A note on wildlife poisoning cases from Kerala, South India.
Wildlife poisoning is an important conservation threat for endangered species in India. There are no publications in the scientific literature that identify the specific poisons or chemicals involved in wildlife poisoning cases from the state of Kerala. In this report, all cases of wildlife mortality recorded between 2011 and 2013 at the office of the Assistant Forest Veterinary Officer, Periyar Tiger Reserve in Kerala were reviewed and cases where poisoning was considered as a differential diagnosis were identified. Specific poisons or chemicals were identified in three cases, while in a fourth, poisoning was determined to have occurred based on physical traces of the poison in gut contents. The poisons identified include carbofuran (a carbamate pesticide) in a bonnet macaque (Macaca radiata), warfarin (a rodenticide) in a mortality event involving four wild boars (Sus scrofa), endosulfan (an organochlorine pesticide) toxicity in a gaur (Bos gaurus) and imidacloprid (a neonicotinoid pesticide) toxicity in a wild adult Asian elephant (Elephas maximus). This communication thus reports for the first time on the specific chemical compounds identified in wildlife poisoning cases from Kerala state and argues for greater regulation of the sale and use of such toxic compounds in India.


[Treatment of femoral fracture on previous implants with minimally-invasive surgery and total weight-bearing: benefit of locking plate. Preliminary report].
We report a consecutive prospective series of femoral fractures on previous implants. The purpose was to assess treatment with locking compression plates and total weight-bearing. From June 2002 to December 2005, we treated 21 patients (16 women, five men) for fractures on previous implants: total hip arthroplasty (n=11), total knee arthroplasty (n=1), unicompartmental prosthesis (n=1), gamma nail (n=4), hip screw (n=1). Mean patient age was 75.8 years (range 39-90). Osteosynthesis was performed on an orthopedic table or on a standard table using a minimally-invasive approach for fixation with a locking compression plate (Synthes) LCP) to bridge the implants in place and avoid any zone of weakness. The rehabilitation protocol included immediate total weight bearing. At last follow-up there were three deaths and one failure so that there were 17 patients with a mean follow-up of 15.9 months (range 6-45 months). The following outcomes were noted. Minimally-invasive surgery was used in 18 cases, access to the fracture focus in three. Total weight bearing was possible immediately after surgery in 12 patients and partial weight bearing (20 kg) for two. There were two infections, two general complications and one early displacement. Healing was achieved at 6-10 weeks. Misalignment greater than 10 degrees was noted in three cases. This work illustrates the use of locking plates for minimally-invasive repair of fractures on previous implants with total weight bearing. This technique combines the principles of closed fixation and preservation of the fracture hematoma with material stability. In this form, use developed progressively. It is now common practice to use plate fixation for femoral fractures. The LISS system was then developed progressively for minimally-invasive repair of distal fractures. We widened the concept to include more proximal approaches. The use of the locking screws in the plate corresponds to what could be called an internal external fixator with three pins (two corresponding to the cortical screws plus the plate), which enable a solid fixation. Screw hold seems to be sufficient to allow early weight bearing. Locking plates have been shown to be an effective treatment for femoral fractures on previous implants allowing a stable fixation sufficient for early weight bearing.


Laparoscopic adrenalectomy for adrenal masses: does size matter?
To examine the impact of adrenal tumor size on perioperative morbidity and postoperative outcomes in patients undergoing laparoscopic adrenalectomy. A total of 227 laparoscopic adrenalectomies were divided in three groups according to size as estimated by pathologic specimen maximum diameter: less than 6 cm (group 1, n = 140), between 6 and 7.9 cm (group 2, n = 47), and equal to or larger than 8 cm (group 3, n = 40). We prospectively recorded and analyzed clinical and pathologic data. Average operative time was 60 minutes (range, 50 to 90 minutes) for group 1, 75 minutes (range, 65 to 105 minutes) for group 2, and 80 minutes (range, 65 to 120 minutes) for group 3. Estimated blood loss, median (interquartile range) was 50 mL (range, 20 to 100 mL), 100 mL (range, 48 to 225 mL), and 100 mL (range, 50 to 475 mL) for groups 1, 2, and 3, respectively. We observed a total of 10, 4, and 4 complications in groups 1, 2, and 3, respectively. Average hospital stay was 2 days (range, 2 to 3 days), 2 days (range, 2 to 3 days), and 3 days (range, 2 to 4 days), respectively, for groups 1, 2, and 3. Operative time, average blood loss, and mean hospital stay were significantly higher (P <or=0.05) for group 3 compared with group 1. Laparoscopic adrenalectomy in large adrenal masses (8 cm or greater) is associated with significantly longer operative time, increased blood loss, and longer hospital stay, without affecting perioperative morbidity.


Comparative tissue and body compartment accumulation and maternal transfer to eggs of perfluoroalkyl sulfonates and carboxylates in Great Lakes herring gulls.
The comparative accumulation of C(4)-C(15) perfluorinated sulfonates (PFSAs) and carboxylates (PFCAs), and several precursors (e.g., perfluorooctane sulfonamide, N-methyl-FOSA, and fluorotelomer unsaturated acids and alcohols) was examined in tissues (liver, brain, muscle, and adipose), plasma/red blood cells (RBCs) and whole egg clutches (yolk and albumen) of female herring gulls collected in 2010 from Chantry Island, Lake Huron of the Laurentian Great Lakes. Highest mean ∑PFSA concentrations were in yolk, followed by adipose, liver, plasma, muscle, RBCs, and brain. Highest mean ∑PFCA concentrations were in yolk, followed by brain, plasma, liver, RBC, adipose and muscle. PFOS accounted for >88% of ∑PFSA in all samples; the liver, plasma/RBCs, muscle and adipose PFCA patterns were dominated by C(8)-C(11) PFCAs, whereas C(10)-C(15) PFCAs in brain and yolk. Among PFSAs and PFCAs there is tissue-specific accumulation, which could be due to a number of pharmacokinetic processes.


Pemetrexed-based chemotherapy for non-small-cell lung cancer patients with EGFR exon 20 insertion mutation: a multicenter study.
Chemotherapy is the major choice for advanced non-small-cell lung cancer (NSCLC) patients with epidermal growth factor receptor exon 20 insertion (EGFR ex20ins). The efficacy of pemetrexed-based with other chemotherapy regimens and EGFR ex20ins subtypes in this population has not been well studied. We screened patients with EGFR ex20ins by next-generation sequencing (NGS) from a large cohort. The clinicopathologic and medical information were collected in advanced NSCLC patients with EGFR ex20ins. We also compared the clinical outcomes among patients with different subtypes of EGFR ex20ins. We retrospectively collected 119 stage IIIB/IV NSCLC patients with EGFR ex20ins from 9142 NSCLC patients across China from June 2013 to December 2018. The subtypes of EGFR ex20ins included A767_V769dupASV (33/119, 27.73%), S768_D770dupSVD (19/119, 15.97%), N771_H773dupNPH (11/119, 9.24%), A763_Y764insFQEA (2/119, 1.68%) and others (54/119, 45.38%). A total of 64.7% (77/119) of patients received pemetrexed-based first-line chemotherapy and 13.45% (16/119) of patients received pemetrexed-based second-line chemotherapy. Pemetrexed-based chemo-treated patients had longer median progression-free survival (PFS) than patients without pemetrexed-based chemo-treated (5.5 vs. 3.0 months, P=0.0026). Survival data was available for 66 patients and the median overall survival (OS) was 24.7 months. Pemetrexed-based chemo-treated patients had longer OS tendency than patients without pemetrexed-based chemo-treated (25.0 vs. 19.6 months, P=0.0769). Patients harboring A767_V769dupASV had better OS than other subtypes of EGFR ex20ins but without statistical significance (P=0.0676). Multivariate analysis revealed that histological type of NSCLC and bone-metastasis before treatment were independent prognostic factors for OS in all patients after adjusting all characteristic and treatment factors (P<0.05). To the best of our knowledge, it is the largest cohort study of advanced NSCLC patients with EGFR ex20ins across China. Pemetrexed-based treatment could have better control of disease than non-pemetrexed-based chemotherapies in this population. Furthermore, more effective agents are expected for patients harboring EGFR ex20ins.


Liver Fibrosis and Perihematomal Edema Growth in Primary Intracerebral Hemorrhage.
Liver disease is associated with altered serum osmolality, increased thrombin generation, and systemic inflammation, all of which may contribute to perihematomal edema (PHE) after intracerebral hemorrhage (ICH). We evaluated the association between a validated liver fibrosis index and PHE growth in a cohort of patients with primary ICH. We performed a retrospective cohort study using data from the Virtual International Stroke Trials Archive-ICH. We included adult patients with primary ICH presenting within 6 h of symptom onset. The exposure of interest was the Fibrosis-4 (FIB-4) score, a validated liver fibrosis index; this was modeled as a continuous variable. The primary outcome was absolute PHE growth over 96 h. Secondary outcomes were absolute admission and 96-h PHE volumes. We used multiple linear regression models adjusted for established determinants of PHE. In a secondary analysis, the FIB-4 score was modeled as a categorical variable to compare patients with versus without liver fibrosis. Among 354 patients with ICH, 8% had evidence of liver fibrosis based on a validated cutoff. The FIB-4 score was not associated with PHE growth in unadjusted (β, 0.03; 95% CI, - 0.01 to 0.12) or adjusted models (β, 0.04; 95% CI, - 0.03 to 0.13). In a secondary analysis treating FIB-4 as a categorical variable, patients with liver fibrosis did not have greater PHE growth than those without liver fibrosis. FIB-4 score was also not associated with absolute admission or 96-h PHE volumes. In a multicenter cohort of patients with primary intracerebral hemorrhage, a liver fibrosis score was not associated with PHE volume or growth.


ICD-10 implementation: no time to delay.
Whatever the ICD-10 launch date, hospitals must keep up their complex preparations. This foldout offers tips and case studies.


An Early Evaluation of Remote Site Visits for ACGME Program Applications.
Prior to the COVID-19 pandemic, accreditation site visit interviews occurred in-person. In response to the pandemic, the Accreditation Council for Graduate Medical Education (ACGME) developed a remote site visit protocol. To perform an early assessment of the remote accreditation site visits for programs applying for initial ACGME accreditation. A cohort of residency and fellowship programs that had remote site visits was evaluated from June to August 2020. Surveys were sent to program personnel, ACGME accreditation field representatives, and executive directors following the site visits. Comparison of accreditation decisions (Initial Accreditation or Accreditation Withheld) was completed for matched residency or fellowship programs having in-person site visits in 2019. Surveys were sent to all program personnel from the 58 residency and fellowship programs that had remote site visits for new program applications, as well as the accreditation field representatives who performed the remote visits. The survey response rate was 58% (352 of 607). Ninety-one percent of all respondents were extremely or very confident that remote site visits provided a thorough assessment of proposed residency or fellowship programs. Fifty-four programs having remote site visits were matched by specialty to programs having had in-person program application site visits in 2019. Forty-six programs that had remote site visits received Initial Accreditation, and 52 programs that had in-person site visits in 2019 received Initial Accreditation (P=.093, 95% CI 0.91-22.38). Most program personnel and accreditation field representatives were confident that remote site visits conducted for program applications provided fair and thorough assessments of the program.


