Engineering a G-quadruplex-based logic gate platform for sensitive assay of dual biomarkers of ovarian cancer.
As most single tumor markers have low sensitivity or specificity, the joint detection of multiple tumor biomarkers is helpful to improve the positive rate and specificity of early diagnosis. To establish a sensitive, specific, and rapid screening method for ovarian cancer, two enzyme-free logic gates were developed to realize the joint detection of carbohydrate antigen 125 (CA125) and carcinoembryonic antigen (CEA). G-quadruplex with peroxidase activity was used as a chromogenic catalyst in this colorimetric diagnosis. For NOR gate, in the absence of CEA and CA125, template DNA (Tem-DNA), CEA aptamer with half of the G-quadruplex sequence (CEA-apt), and CA125 aptamer with the other half of the G-quadruplex sequence (CA125-apt) form a double-stranded DNA equipped with one G-quadruplex structure which can strongly combine with hemin to obtain the peroxidase-like activity; here, the output of this NOR gate is set as 1, which could exclude the risk of ovarian cancer. For AND gate, CEA-apt and CA125-apt are separated from magnetic beads in the co-existence of the dual biomarkers. After adding Tem-DNA, the G-quadruplex structure constructs with hemin to exhibit the output as 1, presenting a high risk of ovarian cancer. Under the optimized condition, this novel assay can not only show a sharp color difference between physiological state and pathological state, but also be employed for the quantitative analysis of every single biomarker. The linear detection range and detection limit for CEA are 5-500 ng mL-1 and 0.88 ng mL-1, while they are for CA125 are 35-500 U mL-1 and 0.91 U mL-1, respectively. Moreover, the established approach was successfully applied in detecting CA125 and CEA in human serum samples, which provides great promise in the fields of clinical examination and disease diagnosis.


The benefit of using narrow-band imaging systems for observation of capillary networks before determining of treatments for early colon cancer.
This study examined whether magnifying endoscopy with narrow-band Imaging observation could be useful selecting the appropriate treatment for early colon cancer. We analyzed 551 cases of colon tumors excised endoscopically or surgically, comprising 68 with large hyperplastic polyps, 25 traditional serrated adenomas, 141 tubular adenomas, 177 intramucosal cancers and 140 submucosal invasive (SM) cancers. We classified capillary network pattern into four types according to the degree of dilatation, irregularity and distribution of microcapillary features. These results were then compared with the histological findings. The comparison of capillary pattern and histological features showed microcapillary networks by magnifying endoscopy with narrow-band imaging observation in intramucosal lesion or SM cancer with remnant neoplastic glands at the superficial layer. The remaining microcapillary network was designed to maintain the architecture of neoplastic glands, even in the presence of subumucosal invasion. Consequently, loss of this network could correlate with depth of tumor invasion and histological reaction. Therefore, even if the tumor, remained of network was diagnosed to invade into SM layer, it should be checked up further examination by using magnifying endoscopy with crystal violet staining.


Intranasal immunization with Ag85B peptide 25 displayed on Lactococcus lactis using the PilVax platform induces antigen-specific B- and T-cell responses.
Mycobacterium tuberculosis (Mtb) remains a global epidemic despite the widespread use of Bacillus Calmette-Guérin (BCG). Consequently, novel vaccines are required to facilitate a reduction in Mtb morbidity and mortality. PilVax is a peptide delivery strategy for the generation of highly specific mucosal immune responses and is based on the food-grade bacterium Lactococcus lactis that is used to express selected peptides engineered within the Streptococcus pyogenes M1T1 pilus, allowing for peptide amplification, stabilization and enhanced immunogenicity. In the present study, the dominant T-cell epitope from the Mtb protein Ag85B was genetically engineered into the pilus backbone subunit and expressed on the surface of L. lactis. Western blot and flow cytometry confirmed formation of pilus containing the peptide DNA sequence. B-cell responses in intranasally vaccinated mice were analyzed by ELISA while T-cell responses were analyzed by flow cytometry. Serum titers of peptide-specific immunoglobulin (Ig) G and IgA were detected, confirming that vaccination produced antibodies against the cognate peptide. Peptide-specific IgA was also detected across several mucosal sites sampled. Peptide-specific CD4+ T cells were detected at levels similar to those of mice immunized with BCG. PilVax immunization resulted in an unexpected increase in the numbers of CD3+ CD4- CD8- [double negative (DN)] T cells in the lungs of vaccinated mice. Analysis of cytokine production following stimulation with the cognate peptide showed the major cytokine producing cells to be CD4+ T cells and DN T cells. This study provides insight into the antibody and peptide-specific cellular immune responses generated by PilVax vaccination and demonstrates the suitability of this vaccine for conducting a protection study.


Frontal cortex dysfunction as a target for remediation in opiate use disorder: Role in cognitive dysfunction and disordered reward systems.
In this chapter, we develop a model of μ- and δ-opioid receptor (OR) effects on cellular activity in the corticostriatal circuit after reviewing clinical data on cognitive and mood impairments in opioid substance use disorder (OUD), we use this model to derive information on the relevance of opioid actions in this circuit for cognition and reward. We find that the cognitive impairments and rewarding properties of acute μ-OR activation can reasonably explained by pharmacological actions in the corticostriatal circuit. However, long-term cognitive impairments and mood dysfunction observed in OUD are probably induced by opiate abuse-related degenerative mechanisms.


MnI complex redox potential tunability by remote lewis acid interaction.
In this work we provide direct experimental evidence on the correlation of remote interactions between a newly synthesized MnI-complex (1) and different alkali cations with redox potential tuning. Furthermore we report the electrochemical behavior of 1 towards carbon dioxide, including the effects of added alkali salts using cyclic voltammetry.


Diffusion-weighted MR volume and apparent diffusion coefficient for discriminating lymph node metastases and good response after chemoradiation therapy in locally advanced rectal cancer.
To determine diagnostic performance of diffusion-weighted (DW) magnetic resonance (MR) volume and apparent diffusion coefficient values (ADCs) for assessing lymph node metastases (LNM) and good response after chemoradiation therapy (CRT) in patients with locally advanced rectal cancer (LARC). This retrospective study consisted of 61 patients with LARC who underwent pre- and post-CRT DW images. Two radiologists independently placed free-hand regions of interest in each tumor-containing section on DW images to calculate pre- and post-CRT tumor volume and tumor volume reduction rates (Δvolume). Regions of interest were drawn to include tumor on maximum cross-sectional slice to obtain ADCs. Areas under the receiver operating characteristic curves (AUCs) were calculated to evaluate diagnostic performance in identifying LNM and good response after CRT using these parameters. Inter-observer agreement and intra-observer agreement were excellent for pre- and post-CRT DW MR volume (intraclass correlation coefficient [ICC], 0.889-0.948) and moderate for pre- and post-CRT ADCs (ICC, 0.535-0.811). AUCs for identifying LNM were 0.508 for pre-CRT DW MR volume versus 0.705 for pre-CRT ADC, 0.855 for post-CRT DW MR volume versus 0.679 for post-CRT ADC, and 0.887 for Δvolume versus 0.533 for ΔADC. AUCs for identifying good response were 0.518 for pre-CRT volume versus 0.506 for pre-CRT ADC, 0.975 for post-CRT volume versus 0.723 for post-CRT ADC, and 0.987 for Δvolume versus 0.655 for ΔADC. DW MR Δvolume provided high diagnostic performance in discriminating LNM after CRT. DW MR Δvolume was equally as accurate as post-CRT DW MR volume for evaluating good response. • Inter-observer agreement and intra-observer agreement were excellent for pre- and post-CRT DW MR volume (intraclass correlation coefficient [ICC], 0.889-0.948) and moderate for pre- and post-CRT ADCs (ICC, 0.535-0.811). • DW MR Δvolume provided high diagnostic performance in identifying LNM after CRT (AUC, 0.887) and good response (AUC, 0.987) and was significantly more accurate than pre-CRT DW MR volume (AUC, 0.508 and 0.518, respectively) and ADCs (AUC, 0.705 and 0.506, respectively). • DW MR Δvolume (AUC, 0.987) was equally as accurate as post-CRT DW MR volume (AUC, 0.975) for evaluating good response, while pre-CRT DW MR volume and ADCs were not reliable for evaluating LNM and good response after CRT (AUC, 0.506-0.723).


Conserved numts mask a highly divergent mitochondrial-COI gene in a species complex of Australian stingless bees Tetragonula (Hymenoptera: Apidae).
Tetragonula carbonaria, Tetragonula davenporti, Tetragonula hockingsi and Tetragonula mellipes comprise a species complex of Australian stingless bee species known as the 'Carbonaria' group. The species are difficult to distinguish morphologically and the major species-defining characters relate to comb architecture and nest entrance ornamentation. The taxonomy of the group is further complicated by likely nuclear mitochondrial pseudogenes (numts) and inter-specific hybrids. Here we demonstrate the existence of COI numts and isolate and characterize the 'true' mt-COI gene in T. carbonaria and T. hockingsi. Numts were isolated from enriched-nuclear DNA extraction followed by PCR amplification and Sanger sequencing, and were recognized by the presence of deletions and/or premature stop codons in the translated sequences. The mt-COI sequences were obtained from NGS sequencing using purified mtDNA. In T. carbonaria, two numts (numt1 and numt2) were identified and a third (numt3) was identified in T. hockingsi. Numt2 and numt3 are similar (1.2% sequence divergence), indicating a recent common origin. The genetic distance between the mt-COI of the two Tetragonula species was higher than might be expected for closely related species, 16.5%, corroborating previous studies in which T. carbonaria and T. hockingsi were regarded as separate species. The three numts are more similar to the COI of other stingless bee species, including Australian Austroplebia australis and South American Melipona bicolor (81.7-83.9%) than to the mt-COI of their own species (70-71.4%). This is because the mt-COI of T. carbonaria and T. hockingsi differ greatly from other Meliponinae. Our findings explain some formerly puzzling aspects of Carbonaria biogeography, and misinterpreted amplifications.


