Adverse Event Detection and Labeling in Pediatric Drug Development: Antiretroviral Drugs.
Pediatric safety studies are conducted for drugs undergoing development for use in pediatric patients. The objective of this study was to describe safety studies and compare adverse events of antiretroviral drugs between pediatric patients and adult subjects. Pediatric and adult adverse event data were obtained from US Food and Drug Administration (FDA)-approved drug labels for 9 antiretroviral drugs with pediatric indications approved by the FDA prior to 2013. For adverse events (AEs) reported in both pediatric patients and adult subjects, the risk difference (RD) and associated confidence interval (CI) were calculated. Of 35 drug-AE combinations, 10 AEs were reported at statistically significantly ( P < .05) higher incidence rates in the pediatric population than in the adult population, and 3 AEs were reported at statistically significantly higher rates in the adult population than in the pediatric population. The largest differences where the risk of an AE was greater in pediatric patients than in adult subjects were for rash with efavirenz (RD = 36.24% [95% CI, 21.1 to 50.53]), diarrhea with efavirenz (RD = 24.53% [95% CI, 9.06 to 39.57]), and rash with nevirapine (RD = 16.14% [95% CI, 9.7 to 24.27]). The largest differences where the risk of an adverse event was lower in pediatric patients than in adult subjects were for headache with abacavir (RD = -12% [95% CI, -16.81 to -6.89]), diarrhea with tipranavir (RD = -11.32% [95% CI, -15.02 to -5.6]), and diarrhea with lamivudine (RD = -9.88% [95% CI, -15.91 to -3.98]). The adult adverse event experience provides preliminary data for pediatric drug safety, yet the specific types of adverse effects and frequencies may not be predicted in children based exclusively on adults. As adult safety data do not fully inform the pediatric safety profile, pediatric safety studies should continue to be conducted separately for drugs undergoing testing in pediatric patients.


Endothelin-1 promotes Ca2+ antagonist-insensitive coronary smooth muscle contraction via activation of epsilon-protein kinase C.
Certain forms of coronary artery disease do not respond to treatment with Ca2+ channel blockers, and a role for endothelin-1 (ET-1) in Ca2+ antagonist-insensitive forms of coronary vasospasm has been suggested; however, the signaling mechanisms involved are unclear. We tested the hypothesis that a component of ET-1-induced coronary smooth muscle contraction is Ca2+ antagonist-insensitive and involves activation of protein kinase C (PKC). Cell contraction was measured in smooth muscle cells isolated from porcine coronary artery, [Ca2+]i was measured in fura-2 loaded cells, and the cytosolic and particulate fractions were examined for PKC activity and reactivity with isoform-specific PKC antibodies using Western blot analysis. In Hank's solution (1 mmol/L Ca2+), ET-1 (10(-7) mol/L) caused a transient increase in [Ca2+]i (236+/-14 nmol/L) followed by a maintained increase in [Ca2+]i (184+/-8 nmol/L) and 35% cell contraction. The Ca2+ channel blockers verapamil and diltiazem (10(-6) mol/L) abolished the maintained ET-1-induced [Ca2+]i, but only partially inhibited ET-1-induced cell contraction to 18%. The verapamil-insensitive component of ET-1 contraction was inhibited by the PKC inhibitors calphostin C and epsilon-PKCV1-2. ET-1 caused translocation of Ca2+-dependent alpha-PKC and Ca2+-independent epsilon-PKC from the cytosolic to the particulate fraction that was inhibited by calphostin C. Verapamil abolished ET-1-induced translocation of alpha-PKC, but not that of epsilon-PKC. Phorbol 12-myristate 13-acetate (10(-6) mol/L), a direct activator of PKC, caused 22% cell contraction, with no increase in [Ca2+]i, and translocation of epsilon-PKC that was inhibited by calphostin C, but not by verapamil. KCl (51 mmol/L), which stimulates Ca2+ influx, caused 35% cell contraction and increase in [Ca2+]i (291+/-11 nmol/L) that were inhibited by verapamil, but not by calphostin C, and did not cause translocation of alpha- or epsilon-PKC. In Ca2+-free (2 mmol/L EGTA) Hank's solution, ET-1 caused 15% cell contraction, with no increase in [Ca2+]i, and translocation of epsilon-PKC that were inhibited by epsilon-PKC V1-2 inhibitory peptide. Thus, a significant component of ET-1-induced contraction of coronary smooth muscle is Ca2+ antagonist-insensitive and involves activation and translocation of Ca2+-independent epsilon-PKC, and may represent a signaling mechanism of Ca2+ antagonist-resistant forms of coronary vasospasm.


COVID-19 aerodynamic evaluation of social distancing in indoor environments, a numerical study.
Many countries worldwide have taken early measures to combat the spread of coronavirus SARS-CoV-2 by implementing social distancing measures. The main aim of the present work is to examine the feasibility of social distancing (i.e. 1.5 m) in closed spaces taking into account the possibility for airborne transmission of SARS-CoV-2. A 3D numerical model of human respiration activities, such as breathing and speaking within indoor environments has been simulated with CFD software AVL FIRE R2020. The Eulerian-Eulerian flow model coupled with k-Ɛ approach were employed. With regard to breathing mode, the infected individual is modelled to be breathing 10 times per minute with a pulmonary rate of 6 L/min with a sinusoidal cycle. The present investigation considered air and droplets/particles as separate phases. The predicted results suggested that the social distancing (i.e. 1.5 m) is not adequate to reduce the risk of contracting diseases like COVID-19, especially when staying for a longer period in an indoor environment. The person directly facing the infected person inhaled more than 1000 aerosol droplets within 30 min. The results also showed approximately 65 % decrease in the number of inhaled droplets the room is well ventilated. Within an indoor environment, 1.5 m distance will not be enough to protect the healthy individuals from the droplets coming from an infected person. Also, the situation may become worse with the change of the air ventilation system.


Measurements and model calculations of activation cross sections for (n,p) reactions on 152Sm isotope between 13.57 and 14.83 MeV neutrons.
The activation cross sections were measured at six neutron energies from 13.57 and 14.83 MeV for (152)Sm(n,p)(152 g)Pm, (152)Sm(n,p)(152 m)Pm reactions. The production of short-lived activity and the spectra accumulation have been carried out by the cyclic activation method. Statistical model calculations, which the pre-equilibrium emission effects were taken into consideration were also performed (STAPRE code). The cross sections were compared with works in the literature, model calculation results, and evaluation data bases (ENDF/B-VII, JENDL-3.3, JEFF-3.1).


The treatment of disabling single-level lumbar discogenic low back pain with total disc arthroplasty utilizing the Prodisc prosthesis: a prospective study with 2-year minimum follow-up.
Prospective, longitudinal minimum 2-year follow-up. To assess the efficacy and safety of the Prodisc implant in patients with disabling single-level discogenic low back pain (LBP). The treatment of debilitating discogenic LBP has been controversial and varied. To date, a longitudinal prospective study of the treatment of single-level incapacitating discogenic LBP using the Prodisc total disc arthroplasty technique has not been described. A prospective analysis was performed on 118 patients treated with single-level lumbar Prodisc total disc arthroplasty. Patients 18 to 60 years of age with disabling and recalcitrant discogenic LBP with or without radicular pain secondary to single-level discogenic LBP from L3 to S1 were included. Patients were assessed before surgery, and outcome measurements were after surgery administered at 3, 6, 12, and 24 months. A total of 104 patients (88%) fulfilled all follow-up criteria. The median age of all patients was 47 years (range, 36-60 years). Statistical improvements in VAS, Oswestry, and patient satisfaction scores occurred 3 months postoperatively. These improvements were maintained at the 24-month follow-up. Radicular pain also decreased significantly. Full-time and part-time work rates increased from 10% to 35% and 3% to 24%, respectively. No additional fusion surgeries were necessary either at the affected or unaffected levels. Radiographic analysis revealed an affected disc height increase from 4 mm to 13 mm (P < 0.001) and an affected disc motion from 3 degrees to 7 degrees (P < 0.004). Single-level Prodisc lumbar total disc arthroplasty is a safe and efficacious treatment method for debilitating lumbar discogenic LBP. Significant improvements in patient satisfaction and disability scores occurred after surgery by 3 months and were maintained at the 2-year follow-up. No device-related complications occurred. Patients with severe to moderate disc height loss as well as those with symptomatic posterior anular defects with minimal disc height loss achieve functional gains and significant pain relief. Careful and appropriate patient selection is essential in ensuring optimal surgical outcomes.


Natural production and functional effects of alternatively spliced interleukin-4 protein in asthma.
We have previously described an alternatively spliced isoform of IL-4 mRNA that omits exon 2 and is termed IL-4δ2. However, the natural production of IL-4δ2 protein and its association with disease have not been previously assessed due to unavailability of an antibody that interacts with IL-4δ2 without cross-reactivity with full length IL-4. We used a unique monoclonal antibody (mAb) that reacts with IL-4δ2, but not with IL-4, and observed that IL-4δ2 is naturally produced by T cells from patients with asthma, but not from healthy controls. The kinetics of IL-4δ2 and IL-4 production by phorbol myristate acetate (PMA)/ionomycin-activated cells differed, with IL-4δ2 increasing at 48-72h and IL-4 peaking at 24h. The steady-state levels of IL-4δ2 mRNA varied significantly among the donors and were discordant with the corresponding protein levels, suggesting post-transcriptional regulation of protein production. Polarized Th1 or Th2 lymphocytes were not a major source of IL-4δ2. Stimulation of cultured T lymphocytes with IL-4δ2 caused elevated production of IFN-γ, IL-10, IL-6, MCP-1, and TNF-α, with notable differences between patients and controls in the production of IFN-γ, IL-10, and IL-6. Thus, IL-4δ2 is natively produced not only as mRNA but also as a protein by cells other than Th1 or Th2. It is regulated post-transcriptionally, is associated with allergic asthma, and regulates production of other cytokines by primary T lymphocytes. Alternatively spliced interleukin-4 may be a new biomarker, a pathophysiological player, and possibly a molecular target for future therapies in asthma.


