servants (2009-18).

BACKGROUND: Previous studies have suggested that firefighters, police officers and civil servants in the education sector, particularly in Western countries, are vulnerable to mental stress and disorders; however, evidence for this association in South Korea is lacking. AIMS: This study aimed to identify whether firefighters, police officers and teachers are at a higher risk for occupational mental health disorders. METHODS: We used workers' compensation claims from civil servants (2009-18). Our target population comprised 46 209 civil servants (9009 civil servants in administrative and technical positions, 23 107 police officers, 4417 firefighters and 8676 civil servants in the educational sector). Occupational and environmental medicine physicians and medical doctors defined and confirmed mental disorders. We conducted Cox proportional hazards regression analyses to evaluate civil servants' risk of occupational mental health disorders. RESULTS: Compared with the civil servants in administrative and technical positions, civil servants in the education sector (hazard ratio [HR] = 2.16; 95% confidence interval [CI]:1.65-2.84) showed a statistically significant increased risk of mental disorders; conversely, firefighters did not (HR = 0.80; 95% CI 0.51-1.27). Police officers had a significantly decreased mental disorder risk compared with civil servants in administrative and technical positions (HR = 0.17; 95% CI 0.11-0.25). CONCLUSIONS: The risk of occupational mental health disorders was higher in civil servants in the education sector but lower in police officers and firefighters than civil servants in administrative and technical positions. Further studies on civil servants' mental health awareness are required to confirm our results.

Risk factors for complicated perioperative recovery in dogs undergoing staphylectomy or folded flap palatoplasty: Seventy-six cases (2018-2022).

OBJECTIVE: To analyze risk factors for complicated perioperative recovery of dogs undergoing either staphylectomy or folded flap palatoplasty. STUDY DESIGN: Retrospective study. ANIMALS: Seventy-six client-owned dogs. METHODS: Medical records of dogs that underwent either staphylectomy or folded flap palatoplasty were reviewed for signalment, brachycephalic risk (BRisk) score, history of gastrointestinal signs, laryngeal collapse grade, presence of preoperative aspiration pneumonia, intraoperative respiratory and cardiovascular complications, length of general anesthesia, number of corrected brachycephalic obstructive airway syndrome (BOAS) components, and gastrointestinal and respiratory postoperative complications. Complicated recovery was defined as requirement for prolonged oxygen treatment and/or tracheostomy or perioperative death. Penalized logistic regression was used to identify risk factors. RESULTS: Seventy-six dogs were enrolled in the study. Multivariate penalized logistic regression identified four risk factors for complicated recovery. These include surgery type (p = .0002), age (p = .0113), laryngeal collapse grade >2 (p < .0001) and length of general anesthesia (p = .0051). CONCLUSIONS: In this population, dogs that had staphylectomy, increasing age, laryngeal collapse grade >2 and increasing length of general anesthesia were at increased risk for perioperative complicated recovery. CLINICAL SIGNIFICANCE: The results of this study identified risk factors for perioperative complicated recovery in dogs undergoing elongated soft palate correction and may assist in surgical planning and early prediction of complications.

Complementary Roles of Two DNA Protection Proteins from Deinococcus geothermalis.

The roles of two interrelated DNA protection protein in starved cells (Dps)-putative Dps Dgeo_0257 and Dgeo_0281-as orthologous proteins to DrDps1 for DNA binding, protection, and metal ion sensing were characterised in a Deinococcus geothermalis strain. Dgeo_0257 exhibited high DNA-binding affinity and formed a multimeric structure but lacked the conserved amino acid sequence for ferroxidase activity. In contrast, the Dgeo_0281 (DgDps1) protein was abundant in the early exponential phase, had a lower DNA-binding activity than Dgeo_0257, and was mainly observed in its monomeric or dimeric forms. Electrophoretic mobility shift assays demonstrated that both purified proteins bound nonspecifically to DNA, and their binding ability was affected by certain metal ions. For example, in the presence of ferrous and ferric ions, neither Dgeo_0257 nor Dgeo_0281 could readily bind to DNA. In contrast, both proteins exhibited more stable DNA binding in the presence of zinc and manganese ions. Mutants in which the dps gene was disrupted exhibited higher sensitivity to oxidative stress than the wild-type strain. Furthermore, the expression levels of each gene showed an opposite correlation under H2O2 treatment conditions. Collectively, these findings indicate that the putative Dps Dgeo_0257 and DgDps1 from D. geothermalis are involved in DNA binding and protection in complementary interplay ways compared to known Dps.

