Suppressive role of NK cells in pokeweed mitogen-induced immunoglobulin synthesis: effect of depletion/enrichment of Leu 11b+ cells.
Natural killer (NK) cells probably have immunoregulatory effects. However, the evidence to date is mainly based on the suppressive effect of enrichment with relatively impure NK populations (large granular lymphocytes, LGL, Leu 7a+ cells). Here we report on the effect of enrichment and depletion of Leu 7a+ and Leu 11b+ cells (the latter containing virtually all NK activity in freshly prepared lymphocytes) on pokeweed mitogen (PWM)-induced immunoglobulin (Ig) synthesis. Enrichment suppressed Ig synthesis to a degree dependent on the number of cells added, and was not enhanced further by their pretreatment with interferon. Furthermore, depletion of Leu 11b+ cells from peripheral blood lymphocytes (PBL) led to marked enhancement (2-25-fold increase) of Ig synthesis, suggesting these cells may normally exert a suppressive effect. The possible underlying mechanisms were investigated further. Enhanced Ig synthesis by Leu 11b-depleted cultures was associated with an increased number of Ig-secreting cells by plaque assay, but with no change in numbers of CD4+ or CD8+ cells. Treatment of PBL with monoclonal antibodies (anti-Leu 7a/Leu 11b) alone suppressed PWM-induced immunoglobulin synthesis. We conclude that NK cells play a role in the regulation of Ig production, at least in part by an effect on activation/differentiation of B cells, but independent of altered T-cell subpopulations. The effect may be unrelated to their cytotoxic function (being unaffected by interferon, IFN), although the direct effects of anti-Leu 11b and Leu 7a in enhancing the suppressive effect suggest an alternative activation pathway.


Inhibin A and activin A in the first trimester of human pregnancy.
Recent studies show that high concentrations of inhibin A and activin A are present in the maternal serum throughout human pregnancy. The aim of this study was to determine whether the corpus luteum produces significant quantities of inhibin A and activin A during the first trimester of pregnancy. This prospective study examined two groups of women who had blood samples taken from 5-12 weeks gestation. One group consisted of 14 women with donor egg pregnancies (8 singletons and 6 multiples) who did not have corpora lutea, and the other group consisted 5 women with spontaneous pregnancies who had corpora lutea. Inhibin A and activin A were measured at weekly intervals using specific enzyme immunoassays. All pregnancies progressed to term, with healthy babies being delivered. Maternal serum concentrations of inhibin A significantly increased throughout the study period in the donor egg pregnancies (P < 0.001) and the control pregnancies (P < 0.001). Circulating concentrations of activin A also increased significantly in both the spontaneous and donor egg pregnancies (P < 0.001) during the study period. However, the concentrations of inhibin A and activin A in the first trimester of human pregnancy were not significantly different in the women with or without corpora lutea, suggesting a fetoplacental origin. Multiple donor egg pregnancies were found to have higher concentrations of inhibin A (P < 0.001) and activin A (P < 0.05) compared with singleton donor egg pregnancies, which also supports a placental source.


Systematic Review of Sleep Disturbances and Circadian Sleep Desynchronization in Autism Spectrum Disorder: Toward an Integrative Model of a Self-Reinforcing Loop.
Background: A compelling number of studies, conducted in both children and adults, have reported an association between sleep disturbances/circadian sleep alterations and autism spectrum disorder (ASD); however, the data are sparse and the nature of this link is still unclear. The present review aimed to systematically collect the literature data relevant on sleep disturbances and circadian sleep dysrhythmicity related to ASD across all ages and to provide an integrative theoretical framework of their association. Methods: A systematic review of the MEDLINE, PubMed, and Cochrane databases was conducted from November 2018 to February 2019. The search strategies used were MeSH headings and keywords for "sleep-wake circadian rhythms" OR "circadian sleep disorders" OR "sleep-wake pattern" OR "sleep disorders" OR "melatonin" AND "autism spectrum disorder" OR "autism". Results: One hundred and three studies were identified, 15 regarded circadian sleep dysrhythmicity, 74 regarded sleep disturbances, and 17 regarded melatonin alterations in children and adults with ASD. Our findings suggested that autistic subjects frequently present sleep disturbances in particular short sleep duration, low sleep quality/efficiency, and circadian sleep desynchronization such as delayed phases and/or eveningness. Sleep disturbances and circadian sleep alterations have been related to the severity of autistic symptoms. Genetic studies have shown polymorphisms in circadian CLOCK genes and in genes involved in melatonin pathways in subjects with ASD. Conclusions: Sleep disturbances and circadian sleep alterations are frequent in subjects with autistic symptoms. These subjects have shown polymorphisms in clock genes expression and in genes involved in melatonin production. The impairment of circadian sleep regulation may increase the individual's vulnerability to develop symptoms of ASD by altering the sleep regulation in toto, which plays a key role in normal brain development. Even though controversies and "research gaps" are present in literature at this point, we may hypothesize a bidirectional relation between circadian sleep dysfunction and ASD. In particular, circadian sleep dysrhythmicity may predispose to develop ASD symptoms and vice versa within a self-reinforcing feedback loop. By targeting sleep disturbances and circadian sleep dysrhythmicity, we may improve treatment strategies for both children and adults with ASD.


Effects of ingestion of grapefruit juice or grapefruit on the hypotensive effect and plasma concentrations of dihydropyridine calcium antagonists (amlodipine and nifedipine): a case study.
The purpose of this study was to examine the effects of ingestion of grapefruit juice or grapefruit on the hypotensive effect and plasma concentration of dihydropyridine calcium antagonists, i.e., amlodipine and nifedipine. A 50-year-old man with essential hypertension was studied. Grapefruit juice (500 ml) was taken together with the antihypertensive drug, while one grapefruit was taken before drug ingestion. Blood pressures were measured using a digital automatic blood pressure monitor over a certain period. A single ingestion of grapefruit juice had no effect on plasma amlodipine concentration, but rapidly increased plasma nifedipine concentration and decreased blood pressure, while the effect on blood pressure was short-lasting. Grapefruit had no effect on either drug. It should be of concern that ingestion of a relatively large volume of grapefruit juice causes rapid decrease in blood pressure when the subject is treated by nifedipine.


