Sublethal fluvalinate negatively affect the development and flight capacity of honeybee (Apis mellifera L.) workers.
Fluvalinate has been heavily used to control the pest Varroa destructor and residues in honeybee colony causing long-term exposure threat for bees. But, little is known about the lifetime trips and homing ability of worker bees under fluvalinate stresses during the development period. In this study, honeybees from 2-day-old larvae to 7-day-old adults were continuously fed with different concentrations of fluvalinate (0, 0.5, 5 and 50 mg/kg) and the effects of fluvalinate on the development of larvae were examined. And then, all the treated bees were reintroduced into the original source colony and were monitored, and the homing ability of 20 days old bees at 1000 and 2000 m away from the beehive were tested using the radio frequency identification (RFID). We found that fluvalinate significantly activates the superoxide dismutase (SOD) activities of larvae and 5 mg/kg fluvalinate reduced the homing rate of workers at 2000 m away from colony. 50 mg/kg fluvalinate reduced proportion of capped worker cells, activated Cytochrome P450 (CYP450) activity of larvae, affected the foraging times, influenced the homing rate and homing time of one trip at 2000 m away from colony. Our results showed that the larvae can activate the activities of SOD and detoxification enzymes in detoxification of fluvalinate and reduce the influence on honeybees. But, when the concentration is higher than 5 mg/kg fluvalinate, it is difficult for bees to detoxify fluvalinate completely, which affect the homing rate. The results reflect the potential risk for honeybees in the development stage continuously exposed to fluvalinate.


Resuscitation after prolonged cardiac arrest: effects of cardiopulmonary bypass and sodium-hydrogen exchange inhibition on myocardial and neurological recovery.
To determine if cardiopulmonary bypass (CPB), together with inhibition of the sodium-hydrogen exchanger (NHE), limits myocardial and neurological injury and improves recovery after prolonged (unwitnessed) cardiac arrest (CA), as NHE inhibition improved recovery after deep hypothermic circulatory arrest. Twenty-seven pigs (31-39 kg) underwent 15 min of prolonged (no-flow) CA followed by 10 min of cardiopulmonary resuscitation-advanced life support (CPR-ALS). Subjects with restoration of spontaneous circulation (ROSC) during CPR-ALS received either no drug (n=6) or an inhibitor of the NHE (HOE-642; n=5). In the 16 unsuccessfully resuscitated animals, peripheral normothermic CPB was instituted, and either no drug (n=9) or similar HOE-642 (n=7) therapy started. Hemodynamic data, a species-specific neurological deficit score (0=normal to 500=brain death), and mortality were recorded at 24h, and biochemical variables of organ injury measured. CPR-ALS restored ROSC in 41% (11/27) of animals, but was unsuccessful in 59% (16/27) that required CPB. Without CPB, HOE-642 increased cardiac index and decreased vascular resistance; with CPB, HOE-642 caused higher pump flows (3.4±0.6 l min(-1)m(-2) vs 2.5±0.7 l min(-1)m(-2); p<0.001) and higher post-arrest cardiac index; but animals required more vasopressors (p=0.019) from drug-induced vasodilation. No differences between biochemical markers of oxidative and organ injury and overall 24-h mortality (20%) were found between groups. Neurological score was improved at 24h compared with 4h only after HOE-642 treatment with (150±34 vs 220±43; p=0.003) or without CPB (162±39 vs 238±48; p≤0.001), but failed to reach statistical difference with respect to the untreated group. CPB is an effective resuscitative tool to treat prolonged CA but there is limited improvement of neurological function. NHE inhibition augments cardiac and neurological function, but its effect was less pronounced than in other studies.


Distinct Immune Signatures Indicative of Treatment Response and Immune-Related Adverse Events in Melanoma Patients under Immune Checkpoint Inhibitor Therapy.
To identify potential early biomarkers of treatment response and immune-related adverse events (irAE), a pilot immune monitoring study was performed in stage IV melanoma patients by flow cytometric analysis of peripheral blood mononuclear cells (PBMC). Overall, 17 patients were treated with either nivolumab or pembrolizumab alone, or with a combination of nivolumab and ipilimumab every three weeks. Of 15 patients for which complete response assessment was available, treatment responders (n = 10) as compared to non-responders (n = 5) were characterized by enhanced PD-1 expression on CD8+ T cells immediately before treatment (median ± median absolute deviation/MAD 26.7 ± 10.4% vs. 17.2 ± 5.3%). Responders showed a higher T cell responsiveness after T cell receptor ex vivo stimulation as determined by measurement of programmed cell death 1 (PD-1) expression on CD3+ T cells before the second cycle of treatment. The percentage of CD8+ effector memory (CD8+CD45RA-CD45RO+CCR7-) T cells was higher in responders compared to non-responders before and immediately after the first cycle of treatment (median ± MAD 39.2 ± 7.3% vs. 30.5 ± 4.1% and 37.7 ± 4.6 vs. 24.0 ± 6.4). Immune-related adverse events (irAE) were accompanied by a higher percentage of activated CD4+ (CD4+CD38+HLADR+) T cells before the second treatment cycle (median ± MAD 14.9 ± 3.9% vs. 5.3 ± 0.4%). In summary, PBMC immune monitoring of immune-checkpoint inhibition (ICI) treatment in melanoma appears to be a promising approach to identify early markers of treatment response and irAEs.


Prevention of intraoperative hypothermia by preoperative skin-surface warming.
Intraoperative hypothermia initially results from internal redistribution of heat facilitated by anesthesia-induced vasodilation. Preinduction skin-surface warming minimizes postinduction hypothermia in anesthetized volunteers. However, its efficacy might be reduced in surgical situations, because of multiple sources of heat loss. Intraoperative core and mean skin temperatures were measured during total hip arthroplasty in 16 patients, randomly assigned to be covered preoperatively with a warming blanket for > or = 90 min (prewarmed group) or not covered (unwarmed group). During the first hour of anesthesia, core temperature decreased more than twice as much in the unwarmed group (-0.7 +/- 0.1 degree C; mean +/- SE) than in the prewarmed patients (-0.3 +/- 0.1 degree C). At the end of surgery, core temperature was 36.3 +/- 0.1 degree C in the prewarmed group and 35.2 +/- 0.2 degree C in the unwarmed group. During recovery, seven patients obviously shivered in the unwarmed group and none in the prewarmed group. Preanesthetic skin-surface warming reduces the initial postinduction hypothermia in surgical patients, preventing intraoperative hypothermia and postoperative shivering even for procedures lasting 3 h or longer.


Pattern of immune infiltration in lung cancer and its clinical implication.
Tumor-infiltrating immune cells play an essential role in prognosis and survival after therapy. However, previous works have not made clear about the diversity of distinct cell types that participate in the immune response. We determined the composition of tumor-infiltrating immune cells and their correlation with prognosis in lung cancer based on a metagene approach (known as CIBERSORT) and online databases. A total of 22 tumor-infiltrating immune cells were estimated to confirm the associations between the immune infiltration pattern and survival. As a result, the proportions of activated NK cell, monocytes, M0 macrophages and M1 macrophages in 56 cancer samples were significantly higher than those in 56 paracancerous samples. Univariate Cox regression analysis displayed that the proportions of NK cell and monocytes were significantly associated with prognosis. Hierarchical clustering analysis predicted five clusters by the method of within sum of squares errors (wss), which exhibited different infiltrating immune cell composition and prognosis. The proportions of tumor-infiltrating immune cells as well as cluster patterns were associated with the prognosis, which provided potential therapeutic targets for lung cancer.


Clinical implications of collateral middle cerebral artery flow in acute ischaemic stroke with internal carotid artery occlusion.
The presence of collateral middle cerebral artery (MCA) flow via the primary collateral pathway is thought to protect against the progression of cerebral ischaemia. However, there have been few reports on early clinical outcomes according to the presence of collateral MCA flow in acute ischaemic stroke (AIS) with internal carotid artery (ICA) occlusion. Therefore, we sought to investigate the early clinical outcomes and lesion patterns according to the presence of collateral MCA flows in AIS with ICA occlusion. This is a retrospective study of patients with AIS with ICA occlusion consecutively admitted to our stroke center between October 2008 and March 2010. Patients were included if they were admitted within 12 h of symptom onset with AIS and symptomatic ICA occlusion. Collateral MCA flow was defined as the presence of MCA signals from proximal M1 to distal MCA branches ipsilateral to the ICA occlusion by magnetic resonance angiography. Early neurological deterioration (END) was defined as a 4-point increase in the National Institutes of Health Stroke Scale (NIHSS) score and persistent neurological deterioration for at least 24 h or newly developed neurological symptoms within 7 days. Sixty-five patients (42 men, 23 women) were finally included. Initial NIHSS scores were significantly lower, and favorable outcomes at 3 months were better in patients with collateral MCA flow than in those without (P < 0.001). Initial lesion patterns were different according to the collateral MCA flow. However, patients with mild AIS might more frequently deteriorate than those with moderate to severe AIS. In our study, collateral MCA flow reduced initial stroke severity and was associated with favorable outcomes at 3 months but did not seem to protect against END in mild AIS patients with ICA occlusion. Therefore, the results of this study suggest that mild AIS patients with ICA occlusion should be carefully managed because their conditions may deteriorate.


Multicentre, open, noncomparative Phase II trial to evaluate the efficacy and tolerability of fotemustine, cisplatin, alpha-interferon and interleukin-2 in advanced melanoma patients.
The efficacy and tolerability of fotemustine, cisplatin, alpha-interferon and interleukin-2 biochemotherapy were evaluated in advanced melanoma patients. The schedule consisted of fotemustine (100 mg/m) and cisplatin (75 mg/m) intravenous on day 1, followed by subcutaneous interleukin-2 at a dose of 4.5 MIU on days 3-5 and 8-12 and alpha-interferon at a dose of 3 MU three times/week, every 3 weeks for six cycles. Sixty patients were evaluated for tumour response, 12 of whom had brain metastases (BM). One patient (1.7%) with BM achieved a complete response and partial responses were observed in 10 patients (16.7%), including one BM patient. Overall response rate was 18.4 and 16.6% in BM patients (median response duration 8.2 months). Disease control, defined as overall response and stable disease, was 58.4% in all patients and 75% in patients with BM. Median time to progression was 3.2 months (4.2 months in BM patients). Median overall survival was 8.9 months (7.6 months in BM patients). Toxic events were mild to moderate. This combination was well tolerated and showed acceptable clinical activity, especially in BM patients.