The effects of morphine on the accumulation of homovanillic and 5-hydroxyindoleacetic acids in the choroid plexus of rats.
1 Choroid plexus obtained from the lateral ventricles of the rat actively accumulated homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA). 2 Morphine 5 X 10(-6) M to 5 X 10(-4)M potentiated 5-HIAA accumulation but did not affect HVA accumulation. Levorphanol and dextorphan had little effect. 3 Naloxone at high concentrations inhibited both HVA and 5-HIAA accumulation. 4 Glutamic acid, glycine, and arginine also decreased 5-HIAA accumulation, but lysine, tryptophan, and aspartic acid had no effect. 5 Probenecid, naloxone, arginine, glycine, and tryptophan blocked the increase of 5-HIAA accumulation induced by morphine. 6 Acute or chronic morphine treatment did not increase the accumulation of 5-HIAA. 7 These results suggest that the increase of 5-HIAA or HVA in brain by morphine is not due to the inhibition of the elimination of these metabolites from the choroid plexus.


miR-155 induces ROS generation through downregulation of antioxidation-related genes in mesenchymal stem cells.
Inflammation-induced reactive oxygen species (ROS) are implicated in cellular dysfunction and an important trigger for aging- or disease-related tissue degeneration. Inflammation-induced ROS in stem cells lead to deterioration of their properties, altering tissue renewal or regeneration. Pathological ROS generation can be induced by multiple steps, and dysfunction of antioxidant systems is a major cause. The identification of the central molecule mediating the above-mentioned processes would pave the way for the development of novel therapeutics for aging, aging-related diseases, or stem cell therapies. In recent years, microRNAs (miRNAs) have been shown to play important roles in many biological reactions, including inflammation and stem cell functions. In inflammatory conditions, certain miRNAs are highly expressed and mediate some cytotoxic actions. Here, we focused on miR-155, which is one of the most prominent miRNAs in inflammation and hypothesized that miR-155 participates to inflammation-induced ROS generation in stem cells. We observed mesenchymal stem cells (MSCs) from 1.5-year-old aged mice and determined that antioxidants, Nfe2l2, Sod1, and Hmox1, were suppressed, while miR-155-5p was highly expressed. Subsequent in vitro studies demonstrated that miR-155-5p induces ROS generation by suppression of the antioxidant genes by targeting the common transcription factor C/ebpβ. Moreover, this mechanism occurred during the cell transplantation process, in which ROS generation is triggering loss of transplanted stem cells. Finally, attenuation of antioxidants and ROS accumulation were partially prevented in miR-155 knockout MSCs. In conclusion, our study suggests that miR-155 is an important mediator connecting aging, inflammation, and ROS generation in stem cells.


Cardiorenal Syndromes: Evaluation and Management.
Cardiorenal syndromes (CRS) describe disorders effecting critically ill and hospitalized patients with concurrent heart and kidney dysfunction. The presence of CRS is associated with a poor prognosis. This article is a review of the epidemiology, pathology, and evidence-based evaluation and management strategies for cardiorenal syndromes. All nurses should understand the significance that chronic heart and kidney disease has upon a patient's risk for CRS. Registered and advanced practice nurses should maintain the knowledge and skills of understanding the pathology of CRS to improve the evaluation and management of patients who present with CRS.


A new dimethyl labeling-based SID-MRM-MS method and its application to three proteases involved in insulin maturation.
The absolute quantification of target proteins in proteomics involves stable isotope dilution coupled with multiple reactions monitoring mass spectrometry (SID-MRM-MS). The successful preparation of stable isotope-labeled internal standard peptides is an important prerequisite for the SID-MRM absolute quantification methods. Dimethyl labeling has been widely used in relative quantitative proteomics and it is fast, simple, reliable, cost-effective, and applicable to any protein sample, making it an ideal candidate method for the preparation of stable isotope-labeled internal standards. MRM mass spectrometry is of high sensitivity, specificity, and throughput characteristics and can quantify multiple proteins simultaneously, including low-abundance proteins in precious samples such as pancreatic islets. In this study, a new method for the absolute quantification of three proteases involved in insulin maturation, namely PC1/3, PC2 and CPE, was developed by coupling a stable isotope dimethyl labeling strategy for internal standard peptide preparation with SID-MRM-MS quantitative technology. This method offers a new and effective approach for deep understanding of the functional status of pancreatic β cells and pathogenesis in diabetes.


[Induction of interferon and activation of NK cells and macrophages in mice by oral administration of Ge-132, an organic germanium compound].
After oral administration of an organic germanium compound, Ge-132 (300 mg/kg), a significant level of interferon (IFN) activity was detected in the sera of mice at 20 hr and it reached a maximum of 320 U/ml at 24 hr. This IFN activity was lost after heat- or acid-treatment, suggesting that the induced IFN is of gamma nature. The molecular weight of this IFN was estimated to be 19,000 daltons by gel filtration. After the oral administration of Ge-132, NK activity of spleen cells had increased at 24 hr and cytotoxic macrophages were induced in the peritoneal cavity at 48 hr. In mice, receiving intraperitoneal (i.p.) injections of trypan blue or carrageenan 2 days before oral administration of Ge-132, neither induction of IFN nor augmentation of NK activity followed. X ray irradiation of mice also rendered the mice incapable of producing IFN, all suggesting that both macrophages and lymphocytes are required for this IFN induction. After i.p. administration of induced IFN, both NK and cytotoxic macrophage activities appeared at 48 hr with as little as 20 U/ml titered IFN. These facts may indicate that the augmentation of NK and activation of macrophages in mice after oral administration of Ge-132 is mediated by induced IFN.


Estimated costs for Duchenne muscular dystrophy care in Brazil.
The economic burden of rare diseases on health systems is still not widely measured, with the generation of accurate information about the costs with medical care for subjects with rare diseases being crucial when defining health policies. Duchenne Muscular Dystrophy (DMD) is the most common form of muscular dystrophy, with new technologies recently being studied for its management. Information about the costs related to the disease in Latin America is scarce, and the objective of this study is to evaluate the annual hospital, home care and transportation costs per patient with DMD treatment in Brazil. Data from 27 patients were included, the median annual cost per patient was R$ 17,121 (IQR R$ 6,786; 25,621). Home care expenditures accounted for 92% of the total costs, followed by hospital costs (6%) and transportation costs (2%). Medications and loss of family, and patient's productivity are among the most representative consumption items. When disease worsening due to loss of the ability to walk was incorporated to the analysis, it was shown that wheelchair users account for an incremental cost of 23% compared with non-wheelchair users. This is an original study in Latin America to measure DMD costs using the micro-costing technique. Generating accurate information about costs is crucial to provide health managers with information that could help establish more sustainable policies when deciding upon rare diseases in emerging countries.


Preterm birth at 23 to 26 weeks' gestation: is active obstetric management justified?
To determine if active perinatal management was justified in preterm deliveries at less than or equal to 26 weeks' gestation, the outcome (survival and short- and long-term morbidity) of 43 infants (group I) born between 23 and 26 weeks' gestation was compared with that of 17 infants (group II) born at 27 weeks' gestation. Of the 12 surviving infants in group I (survival 28%), 11 were ventilated (median = 50 days), eight had moderate to severe bronchopulmonary dysplasia, and four had mild retrolental fibroplasia. At follow-up, two infants had physical disabilities with moderate to severe functional impairment, one had a minor disability, and nine had normal neurodevelopment. In contrast, of the 13 surviving infants in group II (survival 76%), nine were ventilated (median = 8 days), six had moderate to severe bronchopulmonary dysplasia, and six had mild RLF. At follow-up, one infant had a physical disability with moderate to severe functional impairment, four had minor disabilities, and eight had normal development. Perinatal factors that positively influenced survival in the two groups combined included active perinatal management, antenatal steroids, female sex, and absence of clinical chorioamnionitis and asphyxia. Although group I infants had a significantly higher mortality rate (p less than 0.05) and required a longer duration of ventilation (p less than 0.05), no differences in the incidence of postnatal complications or long-term morbidity at 2 to 4 years of age were evident between the two groups.


Conversion of Racemic Alkyl Aryl Sulfoxides into Pure Enantiomers Using a Recycle Photoreactor: Tandem Use of Chromatography on Chiral Support and Photoracemization on Solid Support.
Chiral sulfoxides are valuable in the fields of medicinal chemistry and organic synthesis. A recycle photoreactor utilizing the concept of deracemization, where a racemate is converted into a pure enantiomer, is developed and successfully applied in the syntheses of chiral alkyl aryl sulfoxides. The recycling system consists of rapid photoracemization using an immobilized photosensitizer and separation of the enantiomers via chiral high-performance liquid chromatography, and the desired pure chiral sulfoxides are obtained after 4-6 cycles. The key to the success of the system is the photoreactor site, wherein the photosensitizer 2,4,6-triphenylpyrylium is immobilized on the resin and irradiated (405 nm) to enable the rapid photoracemizations of the sulfoxides. As the green recycle photoreactor requires no chiral components, it should be a useful alternative system for application in producing chiral compounds.


Development of a Sustainable Procedure for the Recovery of Hydroxytyrosol from Table Olive Processing Wastewater Using Adsorption Resin Technology and Centrifugal Partition Chromatography.
The present endeavor aims to establish a novel procedure, applicable to the extraction and isolation of hydroxytyrosol from table olive processing wastewater. A two-step chromatographic separation is presented using non-ionic absorbent resin for the recovery of its phenolic content, followed by purification of hydroxytyrosol with centrifugal partition chromatography. Two table olive processing wastewaters, obtained from Kalamon and Amfissis olive varieties, were used. In the extracts obtained after resin treatment, the hydroxytyrosol content was determined by high-performance liquid chromatography with diode-array detection to be 4.05% and 10.10%, respectively. The extract from Amfissis table olive processing wastewater was further processed with preparative centrifugal partition chromatography for the purification of hydroxytyrosol. High-performance liquid chromatography analysis revealed that the isolated compound was >95% purity.