The effects of the ergosteroid 7-oxo-dehydroepiandrosterone on mitochondrial membrane potential: possible relationship to thermogenesis.
Administered 3 beta-hydroxyandrost-5-ene-7,17-dione (7-oxo-DHEA) is more effective than 3 beta-hydroxyandrost-5-en-7-one (DHEA) as an inducer of liver mitochondrial sn-glycerol-3-phosphate dehydrogenase and cytosolic malic enzyme in rats. Like DHEA, the 7-oxo metabolite enhances liver catalase, fatty acylCoA oxidase, cytosolic sn-glycerol-3-phosphate dehydrogenase, mitochondrial substrate oxidation rate, and the reconstructed sn-glycerol 3-phosphate shuttle. The mitochondrial adenine nucleotide carrier is diminished by thyroidectomy and is restored to normal activity by administering 7-oxo-DHEA. The relationship between respiratory rate and proton motive force across the mitochondrial membrane was measured in the nonphosphorylating state. When treated with increasing concentrations of respiratory inhibitors liver mitochondria from rats treated with 7-oxo-DHEA or thyroid hormones show a more rapid decline of membrane potential than do normal liver mitochondria. Thus 7-oxo-DHEA induces an increased proton leak or slip as has been reported for the thyroid hormone by M.D. Brand [(1990) Biochem. Biophys. Acta 1018, 128-133]. This process may contribute to the enhanced thermogenesis caused by ergosteroids as well as by thyroid hormones.


Multi-day delay to care identified in pediatric trauma cases during COVID-19.
This study aims to establish how pediatric fracture patterns were altered at a level 1 trauma center in a state that implemented a shutdown during the initial height of COVID-19. After IRB approval, we identified 2017 patients treated at a pediatric institution for definitive management of a fracture between 26 March and 31 May 2018, 2019, or 2020. Dates were chosen based on statewide stay-at-home orders for Colorado. Patients were excluded for treatment at another institution (n = 148), no fracture noted in clinic (n = 18), or other (n = 13). Data were retrospectively collected from the remaining 1838 patients regarding demographics, fracture injury, mechanism, and treatment. Odds ratios (ORs) were calculated for each variable during COVID-19 relative to prior years. The number of fractures during 2020 decreased by 26% relative to 2019 and 23% to 2018. A larger proportion of patients experienced at least a 5-day delay to definitive treatment [OR: 1.55, confidence interval (CI): 1.23-1.96, P = 0.0002]. Rates of non-accidental trauma (NAT) increased non-significantly (OR: 2.67, CI: 0.86-8.32, P = 0.0900) during 2020 (1.2%) relative to 2018 (0.6%) and 2019 (0.3%). Fractures occurring at home increased to 79.9% (OR: 6.44, CI: 5.04-8.22, P < 0.0001). Despite less overall trauma during shelter-in-place orders, greater fracture numbers were seen among younger children and severe fractures were likely among older children. Patients may hesitate to seek care during 2020. Rates of NAT doubled during 2020. As communities prepare for future waves, treatment centers should warn against common fracture mechanisms and raise awareness of NAT.


Facial Skin Cancer Reconstruction.
Nonmelanoma skin cancers are the most common skin cancers in the United States and the most common malignancies afflicting the head and neck region. Reconstruction of resulting defects has significant aesthetic and functional implications, and plastic surgeons are frequently consulted for reconstruction. Reconstruction can be accomplished via a multitude of approaches spanning the reconstructive ladder, and the approach should be individualized based upon both patient-related and defect-related factors. Here the authors propose a simplified approach to facial reconstruction broken down by aesthetic region.


Prednisone-induced osteoporosis: an overlooked and undertreated adverse effect.
Glucocorticoids are used for a variety of medical conditions. This class of drugs is arguably the most common cause of iatrogenic osteoporosis, but studies have shown that physicians are not investigating and treating glucocorticoid-induced osteoporosis. To determine whether primary care physicians (osteopathic and allopathic) are evaluating and treating adult patients at risk for osteoporosis secondary to long-term prednisone use. Electronic medical records from three primary care practices (family medicine, geriatric medicine, and internal medicine) were retrospectively reviewed to identify patients who were taking at least 2.5 mg of prednisone per day for 8 weeks or longer. Records were then grouped according to whether patients had undergone bone mineral density screening and had been given therapy to prevent or treat bone loss. Whether patients had comorbid risk factors for secondary osteoporosis (according to the National Institutes of Health Consensus Development Conference Statement on Osteoporosis) was noted to determine whether treatment was given because of prednisone use or because of the comorbid risk factors. Statistical analysis was performed using a Pearson product moment correlation 2-tailed chi2 test. The medical records of 49 patients met inclusion criteria (19 men, 30 women; mean age, 61 years; age range, 21-89 years). A statistically significant difference was found in physician evaluation practices for patients with vs patients without comorbid risk factors (82.1% vs 38.1%; P=.002). Primary care physicians do not routinely evaluate patients for osteoporosis secondary to glucocorticoid treatment, especially when patients do not have comorbid risk factors for osteoporosis.


Green Synthesis of Fluorescent Palladium Nanoclusters.
Metal nanoclusters, with dimensions between atomic and nanoparticles, have attracted a great deal of attention due to their significantly unusual properties. Water-soluble palladium nanoclusters (Pd NCs) with blue-green fluorescence were synthesized by a water bath heating method, with methionine as a stabilizer and ascorbic acid as a reducing agent. We investigated the optimal synthesis conditions, stability, and pH response of the obtained products in detail. The synthesized materials were characterized by ultraviolet-absorption spectroscopy, fluorescence spectroscopy, high-resolution transmission electron microscopy, and atomic force microscopy. These experimental results showed that the Pd NCs had a small size of ~1.91 nm, with a uniform size distribution. Additionally, the Pd NCs emitted blue-green fluorescence under ultraviolet light with a quantum yield of 5.47%. Notably, both stabilizers and reducing agents used in this synthesis method are nutrients for humans, non-toxic, and harmless. This method could be viewed as a biologically friendly and green way of preparing fluorescent metal nanoclusters. The as-prepared fluorescent Pd NCs also possessed excellent fluorescence detection ability and were very sensitive to low concentrations of hemoglobin, with a linear response in the range of 0.25-3.5 μM and a detection limit of 50 nM.