Hybrid Russe Procedure for Scaphoid Waist Fracture Nonunion With Deformity.
To assess the results of a hybrid Russe procedure using a corticocancellous strut, cancellous autologous nonvascularized bone graft, and cannulated headless compression screw to reduce the deformity reliably from a collapsed scaphoid nonunion, provide osteoinductive stimulus, and stabilize the fracture for predictable union. A hybrid Russe procedure was performed for scaphoid waist fracture nonunions with humpback deformity and no evidence of avascular necrosis. A volar distal radius autologous bone graft was harvested and a strut of cortical bone was fashioned and placed into the nonunion site to restore length and alignment. We packed cancellous bone graft in the remainder of the nonunion site and fixed the scaphoid was with a headless compression screw. Union was determined by radiographs or computed tomography, and intrascaphoid, scapholunate, and radiolunate angles were calculated on final radiographs. We recorded wrist range of motion, grip strength, pinch strength, pain, and complications. Fourteen male and 3 female patients (average age, 32 years; range, 16-78 years), with a mean follow-up of 32 months, were examined clinically and radiographically. All 17 scaphoids united with a mean time for union of 3.6 months. The mean postoperative intrascaphoid angle was significantly reduced from 65° preoperatively to 35° postoperatively. The mean radiolunate angle was significantly improved from 20° from neutral (lunate tilted dorsally) preoperatively to 0° postoperatively. The scapholunate angle also demonstrated significant improvement from 70° preoperatively to 56° postoperatively. Grip strength improved from 70% of the contralateral hand to 89% after the procedure. All patients were satisfied with the functional outcome and no donor site morbidity or hardware issues were identified. This straightforward hybrid Russe technique predictably restored radiolunate, scapholunate, and intrascaphoid angles with a 100% union incidence. The technique provides excellent functional results in patients with a challenging clinical problem, and we recommend it for scaphoid fracture waist nonunions with dorsal intercalated segment instability deformity. Therapeutic IV.


[A critical analysis of physical activity recommendations in Spain].
To identify official documents with recommendations on physical activity published by the autonomous regions of Spain with the goal of evaluating their compliance with the physical activity recommendations of the World Health Organization (WHO). We conducted a content analysis of 55 documents of the ministries of health of several regional governments containing recommendations on physical activity. Eighty-four percent of the autonomous regions in Spain made recommendations on aerobic physical activity and 37% made recommendations on strength training. However, the number of documents consistent with the WHO criteria was as follows: aerobic activity (n=11, 58%), adults (n=10, 53%), the elderly (n=5, 26%), children/adolescents (n=1, 5%); strength training, adults (n=6, 32%), the elderly (n=3, 16%), children/adolescents (n=1, 5%); balance (n=5, 26%); at least 10minutes continuous physical activity (n=6, 32%); recommendation of up to 300minutes per week (n=10, 53%); intensity of physical activity (n=2, 11%). The recommendations of the autonomous regions tend to focus on aerobic physical activity and to under-represent strength training. Moreover, only one autonomous region conforms to the WHO recommendations for physical activity. The regions with higher rates of population aging and a higher percentage of children and adolescents fail to make recommendations on physical activity consistent with the WHO guidelines.


People versus machines: The impact of being in an automatable job on Australian worker's mental health and life satisfaction.
This study explores the effect on mental health and life satisfaction of working in an automatable job. We utilise an Australian panel dataset (HILDA), and take a fixed effects linear regression approach, to relate a person being in automatable work to proxies of their wellbeing. Overall, we find evidence that automatable work has a small, detrimental impact on the mental health and life satisfaction of workers within some industries, particularly those with higher levels of job automation risk, such as manufacturing. Furthermore, we find no strong trends to suggest that any particular demographic group is disproportionately impacted across industries. These findings are robust to a variety of specifications. We also find evidence of adaptation to these effects after one-year tenure on the job, indicating a limited role for firm policy.


Can Anyone Hear Me? Does Anyone See Me? A Qualitative Meta-Analysis of Women's Experiences of Heart Disease.
Female heart patients are underdiagnosed and undertreated. The purpose of this qualitative meta-data-analysis was to explain how societal expectations related to gender and the treatment environment influence women's experiences and can inform optimal care. The authors used grounded theory methodology and a social constructionist gender lens to analyze 43 studies (1993-2012) of women's experiences of heart disease. The analysis illustrates how social expectations within both medical and relational contexts led to women experiencing barriers to diagnosis and treatment and inadvertent minimization of their experience and knowledge. Women's descriptions of their experiences suggest three kinds of health care strategies that have the potential to increase women's engagement with heart disease treatment and rehabilitation: (a) support give and take in relational connections, (b) identify and acknowledge unique health-promoting behavior, and (c) focus on empowerment. These findings have interdisciplinary implications for practice with women with heart disease.


Visceral leishmaniasis in immunocompromised hosts.
Visceral leishmaniasis is infrequently reported in immunocompromised hosts; hence, the clinical manifestations and outcome of the disease in these patients are unknown. In a series of 10 patients with visceral leishmaniasis complicating renal transplantation (three), hematologic neoplasms (two), systemic lupus erythematosus (two), or infection with human immunodeficiency virus (three), typical hallmarks of kalaazar such as enlargement of spleen or hyperglobulinemia were absent in three and six patients, respectively. Extensive visceral involvement was noted by biopsies or autopsies in four patients. Diagnosis was made during evaluation for fever of unknown origin. Myriads of amastigotes were seen in bone marrow smears. Measurement of antibodies against Leishmania donovani was positive in each patient tested. Ultimately, three patients died, and chronic infections refractory to treatment developed in two other patients. Visceral leishmaniasis is a potentially fatal infection in immunocompromised hosts. Current antiparasitic therapy frequently fails to eradicate L. donovani from infected tissues.


Involvement of aldolase A in X-ray resistance of human HeLa and UV(r)-1 cells.
To find novel proteins involved in radio-resistance of human cells, we searched for nuclear proteins, whose expression levels alter after X-ray irradiation in HeLa cells, using agarose fluorescent two-dimensional differential gel electrophoresis following mass spectrometry. We identified 6 proteins, whose levels were increased in nuclei 24h after irradiation at 5Gy, including aldolase A. Nuclear aldolase A levels increased twofold after the irradiation, however, total aldolase A levels did not change. When the expression of aldolase A was suppressed by its specific siRNA, sensitization of the suppressed cells to X-ray-induced cell death was observed. In addition, UV(r)-1 cells with higher aldolase A expression exhibited lower sensitivity to X-ray-induced cell death than the parental RSa cells with lower aldolase A expression. These results suggest that aldolase A may play a role in the radio-response of human cells, probably in nuclei, in addition to its glycolytic role in the cytosol.


Major Pathologic Response and Prognostic Score Predict Survival in Patients With Lung Cancer Receiving Neoadjuvant Chemotherapy.
Complete pathologic response (CPR) is an acceptable surrogate for survival in clinical trials but it occurs infrequently in patients with NSCLC receiving neoadjuvant chemotherapy (NCT). Therefore, we studied the impact of major pathologic response (MPR) for predicting survival of patients with NSCLC receiving NCT. We also tested a newly reported scoring system-the prognostic score (PRSC)-which combines T category, lymph node status, and MPR status. We analyzed CPR and MPR, defined as 0% and less than or equal to 10% viable tumor cells, respectively, in 339 patients with NSCLC with various histologic types who had been treated with NCT followed by complete surgical resection. We evaluated the relationships between CPR, MPR, or PRSC and overall survival using the Kaplan-Meier method and Cox regression multivariate models, accounting for known prognostic factors, such as age, gender, histologic subtype, and pathologic stage. Among all 339 patients, the Kaplan-Meier method revealed that patients with CPR and MPR had better survival. MPR identified a favorable group of patients who experienced survival similar to patients with CPR. Nevertheless, patients with no MPR had a significantly reduced probability of survival. Furthermore, univariate and multivariate Cox proportional hazards regression analysis revealed that MPR and PRSC were significantly associated with overall survival. Our data suggest that MPR can be used as an end point for overall survival in different histologic types for evaluation of therapeutic agents in clinical trials exploring NCT. We also confirmed that PRSC had a prognostic impact, differentiating patients into three prognostic groups, but not superior compared with MPR alone or the TNM8 systems.


Catchment and lake network modify export of anaerobic oxidation capacity in boreal freshwaters.
Anaerobic terminal electron acceptors (aTEAs, i.e. NO3, Fe, SO4) enable anaerobic respiration, and each has a specific ability to oxidize reduced compounds. However, little is known about how seasonal and lake-specific aTEA fluxes form anaerobic oxidation capacity (AOC) to oxidize organic carbon in boreal systems. We compiled 26 years of data from two interconnected semi-pristine boreal lakes and defined mean daily imports, pools, and exports of aTEAs. In both lakes, the export of NO3 formed 2 %-3 % of the total AOC in summer and autumn, and up to 11 % in winter and spring. In a predominantly monomictic humic lake surrounded by peatlands, Fe was responsible for 15 %-31 % of the seasonal export of AOC, with a large proportion of Fe originating from the lake bottom. A dimictic clear-water lake downstream retained Fe and exported 87 %-95 % of AOC as SO4. In the humic lake, the annual SO4:Fe:NO3 export ratio for AOC was 10:3:1 and in the clear-water lake 15:0.4:1. In the monomictic lake, exports were specifically regulated by stratification; in the dimictic lake, exports were more regulated by spring flooding and the ascending and descending side of the peak flood. These events modified lake dynamics and caused lake-specific NO3, Fe, and SO4 exports which continued for months. We conclude that a catchment and lake network can cause spatial and temporal variation in exports of NO3, Fe, and SO4 affecting AOC export. Such natural variations in exports have significant potential to modify the system's capacity to oxidize C and resist changes in oxidation-reduction reactions coupled to nutrient cycling and the formation of greenhouse gases in downstream water bodies.


Voxel-based assessments of treatment effects on longitudinal brain changes in the Multidomain Alzheimer Preventive Trial cohort.
The Multidomain Alzheimer Preventive Trial was designed to assess the effect of omega-3 supplementation and multidomain intervention on cognitive decline of subjects with subjective memory complaint. In terms of cognitive testing, no significant effect was found. In this paper, we evaluate the effect of the interventions on the brain morphological changes. Subjects with magnetic resonance imaging acquisitions at baseline and at 36 months were included (N = 376). Morphological changes were characterized by volume measurements and nonlinear deformation. The multidomain intervention was associated with a significant effect on the 3-year brain morphological changes in the deformation-based approach. Differences were mainly located in the left periventricular area next to the temporoparietal junction. These changes were associated with better cognitive performance and mood/behavior stabilization. No effect of the omega-3 supplementation was observed. This result suggests a possible effect on cognition, not yet observable after 3 years. We argue that neuroimaging could help define whether early intervention strategies are effective to delay cognitive decline and dementia.