Effect of intravenous hydrocortisone administration on glucose homeostasis in small for gestational age infants.
The effects of I.V. hydrocortisone (H) (10 mg/kg) on glucose homeostasis were evaluated at 25 to 85 hours of age in 14 infants who were small for gestational age (SGA) in comparison to 17 control SGA infants. Three hours after H administration, higher levels of plasma glucose than in controls were detected (mean +/- S.E.M.): 4.78 +/- 0.2 vs. 2.88 +/- 0.2 mmol/l (p less than 0.01), while lower levels were found for blood pyruvate (38 +/- 7 vs. 89 +/- 12 mumol/l--p less than 0.01), plasma insulin (6.4 +/- 0.5 vs. 12 +/- 0.8 muIU/ml--p less than 0.05) and plasma glucagon (62.25 +/- 6.6 vs. 81.6 +/- 6.6 pmol/l--p less than 0.05). Three hours after H administration, I.V. injection of L-alanine (150 mg/kg) produced a significant rise over baseline of plasma glucose concentration from 4.78 +/- 0.2 to 5.94 +/- 0.2 mmol/l at 50 min (p less than 0.05), whereas no significant change was observed in controls. There was no significant change in plasma glucagon and insulin concentrations after L-alanine injection in either group. These results show that in SGA infants primed with H, the rise of plasma glucose concentration after L-alanine administration is observed with low plasma insulin levels and without stimulation of glucagon secretion. They suggest that H induced a reduced peripheral utilization of glucose by lowering the plasma levels of insulin and a production of glucose from alanine through gluconeogenesis.


GrimAge Outperforms Other Epigenetic Clocks in the Prediction of Age-Related Clinical Phenotypes and All-Cause Mortality.
The aging process is characterized by the presence of high interindividual variation between individuals of the same chronical age prompting a search for biomarkers that capture this heterogeneity. Epigenetic clocks measure changes in DNA methylation levels at specific CpG sites that are highly correlated with calendar age. The discrepancy resulting from the regression of DNA methylation age on calendar age is hypothesized to represent a measure of biological aging with a positive/negative residual signifying age acceleration (AA)/deceleration, respectively. The present study examines the associations of 4 epigenetic clocks-Horvath, Hannum, PhenoAge, GrimAge-with a wide range of clinical phenotypes (walking speed, grip strength, Fried frailty, polypharmacy, Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MOCA), Sustained Attention Reaction Time, 2-choice reaction time), and with all-cause mortality at up to 10-year follow-up, in a sample of 490 participants in the Irish Longitudinal Study on Ageing (TILDA). HorvathAA and HannumAA were not predictive of health; PhenoAgeAA was associated with 4/9 outcomes (walking speed, frailty MOCA, MMSE) in minimally adjusted models, but not when adjusted for other social and lifestyle factors. GrimAgeAA by contrast was associated with 8/9 outcomes (all except grip strength) in minimally adjusted models, and remained a significant predictor of walking speed, .polypharmacy, frailty, and mortality in fully adjusted models. Results indicate that the GrimAge clock represents a step-improvement in the predictive utility of the epigenetic clocks for identifying age-related decline in an array of clinical phenotypes promising to advance precision medicine.


Emotional eating and weight regulation: a qualitative study of compensatory behaviors and concerns.
Emotional eating, or overeating in response to negative emotions, is a behavior endorsed by both normal weight and people with overweight/obesity. For some individuals, emotional eating contributes to weight gain and difficulties losing weight. However, there are also many who engage in emotional eating who maintain a normal weight. Little is known about the mechanisms by which these individuals are able to regulate their weight. The present study seeks to gain insight into the behaviors of individuals of normal weight who engage in emotional eating through a series of one-on-one, 1-h long, qualitative interviews. Interviews were semi-structured and guided by questions pertaining to participants' compensatory behaviors used to regulate weight and concerns regarding their emotional eating. All interviews were transcribed and then objected to a thematic analysis of their content. The results of this analysis showed that participants endorsed using physical activity, controlling their eating behaviors, and engaging in alternative stress reduction and coping strategies to mitigate the effects of their emotional eating. They reported concern over the effects of emotional eating on their weight, body image, and health and saw this behavior as an unhealthy coping mechanism that was difficult to control. These results suggest that programs promoting exercise, mindful eating, emotion regulation, and positive body image could have a positive effect on emotional eaters who struggle to maintain a healthy weight.


Postpartum reversibility of impaired incretin effect in gestational diabetes mellitus.
The potential reversibility of a reduced incretin effect is unclear. We investigated the incretin effect during third trimester and 3 to 4months postpartum in women with and without gestational diabetes mellitus (GDM). Ten women with GDM (plasma glucose (PG) concentration at 120min after 75g-oral glucose tolerance test (OGTT) (PG120min): 10.1±0.6mmol/l (mean±SEM)) and eight women with normal glucose tolerance (NGT; PG120min: 7.0±0.1mmol/l) were investigated on four occasions: 4h 50g-OGTT and isoglycaemic intravenous glucose infusion during third trimester and 3 to 4months postpartum. In women with GDM, the incretin effect increased significantly postpartum (31±6 vs. 56±6%, p=0.02), whereas the increment in women with NGT was insignificant (35±12 vs. 56±9%, p=0.08). Similarly, the gastrointestinal-mediated glucose disposal (GIGD=100%×(glucoseOGTT-glucoseIIGI)/glucoseOGTT) was reduced to diabetic levels in women with GDM (37±3%), but increased (p=0.030) to normal levels post partum (58±6%). GIGD did not change significantly in NGT women (48±3 vs. 57±6%, p=0.94). Women with GDM exhibit a reduced incretin effect which is fully reversible alongside the restoration of normal glucose homeostasis, whereas the reduction in incretin effect during pregnancy in women with NGT was insignificant. Our results suggest that decreased incretin effect in women with GDM is a fully reversible phenomenon.


Progressive accumulation of hyperinflammatory NKG2D low NK cells in early childhood severe atopic dermatitis.
Atopic dermatitis (AD) is a chronic inflammatory skin disease that often precedes the development of food allergy, asthma, and allergic rhinitis. The prevailing paradigm holds that a reduced frequency and function of natural killer (NK) cell contributes to AD pathogenesis, yet the underlying mechanisms and contributions of NK cells to allergic co-morbidities remain ill-defined. Herein, analysis of circulating NK cells in a longitudinal early life cohort of children with AD revealed a progressive accumulation of NK cells with low expression of the activating receptor NKG2D, which was linked to more severe AD and sensitivity to allergens. This was most notable in children co-sensitized to food and aero allergens, a risk factor for development of asthma. Individual-level longitudinal analysis in a subset of children revealed co-incident reduction of NKG2D on NK cells with acquired or persistent sensitization, and this was associated with impaired skin barrier function assessed by transepidermal water loss. Low expression of NKG2D on NK cells was paradoxically associated with depressed cytolytic function but exaggerated release of the proinflammatory cytokine TNF-α. These observations provide important insights into a potential mechanism underlying the development of allergic co-morbidity in early life in children with AD which involves altered NK-cell functional responses, and define an endotype of severe AD.


Bedside Optic Nerve Ultrasonography for Diagnosing Increased Intracranial Pressure: A Systematic Review and Meta-analysis.
Optic nerve ultrasonography (optic nerve sheath diameter sonography) has been proposed as a noninvasive, quick method for diagnosing increased intracranial pressure. To examine the accuracy of optic nerve ultrasonography for diagnosing increased intracranial pressure in children and adults. 13 databases from inception through May 2019, reference lists, and meeting proceedings. Prospective optic nerve ultrasonography diagnostic accuracy studies, published in any language, involving any age group or reference standard. 3 reviewers independently abstracted data and performed quality assessment. Of 71 eligible studies involving 4551 patients, 61 included adults, and 35 were rated as having low risk of bias. The pooled sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio of optic nerve ultrasonography in patients with traumatic brain injury were 97% (95% CI, 92% to 99%), 86% (CI, 74% to 93%), 6.93 (CI, 3.55 to 13.54), and 0.04 (CI, 0.02 to 0.10), respectively. Respective estimates in patients with nontraumatic brain injury were 92% (CI, 86% to 96%), 86% (CI, 77% to 92%), 6.39 (CI, 3.77 to 10.84), and 0.09 (CI, 0.05 to 0.17). Accuracy estimates were similar among studies stratified by patient age, operator specialty and training level, reference standard, sonographer blinding status, and cutoff value. The optimal cutoff for optic nerve sheath dilatation on ultrasonography was 5.0 mm. Small studies, imprecise summary estimates, possible publication bias, and no evaluation of effect on clinical outcomes. Optic nerve ultrasonography can help diagnose increased intracranial pressure. A normal sheath diameter measurement has high sensitivity and a low negative likelihood ratio that may rule out increased intracranial pressure, whereas an elevated measurement, characterized by a high specificity and positive likelihood ratio, may indicate increased intracranial pressure and the need for additional confirmatory tests. None. (PROSPERO: CRD42017055485).


SOX6 suppresses the development of lung adenocarcinoma by regulating expression of p53, p21CIPI , cyclin D1 and β-catenin.
The Sry-related high-mobility group box6 (SOX6) has been implicated in the development of cancer, but its role in lung cancer is incompletely understood. Here, we report that SOX6 expression is frequently down-regulated in lung adenocarcinoma tissues. Moreover, SOX6 can inhibit the proliferation and invasion of lung adenocarcinoma cells, which may occur through cell cycle arrest at G1/S due to up-regulation of p53 and p21CIPI and down-regulation of cyclin D1 and β-catenin. Univariate and multivariate analyses revealed that the expression of SOX6 is significantly associated with patient disease-related survival and is an independent prognostic factor for lung adenocarcinoma. These data suggest that SOX6 may act as a suppressor of lung adenocarcinoma.


CNS remyelination as a novel reparative approach to neurodegenerative diseases: The roles of purinergic signaling and the P2Y-like receptor GPR17.
Oligodendrocytes are the myelin-forming cells in the CNS. They enwrap axons, thus permitting fast impulse transmission and exerting trophic actions on neurons. Demyelination accompanied by neurological deficit is a rather frequent condition that is not only associated with multiple sclerosis but has been also recognized in several other neurodegenerative diseases, including brain trauma and stroke, Alzheimer's disease and amyotrophic lateral sclerosis. Recently, alterations of myelin function have been also reported in neuropsychiatric diseases, like depression and autism. Highly relevant for therapeutic purposes, oligodendrocyte precursor cells (OPCs) still persist in the adult brain and spinal cord. These cells are normally rather quiescent, but under specific circumstances, they can be stimulated to undergo differentiation and generate mature myelinating oligodendrocytes. Thus, approaches aimed at restoring myelin integrity and at fostering a correct oligodendrocyte function are now viewed as novel therapeutic opportunities for both neurodegenerative and neuropsychiatric diseases. Both OPCs and mature oligodendrocytes express purinergic receptors. For some of these receptors, expression is restricted at specific differentiation stages, suggesting key roles in OPCs maturation and myelination. Some of these receptors are altered under demyelinating conditions, suggesting that their dysregulation may contribute to disease development and could represent adequate new targets for remyelinating therapies. Here, we shall describe the current literature available on all these receptors, with special emphasis on the P2Y-like GPR17 receptor, that represents one of the most studied receptor subtypes in these cells. This article is part of the Special Issue entitled 'Purines in Neurodegeneration and Neuroregeneration'.