Risk factors for multi-joint disease in patients with glucocorticoid-induced osteonecrosis.

This study investigated risk factors for osteonecrosis involving multiple joints (MJON) among glucocorticoid-treated patients. The best predictor of MJON was cumulative oral glucocorticoid dose. Risk of MJON was 12-fold higher in patients who had a second risk factor for osteonecrosis. Further research is needed into strategies for prevention of MJON. INTRODUCTION: Osteonecrosis (ON) is a debilitating musculoskeletal condition in which bone cell death can lead to mechanical failure. When multiple joints are affected, pain and disability are compounded. Glucocorticoid treatment is one of the most common predisposing factors for ON. This study investigated risk factors for ON involving multiple joints (MJON) among glucocorticoid-treated patients. METHODS: Fifty-five adults with glucocorticoid-induced ON were prospectively enrolled. MJON was defined as ON in ≥ three joints. Route, dose, duration, and timing of glucocorticoid treatment were assessed. RESULTS: Mean age of enrolled subjects was 44 years, 58% were women. Half had underlying conditions associated with increased ON risk: systemic lupus erythematosus (29%), acute lymphoblastic leukemia (11%), HIV (9%), and alcohol use (4%). Mean daily oral dose of glucocorticoids was 29 mg. Average cumulative oral dose was 30 g over 5 years. The best predictor of MJON was cumulative oral glucocorticoid dose. For each increase of 1,000 mg, risk of MJON increased by 3.2% (95% CI 1.03, 1.67). Glucocorticoid exposure in the first 6 months of therapy, peak dose (oral or IV), and mean daily dose did not independently increase risk of MJON. The risk of MJON was 12-fold in patients who had a second risk factor (95% CI 3.2, 44.4). CONCLUSIONS: Among patients with glucocorticoid-induced ON, cumulative oral dose was the best predictor of multi-joint disease; initial doses of IV and oral glucocorticoids did not independently increase risk. Further research is needed to better define optimal strategies for prevention and treatment of MJON.

The role of clonal haematopoiesis in cardiovascular diseases: epidemiology and experimental studies.

Clonal haematopoiesis results from acquired mutations in haematopoietic stem and progenitor cells (HSPCs). These mutations can confer the HSPC with a competitive advantage, leading to their clonal expansion within the limiting bone marrow niche. This process is often insufficient to produce a haematologic malignancy; however, the expanding HSPC clones increasingly give rise to progeny leucocytes whose phenotypes can be altered by the somatic mutations that they harbour. Key findings from multiple human studies have shown that clonal haematopoiesis in the absence of overt haematologic alterations is common amongst the ageing population and associated with mortality and cardiovascular disease. Key findings from experimental studies have provided evidence for a causative role for clonal haematopoiesis in cardiovascular diseases, and aspects of these mechanisms have been elucidated. Whilst our understanding of the impact and biology of clonal haematopoiesis is in its infancy, analyses of some of the most commonly mutated driver genes suggest promising clinical scenarios involving the development of personalized therapies with immunomodulatory drugs that exploit the perturbation caused by the particular mutation. Herein, we review the accumulating epidemiological and experimental evidence, and summarize our current understanding of the importance of clonal haematopoiesis as a new causal risk factor for atherosclerotic cardiovascular disease and heart failure.