Doppler velocimetry in pregnancy.
Since the late 1970s, Doppler velocimetry has been investigated extensively for use in obstetrics. Initially, this technique showed promise for the management of certain complications of pregnancy; this promise has yet to be fulfilled. Doppler velocimetry of either the uterine or umbilical vessels, which showed some merit in selecting growth-retarded fetuses at particular risk, has neither become a screening tool for intrauterine growth retardation nor proven clinically successful in improving fetal outcome. Likewise, its use for other complications of pregnancy (eg, postdate pregnancy, twin pregnancy, and diabetes) has not led to improved pregnancy outcome. More recently this technique has been used to study other vascular beds. Changes in the Doppler characteristics of these vascular beds may demonstrate the fetal response to its environment. These investigations provide the potential for a better understanding of fetal physiology; however, it has yet to be shown by prospective evaluation that their application results in improved pregnancy outcome. This review defines the uses and limitations of Doppler ultrasound in current obstetric practice.


Alternative activation of macrophages by prostacyclin synthase ameliorates alcohol induced liver injury.
Alcoholic liver disease (ALD) is a major cause of chronic liver disease worldwide. Macrophages exhibit different functional states and are classified as classically activated (M1) and alternatively activated (M2) macrophages. However, the mechanisms that govern M1/M2 polarization in chronic ALD remain to be elucidated. Prostacyclin (PGI2) synthase (PTGIS) is an enzyme of the prostaglandin pathway which catalyzes the conversion of Prostaglandin H2 (PGH2) to PGI2. PTGIS has anti-inflammatory properties. However, the function of PTGIS in ALD has not yet been determined. In this study, we demonstrated that PTGIS was downregulated in ALD and forced PTGIS expression in vivo using recombinant adeno-associated viral vector-packed PTGIS overexpression plasmid, which alleviated the inflammatory response and suppressed the macrophage M1 phenotype in mice. Loss- and gain-of function-experiments demonstrated that forced PTGIS expression inhibited the macrophage switch to the M1 phenotype and promoted M2 polarization. Furthermore, we identified the genes regulated by PTGIS through RNA-sequencing (RNA-seq) analysis. Gene ontology and KEGG pathway analyses showed that PTGIS regulates many genes involved in the immune response and is enriched in the Janus kinase/signal transducers and activators of transcription (JAK/STAT) signal transduction pathway, which plays an important role in regulating macrophage polarization. The proteins interacting with JAKs were predicted using the STRING database. The overlap between the RNA-seq and the STRING database was interleukin-6; this indicated that it was involved in macrophage polarization regulated by JAK/STAT signaling. We further explored the microRNAs that could regulate the expression of PTGIS through TargetScan. The results of luciferase assay illustrated that the expression of PTGIS was regulated by miR-140-3p.1. These results imply that PTGIS plays a pivotal role in ALD, partly by influencing macrophage polarization.


[Roentgeno-morphologic changes in the bones of battered children].
The demonstrated characteristic bone lesions should raise the suspicion of "battered child syndrome". The important role of the radiologist is stressed.


Two different entities of spontaneous ovarian hyperstimulation in a woman with FSH receptor mutation.
Spontaneous ovarian hyperstimulation syndrome (OHSS) is an extremely rare event. Normally OHSS is seen in the context of IVF. In 2003 a mutation of the FSH receptor (FSHR D567N) was identified for the first time as a cause of spontaneous OHSS. In most FSHR mutations, a hypersensitivity to human chorionic gonadotrophin (HCG) or thyroid-stimulating hormone (TSH) is described. This clinical case presents for the first time two occurrences of spontaneous OHSS in a single woman with a FSHR mutation and two different entities. Pathophysiology of both pregnancies was completely different. During the first pregnancy, elevated HCG and androgen concentrations led to spontaneous OHSS and finally to miscarriage. The second pregnancy with spontaneous OHSS was dominated by a latent hypothyroidism and normal HCG concentrations and ended in a delivery of a healthy female newborn. Due to the unusual courses of the pregnancies, the study looked for a mutation in the FSHR and surprisingly identified the same mutation previously described. This report confirms for the first time the in-vitro findings in a single clinical case that TSH as well as HCG leads to spontaneous OHSS in patients with FSHR D567N mutation. Hypothyroidism has to be treated or ruled out.


Avoiding fluoroquinolone resistance. Strategies for primary care practice.
The therapeutic usefulness of fluroquinolones for serious and difficult-to-treat infections is well documented. However, with increasing reports of organisms becoming resistant to the agents (most often the pseudomonads, staphylococci, and streptococci), the usefulness of this class of antibiotics is being threatened. Appropriate and judicious prescribing of this class of antimicrobials can greatly aid in preserving the therapeutic value of fluoroquinolones for the treatment of infections in the future.


Effects of fasting on cadmium toxicity, glutathione metabolism, and metallothionein synthesis in rats.
Acute oral toxicity of Cd (as cadmium chloride) was enhanced in rats fasted 24 hr, as shown by a markedly decreased LD50. To examine the relationship among Cd toxicity, hepatic glutathione (GSH), and metallothionein (MT) during fasting, rats were administered 75 mg Cd/kg orally 24 hr after fasting and euthanized after a further 4 or 24 hr for various assays. Serum glutamic-pyruvic transaminase activity 24 hr after Cd treatment was higher in fasted rats than in fed rats. Both total GSH and nonprotein sulfhydryl (NPSH) concentrations in liver decreased to 50% of control levels after 28 hr of fasting and returned to 75% of control values by 48 hr. Total hepatic GSH concentration in fed rats decreased 4 and 24 hr after Cd treatment, whereas that in fasted rats remained unchanged at 4 hr and decreased significantly at 24 hr. Cd uptake by the liver (both concentration and content) 24 hr after Cd treatment was higher in fasted rats than in fed rats. Hepatic MT concentration was markedly increased by Cd treatment and higher in fasted rats than in fed rats. There was no relationship between Cd toxicity and hepatic thiobarbituric acid (TBA) value, an indicator of lipid peroxidation. Fasting had no effect on hepatic GSH peroxidase and GSH reductase activities. These enzymes probably are not involved in Cd toxicity. On histological examination, focal degenerative and necrotic changes were observed from the midlobular to the pericentral region in the livers of fed rats 24 hr after Cd treatment. These changes were enhanced by fasting, diffusing from the pericentral to the periportal region. Histochemical examination revealed a heterogeneous distribution of GSH in the livers of fed rats, with strong staining of GSH in the periportal region. This heterogeneous distribution of GSH in liver was not observed in fed rats 4 hr after Cd treatment or in fasted rats at 24 hr. The present results suggest that hepatic GSH plays an important role in protection against Cd toxicity before the onset of MT synthesis. Animals in bad condition, such as that resulting from interruption of nutrient supply, cannot be protected against Cd toxicity even if the hepatic MT level is high.


Feasibility and safety of image-guided vacuum-assisted breast biopsy: A PRISMA-compliant systematic review and meta-analysis of 20 000 population from 36 longitudinal studies.
Breast cancer is a serious disease in women. We estimated the global technical success rate and complication rates of percutaneous vacuum-assisted breast biopsy (VABB). PubMed, Embase, Web of Science, and Scopus databases were retrieved up to July 2018 to find studies in which technical success rate and complication rates of VABB were available. Pooled rates were calculated according to location mode (ultrasonography [US] or mammography) and needle type (8- or 11-gauge Mammotome probes). Of the 36 articles with 20 868 cases, we found the pooled technical success rate 0.9999(0.9997, 1.0000) (I2 = 17.1%, P = .187) and low complication risks including haematoma 0.1092(0.0748, 0.1437) (I2 = 98.3%, P < .001), pain 0.0738(0.0334, 0.1141) (I2 = 95.9%, P < .001), vasovagal reflex 0.0281(0.0035, 0.0527) (I2 = 92.5%, P < .001), and infection 0.0027(-0.0019, 0.0073) (I2 = 49.8%, P = .113). In this systematic review and meta-analysis, the pooled data suggested that VABB with US or mammography could be promising for diagnosis and treatment of breast disease. Further studies were necessary to identify strategies for these findings.


Development of an aerogenous Escherichia coli infection model in adult broiler breeders.
Escherichia coli constitutes an immense challenge to the poultry industry due to its devastating effect on productivity, mortality, and carcass condemnations. To aid future studies on disease mechanisms and interventions, an aerogenous infection model was established in adult broiler breeders. Hens (n = 120) were randomly allocated into six groups receiving either aerosolised E. coli or vehicle, or intratracheal E. coli or vehicle. Replication of aerosol inoculation was performed on distinct days. Alternating euthanasia time points were predetermined in order to evaluate the progression of the disease. All animals were thoroughly necropsied, and bacteriological samples were collected as well as tissues for histopathology. Birds inoculated with E. coli exhibited clinical signs and developed characteristic gross and histopathological lesions of colibacillosis, including splenic fibrinoid necrosis, folliculitis, polyserositis and impaction of parabronchi with fibrinoheterophilic exudate and necrotic debris, as well as positive in situ localisation of intralesional E. coli by immunohistochemistry. This study presents a successful development of a discriminative colibacillosis model through aerosol inoculation of adult broiler breeders. Gross and histopathological lesions characteristic of colibacillosis were established in two independent experiments.


Effect of chain length and branching on the in vitro metabolism of a series of parabens in human liver S9, human skin S9, and human plasma.
Parabens are antimicrobial compounds used as preservatives in cosmetics, foods, and pharmaceuticals. Paraben exposure occurs through a variety of routes including dermal absorption, ingestion, and inhalation. Ester bond hydrolysis has been shown to be the predominant biotransformation for this chemical class. Here we evaluated a series of parabens of increasing alkyl chain length and branching in addition to the aryl side chain of phenyl paraben (PhP). We evaluated the parabens under full Michaelis-Menten (MM) parameters to obtain intrinsic clearance values and found different trends between human liver and skin, which correlate with the predominant esterase enzymes in those matrices, respectively. In liver, where carboxylesterase 1 (CES1) is the predominant esterase enzyme, the shorter chain parabens were more readily metabolized, while in skin, where carboxylesterase 2 (CES2) is the predominant esterase enzyme, the longer chain parabens were more readily metabolized. Alkyl chain branching reduced the hydrolysis rates relative to those for the straight chain compounds, while the addition of a phenyl group, as in PhP, showed an increase in hydrolysis, producing the highest observed hydrolysis rate for skin. These data summarize the structure-metabolism relationship for a series of parabens and contribute to the safety assessment of this class of compounds.