Effect of marker position and size on the registration accuracy of HoloLens in a non-clinical setting with implications for high-precision surgical tasks.
Emerging holographic headsets can be used to register patient-specific virtual models obtained from medical scans with the patient's body. Maximising accuracy of the virtual models' inclination angle and position (ideally, ≤ 2° and ≤ 2 mm, respectively, as in currently approved navigation systems) is vital for this application to be useful. This study investigated the accuracy with which a holographic headset registers virtual models with real-world features based on the position and size of image markers. HoloLens® and the image-pattern-recognition tool Vuforia Engine™ were used to overlay a 5-cm-radius virtual hexagon on a monitor's surface in a predefined position. The headset's camera detection of an image marker (displayed on the monitor) triggered the rendering of the virtual hexagon on the headset's lenses. 4 × 4, 8 × 8 and 12 × 12 cm image markers displayed at nine different positions were used. In total, the position and dimensions of 114 virtual hexagons were measured on photographs captured by the headset's camera. Some image marker positions and the smallest image marker (4 × 4 cm) led to larger errors in the perceived dimensions of the virtual models than other image marker positions and larger markers (8 × 8 and 12 × 12 cm). ≤ 2° and ≤ 2 mm errors were found in 70.7% and 76% of cases, respectively. Errors obtained in a non-negligible percentage of cases are not acceptable for certain surgical tasks (e.g. the identification of correct trajectories of surgical instruments). Achieving sufficient accuracy with image marker sizes that meet surgical needs and regardless of image marker position remains a challenge.


Short-term multidisciplinary family-centered workshop for preschool children with global developmental delays.
Children with developmental delays have a great impact on their families. Educating families on how to interact with their children is an important task. Therefore, we assessed the short-term effectiveness of the workshop for children with global developmental delays. In total, 101 children aged 18-36 months with global developmental delays, all with language delay along with other developmental delays, and their parents participated in six 2-h family-centered workshop sessions for six weeks. Measures were taken before and after the workshop, including the Mandarin-Chinese Communicative Developmental Inventory, Peabody Developmental Motor Scales, Emotional Competency Rating Scales, Pediatric Outcomes Data Collection Instrument, Pediatric Evaluation of Disability Inventory, Pediatric Daily Occupation Scale, Pediatric Quality of Life Inventory (PedsQL), Caregiver Strain Index, and PedsQL-Family Impact Module. Significant improvements with a small or intermediate effect size in emotions, upper extremity and physical functioning and global functioning, daily occupation performance in sensorimotor, communication, cognitive autonomy, and psychosocial domains, and parental quality of life and family impact were noted with high workshop satisfaction. Short-term family-centered workshop is effective for children with global developmental delays. However, due to the lack of follow-up after the intervention, it should be careful in inferring the developmental gain effect. The effectiveness of short-term family-centered workshops on children with global developmental delays remains uncertain. Short-term family-centered workshops improved the children's emotions, physical functional performance, and occupational performance in daily life. The short-term family-centered workshop is practical and effective for children with global developmental delays. Further long-term, large-scale, prospective, randomized trials are warranted to confirm these results. ClinicalTrials.gov ID: NCT05418933.


CD248 facilitates tumor growth via its cytoplasmic domain.
Stromal fibroblasts participate in the development of a permissive environment for tumor growth, yet molecular pathways to therapeutically target fibroblasts are poorly defined. CD248, also known as endosialin or tumor endothelial marker 1 (TEM1), is a transmembrane glycoprotein expressed on activated fibroblasts. We recently showed that the cytoplasmic domain of CD248 is important in facilitating an inflammatory response in a mouse model of arthritis. Others have reported that CD248 gene inactivation in mice results in dampened tumor growth. We hypothesized that the conserved cytoplasmic domain of CD248 is important in regulating tumor growth. Mice lacking the cytoplasmic domain of CD248 (CD248CyD/CyD) were generated and evaluated in tumor models, comparing the findings with wild-type mice (CD248WT/WT). As compared to the response in CD248WT/WT mice, growth of T241 fibrosarcomas and Lewis lung carcinomas was significantly reduced in CD248CyD/CyD mice. Tumor size was similar to that seen with CD248-deficient mice. Conditioned media from CD248CyD/CyD fibroblasts were less effective at supporting T241 fibrosarcoma cell survival. In addition to our previous observation of reduced release of activated matrix metalloproteinase (MMP)-9, CD248CyD/CyD fibroblasts also had impaired PDGF-BB-induced migration and expressed higher transcripts of tumor suppressor factors, transgelin (SM22α), Hes and Hey1. The multiple pathways regulated by the cytoplasmic domain of CD248 highlight its potential as a therapeutic target to treat cancer.


Revisiting the Relationship between WIC Participation and Breastfeeding among Low-Income Children in the U.S. after the 2009 WIC Food Package Revision.
The Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) provides breastfeeding support and free formula to low-income participating infants in the U.S. Literature has consistently documented worse breastfeeding outcomes in WIC infants and children than in non-participants, although self-selection bias poses a challenge in examining the relationship between WIC participation and breastfeeding in low-income mother-child dyads. The WIC program adopted a comprehensive food package revision in 2009, the first one in four decades. Since that time, few national studies have examined the relationship between WIC participation and breastfeeding while controlling for the endogeneity of WIC participation with the propensity score method. This paper applied an instrumental variable (IV) approach on a large, nationally representative survey sample of children, the National Immunization Surveys (NIS), to examine the relationship between WIC participation and breastfeeding among children born between 2005 and 2014. We identified state Supplemental Nutrition Assistance Program (SNAP) enrollment rates and SNAP Policy Indices as valid IVs to address WIC participation endogeneity. Without the IVs, WIC participation had a significantly negative relationship with breastfeeding. After addressing endogeneity using the IVs, the relationship became insignificant in the whole sample and in the subpopulations across race/ethnicity and child gender. The neutrality of WIC participation on breastfeeding is important for policy makers to understand in seeking to improve breastfeeding among WIC participants.


Multiple congenital aneurysms of the atria.
Aneurysms of both the left and right atria are very rare congenital abnormalities. A 3-year-old boy underwent operation with preoperative diagnosis of aneurysms of both atria and supraventricular tachyarrhythmia. The multiple aneurysms were resected during cardiopulmonary bypass. The patient was asymptomatic after operation and has maintained sinus rhythm.


Identification of high-risk symptom cluster burden group among midlife peri-menopausal and post-menopausal women with metabolic syndrome using latent class growth analysis.
Midlife peri-menopausal and post-menopausal women with metabolic syndrome experience multiple co-occurring symptoms or symptom clusters, which often result in significant symptom cluster burden. While they are a high-risk symptom burden group, there are no studies that have focused on identifying symptom cluster trajectories in midlife peri-menopausal and post-menopausal women with metabolic syndrome. The objectives were to identify meaningful subgroups of midlife peri-menopausal and post-menopausal women with metabolic syndrome based on their distinct symptom cluster burden trajectories, and to describe the demographic, social, and clinical characteristics of different symptom cluster burden subgroups. This is a secondary data analysis using the longitudinal data from Study of Women's Health Across the Nation. Multi-trajectory analysis using latent class growth analysis was conducted to join the different developmental trajectories of symptom clusters to identify meaningful subgroups and high-risk subgroup for greater symptom cluster burden over time. Then, descriptive statistics were used to explain the demographic characteristics of each symptom cluster trajectory subgroup, and bivariate analysis to examine the association between each symptom cluster trajectory subgroup and demographic characteristics. A total of four classes were identified: Class 1 (low symptom cluster burden), Classes 2 and 3 (moderate symptom cluster burden), and Class 4 (high symptom cluster burden). Social support was a significant predictor of high symptom cluster burden subgroup and highlights the need to provide routine assessment. An understanding and appreciation for the different symptom cluster trajectory subgroups and their dynamic nature will assist clinicians to offer targeted and routine symptom cluster assessment and management in clinical settings.


A survey on operating conditions and quality of commercial frying fats in Hungary.
An extensive survey on commercial frying fats was conducted in Budapest. It was based on sample collection, analysis and questionnaires filled in with each sample. Frying fats and oils were collected from restaurants, fast-food services and public catering facilities. The quality of samples was assessed by determining their polar components. An evaluation of questionnaires containing over 20 questions yielded detailed information on the usage of fats as well as the fryer operators' habits of conducting frying processes and their knowledge on the subject. The survey consisted of two periods. During the first period 252 samples were collected at random. Quality assessment indicated that 53.6% of all samples was of good quality (with concentrations of polar materials below 25%) while the rest were at the discard point or deteriorated. The second part of the survey was aimed at a recheck of the places where fat had been found deteriorated. Second samples were obtained from 53 establishments. The results showed an improvement both in operating conditions and quality of frying fats. Based on the results, the necessity of instructing fryer operators and introducing regulations and routine quality testings of frying fats became obvious.


Technology and pregnancy.
In the USA, depending upon the diagnosis criteria used, 135,000-200,000 women annually develop gestational diabetes mellitus, adding to the number of pregnant women already suffering from either type 1 or type 2 diabetes. Maternal hyperglycaemia and the resultant fetal hyperinsulinaemia are central to the pathophysiology of diabetic complications of pregnancy. These complications include congenital malformations and an increase in neonatal intensive care unit admission and birth trauma. In addition, there is an increased rate of accelerated fetal growth, neonatal metabolic complications and risk for stillbirth. Importantly, during the last century there were two breakthroughs in diabetes management and monitoring that changed the course of treatment: the discovery of insulin and the progress in the understanding of glucose monitoring. As technology has evolved, both glucose monitoring and insulin administration can now be achieved in a continuous fashion. In this review of the literature we focus on the utility of new technologies in the management and monitoring of diabetes in pregnancy.


Visible light induces matrix metalloproteinase-9 expression in rat eye.
Up-regulation of matrix metalloproteinase-9 (MMP-9, gelatinase B) in the nervous system has been demonstrated when excitotoxicity-induced tissue remodeling and neuronal death occurs. Induction of MMP-9 by a natural stimulus has not been observed yet. Using RT-PCR and gelatin-zymography we demonstrated MMP-9 induction at transcriptional and protein levels in different structures of the rat eye following over-stimulation with white light. MMP-9 elevation occurred in the retina without reduction in photoreceptor number or major anatomical reorganization. A transient decrease in electroretinogram b-wave indicated the functional recovery. Retrobulbar injection of a broad-spectrum MMP-inhibitor GM6001, slowed the recovery rate of b-wave amplitude. Even room-light applied to dark-adapted awake animals induced MMP-9 increase in the retina, which suggests a role for MMP-9 in physiological functional plasticity of the nervous system, such as light adaptation. This is the first demonstration of MMP-9 induction by a sensory stimulus.