Intake of Furocoumarins and Risk of Skin Cancer in 2 Prospective US Cohort Studies.

BACKGROUND: In prior studies, higher citrus consumption was associated with higher risk of cutaneous malignant melanoma, squamous cell carcinoma (SCC), and basal cell carcinoma (BCC). Furocoumarins, compounds with phototoxicity and photocarcinogenicity in citrus, may be responsible for the association. OBJECTIVES: The objective of the study was to investigate the association between furocoumarin intake and skin cancer risk. METHODS: A total of 47,453 men from the Health Professionals Follow-Up Study (HPFS) and 75,291 women from the Nurses' Health Study (NHS) with diet data collected every 2-4 y in the 2 prospective cohort studies were included. A furocoumarin food composition database for 7 common furocoumarins [bergaptol, psoralen, 8-methoxypsoralen, bergapten, 6',7'-dihydroxybergamottin (6'7'-DHB), epoxybergamottin, and bergamottin] was developed and used to calculate participants' cumulative average and energy-adjusted furocoumarin intake. Multivariate HRs and 95% CIs of the associations between furocoumarin intake and skin cancer risk were estimated using Cox proportional hazards models. Analyses were performed separately in each cohort as well as pooled using a fixed-effects model. RESULTS: Throughout follow-up (1984-2012 in the NHS and 1986-2012 in the HPFS), we identified 1593 melanoma, 4066 SCC, and 28,630 BCC cases. Higher intake of total furocoumarins was associated with an increased risk of BCC; the pooled HR comparing the top with the bottom quintile was 1.16 (95% CI: 1.11, 1.21; P-trend = 0.002). Higher intakes of bergaptol, bergapten, 6'7'-DHB, and bergamottin were also significantly associated with increased BCC risk. No significant associations were found between intake of total furocoumarins and the risks of SCC or melanoma. CONCLUSIONS: Intakes of total furocoumarins as well as some individual furocoumarins were associated with an increased risk of skin cancer, especially BCC, in 2 cohorts of US health professionals.

Efficacy and safety of evogliptin treatment in patients with type 2 diabetes: A multicentre, active-controlled, randomized, double-blind study with open-label extension (the EVERGREEN study).

AIM: To investigate the efficacy and safety of evogliptin compared with linagliptin in patients with type 2 diabetes. MATERIALS AND METHODS: In this 12-week, multicentre, randomized, double-blind, active-controlled, and 12-week open-label extension study, a total of 207 patients with type 2 diabetes who had HbA1c levels of 7.0%-10.0% were randomized 1:1 to receive evogliptin 5 mg (n = 102) or linagliptin 5 mg (n = 105) daily for 12 weeks. The primary efficacy endpoint was the change from baseline HbA1c at week 12. The secondary endpoint was the change in the mean amplitude of glycaemic excursion (MAGE) assessed by continuous glucose monitoring. In the extension study conducted during the following 12 weeks, evogliptin 5 mg daily was administered to both groups: evogliptin/evogliptin group (n = 95) and linagliptin/evogliptin group (n = 92). RESULTS: After 12 weeks of treatment, the mean change in HbA1c in the evogliptin group and in the linagliptin group was -0.85% and -0.75%, respectively. The between-group difference was -0.10% (95% CI: -0.32 to 0.11), showing non-inferiority based on a non-inferiority margin of 0.4%. The change in MAGE was -24.6 mg/dL in the evogliptin group and -16.7 mg/dL in the linagliptin group. These values were significantly lower than the baseline values in both groups. However, they did not differ significantly between the two groups. In the evogliptin/evogliptin group at week 24, HbA1c decreased by -0.94%, with HbA1c values of <7.0% in 80.2% of the patients. The incidence and types of adverse events were comparable between the two groups for 24 weeks. CONCLUSION: In this study, the glucose-lowering efficacy of evogliptin was non-inferior to linagliptin. It was maintained at week 24 with a 0.94% reduction in HbA1c. Evogliptin therapy improved glycaemic variability without causing any serious adverse events in patients with type 2 diabetes.