Left ventricular hypertrophy in a canine model of reversible pressure overload.
The goal of therapy for left ventricular pressure overload should include regression of the associated left ventricular hypertrophy, but this process is incompletely understood. The aim of the study was to characterise the extent and time course of the progression and regression of pressure overload left ventricular hypertrophy in a canine hypertrophy model. Six puppies were studied longitudinally with haemodynamic and echocardiographic measurements for 10 months. The study animals underwent ascending aortic banding at nine weeks of age which produced an initial gradient of 30 mm Hg. Subsequent growth led to an increase in gradient and the development of left ventricular hypertrophy. Then thoracotomy was again performed to remove the band. One month later, balloon aortoplasty was performed to remove the residual gradient. The animals were then observed for six months. Growth increased the gradient to 105(SEM 10) mm Hg three months after banding. The left ventricular weight to body weight ratio (g.kg-1), an index of hypertrophy, was 7.2(0.5) after three months of pressure overload. Subsequently the band was surgically removed, reducing the gradient to an average of 58(10) mm Hg. Balloon dilatation of the residual aortic stricture reduced the gradient further to 6(5) mm Hg. Over the ensuing six months, echocardiographic determination of left ventricular mass showed the regression in left ventricular hypertrophy. After six months, left ventricular weight to body weight ratio in the previously banded animals was significantly reduced from 7.2(0.5) to 5.3(0.2) (p less than 0.05). The model produced over 100% left ventricular hypertrophy, most of which regressed following removal of the pressure overload.


Multicolored Cathodically Coloring Electrochromism and Electrofluorochromism in Regioisomeric Star-Shaped Carbazole Dibenzofurans.
In this work, a series of fluorescent cathodically coloring electrochromic (EC) small molecules o-, m-, and p-DBFDCz with 3,5-di(9H-carbazol-9-yl)benzene (DCz) linked to dibenzofuran (DBF) at different substitutional positions were synthesized and fully characterized. These compounds are electroactive and undergo quasi-reversible two-step single-electron reduction generating radical anions and dianions. The absorptions of o-, m-, and p-DBFDCz in the neutral states lie in the UV region (λonset ≈ 350 nm), showing high transparency, while the absorption of their reduced states can be largely tuned across the visible region through driving voltage and substitutional positions. Initially generated spectroelectrochemically radical anions show absorption in the short-wavelength region of ∼380-500 nm with weak broad absorptions at longer wavelengths. On further reduction, these bands disappear on the cost of growing intense bands from dianions at longer wavelengths of 500-700 nm with some tail absorptions in the shorter-wavelength region. This renders the colors of the EC devices based on these materials, which are changed from green to red, yellow to magenta, and light to deep blue for o-, m-, and p-DBFDCz, respectively, covering four legs of the L*a*b* color space. Besides excellent optical contrast (>90%) and high coloration efficiency (up to 504 cm2 C-1), the fluorescence observed in solution of neutral o-, m-, and p-DBFDCz can be modulated between the fluorescence and quenched states by direct electrochemical redox reactions. Both EC and electrofluorochromic (EFC) processes are reversible on cycling. This research demonstrates the feasibility of developing multifunctional EC/EFC materials with multicolored electrochromism through exploiting electrochemical properties of traditional fluorescent small molecules.


A feasibility study of the Xpert MTB/RIF test at the peripheral level laboratory in China.
To evaluate the performance of Xpert MTB/RIF (MTB/RIF) in the county-level tuberculosis (TB) laboratory in China. From April 2011 to January 2012, patients with suspected multidrug-resistant tuberculosis (MDR-TB) and non-MDR-TB were enrolled consecutively from four county-level TB laboratories. The detection of Mycobacterium tuberculosis (MTB) by MTB/RIF was compared to detection by Löwenstein-Jensen culture. The detection of rifampin resistance was compared to detection by conventional drug-susceptibility testing. The impact of multiple specimens on the performance of MTB/RIF was also evaluated. A total of 2142 suspected non-MDR-TB cases and 312 suspected MDR-TB cases were enrolled. For MTB detection in suspected non-MDR-TB cases, the sensitivity and specificity of MTB/RIF were 94.4% and 90.2%, respectively. The sensitivity in smear-negative patients was 88.8%. For the detection of rifampin resistance in suspected non-MDR-TB cases, the sensitivity and specificity of MTB/RIF were 87.1% and 97.9%, respectively. For the detection of rifampin resistance in suspected MDR-TB cases, the sensitivity and specificity of MTB/RIF were 87.1% and 91.0%, respectively. Using multiple sputum specimens had no significant influence on the performance of MTB/RIF for MTB detection. The introduction of MTB/RIF could increase the accuracy of detection of MTB and rifampin resistance in peripheral-level TB laboratories in China. One single specimen is adequate for TB diagnosis by MTB/RIF.


Palbociclib as an early-line treatment for Japanese patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer: a review of clinical trial and real-world data.
Breast cancer is the most common type of cancer among women worldwide and in Japan. The majority of breast cancers are hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2‒), and endocrine therapy is an effective therapy for this type of breast cancer. However, recent substantial advances have been made in the management of HR+/HER2‒ advanced breast cancer (ABC) with the advent of targeted therapies, such as cyclin-dependent kinase 4/6 (CDK4/6) inhibitors, resulting in significant improvements in survival outcomes versus endocrine therapy alone. To evaluate the optimal use of palbociclib, a CDK4/6 inhibitor, in HR+/HER2- ABC, this review summarizes clinical trial and real-world data for palbociclib. In addition, current biomarker studies in palbociclib clinical research are reviewed. In Japanese patients, palbociclib was shown to be effective with a manageable safety profile, although differences were observed in the frequency of adverse event and dosing parameters. Current evidence supporting palbociclib as a first-line treatment strategy for patients with HR+/HER2‒ ABC in Asia, and specifically japan, is also discussed.


Comprehensive Biology and Genetics Compendium of Wilms Tumor Cell Lines with Different WT1 Mutations.
WT1 mutant Wilms tumors represent a distinct subgroup, frequently associated with CTNNB1 mutations. The genetic basis for the development of this subtype is currently not fully understood. Live WT1 mutant Wilms tumors were collected during surgery of patients and cell cultures established in mesenchymal stem cell medium. They were studied for mutations in WT1 and CTNNB1, their differentiation capacity and protein activation status. Four cell lines were immortalized with a triple mutant ts SV40 largeT antigen and Telomerase. 11 cell lines were established from Wilms tumors of nine patients, including a left and right tumor from the same patient and a primary and second tumor from another patient. Six patients had germ line and three were tumor specific mutations. All cell lines harbored only mutant or deleted WT1 genes. CTNNB1 was wild type in three, all others carried mutations affecting amino acid S45. They had variable and limited capacities for mesenchymal differentiation, a high migratory capacity and a low invasive potential. All cells showed an activation of multiple receptor tyrosine kinases and downstream signaling pathways. These cell lines represent an important new tool to study WT1 mutant Wilms tumors, potentially leading to new treatment approaches.


Risk assessment of fluoride exposure in drinking water of Tunisia.
The presence of fluoride in drinking water is known to reduce dental cavities among consumers, but an excessive intake of this anion might leads to dental and skeletal fluorosis. This study reports a complete survey of the fluoridated tap water taken from 100 water consumption points in Tunisia. The fluoride concentrations in tap water were between 0 and 2.4 mg L-1. Risk assessment of Fluoride exposure was assessed depending on the age of consumers using a four-step method: hazard identification, toxicity reference values selection (TRVs), daily exposure assessment, and risk characterization. Our findings suggest that approximately 75% of the Tunisian population is at risk for dental decay, 25% have a potential dental fluorosis risk, and 20% might have a skeletal fluorosis risk according to the limits of fluoride in drinking water recommended by WHO. More investigations are recommended to assess the exposure risk of fluoride in other sources of drinking water such as bottled water.


Monitoring the copper content of serum and urine in pregnancies complicated by preeclampsia.
Preeclampsia is an important cause of maternal and perinatal mortality worldwide. The etiology of this relatively common medical complication of pregnancy, however, remains unknown. The aim of this study was to compare the copper concentrations in serum and urine samples of preeclamptic and normotensive pregnant women to establish the possible contribution of this parameter to the etiology of this condition. Ninety-five preeclamptic and 92 normotensive pregnant women were enrolled in a cross-sectional study. The Cu content of serum and 24-h urine was compared among the women. The individual samples were analyzed for copper by atomic absorption spectrometry. The obtained data were recorded and analyzed statistically using t test, X2. Comparing the Cu concentrations in serum and urine samples of preeclamptic and normotensive pregnant women, significant differences between the two groups were observed. Obtained results of this study revealed that Cu content of serum and urine is increased in preeclamptic pregnancy.


PET-CT detection of local residual laryngeal carcinoma after definitive (chemo)radiotherapy.
Positron emission tomography and computed tomography (PET-CT) is currently recommended in evaluating the treatment response after (chemo)radiotherapy ([C]RT). In the larynx, post-treatment changes and physiological uptake make image interpretation more challenging compared to other head and neck sites. Previous research has not addressed imaging factors specifically in the larynx that would help in distinguishing the residual disease and explain the unique challenges of that anatomic area. The study cohorts are small and heterogenous. Our objective was to investigate the ability of PET-CT in diagnosing local residual laryngeal carcinoma, and to uncover imaging factors that could be used in differentiating the residual disease from post-treatment and physiological changes. In the same study cohort, we also aimed to uncover prognostic factors for local residual or recurrent disease. Our retrospective study cohort included 73 patients with T2-T4 laryngeal carcinoma undergoing (C)RT with curative intention, and post-treatment non-contrast-enhanced PET-CT at 2-6 months. Findings were compared between local residual and non-residual disease. Local residual disease was defined as a persistent tumor growth with no evidence of remission in between, confirmed by biopsy, and evident within 6 months from the end of RT. PET-CT was evaluated using a 3-step scale: negative, equivocal, and positive. Nine (12%) had a local residual tumor and 11 (15%) developed local recurrence, based on the biopsy. The median follow-up of surviving patients was 64 months (range, 28-174). In univariate analysis, primary tumor diameter greater than 2.4 cm (median value), and vocal cord fixation were prognostic for local residual or recurrent disease. Sensitivity, specificity, PPV, and NPV were 100%, 75%, 36%, and 100%, respectively, when the equivocal interpretation was grouped with the positive interpretation. All local residuals, and 28% (18/64) non-residuals, had a primary tumor area SUVmax of over 4.0 (p < 0.001). CT showed a persistent mass at the primary tumor area in 56% of residuals, and in 23% of non-residuals (p > 0.05). By combining SUVmax>4.0 and mass, specificity improved to 91%. NPV of post-treatment PET-CT in laryngeal carcinoma is high, but equivocal and positive results have low PPV and require further diagnostics. All local residuals had SUVmax over 4.0. The combination of SUVmax over 4.0 and mass on CT increased specificity, but the sensitivity was low.


