Can Colonoscopy Aspirates be a Substitute for Fecal Samples in Analyses of the Intestinal Microbiota?
There is a growing interest in the study of the human gut microbiota, as correlations between changes in bacterial profiles and diseases are increasingly discovered. Studies in this field generally use fecal samples, but it is often easier to obtain colon content aspirates during colonoscopy. This study used automated ribosomal internal spacer analysis (ARISA) to examine the extent to which the microbiota of colon aspirate samples obtained after bowel cleansing can reflect interindividual differences and serve as a proxy for fecal samples. Pre-bowel preparation fecal samples as well as colonoscopy aspirate samples from the cecum and rectum were obtained from 19 subjects. DNA was extracted from all samples, and comparative analysis was performed, including analysis of similarity (ANOSIM) and nonmetric multidimensional scaling. ANOSIM confirmed that samples from the same individual were well separated from samples from different individuals. Significantly larger differences were found between samples from different individuals than between samples of the same individual (R = 0.7605, p < 0.0001). These findings show that post-bowel preparation aspirates maintain a strong individual signature. Colonoscopy aspirates can therefore serve as a substitute for fecal samples in studies comparing the microbiota of different clinical study groups, especially when fecal samples are unavailable.


A critical view of the use of predictive energy equations for the identification of hypermetabolism in motor neuron disease: A pilot study.
People living with motor neuron disease (MND) frequently struggle to consume an optimal caloric intake. Often compounded by hypermetabolism, this can lead to dysregulated energy homeostasis, prompting the onset of malnutrition and associated weight loss. This is associated with a poorer prognosis and reduced survival. It is therefore important to establish appropriate nutritional goals to ensure adequate energy intake. This is best done by measuring resting energy expenditure (mREE) using indirect calorimetry. However, indirect calorimetry is not widely available in clinical practice, thus dietitians caring for people living with MND frequently use energy equations to predict resting energy expenditure (pREE) and estimate caloric requirements. Energy prediction equations have previously been shown to underestimate resting energy expenditure in over two-thirds of people living with MND. Hypermetabolism has previously been identified using the metabolic index. The metabolic index is a ratio of mREE to pREE, whereby an increase of mREE by ≥110% indicates hypermetabolism. We aim to critically reflect on the use of the Harris-Benedict (1919) and Henry (2005) energy prediction equations to inform a metabolic index to indicate hypermetabolism in people living with MND. mREE was derived using VO₂ and VCO₂ measurements from a GEMNutrition indirect calorimeter. pREE was estimated by Harris-Benedict (HB) (1919), Henry (2005) and kcal/kg/day predictive energy equations. The REE variation, described as the percentage difference between mREE and pREE, determined the accuracy of pREE ([pREE-mREE]/mREE) x 100), with accuracy defined as ≤ ± 10%. A metabolic index threshold of ≥110% was used to classify hypermetabolism. All resting energy expenditure data are presented as kcal/24hr. Sixteen people living with MND were included in the analysis. The mean mREE was 1642 kcal/24hr ranging between 1110 and 2015 kcal/24hr. When REE variation was analysed for the entire cohort, the HB, Henry and kcal/kg/day equations all overestimated REE, but remained within the accuracy threshold (mean values were 2.81% for HB, 4.51% for Henry and 8.00% for kcal/kg/day). Conversely, inter-individual REE variation within the cohort revealed HB and Henry equations both inaccurately reflected mREE for 68.7% of participants, with kcal/kg/day inaccurately reflecting 41.7% of participants. Whilst the overall cohort was not classified as hypermetabolic (mean values were 101.04% for HB, 98.62% for Henry and 95.64% for kcal/kg/day), the metabolic index ranges within the cohort were 70.75%-141.58% for HB, 72.82%-127.69% for Henry and 66.09%-131.58% for kcal/kg/day, indicating both over- and under-estimation of REE by these equations. We have shown that pREE correlates with body weight (kg), whereby the lighter the individual, the greater the underprediction of REE. When applied to the metabolic index, this underprediction biases towards the classification of hypermetabolism in lighter individuals. Whilst predicting resting energy expenditure using the HB, Henry or kcal/kg/day equations accurately reflects derived mREE at group level, these equations are not suitable for informing resting energy expenditure and classification of hypermetabolism when applied to individuals in clinical practice.


Human conjunctivitis. I. Diagnostic evaluation.
One hundred forty-three patients (207 eyes) with conjunctivitis or blepharoconjunctivitis were studied. Attempts were made to establish an etiologic diagnosis by clinical and laboratory methods. The etiologic diagnosis that was made on the basis of the initial clinical examination correlated poorly with the results of standard laboratory tests. Conversely, the standard laboratory evaluation failed to establish a definitive diagnosis in the majority of cases. These findings suggest that the diagnostic dogmatism prevalent in conjunctivitis is unwarranted. Morphologic signs and routine laboratory tests leave us without a verified etiologic diagnosis in a substantial number of cases.¿


Initial assessment of chest X-ray in thoracic trauma patients: Awareness of specific injuries.
To compare the reported injuries on initial assessment of the chest X-ray (CXR) in thoracic trauma patients to a second read performed by a dedicated trauma radiologist. By retrospective analysis of a prospective database, 712 patients with an injury to the chest admitted to the University Medical Center Utrecht were studied. All patients with a CXR were included in the study. Every CXR was re-evaluated by a trauma radiologist, who was blinded for the initial results. The findings of the trauma radiologist regarding rib fractures, pneumothoraces, hemothoraces and lung contusions were compared with the initial reports from the trauma team, derived from the original patient files. A total of 516 patients with both thorax trauma and an initial CXR were included in the study. After re-evaluation of the initial CXR significantly more lung contusions (53.3% vs 34.1%, P < 0.001), hemothoraces (17.8% vs 11.0%, P < 0.001) and pneumothoraces (34.4% vs 26.4%, P < 0.001) were detected. During initial assessment significantly more rib fractures were reported (69.8% vs 62.3%, P < 0.001). During the initial assessment of a CXR from trauma patients in the emergency department, a significant number of treatment-dictating injuries are missed. More awareness for these specific injuries is needed.


Effects of SARS-CoV-2 Alpha, Beta, and Delta variants, age, vaccination, and prior infection on infectiousness of SARS-CoV-2 infections.
In 2021, Qatar experienced considerable incidence of SARS-CoV-2 infection that was dominated sequentially by the Alpha, Beta, and Delta variants. Using the cycle threshold (Ct) value of an RT-qPCR-positive test to proxy the inverse of infectiousness, we investigated infectiousness of SARS-CoV-2 infections by variant, age, sex, vaccination status, prior infection status, and reason for testing in a random sample of 18,355 RT-qPCR-genotyped infections. Regression analyses were conducted to estimate associations with the Ct value of RT-qPCR-positive tests. Compared to Beta infections, Alpha and Delta infections demonstrated 2.56 higher Ct cycles (95% CI: 2.35-2.78), and 4.92 fewer cycles (95% CI: 4.67- 5.16), respectively. The Ct value declined gradually with age and was especially high for children <10 years of age, signifying lower infectiousness in small children. Children <10 years of age had 2.18 higher Ct cycles (95% CI: 1.88-2.48) than those 10-19 years of age. Compared to unvaccinated individuals, the Ct value was higher among individuals who had received one or two vaccine doses, but the Ct value decreased gradually with time since the second-dose vaccination. Ct value was 2.07 cycles higher (95% CI: 1.42-2.72) for those with a prior infection than those without prior infection. The Ct value was lowest among individuals tested because of symptoms and was highest among individuals tested as a travel requirement. Delta was substantially more infectious than Beta. Prior immunity, whether due to vaccination or prior infection, is associated with lower infectiousness of breakthrough infections, but infectiousness increases gradually with time since the second-dose vaccination.


Helicobacter pylori culture supernatant interferes with epidermal growth factor-activated signal transduction in human gastric KATO III cells.
The mechanisms by which Helicobacter pylori infection leads to gastroduodenal ulceration remain poorly understood. Previous studies have shown that H. pylori vacuolating cytotoxin (VacA) inhibits proliferation of gastric epithelial cells, which suggests that H pylori may interfere with gastric mucosal repair mechanisms. In this study, we investigated the effects of H. pylori broth culture supernatants on epidermal growth factor (EGF)-mediated signal transduction pathways in a gastric carcinoma cell line (KATO III). Exposure of these cells to EGF resulted in increased expression and phosphorylation of the EGF receptor (EGF-R), increased ERK2 activity and phosphorylation, and increased c-fos protein levels. Preincubation of cells with broth culture supernatant from VacA (+) H. pylori strain 60190 inhibited the capacity of EGF to induce each of these effects. In contrast, preincubation of cells with broth culture supernatant from an isogenic VacA-mutant strain (H. pylori 60190-v1) failed to inhibit the effects of EGF. These results suggest that the H. pylori vacuolating cytotoxin interferes with EGF-activated signal transduction pathways, which are known to be essential for cell proliferation and ulcer healing.


A Computational Approach to Evaluate the Combined Effect of SARS-CoV-2 RBD Mutations and ACE2 Receptor Genetic Variants on Infectivity: The COVID-19 Host-Pathogen Nexus.
SARS-CoV-2 infectivity is largely determined by the virus Spike protein binding to the ACE2 receptor. Meanwhile, marked infection rate differences were reported between populations and individuals. To understand the disease dynamic, we developed a computational approach to study the implications of both SARS-CoV-2 RBD mutations and ACE2 polymorphism on the stability of the virus-receptor complex. We used the 6LZG PDB RBD/ACE2 3D model, the mCSM platform, the LigPlot+ and PyMol software to analyze the data on SARS-CoV-2 mutations and ACE variants retrieved from GISAID and Ensembl/GnomAD repository. We observed that out of 351 RBD point mutations, 83% destabilizes the complex according to free energy (ΔΔG) differences. We also spotted variations in the patterns of polar and hydrophobic interactions between the mutations occurring in 15 out of 18 contact residues. Similarly, comparison of the effect on the complex stability of different ACE2 variants showed that the pattern of molecular interactions and the complex stability varies also according to ACE2 polymorphism. We infer that it is important to consider both ACE2 variants and circulating SARS-CoV-2 RBD mutations to assess the stability of the virus-receptor association and evaluate infectivity. This approach might offers a good molecular ground to mitigate the virus spreading.