Redox potential change by the cystine importer affected on enzymatic antioxidant protection in Deinococcus geothermalis.

Radiation resistant bacteria genus Deinococcus species were well studied on DNA repair and anti-oxidative stress response mechanisms. There are many protection factors as enzymatic and nonenzymatic involved. One of them is intracellular redox potential as like thiol compounds including cysteine acts as primary protectant against oxidation stress. A gene cluster consisting of the genes Dgeo_1986 and Dgeo_1987 of Deinococcus geothermalis was identified as a cystine importer. The expression levels of dgeo_1986 and dgeo_1987 were up-regulated by over 60-fold and 4-fold during the late exponential (L) growth phase, respectively. The double-knockout mutant of dgeo_1986 and dgeo_1987 was reduced in cystine and thiol concentrations and leading to enhanced sensitivity against H2O2 stress. The expression of catalase (Dgeo_2728) as an enzymatic anti-oxidant is more induced in the wild-type strain than the Δdgeo_1986-87 strain at the late growth phase. The expression level of the oxidative stress response regulator OxyR (Dgeo_1888) is dependent on the intracellular redox balance. That is, when the intracellular thiol content was reduced in the wild-type strain during the L phase, OxyR was clearly induced. Interestingly, the expression level of OxyR was higher in the Δdgeo_1986-87 strain than in the wild-type strain upon H2O2 treatment. Although OxyR was induced by H2O2 treatment in Δdgeo_1986-87 strain, where intracellular redox potential of cystine was reduced as a thiol compound due to reduced cystine import, the relative level of expression of catalase was unexpectedly down-regulated. Therefore, the catalase induction system as an enzymatic antioxidant protection should be affected via the cystine importer but not rely on the OxyR controlled manner.

Combination Therapy of Microneedle Fractional Radiofrequency and Topical Poly-Lactic Acid for Acne Scars: A Randomized Controlled Split-Face Study.

BACKGROUND: Acne scarring occurs at a young age and causes distress for many patients. Various treatment modalities have been tried. OBJECTIVE: This study investigated the efficacy of combination therapy with topical poly-lactic acid and microneedle fractional radiofrequency (MFRF) for acne scars. MATERIALS AND METHODS: Patients with acne scars on both the cheeks were included. Poly-lactic acid was applied to the acne scars on one side of the face before MFRF treatment. The other side of the face was treated with MFRF and normal saline. Patients received 3 treatment sessions and were evaluated based on visual assessment and patient satisfaction. After the last treatment, objective scar assessment of scar smoothness, size, brightness, and overall improvement was performed. RESULTS: Both acne scar assessment scores and patient satisfaction were better with combination therapy (p = .036 and p = .009, respectively) than with monotherapy. Combination therapy resulted in significantly better efficacy for scar smoothness (p < .001), scar size (p = .003), and overall improvement (p < .001), but not for brightness (p = .151). CONCLUSION: Combination therapy resulted in significantly better clinical outcomes, including better scar smoothness and smaller scar size. Therefore, we believe this combination therapy is a safe and effective treatment for acne scars.

[Association between parental socioeconomic status and preschoolers' consumption of sugar-sweetened beverages].