Analysis of clinicopathologic prognostic features in patients with gastric adenocarcinoma.
We evaluated the influence of several clinicopathologic variables on 5-year actuarial survival rate after curative resection of gastric adenocarcinoma. Clinical characteristics were retrieved from the records of all patients who underwent gastric resection for curative intent between 1965 and 1986 at The University of Chicago Medical Center, and follow-up was obtained from our tumor registry. Pathologic characteristics were determined from a detailed review of all available histopathologic slides. One hundred seventy-eight patients underwent a curative resection during the study period at our institution. Overall 5-year actuarial survival rate was 29%. The relationship between clinicopathologic variables and 5-year survival rate was evaluated by Kaplan-Meier survival curve construction and chi-squared analysis. Lymphatic and/or capillary microinvasion (absent vs present, p < 0.001), tumor location (antrum and body vs gastroesophageal junction, p = 0.05), local extent of disease (limited to the gastric wall versus involving adjacent organs, p = 0.003), stage (absence versus presence of lymph node metastases, p < 0.001), Lauren type (intestinal versus diffuse, p < 0.01), and Ming type (expanding versus infiltrative, p < 0.02) significantly influenced survival. When a multivariate analysis with logistic regression of 5-year survival was performed, lymphatic and/or capillary microinvasion emerged as the only statistically significant, independent prognostic factor associated with long-term survival (p = 0.039). If microinvasion was omitted from the analysis, lymph node metastases (p < 0.05) and the extension to adjacent organs (p < 0.04) became the only statistically significant variables. Multiple correlation analyses suggested that microinvasion is an early histopathologic finding that correlates with a more aggressive natural history. Lymphatic and/or capillary microinvasion is a more powerful predictor of 5-year survival than lymph node metastases or tumor extension to adjacent organs. Correlation among clinicopathologic variables suggests that microinvasion may represent an early finding, serving as a potential marker for a biologically more aggressive tumor.


An evaluation of thyroid hormone status and oxidative stress in undialyzed chronic renal failure patients.
Chronic renal failure (CRF) patients on prolonged dialysis have been found to have significant alteration in their thyroid status, but little is known about the same in undialyzed CRF patients. Oxidative stress has been implicated as the key player in altering the levels of thyroid hormone in euthyroid sick syndrome. This study was performed to evaluate the levels of oxidative stress and thyroid status in undialyzed CRF patients. A case control study was performed on 20 undialyzed CRF patients and 20 control subjects. There was a significant decrease in the levels of T3, T4, total protein and albumin levels in CRF patients when compared to control. There was a significant increase in the level of malondialdehyde and total antioxidant status in CRF patients when compared with control subjects. The present study confirms oxidative stress along with altered thyroid status in CRF patients.


Functional characterization of a transition metal ion transporter, OsZIP6 from rice (Oryza sativa L.).
Micronutrients are important for the growth and development of plants, which deploy families of transporters for their uptake and distribution. We have functionally characterized a novel transition metal ion transporter from rice, OsZIP6 (Oryza sativa zinc regulated transporter, iron regulated transporter-like protein 6). The transporter was found to be transcriptionally activated in shoot and root tissues in response to deficiency in Fe(2+), Zn(2+) and Mn(2+). OsZIP6 was expressed in Xenopus laevis oocytes, where currents were observed on addition of Co(2+), Fe(2+) and Cd(2+) but not Zn(2+), Mn(2+) and Ni(2+). This substrate range for OsZIP6, identified using two-electrode voltage clamp electrophysiology was confirmed by atomic absorption spectroscopy. Ion transport by OsZIP6 was found to be pH dependent and enhanced transport was observed at acidic pH. Radioisotope uptake suggested that Co(2+) competitively inhibits Fe(2+) uptake by OsZIP6. Identification and characterization of ZIP family members from crop plants will contribute to an understanding of nutrient mineral homeostasis in these plants.


Oral administration of cyclosporin A for recipients of allogeneic marrow transplants: implications of clinical gut dysfunction.
Cyclosporin A (CyA) was used to minimize graft-versus-host disease (GVHD) in 28 recipients of allogeneic marrow transplants. When given orally, the absorption of CyA was markedly dependent on normal gut function. Patients without gut dysfunction showed normal serum concentration-time curves while those with diarrhoea from any cause (chemo-radiation enteritis, acute GVHD of the gut, infectious enteritis) showed minimal absorption of the drug. These data indicate the desirability of the intravenous administration of CyA during periods of gut dysfunction in marrow transplant recipients.


Copy Number Variation in Acetolactate Synthase Genes of Thifensulfuron-Methyl Resistant Alopecurus aequalis (Shortawn Foxtail) Accessions in Japan.
Severe infestations of Alopecurus aequalis (shortawn foxtail), a noxious weed in wheat and barley cropping systems in Japan, can occur even after application of thifensulfuron-methyl, a sulfonylurea (SU) herbicide. In the present study, nine accessions of A. aequalis growing in a single wheat field were tested for sensitivity to thifensulfuron-methyl. Seven of the nine accessions survived application of standard field rates of thifensulfuron-methyl, indicating that severe infestations likely result from herbicide resistance. Acetolactate synthase (ALS) is the target enzyme of SU herbicides. Full-length genes encoding ALS were therefore isolated to determine the mechanism of SU resistance. As a result, differences in ALS gene copy numbers among accessions were revealed. Two copies, ALS1 and ALS2, were conserved in all accessions, while some carried two additional copies, ALS3 and ALS4. A single-base deletion in ALS3 and ALS4 further indicated that they represent pseudogenes. No differences in ploidy level were observed between accessions with two or four copies of the ALS gene, suggesting that copy number varies. Resistant plants were found to carry a mutation in either the ALS1 or ALS2 gene, with all mutations causing an amino acid substitution at the Pro197 residue, which is known to confer SU resistance. Transcription of each ALS gene copy was confirmed by reverse transcription PCR, supporting involvement of these mutations in SU resistance. The information on the copy number and full-length sequences of ALS genes in A. aequalis will aid future analysis of the mechanism of resistance.


Giant orbital paramagnetism in toroidal carbon nanopeapods.
The electronic structure and the magnetic response of toroidal carbon nanopeapods (TCNPs) are investigated within the sp(3) tight-binding formalism. It is found that in the presence of mirror symmetry, there exists a level crossing at the Fermi level in the energy spectrum of a TCNP, leading to giant orbital paramagnetism (GOP), in spite of the curvatures and hybridizations of the outer toroidal carbon nanotube (TCN). When the mirror symmetry is broken by rotating the inner C(60)s, however, two level crossings appear at the Fermi level, and the GOP changes into a very small diamagnetic response. The results reveal the GOP in a filled TCN, depending on the characteristics of the filling materials and temperature.