Purification and properties of adenylosuccinate synthetase from Yoshida sarcoma ascites tumor cells.
Adenylosuccinate synthetase (IMP:L-aspartate ligase (GDP-forming), EC 126.96.36.199) was purified about 750-fold to a homogeneous state from Yoshida sarcoma ascites tumor cells. A yield of 38% purified enzyme was achieved by a procedure including affinity chromatography on hadacidin-Sepharose 4B. Ultracentrifugal analyses showed that the molecular weight of the native enzyme was 102 000 with an s20,w value of 4.5 and that the molecular weight in 6 M guanidine-HCl was 47 000. These values indicate that the native enzyme is composed of two subunits. The isoelectric point was determined to be 5.9 by isoelectric focusing. The optimum pH for activity was 6.8-7.0. The Km values for IMP, aspartate and GTP were calculated to be 4.1, 9.8 and 0.7 . 10(-4) M, respectively. The antibiotic, hadacidin was strongly inhibitory, causing competitive inhibition with respect to aspartate with a Ki value of 2.5 . 10(-6) M. Nucleoside mono- and diphosphate also inhibited the enzyme activity, but their inhibitions were not apparently specific. The purified enzyme showed full activity in the presence of Mg2+, and Mg2+ could be partially replaced by Mn2+, Co2+, Ca2+ or Cu2+. Divalent metal ions, such as Cd2+, Pb2+, Zn2+, Cu2+ and Mn2+, interfered with the activity by antagonizing Mg2+. Hg2+ or PCMB inactivated the enzyme, suggesting that an SH-group may be important for activity.


Potent and subtype-selective CCK-B/gastrin receptor antagonists: 2,4-dioxo-1,5-benzodiazepines with a plane of symmetry.
A series of CCK-B/gastrin receptor antagonists, 2,4-dioxo-1,5-benzodiazepine derivatives with a plane of symmetry, were designed, synthesized, and evaluated for antagonistic activity. Structure-activity relationship studies revealed that carbonylmethyl groups at both N-1 and N-5 positions and hydrophilic groups, such as the carboxyl group on the benzene ring attached to the ureido group at the C-3 position, brought about potent affinity and subtype selectivity for CCK-B/gastrin receptors. Several compounds showed excellent in vivo inhibition of gastric acid secretion induced by pentagastrin in anesthetized rats.


CT cisternography in intracranial symptomatic arachnoid cysts: classification and treatment.
The symptom and neuroimaging as indications for treating arachnoid cysts (ACs) are not adequate. Understanding the communication between cyst and subarachnoid space is helpful for decision-making. We took a dynamic study of ACs using CT cisternography (CTC) and proposed a classification of arachnoid cysts. Total 52 symptomatic patients with ACs were enrolled in this prospective study. CTC images were ordered, in all enrolled patients, at the 1, 3, 6, 12, 24 and 48 h after the intrathecal Omnipaque administration. Enhancement in cysts was measured quantitatively and was compared with neighboring subarachnoid spaces. All enrolled patients were allocated randomly in 2 groups. The CTC result was considered before treatment in one group (CTC group), while another group was surgically treated without considering CTC results (surgical group). ACs in our study were classified into 3 types: complete (cyst filling time at 1 h), incomplete (filling time began at 3 h) and noncommunicating cysts (no or slight filling after 24 h). Twenty-two patients in CTC group with incomplete communicating, or noncommunicating cysts underwent surgeries. And other 6 patients with complete communicating cysts were closely observed. In CTC group, the symptom of all surgical patients was relieved, and 5 out of 6 observational patients showed clinical improvement or no deterioration during the follow-up. In surgical group, only 18 out of 24 patients showed clinical improvement after surgeries, and there were 6 patients showing no difference before and after surgeries in symptom and in imaging. This classification based on dynamic CT cisternography is useful for the decision of surgical indication. Some symptomatic patients with complete communicating ACs may not need surgical intervention.


Cardiorespiratory fitness and proximity to commercial physical activity facilities among 12th grade girls.
To investigate the relationship between proximity to commercial physical activity (PA) facilities and cardiorespiratory fitness of 12th grade girls. Adolescent girls (n = 786, 60% African American, mean age = 17.6 ± .6 years) performed a submaximal fitness test (Physical Work Capacity 170 test). Commercial PA facilities were mapped and counted within a .75-mile street-network buffer around girls' homes using Geographic Information Systems. Sedentary activities and vigorous physical activity (≥6 metabolic equivalents) were determined by the average number of 30-minute blocks reported per day on the 3-Day Physical Activity Recall. Mixed model regressions were calculated using school as a random variable. Girls had higher weight-relative Physical Work Capacity 170 test scores if there was a commercial PA facility (n = 186, 12.4 ± 4.2 kg m/min/kg) within a .75-mile street-network buffer of home as compared with girls without a nearby facility (n = 600, 11.2 ± 3.6 kg m/min/kg). After adjusting for demographic variables, sports participation, sedentary behaviors, and vigorous physical activity, having one or more commercial PA facilities within a .75-mile street-network buffer of homes was significantly related to cardiorespiratory fitness. Both with and without adjustment for covariates, the presence of a commercial PA facility within a .75-mile street-network buffer of a girl's home was associated with higher cardiorespiratory fitness.


Soft X-ray holographic microscopy of chromosomes with high aspect ratio pinholes.
We used digital in-line soft X-ray holography (DIXH) in the Gabor geometry to image human chromosomes. The divergent wave front was generated by diffraction of synchrotron radiation from a high aspect ratio pinhole. As under our experimental conditions the achievable resolution depends on the pinhole radius, high aspect ratio holes with diameters in the 100 nm range were prepared by focused ion beam (FIB) milling. The central maximum of the obtained Airy pattern was used to image chromosomes prepared from metaphase HeLa cells at experimental resolutions of 370±40 nm with soft X-rays at 260 eV photon energy provided by the BESSY II synchrotron radiation facility.


Combined modified-Dixon and PROPELLER method with low refocusing flip angle for contrast-enhanced fat-suppressed T1-weighted MRI: A prospective cross-sectional study.
To propose the combined modified-Dixon and PROPELLER sequence with low refocusing flip angle (RFA) and investigate whether this sequence can acquire clinical contrast-enhanced (CE), fat-suppressed T1-weighted (T1W) images of the head and neck. The optimal RFA for T1W imaging was investigated in the brain of a healthy volunteer. The motion artifacts, water-fat separation error, contrast ratio (CR), and comprehensive quality were evaluated through comparison with a standard Cartesian modified-Dixon sequence in 50 patients. Two radiologists independently scored motion artifacts and water-fat separation error using a 4-point scale (1, unacceptable; 4, excellent) and comprehensive quality using a 5-point scale (1, substantially inferior; 5, substantially superior). The CR between CE lesions and non-CE muscle was calculated. The optimal RFA of 40° was determined. In the motion artifact assessment, ratings of 3 or 4 points were assigned to 83% (observer-1, 42/50; observer-2, 41/50) and 99% (50/50; 49/50) of cases for the standard and proposed sequences, respectively (p < 0.001; p < 0.001). For the water-fat separation error assessment, ratings of 3 or 4 points were assigned to 100% (50/50; 50/50) and 97% (48/50; 49/50) of cases, respectively (p < 0.001; p = 0.02). In comprehensive evaluation, the proposed sequence was equal, slightly superior, or substantially superior to the standard sequence in 85% (39/50; 46/50). The CR was significantly higher with the proposed sequence [2.27 (1.99-2.97) vs. 2.08 (1.88-2.42), p < 0.001]. The proposed sequence acquired stable fat-suppressed CE T1W images without motion artifacts and yielded superior overall image quality compared with the standard sequence.


Structural basis for the activation of microtubule assembly by the EB1 and p150Glued complex.
Plus-end tracking proteins, such as EB1 and the dynein/dynactin complex, regulate microtubule dynamics. These proteins are thought to stabilize microtubules by forming a plus-end complex at microtubule growing ends with ill-defined mechanisms. Here we report the crystal structure of two plus-end complex components, the carboxy-terminal dimerization domain of EB1 and the microtubule binding (CAP-Gly) domain of the dynactin subunit p150Glued. Each molecule of the EB1 dimer contains two helices forming a conserved four-helix bundle, while also providing p150Glued binding sites in its flexible tail region. Combining crystallography, NMR, and mutational analyses, our studies reveal the critical interacting elements of both EB1 and p150Glued, whose mutation alters microtubule polymerization activity. Moreover, removal of the key flexible tail from EB1 activates microtubule assembly by EB1 alone, suggesting that the flexible tail negatively regulates EB1 activity. We, therefore, propose that EB1 possesses an auto-inhibited conformation, which is relieved by p150Glued as an allosteric activator.


Single-cell profiling identifies mechanisms of inflammatory heterogeneity in chronic rhinosinusitis.
The heterogeneous cellular microenvironment of human airway chronic inflammatory diseases, including chronic rhinosinusitis (CRS) and asthma, is still poorly understood. Here, we performed single-cell RNA sequencing (scRNA-seq) on the nasal mucosa of healthy individuals and patients with three subtypes of CRS and identified disease-specific cell subsets and molecules that specifically contribute to the pathogenesis of CRS subtypes. As such, ALOX15+ macrophages contributed to the type 2 immunity-driven pathogenesis of one subtype of CRS, eosinophilic CRS with nasal polyps (eCRSwNP), by secreting chemokines that recruited eosinophils, monocytes and T helper 2 (TH2) cells. An inhibitor of ALOX15 reduced the release of proinflammatory chemokines in human macrophages and inhibited the overactivation of type 2 immunity in a mouse model of eosinophilic rhinosinusitis. Our findings advance the understanding of the heterogeneous immune microenvironment and the pathogenesis of CRS subtypes and identify potential therapeutic approaches for the treatment of CRS and potentially other type 2 immunity-mediated diseases.


[Analysis of current source density in the superior colliculi of cats in response to punctate visual stimulation].
The EPs in the cat superior colliculus to the punctiform light stimulation were of negative polarity and did not show the potential reversion. The region of EP recording was from 0.1 to 0.9 mm (stratum griseum superficiale). The field potential profile was subjected to the current source density analysis to determine the location and sequence of the current sources and sinks after punctiform light stimulation. The earliest current sink was observed at the depth 0.6--0.8 mm, the later and the most prominent local one--at 0.2--0.3 mm. The EPs to punctiform light stimuli seem to indicate more precisely the location of afferent synapses.


Ewing sarcoma in a geriatric patient.
Ewing Sarcoma has been the second most common primary osseous malignancy in childhood and adolescence. It has been described as a highly aggressive neoplasm. This is the oldest case report in the literature with Ewing Sarcoma.