Objective: To explore the association between parental socioeconomic status (SES) and preschoolers' consumption of sugar-sweetened beverages (SSB). Methods: In June 2018, all preschoolers from 15 kindergartens were selected from the jurisdiction of Education Commission in Dongcheng District of Beijing by using an equal-proportion stratified cluster sampling method in the study. A self-designed questionnaire was used to investigate the parents of preschoolers to obtain the basic information of preschoolers and parents, the consumption situation of preschoolers' sugar-sweetened beverages and the perception of parents to SSB. A tatol of 3 217 preschoolers were finally included in the analysis. A generalized structural equation model was used to analyze the relationship between preschoolers' consumption of sugar-sweetened beverages and their parents' socioeconomic status and the mediating effect of their cognition of sugar-sweetened beverages. The size of mediating effect was estimated by using deviation correction non-parameter percentile Bootstrap method. Results: The age of 3 217 preschoolers was (4.23±0.67) years, of which 52.6% (n=1 692) were boys, and 77.62% (n=2 497) were SSB consumers. Among the parents of 3 217 preschoolers, fathers and mothers accounted for 24.90% (n=801) and 75.10% (n=2 416), and the M (P25, P75) scores of SES were 66.7 (62.5, 69.5) and 69.5 (64.6, 71.4), respectively. The proportion of parents who took the initiative to learn about their children's consumption of SSB, lacked confidence in restricting preschooler's consumption of SSB and read nutrition labels before purchasing food was 74.08% (n=2 383), 82.90% (n=2 667) and 36.24% (n=1 166), respectively. The generalized structural equation model showed that after adjusting for preschoolers' gender, age, body mass index (BMI) of preschoolers and their parents, preschoolers' consumption of SSB was negatively associated with their parents' SES score [path coefficient (95%CI):-4.69×10-2 (-6.56×10-2,-2.69×10-2) ]. The mediating effect of parents' perception of SSB consumption could explain 48.71% of the total effect [path coefficient (95%CI):-2.28×10-2 (-3.54×10-2, -1.10×10-2)]. Conclusion: The consumption of SSB in preschoolers is negatively associated with their parent's SES, and this relationship is partially mediated by parent's perception of SSB consumption.

Anatomy, development, and plasticity of the neurosecretory hypothalamus in zebrafish.

The paraventricular nucleus (PVN) of the hypothalamus harbors diverse neurosecretory cells with critical physiological roles for the homeostasis. Decades of research in rodents have provided a large amount of information on the anatomy, development, and function of this important hypothalamic nucleus. However, since the hypothalamus lies deep within the brain in mammals and is difficult to access, many questions regarding development and plasticity of this nucleus still remain. In particular, how different environmental conditions, including stress exposure, shape the development of this important nucleus has been difficult to address in animals that develop in utero. To address these open questions, the transparent larval zebrafish with its rapid external development and excellent genetic toolbox offers exciting opportunities. In this review, we summarize recent information on the anatomy and development of the neurosecretory preoptic area (NPO), which represents a similar structure to the mammalian PVN in zebrafish. We will then review recent studies on the development of different cell types in the neurosecretory hypothalamus both in mouse and in fish. Lastly, we discuss stress-induced plasticity of the PVN mainly discussing the data obtained in rodents, but pointing out tools and approaches available in zebrafish for future studies. This review serves as a primer for the currently available information relevant for studying the development and plasticity of this important brain region using zebrafish.

Recurrence, death, and secondary malignancy after ovarian conservation for young women with early-stage low-grade endometrial cancer.