The effect of clothes on blood pressure measurement.
To determine the effect of clothes on blood pressure measurement. One group pretest-posttest design was used in this study. The study consisted of 162 undergraduate students studying nursing and physiotherapy at a university in Ankara, Turkey. Blood pressure was measured over the sleeve and below a rolled-up sleeve with a mercury-filled column sphygmomanometer. All blood pressure measurements were performed on the right arm during morning hours by the same nurse. Each participant's height, weight and clothing thickness were measured. The mean age of the participants was 20.71. The median systolic blood pressure values were 110.07 mmHg over the sleeve and 110.37 mmHg below the rolled-up sleeve. There were no statistically significant differences between measurements taken over the sleeve and below a rolled-up sleeve (p=0.222). The median diastolic blood pressure values were 69.56 mmHg over the sleeve and 69.59 mmHg below the rolled-up sleeve. There were no statistically significant differences between measurements taken over the sleeve and below a rolled-up sleeve (p=0.572). It was found that clothes have no statistically significant effect on systolic/diastolic blood pressure measurements. Measuring blood pressure over a sleeve may save time.


Pediatric flexible airway endoscopy.
Flexible airway endoscopy has been used in clinical and research investigations of pediatric airway and pulmonary disorders for nearly 25 years. Not only has clinical use of the flexible bronchoscope improved our evaluation and management of a variety of airway and pulmonary diseases in children, but also research investigations using lavage and biopsy specimens obtained with the flexible bronchoscope have contributed extensively to our understanding of lung inflammation and infection. Improvements and new developments in fiberoptic endoscope technology, training of airway endoscopists, preoperative and sedative medications, patient monitoring, and airway endoscopic techniques, as well as adjunctive minimally invasive and noninvasive diagnostic modalities, continue to refine and enhance the pediatric clinical and research applications of flexible airway endoscopy.


AgRP-Expressing Adrenal Chromaffin Cells Are Involved in the Sympathetic Response to Fasting.
Fasting evokes a homeostatic response that maintains circulating levels of energy-rich metabolites and increases the drive to eat. Centrally, this reflex activates a small population of hypothalamic neurons that are characterized by the expression of AgRP, a neuropeptide with an extremely restricted distribution. Apart from the hypothalamus, the only other site with substantial expression is the adrenal gland, but there is disagreement about which cells synthesize AgRP. Using immunohistochemistry, flow cytometry, and reverse transcription-polymerase chain reaction, we show AgRP is present in the mouse adrenal medulla and is expressed by neuroendocrine chromaffin cells that also synthesize the catecholamines and neuropeptide Y. Short-term fasting led to an increase in adrenal AgRP expression. Because AgRP can act as an antagonist at MC3/4 receptors, we tested whether melanotan II, an MC3/4 receptor agonist, could regulate pre- and postsynaptic signaling within the adrenal medulla. Melanotan II decreased the paired-pulse ratio of evoked synaptic currents recorded in chromaffin cells; this effect was blocked by exogenous AgRP. In contrast, neither melanotan II nor AgRP altered the optogenetically evoked release of catecholamines from isolated chromaffin cells. These results are consistent with the idea that AgRP regulates the strength of the sympathetic input by modulation of presynaptic MC3/4 receptors located on preganglionic neurons. We conclude that a small population of neuroendocrine cells in the adrenal medulla, and the arcuate nucleus of the hypothalamus, express AgRP and neuropeptide Y and are functionally involved in the systemic response to fasting.


Strong uniaxial magnetic anisotropy in Co films on highly ordered grating-like nanopatterned Ge surfaces.
We present a systematic investigation on uniaxial magnetic anisotropy (UMA) in Co thin films induced by high aspect ratio nanopatterned anisotropic substrates. Self-organized long grating-like nanostructures, with extreme regularities, are fabricated on Ge surfaces using Au-ion implantation at room temperature. Subsequently deposition of Co films are carried out on the same at two different angles. Magneto-optical Kerr effect measurements show strong UMA in Co films grown on ion-patterned Ge substrates, fabricated under different ion fluences, along and perpendicular to the direction of the patterns (long grating-like nanostructures). Magnetic force microscopy measurements under different externally applied magnetic fields reveal an easy domain wall motion when the field is applied along the grating-like nanostructures. On the other hand, high amplitude grating-like nanostructures hinder the spin rotation when the field is applied along the hard axis. The present study will be useful for magnetic recording media and ultra-small magnetic field sensors.


Inhibition of mammalian cathepsins by Plesiomonas shigelloides.
To study molecular mechanisms underlying self-defense of the bacterial pathogen Plesiomonas shigelloides against host inflammatory and immune responses, we evaluated its interactions with mammalian papain-like cathepsins that are essential for host immunity. When grown under anaerobic, but not aerobic, conditions, P. shigelloides was shown to bind and inhibit papain, a model representative of the papain family of cysteine proteinases. This points to mammalian cathepsins as likely physiological targets of a novel cysteine-proteinase inhibitor expressed on bacterial cell surface. Both papain and mammalian cathepsins L and B were inhibited by periplasmic extracts of aerobically and anaerobically grown bacteria, the inhibitory activity being higher in the latter. Inhibition by both intact cells and periplasmic samples was rapid and efficient. The results suggest a possible defensive role of bacterial inhibitors of cathepsins during invasion of a mammalian host. The bacteria thus may modulate host protective responses through inhibiting cathepsins involved in antigen processing and presentation.


Re-induction as a possible alternative modality of dose escalation of infliximab: a prospective evaluation in a small series of psoriatic patients.
Infliximab is an anti-tumour necrosis factor-alpha chimeric monoclonal antibody which is highly effective in psoriasis, as well as in other indications. In clinical practice, some patients may require dose escalation to overcome a reduction of the extent and/or duration of response during regular maintenance treatment, possibly due to the loss of stable serum concentrations of the drug. Common strategies of dose escalation are the increase of dose per infusion and the decrease of interval between infusions. Here we report the results of re-induction therapy with infliximab used as a dose escalation strategy in 9 patients whose psoriasis relapsed during maintenance treatment with infliximab 5 mg/kg every 8 weeks. Re-induction was well tolerated and capable of restoring response in 8 of these patients.


Transmural action potential and ionic current remodeling in ventricles of failing canine hearts.
Heart failure (HF) produces important alterations in currents underlying cardiac repolarization, but the transmural distribution of such changes is unknown. We therefore recorded action potentials and ionic currents in cells isolated from the endocardium, midmyocardium, and epicardium of the left ventricle from dogs with and without tachypacing-induced HF. HF greatly increased action potential duration (APD) but attenuated APD heterogeneity in the three regions. Early afterdepolarizations (EADs) were observed in all cell types of failing hearts but not in controls. Inward rectifier K(+) current (I(K1)) was homogeneously reduced by approximately 41% (at -60 mV) in the three cell types. Transient outward K(+) current (I(to1)) was decreased by 43-45% at +30 mV, and the slow component of the delayed rectifier K(+) current (I(Ks)) was significantly downregulated by 57%, 49%, and 58%, respectively, in epicardial, midmyocardial, and endocardial cells, whereas the rapid component of the delayed rectifier K(+) current was not altered. The results indicate that HF remodels electrophysiology in all layers of the left ventricle, and the downregulation of I(K1), I(to1), and I(Ks) increases APD and favors occurrence of EADs.