Coping with COVID-19. Work life experiences of nursing, midwifery and paramedic academics: An international interview study.
The COVID-19 global pandemic was declared in March 2020. By June 2022, the total deaths worldwide attributed to COVID-19 numbered over 6.3 million. Health professionals have been significantly impacted worldwide primarily those working on the frontline but also those working in other areas including nursing, midwifery, and paramedic higher education. Studies of occupational stress have focused on the clinical health professional roles but scant attention has been drawn to the pressures on university-based academic staff supporting and preparing professionals for frontline health work. This qualitative study sought to explore the challenges experienced by health academics (nurses, midwives and paramedics), during COVID-19 and identify strategies enlisted. Six Australian and two United Kingdom universities collaborated, from which 34 health academics were individually interviewed via video or teleconference, using six broad questions. Ethical approval was obtained from the lead site and each participating University. Thematic analysis of the data was employed collaboratively across institutions, using Braun and Clarke's method. Data analysis generated four major themes describing academics': Experiences of change; perceptions of organisational responses; professional and personal impacts; and strategies to support wellbeing. Stress, anxiety and uncertainty of working from home and teaching in a different way were reported. Strategies included setting workday routine, establishing physical boundaries for home-working and regular online contact with colleagues. The ability of nursing, midwifery and, paramedic academic staff to adapt to a sudden increase in workload, change in teaching practices and technology, while being removed from their work environment, and collegial, academic and technological supports is highlighted. It was recognised that these changes will continue post-COVID and that the way academics deliver education is forever altered.


Characterizing germline APC and MUTYH variants in Ashkenazi Jews compared to other individuals.
Germline variants in the APC and MUTYH genes contribute to colorectal cancer (CRC) and adenoma risk, though may occur with varying frequencies in individuals of different ancestries. The aim of this study was to evaluate the prevalence of APC, monoallelic MUTYH and biallelic MUTYH germline variants in Ashkenazi Jewish (AJ) and Other Ancestry (OA) individuals with colorectal adenomas. We studied 7225 individuals with colorectal adenomas who had germline APC and MUTYH testing at a commercial laboratory. Cross-sectional medical history data were extracted from provider-completed test requisition forms. We performed bivariate analysis to compare the frequency of APC and MUTYH variants between AJ and OA, and examined APC p.I1307K and monoallelic MUTYH carrier phenotypes using logistic regression. Pathogenic APC variants occurred in 38/285 AJ (13%) and 1342/6940 OA (19%; P = 0.09); biallelic MUTYH variants in 2/285 (1%) AJ and 399/6940 (6%) OA (P < 0.0001); APC p.I1307K in 35/285 (12%) AJ and 29/6940 (1%) OA (P < 0.0001); and monoallelic MUTYH in 2/285 (1%) AJ and 133/6940 (2%) OA (P = 0.06). Monoallelic MUTYH variants were significantly associated with having a personal history of CRC, regardless of ancestry (OR 1.78; 95% CI 1.21-2.49; P < 0.01), but no significant association was found between APC p.I1307K variants and personal history of CRC (OR 1.38; 95% CI 0.79-2.44; P = 0.26). Ashkenazim with colorectal adenomas rarely have monoallelic or biallelic MUTYH variants, suggesting different genetic etiologies for polyposis in AJ compared to OA individuals. AJ ancestry assessment may be important in clinical evaluation for polyposis.


Gambogic acid inhibits Hsp90 and deregulates TNF-α/NF-κB in HeLa cells.
Gambogic acid (GB) is an important anti-cancer drug candidate, but the target protein by which it exerts its anti-cancer effects has not been identified. This study is the first to show that GB inhibits heat shock protein 90 (Hsp90) and down-regulates TNF-α/NF-κB in HeLa cells. The effects of GB on Hsp90 were studied by characterizing its physical interactions with Hsp90 upon binding, the noncompetitive inhibition of Hsp90 ATPase activity, and the degradation of Hsp90 client proteins (i.e., Akt, IKK) in HeLa cells. GB seems to bind to the N-terminal ATP-binding domain of Hsp90. Additionally, GB suppresses the activation of TNF-α/NF-κB and decreases XIAP expression levels and the ratio of Bcl-2/Bax, which in turn induces HeLa cell apoptosis. Thus, GB represents a promising therapeutic agent for cancer; it may also be useful as a probe to increase understanding of the biological functions of Hsp90.


Accelerating bioinformatics research with International Conference on Intelligent Biology and Medicine 2020.
The International Association for Intelligent Biology and Medicine (IAIBM) is a nonprofit organization that promotes intelligent biology and medical science. It hosts an annual International Conference on Intelligent Biology and Medicine (ICIBM), which was initially established in 2012. Due to the coronavirus (COVID-19) pandemic, the ICIBM 2020 was held for the first time as a virtual online conference on August 9 to 10. The virtual conference had ~ 300 registered participants and featured 41 online real-time presentations. ICIBM 2020 received a total of 75 manuscript submissions, and 12 were selected to be published in this special issue of BMC Bioinformatics. These 12 manuscripts cover a wide range of bioinformatics topics including network analysis, imaging analysis, machine learning, gene expression analysis, and sequence analysis.


Dietary bioaccumulation of UV-absorbing compounds, and post-ingestive fitness in larval planktotrophic crustaceans from coastal SW Atlantic.
Increased ultraviolet radiation (UVR) is a major environmental stressor for marine organisms. The response of planktotrophic larvae of holo- and meroplanktonic crustaceans fed dietary algae grown under different light regimes and contents of UV-absorbing compounds (UACs), was experimentally evaluated. Paracalanus parvus copepodites and Cyrtograpsus angulatus zoeae were fed diatoms grown under two radiation treatments: PAR (400-700 nm, produced by 40 W cool-white fluorescent bulbs) and PAR + UVR (280-700 nm; adding Q-Pannel UV-A-340 lamps to PAR fluorescent bulbs). An absorption peak at 337 nm (UVR range) was observed only for larvae fed UVR-irradiated diatoms. After 144 h of ad libitum feeding, larvae were exposed to UVR for 24 h. Mortality rates were ~80% in individuals fed PAR-reared microalgae, and ~10% for those fed UV-irradiated microalgae. Results point to the importance of UACs conferring some tolerance to planktotrophic larvae under increased environmental UVR stress. Yet, acquired tolerance is differential among larvae, with implications for zooplankton ecology.


Effect of triage training on nurses' practice and triage outcomes of patients with acute coronary syndrome.
Accurate assessment and prompt management of patients with acute coronary syndrome (ACS) is a complex process for emergency department (ED) nurses and has variable clinical outcomes. The aim of the present study was to determine the effectiveness of an educational intervention on nurses' practice during the triage of patients with ACS and the triage outcomes in this group of patients. In this quasi-experimental study, a pretest-posttest group of 24 nurses were included by convenience sampling method and 960 patients with ACS were selected by sequential sampling during the pre-intervention (n = 480) and post-intervention (n = 480) phases. A case-based learning (CBL) intervention was performed for nurses for one month considering the role of the triage nurse according to the American College of Cardiology (ACC) and the American Heart Association (AHA) recommendations as well as the factors affecting the proper identification and management of patients with ACS. During patient triage in the pre- and post-intervention phases, the "Triage Nurse Practice Checklist" and the "Medical Electronic Records" were used to assess nurses' practice and the triage outcomes in patients, respectively. The overall mean score of the triage nurses' practice and its subscales, including Primary monitoring and assessment, cardiovascular risk factors assessment, evaluation of coronary heart disease (CHD) symptoms, chest pain management, and adherence to the ACC/AHA practice guidelines were significantly improved in the post-intervention phase compared with the pre-intervention phase (p < 0.001). There was no significant difference between the triage outcomes, including in-hospital mortality within 24 hours, death in ED, hospitalization in other wards, and discharge from ED in the pre and post-intervention phases (P = 0.723). The development of a cardiac triage-specific educational program could improve the performance of nurses in the evaluation and management of patients with ACS, but had no effect on the triage outcomes in this group of patients. We recommend a quality improvement project or a critical outcomes-based triage system to assess ACS patients' care needs in the ED.


Small weight loss on long-term acarbose therapy with no change in dietary pattern or nutrient intake of individuals with non-insulin-dependent diabetes.
To see if the long-term treatment of non-insulin dependent diabetes (NIDDM) with the alpha-glucosidase inhibitor acarbose affects food intake and body weight. Randomized, double-blind, placebo-controlled, parallel design clinical trial of 12 months duration. Subjects with NIDDM in four treatment strata: 77 on diet alone, 83 also treated with metformin, 103 also treated with sulfonylurea and 91 also treated with insulin. Two 3 day diet records were obtained before randomization to acarbose or placebo therapy, and additional 3 day diet records were obtained at 3, 6, 9 and 12 months after randomization. Body weight was also measured at these times. Of the 354 subjects randomized, 279 (79%) completed at least 9 months of therapy and, of these, 263 (94%) provided at least one diet record during the baseline period and two diet records during the treatment period. After one year, subjects on acarbose had lost 0.46 +/- 0.28 kg, which differed significantly from the 0.33 +/- 0.25 kg weight gain on placebo (P = 0.027). The difference in weight change between acarbose and placebo did not differ significantly in the different treatment strata. Being in the study had significant effects on diet, including a reduction in energy intake from 1760-1700 Kcal/d (P < 0.05), a reduction in simple sugars intake from 18.5-17.4% of energy (P < 0.001), and reductions in the number of different foods consumed (33-30, P < 0.001) and the number of meals eaten per day (4.7-4.3, P < 0.001). However, compared to placebo treatment, acarbose had no effect on energy intake, nutrient intakes, or dietary patterns. In subjects with NIDDM on weight-maintaining diets, long-term acarbose therapy results in a small weight loss, but has no effect on energy or nutrient intakes. The weight loss induced by acarbose may be due partly to reduced doses of concomitant oral agents and insulin and partly to energy loss due to increased colonic fermentation.


Isoxazole-3-hydroxamic acid derivatives as peptide deformylase inhibitors and potential antibacterial agents.
A series of isoxazole-3-hydroxamic acid derivatives has been identified as a new class of small, nonpeptidic inhibitors of peptide deformylase (PDF). The synthesis, enzyme inhibition and preliminary investigation of the binding mode of this potential antibacterial compounds are reported.