Prevalence of meticillin-resistant Staphylococcus pseudintermedius (MRSP) from skin and carriage sites of dogs after treatment of their meticillin-resistant or meticillin-sensitive staphylococcal pyoderma.
Meticillin-resistant staphylococci are significant pathogens in veterinary dermatology, yet longitudinal studies of the impact of routine antimicrobial therapy on emergence or resolution of resistance are lacking. To determine the prevalence of meticillin-resistant staphylococci on skin and carriage sites in dogs with bacterial pyoderma and evaluate the prevalence of meticillin-resistant Staphylococcus pseudintermedius (MRSP) colonization after successful treatment of pyoderma. One hundred and seventy-three dogs that presented to a dermatology referral service with pyoderma and 41 healthy control dogs. Skin, nasal and rectal swabs for bacterial culture were collected at the time of referral and after clinical resolution of the pyoderma. Meticillin resistance was confirmed by demonstration of penicillin binding protein 2a antigen. Initially, skin cultures yielded MRSP in 70 (40.5%) dogs, meticillin-resistant Staphylococcus aureus (MRSA) in three (1.7%) and meticillin-resistant Staphylococcus schleiferi ssp. coagulans (MRSScoag) in five (2.9%). Samples collected from the nose and rectum (carriage sites) yielded MRSP in 59 (34.1%) dogs, MRSA in 11 (6.4%) and MRSScoag in seven (4.0%). One hundred and two dogs were available for follow-up cultures after clinical cure. Of 42 dogs initially diagnosed with MRSP pyoderma, MRSP was isolated at follow-up from skin in 19 (45.2%) and carriage sites in 20 (47.6%). Of 60 dogs that did not have MRSP pyoderma initially, MRSP was isolated post-treatment from the skin in 17 (28.3%), and MRSP from carriage sites increased from 7.8% (initially) to 26.7% (P = 0.0022). Colonization by MRSP often persists after resolution of MRSP pyoderma. Acquisition of MRSP during treatment appears to be common.


The volar extension of the lunate facet of the distal radius: a quantitative anatomic study.
To describe quantitatively the protrusion of the volar part of the lunate facet of the distal radius articular surface anterior to the volar metaphyseal cortex, which is susceptible to fracture and can be difficult to control with plates and screws alone. Quantitative anatomic measurements of 48 3-dimensional computed tomography scans of the distal radius were analyzed to quantify the anatomy of the volar part of the lunate facet of the distal radius. The measurements were scaled to account for overall bone size. Male and female anatomies were compared. The height and width of the volar extension of the lunate facet were 3 +/- 1 mm and 19 +/- 4 mm, respectively. The mean height of the lunate facet was 19 +/- 3 mm. An average of 16% of the lunate facet projects anterior to the flat volar surface of the distal radius. The thickness of the volar extension of the lunate facet averaged 5 +/- 1 mm. There were no statistically significant differences between men and women for any of the scaled measurements. The observation that the volar lunate facet projects approximately 3 mm (or 16% of the dorsal-volar height of the lunate facet) anterior to the flat volar surface of the distal radius and is approximately 5 mm thick helps explain its relative vulnerability to injury and the difficulty encountered when trying to secure it with a plate and screws.


Chromatic response mechanisms in the human fovea as measured by threshold spectral sensitivity.
Threshold sensitivity was measured with 40-degree surrounds of 5.3 and 800 trolands of white, and 509, 580, and 690 mmicro spectral light. With the brighter white surround there appeared peaks at 550, and 570 and a shoulder at 600 mmicro. These were selectively eliminated by the spectral surrounds.


Interferon production by mammalian cells grown in a serum-free medium.
Interferon, produced by rabbit heart cells grown in a serum-free medium, failed to protect rabbit heart serum-free cells, but protected rabbit heart serum-containing-medium cells against vaccinia and vesicular stomatitis virus. Interferon produced in serum-free cells had a greater species specificity than that produced in serum-containing media. The difference in activity was shown to be due to lack of adsorption by serum-free-medium cells.


Endovascular Management of Hemarthrosis in Patients with Bleeding Diatheses: Systematic Review.
In this systematic review, we report the safety and efficacy of embolization for treating hemarthrosis in patients with bleeding diatheses with or without a history of prior arthroplasty. A systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analysis guidelines. A structured search was performed in PubMed, Web of Science, MEDLINE, and SCOPUS databases of patients undergoing embolization for hemarthrosis. Demographic data, clinical history, angiographic findings, interventions, and outcomes were extracted and tabulated. The search identified 97 unique titles of which 15 were deemed relevant comprising 78 patients with coagulopathies undergoing 93 embolization procedures. Mean follow-up time was 29 months (range 3-116.5). In the 29 patients who underwent arthroplasty prior to embolization for hemarthrosis, there were 11 bleeding recurrences (37.9%). Of these patients who experienced recurrences, 10 underwent repeat embolization as coagulation factor replacement was not sufficient to address the re-bleeding. In the 49 patients with bleeding diatheses who underwent embolization for hemarthrosis with no history of prior arthroplasty, there were 11 recurrences (22.4%) and 4 of these patients underwent repeat embolization with favorable results. There were four major procedure-related complications. Transarterial embolization is safe and effective in addressing recurrent hemarthrosis in patients with bleeding diatheses with or without a history of arthroplasty of the affected joint.


Purification and characterization of a beta-D-mannosidase from the marine anaspidean Aplysia fasciata.
A beta-D-mannosidase was purified to homogeneity from visceral mass extract of Aplysia fasciata a mollusc belonging to the order Anaspidea. The purified enzyme is a homodimer with a subunit mass of 130 kDa. Temperature and pH optima of this enzyme were 45 degrees C and 4.5, respectively. Substrate specificity tests revealed that the enzyme exerts only beta-D-mannosidase activity. The K(M) and V(max) values for p-nitrophenyl beta-D-mannopyranoside were determined to be 2.4 mM and 50.3 micromol min(-1)mg(-1), respectively. The catalytic efficiency of this beta-mannosidase (11,519 min(-1)) was significantly higher than those reported for beta-mannosidases from other sources. It was verified that this is an exo-acting glycosyl hydrolase with transglycosidase activity. When the enzyme was incubated in the presence of p-nitrophenyl beta-D-mannopyranoside, self-transfer of the mannosyl group was observed, and a 10-15% yield of a beta-1-4 disaccharide was obtained. When the reaction was performed in the presence of o-nitrophenyl alpha-D-2-deoxy-N-acetyl glucopyranoside in 3:1 molar ratio with respect to the p-nitrophenyl beta-D-mannopyranoside, two regioisomers (85:15, 12% yield) due to the beta-mannosylation of the heteroacceptor in 4 and in 6 positions were formed.


Motor impairment evoked by direct electrical stimulation of human parietal cortex during object manipulation.
In primates, the parietal cortex plays a crucial role in hand-object manipulation. However, its involvement in object manipulation and related hand-muscle control has never been investigated in humans with a direct and focal electrophysiological approach. To this aim, during awake surgery for brain tumors, we studied the impact of direct electrical stimulation (DES) of parietal lobe on hand-muscles during a hand-manipulation task (HMt). Results showed that DES applied to fingers-representation of postcentral gyrus (PCG) and anterior intraparietal cortex (aIPC) impaired HMt execution. Different types of EMG-interference patterns were observed ranging from a partial (task-clumsy) or complete (task-arrest) impairment of muscles activity. Within PCG both patterns coexisted along a medio (arrest)-lateral (clumsy) distribution, while aIPC hosted preferentially the task-arrest. The interference patterns were mainly associated to muscles suppression, more pronounced in aIPC with respect to PCG. Moreover, within PCG were observed patterns with different level of muscle recruitment, not reported in the aIPC. Overall, EMG-interference patterns and their probabilistic distribution suggested the presence of different functional parietal sectors, possibly playing different roles in hand-muscle control during manipulation. We hypothesized that task-arrest, compared to clumsy patterns, might suggest the existence of parietal sectors more closely implicated in shaping the motor output.


Parosteal osteosarcoma associated with a low-grade component mimicking well-differentiated liposarcoma: a case report.
Parosteal osteosarcomas and well-differentiated liposarcomas are both well-differentiated locally aggressive tumors. They both have simple karyotypes with amplification of the 12q13-15 regions including MDM2 and CDK4 genes. In this report, we describe the case of a parosteal osteosarcoma intertwined with a low-grade component similar to a well-differentiated liposarcoma. The association of a bone component with an adipose component was initially overlooked. We describe the histological, imaging, and molecular characteristics of this tumor stressing the importance of radio-pathological correlation. To our knowledge, this is the second report of a parosteal osteoliposarcoma. Awareness of this rare presentation may allow radiologists and surgeons to recognize the peripheral fatty component as an integral part of the tumor.


Suppression of the invasive potential of Glioblastoma cells by mTOR inhibitors involves modulation of NFκB and PKC-α signaling.
Glioblastoma (GBM) is the most aggressive type of brain tumors in adults with survival period <1.5 years of patients. The role of mTOR pathway is documented in invasion and migration, the features associated with aggressive phenotype in human GBM. However, most of the preclinical and clinical studies with mTOR inhibitors are focused on antiproliferative and cytotoxic activity in GBM. In this study, we demonstrate that mTOR inhibitors-rapamycin (RAP), temisirolimus (TEM), torin-1 (TOR) and PP242 suppress invasion and migration induced by Tumor Necrosis Factor-α (TNFα) and tumor promoter, Phorbol 12-myristate 13-acetate (PMA) and also reduce the expression of the TNFα and IL1β suggesting their potential to regulate factors in microenvironment that support tumor progression. The mTOR inhibitors significantly decreased MMP-2 and MMP-9 mRNA, protein and activity that was enhanced by TNFα and PMA. The effect was mediated through reduction of Protein kinase C alpha (PKC-α) activity and downregulation of NFκB. TNFα- induced transcripts of NFκB targets -VEGF, pentraxin-3, cathepsin-B and paxillin, crucial in invasion were restored to basal level by these inhibitors. With limited therapeutic interventions currently available for GBM, our findings are significant and suggest that mTOR inhibitors may be explored as anti-invasive drugs for GBM treatment.


Childhood cancer and the SBLA syndrome.
Two nuclear families showing characteristics of the SBLA syndrome are described wherein progeny of breast cancer-affected mothers manifested early childhood malignant neoplasms. These observations have led us to postulate a novel type genetic-environmental interactive model which incorporates Knudsen's "two-hit" hypothesis as a partial explanation for the exceedingly early onset of cancer in the subject progeny. Given the assumption that the first hit was germinal with transfer of the deleterious SBLA gene at conception, we postulate that the second or somatic-hit occurred early on in utero. This may have involved a complex mechanism of one or more factors including tumor cell products, tumor specific antigens, immunosuppression, de-repressed oncogene, or an activated oncogenic virus via a transplacental communicable phenomenon. The testing of this new hypothesis dealing with carcinogenesis in the SBLA syndrome should employ immunologicalgenetic parameters concurrently in fetuses and mothers.