Neonatal pertussis, cocooning and maternal immunization.
The rising incidence of whooping cough, a highly contagious infection caused by Bordetella pertussis, is particularly significant for young infants who have the highest risk for morbidity and mortality. The pertussis resurgence has led to a shift in primary prevention relying on childhood vaccination to a cocooning strategy, that is, vaccination of close contacts of newborn infants (new mothers, fathers, grandparents, siblings, caretakers, etc.), thereby reducing pertussis exposure. Immunization of women during pregnancy rather than during the immediate postpartum period (the initial cocooning recommendation) appears to be a better approach by directly providing protection through transplacental transfer of maternal vaccine-induced antibodies. This article describes neonatal pertussis, cocooning as a means of reducing neonatal exposure to pertussis and maternal immunization as a means of protecting young infants against pertussis infection.


The effects of COVID-19 vaccines on economic activity.
This paper empirically examines the economic effects of COVID-19 vaccine rollouts using a cross-country daily database of vaccinations and high-frequency indicators of economic activity-nitrogen dioxide (NO2) emissions, carbon monoxide (CO) emissions, and Google mobility indices-for a sample of 46 countries over the period December 16, 2020 to June 20, 2021. Using surprises in vaccines administered, we find that an unexpected increase in vaccination per capita is associated with a significant increase in economic activity. We also find evidence for nonlinear effects of vaccines, with the marginal economic benefits being larger when vaccination rates are higher. Country-specific conditions play an important role, with lower economic gains if strict containment measures are in place or if the country is experiencing a severe outbreak. Finally, the results provide evidence of spillovers across borders, highlighting the importance of equitable access to vaccines across nations.


[Hospital morbidity of elderly population in Andalusia (Spain)].
In recent years we have seen in Spain a significant increase in the number of old people. The aim of this work was to determine hospital morbidity among the elderly. We studied the morbidity among patients older than 65 years admitted at the hospitals of our Andalusian public health system that belongs to the Spanish National Health System. We analysed the minimal basic data set at discharge (MBDSD) over a period from January 1998 to December 1999, both inclusive. In the 32 hospitals studied, a total of 25,255 hospital discharges of patients older than 65 years were recorded. This means an annual hospitalization rate in this age group of 15.2% (95 % CI: 15.1-15.3). The most frequent causes of hospitalisation are: diseases of the circulatory system (20.7%), diseases of the respiratory system (14.0%), diseases of the digestive system (11.6%). The old population of Andalusia (Spain) has a high rate of hospital morbidity, specially for people older than 75 years, and significant variations are seen between the different provinces of the Andalusian Region. Their hospitalization is due mainly to chronic diseases of developed countries.


Toll-like receptor 4-myeloid differentiation factor 88 signaling contributes to ventilator-induced lung injury in mice.
The mechanisms of ventilator-induced lung injury, an iatrogenic inflammatory condition induced by mechanical ventilation, are not completely understood. Toll-like receptor 4 (TLR4) signaling via the adaptor protein myeloid differentiation factor 88 (MyD88) is proinflammatory and plays a critical role in host immune response to invading pathogen and noninfectious tissue injury. The role of TLR4-MyD88 signaling in ventilator-induced lung injury remains incompletely understood. Mice were ventilated with low or high tidal volume (HTV), 7 or 20 ml/kg, after tracheotomy for 4 h. Control mice were tracheotomized without ventilation. Lung injury was assessed by: alveolar capillary permeability to Evans blue albumin, wet/dry ratio, bronchoalveolar lavage analysis for cell counts, total proteins and cytokines, results of histopathological examination of the lung, and plasma cytokine levels. Wild-type mice subjected to HTV had increased pulmonary permeability, inflammatory cell infiltration/lung edema, and interleukin-6/macrophage-inflammatory protein-2 in the lavage compared with control mice. In HTV, levels of inhibitor of kappaB alpha decreased, whereas phosphorylated extracellular signal-regulated kinases increased. TLR4 mutant and MyD88 mice showed markedly attenuated response to HTV, including less lung inflammation, pulmonary edema, cell number, protein content, and the cytokines in the lavage. Furthermore, compared with wild-type mice, both TLR4 mutant and MyD88 mice had significantly higher levels of inhibitor of kappaB alpha and reduced extracellular signal-regulated kinase phosphorylation after HTV. TLR4-MyD88 signaling plays an important role in the development of ventilator-induced lung injury in mice, possibly through mechanisms involving nuclear factor-kappaB and mitogen-activated protein kinase pathways.


Potential Mechanisms of Failure in the Sudden Infant Death Syndrome.
Current evidence suggests that multiple neural mechanisms contribute to the fatal lethal event in SIDS. The processes may develop from a range of otherwise seemingly-innocuous circumstances, such as unintended external airway obstruction or accidental extreme flexion of the head of an already-compromised structure of the infant upper airway. The fatal event may occur in a sleep state which can suppress muscle tone essential to restore airway patency or exert muscle action to overcome a profound loss of blood pressure. Neural processes that could overcome those transient events with reflexive compensation appear to be impaired in SIDS infants. The evidence ranges from subtle physiological signs that appear very early in life, to autopsy findings of altered neurotransmitter, including serotonergic, systems that have extensive roles in breathing, cardiovascular regulation, and thermal control. Determination of the fundamental basis of SIDS is critical to provide biologic plausibility to SIDS risk reduction messages and to develop specific prevention strategies.


Dose-escalation study of weekly 1-hour paclitaxel administration in patients with refractory cancer.
To evaluate the safety and efficacy of weekly low-dose paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) in patients with refractory cancer, participating subjects received standard prophylactic medication followed by intravenous paclitaxel once a week for 3 weeks every 4 weeks. The 50-mg/m2 starting dose was increased by 10 mg/m2 for every five patients, as long as no dose-limiting toxicity had occurred in more than two of five patients treated at the preceding level. Eligibility criteria included metastatic and refractory malignant disease; an Eastern Cooperative Oncology Group performance status of 0, 1, or 2; and adequate hematologic, hepatic, and renal functions. Of 30 patients treated and evaluable for toxicity, 25 were evaluable for response. The majority of patients tolerated the treatment very well. In a total of 114 cycles, the worst toxicities observed were leukopenia (one grade 4, two grade 3), granulocytopenia (one grade 3, one grade 4), anemia (one grade 3, two grade 2), and infection (one grade 5, one grade 3). Three patients had grade 2 gastrointestinal toxicity and three had grade 1 peripheral neuropathy. Only one dose-limiting toxicity, at 100 mg/m2, has occurred. This patient died of bilateral pneumonia with neutropenia. We have observed partial responses in seven of 12 patients with breast cancer and three of eight with non-small cell lung cancer. The study remains open at the current dose level of 100 mg/m2/wk. Weekly low-dose paclitaxel is well tolerated and efficacious. Further phase II studies are warranted, to continue evaluation of this schedule of paclitaxel either alone or in combination with other drugs active in paclitaxel-responsive diseases.


Use of multicriteria decision analysis to support weight of evidence evaluation.
Weight of evidence (WOE) methods are key components of ecological and human health risk assessments. Most WOE applications rely on the qualitative integration of diverse lines of evidence (LOE) representing impact on ecological receptors and humans. Recent calls for transparency in assessments and justifiability of management decisions are pushing the community to consider quantitative methods for integrated risk assessment and management. This article compares and contrasts the type of information required for application of individual WOE techniques and the outcomes that they provide in ecological risk assessment and proposes a multicriteria decision analysis (MCDA) framework for integrating individual LOE in support of management decisions. The use of quantitative WOE techniques is illustrated for a hypothetical but realistic case study of selecting remedial alternatives at a contaminated aquatic site. Use of formal MCDA does not necessarily eliminate biases and judgment calls necessary for selecting remedial alternatives, but allows for transparent evaluation and fusion of individual LOE. It also provides justifiable methods for selecting remedial alternatives consistent with stakeholder and decision-maker values.


Preferentially localized dynein and perinuclear dynactin associate with nuclear pore complex proteins to mediate genomic union during mammalian fertilization.
Fertilization is complete once the parental genomes unite, and requires the migration of the egg nucleus to the sperm nucleus (female and male pronuclei, respectively) on microtubules within the inseminated egg. Neither the molecular mechanism of pronucleus binding to microtubules nor the role of motor proteins in regulating pronuclear motility has been fully characterized, and the failure of zygotic development in some patients suggests that they contribute to human infertility. Based on the minus-end direction of female pronuclear migration, we propose a role for cytoplasmic dynein and dynactin in associating with the pronuclear envelope and mediating genomic union. Our results show that dynein intermediate and heavy chains preferentially concentrate around the female pronucleus, whereas dynactin subunits p150Glued, p50 and p62 localize to the surfaces of both pronuclei. Transfection of antibodies against dynein and dynactin block female pronuclear migration in zygotes. Both parthenogenetic activation in oocytes and microtubule depolymerization in zygotes significantly reduce the localization of dynein to the female pronucleus but do not inhibit the pronuclear association of dynactin. When immunoprecipitated from zygotes, p150Glued associates with nuclear pore complex proteins, as well as the intermediate filament vimentin and dynein. Antibodies against nucleoporins and vimentin inhibit pronuclear apposition when transfected into zygotes. We conclude that preferentially localized dynein and perinuclear dynactin associate with the nuclear pore complex and vimentin and are required to mediate genomic union. These data suggest a model in which dynein accumulates and binds to the female pronucleus on sperm aster microtubules, where it interacts with dynactin, nucleoporins and vimentin.


Effect of Photobiomodulation in Rescuing Lipopolysaccharide-Induced Dopaminergic Cell Loss in the Male Sprague-Dawley Rat.
Photobiomodulation (PBM) provides neuroprotection against dopaminergic cell death and associated motor deficits in rodent and primate models of Parkinson's disease (PD). However, it has not yet been tested in the lipopolysaccharide (LPS) model of PD, which leads to dopaminergic cell death through microglia-evoked neuroinflammation. We investigated whether transcranial PBM could protect against dopaminergic cell death within the substantia nigra in male Sprague-Dawley rats following supranigral LPS injection. PBM fully protected rats from 10 µg LPS which would have otherwise caused 15% cell loss, but there was no significant neuroprotection at a 20 µg dose that led to a 50% lesion. Cell loss at this dose varied according to the precise site of injection and correlated with increased local numbers of highly inflammatory amoeboid microglia. Twenty microgram LPS caused motor deficits in the cylinder, adjusted stepping and rotarod tests that correlated with dopaminergic cell loss. While PBM caused no significant improvement at the group level, motor performance on all three tests no longer correlated with the lesion size caused by 20 µg LPS in PBM-treated rats, suggesting extranigral motor improvements in some animals. These results provide support for PBM as a successful neuroprotective therapy against the inflammatory component of early PD, provided inflammation has not reached a devastating level, as well as potential benefits in other motor circuitries.