High levels of serum hyaluronan is an early predictor of dengue warning signs and perturbs vascular integrity.
A main pathological feature of severe dengue virus infection is endothelial hyper-permeability. The dengue virus nonstructural protein 1 (NS1) has been implicated in the vascular leakage that characterizes severe dengue virus infection, however, the molecular mechanisms involved are not known. A cohort of 250 dengue patients has been followed from the onset of symptoms to the recovery phase. Serum hyaluronan levels and several other clinical parameters were recorded. The effect of NS1 treatment of cultured fibroblasts and endothelial cells on the expressions of hyaluronan synthetic and catabolic enzymes and the hyaluronan receptor CD44, were determined, as have the effects on the formation of hyaluronan-rich matrices and endothelial permeability. Elevated serum hyaluronan levels (≥70 ng/ml) during early infection was found to be an independent predictor for occurrence of warning signs, and thus severe dengue fever. High circulating levels of the viral protein NS1, indicative of disease severity, correlated with high concentrations of serum hyaluronan. NS1 exposure decreased the expression of CD44 in differentiating endothelial cells impairing the integrity of vessel-like structures, and promoted the synthesis of hyaluronan in dermal fibroblasts and endothelial cells in synergy with dengue-induced pro-inflammatory mediators. Deposited hyaluronan-rich matrices around cells cultured in vitro recruited CD44-expressing macrophage-like cells, suggesting a mechanism for enhancement of inflammation. In cultured endothelial cells, perturbed hyaluronan-CD44 interactions enhanced endothelial permeability through modulation of VE-cadherin and cytoskeleton re-organization, and exacerbated the NS1-induced disruption of endothelial integrity. Pharmacological targeting of hyaluronan biosynthesis and/or its CD44-mediated signaling may limit the life-threatening vascular leakiness during moderate-to-severe dengue virus infection. FUND: This work was supported in part by grants from the Swedish Cancer Society (2018/337; 2016/445), the Swedish Research Council (2015-02757), the Ludwig Institute for Cancer Research, Uppsala University, the Ministry of Science and Technology, Taiwan (106-2314-B-037-088- and 106-2915-I-037-501-), Kaohsiung Medical University Hospital (KMUH103-3 T05) and Academy of Finland. The funders played no role in the design, interpretation or writing of the manuscript.


Eosinophilic esophagitis due to red yeast rice (Monacoline K) in a dietary supplement for hypercholesterolemia.
We present a case of eosinophilic esophagitis (EoE) with positive skin-prick testing for type I allergy to red yeast rice (RYR, Artechol®). RYR is an over-the-counter supplement for hypercholesterolemia, since years famous in Asian countries and now also more and more popular in Western countries. The clinical relevance of IgE-mediated inflammation was proven by a rapid clearance of EoE-symptoms upon discontinuation of RYR. The role of skin-prick testing and allergy testing in general in EoE is controversial, but was of high importance in our patient. It demonstrates that in cases of a clear-cut allergy history, together with positive skin-prick (IgE) testing, a broad elimination diet can thus be avoided.


Threonine side chain conformational population distribution of a type I antifreeze protein on interacting with ice surface studied via ¹³C-¹⁵N dynamic REDOR NMR.
Antifreeze proteins (AFPs) provide survival mechanism for species living in subzero environments by lowering the freezing points of their body fluids effectively. The mechanism is attributed to AFPs' ability to inhibit the growth of seed ice crystals through adsorption on specific ice surfaces. We have applied dynamic REDOR (Rotational Echo Double Resonance) solid state NMR to study the threonine (Thr) side chain conformational population distribution of a site-specific Thr ¹³C(γ) and ¹⁵N doubly labeled type I AFP in frozen aqueous solution. It is known that the Thr side chains together with those of the 4th and 8th Alanine (Ala) residues commencing from the Thrs (the 1st) in the four 11-residue repeat units form the peptide ice-binding surface. The conformational information can provide structural insight with regard to how the AFP side chains structurally interact with the ice surface. χ-squared statistical analysis of the experimental REDOR data in fitting the theoretically calculated dynamic REDOR fraction curves indicates that when the AFP interacted with the ice surface in the frozen AFP solution, the conformations of the Thr side chains changed from the anti-conformations, as in the AFP crystal structure, to partial population in the anti-conformation and partial population in the two gauche conformations. This change together with the structural analysis indicates that the simultaneous interactions of the methyl groups and the hydroxyl groups of the Thr side chains with the ice surface could be the reason for the conformational population change. The analysis of the theoretical dynamic REDOR fraction curves shows that the set of experimental REDOR data may fit a number of theoretical curves with different population distributions. Thus, other structural information is needed to assist in determining the conformational population distribution of the Thr side chains.


A contribution to the knowledge of the so-called pyloric band ("double pylorus").
Two new cases of patients with so called muscular pyloric band ("double pylorus") are reported. Both possible genetic mechanisms of this malformation are discussed in detail: primary or congenital, and secondary or acquired by inflammation. After analysis of the hitherto related cases, the opinion is expressed that the so called pyloric band represents a congenital malformation. According to the authors, the striking frequency of simultaneous occurrence of pyloric band and ulcers does not necessarily favour the theory of inflammatory genesis. The accompanying ulcer seems rather to be a "second disease" in the sense of Rossle (1913), manifesting itself at a locus minoris resistentiae.


[Ying-Yang (YY-1) expression and Fas in biopsies of children with type IV lupus nephritis correlates with the clinical condition].
It has been demonstrated that Fasmediated apoptosis participates in the physiopathology of lupus nephritis, although it is not clear whether it contributes to the development of the tissue damage.Since YY-1 down regulates Fas in cancer cell lines, it is reasonable to consider that this transcription factor may control Fas expression in lupus nephritis. The objective was to determine the correlation between YY-1 and Fas expression in renal biopsies from children with type IV lupus nephritis, and their association with the clinical condition of the patients. Eighteen biopsies from children with type IV lupus nephritis and 5 controls were studied. Fas and YY-1 expression were determined by immunochemistry and quantified by densytometric analysis. The clinical conditions at the moment the biopsy were obtained from the clinical records and the results were analyzed through a one-way ANOVA with p<0.005. The results of the densytometric analysis showed an inverse relationship between YY-1 and Fas expression. YY-1 was grouped according to the intensity of expression in low, moderate and high and compared with the expression of Fas. The lupus nephritis biopsies, which revealed high expression of YY-1, corresponded to patients with less number of clinical complications,better outcome and fewer alterations on renal function.In contrast, low expression of YY-1 correlated with high Fas expression and worst clinical conditions. The present study suggests that YY-1regulates Fas expression in lupus nephritis and that it is associated with the clinical outcome of the patients,although further studies are necessary to determine weather it factor may serve as a prognosis factor. This is the first evidence of YY-1 participation in the physiopathology of lupus nephritis.


Does early pulmonary rehabilitation reduce acute health-care utilization in COPD patients admitted with an exacerbation? A randomized controlled study.
In COPD, hospital admissions and readmissions account for the majority of health-care costs. The aim of this prospective randomized controlled study was to determine if early pulmonary rehabilitation, commenced as an inpatient and continued after discharge, reduced acute health-care utilization. Consecutive COPD patients (n = 397), admitted with an exacerbation, were screened: 228 satisfied the eligibility criteria, of whom 97 consented to randomization to rehabilitation or usual care. Both intention-to-treat and per-protocol analyses are reported with adherence being defined a priori as participation in at least 75% of rehabilitation sessions. The participants were elderly with severe impairment of pulmonary function, poor health-related quality of life and high COPD-related morbidity. The rehabilitation group demonstrated a 23% (95% CI: 11-36%) risk of readmission at 3 months, with attendees having a 16% (95% CI: 0-32%) risk compared with 32% (95% CI: 19-45%) for usual care. These differences were not significant. There were a total of 79 COPD-related readmission days (1.7 per patient, 95% CI: 0.6-2.7, P = 0.19) in the rehabilitation group, compared with 25 (1.3 per patient, 95% CI: 0-3.1, P = 0.17) for the attendees and 209 (4.2 per patient, 95% CI: 1.7-6.7) for usual care. The BMI, airflow obstruction, dyspnoea and exercise capacity index showed a non-significant trend to greater improvement among attendees compared with those receiving usual care (5.5 (2.3) and 5.6 (2.7) at baseline, improving to 3.7 (1.9) and 4.5 (2.5), respectively, at 3 months). No adverse effects were identified. Early inpatient-outpatient rehabilitation for COPD patients admitted with an exacerbation was feasible and safe, and was associated with a non-significant trend towards reduced acute health-care utilization.


Improved photostability and reduced skin permeation of tretinoin: development of a semisolid nanomedicine.
The aims of this work were to increase the photostability and to reduce the skin permeation of tretinoin through nanoencapsulation. Tretinoin is widely used in the topical treatment of various dermatological diseases such as acne, psoriasis, skin cancer, and photoaging. Tretinoin-loaded lipid-core polymeric nanocapsules were prepared by interfacial deposition of a preformed polymer. Carbopol hydrogels containing nanoencapsulated tretinoin presented a pH value of 6.08±0.14, a drug content of 0.52±0.01 mg g(-1), pseudoplastic rheological behavior, and higher spreadability than a marketed formulation. Hydrogels containing nanoencapsulated tretinoin demonstrated a lower photodegradation (24.17±3.49%) than the formulation containing the non-encapsulated drug (68.64±2.92%) after 8h of ultraviolet A irradiation. The half-life of the former was seven times higher than the latter. There was a decrease in the skin permeability coefficient of the drug by nanoencapsulation, independently of the dosage form. The liquid suspension and the semisolid form provided K(p)=0.31±0.15 and K(p)=0.33±0.01 cm s(-1), respectively (p≤0.05), while the samples containing non-encapsulated tretinoin showed K(p)=1.80±0.27 and K(p)=0.73±0.12 cm s(-1) for tretinoin solution and hydrogel, respectively. Lag time was increased two times by nanoencapsulation, meaning that the drug is retained for a longer time on the skin surface.


The rebel thyroid of a revolutionary First Lady.
Nadezda Krupskaya, the revolutionary Russian and Lenin's wife, was affected by Graves' disease and many photos and portraits, including the painting of 1933 by Ivan Vladimirovich Kosmin, highlight evident goiter and exoftalmos. To treat Graves' disease, Krupskaya underwent to surgery performed by Theodor Kocher, considered the father of the modern thyroid surgery.


Is multiscaling an artifact in the stochastically forced Burgers equation?
We study turbulence in the one-dimensional Burgers equation with a white-in-time, Gaussian random force that has a Fourier-space spectrum approximately 1/k, where k is the wave number. From very high-resolution numerical simulations, in the limit of vanishing viscosity, we find evidence for multiscaling of velocity structure functions which cannot be falsified by standard tests. We find a new artifact in which logarithmic corrections can appear disguised as anomalous scaling and conclude that bifractal scaling is likely.


Visual hallucinations: A novel complication after hemispherectomy.
Two patients at our center experienced florid visual hallucinations following hemispherectomy. The first patient had drug-resistant left hemispheric focal seizures at 20 months of age from a previous stroke. Following functional hemispherectomy at age 3, he experienced frightening hallucinations 1 month post-operatively lasting 3.5 months. Our second patient underwent subtotal hemispherectomy at age 6 for drug-resistant focal seizures from right hemispheric cortical dysplasia. Eighteen months later he developed scary visual hallucinations during which he would shout and throw things. Hallucinations recurred for 6 months. In our experience in these patients, even though symptoms were florid, they were transient and subsided 3-6 months later.