Hydrogeochemical characterization and evaluation of groundwater quality in Kangayam taluk, Tirupur district, Tamil Nadu, India, using GIS techniques.
The main objective of the present study is to evaluate the hydrogeochemical characteristics of groundwater and its suitability for drinking water supply in Kangayam taluk, Tirupur district, Tamil Nadu, India. To achieve this objective, seventy-eight groundwater samples were collected from the wells spread over the study area during December 2016. The collected groundwater samples were tested in the laboratory for various hydrogeochemical parameters such as hydrogen ion concentration (pH), electrical conductivity, total dissolved solids, total hardness, calcium, magnesium, sodium, potassium, chloride, bicarbonate, carbonate, nitrate, sulphate and fluoride. The analytical results were compared with WHO drinking water standards to assess the suitability of groundwater for drinking purposes. To understand the spatial variation of hydrogeochemical parameters over the study area, choropleth (zonation) maps were prepared using geographical information system (GIS). Overall groundwater quality zones were demarcated by overlaying and integrating all the spatial plots using GIS. Three groundwater quality zones such as (1) most desirable, (2) maximum allowable and (3) not permissible were demarcated based on the limits prescribed by the WHO for drinking purposes. This study indicates that 49% of the study area does not possess potable groundwater. About 21% of the area represents "most desirable" category, and the remaining 30% area represents "maximum allowable" category for drinking purposes. The Piper's trilinear diagram indicates that groundwater of this region is Mixed CaMgCl type. As the groundwater quality is poor nearly 49% of the total area, it is necessary to go for treatment before drinking water supply. It is also essential to recharge the aquifer artificially to improve the quantity and quality of groundwater.


Ixazomib-induced Sweet's syndrome: A case report.
Ixazomib, a proteasome inhibitor commonly used for the treatment of multiple myeloma, is a rare cause of Sweet's syndrome. We present a 62-year-old man who developed drug-induced Sweet's syndrome during his fifth cycle of ixazomib for treatment of refractory multiple myeloma. Monthly rechallenge led to the recurrence of symptoms. The patient was successfully treated with addition of weekly corticosteroids and resumed his cancer treatment.


m-Trifluoromethyl-alpha-ethylbenzhydrol: a new enzyme inducer.
The enzyme inducing effect of m-trifluoromethyl-alpha-ethylbenzhydrol (RGH-3332) has been studied in man, rat and mouse. In man, RGH-3332 decreased the half-life of antipyrine and tolbutamide and increased D-glucaric acid excretion. In rat and mouse the half-life of antipyrine was shortened. It was concluded that in all three species man, rat and mouse the liver microsomal drug metabolizing enzyme system was induced by RGH-3332. No side-effects were found on treatment with RGH-3332.


Conformations of peptides containing a chiral cyclic α, α-disubstituted α-amino acid within the sequence of Aib residues.
A single chiral cyclic α,α-disubstituted amino acid, (3S,4S)-1-amino-(3,4-dimethoxy)cyclopentanecarboxylic acid [(S,S)-Ac(5)c(dOM)], was placed at the N-terminal or C-terminal positions of achiral α-aminoisobutyric acid (Aib) peptide segments. The IR and (1)H NMR spectra indicated that the dominant conformations of two peptides Cbz-[(S,S)-Ac(5)c(dOM)]-(Aib)(4)-OEt (1) and Cbz-(Aib)(4)-[(S,S)-Ac(5)c(dOM)]-OMe (2) in solution were helical structures. X-ray crystallographic analysis of 1 and 2 revealed that a left-handed (M) 3(10)-helical structure was present in 1 and that a right-handed (P) 3(10)-helical structure was present in 2 in their crystalline states.


Familial psychiatric disorders in child DSM-IV ADHD: moderation by child gender.
Examined selected psychiatric disorders in parents of boys and girls with DSM-IV ADHD and control children. Excess parent psychopathology was observed for parents of boys--primarily due to psychopathology in fathers--score potential gender differences in development of ADHD.


Diary of a parliamentary intern.
Parliamentary veterinary intern Anthony Ridge considers the diverse group of people he has met over the past year and how this has changed his perspective on animal health and welfare and the values vets bring to society.


PDE4 inhibition by difamilast regulates filaggrin and loricrin expression via keratinocyte proline-rich protein in human keratinocytes.
Difamilast, a topical phosphodiesterase 4 (PDE4) inhibitor, has been shown to be effective for treating atopic dermatitis (AD), but the molecular mechanism involved is unclear. Since skin barrier dysfunction including reduced expression of filaggrin (FLG) and loricrin (LOR) contributes to AD development, difamilast treatment may be able to improve this dysfunction. PDE4 inhibition increases transcriptional activity of cAMP-responsive element binding protein (CREB). Therefore, we hypothesized that difamilast may affect FLG and LOR expression via CREB in human keratinocytes. To elucidate the mechanism by which difamilast regulates FLG and LOR expression via CREB in human keratinocytes. We analyzed normal human epidermal keratinocytes (NHEKs) treated with difamilast. We observed increases of intracellular cAMP levels and CREB phosphorylation in difamilast (5 μM)-treated NHEKs. Next, we found that difamilast treatment increased mRNA and protein levels of FLG and LOR in NHEKs. Since reduced expression of keratinocyte proline-rich protein (KPRP) is reported to be involved in skin barrier dysfunction in AD, we examined KPRP expression in difamilast-treated NHEKs. We found that difamilast treatment increased mRNA and protein levels of KPRP in NHEKs. Furthermore, KPRP knockdown using siRNA transfection abolished the upregulation of FLG and LOR in difamilast-treated NHEKs. Finally, CREB knockdown canceled the upregulation of FLG, LOR, and KPRP in difamilast-treated NHEKs, indicating that PDE4 inhibition by difamilast treatment positively regulates FLG and LOR expression via the CREB-KPRP axis in NHEKs. These findings may provide further guidance for therapeutic strategies in the treatment of AD using difamilast.


A simulation model of the surface EMG signal for analysis of muscle activity during the gait cycle.
This work describes a model able to synthetize the surface EMG (electromyography) signal acquired from tibialis anterior and gastrocnemious medialis muscles during walking of asymptomatic adult subjects. The model assumes a muscle structure where the volume conductor is represented by multiple layers of anisotropic media. This model originates from analysis of the single fiber action potential characterized by the conduction velocity. The surface EMG of voluntary contraction is calculated by gathering motor unit action potentials estimated by the summation of all activities of muscle fibers assumed to have a uniformly parallel distribution. The parameters related to the gait cycle, such as onset and cessation timings of muscle activation, amplitude of muscle contraction, periods and sequences of motor units' recruitment, are included in the model presented. In addition, the relative positions of the electrodes during gait can also be specified in order to adapt the simulation to the different acquisition settings.


Treatment of recalcitrant lateral epicondylitis with suture anchor repair.
Chronic lateral epicondylitis has been treated with various surgical procedures with varying and often less-than-satisfactory outcomes. The use of suture anchor repair of the extensor carpi radialis brevis to the lateral epicondyle in the treatment of chronic lateral epicondylitis will result in a more anatomical repair, with resultant improvements in strength, pain, and return to previous sport. Case series; Level of evidence, 4. A total of 20 patients (22 elbows) were treated surgically and were observed for a minimum of 2 years. All patients had debridement of the degenerative tissue, followed by repair of the extensor carpi radialis brevis to the lateral epicondyle with a suture anchor. The average time to follow-up was 4.2 years (range, 2.2-9.5 years). All patients completed a Disabilities of the Arm, Shoulder, and Hand questionnaire to assess residual disability, and 16 patients underwent a physical examination. The objective evaluation included the assessment of range of motion, grip strength, and pinch strength. Pain was assessed preoperatively and postoperatively using a visual analog pain scale. Patients were also questioned with regard to a return to their previous level of activities. The grip and pinch strengths achieved for the operative extremity were 110% and 106%, respectively, of the nonoperative limb. The 16 patients who underwent a physical examination had achieved full range of motion, with 15 (94%) returning to their previous level of activity at an average time of 4.1 months. The mean preoperative pain score was 8.1 (range, 4.0-10.0), whereas the mean postoperative pain score was 0.41 (range, 0-1.5), indicating significant pain relief (P < .001). The Disabilities of the Arm, Shoulder, and Hand scores demonstrated only mild residual disability (mean, 6.6) at follow-up. The use of a suture anchor to repair the extensor carpi radialis brevis to the epicondyle after debridement was a satisfactory procedure for recalcitrant lateral epicondylitis with regard to strength, return to previous activities, and pain relief.


Recommendation for collection of skin puncture blood from children, with special reference to production of reference values.
Reliable reference values need to be collected under standardized conditions. In order to enable comparison of values observed on patients with reference values, it is also desirable to use the same standardized conditions on patients. The present recommendation was produced as a joint effort of representatives of the clinical chemists and paediatricians of Scandinavia and describes the following details. Preparation of the child before specimen collection (food intake, time of day, physical activity, posture, environment), preparation of skin puncture site (warming, disinfection, ointment), instruments for blood collection (lancet, blood collection vessel), site of puncture (plantar surface of foot, finger, ear lobe), collection of emerging blood and handling and storage of the specimen.


Safety of a novel high tibial osteotomy locked plate fixation for immediate full weight-bearing: a case-control study.
The safety and efficacy of the novel Limmed® system (locked plate fixation) for immediate full weight-bearing after medial opening wedge high tibial osteotomy (HTO) were evaluated in patients with symptomatic varus gonarthrosis. A case series of 85 consecutive osteotomies performed with Limmed® locked plate fixation for medial opening wedge HTO was compared to a historical matched case-control series of 85 HTOs (85 patients) performed using the same implant without locked screws. Subjects were observed at seven and 15 days and three, six and 12 months after surgery. Endpoints for evaluation included the reporting of adverse events, weight-bearing status without pain, radiographic evidence of bony union and changes in correction angle during healing. Statistically significant differences were seen between groups in terms of safety (thrombophlebitis), time to weight-bearing, radiographic union and radiographic stability between the two groups. Patients of the Limmed® group reported less thrombophlebitis (one versus nine), outcome with shorter time for full weight-bearing (average 45 days difference, p = 0.01) and a shorter time for union (average four weeks difference). At the one-year follow-up the post-operative hip-knee-ankle angle was 4.2° of valgus in the Limmed® group and 2° of valgus in the control group. The adjusted mean difference of 2.2° was significant (p = 0.02) and related to loss of correction during healing in the control group with difference in implant stability. The severity of pain, knee score and walking ability improved in both groups with a significant difference before the third month (quicker for Limmed® group), while at the most recent follow-up only the difference for mobility in flexion was significant. The Limmed® medial opening wedge HTO system represents a novel method of achieving a reliable correction while producing a stable fixation allowing satisfactory stability and bone healing with immediate full weight-bearing.