Spatiotemporal mapping of oxygen in a microbially-impacted packed bed using 19F Nuclear magnetic resonance oximetry.
19F magnetic resonance has been used in the medical field for quantifying oxygenation in blood, tissues, and tumors. The 19F NMR oximetry technique exploits the affinity of molecular oxygen for liquid fluorocarbon phases, and the resulting linear dependence of 19F spin-lattice relaxation rate R1 on local oxygen concentration. Bacterial biofilms, aggregates of bacteria encased in a self-secreted matrix of extracellular polymers, are important in environmental, industrial, and clinical settings and oxygen gradients represent a critical determinant of biofilm function. However, measurement of oxygen distribution in biofilms and biofouled porous media is difficult. Here the ability of 19F NMR oximetry to accurately track oxygen profile development in microbial impacted packed bed systems without impacting oxygen transport is demonstrated. Time-stable and inert fluorocarbon containing particles are designed which act as oxygen reporters in porous media systems. Particles are generated by emulsifying and entrapping perfluorooctylbromide (PFOB) into alginate gel, resulting in oxygen-sensing alginate beads that are then used as the solid matrix of the packed bed. 19F oxygenation maps, when combined with 1H velocity maps, allow for insight into the interplay between fluid dynamics and oxygen transport phenomena in these complex biofouled systems. Spatial maps of oxygen consumption rate constants are calculated. The growth characteristics of two bacteria, a non-biofilm forming Escherichia coli and Staphylococcus epidermidis, a strong biofilm-former, are used to demonstrate the novel data provided by the method.


[Optimization of protective properties of interferons in human cells exposed to mutagens estimated by the DNA repair activity].
Protective properties of human interferons against physical and chemical mutagens have been described earlier. This work was aimed at detecting an optimum of protective action of interferons in human fibroblasts using two criteria: the number of single-strand DNA breaks formed and the index of DNA repair synthesis. The protective ability of interferon was shown to be expressed starting after 4 h of cells' pretreatment and proceeding through 40 h in experiments with N-methyl-N-nitro-N-nitrosoquanidin. The phenomenon of stimulation of DNA repair synthesis in human cells pretreated with interferon proceeded even after replating cells during 8 h in the experiments with UV irradiation.


Diagnostic value of contrast-enhanced fluid-attenuated inversion-recovery MRI for intracranial tumors in comparison with post-contrast T1W spin-echo MRI.
Contrast-enhanced fluid-attenuated inversion-recovery (FLAIR) magnetic resonance imaging (MRI) has been reported to have higher sensitivity for detecting leptomeningeal disease compared with contrast-enhanced T1-weighted MRI (CE T1WI). However, currently there are no studies showing the potential value of clinical applications of contrast-enhanced FLAIR (CE FLAIR) sequence in diagnosing intracranial tumors in a larger group of patients. The purpose of this study was to evaluate the diagnostic value of CE FLAIR in comparison with CE T1WI for intracranial tumors and to provide more information for clinical diagnosis and therapy. One hundred and four consecutive cases of intracranial tumors referred for CE brain MRI were analyzed with regard to FLAIR and T1WI pre- and post-administration of Gd-DTPA. The CE FLAIR and CE T1WI were evaluated independently by two radiologists for the number of examinations with one or more enhanced lesions, the number and location of enhanced lesions per examination, signal-to-noise ratio (SNR) and contrast-enhancement ratio (CER) of lesions, as well as the size and extent of the enhanced lesions. In 98 of 104 cases, enhanced lesions were seen both on the FLAIR and T1W images. More lesions were seen on CE T1WI (n = 120) than those on CE FLAIR sequence (n = 117), but no differences of statistical significance were found between the two sequences (P > 0.05). Four lesions were revealed only on the CE FLAIR images whereas 7 lesions were only found on CE T1WI. Enhanced lesions located in the cerebral hemisphere or the forth ventricle were revealed much more on CE T1WI than on CE FLAIR images. However, CE FLAIR images may be useful in showing superficial abnormalities and those located in the sulcus or lateral ventricle. The CER and contrast-to-noise ratio (CNR) on CE T1WI was significantly higher (t = 7.10, P = 0.00; t = 9.67, P = 0.00, respectively), but grey matter/white matter contrast was lower (t = 2.46, P = 0.02) than those on CE FLAIR images. The SNR did not show any statistically significant difference between the two sequences (t = 1.1, P = 0.27). The size and extent of lesions on the CE FLAIR images were significantly larger than those on CE T1WI (t = 4.13, P = 0.00). CE FLAIR and CE T1WI may complement each other in showing intracranial tumors and the CE FLAIR sequence should be selected as a routine MRI sequence.


Glucagon degradation by luminal and basolateral rabbit tubular membranes.
Glucagon is avidly degraded by the kidney, but the relative contribution of the luminal and basolateral tubular membranes to this process is unknown. We studied 125I-glucagon degradation by purified luminal (L) and basolateral (BL) tubular membranes prepared from rabbit kidney cortex, which showed enrichment vs. homogenate of marker enzyme activities (Na-K-ATPase for BL and maltase for L) of 10- and 14-fold, respectively. Renal homogenates and both tubular membrane fractions degraded glucagon avidly without reaching saturation even at pharmacologic concentration (10(-5) M) of the hormone. At physiologic concentration (3 x 10(-11) M) BL membranes degraded substantial amounts of glucagon (8.1 +/- 0.9 pg . micrograms protein-1 . h-1) even though at lesser rates (P less than 0.001) than the luminal fraction (33.3 +/- 1.9 pg . micrograms protein-1 . h-1). Competition experiments suggested that glucagon-degrading activity in both fractions includes both specific and nonspecific components, and the potency of different enzyme inhibitors to decelerate glucagon degradation was strikingly similar in the two membrane preparations. Glucagon degradation differed in several important aspects from the manner in which tubular membranes catabolize insulin, including absolute degradation rates and relative degrading capacity of the membranes vs. homogenates, both being substantially higher for glucagon. These results provide direct evidence that the renal metabolism of glucagon also involves its degradation by peritubular cell membranes.


[Multiple microthromboses with autoimmune hemolytic anemia after BNT162b2 mRNA vaccination].
A 68-year-old man was referred to our hospital with dizziness and mild fever one week after receiving the second dose of the COVID-19 mRNA vaccine (BNT162b2). Laboratory tests showed hemolytic anemia and a positive direct Coombs test, and he was diagnosed with autoimmune hemolytic anemia (AIHA). On admission, the patient had impaired consciousness with auditory hallucinations, and a head MRI scan showed multiple high-signal areas on diffusion-weighted imaging, suggesting multiple recent infarctions. Echocardiography also showed decreased wall motion in the inferior and posterior walls. A skin biopsy to investigate the cause revealed many platelets and fibrin thrombi in the capillaries and small veins, which was considered the cause of the organ damage. After starting prednisolone (1 mg/kg) for AIHA, hemolytic anemia as well as impaired consciousness, and decreased wall motion rapidly improved. Microthrombosis after BNT162b2 mRNA vaccination is rare, and autoimmune abnormalities appeared to contribute to onset in this case.


Solubilization and reconstitution of alpha 2-adrenergic receptors from rat and calf brain.
Sodium cholate and digitonin were used to solubilize alpha2-adrenergic receptors from rat and calf brain. Sodium cholate extracted 40-50% of the membrane protein and 25-30% of the binding capacity. Digitonin extracted only 20-30% of the membrane protein and only 10-15% of the binding capacity of the native membranes. Both detergents were removed by dialysis in the presence of phospholipids, and the solubilized protein was precipitated upon addition of poly(ethyleneglycol) and magnesium. In the solubilization/reconstitution process no purification of the alpha2-adrenergic receptor was obtained, most probably due to its inactivation by the solubilization conditions. The reconstituted protein(s) tested for binding properties, using p-[3H]aminoclonidine and/or [3H]clonidine, maintained the pharmacological profile of the native alpha2-adrenergic receptor. The potency order of various alpha2-agonists and alpha2-antagonists as well as their stereoselectivity were identical to those of the native alpha2-receptor. Specific receptor binding decreases in the presence of the guanyl nucleotides GTP or guanosine 5'-[beta, gamma-imido]-triphosphate but not ATP, thus indicating a co-solubilization of GTP regulatory components (stimulatory protein Ns or inhibitory protein Ni or both). Adenylate cyclase activity of the reconstituted preparation is stimulated threefold by sodium fluoride, suggesting the presence of both Ns-protein and the catalytic unit (C) in the reconstituted protein(s).


Highly luminescent copper(i) halide complexes chelated with a tetradentate ligand (PNNP): synthesis, structure, photophysical properties and theoretical studies.
Two emissive copper(i) halide complexes (PNNP)Cu2Br2 (1) and (PNNP)Cu2I2 (2), which are constructed from butterfly-shaped dinuclear Cu2X2 cores and a new tetradentate ligand (PNNP = 1,3-bis(1-(2-(diphenylphosphanyl)phenyl)-1H-pyrazol-3-yl)benzene), were synthesized and characterized. These chelates exhibit bright green (λmax = 517 nm, 1) and bluish-green (λmax = 492 nm, 2) photoluminescence in the solid state with quantum yields of 42% (1) and 58% (2), and lifetimes of 13 μs (1) and 8.8 μs (2) at room temperature. Computational density functional theory/time-dependent density functional theory (DFT/TDDFT) calculations were performed to elucidate the nature of their electronic transitions and to predict their detailed photophysical properties. The results of DFT/TDDFT calculations, combined with the temperature dependence of spectroscopic properties and emission decay behaviors, suggest that the emission in the solid state originates from the 1,3(MLCT + XLCT + ILCT) excited states, which are in thermal equilibrium with small energy differences of about 0.1 eV. A comparative study of the titled complexes reveals that the emissive-state characteristics and photophysical properties of these complexes are significantly affected by the ligand field strength and atomic number of the halogen atom, as well as by the percentage of the XLCT transition involved in the lowest excited states. Compared with its bromide counterpart (1), the iodide complex (2) shows a much higher phosphorescence quantum yield (0.94 vs. 0.50), a much shorter phosphorescence decay time (58 μs vs. 274 μs), a much larger phosphorescence rate constant (1.6 × 104 s-1vs. 1.8 × 103 s-1), and a larger phosphorescence contribution (25% vs. 8%) in room-temperature emission, due to the more efficient spin-orbit coupling (SOC).