Transfer of nuclear and ribosomal material from Sox10-lineage cells to neurons in the mouse brain.
Material transfer is an essential form of intercellular communication to exchange information and resources between cells. Material transfer between neurons and from glia to neurons has been demonstrated to support neuronal survival and activity. Understanding the extent of material transfer in the healthy nervous system is limited. Here we report that in the mouse central nervous system (CNS), neurons receive nuclear and ribosomal material of Sox10-lineage cell (SOL) origin. We show that transfer of SOL-derived material to neurons is region dependent, establishes during postnatal brain maturation, and dynamically responds to LPS-induced neuroinflammation in the adult mouse brain. We identified satellite oligodendrocyte-neuron pairs with loss of plasma membrane integrity between nuclei, suggesting direct material transfer. Together, our findings provide evidence of regionally coordinated transfer of SOL-derived nuclear and ribosomal material to neurons in the mouse CNS, with potential implications for the understanding and modulation of neuronal function and treatment of neurological disorders.


Quantitative real-time analysis of the efflux by the MacAB-TolC tripartite efflux pump clarifies the role of ATP hydrolysis within mechanotransmission mechanism.
Tripartite efflux pumps built around ATP-binding cassette (ABC) transporters are membrane protein machineries that perform vectorial export of a large variety of drugs and virulence factors from Gram negative bacteria, using ATP-hydrolysis as energy source. Determining the number of ATP molecules consumed per transport cycle is essential to understanding the efficiency of substrate transport. Using a reconstituted pump in a membrane mimic environment, we show that MacAB-TolC from Escherichia coli couples substrate transport to ATP-hydrolysis with high efficiency. Contrary to the predictions of the currently prevailing "molecular bellows" model of MacB-operation, which assigns the power stroke to the ATP-binding by the nucleotide binding domains of the transporter, by utilizing a novel assay, we report clear synchronization of the substrate transfer with ATP-hydrolysis, suggesting that at least some of the power stroke for the substrate efflux is provided by ATP-hydrolysis. Our findings narrow down the window for energy consumption step that results in substrate transition into the TolC-channel, expanding the current understanding of the efflux cycle of the MacB-based tripartite assemblies. Based on that we propose a modified model of the MacB cycle within the context of tripartite complex assembly.


Combined Phacoemulsification and Pars Plana Vitrectomy for the Treatment of Cataract in Patients With Noninfectious Uveitis.
This work evaluates the role of combined phacoemulsification and vitrectomy surgery in the management of cataract associated with noninfectious uveitis. A retrospective chart review was conducted of all patients aged 7 years or older who underwent a combined surgical approach from 2005 to 2018. Eighty-five eyes of 67 patients were included in the study; 10.7% of eyes had a best-corrected visual acuity (BCVA) of 20/40 or better at time of surgery. At 1-year follow-up, 63.4% of eyes had a BCVA 20/40 or better and 7.6% had a BCVA of 20/200 or worse. There was an overall decrease in cystoid macular edema after surgery compared with preoperatively (47.6% vs 34.5% presurgery and postsurgery, respectively). Complete inflammatory disease remission off immunomodulatory therapy and systemic steroids was achieved in 21.1% of patients. A combined surgical approach is effective in visual rehabilitation in patients with uveitic cataracts and may promote inflammatory disease remission specifically in intermediate uveitis.


Enhancing effect of misonidazole on the response of the RIF-1 tumour to cyclophosphamide.
The effect of misonidazole (MISO) on the cytotoxicity of cyclophosphamide (CY) was investigated in the mouse. The response of the RIF-1 tumour was measured by growth delay and by cell survival in a cloning assay. MISO enhanced the cytotoxicity of CY. For single treatment, enhancement was maximal when MISO was given 30 min to 2 h before CY. The enhancement ratio (i.e. the dose of CY alone divided by the dose of CY with MISO required to cause the same response) increased with increasing dose of MISO up to 250 mg/kg, but decreased with increasing dose of CY above 50 mg/kg. For 5 daily treatments, enhancement increased with CY dose up to approximately 25 mg/kg/injection. Survival of marrow stem cells was measured using the spleen-colony assay. MISO did not enhance significantly the cytotoxicity of CY at doses under 100 mg/kg. Enhancement was seen at higher doses, but the effect was less than in tumours. CY reduced the number of circulating white blood cells. Neutrophils were most severely depleted. The WBC count was slightly lower when CY was given in combination with MISO than after CY alone, but the effect could be accounted for by direct MISO cytotoxicity. These experiences suggest that a therapeutic gain may be achieved if MISO is combined with doses of CY in the clinical range. From experiments performed to investigated the possible mechanisms involved, we conclude that for the RIF-1 tumour the major effect of MISO is to inhibit the repair from CY-induced potentially lethal damage.


Photochemical oxidation and autoxidation of chlorophyll phytyl side chain in senescent phytoplanktonic cells: potential sources of several acyclic isoprenoid compounds in the marine environment.
Visible light-induced degradation of the chlorophyll phytyl side chain was studied in senescent cells of two phytoplanktonic strains (Skeletonema costatum and Thalassiosira weissflogii). Particular attention was paid to the induction of autoxidation processes on the phytyl chain and its photoproducts by photochemically produced hydroperoxides. The combination of photochemical oxidation and autoxidation reactions resulted in the production of several acyclic isoprenoid compounds that have been unambiguously identified by comparison of their retention times and mass spectra with those of appropriate standards. Various mechanisms are proposed to explain the formation of these oxidation products. These processes appear to be potential sources of numerous oxidized acyclic isoprenoids that previously have been detected in lacustrine and marine environments. Some oxidation products newly described or whose presence in natural samples was never reported in the literature were then sought in particulate matter, sediment, and microbial mat samples. The results obtained supported the significance of photochemical oxidation and autoxidation of phytoplanktonic chlorophyll phytyl side chain in the marine environment.


Medications adherence and associated factors among patients with stroke in the Kingdom of Saudi Arabia.
Stroke is one of the most significant neurological problems around the world, and is considered a leading cause of death. Due to polypharmacy and multimorbidity, stroke patients are susceptible to have lower levels of adherence to their medications and self-care activities. Patients who have suffered a stroke and had recently been admitted to public hospital were approached for recruitment. Patients' adherence to their medications was examined using a validated questionnaire during an interview between the principal investigator and the patients, where patients' adherence to their self-care activities was assessed using a developed, validated and previously published questionnaire as well. Reasons for lack of adherence was explored from the patients. Verification of patient's details and medications was done via the patient's hospital file. The mean age of the participants (n=173) was 53.21 (SD= 8.61) years. Assessing patients' adherence to medications showed that more than half of them stated that they sometimes/often forgot to take their medication/s, while 41.0% sometimes/often stopped their medication/s from time to time. The mean adherence to medications score (out of 28) was 18.39 (SD=2.1), with 83.8% having a low adherence level. It is found that patients who did not take their medications were due to forgetfulness (46.8%) and complications from taking the medications (20.2%). Better adherence was associated with higher educational level, higher number of medical conditions, and higher frequency of glucose monitoring. Adherence to self-care activities showed that majority of patients performed correct self-care activities three times a week. Post-stroke patients in Saudi Arabia have indicated low levels of medication adherence, while reporting good adherence to their self-care activities. Better adherence was associated with certain patient characteristics such as higher educational level. These findings can help in focusing the efforts to improve adherence and health outcomes for stroke patients in the future.


Techniques of Yang's arthroscopic discopexy for temporomandibular joint rotational anterior disc displacement.
Disc displacement is a common disorder affecting the temporomandibular joint. According to previous publications, the displaced disc can be categorized into pure anterior displacement and rotational displacement (anteromedial and anterolateral). However, the technique of arthroscopy treatment has only been reported for patients with pure anterior disc displacement. In this study, an arthroscopic discopexy for rotational anterior disc displacement was developed and its effectiveness evaluated over 24 months of follow-up. A total of 532 patients (749 joints) with rotational anterior disc displacement, admitted to Shanghai Ninth People's Hospital between January 2011 and December 2015, were included. The success rate was based on clinical parameters (visual analogue scale (VAS) for pain, maximum inter-incisal opening (MIO), and complications) and radiographic data. The clinical and radiographic data were collected preoperatively and at 1, 6, 12, and 24months postoperative. The VAS score decreased to 0.73±1.43 following surgery (P<0.001). A significant improvement in MIO (34.73±6.28mm) was also detected (P<0.001). Magnetic resonance imaging showed discs repositioned in both sagittal and coronal images for 714 of the 749 joints, giving a success rate of 95.3%. This study reports an effective and predictable technique of arthroscopic discopexy for rotational anterior disc displacement.


Rationale and Study Design of the PARERE Trial: Randomized phase II Study of Panitumumab Re-Treatment Followed by Regorafenib Versus the Reverse Sequence in RAS and BRAF Wild-Type Chemo-Refractory Metastatic Colorectal Cancer Patients.
A recent phase II randomized Japanese study reported better survival with regorafenib followed at progression by cetuximab ± irinotecan compared with the reverse standard sequence in chemo-refractory and anti-EGFR-naïve, RAS wild-type (wt) mCRC patients. Nowadays the use of anti-EGFR antibodies is more frequently anticipated to the first-line of therapy especially in patients with left-sided RAS/BRAF wt tumours. However, retrospective analyses and phase II single-arm trials showed promising activity of re-using anti-EGFRs in metastatic colorectal cancer (mCRC) patients who previously achieved benefit from a first-line anti-EGFR-based treatment. Post-hoc analyses of these trials revealed that the detection of RAS mutations in circulating tumour DNA (ct-DNA) at the time of re-treatment may be useful to identify resistant patients. PARERE (NCT04787341) is a prospective, open label, multicentre phase II study in which 214 RAS/BRAF wt chemo-refractory mCRC patients with previous benefit from first-line anti-EGFR-based treatment and RAS/BRAF wt ct-DNA in the liquid biopsy collected at the time of inclusion will be randomized in a 1:1 ratio to receive panitumumab followed after progression by regorafenib versus the reverse sequence. Primary endpoint is overall survival. Secondary endpoints are 1st-progression free-survival (PFS), 2nd-PFS, time to failure strategy, objective response rate, and safety. The aim of this study is to validate the role of anti-EGFR retreatment and its proper placement in the therapeutic route of mCRC patients selected according to the analysis of ct-DNA in liquid biopsy. Results are expected at the end of 2023.


Two antibacterial spiro compounds from the roots of Artemisia pallens wall: evidence from molecular docking.
Bioassay-guided isolation from acetone extract of the roots of Artemisia pallens Wall yielded two spiro compounds (1 and 2). The structures of these compounds were determined on the basis of spectroscopic techniques such as IR, MS, 1 D and 2 D- NMR. The acetone extract, fractions and the isolated two compounds were investigated for their antibacterial activity against two gram negative (E. coli, P. aeruginosa) and two gram positive (S. aureus, B. subtilis) bacterial strains. Compound (2) showed the best spectra of activity with IC50 and MIC values between 2.48-3.08 and 12.78 - 21.77 µM and Compound (1) with 2.57-3.69 and 38.17 - 80.57 µM, respectively, for the four bacterial strains, whereas inactive against Mycobacterium tuberculosis. Molecular docking study could further help in understanding the various interactions between these compounds and DNA gyrase active site in detail and thereby could provide valuable insight into the mechanism of action.