Cerebral blood flow and metabolism during and after prolonged hypocapnia in newborn lambs.
We studied the effects of prolonged (6 hours) hypocapnia and the abrupt termination thereof on cerebral blood flow and metabolism in six paralyzed, sedated (but not anesthetized) newborn lambs. Thirty minutes after institution of hyperventilation to an arterial carbon dioxide pressure of 15 +/- 2 torr, hyperventilation, cerebral blood flow had returned to baseline. Abrupt termination of hyperventilation after 6 hours resulted in a 110 +/- 71% increase in cerebral blood flow over baseline after 30 minutes of normocapnia. This cerebral hyperemia persisted for at least 90 minutes after hyperventilation was discontinued. Cerebral oxygen consumption did not change throughout the study. The posthypocapnia hyperemia noted in these animals after abrupt normalization of arterial carbon dioxide pressure may contribute to the increased risk of intracranial hemorrhage in newborn infants who are treated similarly in the management of pulmonary hypertension.


Empagliflozin attenuates acute kidney injury after myocardial infarction in diabetic rats.
Acute kidney injury (AKI) predicts poor prognosis in patients with acute myocardial infarction (MI) and diabetes mellitus (DM) is an independent risk factor of AKI. Recent clinical studies have shown the beneficial effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors on cardiovascular and renal outcomes in patients with DM. We recently reported that canagliflozin normalized susceptibility of diabetic rats to AKI after acute MI via β-hydroxybutyrate-mediated suppression of NOX expression. Here we examined whether the same renoprotective effect is shared by empagliflozin. Serum creatinine levels were not changed by MI induced by coronary artery occlusion in LETO, non-diabetic control rats, and OLETF, obese type 2 diabetic rats. However, immunohistochemistry revealed that MI increased renal expression of NGAL and KIM-1, early markers of tubular injury, by 3.2-fold and 2.6-fold, respectively, in OLETF. These increases in injury markers were not observed in LETO. Pretreatment with empagliflozin of OLETF for 2 weeks improved hyperglycemia, increased blood β-hydroxybutyrate level, and suppressed MI-induced expression of NGAL and KIM-1. Empagliflozin suppressed upregulation of NOX2 and NOX4 in the kidney of OLETF. Taken together with the results of our previous study, it was concluded that treatment with the SGLT2 inhibitor protects the diabetic kidney from MI-induced AKI.


Effects of some conformationally restricted GABA analogues on GABA membrane binding and nerve ending transport.
By using a series of aminocyclopentane- and aminocyclohexanecarboxylic acids, as well as some naturally occurring amino acids, it was possible to determine some aspects of the spatial topography of the GABA membrane binding and transport sites. The NA-independent GABA binding site was found to have a different spatial topography than the Na-dependent binding site in that trans-3-aminocyclopentanecarboxylic acid (trans-3-ACPC) was 7 times more potent than cis-3-ACPC to inhibit Na-independent binding, but only 1.6 times more potent to inhibit Na-dependent binding. The nerve ending GABA transport site was found to be similar to the Na-dependent GABA binding site in that it will accommodate both cis- and trans-3-ACPC. However, the transport site differs from the binding site in that cis-3-aminocyclohexanecarboxylic acid (cis-3-ACHC) is a potent inhibitor of transport but a weak inhibitor of binding. In addition to the differences in spatial characteristics, differences in the subcellular distribution of Na-independent and Na-dependent binding sites were observed. The former were found primarily in the nerve ending-mitochondrial fraction, while the latter were primarily found in the microsomal fraction.


Reduction in metabolite transverse relaxation times in amyotrophic lateral sclerosis.
Proton magnetic resonance spectroscopy (1H MRS) is used frequently to evaluate normal and pathological states in brain. MRS results are often reported as ratios of peak areas from spectra acquired at a single echo time, primarily for the peaks arising from N-acetyl groups (NA), creatine/phosphocreatine (t-Cr), and choline (Cho). Peak areas, however, are affected not only by metabolite concentration, but also by transverse relaxation times (T(2)). While the ratio approach appears to be valid in normal brain, pathology may affect T(2), thereby leading to misinterpretation of the apparent changes in metabolite ratios. The objective of the present study was to determine if any T(2) changes might affect the apparent metabolite ratio measures, which we have previously reported as being abnormal in amyotrophic lateral sclerosis (ALS). 1H MRS data were acquired from the brainstems of ALS and control subjects, for a range of TE times, to calculate T(2) times for each of NA, t-Cr, and Cho. Metabolite ratios were measured experimentally at TE=120 ms and calculated for TE=0 ms, based on measured T(2) values. The T(2)'s for the ALS vs. control group were NA=272+/-10 ms vs. 351+/-58 ms (p<0.01), t-Cr=132+/-17 vs. 184+/-42 ms (p<0.02), and Cho=223+/-55 vs. 245+/-50 ms (p>0.05). The effect of these T(2) changes on metabolite ratios showed both the NA/t-Cr (ALS=0.98+/-0.13, Control=1.44+/-0.10, p<0001) and Cho/t-Cr (ALS=1.01+/-0.12, Control=1.34+/-0.24, p<0.001) ratios to differ significantly between groups. This study confirms the presence of significant abnormalities in metabolite concentration in ALS brainstem and the importance of evaluating the effects of metabolite T(2) values when making ratio measurements in disease states.


Leukaemia and paternal radiation exposure.
Recently, Gardner and colleagues inferred, from a case-control study of leukaemia incidence in young people near the Sellafield nuclear facility in West Cumbria, that an increase near Sellafield was real, and was probably caused by occupational exposure of the father to ionising radiation at the Sellafield plant. The intent of this paper is to dispute that attribution, and to suggest that confirmation of such an alarming and prejudicial conclusion should precede its dissemination. MATERIAL CONSIDERED: Critical comment is limited to the paper by the Gardner group presenting their results, the accompanying paper outlining their methods, a review from Mathews that provides some support for the Gardner proposal by suggesting a pathogenetic mechanism, and some observations on inherited tumours by Nomura that are quoted by Gardner et al. and Mathews in support of their beliefs. Other material quoted is from the general medical literature of the past 20 years relating to radiation biology, mutagenesis and carcinogenesis with some relevance to the Gardner contention; it is not exhaustive. Statistical arguments suggest that it is almost impossible to be sure that a specific leukaemia "cluster", such as that near Sellafield, is not a chance finding. The study by Gardner et al. provides only weak statistical evidence for an association between leukaemia in children and parental occupational radiation exposure at Sellafield. The postulate of a causal relation between parental exposure at Sellafield and leukaemia in progeny is incompatible with what is known of the role of genetic mechanisms in leukaemia, with current views on the quantitative relation between radiation dose and mutagenetic effect, and with observations on the children of people exposed to radiation by the nuclear bombs used in Japan in 1945. The suggestion that occupational exposure to ionising radiation of a father may be responsible for an increased risk of leukaemia in his children cannot be substantiated. It would be proper to seek confirmation from other groups of occupationally exposed persons before undertaking precipitous, and inevitably disturbing, action to remedy the supposed problem.


A cytoskeletal spring for the control of cell shape in outer hair cells isolated from the guinea pig cochlea.
A two-dimensional cortical cytoskeletal lattice associated with the lateral plasma membranes of mammalian outer hair cells maintains cell shape and provides a restoring force to oppose active changes in cell length. The lattice is composed of two morphologically distinct filaments which are arranged to reinforce the cell circumferentially whilst allowing limited changes in cell length and diameter. This function can only be fulfilled if intracellular pressure is high enough to put the lattice under tension.


Bioactive lipid lysophosphatidic acid species are associated with disease progression in idiopathic pulmonary fibrosis.
Idiopathic pulmonary fibrosis (IPF) is a progressive disease with significant mortality. Prognostic biomarkers to identify rapid progressors are urgently needed to improve patient management. Since the lysophosphatidic acid (LPA) pathway has been implicated in lung fibrosis in preclinical models and identified as a potential therapeutic target, we aimed to investigate if bioactive lipid LPA species could be prognostic biomarkers that predict IPF disease progression. LPAs and lipidomics were measured in baseline placebo plasma of a randomized IPF-controlled trial. The association of lipids with disease progression indices were assessed using statistical models. Compared to healthy, IPF patients had significantly higher levels of five LPAs (LPA16:0, 16:1, 18:1, 18:2, 20:4) and reduced levels of two triglycerides species (TAG48:4-FA12:0, -FA18:2) (false discovery rate < 0.05, fold change > 2). Patients with higher levels of LPAs had greater declines in diffusion capacity of carbon monoxide over 52 weeks (P < 0.01); additionally, LPA20:4-high (≥median) patients had earlier time to exacerbation compared to LPA20:4-low (<median) patients (hazard ratio (95% CI)): 5.71 (1.17-27.72) (P = 0.031). Higher baseline LPAs were associated with greater increases in fibrosis in lower lungs as quantified by high-resolution computed tomography at week 72 (P < 0.05). Some of these LPAs were positively associated with biomarkers of profibrotic macrophages (CCL17, CCL18, OPN, and YKL40) and lung epithelial damage (SPD and sRAGE) (P < 0.05). In summary, our study established the association of LPAs with IPF disease progression, further supporting the role of the LPA pathway in IPF pathobiology.


Partial purification of the superoxide-generating system of macrophages. Possible association of the NADPH oxidase activity with a low-potential (-247 mV) cytochrome b.
NADPH oxidase activity was solubilized by detergent treatment of subcellular particles obtained from guinea-pig peritoneal macrophages stimulated with phorbol myristate acetate. Gel filtration of the material containing the NADPH oxidase activity gave two peaks of proteins, one of which eluted with the void and the other with the included volume of an AcA 22 column. The material eluted in the void volume contained more than 50% of the NADPH oxidase activity and less than 10% of the NAD(P)H cytochrome c reductase activity. A b-type cytochrome with peaks of absorption at 558, 528 and 426 nm was also enriched in the fraction which contained the NADPH oxidase activity. The distribution of flavoproteins as revealed by the measurement of FAD was different from that of NADPH oxidase and cytochrome b, and followed the elution profile of NADH cytochrome c reductase. Studies in subcellular particles showed that the b cytochromes of mitochondria and endoplasmic reticulum reduced by selective biochemical means accounted for only a minor part of the total b-type cytochromes and that the new cytochrome b previously described in neutrophils is the major chromophore also in macrophages. Oxidation-reduction midpoint potential of the partially purified cytochrome b was shown to be -247 mV. Association of cytochrome b with the NADPH oxidase activity and its very low Em7.0 makes it a suitable candidate to be part of the superoxide-generating system also in macrophages.


Orientation of Ambystoma maculatum: Movements to and from Breeding Ponds.
Migrating Ambystoma maculatum tend to utilize the same track on entering and leaving breeding ponds. The movements are usually accom plished at night in rain, fog, or cloudy, weather when visible celestial cues may not be available. The sensory basis for the orienting ability is unknown.