Changes in seasonal expression patterns of ecdysone receptor, retinoid X receptor and an A-type allatostatin in the copepod, Calanus finmarchicus, in a sea loch environment: an investigation of possible mediators of diapause.
The marine copepod, Calanus finmarchicus, is a crucial component of the pelagic food web in the North Atlantic and peripheral seas where it is a major player in biogeochemical cycles and the productivity of commercially important fisheries. A key stage in its life cycle is the emergence of the pre-adult, copepodite developmental stage five (CV) from a period of overwintering dormancy, known as diapause. As is the case in many insect species, diapause is also likely to be under endocrine control in C. finmarchicus. To investigate the hormonal regulation of diapause behaviour of stage CV C. finmarchicus, the expression of three key genes: ecdysone receptor (EcR), retinoid X receptor (RXR) and an A-type allatostatin (A-type AST), were measured in specimens collected at monthly intervals from Loch Etive, a ca. 150m deep sea loch on the west coast of Scotland, between June 2006 and May 2007. The full length RXR gene was cloned and sequenced from C. finmarchicus, and was found to share 49-53% total identity with equivalent genes encoding proteins from other crustaceans, and >80% identity in the DNA binding domain with other crustaceans, insects and vertebrates. EcR expression was least in December when the animals are expected to be in diapause, but began to increase in January, when the animals were terminating diapause. Concomittant with the rise in EcR in January was low expression of A-type AST and high expression of RXR.


Electrophoretic Mobility Shift Assay (EMSA) and Microscale Thermophoresis (MST) Methods to Measure Interactions Between tRNAs and Their Modifying Enzymes.
The Elongator complex is a unique tRNA acetyltransferase; it was initially annotated as a protein acetyltransferase, but in-depth biochemical analyses revealed its genuine function as a tRNA modifier. The substrate recognition and binding of the Elongator is mainly mediated by its catalytic Elp3 subunit. In this chapter, we describe protocols to generate fluorescently labeled RNAs and outline the principles underlying electrophoretic mobility shift assays (EMSA) and microscale thermophoresis (MST). These two methods allow qualitative and quantitative examinations of the binding affinity of various tRNAs toward the homologs of Elp3 from various organisms. The rather qualitative results from EMSA analyses can be nicely complemented by MST measurements allowing precise determination of the dissociation constant (KD). We also provide detailed notes for users to mitigate potential ambiguities and technical pitfalls during the procedures.


A profile of methicillin resistant Staphylococcus aureus infection in the burn center of the Sultanate of Oman.
A retrospective study of patterns of infection in 168 patients admitted during 1995 and 1996 in the burns-unit of Khoula hospital at Muscat, Oman was performed. Out of 819 isolates positive for pathogenic bacterial culture, there were 326 (39.8%) isolates positive for methicillin resistant Staphylococcus aureus (MRSA) infection. Incidence of MRSA infection was marginally more than that of Pseudomonas aeroginosa. The proportion of patients developing MRSA infection sometime or the other during their burns-unit stay ranging from 1 to 112 days rose from 48% in 1995 to 52.7% in 1996. No sophisticated tests were done to identify the MRSA strain but study of the antibiograms of each MRSA positive isolate showed very similar patterns of sensitivity to different antibiotics. This suggests the source of infection to be common and in all probability 'noscomial', since all patients acquired MRSA infection in the hospital. The susceptibility of MRSA to ciprofloxacin, cotrimoxazole and fucidin was 76, 51 and 37% of isolates in 1995, and 59, 44 and 26% in 1996 were susceptible to these drugs. Vancomycin was the antibiotic to which most MRSA cultures were susceptible, but partial resistance was reported due to very low susceptibility observed in 1.4% of the isolates in 1995 and 1.1% of the isolates in 1996. The control measures being practiced in the burns-unit of Khoula Hospital, especially mechanical cleaning and chemical disinfection of all surfaces, are discussed in detail. This paper emphasizes the need for preventive measures against MRSA infection in the burns-unit.


Conceptual and methodological problems in research on the quality of life in clinical medicine.
This introductory paper discusses three issues: theory, validity of measurement and benefits of assessment. It is argued that the conceptual entity 'quality of life' remains ill-defined, although researchers commonly agree on its multi-dimensional nature. The selectivity of dimensions under study is illustrated by referring to recent work on the quality of life in cancer and in cardiovascular disease. Despite conceptual weaknesses, promising developments are apparent in research methodology. The issue is discussed with special reference to the convergent and discriminant validity of some widely used research methods. Improvements in therapy and patient-physician relationships are considered among the major benefits of assessing the quality of life in clinical practice. In conclusion, this field of research, if based on appropriate theory, opens important opportunities for cross-fertilization between advanced medicine and the social sciences.


Kinetic properties of tartrate-resistant acid phosphatase isolated from human spleen with leukemic reticuloendotheliosis.
The tartrate-resistant acid phosphatase was isolated from the spleen of a patient with leukemic reticuloendotheliosis. The unique characteristic of the enzyme is its similar reactivity toward p-nitrophenylphosphate, inorganic pyrophosphate ADP, and ATP. When ATP was incubated with the enzyme, the initial products were ADP and inorganic phosphate. The kinetic data confirmed that these substrates were hydrolyzed by the same enzyme. This type of substrate specificity is clearly different from acid phosphatase and pyrophosphatases previously described in the literature.


Photosystem II energy coupling in chloroplasts with H2O2 as electron donor.
NH2OH-treated, non-water-splitting chloroplasts can oxidize H2O2 to O2 through Photosystem II at substantial rates (100--250 muequiv . h-1 . mg-1 chlorophyll with 5 mM H2O2) using 2,5-dimethyl-p-benzoquinone as an electron acceptor in the presence of the plastoquinone antagonist dibromothymoquinone. This H2O2 leads to Photosystem II leads to dimethylquinone reaction supports phosphorylation with a P/e2 ratio of 0.25--0.35 and proton uptake with H+/e values of 0.67 (pH 8)--0.85 (pH 6). These are close to the P/e2 value of 0.3--0.38 and the H+/e values of 0.7--0.93 found in parallel experiments for the H2O leads to Photosystem II leads to dimethylquinone reaction in untreated chloroplasts. Semi-quantitative data are also presented which show that the donor leads to Photosystem II leads to dibromothymoquinone (leads to O2) reaction can support phosphorylation when the donor used is a proton-releasing reductant (benzidine, catechol) but not when it is a non-proton carrier (I-, ferrocyanide).


Determination of strontium radioisotopes in routine and emergency samples.
We present the radioanalytical strategies used for the determination of strontium radioisotopes in routine and emergency samples. While in routine monitoring, the main goal is to achieve limits of detection as low as possible. In emergency, priority is given to the rapid procurement of data about a contamination. The parameters accuracy, precision and detection limit of the radiochemical methods are shown. We present the results obtained over the past 22 years in proficiency tests and in the analysis of reference materials.


Beliefs about the satiating effect of bread with spread varying in macronutrient content.
Beliefs about the satiating effect of foods varying in contents of proteins, fats, carbohydrates, and fibre were investigated by face-to-face interviews with a random telephone sample of 101 subjects. Respondents were presented with photographs of two slices of bread covered with common spreads. Fibre level was manipulated by using white bread or wholemeal bread. Levels of proteins, fats and carbohydrates were manipulated by using different kinds of spread. Low and high levels of proteins, fats and carbohydrates had similar energy contents. The results showed that protein-rich spreads (lean meat products) and high-fibre (wholemeal) bread were believed to have a strong satiating effect. The satiating effect of high-fat spreads (butter, bacon) was believed to be much smaller, whereas the sweet carbohydrate spreads (jam, honey) were believed to have no satiating effect.


Inhibition of anaesthetic-induced emesis by a NK1 or 5-HT3 receptor antagonist in the house musk shrew, Suncus murinus.
The effects of a NK1 antagonist, GR205171, and a 5-HT3 antagonist, ondansetron, in a novel model of post-anaesthesia-induced emesis in Suncus murinus is described. GR205171 (1 and 3 mg k(-1) s.c) and ondansetron (3 mg kg(-1) s.c.) each significantly inhibited emesis. This model may be useful for studying drugs to treat post-operative nausea and vomiting in man.


Study on self-management of real-time and individualized support in stroke patients based on resilience: a protocol for a randomized controlled trial.
The transitional period from hospital to home is vital for stroke patients, but it poses serious challenges. Good self-management ability can optimize disease outcomes. However, stroke patients in China have a low level of self-management ability during the transitional period, and a lack of effective support may be the reason. With the rapid development of technology, using wearable monitors to achieve real-time and individualized support may be the key to solving this problem. This study uses a randomized controlled trial design to assess the efficacy of using wearable technology to realize real-time and individualized self-management support in stroke patients' self-management behavior during the transitional period following discharge from hospital. This parallel-group randomized controlled trial will be conducted in two hospitals and patients' homes. A total of 183 adult stroke patients will be enrolled in the study and randomly assigned to three groups in a 1:1:1 ratio. The smartwatch intervention group (n = 61) will receive Real-time and Individualized Self-management Support (RISS) program + routine care, the wristband group (n = 61) will wear a fitness tracker (self-monitoring) + routine care, and the control group (n = 61) will receive routine stroke care. The intervention will last for 6 months. The primary outcomes are neurological function status, self-management behavior, quality of life, biochemical indicators, recurrence rate, and unplanned readmission rate. Secondary outcomes are resilience, patient activation, psychological status, and caregiver assessments. The analysis is intention-to-treat. The intervention effect will be evaluated at baseline (T0), 2 months after discharge (T1), 3 months after discharge (T2), and 6 months after discharge (T3). The cloud platform designed in this study not only has the function of real-time recording but also can push timely solutions when patients have abnormal conditions, as well as early warnings or alarms. This study could also potentially help patients develop good self-management habits through resilience theory, wearable devices, and individualized problem-solution library of self-management which can lay the foundation for long-term maintenance and continuous improvement of good self-management behavior in the future. The ethics approval has been granted by the Ethics Committee of West China Hospital, Sichuan University (2022-941). All patients will be informed of the study details and sign a written informed consent form before enrollment. The research results will be reported in conferences and peer-reviewed publications. The trial registration number is ChiCTR2300070384 . Registered on 11 April 2023.


Frequently asked questions about diabetic peripheral neuropathies.
A number of issues pertaining to the diabetic peripheral neuropathies remain unanswered or controversial. The final solution to the disabling problem of diabetic neuropathy might well await the discovery of the exact pathogenesis and treatment of diabetes.