Species composition of Bacteroidales order bacteria in the feces of healthy people of various ages.
A study of species distribution of numerically predominant Bacteroidales order isolates in feces of healthy people aged 1-33 years was accomplished using a combination of amplified ribosomal DNA restriction analysis (ARDRA) and 16S ribosomal DNA (rDNA) sequencing. It was found that the majority of isolates in all age groups belonged to species B. xylanisolvens, B. vulgatus, and B. uniformis. Members of genera Alistipes, Parabacteroides, Odoribacter, Barnesiella, and Prevotella were also detected frequently.


Cytomegalovirus Infection Post-Allogeneic Stem Cell Transplantation: Experience from a Country with High Seropositivity.
Cytomegalovirus (CMV) infection is a major cause of morbidity and mortality after hematopoietic stem cell transplantation (HSCT). Limited data are available from developing countries regarding the frequency of CMV infection and treatment outcomes. We enrolled 230 consecutive patients undergoing allogeneic HSCT for various hematologic disorders at the Armed Forces Bone Marrow Transplant Center/National Institute of Blood And Marrow Transplant between February 2017 and December 202. CMV reactivation post-HSCT was monitored weekly starting at day +30 and continuing until day +100, and preemptive antiviral therapy was administered to prevent CMV disease in all HSCT recipients with ≥2000 CMV copies/mL. The median age of the study cohort was 9.5 years (range, .6 to 53 years), and the male:female ratio was 2.4:1. The most frequent indication for HSCT was beta thalassemia major (36.1%), followed by aplastic anemia (23.9%). Malignant disorders constituted 20% of all the patients. Pretransplantation CMV seropositivity was 99.1% for the recipients and 99.5% for the donors. CMV infection was seen in 66.1% of the patients, and the median time to CMV DNAemia was 36 days (range, 12 to 95 days). Preemptive antiviral therapy was administered to 140 patients with a CMV viral load ≥2000 copies/mL (61%). In multivariate analysis, patient age >12 years, steroid administration, and use of mycophenolate mofetil with or without post-transplantation cyclophosphamide was associated with the greatest probability of CMV reactivation. Overall survival was 97.4% in patients without CMV reactivation, compared to 80.3% in those with CMV reactivation (P = .001). Event-free survival was 78.7% in the total study cohort, including 89.7% for patients without CMV reactivation and 73% for patients with CMV reactivation (P = .003). Our study is the first from this region to explore the frequency of CMV seropositivity and CMV infection, risk factors for CMV reactivation, and outcomes of antiviral therapy in HSCT recipients.


The impact of albumin infusion on the risk of rebleeding and in-hospital mortality in cirrhotic patients admitted for acute gastrointestinal bleeding: a retrospective study of a single institute.
To investigate the effect of albumin infusion on cirrhotic patients admitted for acute gastrointestinal bleeding. Medical records of cirrhotic patients who admitted due to acute gastrointestinal bleeding through January 2009 to December 2018 were reviewed. Clinical data and the total amount of albumin and red blood cell used during hospitalization were recorded. For patients with rebleeding, the amount of albumin and red blood cell used before rebleeding was also documented. The primary outcome was the occurrence of rebleeding, and the second outcome was in-hospital mortality. Univariate and multivariate logistic analysis was performed to identify risk factors associated with rebleeding and in-hospital mortality. A total of 1503 cirrhotic patients were included in the analysis. There were 146 episodes of in-patient rebleeding occurred, while 81 patients died. Overall, more red blood cells and albumin were prescribed to patients who suffered rebleeding. In terms of the amount before rebleeding, the red blood cell was higher in patients with rebleeding, but the albumin infusion was similar. In the multivariate model, the albumin infusion before rebleeding was an independent risk factor associated with rebleeding (adjusted OR for ≤40 g vs 0 g, 0.469 [0.269-0.793], p = 0.006; adjusted OR for > 40 g vs 0 g, 0.272 [0.115-0.576], p = 0.001). In Child-Pugh C class patients, the use of albumin more than 40 g during hospitalization associated with a lower risk of in-patient mortality (adjusted OR for > 40 g vs 0 g, 0.136 [0.019-0.741], p = 0.031). Albumin infusion was associated with a lower risk of rebleeding and in-hospital deaths in cirrhosis admitted for acute gastrointestinal bleeding.


Tamoxifen impairs prepubertal mammary development and alters expression of estrogen receptor α (ESR1) and progesterone receptors (PGR).
Research has shown that prepubertal heifers experience allometric mammary growth that is influenced by the ovaries. Our purpose was to determine the role of estrogen in prepubertal mammary gland development. Sixteen Holstein calves were randomly assigned to 1 of 2 treatment groups: tamoxifen-injected (TAM) or control (CON). Calves were administered the antiestrogen tamoxifen (0.3 mg kg(1) d(1)) or placebo from 28 to 120 d of age. At 120 d, calves were euthanized and udders removed. Weight and DNA content of trimmed parenchymal tissue were halved (P ≤ 0.0001) in TAM compared with CON calves. Parenchymal samples from 3 zones of the left rear mammary gland (lower, middle, and outer regions) were processed for immunohistochemical staining for estrogen receptor α (ESR1) and progesterone receptor (PGR), Ki67-positive cells, and 5-bromo-2'-deoxyuridine label retaining cells (LRCs). Overall, neither the percentage nor location within the epithelial tissue layer of either ESR1- or PGR-positive cells was impacted by TAM treatment. However, image analysis indicated a 6.2-fold lower (P = 0.0001) level of ESR1 protein expression in TAM calves. Similarly, messenger RNA expression of ESR1 was also reduced (P = 0.0001) in TAM heifers. In contrast, expression of PGR protein was greater by 43% (P = 0.03) in TAM calves, but messenger RNA expression did not differ between treatments. Overall, TAM calves had a higher (P ≤ 0.03) percentage and density (cells per tissue area) of Ki67-positive cells. Irrespective of treatment, there were also more Ki67-labeled cells in the outer zones of the mammary gland (P ≤ 0.001). We were able to effectively use multispectral imaging to identify positive cells and quantify the expression of ESR1 and PGR protein. We also identified and counted the proportion of label retaining cells (LCR) (putative epithelial stem cells). We noted an overall 2.9-fold greater number of LRCs in TAM heifers and more LRCs in the outer sampling zones. This suggests that a cohort of LCR cells in TAM remained inactivated in comparison with CON heifers, which exhibited markedly increased growth of the mammary parenchymal tissue over the treatment period. These results suggest that the impacts of ovariectomy are partially explained by loss of ESR1 expression and/or estrogen receptor signaling in the prepubertal bovine mammary gland. The significance of mammary expression of PGR in control of prepubertal bovine mammary development remains unresolved.


The nucleotide sequence of the Pseudomonas aeruginosa pyrE-crc-rph region and the purification of the crc gene product.
The gene (crc) responsible for catabolite repression control in Pseudomonas aeruginosa has been cloned and sequenced. Flanking the crc gene are genes encoding orotate phosphoribosyl transferase (pyrE) and RNase PH (rph). New crc mutants were constructed by disruption of the wild-type crc gene. The crc gene encodes an open reading frame of 259 amino acids with homology to the apurinic/apyrimidinic endonuclease family of DNA repair enzymes. However, crc mutants do not have a DNA repair phenotype, nor can the crc gene complement Escherichia coli DNA repair-deficient strains. The crc gene product was overexpressed in both P. aeruginosa and in E. coli, and the Crc protein was purified from both. The purified Crc proteins show neither apurinic/apyrimidinic endonuclease nor exonuclease activity. Antibody to the purified Crc protein reacted with proteins of similar size in crude extracts from Pseudomonas putida and Pseudomonas fluorescens, suggesting a common mechanism of catabolite repression in these three species.


Exosomal circGSE1 promotes immune escape of hepatocellular carcinoma by inducing the expansion of regulatory T cells.
Studies have shown exosomal circRNAs can regulate the immune escape of tumors by carrying cancer-derived molecules. Regulatory T cells (Tregs) participate in the process of tumor immune escape. However, the mechanism by which exosomal circRNAs regulate Tregs to create a microenvironment for tumor immune escape is unclear. The effect of exosomes on the proliferation, migration, and invasion of tumor cells was evaluated by CCK-8, transwell, and wound-healing assays. The expression of circGSE1 was evaluated by real-time quantitative PCR, and the function of exosomal circGSE1 was explored by Western blot and RNA pull-down assays. In vivo animal metastasis models and bioluminescence imaging were used to verify the effect of exosomal circGSE1 on tumor progression. Collectively, we revealed that exosomal circGSE1 derived from hepatocellular carcinoma (HCC) cells promotes the progression of HCC by inducing Tregs expansion via regulating the miR-324-5p/TGFBR1/Smad3 axis. Therefore, in the future, exosomal circGSE1 can be used as a promising biomarker for immunotherapy of HCC.


In vivo specific binding of [3H]1-nicotine in the mouse brain.
[3H] 1-Nicotine was used as a receptor ligand in the intact mouse. It was injected i.v., and radioactivity in brain regions was assayed. Nonspecific binding was estimated by pretreatment with unlabelled 1-nicotine. Radioactivity entered the brain rapidly, was heterogeneously distributed, and declined after 5 min. Estimated specific binding was highest in the medial and posterior cortex, midbrain, thalamus/hypothalamus and medulla/pons; intermediate in the cerebellum, caudate/putamen, frontal and frontoparietal cortex; and lowest in the hippocampus and olfactory bulb. Autoradiography showed similar patterns. Coinjection of unlabelled 1-nicotine reduced specific binding so that it approached estimated nonspecific binding. Nicotinic agonists reduced radioactivity in the thalamus/hypothalamus, but nicotinic antagonists were less active. Non-nicotinic drugs did not reduce brain radioactivity. The results suggest that radiolabelled nicotine may be used for in vivo receptor studies despite problems in estimating nonspecific binding.