Hydromechanical Structure of the Cochlea Supports the Backward Traveling Wave in the Cochlea In Vivo.
The discovery that an apparent forward-propagating otoacoustic emission (OAE) induced basilar membrane vibration has created a serious debate in the field of cochlear mechanics. The traditional theory predicts that OAE will propagate to the ear canal via a backward traveling wave on the basilar membrane, while the opponent theory proposed that the OAE will reach the ear canal via a compression wave. Although accepted by most people, the basic phenomenon of the backward traveling wave theory has not been experimentally demonstrated. In this study, for the first time, we showed the backward traveling wave by measuring the phase spectra of the basilar membrane vibration at multiple longitudinal locations of the basal turn of the cochlea. A local vibration source with a unique and precise location on the cochlear partition was created to avoid the ambiguity of the vibration source in most previous studies. We also measured the vibration pattern at different places of a mechanical cochlear model. A slow backward traveling wave pattern was demonstrated by the time-domain sequence of the measured data. In addition to the wave propagation study, a transmission line mathematical model was used to interpret why no tonotopicity was observed in the backward traveling wave.


Proximal diverting jejunostomy for compromised small bowel.
The use of a totally diverting proximal jejunostomy in the surgical therapy of five cases of compromised small bowel is reported. In each case a diverting end-on jejunostomy was constructed 30 to 100 cm beyond the ligament of Treitz. The oversewn distal end of bowel was anchored intraperitoneally at the jejunum, and a tube was introduced into the distal intestine for subsequent radiologic study. In three of five cases small bowel leaks were demonstrated after operation by x-ray examination. The leaks caused no clinical problems. The jejunostomy remained in place for 4 to 13 weeks. The mean daily stoma output ranged from 200 to 2800 ml/day. Fluid and electrolyte losses were replaced and total parenteral nutrition was supplied. No stomal complications occurred. Intestinal continuity was restored when contrast medium passed through the intestine without leak or obstruction. Reanastomosis of the intestinal tract was accomplished with minimal dissection through a small peristomal incision because the distal closed end of the divided bowel had been fixed to the stoma base. Each of the patients recovered gastrointestinal function without further complication and was discharged from the hospital on a general diet. With parenteral nutritional support, a high jejunostomy is well tolerated. Proximal intestinal diversion can salvage an otherwise hopeless situation.


Was it something I ate? Understanding the bidirectional interaction of migraine and appetite neural circuits.
Migraine attacks can involve changes of appetite: while fasting or skipping meals are often reported triggers in susceptible individuals, hunger or food craving are reported in the premonitory phase. Over the last decade, there has been a growing interest and recognition of the importance of studying these overlapping fields of neuroscience, which has led to novel findings. The data suggest additional studies are needed to unravel key neurobiological mechanisms underlying the bidirectional interaction between migraine and appetite. Herein, we review information about the metabolic migraine phenotype and explore migraine therapeutic targets that have a strong input on appetite neuronal circuits, including the calcitonin gene-related peptide (CGRP), the pituitary adenylate cyclase-activating polypeptide (PACAP) and the orexins. Furthermore, we focus on potential therapeutic peptide targets that are involved in regulation of feeding and play a role in migraine pathophysiology, such as neuropeptide Y, insulin, glucagon and leptin. We then examine the orexigenic - anorexigenic circuit feedback loop and explore glucose metabolism disturbances. Additionally, it is proposed a different perspective on the most reported feeding-related trigger - skipping meals - as well as a link between contrasting feeding behaviors (skipping meals vs food craving). Our review aims to increase awareness of migraine through the lens of appetite neurobiology in order to improve our understanding of the earlier phase of migraine, encourage better studies and cross-disciplinary collaborations, and provide novel migraine-specific therapeutic opportunities.


Structural analysis of articular cartilage using multiphoton microscopy: input for biomechanical modeling.
The 3-D morphology of chicken articular cartilage was quantified using multiphoton microscopy (MPM) for use in continuum-mechanical modeling. To motivate this morphological study we propose aspects of a new, 3-D finite strain constitutive model for articular cartilage focusing on the essential load-bearing morphology: an inhomogeneous, poro-(visco)elastic solid matrix reinforced by an anisotropic, (visco)elastic dispersed fiber fabric which is saturated by an incompressible fluid residing in strain-dependent pores. Samples of fresh chicken cartilage were sectioned in three orthogonal planes and imaged using MPM, specifically imaging the collagen fibers using second harmonic generation. Employing image analysis techniques based on Fourier analysis, we derived the principal directionality and dispersion of the collagen fiber fabric in the superficial layer. In the middle layer, objective thresholding techniques were used to extract the volume fraction occupied by extracellular collagen matrix. In conjunction with information available in the literature, or additional experimental testing, we show how this data can be used to derive a 3-D map of the initial solid volume fraction and Darcy permeability.


Intelligibility as a clinical outcome measure following intervention with children with phonologically based speech-sound disorders.
The effectiveness of two treatment approaches (phonological therapy and articulation therapy) for treatment of 14 children, aged 4;0-6;7 years, with phonologically based speech-sound disorder (SSD) has been previously analysed with severity outcome measures (percentage of consonants correct score, percentage occurrence of phonological processes and phonetic inventory). Considering that the ultimate goal of intervention for children with phonologically based SSD is to improve intelligibility, it is curious that intervention studies focusing on children's phonology do not routinely use intelligibility as an outcome measure. It is therefore important that the impact of interventions on speech intelligibility is explored. This paper investigates the effectiveness of the two treatment approaches (phonological therapy and articulation therapy) using intelligibility measures, both in single words and in continuous speech, as the primary outcome. Fourteen children with phonologically based SSD participated in the intervention. The children were randomly assigned to phonological therapy or articulation therapy (seven children in each group). Two assessment methods were used for measuring intelligibility: a word identification task (for single words) and a rating scale (for continuous speech). Twenty-one unfamiliar adults listened and judged the children's intelligibility. Reliability analyses showed overall high agreement between listeners across both methods. Significant improvements were noted in intelligibility in both single words (paired t(6)=4.409, p=0.005) and continuous speech (asymptotic Z=2.371, p=0.018) for the group receiving phonology therapy pre- to post-treatment, but no differences in intelligibility were found for those receiving the articulation therapy pre- to post-treatment, either for single words (paired t(6)=1.763, p=0.128) or continuous speech (asymptotic Z=1.442, p=0.149). Intelligibility measures were sensitive enough to show changes in the phonological therapy group but not in the articulation therapy group. These findings emphasize the importance of using intelligibility as an outcome measure to complement the results obtained with other severity measures when exploring the effectiveness of speech interventions. This study presents new evidence for the effectiveness of phonological therapy in improving intelligibility with children with SSD.


Reconstructing tritium exposure using tree rings at Lawrence Berkeley National Laboratory, California.
Annual tritium exposures were reconstructed using tree cores from Pinus jeffreyi and Eucalyptus globulus near a tritiated water vapor release stack. Both tritium (3H) and carbon-14 (14C) from the wood were measured from milligram samples using accelerator mass spectrometry. Because the annual nature of the eucalyptus tree rings was in doubt, 14C measurements provided growth rates used to estimate the age for 3H determinations. A 30-yr comparison of organically bound tritium (OBT) levels to reported 3H release data is achieved using OBT measurements from three trees nearthe stack. The annual average 3H, determined from atmospheric water vapor monitoring stations, is comparable to the OBT in proximal trees. For situations without adequate historical monitoring data, this measurement-based historical assessment provides the only independent means of assessing exposure as compared to fate and transport models that require prior knowledge of environmental conditions and 3H discharge patterns.


High-fat diet: bacteria interactions promote intestinal inflammation which precedes and correlates with obesity and insulin resistance in mouse.
Obesity induced by high fat (HF) diet is associated with inflammation which contributes to development of insulin resistance. Most prior studies have focused on adipose tissue as the source of obesity-associated inflammation. Increasing evidence links intestinal bacteria to development of diet-induced obesity (DIO). This study tested the hypothesis that HF western diet and gut bacteria interact to promote intestinal inflammation, which contributes to the progression of obesity and insulin resistance. Conventionally raised specific-pathogen free (CONV) and germ-free (GF) mice were given HF or low fat (LF) diet for 2-16 weeks. Body weight and adiposity were measured. Intestinal inflammation was assessed by evaluation of TNF-alpha mRNA and activation of a NF-kappaB(EGFP) reporter gene. In CONV but not GF mice, HF diet induced increases in body weight and adiposity. HF diet induced ileal TNF-alpha mRNA in CONV but not GF mice and this increase preceded obesity and strongly and significantly correlated with diet induced weight gain, adiposity, plasma insulin and glucose. In CONV mice HF diet also resulted in activation of NF-kappaB(EGFP) in epithelial cells, immune cells and endothelial cells of small intestine. Further experiments demonstrated that fecal slurries from CONV mice fed HF diet are sufficient to activate NF-kappaB(EGFP) in GF NF-kappaB(EGFP) mice. Bacteria and HF diet interact to promote proinflammatory changes in the small intestine, which precede weight gain and obesity and show strong and significant associations with progression of obesity and development of insulin resistance. To our knowledge, this is the first evidence that intestinal inflammation is an early consequence of HF diet which may contribute to obesity and associated insulin resistance. Interventions which limit intestinal inflammation induced by HF diet and bacteria may protect against obesity and insulin resistance.