Diagnostic Accuracy of Inflammatory Markers for Diagnosing Occupational Asthma.
The assessment of airway responsiveness and inflammation is key to the investigation of occupational asthma (OA). We sought to assess and compare the diagnostic accuracies of the blood and sputum eosinophil counts and the methacholine challenge for the diagnosis of OA. We conducted a retrospective study assessing 618 patients who underwent specific inhalation challenges (SICs) for symptoms suggestive of OA between 2000 and 2015. A sputum induction and a methacholine challenge were performed before and after SICs. Blood samples were collected in all subjects before the SICs and in 100 subjects before and after SICs. The diagnostic accuracies of blood and sputum eosinophil counts and methacholine challenge were calculated for diagnosing OA. The change in blood eosinophil count failed to differentiate workers with positive and negative SICs. The change in sputum eosinophil counts induced by the exposure to the offending agent had the highest diagnostic accuracy (receiver operating characteristic area under the curve: 86% [95% confidence interval: 0.8-0.9, P < .001]) for diagnosing OA compared with changes in concentration of methacholine inducing a 20% fall in forced expiratory volume in 1 second (PC20) and blood eosinophils. Combining a 2-fold or greater decrease in PC20 or a 3% or greater increase in sputum eosinophil count achieved a sensitivity of 84% and a specificity of 74% with a negative predictive value of 91% for the diagnosis of OA. Blood eosinophil counts do not appear to be an effective aid for diagnosing OA. The performance of both sputum cell count analysis and a methacholine challenge before and after exposure to the offending agent may represent an effective alternative in diagnosing OA when SICs are unavailable.


The discovery of immunologic tolerance.
The phenomenon of tolerance can be said to have begun with the seminal observations in 1945 by R. D. Owen that cattle dizygotic twins display red cell (chimerism--mosaicism as he called it--in adult life. Owen interpreted this extraordinary finding in terms of the much earlier discovery by F. R. Lillie that the placentae of cattle dizygotic twins undergo anastomosis early in fetal life, and he speculated that this would have permitted blood cells and their precursors to move from one twin to the other. Owen's discovery came out of the blue and it was ignored by immunologists until F. M. Burnet and F. Fenner highlighted it four years later in their influential monograph The Production of Antibodies, in which they predicted the existence of tolerance as a general phenomenon and developed their notion of "self-markers" to explain why the body does not react against self. Though it was Medawar's group that showed conclusively in 1953 that tolerance can be experimentally induced in fetal mice and in chick embryos, their entry into this field came from a totally different direction, an attempt to distinguish between mono- and dizygotic cattle twins by the exchange of skin grafts. This led to the seemingly paradoxic result that grafts exchanged between dizygotic twins were accepted (1951) and it was not until their cattle experiments had been virtually completed that they became aware of Owen's earlier discovery. Following the work of Billingham, Brent, and Medawar, and of Hasek, tolerance became incorporated into general immunologic theory and it helped to explain the fact that mammals do not normally suffer from injurious autoimmune manifestations. Ray Owen's discovery therefore has a secure place in the history of immunology.


Neuromodulatory effect of cinnamon oil on behavioural disturbance, CYP1A1, iNOStranscripts and neurochemical alterations induced by deltamethrin in rat brain.
The objective of this study was to investigate the influence of deltamethrin (DLM)on brain function and to find whether DLM-induced neurotoxicity is prevented by the treatment with cinnamon oil. Four groups of ten Wistar albino male rats each were used. Group I (control) received saline only. Group II received cinnamon oil alone at 0.5 mg/kg B.W. intraperitonally, whereas Group III received orally DLM alone at 6 mg/kg B.W. Groups IV was treated with cinnamon oil plus DLM for 21 days to induce neurotoxicity. Rat behaviour, brain acetylcholine esterase (AChE), serotonin, oxidative stress profile were assessed. Serum sampling for the assessment of corticosterone concentration was also carried out. Finally, we demonstrate the gene expression of CYP1A1 and iNOS and the histological picture of the brain. Considering the behaviour assessment, DLM administration alone caused neurobehavioral deficits manifested by anxiety-like behavior which represented ina marked decrease in the sleeping frequency and duration, and marked increase the digging frequency and a wake non-active behavior duration. Moreover, the open field result showed a significant decrease in central square entries and duration. The neurochemical analysis revealed that DLM significantly suppressed AChE activity and elevated serotonin and corticosterone concentrations. Furthermore, results revealed thatthe brain reduced glutathione (GSH) content, superoxide dismutase (SOD) activity and malondialdehyde (MDA) concentration were significantly altered in DLM treated rats. Neurochemical disturbances were confirmed by histopathological changes in the brain. Furthermore, DLM up-regulates the mRNA expression of brain CYP1A1 and iNOS. Co-treatment with cinnamon oil exhibited significant improvement in behavioural performance and the brain antioxidant capacities with an increase in AChE activity and diminished the concentration of serotonin, serum corticosterone and MDA. Cinnamon oil treatment resulted in down-regulation of CYP1A1 and iNOS and improve the histologically picture. In conclusion, cinnamon oil ameliorated DLM-induced neurotoxicity through preventing oxidative stress-induced genotoxicity and apoptosis of brain in rats.


Brucellosis seroprevalence in dairy cattle in China during 2008-2018: A systematic review and meta-analysis.
Brucellosis remains one of the most common zoonotic diseases globally with more than a half million human cases reported annually. The Brucella reservoir associated with livestock brucellosis poses a significant threat to public health, and awareness of the seroprevalence and spatial distribution of livestock brucellosis is valuable for the prevention and control of diseases caused by Brucella, especially human brucellosis. Therefore, we conducted a systematic review and meta-analysis to evaluate the seroprevalence of brucellosis in dairy cattle in China. We retrieved 88 studies related to the seroprevalence of brucellosis in dairy cattle in China in which samples were harvested between 2008 and 2018. The results of our systematic review and meta-analysis reveal that the overall seroprevalence of brucellosis in dairy cattle herds in China was 1.9% during the selected period, rising from 1.6% in 2008-2012 to 2.6% in 2013-2018. In Northern China, where the traditional agropastoral areas with more developed animal breeding industry are located, the brucellosis seroprevalence was >10%. In contrast, the seroprevalence of brucellosis in Southern China reached only 5.5%. At the provincial level, the highest brucellosis seroprevalence in dairy cattle was estimated at >30% in Jilin province, followed by Shanxi, Ningxia, Inner Mongolia, and Guizhou, each with a prevalence of 10-20%. Additionally, the seroprevalence of brucellosis in some local areas was >30% or even >50%, indicating that Brucella infection was highly endemic in dairy herds in China. Our data may facilitate the prevention and control of brucellosis in domestic animals in China. Further epidemiological surveillance and the administration of a comprehensive monitoring program to determine the risk factors associated with brucellosis incidence in humans and domestic animals are recommended to refine brucellosis control strategies.


The landscape of expression and alternative splicing variation across human traits.
Understanding the consequences of individual transcriptome variation is fundamental to deciphering human biology and disease. We implement a statistical framework to quantify the contributions of 21 individual traits as drivers of gene expression and alternative splicing variation across 46 human tissues and 781 individuals from the Genotype-Tissue Expression project. We demonstrate that ancestry, sex, age, and BMI make additive and tissue-specific contributions to expression variability, whereas interactions are rare. Variation in splicing is dominated by ancestry and is under genetic control in most tissues, with ribosomal proteins showing a strong enrichment of tissue-shared splicing events. Our analyses reveal a systemic contribution of types 1 and 2 diabetes to tissue transcriptome variation with the strongest signal in the nerve, where histopathology image analysis identifies novel genes related to diabetic neuropathy. Our multi-tissue and multi-trait approach provides an extensive characterization of the main drivers of human transcriptome variation in health and disease.


Complication from Plastibell circumcision ring.
We describe the cases of 4 neonates with retained Plastibell rings and discuss the potential seriousness of this problem. Removal of the rings was accomplished by use of wire cutters. Local wound care resulted in perfect healing in 3 and slight scarring with ventral curvature in 1. None of these patients required skin grafting.


Functional characterization of a putative β-lactamase gene in the genome of Zymomonas mobilis.
Zymomonas mobilis ZM4 is resistant to β-lactam antibiotics but there are no reports of a β-lactam resistance gene and its regulation. A putative β-lactamase gene sequence (ZMO0103) in the genome of Z. mobilis showed a 55% amino acid sequence identity with class C β-lactamase genes. qPCR analysis of the β-lactamase transcript indicated a higher level expression of the β-lactamase compared to the relative transcript quantities in antibiotic-susceptible bacteria. The putative β-lactamase gene was cloned, expressed in Escherichia coli BL21 and the product, AmpC, was purified to homogeneity. Its optimal activity was at pH 6 and 30 °C. Further, the β-lactamase had a higher affinity towards penicillins than cephalosporin antibiotics.


Advances in controlled release hormonal technologies for contraception: A review of existing devices, underlying mechanisms, and future directions.
This article presents a comprehensive review on controlled release hormonal contraceptive systems that include transdermal patches, intravaginal rings (IVRs), intrauterine devices (IUDs), injectables and subdermal implants. These systems represent a substantial advance from traditional oral contraceptive pills, to improve upon safety, efficiency, and compliance among women. The widespread use of controlled release systems is hindered by limitations, which are discussed in this review. Biodegradable polymers such as poly (lactic-co-glycolic acid) and polycaprolactone have been used to formulate subdermal implants and injectable microspheres to eliminate the need for implant removal and reduce provider intervention. To address low permeability in transdermal patches, permeation enhancers such as alkanols, fatty acids, prodrugs, and vesicular delivery for steroids have been investigated. Local anesthetics in the form of creams, gels and sprays have been evaluated to alleviate the pain associated with IUD insertion. Among methods for device fabrication, 3D printing has emerged as a potential approach for fabricating customizable IVRs and IUDs. Several other modified delivery systems such as transdermal microneedle patches, in situ forming injectable implants, microspheres embedded in implants and IVRs addressing multiple clinical conditions have been investigated for controlled release of contraceptive hormones. To ensure drug release at zero-order rates, empirical and theoretical modelling have been extensively employed and evaluated. The limitations of low predictive power associated with empirical modelling may be overcome through theoretical modelling and simulation that consider underlying mechanisms. Newer approaches such as Monte Carlo based simulation and deep learning models based on artificial neural networks can prove highly beneficial in developing precise contraceptive delivery system, to enhance the quality of life for women worldwide.