OBJECTIVE: To examine the association between ovarian conservation and oncologic outcome in surgically-treated young women with early-stage, low-grade endometrial cancer. METHODS: This multicenter retrospective study examined women aged <50 with stage I grade 1-2 endometrioid endometrial cancer who underwent primary surgery with hysterectomy from 2000 to 2014 (US cohort n = 1196, and Japan cohort n = 495). Recurrence patterns, survival, and the presence of a metachronous secondary malignancy were assessed based on ovarian conservation versus oophorectomy. RESULTS: During the study period, the ovarian conservation rate significantly increased in the US cohort from 5.4% to 16.4% (P = 0.020) whereas the rate was unchanged in the Japan cohort (6.3-8.7%, P = 0.787). In the US cohort, ovarian conservation was not associated with disease-free survival (hazard ratio [HR] 0.829, 95% confidence interval [CI] 0.188-3.663, P = 0.805), overall survival (HR not estimated, P = 0.981), or metachronous secondary malignancy (HR 1.787, 95% CI 0.603-5.295, P = 0.295). In the Japan cohort, ovarian conservation was associated with decreased disease-free survival (HR 5.214, 95% CI 1.557-17.464, P = 0.007) and an increased risk of a metachronous secondary malignancy, particularly ovarian cancer (HR 7.119, 95% CI 1.349-37.554, P = 0.021), but was not associated with overall survival (HR not estimated, P = 0.987). Ovarian recurrence or metachronous secondary ovarian cancer occurred after a median time of 5.9 years, and all cases were salvaged. CONCLUSION: Our study suggests that adoption of ovarian conservation in young women with early-stage low-grade endometrial cancer varies by population. Ovarian conservation for young women with early-stage, low-grade endometrial cancer may be potentially associated with increased risks of ovarian recurrence or metachronous secondary ovarian cancer in certain populations; nevertheless, ovarian conservation did not negatively impact overall survival.

Data-Driven Method for Efficient Characterization of Rare Event Probabilities in Biochemical Systems.

As mathematical models and computational tools become more sophisticated and powerful to accurately depict system dynamics, numerical methods that were previously considered computationally impractical started being utilized for large-scale simulations. Methods that characterize a rare event in biochemical systems are part of such phenomenon, as many of them are computationally expensive and require high-performance computing. In this paper, we introduce an enhanced version of the doubly weighted stochastic simulation algorithm (dwSSA) (Daigle et al. in J Chem Phys 134:044110, 2011), called dwSSA[Formula: see text], that significantly improves the speed of convergence to the rare event of interest when the conventional multilevel cross-entropy method in dwSSA is either unable to converge or converges very slowly. This achievement is enabled by a novel polynomial leaping method that uses past data to detect slow convergence and attempts to push the system toward the rare event. We demonstrate the performance of dwSSA[Formula: see text] on two systems-a susceptible-infectious-recovered-susceptible disease dynamics model and a yeast polarization model-and compare its computational efficiency to that of dwSSA.

[The surveillance of Yersiniosis among children in central area of Beijing from 2011 to 2018].

Objective: To illuminate the epidemic characteristics of Yersiniosis among children in the central city of Beijing and the accuracy of current clinical diagnosis towards Yersiniosis. Methods: Etiological surveillance of diarrheal patients, a total of 3 493 cases, was performed in a children hospital in central area of Beijing from 2011 to 2018 continuously. Collected the epidemiological and clinical information of the cases, analyzed the clinical and etiological diagnosis for Yersiniosis and bacterial dysentery and compared the distribution of Yersiniosis cases with the different symptoms. Results: A total of 3 493 acute diarrhea cases distributed from the age of 6 months to 13 years old, M (P(25), P(75)) was 1.50 (0.75, 3.17) years old. The 28 cases were isolated Yersinia enterocolitica (isolation rate of 0.80%) and they could be diagnosed as Yersiniosis by etiology. The isolation peaked in May and February. A total of 85.71% (24/28) of Yersiniosis cases were under 5-year old. The children of 3-4 age group had the highest isolation rate (1.52%) while the rate (0.18%) of 0-1 age group was the lowest (P=0.025). The Yersinia enteroclitica isolation rates of diarrheal patients with the symptoms including mucus feces, fever, white blood cell (WBC) and red blood cell (RBC) in feces were higher than the patients without these symptoms (P>0.05). The 9 of 28 Yersiniosis cases by etiology diagnosis were clinical diagnosed as bacillary dysentery. Conclusion: The infants and young children under 5-year old were the main population of Yersiniosis adolescent patients under 14-year old. The typical symptoms characterized with mucus stool, fever, WBC and RBC by routine microscopic examination. The preliminary clinical diagnosis of Yersiniosis is easily confused with bacterial dysentery.