Survive or thrive: tradeoff strategy for cellular senescence.
Aging-dependent cellular behaviors toward extrinsic stress are characterized by the confined localization of certain molecules to either nuclear or perinuclear regions. Although most growth factors can activate downstream signaling in aging cells, they do not in fact have any impact on the cells because the signals cannot reach their genetic targets in the nucleus. For the same reason, varying apoptotic stress factors cannot stimulate the apoptotic pathway in senescent cells. Thus, the operation of a functional nuclear barrier in an aging-dependent manner has been investigated. To elucidate the mechanism for this process, the housekeeping transcription factor Sp1 was identified as a general regulator of nucleocytoplasmic trafficking (NCT) genes, including various nucleoporins, importins, exportins and Ran GTPase cycle-related genes. Interestingly, the posttranslational modification of Sp1 is readily influenced by extrinsic stress, including oxidative and metabolic stress. The decrease in SP1 O-GlcNAcylation under oxidative stress or during replicative senescence makes it susceptible to proteosomal degradation, resulting in defective NCT functions and leading to nuclear barrier formation. The operation of the nuclear barrier in aging provides a fundamental mechanism for cellular protection against stress and promotes survival at the expense of growth via stress-sensitive transcriptional control.


The impact of heavy metals from environmental tobacco smoke on indoor air quality as determined by Compton suppression neutron activation analysis.
The method of instrumental neutron activation analysis (NAA) has been improved for air filter samples in the determination of low level heavy metals in indoor air. By using the techniques of epithermal neutron irradiation in conjunction with Compton suppression, the detection limits of cadmium, arsenic and antimony measurements have been dramatically reduced to 2 ng for Cd, 0.2 ng for As, and 0.03 ng for Sb. The determination of these heavy metals in particulate material generated from cigarette smoking in indoor environments has been conducted. Other elements, Br, Cl, Na, K, Zn were also found at elevated levels.


New law's big payout for farming has uncertain climate payoff.
Measures to capture carbon in soil may be less effective than hoped, scientists say.


A rapid screening method to evaluate acidifying activity by lactic acid bacteria.
The determination of pH in fermented milk is an important parameter for monitoring the production of acid by lactic acid bacteria (LAB). In this work, a colorimetric method is proposed that allows a fast determination of LAB acidification ability by evaluation of pH drop in whey fermentation. The proposed method uses spectrophotometry to measure the pH change by bacteria and uses bromocresol purple as a pH indicator dye. The absorbance at 430 nm of a buffer solution with bromocresol purple was found to be correlated with pH values. This colorimetric assay was linear within the pH range of 4.6-7.0. Upon regression analysis, linear equation y = -0.1267× + 0.9196 was obtained having r2 value of 0.9927. The assay was validated by the use of LAB fermentation in sweet whey and comparison to the values obtained by glass electrode/pH meter. Estimation of acidification activity of LAB in whey was found to be similar in both methods (r = 0.801, p > 0.05). The proposed procedure presents a viable alternative to the measurement of pH by the standard method and allows the simultaneous and fast screening of LAB acidifying activity.


High incidence of inguinal hernias among patients with congenital abdominal wall defects: a population-based case-control study.
The aim of this nationwide population-based case-control study was to assess the incidence of inguinal hernia (IH) among patients with congenital abdominal wall defects. All infants born with congenital abdominal wall defects between Jan 1, 1998, and Dec 31, 2014, were identified in the Finnish Register of Congenital Malformations. Six controls matched for gestational age, sex, and year of birth were selected for each case in the Medical Birth Register. The Finnish Hospital Discharge Register was searched for relevant diagnosis codes for IH, and hernia incidence was compared between cases and controls. We identified 178 infants with gastroschisis and 150 with omphalocele and selected randomly 1968 matched, healthy controls for comparison. Incidence of IH was significantly higher in gastroschisis girls than in matched controls, relative risk (RR) 7.20 (95% confidence interval [CI] 2.25-23.07). In boys with gastroschisis, no statistically significant difference was observed, RR 1.60 (95% CI 0.75-3.38). Omphalocele was associated with higher risk of IH compared to matched controls, RR 6.46 (95% CI 3.90-10.71), and the risk was equally elevated in male and female patients.Conclusion: Risk of IH is significantly higher among patients with congenital abdominal wall defects than in healthy controls supporting hypothesis that elevated intra-abdominal pressure could prevent natural closure of processus vaginalis. Parents should be informed of this elevated hernia risk to avoid delays in seeking care. We also recommend careful follow-up during the first months of life as most of these hernias are diagnosed early in life. What is Known: • Inguinal hernia is one of the most common disorders encountered by a pediatric surgeon. • Prematurity increases the risk of inguinal hernia. What is New: • Children with congenital abdominal wall defects have a significantly higher risk of inguinal hernia than general population. • Families should be informed of this elevated hernia risk to avoid delays in seeking care.


Exploring the bone sparing effects of postbiotics in the post-menopausal rat model.
Post-menopausal osteoporosis is a concern of health organizations, and current treatments do not seem enough. Postbiotics as bioactive compounds produced by probiotics may be an attractive alternative for bone health. In this study, we prepared, formulated, and compared the effects of cell lysate and supernatant of five native probiotic strains (Lactobacillus acidophilus, Lactobacillus reuteri, Lactobacillus casei, Bifidobacterium longum, and Bacillus coagulans) in ovariectomized (OVX) rats. The probiotic strains were isolated, and their cell-free supernatants and biomasses as postbiotics were extracted and formulated using standard microbial processes. The Sprague-Dawley rats were fed by 1 × 109 CFU/ml/day postbiotic preparations for 4 weeks immediately after ovariectomy. Dual-energy X-ray absorptiometry (DEXA) scans were accomplished to evaluate femur, spine, and tibia BMD. The serum biochemical markers [calcium, phosphorus, and alkaline phosphatase] were assessed. Postbiotics could considerably improve the global and femur area in OVX rats. In the case of global bone mineral density (BMD), Lactobacillus casei lysate and supernatant, Bacillus coagulans lysate and supernatant, lysate of Bifidobacterium longum and Lactobacillus acidophilus, and Lactobacillus reuteri supernatant significantly increased BMD. We found Bacillus coagulans supernatant meaningfully enriched tibia BMD. Postbiotic could ameliorate bone loss resulting from estrogen deficiency. Also, the effects of postbiotics on different bone sites are strain-dependent. More clinical studies need to explore the optimal administrative dose and duration of the specific postbiotics in protecting bone loss.


Oxidative stress controls regulatory T cell apoptosis and suppressor activity and PD-L1-blockade resistance in tumor.
Live regulatory T cells (Treg cells) suppress antitumor immunity, but how Treg cells behave in the metabolically abnormal tumor microenvironment remains unknown. Here we show that tumor Treg cells undergo apoptosis, and such apoptotic Treg cells abolish spontaneous and PD-L1-blockade-mediated antitumor T cell immunity. Biochemical and functional analyses show that adenosine, but not typical suppressive factors such as PD-L1, CTLA-4, TGF-β, IL-35, and IL-10, contributes to apoptotic Treg-cell-mediated immunosuppression. Mechanistically, apoptotic Treg cells release and convert a large amount of ATP to adenosine via CD39 and CD73, and mediate immunosuppression via the adenosine and A2A pathways. Apoptosis in Treg cells is attributed to their weak NRF2-associated antioxidant system and high vulnerability to free oxygen species in the tumor microenvironment. Thus, the data support a model wherein tumor Treg cells sustain and amplify their suppressor capacity through inadvertent death via oxidative stress. This work highlights the oxidative pathway as a metabolic checkpoint that controls Treg cell behavior and affects the efficacy of therapeutics targeting cancer checkpoints.


Bacteriological survey of the frozen prepared foods industry. IV. Frozen breaded fish.
During sanitation-inspections of 23 breaded-fish processors, 573 finished product units and 604 line samples were collected and analyzed bacteriologically. Data for finished product units processed on the same data are presented in groups; most of the groups consisted of 10 units. Groups of frozen, raw-breaded fish produced under good and poor conditions of sanitation were studied. No more than 20% of the units in each group produced under good conditions of sanitation were positive for Escherichia coli or coagulase-positive staphylococci. Groups of frozen, fried-breaded fish produced under good and poor sanitary conditions were also studied. No more than 10% of the units in each good-sanitation group were positive for E. coli or coagulase-positive staphylococci. However, approximately 30% of the groups processed under poor sanitary conditions also did not exceed these viable bacterial counts because of the lethal effect of the terminal fry to which the product is subjected. It was found that line samples collected from the processing lines reflected the sanitary conditions of the plant and provided bacteriological support for inspectional evidence of plant insanitation.


The development of ultrashort acting neuromuscular relaxant tropane derivatives.
There is a need for neuromuscular relaxant (NMR) agents that are of the "nondepolarizing type" and produce rapidly developing and short-lasting skeletal muscle relaxation in anesthesiology. Many efforts have been directed to produce such agents. Our research focused on the design, synthesis, and evaluation of numerous "bisquaternary" derivatives of the cyclic aminoalkanes: tropane and granatane. Through systematic "steric structure-activity relationship" studies, we arrived at some new bisquaternary tropine and granatanol diesters, which in laboratory studies appeared to be the fastest and shortest acting NMRs recognized so far. Their ultrashort duration action-mechanism was, however, linked to the formation of nephrotoxic metabolites, precluding further development. Even so, we believe that the scientific information gained from more than a thousand such agents, will be useful toward developing the "ideal," ultrashort-acting NMR that could be clinically successful without the use of "reversing" agents, at least until "new biotechnology" may solve all problematic aspects of "transient" muscle relaxation.


Effects of taking selfies on women's self-objectification, mood, self-esteem, and social aggression toward female peers.
This study investigated the effects of taking photos (of the self or objects) on women. Objectification theory states that women are subjected to societal pressure to focus on their physical appearance. The emergence of social media as a communication channel has further reinforced the emphasis on women's appearance, beauty ideals, and body image. On social media, selfies serve as a self-presentation of one's appearance to an online audience. In this 2 × 2 experiment, women (N = 120, Mage = 19.87) took pictures of themselves (i.e., selfies) or objects. They were told beforehand that these pictures would be kept private or that they would be posted online on social media. After taking pictures, we assessed women's self-objectification, mood, and self-esteem. Women then engaged in a photo tagging task in which they selected hashtags for selfies of other women. Selfie takers expressed higher self-objectification, more negative mood, and diminished self-esteem compared to those taking pictures of objects. Selfie takers also demonstrated comparatively less social aggression, using fewer derogatory tags on other women's pictures. Although taking selfies may negatively affect producers, there may be benefits for online social interaction with peers.