Ultracytochemical localization of alkaline phosphatase in swine gonadotropic cells.
In swine gonadotropic (SGT) cells, the alkaline phosphatase (APase) activity was ultracytochemically demonstrated on the outer surface of the plasma membrane and in some vesicles in the cytoplasm. The plasma membrane-associated APase activity was sporadically detected on the outer surface and was intense at the site adjacent to the next SGT cells or follicular cells. APase-positive vesicles occurred around the Golgi apparatus and in the periphery of SGT cells. Some of the vesicles positive for APase activity attached to the plasma membrane. These results suggest that APase is synthesized in SGT cells and moves to the plasma membrane.


Experimental study of the incoherent spectral weight in the photoemission spectra of the misfit cobaltate [Bi_{2}Ba{2}O{4}][CoO{2}]{2}.
Previous angle-resolved photoemission spectroscopy experiments in NaxCoO2 reported both a strongly renormalized bandwidth near the Fermi level and moderately renormalized Fermi velocities, leaving it unclear whether the correlations are weak or strong and how they could be quantified. We explain why this situation occurs and solve the problem by extracting clearly the coherent and incoherent parts of the band crossing the Fermi level. We show that one can use their relative weight to estimate self-consistently a quasiparticle weight Z=0.15+/-0.05. We suggest this method could be a reliable way to study the evolution of correlations in cobaltates and for comparison with other strongly correlated systems.


Human eccrine hamartoma of the forearm-antebrachial organ of the ringtailed lemur (Lemur catta). A possible phylogenetic relationship?
A 31-year-old woman presented with a clinically otherwise unsuspicious area of profuse sweating on her right forearm. Without triggering agents, sweating attacks producing a clear, serous fluid were observed daily. Histopathologic examination of a biopsy specimen showed hyperplastic eccrine glands with pale, stippled cytoplasm characteristic of eccrine hamartoma. No explanation, however, has been given for the fact that several authors observed eccrine hamartomas in the same anatomical location. Adolescent lemurs of the species catta (ringtailed lemur) are equipped with a pair of antebrachial cutaneous glands located on the volar surface of the wrist. They exude a clear secretion enabling them to "brachial branch mark" their territories. Histopathologic findings in the ringtailed lemur's antebrachial organ show characteristics of both apocrine and eccrine glands. In contrast to normal apocrine glands, however, the antebrachial organs of ringtailed lemurs reach the epidermis directly and are not connected to hair follicles. According to the "biogenetic law" of Ernst Haeckel, stating that ontogeny has to be seen as a short and incomplete repetition of phylogeny, a human fetus passes all evolutional stages from a single cell via amphibians and mammals to a human being. Thus, the antebrachial organ of the ringtailed lemur may be the "phylogenetic explanation" for eccrine hamartomas of the forearm in humans. The histopathologic findings of the antebrachial organ and of eccrine hamartomas are in accordance with this hypothesis.


Aberrant Resting-State Functional Brain Connectivity of Insular Subregions in Obstructive Sleep Apnea.
The insular cortex is a cortical regulatory area involved in dyspnea, cognition, emotion, and sensorimotor function. Previous studies reported that obstructive sleep apnea (OSA) shows insular tissue damage and abnormal functional connections for the whole insula. The insula can be divided into different subregions with distinct functional profiles, including the ventral anterior insula (vAI) participating in affective processing, dorsal anterior insula (dAI) involved in cognitive processing, and posterior insula (PI) involved in the processing of sensorimotor information. However, the functional connectivity (FC) of these insular subregions in OSA has yet to be established. Hence, the purpose of this study was to explore the resting-state FC of the insular subregions with other brain areas and its relationship with clinical symptoms of OSA. Resting-state functional magnetic resonance imaging data from 83 male OSA patients and 84 healthy controls were analyzed by whole-brain voxel-based FC using spherical seeds from six insular subregions, namely, the bilateral vAI, dAI, and PI, to identify abnormalities in the insular subregions network and related brain regions. Ultimately, the Pearson correlation analysis was carried out between the dysfunction results and the neuropsychological tests. Compared with the healthy control group, the OSA patients exhibited disturbed FC from the dAI to areas relevant to cognition, such as the bilateral cerebellum posterior lobe, superior frontal gyrus, right middle frontal gyrus and middle temporal gyrus; decreased FC from the vAI to areas linked with emotion, such as the bilateral fusiform gyrus, superior parietal lobule, precuneus and cerebellum posterior lobe; and abnormal FC from the PI to the brain regions involved in sensorimotor such as the bilateral precentral gyrus, right superior/middle temporal gyrus and left superior frontal gyrus. The linear regression result showed that the apnea-hypopnea index was positively correlated with the increased FC between the right PI and the right precuneus (after Bonferroni correlation, P < 0.001) In conclusion, the abnormal FC between insular subregions and other brain regions were related to cognitive, emotional and sensorimotor networks in OSA patients. These results may provide a new imaging perspective for further understanding of OSA-related cognitive and affective disorders.


Ringer's acetate and dextran-70 with or without hypertonic saline in endotoxin-induced shock in pigs.
The effects of Ringer's acetate, 6% dextran-70, 7.5% NaCl, and the combination of 7.5% NaCl and dextran-70 were tested in resuscitation from endotoxin shock induced by continuous iv infusion of Escherichia coli endotoxin in pigs. After about 3 h, a reproducible shock state was achieved and treatment was started, governed by the left atrial pressure. The hypertonic solutions (7.5% NaCl and 7.5% NaCl in dextran-70) did not show any overall advantages over the isotonic solutions (Ringer's acetate and dextran-70). Only transient beneficial hemodynamic effects lasting less than 30 min after infusion were seen. When dextran-70 was administered, cardiovascular function was markedly improved and oxygen delivery (DO2) and survival were significantly higher compared with the crystalloid groups (Ringer's acetate and 7.5% NaCl). Administration of large amounts of Ringer's acetate resulted in an immediate deterioration of pulmonary function. It was difficult to elevate left atrial pressure or even to keep it at baseline level, and cardiac index was only transiently increased. The overall result was a deterioration of DO2 and poor survival compared with the dextran-70 treated pigs. We conclude that dextran-70 is superior to Ringer's acetate in resuscitation from endotoxin-induced shock in pigs. Furthermore, we found no role for the use of hypertonic saline, alone or in combination with dextran, in the treatment of this type of prolonged endotoxin shock.