Development of a risk prediction score for hypertension incidence using Japanese health checkup data.
Hypertension is a risk factor for cardiovascular disease. We developed a simple scoring method for predicting future hypertension using health checkup data. A total of 41,902 participants aged 30-69 years without baseline hypertension who underwent annual health checkups (mean age, 52.3 ± 10.2 years; male, 47.7%) were included. They were randomly assigned to derivation (n = 27,935) and validation cohorts (n = 13,967) at a ratio of 2:1. In the derivation cohort, we performed multivariable logistic regression analysis and assigned scores to each factor significantly associated with 5-year hypertension. We evaluated the predictive ability of the scores using area under the curve (AUC) analysis and then applied them to the validation cohort to assess their validity. The score including items requiring blood sampling ranged from 0 to 14 and included seven indicators (age, body mass index, blood pressure, current smoking, family history of hypertension, diabetes, and hyperuricemia). The score not including items requiring blood sampling ranged from 0 to 12 and included five indicators (the above indicators, except diabetes and hyperuricemia). The score not including items requiring blood sampling was better; blood sampling did not improve diagnostic ability. The AUC of the score not including items requiring blood sampling was 0.76, with a sensitivity and specificity of 0.82 and 0.60, respectively, for scores ≥6 points. The incidence of hypertension gradually and constantly increased (from 0.9 to 49.6%) as the score increased from 0 to ≥10. Analysis in the validation cohort yielded similar results. We developed a simple and useful clinical prediction model to predict the 5-year incidence of hypertension among a general Japanese population. The model had reasonably high predictive ability and reproducibility.


A novel flow diverter device (Tubridge) for the treatment of intracranial aneurysms: a systematic review and meta-analysis.
The flow diverter (FD) device has become a feasible and effective option for treating intracranial aneurysms. This study aimed to evaluate the efficacy and safety of Tubridge FD (TFD) in treating intracranial aneurysms and provide evidence for further research and clinical application. Electronic databases, including PubMed, Web of Science, Embase, and the Cochrane Library from inception to July 31, 2022, were searched. The eligible studies should include TFD investigations in treating intracranial aneurysms. Pooled technical success rate, complete occlusion rate, improvement rate, stable rate, symptom elimination rate, and adverse events rate were calculated with either the fixed-effects model or the random-effects model, depending on the results of tests for heterogeneity. Egger's tests were performed to assess the potential publication bias. A total of 7 studies (145 patients) were included in this study. The pooled technical success rate was 0.98, the complete occlusion rate was 0.79, the improvement rate was 0.21, and the stable rate was 0.05. One included study reported that the surgery-related mortality rate in the Tubridge group was higher than that in the control group (3.66% vs. 1.61%), while the surgery-related morbidity rate in the Tubridge group was 2.4% and that in the control group was 0. Findings of this meta-analysis indicate that TFD manifests promising and effective performance with acceptable adverse events in the treatment of intracranial aneurysms.


The effectiveness of financial incentives for COVID-19 vaccination: A systematic review.
Financial incentives are a controversial strategy for increasing vaccination. In this systematic review, we evaluated: 1) the effects of incentives on COVID-19 vaccinations; 2) whether effects differed based on study outcome, study design, incentive type and timing, or sample sociodemographic characteristics; and 3) the cost of incentives per additional vaccine administered. We searched PubMed, EMBASE, Scopus, and Econlit up to March 2022 for terms related to COVID, vaccines, and financial incentives, and identified 38 peer-reviewed, quantitative studies. Independent raters extracted study data and evaluated study quality. Studies examined the impact of financial incentives on COVID-19 vaccine uptake (k = 18), related psychological outcomes (e.g., vaccine intentions, k = 19), or both types of outcomes. For studies of vaccine uptake, none found that financial incentives had a negative effect on uptake, and most rigorous studies found that incentives had a positive effect on uptake. By contrast, studies of vaccine intentions were inconclusive. While three studies concluded that incentives may negatively impact vaccine intentions for some individuals, they had methodological limitations. Study outcomes (uptake versus intentions) and study design (experimental versus observational frameworks) appeared to influence results more than incentive type or timing. Additionally, income and political affiliation may moderate responses to incentives. Most studies evaluating cost per additional vaccine administered found that they ranged from $49-75. Overall, fears about financial incentives decreasing COVID-19 vaccine uptake are not supported by the evidence. Financial incentives likely increase COVID-19 vaccine uptake. While these increases appear to be small, they may be meaningful across populations. Registration: PROSPERO, CRD42022316086 (https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022316086).


Development of a maturation antigen on the plasma membrane of rat spermatozoa in the epididymis and its fate during fertilization.
The ontogeny of a surface membrane antigen on rat spermatozoa has been investigated using the monoclonal antibody, 2D6. Using indirect immunofluorescence microscopy the 2D6 antigen was first detected on spermatozoa from the proximal corpus epididymidis; no reaction was present on testicular cells. The 2D6 antibody also bound to spermatozoa flushed from the uterus of mated rats and to a sperm-derived antigen on the surface of newly fertilized eggs. When frozen sections of epididymal tissues were stained with 2D6 monoclonal antibody immunofluorescence was confined to the epithelium lining the duct in the proximal and distal corpus epididymidis. Fluorescence in the tissue was androgen-dependent. Immunoblots of proteins in luminal secretions collected by micropuncture from different sites along the epididymal duct showed that in the proximal corpus epididymidis the 2D6 monoclonal antibody recognized a 32 kD antigen, but in secretions from the distal corpus and cauda epididymidis the monoclonal antibody also recognized antigens with molecular weights of 28, 23 and 20 kD. Immunoblots of proteins from spermatozoa collected from the corpus epididymidis revealed a reaction over a 32 kD antigen, while on spermatozoa from the cauda epididymidis the 2D6 monoclonal antibody recognized only a 23 kD antigen. Two hypotheses are proposed to account for the varied reactivity of the monoclonal antibody and their relative merits are discussed.


Clinical and Molecular Characterization of Microphthalmia-associated Transcription Factor (MITF)-related Renal Cell Carcinoma.
To characterize the clinical presentation, genomic alterations, pathologic phenotype and clinical management of microphthalmia-associated transcription factor (MITF) familial renal cell carcinoma (RCC), caused by a member of the TFE3, TFEB, and MITF family of transcription factor genes. The clinical presentation, family history, tumor histopathology, and surgical management were evaluated and reported herein. DNA sequencing was performed on blood DNA, tumor DNA and DNA extracted from adjacent normal kidney tissue. Copy number and gene expression analyses on tumor and normal tissues were performed by Real-Time Polymerase chain reaction. TCGA gene expression data were used for comparative analysis. Protein expression and subcellular localization were evaluated by immunohistochemistry. Germline genomic analysis identified the MITF p.E318K variant in a patient with bilateral, multifocal type 1 papillary RCC and a family history of RCC. All tumors displayed the MITF variant and were characterized by amplification of chromosomes 7 and 17, hallmarks of type 1 papillary RCC. We demonstrated that MITF p.E318K variant results in altered transcriptional activity and that downstream targets of MiT family members, such as GPNMB, are dysregulated in the tumors. Association of the pathogenic MITF variant with bilateral and multifocal type 1 papillary RCC in this family supports its role as a risk allele for the development of RCC and emphasizes the importance of screening for MITF variants irrelevant of the RCC histologic subtype. This study identifies potential biomarkers for the disease, such as GPNMB expression, that may facilitate the development of targeted therapies for patients affected with MITF-associated RCC.


Emerging biotechnologies for production of itaconic acid and its applications as a platform chemical.
Recently, itaconic acid (IA), an unsaturated C5-dicarboxylic acid, has attracted much attention as a biobased building block chemical. It is produced industrially (>80 g L-1) from glucose by fermentation with Aspergillus terreus. The titer is low compared with citric acid production (>200 g L-1). This review summarizes the latest progress on enhancing the yield and productivity of IA production. IA biosynthesis involves the decarboxylation of the TCA cycle intermediate cis-aconitate through the action of cis-aconitate decarboxylase (CAD) enzyme encoded by the CadA gene in A. terreus. A number of recombinant microorganisms have been developed in an effort to overproduce it. IA is used as a monomer for production of superabsorbent polymer, resins, plastics, paints, and synthetic fibers. Its applications as a platform chemical are highlighted. It has a strong potential to replace petroleum-based methylacrylic acid in industry which will create a huge market for IA.


The acute effects of bilateral ovariectomy or adrenalectomy on progesterone, testosterone and estradiol serum levels depend on the surgical approach and the day of the estrous cycle when they are performed.
Bilateral ovariectomy or adrenalectomy are experimental tools used to understand the mechanisms regulating the hypothalamus-pituitary-ovarian and the hypothalamus-pituitary-adrenal axis. There is evidence that acute unilateral perforation of the dorsal peritoneum in rats results in significant changes in progesterone, testosterone and estradiol serum concentrations. Because different surgical approaches for unilateral or bilateral ovariectomy or adrenalectomy, sectioning the superior ovarian nerve or the vagus nerve are used, we compare the acute effects on hormone serum concentrations resulting from the unilateral or bilateral dorsal approach to performing bilateral ovariectomy or adrenalectomy with those obtained when an unilateral incision is performed in the ventral abdomen. In general, the progesterone, testosterone and estradiol serum concentrations were higher in animals with ventral approach than in those with dorsal surgery, the effects varying depending on the day of the estrous cycle when surgery was performed. The results suggest that the neural signals arising from different zones of the peritoneum and/or the abdominal wall play different roles in the mechanisms regulating steroid hormones concentrations.


Methodological approaches to primate behavioral toxicological testing.
The monkey may often be the best model with which to characterize low-level effects of neurotoxicants, including those produced by developmental exposure. The nervous system of the monkey is very similar to the human and, like humans, monkeys have a long period of gestation, infancy, and sexual immaturity during which the nervous system continues to develop. The sensory systems of monkeys are very similar to humans, and intellectual capabilities may be tested that are not possible using other common laboratory species. The effects of low-level developmental exposure to neurotoxicants have been studied in the cynomolgus monkey using operant conditioning techniques to detect subtle defects. Intermittent schedules, a standard tool in behavioral pharmacology, have proved sensitive indicators of toxicity produced by developmental lead exposure. Such intellectual functions as learning, memory, adaptability, and distractibility have been explored by techniques including discrimination reversal, matching to sample, and delayed alternation. Such techniques have revealed impairment produced by lead similar to that observed in lead-exposed children. Visual deficits produced by methylmercury have been revealed by psychophysical techniques, in the absence of any obvious signs of toxicity.


GnIH plays a negative role in regulating GtH expression in the common carp, Cyprinus carpio L.
In birds and mammals, the gonadotrophin-inhibitory hormone (GnIH) effectively inhibits the expression of gonadotrophin (GtH). In teleosts, the effects of GnIH are still unclear and under much debate. The aim of this study is to evaluate the functions of GnIH/receptors of gonadotrophin-inhibitory hormone (GnIHRs) system during reproduction in the common carp, Cyprinus carpio L. We cloned the full cDNA sequences of GnIH /GnIHRs. Real-time PCR results showed that GnIH/GnIHRs were distributed extensively across the whole hypothalamus-pituitary-gonad (HPG) axis. We also examined the changes of GnIH/GnIHRs in the HPG axis during reproduction. GnIH mRNA expression was decreased to the minimum value in Apr, the spawning month, and increased immediately after the completion of reproduction. Expression pattern of GnIH during reproduction was the opposite to those of Gonadotrophin release hormone 3 (GnRH3) and luteinizing hormone (LH). Expression patterns of GnIHRs were similar to that of GnIH in the hypothalamus. In the pituitary, GnIHR2/3 peaked in March before spawning. In the ovaries, the GnIHR1 decreased to the minimum value in April, but GnIHR2/3 increased. By injection and incubation with synthesized GnIH-III peptide, we confirmed the negative influence of GnIH on mRNAs of the follicle-stimulating hormone-β and LH-β subunits in the common carp. These results show that the GnIH/GnIHRs system is involved in the negative regulation of reproduction in HPG axis of the common carp.