Post-transcriptional elevation of mouse brain Mn-SOD protein by mercuric chloride.
Alterations in gene expression, protein content and enzyme activity of brain Mn-SOD following mercuric chloride (HgCl2) exposure were examined in ICR male mice. Subcutaneous administration of HgCl2 (1 mg Hg/kg) resulted in a significant increase (4-fold) in the brain Mn-SOD content at 6 h after injection while the total mercury concentration was about 0.11 microg/g of brain. The enhancement of Mn-SOD protein caused by HgCl2 was completely abolished by pretreatment with dexamethasone (3 mg/kg) 1 h prior to HgCl2 administration, suggesting involvement of inflammation in inorganic mercury-induced increase in the antioxidant enzyme. This increase in level of Mn-SOD content coincided with a substantial rise in the enzyme activity; however, Northern blot analysis revealed that the induction of protein level was not due to that of its gene expression. The results of the present study indicate that mouse brain Mn-SOD appears to undergo post-translational modification by the environmental toxic metal, and induction of the antioxidant enzyme could be of an initial response to the metal-induced oxidative stress.


Implications for microglial sex differences in tau-related neurodegenerative diseases.
Tauopathies are a group of neurodegenerative diseases that involve pathological changes to the tau protein. Neuroinflammation is a commonly reported feature of tauopathies that has been demonstrated to exacerbate tau pathology and, hence, neurodegeneration. Microglia can mediate the inflammatory response in order to maintain brain homeostasis. In the aged brain, microglia are reported to undergo morphological and functional changes, adopting a pro-inflammatory profile and loss of homeostatic functions. Dystrophic and dysfunctional microglia are associated with tau pathology in the healthy and diseased brain which is proposed to contribute to disease development and progression. Microglia have also been recently demonstrated to possess sexually dimorphic roles in the developing, adult and aged brain. The sex differences in microglial functionality suggest that microglia may contribute to tauopathies which may differ between sexes. This review highlights the detrimental loop between age-related microglial changes and tau pathology with implications for microglial sexual dichotomy.


Biosurfactant is a powerful tool for the bioremediation of heavy metals from contaminated soils.
Heavy metal toxicity has become a pressing ecological problem that affects the ecosystems through bioaccumulation, representing a serious public health hazard. Many conventional strategies have been developed and applied to decontaminate and restore metal-contaminated areas. However, these conventional approaches are not very suitable and environmentally safe for heavy metal remediation because of their high operational costs, high energy requirements, post-waste disposal problems, and secondary pollutant generation. Thus, biosurfactant-based bioremediation of heavy metals is a sustainable and promising approach because of its biodegradation capability, economic effectiveness, and ecofriendly nature. Pseudomonas sp., Bacillus sp., Citrobacter freundii, and Candida tropicalis have been isolated as potential sources of biosurfactants and produce compounds such as surfactin, rhamnolipids, and sophorolipids. Owing to the severity of heavy metal pollution in certain parts of the environment, biosurfactants have garnered great interest and attention as an emerging multi-functional technology of the new century for successful removal of heavy metal pollutants. The present study describes the role of biosurfactants in the bioremediation of heavy metals from contaminated environments. Moreover, the interaction mechanism underlying biosurfactant-metal complexation and metal remediation are discussed. Based on the review of the literature, further research is warranted to elucidate the mechanistic roles and explore the structural characterization and gene regulation of biosurfactants to improve their productivity and expand their applicability in bioremediation.


Platelet function and Isoprostane biology. Should isoprostanes be the newest member of the orphan-ligand family?
While there have been many reports investigating the biological activity and signaling mechanisms of isoprostanes, their role in biology, particularly in platelets, appears to still be underestimated. Moreover, whether these lipids have their own receptors is still debated, despite multiple reports that discrete receptors for isoprostane do exist on platelets, vascular tissues, amongst others. This paper provides a review of the important literature of isoprostanes and provides reasoning that isoprostanes should be classified as orphan ligands until their receptor(s) is/are identified.


Differential effects of REV-ERBα/β agonism on cardiac gene expression, metabolism, and contractile function in a mouse model of circadian disruption.
Cell-autonomous circadian clocks have emerged as temporal orchestrators of numerous biological processes. For example, the cardiomyocyte circadian clock modulates transcription, translation, posttranslational modifications, ion homeostasis, signaling cascades, metabolism, and contractility of the heart over the course of the day. Circadian clocks are composed of more than 10 interconnected transcriptional modulators, all of which have the potential to influence the cardiac transcriptome (and ultimately cardiac processes). These transcriptional modulators include BMAL1 and REV-ERBα/β; BMAL1 induces REV-ERBα/β, which in turn feeds back to inhibit BMAL1. Previous studies indicate that cardiomyocyte-specific BMAL1-knockout (CBK) mice exhibit a dysfunctional circadian clock (including decreased REV-ERBα/β expression) in the heart associated with abnormalities in cardiac mitochondrial function, metabolism, signaling, and contractile function. Here, we hypothesized that decreased REV-ERBα/β activity is responsible for distinct phenotypical alterations observed in CBK hearts. To test this hypothesis, CBK (and littermate control) mice were administered with the selective REV-ERBα/β agonist SR-9009 (100 mg·kg-1·day-1 for 8 days). SR-9009 administration was sufficient to normalize cardiac glycogen synthesis rates, cardiomyocyte size, interstitial fibrosis, and contractility in CBK hearts (without influencing mitochondrial complex activities, nor normalizing substrate oxidation and Akt/mTOR/GSK3β signaling). Collectively, these observations highlight a role for REV-ERBα/β as a mediator of a subset of circadian clock-controlled processes in the heart.


Single and simple antibiotic prophylaxis for elective cholecystectomy.
To determine the postoperative infection result after use of a single and simple antibiotics for prophylaxis in open elective cholecystectomy. Descriptive (quasi-experimental) study. This study was conducted in Military Hospital, Rawalpindi from December 2006 to January 2008. One hundred and sixteen patients requiring elective open cholecystectomy were included. Patients with acute cholecystitis, jaundice and choledocholithiasis were excluded. Only two doses of Gentamycin were used as prophylactic antibiotic for operation. Special precautions were taken for maintaining sterilization during surgery. Out of 116 cases, 111 (95.7%) patients had smooth postoperative recovery and only 5 (4.3%) patients developed surgical site infection. Culture sensitivity of these 5 patients revealed E. coli in 2 (40%) cases, 01 (20%) patient had Klebsiella, while 2 (40%) had mixed growth. Single antibiotic prophylaxis for elective cholecystectomy is recommended provided strict aseptic measures are taken during surgery along with good surgical technique.


The effect of minor tranquilizers on psychomotor performance.
The effect of a standard daily regimen of chlordiazepoxide, prazepam (a new benzodiazepine tranquilizer), and placebo were examined in a three way double-blind comparison for a sample of normal volunteers. The criteria include a limited spectrum of psychomotor functions. A learning effect was conspicuous for all drugs on all criteria during the day-long sequence of ten trials. For the most part the differences between the drug groups were insignificant, but there were distinctive modifications in the performance of the chlordiazepoxide group. The clearest effect of the tranquilizer medications was found in the time estimation tests. Paradoxically, the drugs correct a naturally occurring perceptual error.


Perinatal depression and children's developmental outcomes at 2 years postpartum.
Perinatal depression has been associated with a range of adverse outcomes for children's neurodevelopment. This study sought to examine the impact of maternal perinatal depression on 2-year-olds' social-emotional, cognitive, language, and adaptive behavioural development, using data collected at the fifth timepoint of a prospective longitudinal study, which followed participants from pregnancy through to toddlerhood. 61 women and their children (M age = 26 months, SD = 1.83; 35 boys and 26 girls), of the original cohort of 98, who had been recruited during pregnancy, and stratified into three participant groups: 1. Depressed (those with a clinical diagnosis of Major Depressive Disorder [MDD]); 2. History (currently euthymic with a previous MDD episode); 3. Control (no history of psychiatric disorder). Depression severity was assessed using the Hamilton Depression Rating Scale (HAM-D), and children's developmental outcomes were measured using the Bayley Scales of Infant and Toddler Development, 3rd Edition (BSID-III). No direct associations between mothers' depression and children's social-emotional, cognitive or language development were observed. However, an unexpected positive association between maternal depression and children's social adaptive behaviour was found, which conferred an advantage on children whose mothers had suffered from depression. The current findings contribute to the literature examining the impact of perinatal depression on early childhood outcomes. The unexpected positive association found between maternal depression and children's adaptive behaviour should prompt further research examining the adaptive resilience of young children exposed to maternal depression. This is discussed in the context of differential-susceptibility theory.


Analysis and sequencing of the active-site peptide from native and organophosphate-inactivated acetylcholinesterase by electrospray ionization, quadrupole/time-of-flight (QTOF) mass spectrometry.
A method to identify and sequence recombinant mouse acetylcholinesterase (rMoAChE) including the native and organophosphate-modified active-site peptides was developed using capillary liquid chromatography with electrospray ionization, quadrupole/time-of-flight mass spectrometry. Addition of 2-propanol to the reversed-phase gradient system and a decreased gradient slope improved the peptide resolution and the signal of the active-site peptide. The highest protein coverage and active-site peptide signal were achieved when the rMoAChE:chymotrypsin ratio of 5:1 was used with digestion at 37 degrees C. rMoAChE and the active-site peptide were identified and sequenced from chymotryptic digests of native, methyl paraoxon-, and ethyl paraoxon-inactivated rMoAChE showing unequivocally that the exact modification site was the active-site serine.


Treatment of atrial fibrillation with doxapram: TASK-1 potassium channel inhibition as a novel pharmacological strategy.
TASK-1 (K2P3.1) two-pore-domain potassium channels are atrial-specific and significantly up-regulated in atrial fibrillation (AF) patients, contributing to AF-related electrical remodelling. Inhibition of TASK-1 in cardiomyocytes of AF patients was shown to counteract AF-related action potential duration shortening. Doxapram was identified as a potent inhibitor of the TASK-1 channel. In this study, we investigated the antiarrhythmic efficacy of doxapram in a porcine model of AF. Doxapram successfully cardioverted pigs with artificially induced episodes of AF. We established a porcine model of persistent AF in domestic pigs via intermittent atrial burst stimulation using implanted pacemakers. All pigs underwent catheter-based electrophysiological investigations prior to and after 14 days of doxapram treatment. Pigs in the treatment group received intravenous administration of doxapram once per day. In doxapram-treated AF pigs, the AF burden was significantly reduced. After 14 days of treatment with doxapram, TASK-1 currents were still similar to values of sinus rhythm animals. Doxapram significantly suppressed AF episodes and normalized cellular electrophysiology by inhibition of the TASK-1 channel. Patch-clamp experiments on human atrial cardiomyocytes, isolated from patients with and without AF could reproduce the TASK-1 inhibitory effect of doxapram. Repurposing doxapram might yield a promising new antiarrhythmic drug to treat AF in patients.