[Feasibility of using human spleen cells to produce interferon].
Spleen cells of subjects who died suddenly are capable of producing large amounts of interferon in response to induction with Newcastle disease virus (NDV) and Sendai virus (1-2.5 IU per 1000 cells). The optimal conditions for interferon production by these cells include using NDV, the H strain, as an inducer in a dose of 10 ID50/cell and fresh spleen cells stored no more than 24 hours at 4-6 degrees C in a concentration of 0.5-1.0 x 10(7)/ml, with the incubation time of 20-24 hours. It is recommended that spleen cells from subjects who died suddenly be used for human interferon production.


Development and Implementation of an Asynchronous Online Interprofessional Course in LGBTQ+ Health.
The lesbian, gay, bisexual, transgender, and queer or questioning (LGBTQ+) community faces discrimination in health care. Nurses interact with LGBTQ+ individuals in a wide variety of health care settings. Baccalaureate nursing and health professions students do not receive adequate education on topics of LGBTQ+ health in academic or clinical settings, and additional nursing education is needed on LGBTQ+ health. Existing courses were analyzed, and themes and structures were assessed. Course learning outcomes were developed, along with a timeline and a course outline. The course was structured as an asynchronous online course to be deployed in a learning management system. A senior-level asynchronous online nursing elective course was developed on LGBTQ+ health for an urban public university. The course was structured using a life-span approach with additional topics. Widespread development of courses on LGBTQ+ health should be implemented in all schools of nursing. [J Nurs Educ. 2023;62(10):584-588.].


Growth enhancement in suppressor of cytokine signaling 2 (SOCS-2)-deficient mice is dependent on signal transducer and activator of transcription 5b (STAT5b).
Mice lacking suppressor of cytokine signaling-2 (SOCS-2) exhibit accelerated postnatal growth resulting in adult mice that are 1.3 to 1.5 times the size of normal mice. In this study we examined the somatotrophic pathway to determine whether the production or actions of GH or IGF-I are altered in these mice. We demonstrated that SOCS-2(-/-) mice do not have elevated GH levels and suffer no major pituitary dysmorphogenesis, and that SOCS-2-deficient embryonic fibroblasts do not have altered IGF-I signaling. Primary hepatocytes from SOCS-2(-/-) mice, however, did have moderately prolonged signal transducer and activator of transcription 5 signaling in response to GH stimulation. Furthermore, the deletion of SOCS-2 from mice also lacking signal transducer and activator of transcription 5b had little effect on growth, suggesting that the action of SOCS-2 may be the regulation of the GH signaling pathway.


[«Verschroben»-phenomenon in schizophrenia and schizophrenia spectrum disorders: aspects of systematics].
Psychopathological analysis and typological differentiation of «verschroben»-phenomenon as the full-blown syndrome of defect in schizophrenia and schizophrenia spectrum disorders. Fifty patients, 33 female and 17 male, mean age 44.8±8.5 years, with ICD-10 diagnosis of schizotypal disorder (F21) and residual schizophrenia (F20.5) were included in the study. Patients were examined using psychopathological and psychometric (SPQ-74) methods. There was clinical heterogeneity of the «verschroben» type defect: the differentiation of primary defect syndrome and the «second life» defect was confirmed. This typological classification is based not only on the differences in psychopathological symptoms and impaired social functioning but on the trajectory of the development of deficit syndromes related with the features of the course of endogenous disease. The typology would be useful for future studies of deficit changes in view of clinical prognosis, social context of schizophrenia spectrum disorders with negative «verschroben» type changes.


Nonhuman Primate Studies to Advance Vision Science and Prevent Blindness.
Most primate behavior is dependent on high acuity vision. Optimal visual performance in primates depends heavily upon frontally placed eyes, retinal specializations, and binocular vision. To see an object clearly its image must be placed on or near the fovea of each eye. The oculomotor system is responsible for maintaining precise eye alignment during fixation and generating eye movements to track moving targets. The visual system of nonhuman primates has a similar anatomical organization and functional capability to that of humans. This allows results obtained in nonhuman primates to be applied to humans. The visual and oculomotor systems of primates are immature at birth and sensitive to the quality of binocular visual and eye movement experience during the first months of life. Disruption of postnatal experience can lead to problems in eye alignment (strabismus), amblyopia, unsteady gaze (nystagmus), and defective eye movements. Recent studies in nonhuman primates have begun to discover the neural mechanisms associated with these conditions. In addition, genetic defects that target the retina can lead to blindness. A variety of approaches including gene therapy, stem cell treatment, neuroprosthetics, and optogenetics are currently being used to restore function associated with retinal diseases. Nonhuman primates often provide the best animal model for advancing fundamental knowledge and developing new treatments and cures for blinding diseases.


Na,K-ATPase subunit isoforms in human reticulocytes: evidence from reverse transcription-PCR for the presence of alpha1, alpha3, beta2, beta3, and gamma.
The objective of this study has been to determine which Na,K-ATPase isoforms are expressed in red blood cells and whether kinetic differences in the uncoupled sodium efflux mode between the human red blood cell Na,K-ATPase and other preparations can be explained by differences in the underlying subunit composition. To this end, human reticulocyte RNA was isolated, reverse transcribed, amplified by PCR and appropriate primers, and sequenced. Primers from highly conserved areas as well as isoform-specific primers were used. The alpha1 and alpha3 isoforms of the alpha subunit, and the beta2 and beta3 isoforms of the beta subunit were found. The complete coding regions of the cDNAs for the reticulocyte subunits were sequenced from overlapping PCR fragments. No difference was found between the reticulocyte isoforms and the ones already known. The fact that we found beta2 but not beta1 in reticulocyte single-stranded cDNA, and beta1 but not beta2 in a leukocyte library indicates that leukocyte contamination of our reticulocyte preparation was negligible. Analysis of a human bone marrow library showed that alpha1, alpha2, and alpha3 as well as all three beta isoforms were present. The extent to which the kinetic properties of uncoupled sodium efflux might depend on different isoform combinations is not yet known.