Hypersensitivity incidence after sugammadex administration in healthy subjects: a randomised controlled trial.

BACKGROUND: We evaluated the incidence of hypersensitivity or anaphylaxis after repeated single-dose sugammadex administration in non-anaesthetised adults. METHODS: In this multicentre, double-blind study (NCT02028065), healthy volunteer subjects were randomised (2:2:1 ratio) to one of three groups to receive three repeated intravenous injections of sugammadex 4 or 16 mg kg-1, or placebo, separated by a ∼5 week intervals. Targeted hypersensitivity assessments were performed 0.5, 4, and 24 h post-dosing, and hypersensitivity signs/symptoms were referred to a blinded independent Adjudication Committee. Anaphylaxis was determined per Sampson (Criterion 1). The primary endpoint was the proportion with confirmed hypersensitivity. RESULTS: Of 375 evaluable subjects, 25 had confirmed hypersensitivity [sugammadex 4 mg kg-1: 10/151 (6.6%); sugammadex 16 mg kg-1: 14/148 (9.5%); placebo: 1/76 (1.3%)]. The differences in incidence rates vs placebo were 5.3% (95% confidence interval: -0.9, 10.7) for sugammadex 4 mg kg-1 and 8.1% (1.7, 14.2) for 16 mg kg-1. Incidence was similar across sugammadex doses and dosing occasions, including in subjects with reactions to previous doses. Three subjects (16 mg kg-1 group) required antihistamines/corticosteroids and discontinued the study, per protocol; symptoms resolved and no subject required epinephrine. One subject with anaphylaxis after the first 16 mg kg-1 dose recovered completely post-treatment. There were no clinically relevant anti-sugammadex antibody or tryptase findings. CONCLUSIONS: Hypersensitivity in response to sugammadex administration can occur in healthy subjects without history of previous sugammadex exposure. Hypersensitivity incidence was similar across sugammadex doses and numerically higher than placebo, with no evidence of sensitisation with repeated administration. Hypersensitivity is unlikely to be mediated through sugammadex-specific immunoglobulin G- or E-mediated mast cell stimulation in healthy volunteers. CLINICAL TRIAL REGISTRATION: NCT02028065.

Sugammadex hypersensitivity and underlying mechanisms: a randomised study of healthy non-anaesthetised volunteers.

BACKGROUND: We investigated potential for hypersensitivity reactions after repeated sugammadex administration and explored the mechanism of hypersensitivity. METHODS: In this double-blind, placebo-controlled study (NCT00988065), 448 healthy volunteers were randomised to one of three arms to receive three repeat i.v. administrations of either sugammadex 4 mg kg-1, 16 mg kg-1, or placebo. Primary endpoint was percentage of subjects with hypersensitivity (assessed by an independent adjudication committee). Secondary endpoint of anaphylaxis was classified per Sampson and Brighton criteria. Exploratory endpoints included skin testing, serum tryptase, anti-sugammadex antibodies [immunoglobulin (Ig) E/IgG], and other immunologic parameters. RESULTS: Hypersensitivity was adjudicated for 1/148 (0.7%), 7/150 (4.7%), and 0/150 (0.0%) subjects after sugammadex 4 mg kg-1, 16 mg kg-1, and placebo, respectively. After sugammadex 16 mg kg-1, one subject met Sampson criterion 1 and Brighton level 1 (highest certainty) anaphylaxis criteria; two met Brighton level 2 criteria. After database lock it was determined that certain protocol deviations could have introduced bias in the reporting of hypersensitivity signs/symptoms in a subject subset. Objective laboratory investigations indicated that potential underlying hypersensitivity mechanisms were unlikely to have been activated; the results suggest that most of the observed hypersensitivity reactions were unlikely IgE/IgG-mediated. CONCLUSION: Dose-dependent hypersensitivity or anaphylaxis reactions to sugammadex were observed when administered without prior neuromuscular blocking agent. Laboratory investigations do not suggest prevalent allergen-specific IgE/IgG-mediated immunologic hypersensitivity. Because it could not be fully excluded that estimates of hypersensitivity/anaphylaxis incidence were unbiased, an additional study was conducted to characterise the potential for hypersensitivity reactions and is described in a companion report. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov NCT00988065; Protocol number P06042.