Lysine-specific demethylase 1: an epigenetic regulator of salt-sensitive hypertension.
Hypertension (HTN) represents a complex heritable disease in which environmental factors may directly affect gene function via epigenetic mechanisms. The aim of this study was to test the hypothesis that dietary salt influences the activity of a histone-modifying enzyme, lysine-specific demethylase 1 (LSD-1), which in turn is associated with salt-sensitivity of blood pressure (BP). Animal and human studies were performed. Salt-sensitivity of LSD-1 expression was assessed in wild-type (WT) and LSD-1 heterozygote knockout (LSD-1(+/-)) mice. Clinical relevance was tested by multivariate associations between single-nuclear polymorphisms (SNPs) in the LSD-1 gene and salt-sensitivity of BP, with control of dietary sodium, in a primary African-American hypertensive cohort and two replication hypertensive cohorts (Caucasian and Mexican-American). LSD-1 expression was modified by dietary salt in WT mice with lower levels associated with liberal salt intake. LSD-1(+/-) mice expressed lower LSD-1 protein levels than WT mice in kidney tissue. Similar to LSD-1(+/-) mice, African-American minor allele carriers of two LSD-1 SNPs displayed greater change in systolic BP (SBP) in response to change from low to liberal salt diet (rs671357, P = 0.01; rs587168, P = 0.005). This association was replicated in the Hispanic (rs587168, P = 0.04) but not the Caucasian cohort. Exploratory analyses demonstrated decreased serum aldosterone concentrations in African-American minor allele carriers similar to findings in the LSD-1(+/-) mice, decreased α-EnaC expression in LSD-1(+/-) mice, and impaired renovascular responsiveness to salt loading in minor allele carriers. The results of this translational research study support a role for LSD-1 in the pathogenesis of salt-sensitive HTN.


Imbalance between the function of Na+-K+-2Cl and K+-Cl impairs Cl- homeostasis in human focal cortical dysplasia.
Altered expression patterns of Na+-K+-2Cl- (NKCC1) and K+-Cl- (KCC2) co-transporters have been implicated in the pathogenesis of epilepsy. Here, we assessed the effects of imbalanced NKCC1 and KCC2 on γ-aminobutyric acidergic (GABAergic) neurotransmission in certain brain regions involved in human focal cortical dysplasia (FCD). We sought to map a micro-macro neuronal network to better understand the epileptogenesis mechanism. In patients with FCD, we resected cortical tissue from the seizure the onset zone (SOZ) and the non-seizure onset zone (non-SOZ) inside the epileptogenic zone (EZ). Additionally, we resected non-epileptic neocortical tissue from the patients with mesial temporal lobe epilepsy (MTLE) as control. All of tissues were analyzed using perforated patch recordings. NKCC1 and KCC2 co-transporters expression and distribution were analyzed by immunohistochemistry and western blotting. Results revealed that depolarized GABAergic signals were observed in pyramidal neurons in the SOZ and non-SOZ groups compared with the control group. The total number of pyramidal neurons showing GABAergic spontaneous postsynaptic currents was 11/14, 7/17, and 0/12 in the SOZ, non-SOZ, and control groups, respectively. The depolarizing GABAergic response was significantly dampened by the specific NKCC1 inhibitor bumetanide (BUM). Patients with FCD exhibited higher expression and internalized distribution of KCC2, particularly in the SOZ group. Our results provide evidence of a potential neurocircuit underpinning SOZ epileptogenesis and non-SOZ seizure susceptibility. Imbalanced function of NKCC1 and KCC2 may affect chloride ion homeostasis in neurons and alter GABAergic inhibitory action, thereby contributing to epileptogenesis in FCDs. Maintaining chloride ion homeostasis in the neurons may represent a new avenue for the development of novel anti-seizure medications (ASMs).


Correction: Fast, quantitative, murine cardiac 19F MRI/MRS of PFCE-labeled progenitor stem cells and macrophages at 9.4T.
[This corrects the article DOI: 10.1371/journal.pone.0190558.].


Pulmonary hypertension as a risk factor for death in patients with sickle cell disease.
The prevalence of pulmonary hypertension in adults with sickle cell disease, the mechanism of its development, and its prospective prognostic significance are unknown. We performed Doppler echocardiographic assessments of pulmonary-artery systolic pressure in 195 consecutive patients (82 men and 113 women; mean [+/-SD] age, 36+/-12 years). Pulmonary hypertension was prospectively defined as a tricuspid regurgitant jet velocity of at least 2.5 m per second. Patients were followed for a mean of 18 months, and data were censored at the time of death or loss to follow-up. Doppler-defined pulmonary hypertension occurred in 32 percent of patients. Multiple logistic-regression analysis, with the use of the dichotomous variable of a tricuspid regurgitant jet velocity of less than 2.5 m per second or 2.5 m per second or more, identified a self-reported history of cardiovascular or renal complications, increased systolic blood pressure, high lactate dehydrogenase levels (a marker of hemolysis), high levels of alkaline phosphatase, and low transferrin levels as significant independent correlates of pulmonary hypertension. The fetal hemoglobin level, white-cell count, and platelet count and the use of hydroxyurea therapy were unrelated to pulmonary hypertension. A tricuspid regurgitant jet velocity of at least 2.5 m per second, as compared with a velocity of less than 2.5 m per second, was strongly associated with an increased risk of death (rate ratio, 10.1; 95 percent confidence interval, 2.2 to 47.0; P<0.001) and remained so after adjustment for other possible risk factors in a proportional-hazards regression model. Pulmonary hypertension, diagnosed by Doppler echocardiography, is common in adults with sickle cell disease. It appears to be a complication of chronic hemolysis, is resistant to hydroxyurea therapy, and confers a high risk of death. Therapeutic trials targeting this population of patients are indicated.


[Morphology of surface and atrophic gastritis in eradication of Helicobacter pylori (HP)].
It is shown with the use of immunohistochemical detection of Bcl-2, caspase-3 and Ki-67 that eradication of HP does not result in immediate reverse development of atrophic changes. This depends on duration of persistence of mononuclear inflammatory cells.


Genetic polymorphism of merozoite surface proteins 1 and 2 of Plasmodium falciparum in the China-Myanmar border region.
Malaria is a major public health problem in the China-Myanmar border region. The genetic structure of malaria parasite may affect its transmission model and control strategies. The present study was to analyse genetic diversity of Plasmodium falciparum by merozoite surface proteins 1 and 2 (MSP1 and MSP2) and to determine the multiplicity of infection in clinical isolates in the China-Myanmar border region. Venous blood samples (172) and filter paper blood spots (70) of P. falciparum isolates were collected from the patients of the China-Myanmar border region from 2006 to 2011. The genomic DNA was extracted, and the msp1 and msp2 genes were genotyped by nested PCR using allele-specific primers for P. falciparum. A total of 215 P. falciparum clinical isolates were genotyped at the msp1 (201) and msp2 (204), respectively. For the msp1 gene, MAD20 family was dominant (53.49%), followed by the K1 family (44.65%), and the RO33 family (12.56%). For the msp2 gene, the most frequent allele was the FC27 family (80.93%), followed by the 3D7 family (75.81%). The total multiplicity of infection (MOI) of msp1 and msp2 was 1.76 and 2.21, with a prevalence of 64.19% and 72.09%, respectively. A significant positive correlation between the MOI and parasite density was found in the msp1 gene of P. falciparum. Sequence analysis revealed 38 different alleles of msp1 (14 K1, 23 MAD20, and 1 RO33) and 52 different alleles of msp2 (37 3D7 and 15 FC27). The present study showed the genetic polymorphisms with diverse allele types of msp1 and msp2 as well as the high MOI of P. falciparum clinical isolates in the China-Myanmar border region.


Studies on the cellular defense reactions of the madeira cockroach, Leucophaea maderae: in vitro phagocytosis of different strains of Bacillus cereus and their effect on hemocyte viability.
Monolayers of Leucophaea maderae hemocytes, consisting of mainly plasmatocytes and coagulocytes, were incubated with three strains of Bacillus cereus of differing pathogenicities, and the levels of phagocytosis and hemocyte viability were determined. Incubation with viable B. cereus strains NCTC 2599, NCIB 3329, and B1 resulted in a significant drop in hemocyte viability after 60 min of incubation compared with the saline-only controls. The greatest effect, however, resulted from incubation with B. cereus B1 which is the most pathogenic of the three strains studied. The killing effect of the three B. cereus strains was abolished following their UV irradiation. Incubation of monolayers with viable B. cereus B1 resulted in a level of phagocytic activity at all time periods lower than that with the other two strains. The highest levels of phagocytosis were achieved with UV-killed B. cereus, although no significant differences were found in these values between the three strains at any of the incubation times. Phospholipase C, a lytic enzyme shown to be released by all three strains of B. cereus, although in varying amounts, also caused hemocyte death following its incubation with the monolayers. These data suggest that the hemocyte killing and resistance to phagocytosis by B. cereus are caused by the release of phospholipase C, or some other related toxin(s) by the bacteria.


Critical carboxyl group(s) in Na+-dependent cotransporters of the intestinal brush-border membrane.
We have previously provided functional evidence for a role of carboxyl group(s) in the mechanism of coupling of Na+ and D-glucose fluxes by the small-intestinal cotransporter(s) (Kessler, M. and Semenza, G. (1983) J. Membrane Biol. 76, 27-56). We present here a study on the inactivation of the Na+-dependent transport systems, but not of the Na+-independent ones, in the small-intestinal brush-border membrane, by hydrophobic carbodiimides. Although marginal or insignificant protection by the substrates or by Na+ was observed, the parallelism between Na+-dependence and inactivation by these carbodiimides strongly indicates the role of carboxyl group(s) previously indicated. Contrary to the carboxyl group identified by Turner [1986) J. Biol. Chem. 261, 1041-1047) in the sugar binding site of the renal Na+/D-glucose cotransporter, the carboxyl group(s) studied here probably occur elsewhere in the cotransporter molecule.


Association of serotonin transporter promoter regulatory region polymorphism and cerebral activity to visual presentation of food.
Recent functional magnetic resonance imaging (fMRI) studies have revealed links between genetic polymorphisms and cognitive and behavioural processes. Serotonin is a classical neurotransmitter of central nervous system, and it is connected to the control of appetite and satiety. In this study, the relationship between the functional variation in the serotonin transporter gene and the activity in the left posterior cingulate cortex (PCC), a brain area activated by visual food stimuli was explored. Thirty subjects underwent serial fMRI studies and provided DNA for genetic analyses. Subjects homozygous for the long allele exhibited greater left PCC activity in the comparison food > non-food compared with individuals heterozygous or homozygous for the short allele. The association between genotype and activation was linear, the subjects with two copies of the long allele variant having the strongest activation. These results demonstrate the possible genetically driven variation in the response of the left PCC to visual presentation of food in humans.


[Studies on the anti-hemorrhagic substances in herbs classified as hemostatics in Chinese medicine. X. On hemostatic activities of the parched herbs for hemostatics].
The effect of heat treatment on the anti-hemorrhagic action of seven hemostatic herbs employed especially after parching in order to work effectively as an anti-hemorrhagic agent in traditional Chinese medicine, was examined. It was found that the anti-hemorrhagic activities of the following 5 herbs are apparently increased by parching: Kaika (Sophorae immaturus Flos), Renbo.(Nelumnbins Receptaculum), Gusetsu (Nelumnbins Rhizomatis Nodus), Chiyu (Sanguisorbae Radix) and Gaiyou (Artemisiae argyi Folium).