Evaluation of CB1 receptor knockout mice in the Morris water maze.
The endocannabinoid system has been proposed to modulate a variety of physiological processes, including those that underlie cognition. The present study tested whether this system is tonically active in learning and memory by comparing CB(1) receptor knockout mice (CB(1)(-/-)) to wild-type mice (CB(1)(+/+)) in several Morris water maze tasks. Also, the effects of three cannabinoid agonists, Delta(9)-tetrahydrocannabinol (Delta(9)-THC), R-(+)-[2,3-dihydro-5-methyl-3[morpholinyl)methyl]-pyrrolo[1,2,3-de]-1, 4-benzoxazinyl]-(1-naphthalenyl)methanone mesylate (WIN 55,212-2), and methanandamide, were evaluated in a working memory procedure. Both genotypes exhibited identical acquisition rates in a fixed platform procedure; however, the CB(1)(-/-) mice demonstrated significant deficits in a reversal task in which the location of the hidden platform was moved to the opposite side of the tank. This phenotype difference was most likely due to an increased perseverance of the CB(1)(-/-) mice in that they continued to return to the original platform location, despite being repeatedly shown the new platform location. In addition, Delta(9)-THC (ED(50) = 1.3 mg/kg), WIN 55,212-2 (ED(50) = 0.35 mg/kg), and methanandamide (ED(50) = 3.2 mg/kg) disrupted the performance of CB(1)(+/+) mice in the working memory task at doses that did not elicit motivational or sensorimotor impairment as assessed in a cued version of the task. Furthermore, doses of each drug that were maximally disruptive in CB(1)(+/+) mice were ineffective in either N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide HCl (SR 141716A)-treated CB(1)(+/+) or CB(1)(-/-) mice. These results provide strong evidence that cannabinoids disrupt working memory through a CB(1) receptor mechanism of action, and suggest that the endocannabinoid system may have a role in facilitating extinction and/or forgetting processes.


[Huntington's disease with childhood and adolescent onset: course of disease, clinical presentation and diagnostic challenges].
Huntington's disease (HD) is an autosomal-dominant neurodegenerative disorder caused by a gene mutation in chromosome 4 that leads to an expansion of CAG - triplet repeats. It occurs mainly between the age of 30 and 50. Only less than 10 % of HD patients are younger than 20 years. In contrast to adult patients young HD patients show more often psychiatric and cognitive symptoms at disease onset than chorea. One third of the children with HD develops an epilepsy.We present 6 children diagnosed with HD in different stages of childhood. We describe first symptoms as well as genetic characteristics and other distinctive features.Both, the clinical presentation and the course of HD in childhood differ from HD in adults. In adolescents the clinical symptoms at onset are often psychiatric (like depression or attention deficit disorder). Choreatic movements typical for adult HD patients are missing.Due to the low prevalence of HD in childhood and the variability of clinical symptoms the process of diagnosing HD in children is difficult. Very often the diagnosis is made years after the first symptoms. Early diagnosis, however, is often important for managing social problems and problems in school.


Evolutionary relationships within the human rhinovirus genus: comparison of serotypes 89, 2, and 14.
The complete nucleotide sequence of the genome of human rhinovirus type 89 was determined from the cDNA that had been cloned into Escherichia coli. The genome is 7152 nucleotides long and contains a single large open reading frame of 2164 codons. Translation commences at position 619 and ends 42 nucleotides before the poly(A) tract. The positions of three proteolytic cleavage sites in the polyprotein were determined by N-terminal amino acid sequencing of the capsid proteins; the remainder were predicted from comparisons with other picornaviruses. Extensive similarity between the derived amino acid sequences of human rhinovirus types 89 and 2 was found, whereas the similarity between human rhinovirus types 89 and 14 was considerably less. It is apparent that human rhinoviruses may be more closely related than has been previously thought.


Strengthening Purity: Moral Purity as a Mediator of Direct and Extended Cross-Group Friendships on Sexual Prejudice.
The present research investigated whether enhanced perceptions of moral purity drive the effects of intergroup cross-group friendships on the intentions to interact with homosexuals. High-school students (N = 639) reported their direct and extended cross-group friendships with homosexuals as well as their beliefs regarding the moral character of the sexual minority. Participants further reported their desire to interact with homosexuals in the future. Results showed that both face-to-face encounters and extended contact with homosexuals increased their perceived moral purity, which in turn fostered more positive behavioral intentions. Results further revealed the specific role of moral purity in this sense, as differential perceptions along other moral domains (autonomy and community) had no mediation effects on behavioral tendencies toward homosexuals. The importance of these findings for improving intergroup relations is discussed, together with the importance of integrating research on intergroup contact and morality.


Friedel Oscillations of Vortex Bound States under Extreme Quantum Limit in KCa_{2}Fe_{4}As_{4}F_{2}.
We report the observation of discrete bound states with the energy levels deviating from the widely believed ratio of 1∶3∶5 in the vortices of an iron-based superconductor KCa_{2}Fe_{4}As_{4}F_{2} through scanning tunneling microscopy (STM). Meanwhile Friedel oscillations of vortex bound states are also observed for the first time in related vortices. By doing self-consistent calculations of Bogoliubov-de Gennes equations, we find that at extreme quantum limit, the superconducting order parameter exhibits a Friedel-like oscillation, which modifies the energy levels of the vortex bound states and explains why it deviates from the ratio of 1∶3∶5. The observed Friedel oscillations of the bound states can also be roughly interpreted by the theoretical calculations, however some features at high energies could not be explained. We attribute this discrepancy to the high energy bound states with the influence of nearby impurities. Our combined STM measurement and the self-consistent calculations illustrate a generalized feature of vortex bound states in type-II superconductors.


Quadriceps muscle electromyography activity during physical activities and resistance exercise modes in younger and older adults.
Understanding the root cause of the age-related impairment in muscle adaptive remodelling with resistance exercise training (RET) and developing pragmatic and accessible resistance exercise for older adults, are essential research directives. We sought to determine whether indices of quadriceps muscle EMG activity in response to different modes of RET and activities of daily living (ADL), differed between 15 healthy younger (25 ± 3 years) and 15 older (70 ± 5 years) adults. On four separate days, participants completed a maximal voluntary contraction (MVC) of the knee extensors, followed by a 15 m walking task, stair climbing task (i.e. ADL) and lower-limb RET through body-weight squats (BW-RET) and seated knee extensions on a machine (MN-RET) or via elastic bands (EB-RET). Surface quadriceps electromyography (EMG) was measured throughout all tasks to provide indirect estimates of changes in muscle activity. MVC was significantly greater in young vs. older adults (Young: 256 ± 72 vs. Old: 137 ± 48 N·m, P < 0.001). EMG activity during all exercise tasks was significantly higher in older vs. younger adults when expressed relative to maximal EMG achieved during MVC (P < 0.01, for all). In addition, relative quadriceps muscle EMG activity was significantly greater in EB-RET (Young: 20.3 ± 8.7 vs. Old: 37.0 ± 10.7%) and MN-RET (Young: 22.9 ± 10.3, vs. Old: 37.8 ± 10.8%) compared with BW-RET (Young: 8.6 ± 2.9 vs. Old: 27.0 ± 9.3%), in young and older adults (P < 0.001). However, there was no significant difference in quadriceps EMG between EB-RET and MN-RET (P > 0.05). In conclusion, relative quadriceps muscle EMG activity was higher across a range of activities/exercise modes in older vs. younger adults. The similar quadriceps muscle EMG activity between EB-RET and MN-RET provides a platform for detailed investigation of the neuromuscular and muscle metabolic responses to such pragmatic forms of RET to strengthen the evidence-base for this mode of RET as a potential countermeasure to sarcopenia.