Relationship between brain damage and memory impairment in rats exposed to transient forebrain ischemia.
The relationship between changes in learning behavior and neurological damage following transient forebrain ischemia was studied in rats. The transient forebrain ischemia was induced by 4-vessel occlusion, and behavioral experiments were started 4 weeks later when histological damage to the brain seemed to have stabilized. Histological evaluation of brain damage was conducted after completion of the behavioral studies. The rats showed marked learning impairment in a radial maze task done from 4 to 10 weeks after ischemia. In particular, there was an increase in the number of working memory errors according to the duration of forebrain ischemia. However, the same rats showed good avoidance responses in a passive avoidance task done 12 weeks after ischemia. The rats also showed good acquisition of escape response in a water maze task carried out 13 weeks after ischemia, but showed slight impairment of spatial navigation in the transfer test. Marked neuronal degeneration was observed in the hippocampal pyramidal cells of the rats exposed to ischemia. This neuronal damage was closely related to memory impairment in the radial maze task, as demonstrated by a significant negative correlation (r = -0.609 or -0.709) between the number of surviving neurons and the number of reference or working memory errors. These results suggest that rats exposed to transient forebrain ischemia show marked impairment of both reference and working memories as a result of postischemic hippocampal damage.


Application of the Rosner-Colditz risk prediction model to estimate sexual orientation group disparities in breast cancer risk in a U.S. cohort of premenopausal women.
Lesbian and bisexual women may be at greater risk of breast cancer than heterosexual women during the premenopausal period due to disparities in risk factors. With 16 years of prospective data from a large cohort of U.S. women ages 25-58 years, we conducted a breast cancer risk assessment for 87,392 premenopausal women by applying the Rosner-Colditz biomathematical risk prediction model to estimate breast cancer risk based on known risk factors. On the basis of each woman's comprehensive risk factor profile, we calculated the predicted 1-year incidence rate (IR) per 100,000 person-years and estimated incidence rate ratios (IRR) and 95% confidence intervals (CI) for lesbian and bisexual women compared with heterosexual women. A total of 87,392 premenopausal women provided 1,091,871 person-years of data included in analyses. Mean predicted 1-year breast cancer IRs per 100,000 person-years for each sexual orientation group were heterosexual, 122.55; lesbian, 131.61; and bisexual, 131.72. IRs were significantly elevated in both lesbian (IRR, 1.06; 95% CI, 1.06-1.06) and bisexual (IRR, 1.10; 95% CI, 1.10-1.10) women compared with heterosexual women. Our findings suggest that both lesbian and bisexual women have slightly elevated predicted breast cancer incidence compared with heterosexual women throughout the premenopausal period. Health professionals must ensure that breast cancer prevention efforts are reaching these women. As more health systems around the country collect data on patient sexual orientation, the National Cancer Institute's SEER cancer registry should add this information to its data system to monitor progress in reducing sexual orientation-related disparities in cancer incidence and mortality.


Accelerated starvation in late pregnancy: a comparison between obese women with and without gestational diabetes mellitus.
We compared the glucose, insulin, free fatty acid, and 3-hydroxybutyrate responses to a briefly extended overnight fast during the third trimester of pregnancy between two groups: obese women with normal glucose tolerance (n = 10) and age- and weight-matched women with gestational diabetes mellitus (n = 10). After a 12-hour overnight fast, plasma glucose (95 +/- 4 vs. 78 +/- 2 mg/dl; p less than 0.01), insulin (32 +/- 5 vs. 17 +/- 2 microU/ml; p less than 0.02), and free fatty acid (860 +/- 63 vs. 639 +/- 79 mmol/L; p less than 0.05) levels were higher in the patients with gestational diabetes mellitus. 3-Hydroxybutyrate levels were similar in the two groups at that time (0.23 +/- 0.04 vs. 0.18 +/- 0.03 mmol/L; p greater than 0.3). When the fast was extended to 18 hours by having the patients skip breakfast, glucose levels fell more rapidly in the group with gestational diabetes mellitus but remained elevated compared with the nondiabetic women. Insulin levels declined at a similar rate in the two groups. Free fatty acid levels did not increase significantly in the group with gestational diabetes mellitus during the extended fast. In contrast, free fatty acid levels increased by 44% in the normal pregnant women, reaching the level observed in the group with gestational diabetes mellitus after 18 hours. 3-Hydroxybutyrate levels remained virtually identical in the two groups throughout the brief fast. Thus, compared with that of normal pregnant women, the response of obese women with gestational diabetes mellitus to brief caloric deprivation during late pregnancy was characterized by a greater fall in plasma glucose values without a greater propensity to ketosis. Our findings may have important implications for the dietary management of obese patients with gestational diabetes mellitus.


Overactive autophagy is a pathological mechanism underlying premature suture ossification in nonsyndromic craniosynostosis.
Nonsyndromic craniosynostosis (NSC) is the most common craniosynostosis with the primary defect being one or more fused sutures. In contrast to syndromic craniosynostosis, the etiopathogenesis of NSC is largely unknown. Here we show that autophagy, a major catabolic process required for the maintenance of bone homeostasis and bone growth, is a pathological change associated with NSC. Using calvarial suture mesenchymal cells (SMCs) isolated from the fused and unfused sutures of NSC patients, we demonstrate that during SMC differentiation, the level of the autophagosomal marker LC3-II increases as osteogenic differentiation progresses, particularly at differentiation day 7, a stage concurrent with mineralization. In fused SMCs, autophagic induction was more robust than that in unfused SMCs, which consequently led to enhanced mineralized nodule formation. Perturbation of autophagy with rapamycin or wortmannin promoted or inhibited the ossification of SMCs, respectively. Our findings suggest that autophagy is essential for the osteogenic differentiation of SMCs and that overactive autophagy is a molecular abnormality underlying premature calvarial ossification in NSC.


Gender differences in the associations between body mass index, depression, anxiety, and stress among endocrinologists in China.
Depression, anxiety, and stress symptoms have been found to be associated with overweight or obesity, but the gender differences in the associations have not been well-examined. Based on a national sample of endocrinologists in China, we examined such associations with a focus on gender differences. Data were collected from endocrinologists in China using an online questionnaire, which included demographic data, body weight, and height. Depression, anxiety, and stress symptoms were assessed using the Depression, Anxiety, and Stress Scale-21 (DASS-21). In total, 679 endocrinologists (174 males and 505 females) completed the survey. One-fourth (25.6%) were classified as overweight, with a significant gender difference (48.9% in males vs. 17.6% in females, p < 0.05). Overall, 43.4% of the participants endorsed probable depressive symptoms (54.6% in males and 39.6% in females, p = 0.004), 47.6% for anxiety (51.7% in males vs. 46.1% in females, p = 0.203), and 29.6% for stress symptoms (34.5% in males vs. 27.92% in females, p = 0.102). After controlling for confounders, in the whole group, male gender (aOR = 4.07, 95% CI:2.70-6.14, p < 0.001), depression (aOR = 1.05, 95% CI:1.00-1.10, p = 0.034) and age (aOR = 1.03, 95% CI:1.00-1.05, p = 0.018) were positively associated with overweight. In males, depression (aOR = 1.14, 95% CI:1.05-1.25, p = 0.002), administration position (aOR = 4.36, 95% CI:1.69-11.24, p = 0.002), and night shifts/month (aOR = 1.26, 95% CI:1.06-1.49, p = 0.008) were positively associated with overweight, while anxiety (aOR = 0.90, 95% CI:0.82-0.98, p = 0.020) was negatively associated with overweight. In females, only age (aOR = 1.04, 95% CI:1.01-1.07, p = 0.014) was significantly associated with overweight status, while depression and anxiety were not associated with overweight. Stress symptoms were not associated with overweight in either gender. One-fourth of endocrinologists in China are overweight, with a rate in males nearly triple the one in females. Depression and anxiety are significantly associated with overweight in males but not females. This suggests possible differences in the mechanism. Our findings also highlight the need to screen depression and overweight in male physicians and the importance of developing gender-specific interventions.


Effects of fructose restriction on liver steatosis (FRUITLESS); a double-blind randomized controlled trial.
There is an ongoing debate on whether fructose plays a role in the development of nonalcoholic fatty liver disease. The aim of this study was to investigate the effects of fructose restriction on intrahepatic lipid (IHL) content in a double-blind randomized controlled trial using an isocaloric comparator. Between March 2017 and October 2019, 44 adult overweight individuals with a fatty liver index ≥ 60 consumed a 6-wk fructose-restricted diet (<7.5 g/meal and <10 g/d) and were randomly assigned to supplementation with sachets of glucose (= intervention group) or fructose (= control group) 3 times daily. Participants and assessors were blinded to the allocation. IHL content, assessed by proton magnetic resonance spectroscopy, was the primary outcome and glucose tolerance and serum lipids were the secondary outcomes. All measurements were conducted in Maastricht University Medical Center. Thirty-seven participants completed the study protocol. After 6 wk of fructose restriction, dietary fructose intake and urinary fructose excretion were significantly lower in the intervention group (difference: -57.0 g/d; 95% CI: -77.9, -39.5 g/d; and -38.8 μmol/d; 95% CI: -91.2, -10.7 μmol/d, respectively). Although IHL content decreased in both the intervention and control groups (P < 0.001 and P = 0.003, respectively), the change in IHL content was more pronounced in the intervention group (difference: -0.7% point, 95% CI: -2.0, -0.03% point). The changes in glucose tolerance and serum lipids were not significantly different between groups. Six weeks of fructose restriction per se led to a small, but statistically significant, decrease in IHL content in comparison with an isocaloric control group.This trial was registered at clinicaltrials.gov as NCT03067428.