Mental health-related quality of life is related to delirium in intensive care patients.
Delirium during intensive care unit (ICU) stay may be related to premorbid mental illness. In addition, delirium during ICU stay may also negatively affect long-term health-related quality of life. The aim of our study was to investigate if delirium in the ICU is related to premorbid mental quality of life and affects long-term mental quality of life after ICU stay. We performed a prospective cohort study in 1021 patients admitted for longer than 48 h in a medical-surgical ICU. We evaluated mental and physical quality of life using the Short-form-12 before ICU admission, at hospital discharge, and 3, 6 and 12 months after hospital discharge. Mixed model and logistic regression models were used to analyze the data. Patients who experienced a delirium during ICU stay reported a worse pre-admission mental quality of life than those without delirium (p < 0.001). Furthermore, patients who suffered from delirium during their ICU stay exhibited a significant decrease in mental quality of life over time relative to patients without delirium (p = 0.035). In this large follow-up study, we demonstrated that ICU survivors who experienced a delirium during ICU stay reported a significantly worse pre-admission mental health-related quality of life and a significant decrease in mental health-related quality of life in the year after hospital discharge compared with patients without delirium.


Proliferative index in breast carcinoma determined in situ by Ki67 immunostaining and its relationship to clinical and pathological variables.
Sixty cases of primary breast carcinoma have been studied using a monoclonal antibody, Ki67, which recognizes an antigen expressed by cells in G1, S, G2, and M phases of the cell cycle but not Go. A Ki67 score (positive cells/total tumour cells) was determined, and possible relationships between this index of cellular proliferation and a number of clinical and pathological parameters were investigated. There was a strong positive correlation between the Ki67 score and mitotic index (p less than 0.001), a weak negative correlation with age (p less than 0.02), and weak positive correlations with histological tumour grade (p less than 0.03), tumour necrosis (p less than 0.01), and cellular reaction (p less than 0.01). No relationship was noted between the Ki67 score and tumour size, nodal status, tumour oestrogen receptor levels, or menopausal status. The Ki67 score may prove to be an objective indicator of biological behaviour and thus be of clinical significance, particularly since it is not strongly related to other clinical and pathological parameters used in predicting outcome in breast carcinoma.


Collective aeromedical transport of COVID-19 critically ill patients in Europe: A retrospective study.
In early 2020, the coronavirus disease 2019 (COVID-19) pandemic outbreak has posed the risk of critical care resources overload in every affected country. Collective interhospital transport of critically ill COVID-19 patients as a way to mitigate the localised pressure from overloaded intensive care units at a national or international level has not been reported yet. The aim of this study was to provide descriptive data about the first six collective aeromedical evacuation (MEDEVAC) of COVID-19 patients performed within Europe. This retrospective study included all adult patients transported by the first six collective MEDEVAC missions for COVID-19 patients performed within Europe on the 18th, 21st, 24th, 27th, 31st of March and the 3rd of April 2020. Thirty-six patients with acute respiratory distress syndrome (ARDS) were transported aboard six MEDEVAC missions. The median duration of mechanical ventilation in ICU before transportation was 4 days (3-5.25). The median PaO2/FiO2 ratio obtained before, during the flight and at day 1 after the transport was 180 mmHg (156-202,5), 143 mmHg (118,75-184,75) and 174 mmHg (129,5-205,5), respectively, with no significant difference. The median norepinephrine infusion rate observed before, during the flight and at day 1 after the transport was 0,08 µg/kg-1. min-1 (0,00-0,20), 0,08 (0,00-0,25), and 0,07 (0,03-0,18), respectively, with no significant difference. No life-threatening event was reported. Collective aero-MEDEVAC of COVID-19 critically ill patients could provide a reliable solution to help control the burden of the disease at a national or international level.


Individuals' expectations and challenges following total hip replacement: a qualitative study.
Hip replacements are one of the most common operations for individuals with hip osteoarthritis. There have been numerous quantitative studies investigating the recovery from joint replacement surgery and these show how effective and satisfied patients are. However, little qualitative work has been conducted to explore patients' actual experiences. Therefore, this study aimed to detail the experiences of individuals undergoing a total hip replacement (THR) to determine whether their expectations were met. The qualitative study was nested within a longitudinal study (n = 215) that was investigating biomedical and psychosocial outcomes from THR. We interviewed a purposive sample of individuals (n = 25) 6 months after THR to explore their experiences of having a THR. Participants were aged 48-82 years. They felt disabled following the THR and some had unrealistic expectations of recovery. Most of them received minimal information and health professional support. Participants had to overcome a number of challenges such as diminished confidence, frustration over slow progress and reduced physical functioning. Individuals undergoing THR need to have the opportunity to discuss their expectations of THR, so there is no "false optimism". Support requirements, following THR, need to be reviewed as they were often underestimated by patients and health professionals.


Intrauterine tobacco smoke exposure and hyaline membrane disease amongst triplets.
We assessed the association between prenatal smoking and respiratory distress syndrome (RDS) among triplets using a population-based retrospective cohort of 12,169 triplet live births in the United States between 1995 and 1997. Analysis was conducted using the generalised estimating equation framework to adjust for intra-cluster correlations. A total of 938 cases of RDS were reported comprising 35 among smoking (7.2%) and 903 among non-smoking gravidas (7.7%). The likelihood of RDS was comparable in both smoking categories [adjusted odds ratio (OR) = 0.93; 95% confidence interval (CI) = 0.65-1.32]. The risk for RDS due to smoking diminished with declining birth weight albeit non-significantly: low birth weight (OR = 0.99; 95% CI = 0.40-2.42), very low birth weight (OR = 0.85; 95% CI = 0.39-1.86), and extremely low birth weight (OR = 0.69; 95% CI = 0.30-1.58). In conclusion, among triplet neonates, smoking during pregnancy was not associated with respiratory distress syndrome.


Development of a new method for isolating zebrafish oocytes (Danio rerio) from ovary tissue masses.
In order to study cryopreservation of zebrafish (Danio rerio) oocytes, large numbers of oocytes need to be isolated from the ovaries for experimental use. Zebrafish oocytes have been previously separated from ovaries mechanically and the method is laborious and time consuming. The aim of the present study was to develop a simple and rapid method for obtaining large number of morphologically and functionally intact zebrafish oocytes at different stages of development. Zebrafish ovaries were treated with three enzymes-trypsin, collagenase or hyaluronidase at different concentrations (0.2-1.6 mg/ml) for different time periods (5-20 min). Membrane integrity and development competence of the oocytes isolated mechanically and enzymatically from zebrafish ovary were assessed. The results showed that when optimal concentration and treatment time combinations were used, high separation and viability rates of oocytes could be obtained with all the three enzymes. The best conditions were confirmed as 1.6 mg/ml hyaluronidase treatment for 10 min or 0.4 mg/ml collagenase treatment for 10 min at 22 degrees C. Oocytes survivals after optimal hyaluronidase enzymatic separation were 96.6+/-0.7%, 92.9+/-1.3% and 94.6+/-0.9% for stages I, II and III oocytes, respectively using trypan blue staining. Successful enzymatic separation of zebrafish oocytes is reported here for the first time. The method developed in this study will undoubtedly assist investigations on cryopreservation of zebrafish oocytes and studies on zebrafish oocytes in general.


The performance of different propensity-score methods for estimating relative risks.
The propensity score is the probability of treatment conditional on observed variables. Conditioning on the propensity-score results in unbiased estimation of the expected difference in observed responses to two treatments. The performance of propensity-score methods for estimating relative risks has not been studied. Monte Carlo simulations were used to assess the performance of matching, stratification, and covariate adjustment using the propensity score to estimate relative risks. Matching on the propensity score and stratification on the quintiles of the propensity score resulted in estimates of relative risk with similar mean squared error (MSE). Propensity-score matching resulted in estimates with less bias, whereas stratification on the propensity score resulted in estimates of with greater precision. Including only variables associated with the outcome or including only the true confounders in the propensity-score model resulted in estimates with lower MSE than did including all variables associated with treatment or all measured variables in the propensity-score model. When estimating relative risks, propensity-score matching resulted in estimates with less bias than did stratification on the quintiles of the propensity score, but stratification on the quintiles of the propensity score resulted in estimates with greater precision.


Characterization of thermostructural damages observed in a seaweed used for biosorption of cadmium: effects on the kinetics and uptake.
The effect of drying Sargassum filipendula on the kinetics and uptake of cadmium was studied. The maximum uptake was not reduced when ovendried biomass was used for cadmium concentrations from 10.0 to 500.0 mg/L. Kinetics indicated better performance of the in natura biomass. Drying at 333 K affected the uptake capacity. Results fit the Langmuir model better than the Freundlich. This process followed pseudo-second-order kinetics. Thermogravimetric and infrared analysis confirmed that no structural damage occurred after drying, and no differences between the biomasses were observed. Temperatures from 303 to 328 K affected cadmium uptake capacity.


Epidemiological characteristics of leukemia in China, 2005-2017: a log-linear regression and age-period-cohort analysis.
Leukemia is a threat to human health, and there are relatively few studies on the incidence, mortality and disease burden analysis of leukemia in China. This study aimed to analyze the incidence and mortality rates of leukemia in China from 2005 to 2017 and estimate their age-period-cohort effects, it is an important prerequisite for effective prevention and control of leukemia. Leukemia incidence and mortality data from 2005 to 2017 were collected from the Chinese Cancer Registry Annual Report. Joinpoint regression model was used to estimate the average annual percentage change (AAPC) and annual percentage change (APC) response time trend. Age-period-cohort model was constructed to analyze the effects of age, period and cohort. The age-standardized incidence rate of leukemia was 4.54/100,000 from 2005 to 2017, showed an increasing trend with AAPC of 1.9% (95% CI: 1.3%, 2.5%). The age-standardized mortality rate was 2.91/100,000, showed an increasing trend from 2005 to 2012 with APC of 2.1% (95%CI: 0.4%, 3.9%) and then a decreasing trend from 2012 to 2017 with APC of -2.5% (95%CI: -5.3%, 0.3%). The age-standardized incidence (mortality) rates of leukemia were not only higher in males than that in females, but also increased more rapidly. The incidence of leukemia in rural areas was lower than in urban areas, but the AAPC was 2.2 times higher than urban areas. Children aged 0-4 years were at higher risk of leukemia. The risk of leukemia incidence and mortality increased with age. The period effect of leukemia mortality risk showed a decreasing trend, while the cohort effect showed an increasing and then decreasing trend with the turning point of 1955-1959. The age-standardized incidence rate of leukemia in China showed an increasing trend from 2005 to 2017, while the age-standardized mortality rate increased first and then decreased in 2012 as a turning point. Differences existed by gender and region. The risk of leukemia incidence and mortality increased accordingly with age. The risk of mortality due to leukemia gradually decreased from 2005 to 2017. Leukemia remains a public health problem that requires continuous attention.