Individual differences in cocaine-induced locomotor activity in rats: behavioral characteristics, cocaine pharmacokinetics, and the dopamine transporter.
Outbred male Sprague-Dawley rats can be classified as either low or high cocaine responders (LCRs or HCRs, respectively) based on their locomotor response to acute cocaine. Concomitant measurement of dopamine clearance in these rats revealed that the differential behavioral responses are associated with the magnitude of dopamine transporter (DAT) inhibition by cocaine. Here, we investigated several factors that might contribute to cocaine-induced behavioral variability and its association with differential inhibition of DAT function. In rats classified as LCRs or HCRs after 10 mg/kg cocaine injection, we found no differences in (1) novelty-induced locomotion, (2) cocaine levels in dorsal striatum or nucleus accumbens (NAc), (3) DAT number or affinity in NAc, or (4) DAT affinity for cocaine in NAc. In rats given 20 mg/kg cocaine, behavior was more uniform across individuals, but still warranted separation into LCR/HCR categories. Additionally, we analyzed the stability of the LCR/HCR classification made during the first test with 10 or 20 mg/kg cocaine by retesting rats 7 days later with saline or cocaine (10 or 20 mg/kg). Before injection, HCRs were more active relative to LCRs and to their own behavior on the first test day. Following cocaine, LCRs and HCRs exhibited similar drug-induced changes in locomotion, but there were unique effects that depended on the cocaine dose given on the first and second test days. Our results argue against several likely explanations for individual differences in cocaine-induced behavior and highlight the influence of a single cocaine exposure on subsequent behavioral responses to the drug.


Differences between patients in whom physicians agree versus disagree about the preoperative diagnosis of heart failure.
To quantify preoperative heart failure (HF) diagnostic agreement and identify characteristics of patients in whom physicians agreed versus disagreed about the diagnosis. Observational cohort study. Patients undergoing major non-cardiac surgery at an academic center between 2015 and 2019. 40,659 patients undergoing major non-cardiac surgery, among which a stratified subsample of 1018 patients with and without documented HF was reviewed. Via a panel of physicians frequently managing patients with HF (cardiologists, cardiac anesthesiologists, intensivists), detailed chart reviews were performed (two per patient; median review time 32 min per reviewer per patient) to render adjudicated HF diagnoses. Adjudicated diagnostic agreement measures (percent agreement, Krippendorf's alpha) and univariate comparisons (standardized differences) between patients in whom physicians agreed versus disagreed about the preoperative HF diagnosis. Among patients with documented HF, physicians agreed about the diagnosis in 80.0% of cases (consensus positive), disagreed in 13.8% (disagreement), and refuted the diagnosis in 6.3% (consensus negative). Conversely, among patients without documented HF, physicians agreed about the diagnosis in 88.0% (consensus negative), disagreed in 8.4% (disagreement), and refuted the diagnosis in 3.6% (consensus positive). The estimated agreement for the 40,659 cases was 91.1% (95% CI 88.3%-93.9%); Krippendorff's alpha was 0.77 (0.75-0.80). Compared to patients in whom physicians agreed about a HF diagnosis, patients in whom physicians disagreed exhibited fewer guideline-defined HF diagnostic criteria. Physicians usually agree about HF diagnoses adjudicated via chart review, although disagreement is not uncommon and may be partly explained by heterogeneous clinical presentations. Our findings inform preoperative screening processes by identifying patients whose characteristics contribute to physician disagreement via chart review. Clinical Trial Number / Registry URL: Not applicable.


Antibiotic therapy in early erythema migrans disease and related disorders.
Between December 1978 and July 1985, we used various antibiotics for the treatment of 97 adult patients with early erythema migrans disease (EMD). Six patients with borrelial lymphocytoma (BL) and 20 with acrodermatitis chronica atrophicans (ACA) were treated similarly. Follow-up was for a median of 20, 14, and 12 months, respectively. The erythema migrans and all associated symptoms resolved within a median of 3 weeks (0.5-18.4), BL within 7 weeks (4-16), and ACA partly or completely within several months. A Jarisch-Herxheimer (-like) reaction was observed in 8 patients with EMD. Fourteen patients with EMD and one with ACA developed an exacerbation of symptoms or new manifestations between the 2nd and 20th day, and 28 patients with EMD and one with ACA continued to have or acquired various symptoms greater than or equal to 3 weeks after initiation of therapy. Arthralgia, neurologic and constitutional symptoms, and in one instance a slight pulmonary interstitial edema developed in EMD. More severe initial illness was a risk factor for the development of later symptoms in EMD. Retreatment was more often necessary in ACA than in EMD. A patient with ACA had a recurrence after 5 1/2 years. IgG antibody titers rose at least fourfold in 5 patients with ACA and in 1 with EMD despite therapy. We tentatively recommend minocycline or high doses of parenteral penicillin for the treatment of these disorders.


Transmembrane and Coiled-Coil Domain 1 Impairs the AKT Signaling Pathway in Urinary Bladder Urothelial Carcinoma: A Characterization of a Tumor Suppressor.
Purpose: Urinary bladder urothelial carcinoma (UBUC) is a common malignant disease in developed countries. Cell-cycle dysregulation resulting in uncontrolled cell proliferation has been associated with UBUC development. This study aimed to explore the roles of TMCO1 in UBUCs.Experimental Design: Data mining, branched DNA assay, immunohistochemistry, xenograft, cell culture, quantitative RT-PCR, immunoblotting, stable and transient transfection, lentivirus production and stable knockdown, cell-cycle, cell viability and proliferation, soft-agar, wound-healing, transwell migration and invasion, coimmunoprecipitation, immunocytochemistry, and AKT serine/threonine kinase (AKT) activity assays and site-directed mutagenesis were used to study TMCO1 involvement in vivo and in vitroResults: Data mining identified that the TMCO1 transcript was downregulated during the progression of UBUCs. In distinct UBUC-derived cell lines, changes in TMCO1 levels altered the cell-cycle distribution, cell viability, cell proliferation, and colony formation and modulated the AKT pathway. TMCO1 recruited the PH domain and leucine-rich repeat protein phosphatase 2 (PHLPP2) to dephosphorylate pAKT1(serine 473) (S473). Mutagenesis at S60 of the TMCO1 protein released TMCO1-induced cell-cycle arrest and restored the AKT pathway in BFTC905 cells. Stable TMCO1 (wild-type) overexpression suppressed, whereas T33A and S60A mutants recovered, tumor size in xenograft mice.Conclusions: Clinical associations, xenograft mice, and in vitro indications provide solid evidence that the TMCO1 gene is a novel tumor suppressor in UBUCs. TMCO1 dysregulates cell-cycle progression via suppression of the AKT pathway, and S60 of the TMCO1 protein is crucial for its tumor-suppressor roles. Clin Cancer Res; 23(24); 7650-63. ©2017 AACR.


Laparoscopic ultrasound as the primary method for bile duct imaging during cholecystectomy.
Intraoperative fluorocholangiography (IOC) has been the standard method for bile duct imaging during cholecystectomy. Laparoscopic ultrasound (LUS) has been evaluated as a possible alternative, but has been used less frequently. The authors examined the evolving use of these two methods to assess the relative utility of LUS as the primary method for routine bile duct imaging during laparoscopic cholecystectomy (LC). This study analyzed a prospective database containing 423 consecutive cholecystectomies performed by one attending surgeon in an academic medical center between 1995 and 2005. Intraoperative bile duct imaging was performed in 371 (94%) of 396 LCs performed for cholelithiasis. As recorded, IOC was performed in 239 cases, LUS in 236 cases, and both in 104 cases. Choledocholithiasis was present in 50 patients (13%). Common bile duct stones (CBDS) were identified by LUS in 3% of the patients without preoperative indicators of CBDS, and in 10% of the patients with one or more indicators. As shown by the findings, LUS had a positive predictive value of 100%, a negative predictive value of 99.6%, a sensitivity of 92.3%, and a specificity of 100% for detecting CBDS. Also, LUS identified clinically significant bile duct anatomy in 6% of the patients. In 1995, LUS was used for 20% of cases, whereas by 2005, it was used for 97% of cases. Conversely, the use of IOC decreased from 93% to 23%. With moderate experience, LUS can become the primary routine imaging method for evaluating the bile duct during LC. It is as reliable as IOC for detecting choledocholithiasis. In addition, LUS can locate the common bile duct during difficult dissections. On the basis of this experience, LUS is used currently in nearly all LCs and is the sole method for bile duct imaging in 75% of these cases. IOC is used as an adjunct to LUS when LUS imaging is inadequate, when stronger clinical indicators of choledocholithiasis are present, or when biliary anatomy remains uncertain.


[Variation of 3'-terminal fragment of 16S rRNA gene in closely related species of Drosophila virilis group].
Primary sequence of 3-terminal fragment of the mitochondrial 16S rRNA gene has been determined in 12 Drosophila species of the virilis group. The functionally important elements in secondary structure of the RNA product were defined. The region corresponding to the peptidyltransferase center has been localized. Variation of the 3'-terminal region of 16S rRNA gene has been described in 12 species of the virilis group. Phylogeny of the Drosophila virilis species group is discussed.


Isozymes of Culex p. fatigans. I. An esterase locus in linkage group III and its variability in natural populations.
Acrylamide gel electrophoresis revealed 19 frequent and 4 rare sites of esterase activity in various Brazilian populations of Culex p. fatigans. One pair of allozymes designated as Est-1 F and Est-1 S was selected for detailed investigation. Est-1 locus shows independent assortment from linkage group I marker, sex, and linkage group II markers, yellow and ruby, and therefore is assigned to linkage group III. Gene frequencies of Est-1 F varied from 0.49 to 0.92 in various Brazilian populations. Inhibition studies suggest that Est-1 F and Est-1 S are ali-esterases.