The mechanism of attenuation of epithelial-mesenchymal transition by a phosphodiesterase 5 inhibitor via renal klotho expression.

Phosphodiesterase-5 (PDE-5) inhibitors induces vasodilation in several organs by blocking cyclic GMP (guanosine monophosphate) degradation. However, the existence of alternative mechanism of action in case of an impaired nitric oxide (NO) system remains controversial. Previous studies suggested that decreased NO bioavailability may result in the downregulation of klotho expression, but the relationship between klotho and NO remains obscure. Therefore, we investigated whether a PDE-5 inhibitor could preserve epithelial-mesenchymal transition (EMT) and relationship exists between the NO and renal klotho expression. Ten-week-old SD rats (N = 24, 200 g, male) were divided (N = 6) into four groups, which received: A LSD, L-NAME 1 mg/mL in drinking water, Udenafil 5 mg/kg subcutaneously and both for 4 weeks. Urine nitrate/nitrite, NGAL (Neutrophil gelatinase-associated lipocalin), and cGMP were measured using ELISA. Kidney was subjected to evaluate PCNA (proliferative cell nuclear antigen), α-SMA (smooth muscle cell antigen), E-cadherin, and klotho expression. Urine cGMP decreased after treatment of PDE-5 inhibitor compared with control due to blocking degradation of cGMP (P < .05, control vs Udenafil and L-NAME with Udenafil groups). Urine NGAL increased after treating of L-NAME and attenuated after using PDE-5 inhibitor (P < .05, control vs L-NAME and L-NAME with Udenafil). PCNA, α-SMA, and E-cadherin (EMT markers) increased after L-NAME treatment and normalized after using PDE-5 inhibitor. Klotho expression showed trend to increase in the L-NAME with PDE-5 inhibitor group compared with the L-NAME group, however, eNOS expression did not change after treatment of L-NAME or PDE-5 inhibitor compared with control. PDE-5 inhibitor alleviates EMT in the kidney via klotho modulation independent of the NO system.

Flux balance analysis of primary metabolism in the diatom Phaeodactylum tricornutum.

Diatoms (Bacillarophyceae) are photosynthetic unicellular microalgae that have risen to ecological prominence in oceans over the past 30 million years. They are of interest as potential feedstocks for sustainable biofuels. Maximizing production of these feedstocks will require genetic modifications and an understanding of algal metabolism. These processes may benefit from genome-scale models, which predict intracellular fluxes and theoretical yields, as well as the viability of knockout and knock-in transformants. Here we present a genome-scale metabolic model of a fully sequenced and transformable diatom: Phaeodactylum tricornutum. The metabolic network was constructed using the P. tricornutum genome, biochemical literature, and online bioinformatic databases. Intracellular fluxes in P. tricornutum were calculated for autotrophic, mixotrophic and heterotrophic growth conditions, as well as knockout conditions that explore the in silico role of glycolytic enzymes in the mitochondrion. The flux distribution for lower glycolysis in the mitochondrion depended on which transporters for TCA cycle metabolites were included in the model. The growth rate predictions were validated against experimental data obtained using chemostats. Two published studies on this organism were used to validate model predictions for cyclic electron flow under autotrophic conditions, and fluxes through the phosphoketolase, glycine and serine synthesis pathways under mixotrophic conditions. Several gaps in annotation were also identified. The model also explored unusual features of diatom metabolism, such as the presence of lower glycolysis pathways in the mitochondrion, as well as differences between P. tricornutum and other photosynthetic organisms.