Environmentally-induced modification of the benzodiazepine/GABA receptor coupled chloride ionophore.
The benzodiazepine/GABA receptor coupled chloride ionophore was examined in brain membranes of rats maintained in either a conventional animal facility or a "protected" (low-stress) environment. Following a 10 min ambient temperature swim, animals maintained in both environments had qualitatively similar increases in the number (Bmax) of [35S]t-butylbicyclophosphorothionate (TBPS) binding sites, the apparent affinity of this radioligand, and the efficacy and potency of Cl- to enhance [3H]flunitrazepam binding. Nonetheless, the Bmax of [35S]TBPS and efficacy of Cl- to enhance [3H]flunitrazepam binding were significantly lower in animals housed in the protected environment compared to those maintained in a conventional facility both before and after swim stress. Furthermore, in rats housed in a protected environment, sequential removal of animals from a common cage (cohort removal), produced a very rapid increase (less than or equal to 15 s) in Cl(-)-enhanced [3H]flunitrazepam binding in cortical and hippocampal but not cerebellar membranes. Cohort removal also produced a sequential increase in the number of [35S]TBPS binding sites and apparent affinity of this radioligand in cerebral cortical membranes. The effects of cohort removal were not observed in animals subjected to ambient temperature swim or if animals were removed from different cages. Changes in the benzodiazepine/GABA receptor coupled chloride ionophore produced by cohort removal from a common cage preceded any statistically significant changes in circulating levels of alpha-MSH, beta-endorphin, ACTH or corticosterone. These findings suggest that the benzodiazepine/GABA receptor chloride ionophore complex (supramolecular complex) is under both tonic and acute regulation by the environment, and may subserve a physiologically relevant function in the response to stressful or anxiety producing stimuli.


Factors Associated with a Low-sodium Diet: The Fourth Korean National Health and Nutrition Examination Survey.
The low-sodium diet is a known preventive factor for hypertension and cardiovascular disease. Factors associated with low-sodium diets should be identified to reduce sodium intake effectively. This study was conducted to identify factors correlated with a low-sodium diet. This cross-sectional study analyzed data from a total of 14,539 Koreans aged 20 years or older, who participated in the Fourth (2007-2009) Korean National Health and Nutrition Examination Survey. A low-sodium diet was defined as having ≤2,000 mg/day based on 24-hour recalls. Multiple logistic regression models were used to assess sex, age, education, number of family members, household income, occupation, alcohol drinking, total energy intake, frequency of eating out, and hypertension management status for their associations with low-sodium diets. Among all participants, only 13.9% (n=2,016) had low-sodium diets. In the multivariate analysis, 40-49 years of age, clerical work jobs, higher total energy intake, and frequent eating out were inversely associated with low-sodium diets. And female sex and living-alone were associated with low-sodium diets. Lower frequency of eating out was significantly associated with low-sodium diets, even after adjusting for total energy intake and other potential confounders. Adjusted odds ratios (95% confidence interval) for a low-sodium diet were 1.97 (1.49-2.61), 1.47 (1.13-1.91), 1.24 (0.96-1.61), and 1.00 (reference) in people who eat out <1 time/month, 1-3 times/month, 1-6 times/week, and ≥1 time/day, respectively. Our study suggests that sex, age, number of family members, occupation, total energy intake, and lower frequency of eating out were associated with a low-sodium diet in Korean adults.


Health services utilization of a care coordination/home-telehealth program for veterans with diabetes: a matched-cohort study.
This study examined the effectiveness of a veterans affairs (VA) patient-centered care coordination/home-telehealth (CC/HT) program as an adjunct to treatment for veterans with diabetes. Using an adapted version of the Chronic Care Model, we analyzed the differences in healthcare service use between a cohort of 400 veterans with diabetes who were enrolled in a VA CC/HT program and a matched comparison cohort of 400 veterans with diabetes who received no CC/HT intervention. Propensity scores were used to improve the balance between the treatment and comparison groups. Service use outcomes were assessed at 12 months before and after enrollment. A difference-in-differences approach was used in the multivariate models to assess the treatment effect for patients in the CC/HT programs. Twelve months after enrollment, there was a significant difference between the treatment and comparison groups in terms of need-based primary care visits (newly scheduled visits that enable the veteran to be seen "just in time," where the health status is monitored and met before health deteriorates), increasing in the treatment group and decreasing in the comparison group (P < .01). In a subgroup analysis, where we were able to control for the patients' Hb A1c values, we found that the treatment group had a lower likelihood of having 1 or more hospitalizations than patients in the comparison group. Our findings have implications for management in that the CC/HT program appears to improve the ability of older veterans with diabetes to receive appropriate, timely care, thereby improving the quality of care for them and making more efficient use of VA healthcare resources.


Late onset adrenal insufficiency after adrenalectomy due to latent nonclassical 21-hydroxylase deficiency: A case report.
Adrenal incidentaloma is sometimes complicated with 21-hydroxylase deficiency (21-OHD). Latent nonclassical 21-OHD in incidentaloma is difficult to diagnose. Although adrenalectomy in 21-OHD has been conducted when malignancy could not be excluded, adrenal insufficiency sometimes occurs, and it might not be observed immediately after operation. Here, we report a case of a 71-year-old man who experienced adrenal insufficiency over 2 decades postadrenalectomy, leading to a diagnosis of latent nonclassical 21-OHD. A 71-year-old man was admitted to the hospital due to difficulty in movements and a sodium level of 119 mEq/L. His medical history revealed precocious puberty and left adrenalectomy because of an incidentaloma at 49 years of age, diagnosed pathologically as an adenoma. He did not attend follow-up visits because he did not have any symptoms. In 2017, 3 months before hospitalization, he experienced general fatigue. A few days before admittance, he complained of difficulty in moving and visual hallucination of small animals. Laboratory evaluations revealed a high level of adrenocorticotropic hormone (ACTH) and low cortisol level. ACTH-stimulating test revealed a low basal level and low response for cortisol, and a high basal level and low response for 17-hydroxyprogesterone. We analyzed large gene deletion or conversion and the 9 most common micro mutations in the CYP21A2 gene by polymerase chain reaction; micro mutation of I172N and heterozygous large gene deletion or conversion were detected leading to the diagnosis of nonclassical 21-OHD. Immediately, 100 mg hydrocortisone was administered, followed by daily hydrocortisone and saline. The symptoms and hyponatremia improved in a few days. He was discharged from the hospital on day 34 with a daily dose of 15 mg hydrocortisone. Clinicians should be aware of late onset of adrenal insufficiency after adrenalectomy. In such cases, clinicians should not overlook the latent nonclassical 21-OHD.


Tracking cells and monitoring proliferation.
In many areas of immunology it is desirable to be able to track particular cells throughout an assay, whether it be in vivo or in vitro. There are two classes or reagents used for this purpose-general protein labels (reactive compounds that form random covalent bonds with amino groups on cellular proteins) and general membrane labels (lipophilic compounds that partition stably but non-covalently into the plasma membrane). The fluorescein derivative, carboxyfluorescein diacetate succinimidyl ester, CFDA-SE (general protein label), has been found to be particularly well suited for the purpose of cell tracking. Once labeled, cells can be tracked both in vivo and in vitro. Moreover, due to the randomness of the labeling, cells undergoing division maintain half of the staining intensity of the parent cell. This halving of the staining intensity additionally allows for monitoring of cells undergoing division for 6-8 consecutive cycles.


Sleep Difficulties and Symptoms of Attention-deficit Hyperactivity Disorder in Children with Mouth Breathing.
Persistent mouth breathing affects stomatognathic functions along with effects on the academics and social life of a child. Sleep-related problems and behavioral symptoms similar to that found in attention-deficit hyperactivity disorder (ADHD) can be present in mouth breathers. This study aims at assessing the sleep disturbances and pattern of symptoms of ADHD in children with mouth breathing. A cross-sectional study was carried out on 100 children of mouth breathing (consecutively selected) in 7-12 years of age using semi-structured proforma, children's sleep habit questionnaire (CSHQ), and diagnostic and statistical manual of mental disorders, version 5 (DSM 5). Statistical analysis was done using SPSS software version 21. Mean, standard deviation, Chi-square, and Pearson's correlation coefficient test were utilized during the analysis. p value of <0.05 was considered significant. Out of 100 children, 70 were males and 30 were females. On the CSHQ scale, the highest score was found on sleep-disordered breathing followed by sleep onset delay and daytime sleepiness. The commonest symptom of inattention was "failing to give close attention in school" (73%) whereas the commonest symptom of hyperactivity was "trouble waiting for his/her turn" (66%). Seven participants satisfied complete criteria for ADHD. Sleep duration and daytime sleepiness had a significant negative correlation with hyperactivity (p < 0.05). A positive correlation was observed between daytime sleepiness and inattention (p < 0.01). Children with sleep disturbances or ADHD should be assessed for the presence of mouth breathing, as early identification and correction of mouth breathing may help to prevent unnecessary exposure to the medication. Children with ADHD or sleep disturbances should always be assessed for the presence of mouth breathing. Early identification and correction of mouth breathing may help in preventing unnecessary exposure to medication for treating ADHD. Kalaskar R, Bhaje P, Kalaskar A, et al. Sleep Difficulties and Symptoms of Attention-deficit Hyperactivity Disorder in Mouth Breathing. Int J Clin Pediatr Dent 2021;14(5):604-609.


Rapid estrogen signaling in the brain: implications for the fine-tuning of neuronal circuitry.
Rapid actions of estrogens were first described >40 years ago. However, the importance of rapid estrogen-mediated actions in the CNS is only now becoming apparent. Several lines of evidence demonstrate that rapid estrogen-mediated signaling elicits potent effects on molecular and cellular events, resulting in the "fine-tuning" of neuronal circuitry. At an ultrastructural level, the details of estrogen receptor localization and how these are regulated by the circulating hormone and age are now becoming evident. Furthermore, the mechanisms that allow membrane-associated estrogen receptors to couple with intracellular signaling pathways are also now being revealed. Elucidation of complex actions of rapid estrogen-mediated signaling on synaptic proteins, connectivity, and synaptic function in pyramidal neurons has demonstrated that this neurosteroid engages specific mechanisms in different areas of the brain. The regulation of synaptic properties most likely underlies the fine-tuning of neuronal circuitry. This in turn may influence how learned behaviors are encoded by different circuitry in male and female subjects. Importantly, as estrogens have been suggested as potential treatments of a number of disorders of the CNS, advancements in our understanding of rapid estrogen signaling in the brain will serve to aid in the development of potential novel estrogen-based treatments.


Shopping in the genome market with EnsMart.
Life scientists who work with the supermarket of genome data will find the EnsMart database and software package offers a valuable door to a wealth of genes and genome features. Not only available to lab biologists on the web, this popular multi-organism genome database can be installed and used on your own Unix computer with relative ease. It offers a flexible, fast and practical data-mining framework for computer-savvy biologists and bioinformaticians.