Astrocyte plasticity in mice ensures continued endfoot coverage of cerebral blood vessels following injury and declines with age.
Astrocytes extend endfeet that enwrap the vasculature, and disruptions to this association which may occur in disease coincide with breaches in blood-brain barrier (BBB) integrity. Here we investigate if focal ablation of astrocytes is sufficient to disrupt the BBB in mice. Targeted two-photon chemical apoptotic ablation of astrocytes induced a plasticity response whereby surrounding astrocytes extended processes to cover vascular vacancies. In young animals, replacement processes occur in advance of endfoot retraction, but this is delayed in aged animals. Stimulation of replacement astrocytes results in constriction of pre-capillary arterioles, suggesting that replacement astrocytes are functional. Pharmacological inhibition of pSTAT3, as well as astrocyte specific deletion of pSTAT3, reduces astrocyte replacement post-ablation, without perturbations to BBB integrity. Similar endfoot replacement occurs following astrocyte cell death due to reperfusion in a stroke model. Together, these studies uncover the ability of astrocytes to maintain cerebrovascular coverage via substitution from nearby cells.


Crystal structure of the cytokinin-producing enzyme "lonely guy" (LOG) from Mycobacterium tuberculosis.
Mycobacterium tuberculosis (Mtb) is an extremely successful intracellular pathogen that cause a large number of death worldwide. It is interesting that this non-phytopathogen can synthesize cytokinin by "lonely guy" (LOG) protein. The cytokinin biosynthesis pathway in Mtb is not clear. Here we determined the crystal structure of LOG from Mtb (MtLOG) at a high resolution of 1.8 Å. MtLOG exists as dimer which belongs to type-I LOG and shows a typical α-β Rossmann fold. Like other LOGs, MtLOG also contains a conserved "PGGXGTXXE" motif that contributes to the formation of an active site. For the first time, we found that the MtLOG binds to Mg2+ in the negative potential pocket. According to the docking result, we found that Arg78, Arg98 and Tyr162 should be the key amino acid involved in substrate binding. Our findings provide a structural basis for cytokinin study in Mtb and will play an important role in design and development of enzyme inhibitors.


Preclinical and Clinical Advances of GalNAc-Decorated Nucleic Acid Therapeutics.
A main challenge in realizing the full potential of nucleic acid therapeutics is efficient delivery of them into targeted tissues and cells. N-acetylgalactosamine (GalNAc) is a well-defined liver-targeted moiety benefiting from its high affinity with asialoglycoprotein receptor (ASGPR). By conjugating it directly to the oligonucleotides or decorating it to a certain delivery system as a targeting moiety, GalNAc has achieved compelling successes in the development of nucleic acid therapeutics in recent years. Several oligonucleotide modalities are undergoing pivotal clinical studies, followed by a blooming pipeline in the preclinical stage. This review covers the progress of GalNAc-decorated oligonucleotide drugs, including siRNAs, anti-miRs, and ASOs, which provides a panorama for this field.


Snapshot of suspected acute coronary syndrome assessment processes in the emergency department: A national cross-sectional survey.
The Snapshot of Suspected ACS Assessment (SSAASY) study aims to describe the assessment processes for patients with suspected acute coronary syndrome (ACS) in Australian EDs, and to compare these processes with the National Heart Foundation of Australia and Cardiac Society of Australia and New Zealand (NHFA/CSANZ) guidelines. Between March and May 2021, a cross-sectional survey of Australian EDs was undertaken to investigate the assessment strategies used within the ED. All public and private hospitals identified as having dedicated EDs were invited to participate. Respondents provided data on hospital, ED and cardiac service characteristics. They also provided data on the risk stratification process recommended within their department (risk scores, troponin testing, objective testing for coronary artery disease). Awareness of the NHFA/CSANZ guidelines was assessed. Responses were received from 109/162 departments (67%). Most sites (n = 100, 92%) reported using dedicated protocols developed by ED clinicians that included risk stratification scores. Highly sensitive troponin assays were used at 103 (94%) sites. Serial troponin testing was performed over 2 h for low-risk patients in 53 (49%) sites and 2-3 h for intermediate and high-risk patients in 74 (68%) sites. Further investigations included exercise stress tests (48%) and stress echocardiography (38%), with 45% of sites ordering outpatient investigations. The SSAASY study reported the strategies used to assess suspected ACS. In line with current NHFA/CSANZ guidelines, highly sensitive troponin assays are widely utilised. However, serial sampling intervals were longer than guideline recommendations, suggesting a translational gap between guidelines and clinical practice.


Coregulation: A Multilevel Approach via Biology and Behavior.
In this article, we explore the concept of coregulation, which encompasses the mutual adaptation between partners in response to one another's biology and behavior. Coregulation operates at both biological (hormonal and nervous system) and behavioral (affective and cognitive) levels and plays a crucial role in the development of self-regulation. Coregulation extends beyond the actions of individuals in a dyad and involves interactive contributions of both partners. We use as an example parent-child coregulation, which is pervasive and expected, as it emerges from shared genetic relatedness, cohabitation, continuous interaction, and the influence of common factors like culture, which facilitate interpersonal coregulation. We also highlight the emerging field of neural attunement, which investigates the coordination of brain-based neural activities between individuals, particularly in social interactions. Understanding the mechanisms and significance of neural attunement adds a new dimension to our understanding of coregulation and its implications for parent-child relationships and child development.


Scoping Review of Measures of Comorbidities in Heart Failure.
Comorbidities are risk factors for poor clinical outcomes in patients with heart failure. However, no consensus has been reached on how to assess comorbidities related to clinical outcomes in patients with heart failure. The aims of this study were to review (1) how comorbidities have been assessed, (2) what chronic conditions have been identified as comorbidities and (3) the rationale for choosing the comorbidity instruments and/or specific comorbidities when exploring clinical outcomes in patients with heart failure. The clinical outcomes of interest were mortality, hospitalization, quality of life, and self-care. Three electronic databases and reference list searches were used in the search. In this review, we included 39 articles using 3 different ways to assess comorbidities in the relationship with clinical outcomes: using an instrument (ie, Charlson Comorbidity Index), disease count, and including individual comorbidities. A total of 90 comorbidities were investigated in the 39 articles; however, definitions and labels for the diseases were inconsistent across the studies. More than half of the studies (n = 22) did not provide a rationale for selecting the comorbidity instruments and/or all of the specific comorbidities. Some of the rationale for choosing the instruments and/or specific comorbidities was inappropriate. We found several issues related to measuring comorbidities when examining clinical outcomes in patients with heart failure. Researchers need to consider these methodological issues when measuring comorbidities in patients with heart failure. Further efforts are needed to develop guidelines on how to choose proper measures for comorbidities.


Soluble proteins incorporate into ISCOMs after covalent attachment of fatty acid.
The immune stimulating complex (ISCOM) is a potent adjuvant which has the ability to induce both humoral and cellular immune reactions to protein antigens when they are physically associated with the ISCOM structure. However, in general only proteins with an exposed hydrophobic domain can associate with ISCOMs. As many soluble proteins are available as candidate subunit antigens there is a requirement for a method which promotes efficient incorporation of soluble protein into ISCOMs. Here it is demonstrated that following covalent attachment of palmitic acid, two soluble proteins, cytochrome C and ovalbumin, quantitatively incorporate into ISCOMs. ISCOMs containing ovalbumin prepared in this way have been shown to be highly immunogenic, generating humoral, delayed-type hypersensitivity and class I restricted T-cell immune responses following both parenteral and oral administration. The technique of incorporating soluble proteins into ISCOMs by covalent attachment of fatty acid should be generally applicable and extends the use of the ISCOM as an adjuvant.


Genistein, a tyrosine kinase inhibitor, blocks the cell cycle progression but not Ca2+ influx induced by BAY K8644 in FRTL-5 cells.
IGF-I, when added to TSH-primed FRTL-5 cells, induces a long lasting Ca2+ influx and then DNA synthesis. Ca2+ channel agonist, BAYK 8644, is capable to mimic these effects on cell proliferation. We studied the effect of genistein, a specific tyrosine kinase inhibitor, on BAY K8644- or IGF-I- induced cell cycle progression in FRTL-5 cells. Genistein inhibited DNA synthesis induced by BAY K8644 and by IGF-I. In contrast, Ca2+ influx stimulated by BAY K8644 was not inhibited. These data demonstrate that the signal transduction pathway induced by BAY K8644 or IGF-I may possibly involve genistein-sensitive process at the downstream step of Ca2+ entry.


MDHM, a macrophage-activating product of Mycoplasma fermentans, stimulates murine macrophages to synthesize nitric oxide and become tumoricidal.
In continuation of previous work on macrophage activation by a Mycoplasma fermentans-derived product, originally named "mycoplasma-derived high mol. wt. material" (MDHM), we have investigated whether MDHM was capable of inducing synthesis of the reactive nitrogen intermediate nitric oxide (NO), thus rendering macrophages cytocidal. Mycoplasmas were first delipidated with acetone, and MDHM activity was then extracted with 50 mM 1-O-octyl-beta-D-glucopyranoside to yield a particularly active new preparation of MDHM which we have named MDHM-D (D for detergent). In combination with IFN-gamma, MDHM-D activated macrophages to produce reactive nitrogen intermediates and kill P815 mastocytoma cells in co-culture. P815 target cells were chosen because they are TNF-resistant. Macrophages from the LPS-low responder strain C3H/HeJ were used to minimize interference from possible LPS contamination. MDHM-D activity in this system was strictly IFN-gamma-dependent. In the presence of 25 U/ml IFN-gamma MDHM-D gave a half maximal response at a dilution of 1/100,000, showing a parallel concentration dependency for nitrite production and cytocidal activity.


Effects of laminarin zwitterionic carboxylate and sulfonate on the intestinal barrier function and gut microbiota.
Ulcerative colitis (UC) has become a global chronic disease that keeps increasing. This study was to explore the treatment effectiveness of two functional zwitterionic laminarins, zwitterionic sulfonate (LZS) and zwitterionic carboxylate (LZC), in dextran sulfate sodium (DSS) induced mouse model. FT-IR and NMR techniques were used to characterize the aforementioned functional zwitterion. Compared to UC mice, the composition and diversity of gut microbiota were significantly increased in the treated mice. Specifically, the composition of Bacteroidetes increased and the level of Firmicutes decreased. Moreover, we demonstrated the alleviation of colitis by LZS and LZC reflected by the improved integrity of intestinal mucosa, which includes increased number of goblet cells, mucin protein production, maintenance of collagens, as well as the lower extent of intestinal fibrosis. These findings indicated the potentials of LZC and LZS as promising agents to prevent colitis via adjusting gut microbiota and maintaining intestinal barrier integrity.