Bioaccumulation and enantiomeric profiling of organochlorine pesticides and persistent organic pollutants in the killer whale (Orcinus orca) from British and Irish waters.
Concentrations and enantiomeric profiles for a range of organochlorine compounds are reported in blubber samples from a number of individual killer whales (Orcinus orca) from British and Irish waters. Elevated contaminant levels and enriched isotopic ratios were determined in one individual whale sampled in the Scottish Western Isles compared to the others suggesting marine mammal based dietary influences. The potential application of isotopic ratios to model contaminant uptake, enantioselective enrichment and accumulation is demonstrated. Data are presented which provide information on enantioselective enrichment factors (EFs) for o,p'-DDT, alpha-HCH and toxaphene congeners CHB26 and CHB 50. This dataset further improves the current database on reported levels of a number of contaminants and provides additional background information on potential metabolic processes in killer whales from British and Irish waters.


The kidney, COVID-19, and the chemokine network: an intriguing trio.
On December 30th 2019, some patients with pneumonia of unknown etiology were reported in the Program for Monitoring Emerging Diseases (ProMED), a program run by the International Society for Infectious Diseases (ISID), hypothesized to be related to subjects who had had contact with the seafood market in Wuhan, China. Chinese authorities instituted an emergency agency aimed at identifying the source of infection and potential biological pathogens. It was subsequently named by the World Committee on Virus Classification as 2019-nCoV (2019-novel coronavirus) or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A number of studies have demonstrated that 2019-nCoV and the SARS-CoV shared the same cell entry receptor named angiotensin-converting enzyme 2 (ACE2). This is expressed in human tissues, not only in the respiratory epithelia, but also in the small intestines, heart, liver, and kidneys. Here, we examine the most recent findings on the effects of SARS-CoV-2 infection on kidney diseases, mainly acute kidney injury, and the potential role of the chemokine network.


Tolerance of the Brachial Plexus to High-Dose Reirradiation.
To study the tolerance of the brachial plexus to high doses of radiation exceeding historically accepted limits by analyzing human subjects treated with reirradiation for recurrent tumors of the head and neck. Data from 43 patients who were confirmed to have received overlapping dose to the brachial plexus after review of radiation treatment plans from the initial and reirradiation courses were used to model the tolerance of this normal tissue structure. A standardized instrument for symptoms of neuropathy believed to be related to brachial plexus injury was utilized to screen for toxicity. Cumulative dose was calculated by fusing the initial dose distributions onto the reirradiation plan, thereby creating a composite plan via deformable image registration. The median elapsed time from the initial course of radiation therapy to reirradiation was 24 months (range, 3-144 months). The dominant complaints among patients with symptoms were ipsilateral pain (54%), numbness/tingling (31%), and motor weakness and/or difficulty with manual dexterity (15%). The cumulative maximum dose (Dmax) received by the brachial plexus ranged from 60.5 Gy to 150.1 Gy (median, 95.0 Gy). The cumulative mean (Dmean) dose ranged from 20.2 Gy to 111.5 Gy (median, 63.8 Gy). The 1-year freedom from brachial plexus-related neuropathy was 67% and 86% for subjects with a cumulative Dmax greater than and less than 95.0 Gy, respectively (P=.05). The 1-year complication-free rate was 66% and 87%, for those reirradiated within and after 2 years from the initial course, respectively (P=.06). The development of brachial plexus-related symptoms was less than expected owing to repair kinetics and to the relatively short survival of the subject population. Time-dose factors were demonstrated to be predictive of complications.


Changes in quantitative ultrasound in preterm and term infants during the first year of life.
Since most of in utero bone mass accretion occurs during the third trimester and postnatal need for bone nutrients is increased, preterm infants have an increased risk of low bone mass. Early identification of the risk is of crucial importance. Quantitative ultrasound, which is a relatively inexpensive, portable, noninvasive, and radiation-free method, gives information about bone density, cortical thickness, elasticity and microarchitecture. The aim of this study was to obtain quantitative ultrasound measurements of tibial speed of sound of preterm and term infants and to assess clinical factors associated with these measurements during the first year of life. Seventy-eight preterm and 48 term infants were enrolled in this study. Measurements were made on the 10th day of life in both groups, and were repeated on the 2nd, 6th and 12th months for preterm infants and on the 12th month for the term infants. Speed of sound on preterm infants was significantly decreased on the 2nd month but significantly increased on the 12th month (P=0.00). Comparing speed of sound of term and preterm infants, 10th day measurements were significantly different (P=0.00), but there was not any significant difference between the 12th month values (P=0.26). There was not any relation between biochemical parameters and speed of sound. The technique has potential clinical value for assessment of bone status. Further studies with long term follow up are needed to evaluate the value of quantitative ultrasound with other bone markers to predict the risk of fracture.


Meiotic homologue alignment and its quality surveillance are controlled by mouse HORMAD1.
Meiotic crossover formation between homologous chromosomes (homologues) entails DNA double-strand break (DSB) formation, homology search using DSB ends, and synaptonemal-complex formation coupled with DSB repair. Meiotic progression must be prevented until DSB repair and homologue alignment are completed, to avoid the formation of aneuploid gametes. Here we show that mouse HORMAD1 ensures that sufficient numbers of processed DSBs are available for successful homology search. HORMAD1 is needed for normal synaptonemal-complex formation and for the efficient recruitment of ATR checkpoint kinase activity to unsynapsed chromatin. The latter phenomenon was proposed to be important in meiotic prophase checkpoints in both sexes. Consistent with this hypothesis, HORMAD1 is essential for the elimination of synaptonemal-complex-defective oocytes. Synaptonemal-complex formation results in HORMAD1 depletion from chromosome axes. Thus, we propose that the synaptonemal complex and HORMAD1 are key components of a negative feedback loop that coordinates meiotic progression with homologue alignment: HORMAD1 promotes homologue alignment and synaptonemal-complex formation, and synaptonemal complexes downregulate HORMAD1 function, thereby permitting progression past meiotic prophase checkpoints.


Corrigendum: Prevalence and clinical characteristics associated with peripheral neuropathy amongst persons on HAART in Busia County, Kenya.
[This corrects the article DOI: 10.4102/sajp.v76i1.1430.].


Childhood experiences of threat and deprivation predict distinct depressive symptoms: A parallel latent growth curve model.
There is growing awareness that specific childhood trauma (CT) may confer to the unique risk of depression, but little is known about this. The present study seeks to provide insight into how CT subtypes may impact distinct depressive symptoms over time based on the dimensional model of adversity (DMA). A total of 3535 college freshmen participated in a 2-year, four waves longitudinal tracking study. A conditional parallel latent growth curve model (LGCM) was constructed to examine the impacts of different types of CT (threat and deprivation) on the development of depressed mood and anhedonia, and whether these relationships vary across gender. Our findings revealed that threat and deprivation could differentially relate to depressed mood and anhedonia. Both threat and deprivation predicted initial depressed mood levels (β = 0.309, p < 0.001; β = 0.175, p < 0.001, respectively) and its trajectory (β = -0.139, p = 0.068; β = -0.168, p < 0.05, respectively). Only deprivation predicted anhedonia levels (β = 0.318, p < 0.001) and trajectory (β = -0.218, p < 0.001). This pattern of relationships between CT and depressive symptoms varied across gender. These findings highlight specific pathways and symptomatic manifestations of the impacts of different CT subtypes on depression and are consistent with the hypothesis of DMA. Threat and deprivation predicted more severe depressed mood, whereas deprivation uniquely conferred to the risk of depression via elevated anhedonia. Meanwhile, the deleterious effects of CT would persist during early adulthood. Gender differences were also discussed.


Molecular dynamics simulations as a complement to nuclear magnetic resonance and X-ray diffraction measurements.
Advances in the field of atomic-level membrane simulations are being driven by continued growth in computing power, improvements in the available potential energy functions for lipids, and new algorithms that implement advanced sampling techniques. These developments are allowing simulations to assess time- and length scales wherein meaningful comparisons with experimental measurements on macroscopic systems can be made. Such comparisons provide stringent tests of the simulation methodologies and force fields, and thus, advance the simulation field by pointing out shortcomings of the models. Extensive testing against available experimental data suggests that for many properties modern simulations have achieved a level of accuracy that provides substantial predictive power and can aid in the interpretation of experimental data. This combination of closely coupled laboratory experiments and molecular dynamics simulations holds great promise for the understanding of membrane systems. In the following, the molecular dynamics method is described with particular attention to those aspects critical for simulating membrane systems and to the calculation of experimental observables from the simulation trajectory.


Determining the ability of xenobiotic metals to bind a specific protein domain by electrophoresis.
Environmental metals are potentially toxic and can interfere with the metal-binding motifs of various critical proteins. This unit describes an electrophoretic method that can be used to measure the ability of a xenobiotic metal to bind a zinc-finger motif. Information gained using this protocol can lead to the identification of protein targets of metals and shed better light on their mechanisms of action.


Proposed new clinicopathological surrogate definitions of luminal A and luminal B (HER2-negative) intrinsic breast cancer subtypes.
The St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2013 recognized substantial progress in the pathological characterization of breast cancer subtypes. A useful surrogate definition was developed to distinguish luminal A-like breast cancer from luminal B-like disease based on a combination of estrogen receptor (ER), progesterone receptor (PgR) and Ki-67 status, without a requirement for molecular diagnostics. Differences depend upon the choice of the threshold value for Ki-67 and the requirement for substantial PgR positivity. We aimed to verify the suitability of the new surrogate definitions of luminal subtypes in terms of distant disease control in a large series of patients. We studied 9,415 women with a median follow-up of 8.1 years who (1) had ER-positive, human epidermal growth factor receptor 2 (HER2)-negative early breast cancer and (2) had undergone surgery at the European Institute of Oncology between 1994 and 2006. We evaluated distant disease-free survival of patients with "low" (<14%), "intermediate" (14% to 19%) or "high" (≥20%) Ki-67 positivity stratified by PgR expression (negative or low versus high). We calculated the cumulative incidence of distant events, considered competing events and performed multivariable analysis adjusted for pathologic tumor stage, pathologic node stage, tumor grade, peritumoral vascular invasion and menopausal status. Lack of substantial PgR positivity was associated with poorer outcomes only for patients with an intermediate Ki-67 level (P<0.001). The 4,890 patients (51.9%) with low Ki-67 level (any PgR expression level) or with intermediate Ki-67 level but substantial PgR positivity had comparably good outcomes and thus may represent a most advantageous grouping of those with luminal A-like disease. The updated pathological definition of intrinsic molecular subtypes may maximize the number of patients classified as having the luminal A-like intrinsic subtype of breast cancer and for whom the use of cytotoxic drugs could mostly be avoided.