Plasma Concentrations of Per- and Polyfluoroalkyl Substances at Baseline and Associations with Glycemic Indicators and Diabetes Incidence among High-Risk Adults in the Diabetes Prevention Program Trial.
Several per- and polyfluoroalkyl substances (PFAS) are ubiquitous anthropogenic pollutants almost universally detected in humans. Experimental evidence indicates that PFAS alter glucose metabolism and insulin secretion. However, epidemiological studies have yielded inconsistent results. We sought to examine associations between plasma PFAS concentrations, glycemic indicators, and diabetes incidence among high-risk adults. Within the Diabetes Prevention Program (DPP), a trial for the prevention of type 2 diabetes among high-risk individuals, we quantified baseline plasma concentrations of nine PFAS among 957 participants randomized to a lifestyle intervention or placebo. We evaluated adjusted associations for plasma PFAS concentrations with diabetes incidence and key glycemic indicators measured at baseline and annually over up to 4.6 y. Plasma PFAS concentrations were similar to those reported in the U.S. population in 1999-2000. At baseline, in cross-sectional analysis, a doubling in plasma perfluorooctanesulfonic acid (PFOS) and perfluorooctanoic acid (PFOA) concentrations was associated with higher homeostatic model assessment of insulin resistance (HOMA-IR) [βPFOS=0.39; 95% confidence interval (CI): 0.13, 0.66; βPFOA=0.64; 95% CI: 0.34, 0.94], β-cell function (HOMA-β) (βPFOS=9.62; 95% CI: 1.55, 17.70; βPFOA=15.93; 95% CI: 6.78, 25.08), fasting proinsulin (βPFOS=1.37 pM; 95% CI: 0.50, 2.25; βPFOA=1.71 pM; 95% CI: 0.72, 2.71), and glycated hemoglobin (HbA1c) (βPFOS=0.03%; 95% CI: 0.002, 0.07; βPFOA=0.04%; 95% CI: 0.001, 0.07). There was no strong evidence of associations between plasma PFAS concentrations and diabetes incidence or prospective changes in glycemic indicators during the follow-up period. At baseline, several PFAS were cross-sectionally associated with small differences in markers of insulin secretion and β-cell function. However, there was limited evidence suggesting that PFAS concentrations are associated with diabetes incidence or changes in glycemic indicators during the follow-up period. https://doi.org/10.1289/EHP1612.


Prolongation of allograft survival in ccr7-deficient mice.
Lymphocyte homing to secondary lymphoid organs is thought to be required for initiation of the alloreactive immune response. Because CCR7 is the essential chemokine receptor responsible for lymphocyte and dendritic cell homing to secondary lymphoid organs, allograft survival was analyzed in CCR7-deficient (CCR7) mice. Heterotopic heart and skin allotransplantation was performed in CCR7 and wild-type (WT) recipients. Graft survival was monitored daily. Grafts and draining lymph nodes were analyzed by immunohistology and flow cytometry at different time points. Groups of mice were splenectomized at the day of allotransplantation. A significant though modest prolongation of allograft survival in CCR7 recipients was observed for heart grafts (WT, 7.3 +/- 0.5 days; CCR7, 10.7 +/- 2.8 days) and skin grafts (WT, 8.9 +/- 0.9 days; CCR7, 12.3 +/- 0.9 days). This was accompanied by a delay in the cellular infiltration of allografts. T-cell accumulation and expansion in the draining lymph nodes in CCR7 recipients was severely impaired. Splenectomy had only a moderate prolongation effect on allograft survival in CCR7 mice. These results suggest that CCR7-dependent processes support allograft rejection yet are dispensable for the rejection response.


Antibodies anti-Toxoplasma gondii and anti-Neospora caninum in backyard pigs from the state of Mato Grosso, Brazil.
To estimate the seroprevalence of Toxoplasma gondii and Neospora caninum, using an indirect immunofluorescent assay (IFA), and identify the risk factors associated, serum samples were collected from 1,070 pigs from 320 backyard pig farming in the of Mato Grosso state. The animal-level seroprevalence of T. gondii and N. caninum was 32.48% and 13.49%, respectively, with a herd seroprevalence of 55.63% for T. gondii and 27.81% for N. caninum. Feeding the animals with leftovers increases the probability of the presence of anti-T. gondii antibodies in pigs by 1.09-fold. Unlike to T. gondii, feeding with leftovers was found to be negatively associated with N. caninum seropositivity in farm-level analysis and in the animal-level model, so decreasing the chances of positivity. Yet, age was considered a risk factor for N. caninum seropositivity. Further studies are necessary to evaluate the impact of T. gondii infection on backyard pig farming production, and its importance as a source of toxoplasmosis infection in humans in the Mato Grosso state, as well as, the role of domestic pigs in the epidemiology of neosporosis.


Interaction of H+ with the extracellular and intracellular aspects of hMATE1.
Human multidrug and toxin extrusion 1 (hMATE1, SLC47A1) is a major candidate for being the molecular identity of organic cation/proton (OC/H(+)) exchange activity in the luminal membrane of renal proximal tubules. Although physiological function of hMATE1 supports luminal OC efflux, the kinetics of hMATE1-mediated OC transport have typically been characterized through measurement of uptake, i.e., the interaction between outward-facing hMATE1 and OCs. To examine kinetics of hMATE1-mediated transport in a more physiologically relevant direction, i.e., an interaction between inward-facing hMATE1 and cytoplasmic substrates, we measured the time course of hMATE1-mediated efflux of the prototypic MATE1 substrate, [(3)H]1-methyl-4-phenylpyridinium, under a variety of intra- and extracellular pH conditions, from Chinese hamster ovary cells that stably expressed the transporter. In this study, we showed that an IC(50)/K(i) for interaction between extracellular H(+) and outward-facing hMATE1 determined from conventional uptake experiments [12.9 ± 1.23 nM (pH 7.89); n = 9] and from the efflux protocol [14.7 ± 3.45 nM (pH 7.83); n = 3] was not significantly different (P = 0.6). Furthermore, kinetics of interaction between intracellular H(+) and inward-facing hMATE1 determined using the efflux protocol revealed an IC(50) for H(+) of 11.5 nM (pH 7.91), consistent with symmetrical interactions of H(+) with the inward-facing and outward-facing aspects of hMATE1.


Cell adhesion control by photoinduced LCST shift of PNIPAAm-based brush scaffolds.
Poly(N-isopropylacrylamide) (PNIPAAm)-brush substrates are one of the most successful dynamic scaffolds for thermally controlling cell adhesion. Endowing substrates with photocontrollability promises further development and applications in the biomedical and bioengineering fields. In this study, we developed photoresponsive PNIPAAm copolymers by incorporation of spiropyran into the polymer chain, enabling the photoinduced shift of the lower critical solution temperatures. Their brush substrates were fabricated in a simple, facile grafting-to manner. Co-grafting with non-cell-adhesive poly(ethylene glycol) enhanced the modulation of surface chemical properties upon photostimulation; it enabled significant photocontrol of cell adhesion of several types with keeping culture temperature constant.


Bariatric surgery and nonalcoholic fatty liver disease.
The rising prevalence of nonalcoholic fatty liver disease (NAFLD) is associated with the increasing global pandemic of obesity. These conditions cluster with type II diabetes mellitus and the metabolic syndrome to result in obesity-associated liver disease. The benefits of bariatric procedures on diabetes and the metabolic syndrome have been recognized for some time, and there is now mounting evidence to suggest that bariatric procedures improve liver histology and contribute to the beneficial resolution of NAFLD in obese patients. These beneficial effects derive from a number of weight-dependent and weight-independent mechanisms including surgical BRAVE actions (bile flow changes, restriction of stomach size, anatomical gastrointestinal rearrangement, vagal manipulation, enteric hormonal modulation) and subsequent effects such as reduced lipid intake, adipocytokine secretion, modulation of gut flora, improvements in insulin resistance and reduced inflammation. Here, we review the clinical investigations on bariatric procedures for NAFLD, in addition to the mounting mechanistic data supporting these findings. Elucidating the mechanisms by which bariatric procedures may resolve NAFLD can help enhance surgical approaches for metabolic hepatic dysfunction and also contribute toward developing the next generation of therapies aimed at reducing the burden of obesity-associated liver disease.


Screening for colorectal cancer.
Colorectal cancer remains a major cause of mortality in the United States. Of all persons diagnosed with this tumor, less than 50 percent survive five years. Useful preventive measures have not been established. Screening programs, however, offer the prospect of detecting cancers early in their course, when the prognosis for survival is more favorable. To date, no screening test has clearly demonstrated its effectiveness in reducing mortality from colorectal cancer. Periodic rigid sigmoidoscopy and stool occult blood testing have gained many advocates, but have yet to be proved worthwhile in adequately controlled clinical trials. Uncontrolled studies indicate that both these techniques discover approximately 2 cancers per 1000 screenees. There is suggestive evidence that the cancers discovered are more likely to be localized. For the present, physicians should limit colorectal cancer screening to persons at relatively high risk: persons aged over 45 years, with a family history of bowel cancer, or with polyps. Protocols should be designed to ensure high specificity. The recommendations of the National Cancer Institute's consensus conference provide practical guidelines pending the outcome of randomized controlled trials.


Primary cilia and aberrant cell signaling in epithelial ovarian cancer.
Ovarian cancer is the fourth leading cause of cancer-related deaths among women in Denmark, largely due to the advanced stage at diagnosis in most patients. Approximately 90% of ovarian cancers originate from the single-layered ovarian surface epithelium (OSE). Defects in the primary cilium, a solitary sensory organelle in most cells types including OSE, were recently implicated in tumorigenesis, mainly due to deregulation of ciliary signaling pathways such as Hedgehog (Hh) signaling. However, a possible link between primary cilia and epithelial ovarian cancer has not previously been investigated. The presence of primary cilia was analyzed in sections of fixed human ovarian tissue as well as in cultures of normal human ovarian surface epithelium (OSE) cells and two human OSE-derived cancer cell lines. We also used immunofluorescence microscopy, western blotting, RT-PCR and siRNA to investigate ciliary signaling pathways in these cells. We show that ovarian cancer cells display significantly reduced numbers of primary cilia. The reduction in ciliation frequency in these cells was not due to a failure to enter growth arrest, and correlated with persistent centrosomal localization of aurora A kinase (AURA). Further, we demonstrate that ovarian cancer cells have deregulated Hh signaling and platelet-derived growth factor receptor alpha (PDGFRα) expression and that promotion of ciliary formation/stability by AURA siRNA depletion decreases Hh signaling in ovarian cancer cells. Lastly, we show that the tumor suppressor protein and negative regulator of AURA, checkpoint with forkhead-associated and ring finger domains (CHFR), localizes to the centrosome/primary cilium axis. Our results suggest that primary cilia play a role in maintaining OSE homeostasis and that the low frequency of primary cilia in cancer OSE cells may result in part from over-expression of AURA, leading to aberrant Hh signaling and ovarian tumorigenesis.