Perilla, sunflower, and tea seed oils as potential dietary supplements with anti-obesity effects by modulating the gut microbiota composition in mice fed a high-fat diet.
Obesity has become a serious public health problem with its alarmingly increasing prevalence worldwide, prompting researchers to create and develop several anti-obesity drugs. Here, we aimed to investigate the protective effects of perilla seed oil (PSO), sunflower oil (SFO), and tea seed oil (TSO) against obesity through the modulation of the gut microbiota composition and related metabolic changes in mice fed a high-fat diet (HFD). Mice were divided into six equal groups: ND (normal diet); HFD; ORL (HFD supplemented with 20 mg/kg body weight of orlistat); PSO, SFO, and TSO (HFD supplemented with 2 g/kg body weight of PSO, SFO, and TSO, respectively). Our findings showed that PSO, SFO, and TSO supplementation significantly reduced body weight, organ weight, blood glucose, lipopolysaccharides (LPS), insulin resistance, and improved serum lipid levels (TG, TC, LDL-C, and HDL-C). Meanwhile, the three treatments alleviated oxidative stress and hepatic steatosis and reduced liver lipid accumulation. Relative mRNA expression levels of inflammatory cytokines (TNF-α, IL-1β, IL-6, and MCP-1) and lipid synthesis-related genes (PPAR-γ, FAS, and SREBP-1) were down-regulated, while β-oxidation-related genes (PPAR-α, CPT1a, and CPT1b) were up-regulated in the liver tissue of treated mice. Besides, dietary oil supplementation alleviated HFD-induced gut microbiota dysbiosis by promoting gut microbiota richness and diversity, decreasing the Firmicutes-to-Bacteroidetes ratio, and boosting the abundance of some healthy bacteria, like Akkermansia. PSO, SFO, and TSO supplementation could alleviate inflammation, oxidative stress, and hepatic steatosis, likely by modulating the gut microbiota composition in HFD-fed mice.


D Amino Acids Highlight the Catalytic Power of the Ribosome.
The possible mechanism(s) by which ribosomes make peptide bonds during protein synthesis have been explored for decades. Yet, there is no agreement on how the catalytic site, the peptidyl transferase center (PTC), promotes this reaction. Here, we discuss the results of recent investigations of translation with D amino acids that provide fresh insights into that longstanding question.


Bacteriophage lambda surface display of a bacterial biotin acceptor domain reveals the minimal peptide size required for biotinylation.
Phage display is a powerful technique for identifying specific ligands to a given target. In this work random peptides derived from the biotin accepting domain of the Klebsiella pneumoniae oxaloacetate decarboxylase were displayed on bacteriophage lambda heads to determine the minimal sequence length that is necessary to effect biotinylation in vivo. Phages with a functional biotinylation domain were identified after affinity purification with immobilised avidin. All biotinylated phages isolated this way were found to have a sequence of 66 amino acids from the parental protein in common. This minimal biotinylation domain is fully functional as a biotin acceptor and more resistant to proteolytic attack compared to domains of larger size derived from the same protein. The data present the first example of a posttranslational protein modification analysed in a phage display system. Moreover, a biotin domain of reduced size and improved stability was identified, that should be superior to the larger parental protein as a tag to generate biotinylated fusion proteins.


Software that detects and analyzes bioelectrical events by assessing the fit of modeled subintervals.
A software system is described which has been used to identify, average, and otherwise analyse different kinds of electrophysiological events. Spontaneous miniature end-plate potentials were identified by assessing the fit of subintervals within suspected event-containing intervals to flexibly defined model subevents. It was thus practical to apply complex, explicit, and stable criteria in the estimation of the frequency and mean time course of these spontaneous events. This software also mediated the objective rejection of noise-contaminated elements from samples of either evoked or spontaneous potentials. Average event time courses were comprised of a series of estimates of the standard deviations as well as the means. Each analysis generated thousands of individual event amplitudes which were used to improve estimates of quantal release and response parameters. This software allowed more complete analysis of tape-recorded experiments which conserved test compounds and animals, and enabled the observation of simultaneous and equal degrees of action upon spontaneous and evoked potentials, which suggested that a common mechanism was involved.


Lipid nanoparticles for siRNA delivery in cancer treatment.
RNA-based therapies, and siRNAs in particular, have attractive therapeutic potential for cancer treatment due to their ability to silence genes that are imperative for tumor progression. To be effective and solve issues related to their poor half-life and poor pharmacokinetic properties, siRNAs require adequate drug delivery systems that protect them from degradation and allow intracellular delivery. Among the various delivery vehicles available, lipid nanoparticles have emerged as the leading choice. These nanoparticles consist of cholesterol, phospholipids, PEG-lipids and most importantly ionizable cationic lipids. These ionizable lipids enable the binding of negatively charged siRNA, resulting in the formation of stable and neutral lipid nanoparticles with exceptionally high encapsulation efficiency. Lipid nanoparticles have demonstrated their effectiveness and versatility in delivering not only siRNAs but also multiple RNA molecules, contributing to their remarkable success. Furthermore, the advancement of efficient manufacturing techniques such as microfluidics, enables the rapid mixing of two miscible solvents without the need for shear forces. This facilitates the reproducible production of lipid nanoparticles and holds enormous potential for scalability. This is shown by the increasing number of preclinical and clinical trials evaluating the potential use of siRNA-LNPs for the treatment of solid and hematological tumors as well as in cancer immunotherapy. In this review, we provide an overview of the progress made on siRNA-LNP development for cancer treatment and outline the current preclinical and clinical landscape in this area. Finally, the translational challenges required to bring siRNA-LNPs further into the clinic are also discussed.


Overview of N- and O-linked oligosaccharide structures found in various yeast species.
Yeast and most higher eukaryotes utilize an evolutionarily conserved N-linked oligosaccharide biosynthetic pathway that involves the formation of a Glc3Man9GlcNAc2-PP-dolichol lipid-linked precursor, the glycan portion of which is co-translationally transferred in the endoplasmic reticulum (ER) to suitable Asn residues on nascent polypeptides. Subsequently, ER processing glycohydrolases remove the three glucoses and, with the exception of Schizosaccharomyces pombe, a single, specific mannose residue. Processing sugar transferases in the Golgi lead to the formation of core-sized structures (Hex<15GlcNac2) as well as cores with an extended poly-alpha1,6-Man 'backbone' that is derivatized with various carbohydrate side chains in a species-specific manner (Hex50-200GlnNAc2). In some cases these are short alpha1,2-linked Man chains with (Saccharomyces cerevisiae) or without (Pichia pastoris) alpha1,3-Man caps, while in other yeast (S. pombe), the side chains are alpha1,2-linked Gal, some of which are capped with beta-1,3-linked pyruvylated Gal residues. Charged groups are also found in S. cerevisiae and P. pastoris N-glycans in the form of mannose phosphate diesters. Some pathogenic yeast (Candida albicans) add poly-beta1,2-Man extension through a phosphate diester to their N-glycans, which appears involved in virulence. O-Linked glycan synthesis in yeast, unlike in animal cells where it is initiated in the Golgi using nucleotide sugars, begins in the ER by addition of a single mannose from Man-P-dolichol to selected Ser/Thr residues in newly made proteins. Once transported to the Golgi, sugar transferases add one (C. albicans) or more (P. pastoris) alpha1,2-linked mannose that may be capped with one or two alpha1,3-linked mannoses (S. cerevisiae). S. pombe is somewhat unique in that it synthesizes a family of mixed O-glycans with additional alpha1,2-linked Man and alpha1,2- and 1, 3-linked Gal residues.


Development and Validation of the Guide for Effective Nutrition Interventions and Education (GENIE): A Tool for Assessing the Quality of Proposed Nutrition Education Programs.
To develop and validate the Guide for Effective Nutrition Interventions and Education (GENIE), a checklist of research-based quality indicators for nutrition education programs. A prospective test of criterion validity and inter-rater reliability of a new tool comparing expert assessments and trained reviewer GENIE scores of the same nutrition education proposals. Ten nutrition education experts; 13 volunteer reviewers. GENIE's face, content, and criterion validity and inter-rater reliability compared using expert assessments and reviewer objective and subjective scores. Reviewer scores compared using Spearman correlation. Inter-rater reliability tested using intra-class correlation (ICC), Cronbach alpha, and ANOVA. Criterion validity tested using independent t test and point bi-serial correlation to compare reviewer with expert scores. Correlation found between total objective and total subjective scores. Agreement found between reviewers across proposals and categories considering subjective scores (F = 7.21, P < .001; ICC = 0.76 [confidence interval, 0.53-0.92]) and objective scores (F = 7.88, P < .001; ICC = 0.82 [confidence interval, 0.63-0.94]). Relationship was not significant (r = .564, P = .06) between expert and reviewer proposal scoring groups (high, medium, and low). Results support the validity and reliability of GENIE as a tool for nutrition education practitioners, researchers, and program funding agencies to accurately assess the quality of a variety of nutrition program plans.


Prenatal arsenic exposure alters the placental expression of multiple epigenetic regulators in a sex-dependent manner.
Prenatal exposure to arsenic has been linked to a range of adverse health conditions in later life. Such fetal origins of disease are frequently the result of environmental effects on the epigenome, leading to long-term alterations in gene expression. Several studies have demonstrated effects of prenatal arsenic exposure on DNA methylation; however the impact of arsenic on the generation and decoding of post-translational histone modifications (PTHMs) is less well characterized, and has not been studied in the context of prenatal human exposures. In the current study, we examined the effect of exposure to low-to-moderate levels of arsenic in a US birth cohort, on the expression of 138 genes encoding key epigenetic regulators in the fetal portion of the placenta. Our candidate genes included readers, writers and erasers of PTHMs, and chromatin remodelers. Arsenic exposure was associated with the expression of 27 of the 138 epigenetic genes analyzed. When the cohort was stratified by fetal sex, arsenic exposure was associated with the expression of 40 genes in male fetal placenta, and only 3 non-overlapping genes in female fetal placenta. In particular, we identified an inverse relationship between arsenic exposure and expression of the gene encoding the histone methyltransferase, PRDM6 (p < 0.001). Mutation of PRDM6 has been linked to the congenital heart defect, patent ductus arteriosus. Our findings suggest that prenatal arsenic exposure may have sex-specific effects on the fetal epigenome, which could plausibly contribute to its subsequent health impacts.