Comparative study of dezocine, pentazocine and tapentadol on antinociception and physical dependence.
Dezocine and pentazocine, widely prescribed in China for postoperative pain, were initially considered as mixed agonist/antagonist targeting μ-opioid receptors (MORs) and κ-opioid receptors (KORs). However, dezocine has been revealed to alleviate chronic neuropathic pain through MOR activation and norepinephrine reuptake inhibition (NRI). This study investigated dezocine- and pentazocine-induced antinociception and physical dependence development, compared to the typical MOR-NRI opioid tapentadol. Calcium mobilization assay was conducted to assess the potency of the drugs while hot-plate test was performed to compare the antinociception. Physical dependence development was compared with morphine. Treatment with dezocine, pentazocine and tapentadol stimulated calcium mobilization in HEK293 cells stably expressed MORs but not KORs, whereas dezocine and pentazocine inhibited KOR activities. Subcutaneously injected dezocine-, tapentadol- and pentazocine-induced antinociception dose-dependently, in hot-plate test. Intrathecally injected MOR antagonist CTAP, norepinephrine depletor 6-OHDA and α2-adrenoceptor (α2-AR) antagonist yohimbine partially antagonized dezocine, pentazocine and tapentadol antinociception. Whereas specific KOR antagonist GNTI did not alter their antinociception, the putative inverse KOR agonist nor-BNI reduced dezocine and pentazocine antinociception. Moreover, combined CTAP and 6-OHDA or yohimbine blocked dezocine and tapentadol antinociception but displayed the same partial inhibition on pentazocine antinociception as CTAP alone. Furthermore, compared to morphine and pentazocine, long-term treatment with dezocine and tapentadol produced much less physical dependence-related withdrawal signs, which were restored by spinal 6-OHDA or yohimbine treatment. Our findings illustrated that dezocine and tapentadol, but not pentazocine, exert remarkable antinociception in nociceptive pain with less abuse liability via dual mechanisms of MOR activation and NRI.


Using Liminality and Subjunctivity to Better Understand How Patients With Cancer Experience Uncertainty Throughout Their Illness Trajectory.
Uncertainty is a central theme in the illness experiences of older cancer patients throughout their illness trajectory. Mishel's popular theory on uncertainty during illness approaches uncertainty as an outcome and is characterized by the patient's inability to find meaning in illness events. This study used the concepts of liminality and subjunctivity to explore uncertainty throughout the illness trajectory of cancer patients. We interviewed 18 older (age range = 57-92 years) patients with breast cancer or gastro-intestinal cancer 3 to 4 years post diagnosis. Our analysis is based on the QUAGOL guide that draws on elements of grounded theory such as constant comparison. We found that liminality and subjunctivity provide a useful frame for understanding uncertainty with a specific focus on its productive potential and meaning making. Health care professionals should be open to acquiring a complete picture of patients' diverse and dynamic experiences of uncertainty in the different stages of their illness trajectory.


Timing of HIV testing among pregnant and breastfeeding women and risk of mother-to-child HIV transmission in Malawi: a sampling-based cohort study.
Pregnant women living with HIV can achieve viral suppression and prevent HIV mother-to-child transmission (MTCT) with timely HIV testing and early ART initiation and maintenance. Although it is recommended that pregnant women undergo HIV testing early in antenatal care in Malawi, many women test positive during breastfeeding because they did not have their HIV status ascertained during pregnancy, or they tested negative during pregnancy but seroconverted postpartum. We sought to estimate the association between the timing of last positive HIV test (during pregnancy vs. breastfeeding) and outcomes of maternal viral suppression and MTCT in Malawi's PMTCT programme. We conducted a two-stage cohort study among mother-infant pairs in 30 randomly selected high-volume health facilities across five nationally representative districts of Malawi between 1 July 2016 and 30 June 2017. Log-binomial regression was used to estimate prevalence ratios (PR) and risk ratios (RR) for associations between timing of last positive HIV test (i.e. breastfeeding vs. pregnancy) and maternal viral suppression and MTCT, controlling for confounding using inverse probability weighting. Of 822 mother-infant pairs who had available information on the timing of the last positive HIV test, 102 mothers (12.4%) had their last positive test during breastfeeding. Women who lived one to two hours (PR = 2.15; 95% CI: 1.29 to 3.58) or >2 hours (PR = 2.36; 95% CI: 1.37 to 4.10) travel time to the nearest health facility were more likely to have had their last positive HIV test during breastfeeding compared to women living <1 hour travel time to the nearest health facility. The risk of unsuppressed VL did not differ between women who had their last positive HIV test during breastfeeding versus pregnancy (adjusted RR [aRR] = 0.87; 95% CI: 0.48 to 1.57). MTCT risk was higher among women who had their last positive HIV test during breastfeeding compared to women who had it during pregnancy (aRR = 6.57; 95% CI: 3.37 to 12.81). MTCT in Malawi occurred disproportionately among women with a last positive HIV test during breastfeeding. Testing delayed until the postpartum period may lead to higher MTCT. To optimize maternal and child health outcomes, PMTCT programmes should focus on early ART initiation and providing targeted testing, prevention, treatment and support to breastfeeding women.


Sodium/Glucose Cotransporter 2 Inhibitors and the Risk of Diabetic Ketoacidosis: An Example of Complementary Evidence for Rare Adverse Events.
Evidence from observational studies may be considered complementary to that of randomized controlled trials (RCTs), particularly when assessing rare outcomes of drug therapies. Sodium/glucose cotransporter 2 (SGLT-2) inhibitors are a novel class of antidiabetic agents that have been linked to an increased risk of diabetic ketoacidosis (DKA). We conducted a systematic review and separately meta-analyzed data from RCTs (n = 18; 2013-2019) and cohort studies (n = 7; 2017-2020) to assess the consistency of the magnitude of association between SGLT-2 inhibitors and DKA risk. We illustrate the strengths and weaknesses of the 2 designs. Results from RCTs and observational studies consistently showed almost a doubling in the risk of DKA among patients using an SGLT-2 inhibitor as compared with placebo or an active comparator. In a random-effects model, the pooled relative risk was 2.08 (95% confidence interval (CI): 1.28, 3.40) from placebo-controlled RCTs and 0.82 (95% CI: 0.25, 2.68) from active-comparator RCTs. The pooled adjusted hazard ratio from observational studies was 1.74 (95% CI: 1.28, 2.38). Notably, the 2 designs complement each other in several domains, including external and internal validity and power. This demonstrates a need for more comprehensive evidence when assessing rare adverse events for both sources.


Emission characteristics of benzene series in FCC flue gas.
Benzene series are considered as air pollutants in refineries. However, the emissions of benzene series in fluid catalytic cracking (FCC) flue gas are poorly understand. In this work, we conduct stack tests on three typical FCC units. Benzene series, including benzene, toluene, xylene and ethyl benzene, are monitored in the flue gas. It shows that the coking degree of the spent catalysts affect the emissions of benzene series significantly, and there are four kinds of carbon-containing precursors in the spent catalyst. A fixed-bed reactor is used to conduct the regeneration simulation experiments, and the flue gas is monitored by TG-MS and FTIR. The emissions of toluene and ethyl benzene are mainly emitted in the early and middle stage of the reaction (250-650 °C), while the emission of benzene is mainly detected in the middle and late stage of the reaction (450-750 °C). Xylene group is not detected in the stack tests and regeneration experiments. Higher emissions of benzene series are released from the spent catalyst with lower C/H ratio during regeneration process. With the increase of oxygen content, the emissions of benzene series decrease, and the initial emission temperature is advanced. These insights can improve the refinery's awareness and control of benzene series in the future.


HIV reservoir quantification by five-target multiplex droplet digital PCR.
Most latent human immunodeficiency virus (HIV) proviruses are defective and cannot produce infectious virions. Thus, the number of HIV proviruses with intact genomes is a relevant clinical parameter to assess therapies for HIV cure. We describe high-molecular-weight DNA isolation, followed by restriction enzyme fragmentation that limits cutting within the HIV genome. Multiplexed droplet digital PCR quantifies five targets spanning the HIV genome to estimate potentially intact proviral copies. A reference assay counts the number of T lymphocytes and assesses the level of DNA shearing. For complete details on the use and execution of this protocol, please refer to Levy et al. (2021).


Non-aneurysmal ascending aorta diameter changes after aortic valve replacement in patients with stenotic bicuspid and tricuspid aortic valve.
The appropriate timing of aortic repair in patients with bicuspid aortic valve-related aortopathy remains controversial. We describe the changes in diameter of the non-aneurysmal ascending aorta after aortic valve replacement for bicuspid or tricuspid aortic valve stenosis. This retrospective review included 189 patients who had undergone aortic valve replacement for severe stenotic aortic valve with a non-aneurysmal ascending aorta diameter of 45 mm or less between January 2008 and December 2018. A linear mixed-effect model was used to analyze and compare the enlargement rates of the non-aneurysmal ascending aorta at the tubular portion after aortic valve replacement in bicuspid and tricuspid aortic valve patients. The enlargement rate of the non-aneurysmal ascending aorta after aortic valve replacement was significantly greater in the bicuspid aortic valve group than in the tricuspid aortic valve group (0.36 mm/year vs. 0.09 mm/year, p < 0.001). The specific form of bicuspid aortic valve also affected aorta diameter enlargement: the enlargement rate of 0.85 mm/year in the Type 0 (according to Sievers' classification) group was approximately five times that in the Non-Type 0 group (p < 0.001). No aortic events were observed, and no patients needed reoperations for the ascending aorta, in either the bicuspid or tricuspid aortic valve groups. The persistent possibility of progressive ascending aortic dilatation after aortic valve replacement for bicuspid aortic valve stenosis, especially in Type 0 bicuspid aortic valve patients, demands careful post-procedural evaluation of the ascending aorta.


Rapid purification of human high molecular weight kininogen.
Human high molecular weight kininogen was isolated by a rapid procedure, using anion exchange chromatography on QAE-Sephadex, ammonium sulfate precipitation and cation exchange chromatography on CM-Sephadex. The poor recovery and relatively low specific activity observed in earlier experiments was found to be due to a contaminant, presumably enzymatic, capable of releasing kinin from the kininogen. The "spontaneous" kinin release was blocked by soy bean trypsin inhibitor and by C1-inactivator. The isolated kininogen was stable at different temperatures, did not contain free kinin and was a good substrate for plasma kallikrein and plasmin.


[Effects of an extract of the bark of Pygeum africanum (V.1326) on prostatic secretions in the rat and in man].
Treatment with V.1326 in the rat induces an increase in prostatic secretion. In men with insufficient prostatic secretion, this treatment also induces an increased secretion.