A survey of practice in the management of haemolysis, icterus and lipaemia in blood specimens in the United Kingdom and Republic of Ireland.
Haemolysis, icterus and lipaemia (HIL) are common interferants in laboratory medicine, potentially impacting patient care. This survey investigates HIL management in medical laboratories across the UK and Republic of Ireland (ROI). A survey was sent to members of key professional organisations for laboratory medicine in the UK and ROI. Questions related to the detection, monitoring, quality control, and management of HIL. In total, responses from 124 laboratories were analysed, predominantly from England (52%) and ROI (36%). Most responses were from public hospitals with biochemistry services (90%), serving primary care (91%), inpatients (91%), and outpatients (89%). Most laboratories monitored H (98%), I (88%), and L (96%) using automated indices (93%), alone or in combination with visual inspection.Manufacturer-stated cut-offs were used by 83% and were applied to general chemistries in 79%, and immunoassays in 50%. Where HIL cut-offs are breached, 64% withheld results, while 96% reported interference to users. HIL were defined using numeric scales (70%) and ordinal scales (26%). HIL targets exist in 35% of laboratories, and 54% have attempted to reduce HIL. Internal Quality Control for HIL was lacking in 62% of laboratories, and just 18% of respondents have participated in External Quality Assurance. Laboratories agree manufacturers should: standardise HIL reporting (94%), ensure comparability between platforms (94%), and provide information on HIL cross-reactivity (99%). Respondents (99%) showed interest in evidence-based, standardised HIL cut-offs. Most respondents monitor HIL, although the wide variation in practice may differentially affect clinical care. Laboratories seem receptive to education and advice on HIL management.


The mobilization of maternal histone messenger RNA after fertilization of the sea urchin egg.
The extent of protein, RNA and DNA synthesis in early cleavage stages of the sea urchin embryo (Parechinus angulosus) was determined. A histone mRNA specific cDNA was used in hybridization experiments to investigate the cytoplasmic localization of maternal histone mRNA in the unfertilized sea urchin egg and first cleavage stage embryo. In the unfertilized egg histone mRNA was localized exclusively in ribonucleoprotein particles with none in ribosomes or polyribosomes. This distribution changed after fertilization, in particular, coupled with the first cleavage telophase there was a significant transfer of histone mRNA from the ribonucleoprotein fraction to the polyribosomes. The results indicate mRNA specific translational control mechanisms.


Effectiveness and safety of deep brain stimulation for patients with refractory obsessive compulsive disorder and comorbid autism spectrum disorder; A case series.
Deep brain stimulation (DBS) is effective for patients with treatment refractory obsessive-compulsive disorder (OCD). Autism spectrum disorder (ASD) is present in up to a third of all patients with OCD, but it is unknown whether effectiveness of DBS for OCD also applies for patients with comorbid ASD. The present case series is the first to examine effectiveness on OCD symptoms and safety of DBS in patients with OCD and ASD specifically. Six consecutive patients with treatment-refractory OCD and comorbid ASD received DBS of the ventral anterior limb of the internal capsule (vALIC) or medial forebrain bundle (MFB). We examined effectiveness of DBS on symptoms of OCD and depression with the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) and Hamilton Depression Rating Scale (HAM-D), respectively. We included qualitative data to describe the course of treatment in individual patients with OCD and ASD. We found that DBS significantly decreased symptoms of OCD (p < .001) and depression (p = .007). Four out of six patients with OCD and comorbid ASD were responders (decrease ≥ 35% in Y-BOCS), one patient was partial-responder (decrease 25-35% in Y-BOCS) and one patient did not respond (decrease ≤ 25% in Y-BOCS). Serious adverse events were an infection of the DBS system, and a suicide attempt. Though present results are preliminary, DBS reduced symptoms of OCD and depression in patients with OCD and comorbid ASD. Comorbid ASD should therefore not be seen as a contra-indication for DBS in OCD.


Macrofollicular variant of papillary thyroid carcinoma. Report of a case with fine needle aspiration biopsy findings.
Macrofollicular variant of papillary thyroid carcinoma is defined as a combination of numerous macrofollicles occupying 50% of the tumor and foci of the conventional follicular variant of papillary carcinoma. To the best of our knowledge, there have been no English-language reports on its cytologic findings. A fine needle aspiration specimen from a mass of the thyroid in a 59-year-old female showed a large collection of dense, inspissated colloid and a few sheets of tumor cells with nuclei characteristic of papillary carcinoma. There were no three-dimensional, branching papillae with fibrovascular cores. Although macrofollicular variant of papillary carcinoma is very rare, fine needle aspiration cytology may contribute to its correct diagnosis.


Effect of CPB glucose levels on inflammatory response after pediatric cardiac surgery.
Systemic inflammatory response syndrome (SIRS) is a common complication after cardiac surgery. There are no definite optimal glycemic threshold for pediatric patients receiving open-heart surgery with CPB. The study aimed to investigate the optimal cardiopulmonary bypass (CPB) glucose in patients undergoing cardiac surgery. We enrolled children with congenital heart disease who underwent surgical repair between June 2012 and December 2020. We included only patients who underwent cardiac surgery with CPB. The primary outcome was severe SIRS. A two-piece-wise regression model was applied to examine threshold effect of CPB glucose on severe SIRS. A total of 7350 patients were enrolled in the present study, of whom 3895 (52.99%) are female. After potential confounders were adjusted, non-linear relationship was detected between CPB glucose and severe SIRS, whose turning point was 8.1. With CPB glucose < 8.1 mmol/L, the estimated dose-response curve was consistent with a horizontal line. However, the prevalence of severe SIRS increased with increasing glucose up to the turning point (Glucose > 8.1 mmol/L); the odds ratio (OR) of the Glucose was 1.35 (95% CI 1.21, 1.50). The present study indicates the association of CPB glucose with inflammatory response after pediatric cardiac surgery. The patients might have the best outcomes with the optimal CPB glucose no more than 8.1 mmol/L.


Altering memory through recall: the effects of cue-guided retrieval processing.
Three experiments were designed to investigate the influence of initial recall on memory by assessing delayed recall after different immediate cued-recall tests. In all experiments, subjects performed semantic and phonemic encoding tasks on a word list. The subjects then received a cued-recall test that cued the target using the same word as the context word in the encoding task, a test that cued the target with a word from the same level at which the target was encoded, a test that cued the target with a cue from a different level at which the target was encoded, or no immediate-recall test. One day later, the subjects performed a final cued-recall test in which the type of cue (semantic or phonemic) was varied. Consistently, delayed recall was facilitated primarily when the cue on the immediate test was from the same level as the cue on the delayed test. This pattern of facilitation suggests that immediate cued-recall produces an elaboration of an existing memory representation that is closely tied to the type of cue used on the immediate test.


Constructing isoluminant stimuli for word recognition research: a precautionary study.
Isoluminant stimuli are used increasingly often to investigate processes underlying visual word recognition. However, construction of isoluminant stimuli is not straightforward, and inappropriate construction may have the result of misinforming theories that relate word recognition to neurological function. To inform the use of isoluminant stimuli in studies of word recognition, the present article details two experiments in which isoluminant stimuli were constructed using physical onscreen luminance matching and heterochromatic flicker photometry (HFP) with four different stimulus types: disks, squares, rectangles, and letter strings. The findings reveal (1) substantial differences between isoluminance determined by physical onscreen luminance matching and HFP, (2) substantial differences in HFP isoluminance across stimulus types, and (3) substantial differences in HFP isoluminance across participants. These findings indicate that, in contrast to common practice in word recognition research, HFP provides a better indication of isoluminance than physical onscreen matching; but HFP stimuli should match those used in the experiment proper and should be used to assess isoluminance individually for each participant.


Effect of magnesium ion on crt gene expression in improving carotenoid yield of Rhodobacter sphaeroides.
This study aimed at increasing carotenoid yield of Rhodobacter sphaeroides in wastewater treatment by adding magnesium ion (Mg(2+)). Results showed that Mg(2+) could improve R. sphaeroides biomass and carotenoid yield effectively. The highest carotenoid yield of 4.83 ± 0.14 mg/g biomass and biomass production of 3900 ± 180 mg/L were achieved at optimal Mg(2+) concentration of 15 mmol/L. Mechanism analysis revealed that Mg(2+) could promote carotenoid production by regulating the expressions of crt genes. Up-regulation of crtBDA genes improved carotenoid biosynthesis of R. sphaeroides.


Factors associated with failure of cardiopulmonary function recovery after lung cancer surgery.
This study aimed to evaluate the longitudinal changes in cardiopulmonary function (CPF) and identify predictors of cardiopulmonary recovery failure after lung cancer surgery. Data was obtained from a prospective CATCH-LUNG cohort study, where patients were divided into two groups based on 6-min walk distance (6MWD) at baseline and 6 months after surgery. CPF recovery failure was defined as a participant whose 6MWD dropped over 50 m from baseline to 6 months after surgery. Patients with a baseline 6MWD less than 400 m were excluded. The analysis was investigated using mixed effects models, and the relative estimates for the predictors were expressed relative risk (RR) and 95% CI using a Poisson regression. Among 419 patients, 24.1% and 17.7% showed failure of CPF recovery at 6 months and 1 year after surgery, respectively. In the multivariable analysis, baseline step count [RR per 1000 steps lower = 1.05 (95% CI, 1.01-1.09)], baseline dyspnoea [RR per 10 points higher = 1.15(1.07-1.23)], decreased FEV1 % predicted from baseline to 2 weeks after surgery [RR per 10% lower = 1.30(1.10-1.53)] and decreased moderate-to-vigorous physical activity (MVPA) from baseline to 2 weeks [RR = 1.95(1.22, 3.11)] or persistent low MVPA at baseline and 2 weeks after surgery [RR = 1.63(1.04, 2.54)] were significant factors for loss of CPF. The inability to recover CPF at 6 months after surgery was linked to reduction of lung function and MVPA from baseline to 2 weeks as well as baseline physical activity (PA) and dyspnoea. These results imply that engagement of perioperative PA is necessary to facilitate recovery of CPF after lung cancer surgery.


Systemic light chain amyloidosis myopathy responsive to daratumumab monotherapy.
Amyloid myopathy is a rare and severe manifestation of systemic light chain (AL) amyloidosis. Early diagnosis and staging are mandatory for optimal therapy, given the rapid progression of muscle weakness. Despite the efficacy of bortezomib-based treatment regimens, there is a lack of therapeutic alternatives in non-responsive patients. The case report of a patient with systemic AL amyloidosis myopathy treated with daratumumab is presented. A 70-year-old man displayed severe proximal muscle weakness which had developed over a 10-month period. Blood tests revealed an immunoglobulin A lambda monoclonal gammopathy, whilst muscle biopsy showed amyloid deposits within the arteriolar walls, confirming the diagnosis of amyloid myopathy associated with AL amyloidosis. Initial treatment with a bortezomib-based regimen showed no clinical or hematological improvement. After switching to daratumumab monotherapy, our patient achieved a favorable evolution with respect to functional muscle scoring and a complete hematological response. To our knowledge, this is the first case report of an amyloid myopathy showing a remarkable clinical improvement in response to daratumumab monotherapy. It thereby highlights the potential of daratumumab as a monotherapeutical approach to the treatment of amyloid myopathy complicating AL amyloidosis.