[Metabolic alterations triggered by low calcium diets].
Calcium is essential for bone and tooth formation, achievement of optimal peak bone mass and also for regulation of physiological processes. The calcium demand depends on age, gender and different physiological processes. These requirements are higher during childhood, pregnancy and lactation. Dietary Ca2+ deficiency modifies Ca2+ homeostasis and the metabolism of calciotropic hormones and increases the efficiency of intestinal Ca2+ absorption and renal reabsorption, altering bone metabolism. The low Ca2+ diet is associated with hypertension and risk of cancer.


The flexion synergy, mother of all synergies and father of new models of gait.
Recently there has been a growing interest in the modular organization of leg movements, in particular those related to locomotion. One of the basic modules involves the flexion of the leg during swing and it was shown that this module is already present in neonates (Dominici et al., 2011). In this paper, we question how these finding build upon the original work by Sherrington, who proposed that the flexor reflex is the basic building block of flexion during swing phase. Similarly, the relation between the flexor reflex and the withdrawal reflex modules of Schouenborg and Weng (1994) will be discussed. It will be argued that there is large overlap between these notions on modules and the older concepts of reflexes. In addition, it will be shown that there is a great flexibility in the expression of some of these modules during gait, thereby allowing for a phase-dependent modulation of the appropriate responses. In particular, the end of the stance phase is a period when the flexor synergy is facilitated. It is proposed that this is linked to the activation of circuitry that is responsible for the generation of locomotor patterns (CPG, "central pattern generator"). More specifically, it is suggested that the responses in that period relate to the activation of a flexor burst generator. The latter structure forms the core of a new asymmetric model of the CPG. This activation is controlled by afferent input (facilitation by a broad range of afferents, suppression by load afferent input). Meanwhile, many of these physiologic features have found their way in the control of very flexible walking bipedal robots.


Immunologic responses in vascularized and nonvascularized skin allografts.
The skin is a protective interface between internal organs and the environment; it is the largest tissue of the human body. However, the skin does not serve merely as a physical barrier. It is also an active immune organ, traversed by a network of lymphatic and blood vessels. This immunologic structure contains immunologic cells such as T lymphocytes, Langerhans cells (LCs), dendritic cells, and keratinocytes. Langerhans cells represent the cutaneous counterpart of dendritic cells. LCs not only act as professional antigen-presenting cells to induce antigen-specific T cells for adaptive immune responses, but they also initiate a cascade of innate immune responses by antigenic stimulus such as transplant tissue. In transplantation immunology, either donor or recipient LCs fulfill an important mission in rejection or acceptance of donor tissue. Vascularized or nonvascularized skin allografts may create an immunologic response through different pathways. In both transplant models, skin diameter may change antigenic load, thereby determining rejection or acceptance response. This article discusses the effects of the cellular component in the skin immune system on immunologic responses of vascularized or nonvascularized skin allografts and describes the differences between the two immunologic cascades.


Visualizing myeloarchitecture with magnetic resonance imaging in primates.
The pattern of myelination over the cerebral cortex, termed myeloarchitecture, is an established and often-used feature to visualize cortical organization with histology in a variety of primate species. In this paper, we use in vivo magnetic resonance imaging (MRI) and advanced image processing using surface rendering to visualize and characterize myeloarchitecture in a small nonhuman primate, the common marmoset (Callithrix jacchus). Through images made in four female adult marmosets, we produce a representative 3D map of marmoset myeloarchitecture and flatten and annotate this map to show the location and extent of a variety of major areas of the cortex, including the primary visual, auditory, and somatosensory areas. By treating our MRI data as a surface, we can measure the surface area of cortical areas, and we present these measurements here to summarize cortical organization in the marmoset.


Plastid-expressed 5-enolpyruvylshikimate-3-phosphate synthase genes provide high level glyphosate tolerance in tobacco.
Plastid transformation (transplastomic) technology has several potential advantages for biotechnological applications including the use of unmodified prokaryotic genes for engineering, potential high-level gene expression and gene containment due to maternal inheritance in most crop plants. However, the efficacy of a plastid-encoded trait may change depending on plastid number and tissue type. We report a feasibility study in tobacco plastids to achieve high-level herbicide resistance in both vegetative tissues and reproductive organs. We chose to test glyphosate resistance via over-expression in plastids of tolerant forms of 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS). Immunological, enzymatic and whole-plant assays were used to prove the efficacy of three different prokaryotic (Achromobacter, Agrobacterium and Bacillus) EPSPS genes. Using the Agrobacterium strain CP4 EPSPS as a model we identified translational control sequences that direct a 10,000-fold range of protein accumulation (to >10% total soluble protein in leaves). Plastid-expressed EPSPS could provide very high levels of glyphosate resistance, although levels of resistance in vegetative and reproductive tissues differed depending on EPSPS accumulation levels, and correlated to the plastid abundance in these tissues. Paradoxically, higher levels of plastid-expressed EPSPS protein accumulation were apparently required for efficacy than from a similar nuclear-encoded gene. Nevertheless, the demonstration of high-level glyphosate tolerance in vegetative and reproductive organs using transplastomic technology provides a necessary step for transfer of this technology to other crop species.


Review of 103 Swedish Healthcare Quality Registries.
In the past two decades, an increasing number of nationwide, Swedish Healthcare Quality Registries (QRs) focusing on specific disorders have been initiated, mostly by physicians. Here, we describe the purpose, organization, variables, coverage and completeness of 103 Swedish QRs. From March to September 2013, we examined the 2012 applications of 103 QRs to the Swedish Association of Local Authorities and Regions (SALAR) and also studied the annual reports from the same QRs. After initial data abstraction, the coordinator of each QR was contacted at least twice between June and October 2013 and asked to confirm the accuracy of the data retrieved from the applications and reports. About 60% of the QRs covered ≥80% of their target population (completeness). Data recorded in Swedish QRs include aspects of disease management (diagnosis, clinical characteristics, treatment and lead times). In addition, some QRs retrieve data on self-reported quality of life (EQ5D, SF-36 and disease-specific measures), lifestyle (smoking) and general health status (World Health Organization performance status, body mass index and blood pressure). Detailed clinical data available in Swedish QRs complement information from government-administered registries and provide an important source not only for assessment and development of quality of care but also for research.


A Machine Learning Model for the prediction of the progression of carotid arterial stenoses.
Atherosclerotic carotid plaque development results in a steady narrowing of the artery lumen, which may eventually trigger catastrophic plaque rupture leading to thromboembolism and stroke. The primary cause of ischemic stroke in the EU is carotid artery disease, which increases the demand for tools for risk stratification and patient management in carotid artery disease. Additionally, advancements in cardiovascular modeling over the past few years have made it possible to build accurate three-dimensional models of patient-specific primary carotid arteries. Computational models then incorporate the aforementioned 3D models to estimate either the development of atherosclerotic plaque or a number of flow-related parameters that are linked to risk assessment. This work presents an attempt to provide a carotid artery stenosis prognostic model, utilizing non-imaging and imaging data, as well as simulated hemodynamic data. The overall methodology was trained and tested on a dataset of 41 cases with 23 carotid arteries with stable stenosis and 18 carotids with increasing stenosis degree. The highest accuracy of 71% was achieved using a neural network classifier. The novel aspect of our work is the definition of the problem that is solved, as well as the amount of simulated data that are used as input for the prognostic model.Clinical Relevance-A prognostic model for the prediction of the trajectory of carotid artery atherosclerosis is proposed, which can support physicians in critical treatment decisions.


The Far Nasal Part of the Visual Field - Part I.
The aim of the study was to determine the limits of the far nasal part of the visual field. Visual field examination was performed in 15 healthy subjects (30 eyes), specifically nine women aged 20-43 years and six men aged 22-35 years. All eyes were found to have physiological ocular findings and visual acuity of 1.0 with correction less than or equal to 3 diopters. The visual field was examined with a Medmont M700 instrument by shifting the fixation point 40 degrees temporally and simultaneously turning the head nasally, with a spatial accommodation program. A total of 89 examination points were included using flicker stimuli. The far nasal limit of the visual field reached 100° in 13.3% of eyes, 105° in 20% of eyes and up to 110° in 66.7% of eyes. The limit of the far nasal part of the field of vision reached 100-110 degrees (when nose shielding was eliminated).


Association of potentially inappropriate medication use with patient and prescriber characteristics in Medicare Part D.
The use of potentially inappropriate medications (PIMs) in older people is associated with increased risk of adverse drug events and hospitalization. This study aimed to determine the contribution of primary prescribers to variation in PIM use. This was a retrospective cohort study using 2008 Medicare Part D event files and claims data for a 100% sample of Texas beneficiaries. PIM use was defined as receiving any of 48 medications on the Beers 2003 list of PIMs. Patient characteristics associated with PIM use were determined using a multivariable model. A multilevel model for the odds of PIM use was constructed to evaluate the amount of variation in PIM use at the level of primary care prescriber, controlling for patient characteristics. Of 677,580 patients receiving prescriptions through Part D in 2008, 31.9% received a PIM. Sex, ethnicity, low-income subsidy eligibility, and hospitalization in 2007 were associated with PIM use. The strongest associations with higher PIM use were increasing number of prescribers and increasing number of medications. The odds ratio for PIM use was 1.50 (95%CI 1.47-1.53) for ≥4 prescribers versus only 1 prescriber. In the multilevel model, the adjusted average percent of patients prescribed a PIM ranged from 17.5% for the lowest decile to 28.9% for the highest decile of prescribers. PIM use was prevalent in Part D beneficiaries and varied among individual primary care prescribers. The association of PIM use with increasing numbers of prescribers suggests the need to reduce fragmentation of care to reduce inappropriate prescribing.


Immune Alterations in a Patient with SARS-CoV-2-Related Acute Respiratory Distress Syndrome.
We report a longitudinal analysis of the immune response associated with a fatal case of COVID-19 in Europe. This patient exhibited a rapid evolution towards multiorgan failure. SARS-CoV-2 was detected in multiple nasopharyngeal, blood, and pleural samples, despite antiviral and immunomodulator treatment. Clinical evolution in the blood was marked by an increase (2-3-fold) in differentiated effector T cells expressing exhaustion (PD-1) and senescence (CD57) markers, an expansion of antibody-secreting cells, a 15-fold increase in γδ T cell and proliferating NK-cell populations, and the total disappearance of monocytes, suggesting lung trafficking. In the serum, waves of a pro-inflammatory cytokine storm, Th1 and Th2 activation, and markers of T cell exhaustion, apoptosis, cell cytotoxicity, and endothelial activation were observed until the fatal outcome. This case underscores the need for well-designed studies to investigate complementary approaches to control viral replication, the source of the hyperinflammatory status, and immunomodulation to target the pathophysiological response. The investigation was conducted as part of an overall French clinical cohort assessing patients with COVID-19 and registered in clinicaltrials.gov under the following number: NCT04262921.


Autoantibodies against human insulin.
Sera from 680 non-diabetic subjects with suspected autoimmune disease were screened for 13 different antibodies. Of the 582 sera found to contain these antibodies, nine bound insulin in an IgG specific enzyme linked immunosorbent assay (micro ELISA). Four of the sera bound human, porcine, and bovine insulins and five bound exclusively human insulin. "Cold" human, porcine, and bovine insulins each displaced, in a dose dependent manner, the four sera which bound all three insulins, but only human insulin displaced the remaining five, porcine and bovine insulins having little or no effect in concentrations up to 1000 U/1. These observations point to the existence of autoantibodies specifically against human insulin in some subjects with established autoimmunity.


[Association of age and sex with intensity of exposure to bicycle use in Spain, 1993-2009].
To estimate the association of age and sex with the intensity of exposure of cyclists in Spain, between 1993 and 2009, in a global way and for subtypes of use. From the distribution of cyclists passively involved in collisions with other vehicles included in the register of the Spanish General Traffic Directorate between 1993 and 2009, we have estimated the increase in intensity of exposure by age groups and sex, for global exposure and for subtypes of exposure (e.g. riding with or without a helmet, or riding on an open road or in urban areas), using males aged 45-49 as a reference. Males have a greater exposure than females and this difference increases with age, although it has tended to decrease in recent years. In both sexes the exposure is greater in young people and goes down with age, while in males the excess in young people has disappeared in recent years. Regarding subtypes of use, female underexposure riding on an open road should be highlighted, as well as overexposure in both women and extreme age groups among non-helmet users. There is a close association of age and sex with the intensity of bicycle use, which changes depending on the type of use and the time period considered. Consequently, estimations of the effect of factors affecting the accident rate and the morbidity and mortality of cyclists in Spain have to be adjusted by the age and sex of the cyclist.


Two Earth-sized planets orbiting Kepler-20.
Since the discovery of the first extrasolar giant planets around Sun-like stars, evolving observational capabilities have brought us closer to the detection of true Earth analogues. The size of an exoplanet can be determined when it periodically passes in front of (transits) its parent star, causing a decrease in starlight proportional to its radius. The smallest exoplanet hitherto discovered has a radius 1.42 times that of the Earth's radius (R(⊕)), and hence has 2.9 times its volume. Here we report the discovery of two planets, one Earth-sized (1.03R(⊕)) and the other smaller than the Earth (0.87R(⊕)), orbiting the star Kepler-20, which is already known to host three other, larger, transiting planets. The gravitational pull of the new planets on the parent star is too small to measure with current instrumentation. We apply a statistical method to show that the likelihood of the planetary interpretation of the transit signals is more than three orders of magnitude larger than that of the alternative hypothesis that the signals result from an eclipsing binary star. Theoretical considerations imply that these planets are rocky, with a composition of iron and silicate. The outer planet could have developed a thick water vapour atmosphere.


'A disastrous blow': psychiatric risk, social indicators and medical authority in abortion reform in post-war Britain.
The Second World War lent impetus to the creation of new models and explanatory frameworks of risk, encouraging a closer reading of the relationship between individual psychiatric disorder and social disarray. This article interrogates how conceptions of psychiatric risk were animated in debates around abortion reform to forge new connections between social conditions and psychiatric vulnerability in post-war Britain. Drawing upon the arguments that played out between medical practitioners, I suggest that abortion reform, culminating in the 1967 Abortion Act, was both a response to and a stimulus for new ideas about the interaction between social aetiologies and medical pathologies; indeed, it became a site in which the medical and social domains were recognised as mutually constitutive. Positioned in a landscape in which medical professionals were seeking to assert their authority and to defend their areas of practice, abortion reform offered new opportunities for medical professionals to intervene in the social sphere under the guise of risk to women's mental health. The debate in medical journals around the status of issues that were seen to bridge the social and the medical were entangled with increasing anxiety about patient agency and responsibility. These concerns were further underscored as conversations about psychiatric risk extended towards considerations of the potential impact on women's existing families, bringing domestic conditions and the perceived psychosocial importance of family life into relief within medical journals. This article, then, argues that conceptions of psychiatric risk, as refracted through the creation of new synapses connecting the social and the medical domains, were critical to medical debates over abortion reform in post-war Britain.


Recent advances in date palm genomics: A comprehensive review.
As one of the oldest fruit trees of the Arabian peninsula, other Middle-Eastern countries, and also North Africa, the date palm (Phoenix dactylifera L.), is highly significant for the economy of the region. Listed as part of UNESCO's Intangible Cultural Heritage of Humanity, the date palm is believed to be the first tree cultivated by human beings, and was probably first harvested for its fruit nearly 7,000 years ago. Initial research efforts in date palm genetics focused on understanding the genetic diversity of date palm germplasm collections and its phylogenetic history, both important prerequisites for plant improvement. Despite various efforts, the center of origin of the date palm is still unclear, although genomic studies suggest two probable domestication events: one in the Middle East and the other in North Africa, with two separate gene pools. The current review covers studies related to omics analyses that have sought to decipher the present genetic diversity of the date palm. With advances and cost reductions in sequencing technologies, rapid progress has been made in the past few years in date palm genomics research. Along with organellar genomes, several reference genomes of the date palm are now available. In addition, several genotypes have been re-sequenced, either to detect single nucleotide polymorphisms (SNPs), or to study domestication and identification of key genes/loci associated with important agronomic traits, such as sex, fruit color, and sugar composition. These genomics research progress has paved the way to perform fast-track and precise germplasm improvement processes in date palm. In this study, we review the advances made in the genetics and genomics of the date palm so as to strategize targeted crop improvement plans for marginal areas of the Middle Eastern peninsula, North Africa, and other parts of the world.


The pathogenesis and therapeutic option of encapsulating peritoneal sclerosis.
Since the first peritoneal dialysis (PD) patients with encapsulating peritoneal sclerosis (EPS) were reported in 1980, EPS has been considered primarily a fatal complication. The incidence of EPS in PD patients has been reported to be from 0.7% to 7.3%, and the rate appears to be higher in patients receiving long-term treatment. Most data from Japan has shown an overall incidence of 2.5% with an evident negative effect of increasing duration of PD, which also augments mortality. Since EPS occurred after withdrawal from PD in more than half of the patients, strict monitoring is necessary when a long-term PD patient is withdrawn from PD. Maintaining patients on standard PD for more than 8 years using conventional solutions is associated with a substantial risk for development of EPS. Appropriate treatment according to the disease stage is most important in EPS treatment. Therefore, when examining a PD patient complaining of gastrointestinal symptoms, the possibility of EPS has to be kept in mind. Basic therapeutic tactics for EPS include an appropriate use of steroids. If the state of bowel obstruction persists, laparotomy and enterolysis should be performed to obtain complete cure. It is now recognized that EPS is not a fatal complication of PD.


Validation and reliability analysis of the Questionnaire on the Emotional Impact of Vertigo-CIEV version translated to the Brazilian Portuguese language.
To determine the internal consistency and reliability of the "Questionário de Impacto Emocional da Vertigem (CIEV)" and to validate the instrument with respect to the Dizziness Handicap Inventory (DHI) in a sample of individuals with balance disorders. 38 subjects participated in the study, males and females, aged from 23 to 85 years, who presented dizziness, vertigo, and/or falls complaints and attended to the Vestibular Disorders clinic at the University Hospital. Individuals with hearing complaints and/or tinnitus unrelated to dizziness, previous psychiatric comorbidities, and/or cognitive impairments were excluded. We performed an anamnesis and collected complementary data from the medical records. After that, the self-perception questionnaires, DHI, and CIEV, were applied. Statistical analysis was performed in which the Cronbach's alpha verified the internal consistency of the CIEV. Reliability and validity of the CIEV related to the DHI were calculated using Intraclass Correlation Index (ICC) and Pearson's correlation test, respectively. There was a statistically significant correlation between the scores obtained, for both reliability and validation analysis (p<0.001). The mean ICC showed a moderate correlation between the total scores (0.695) and a strong correlation with the physical, emotional, and functional DHI domains (0.706 to 0.869), being the emotional aspect the highest degree (0.869). Pearson's correlation showed strong correlation between the total scores (r=0.820) and varied from moderate to strong, with strongest correlations to the DHI emotional domain (r=0.788). The outcomes illustrate important contribution to validation parameters to consider clinical use of the CIEV in the Brazilian population, aiming to identify emotional aspects in patients with balance disorders.


Coadaptation: a unifying principle in evolutionary thermal biology.
Over the last 50 yr, thermal biology has shifted from a largely physiological science to a more integrated science of behavior, physiology, ecology, and evolution. Today, the mechanisms that underlie responses to environmental temperature are being scrutinized at levels ranging from genes to organisms. From these investigations, a theory of thermal adaptation has emerged that describes the evolution of thermoregulation, thermal sensitivity, and thermal acclimation. We review and integrate current models to form a conceptual model of coadaptation. We argue that major advances will require a quantitative theory of coadaptation that predicts which strategies should evolve in specific thermal environments. Simply combining current models, however, is insufficient to understand the responses of organisms to thermal heterogeneity; a theory of coadaptation must also consider the biotic interactions that influence the net benefits of behavioral and physiological strategies. Such a theory will be challenging to develop because each organism's perception of and response to thermal heterogeneity depends on its size, mobility, and life span. Despite the challenges facing thermal biologists, we have never been more pressed to explain the diversity of strategies that organisms use to cope with thermal heterogeneity and to predict the consequences of thermal change for the diversity of communities.