Permeability of neutral vs. anionic dextrans in cultured brain microvascular endothelium.
The luminal surface of vascular endothelium contains glycocalyx residues that establish an overall negative charge. Recent evidence has suggested that local endothelial surface charge properties may account for the permeability properties of various macromolecules. It has also been suggested that altered membrane charge on the luminal side may play a role in thrombogenesis and atherogenesis. The relationship of macromolecule charge to endothelial cell permeability was examined in vitro using mouse brain microvessel endothelial cells grown to confluence on a nitrocellulose filter separating a double-chamber system. Endothelial permeability to 4K and 10K fluorescein-labeled neutral dextrans was compared with the permeability to 4K and 10K fluorescein-labeled anionic dextrans (sulfated). After 1 h, there was significantly greater permeability of neutral fluorescein-labeled dextran than of anionic fluorescein-labeled dextran in each particle size. In addition, there was significantly greater permeability of 4K than 10K fluorescein-labeled dextrans of either charge. The findings indicate that charge in addition to size plays an important role in the movement of macromolecules across cultured microvascular endothelial cells.


Synthesis of 2-Amino-3-hydroxy-3H-indoles via Palladium-Catalyzed One-Pot Reaction of Isonitriles, Oxygen, and N-Tosylhydrazones Derived from 2-Acylanilines.
A cyanide-free one-pot procedure was developed to access 2-amino-3-hydroxy-3H-indoles, which involved: (1) in situ formation of ketenimines by the reaction of N'-(1-(2-aminophenyl)ethylidene)-p-tosylhydrazones with isonitriles; (2) the intramolecular nucleophilic attack of ketenimines by the amino in phenyl furnishing the ring closure leading to 2-aminoindoles; (3) the oxidation of 2-aminoindoles by O2 leading to 2-amino-3-hydroxy-3H-indoles. This strategy represents not only a key compliment to the sporadic synthetic methods toward 2-amino-3-hydroxy-3H-indoles but also progress in N-tosylhydrazone, isonitrile, and ketenimine chemistry.


Human geminin promotes pre-RC formation and DNA replication by stabilizing CDT1 in mitosis.
Geminin is an unstable inhibitor of DNA replication that negatively regulates the licensing factor CDT1 and inhibits pre-replicative complex (pre-RC) formation in Xenopus egg extracts. Here we describe a novel function of Geminin. We demonstrate that human Geminin protects CDT1 from proteasome-mediated degradation by inhibiting its ubiquitination. In particular, Geminin ensures basal levels of CDT1 during S phase and its accumulation during mitosis. Consistently, inhibition of Geminin synthesis during M phase leads to impairment of pre-RC formation and DNA replication during the following cell cycle. Moreover, we show that inhibition of CDK1 during mitosis, and not Geminin depletion, is sufficient for premature formation of pre-RCs, indicating that CDK activity is the major mitotic inhibitor of licensing in human cells. Taken together with recent data from our laboratory, our results demonstrate that Geminin is both a negative and positive regulator of pre-RC formation in human cells, playing a positive role in allowing CDT1 accumulation in G2-M, and preventing relicensing of origins in S-G2.


A new surgical approach for punctal occlusion using fibrous tissue from under the lacrimal caruncle.
Surgical punctal occlusion is indispensable for the treatment of severe dry eye in cases where punctal-plug insertion is not applicable due to an enlarged or deformed punctum. However, permanent punctal occlusion is difficult in some cases. In our aim to establish a more reliable punctal occlusion, we have devised a new surgical approach for punctal occlusion. This study involved 20 puncta of 12 eyes of 12 patients (1 male and 11 females; mean age: 65.2 years) with severe aqueous-tear-deficient dry eye. A new surgical procedure for punctal occlusion using fibrous tissue from under the lacrimal caruncle into the diathermy-induced deepithelialized canaliculus as supporting tissue for punctal closure was performed. In all patients, the assessment of eye symptoms, as well as the condition of punctal occlusion by slit-lamp biomicroscopy, tear volume (tear-meniscus radius [TMR] measurement by meniscometry), the condition of precorneal tear film (graded by interferometry [IG]), measurement of fluorescein breakup time (FBUT), and scoring of ocular surface staining (fluorescein score of area [FSA] and density [FSD], and lissamine green score [LGS]) were performed, and the preoperative and 6-month-postoperative values were compared. In regard to the postoperative improvement of symptoms, 11 patients showed remarkable improvement, 1 patient showed improvement, and no reopening of the closed punctum was found in any patient. Test values were all significantly improved post surgery (all: P<0.05) as compared to those prior to surgery (respective values [mean ± SD], and the pre- and postoperative P-values were: TMR (mm) [0.18±0.08; 0.56±0.28, P=0.002], IG [4.3±0.9; 2.7±0.8, P=0.009], FBUT [0.4±0.6; 4.1±2.9, P=0.004], FSA [1.6±0.7; 0.7±0.9, P=0.03], FSD [2.7±0.7; 0.6±0.7, P=0.003], and LGS [5.1±2.7; 1.1±2.1, P=0.005]). Moreover, no postoperative complications were observed. The findings of this study showed that our novel surgical procedure for punctal occlusion is highly successful and that it results in improved and more complete punctal occlusion.


Analysis of multidisciplinary lung cancer practice.
The aim of this study was to describe the activity of a lung cancer multidisciplinary clinic (MDC) and examine whether this model of clinical practice results in adherence to best-practice guidelines. Prospective analysis of demographic and clinical data in 431 patients referred to a lung cancer MDC for the management of known or suspected thoracic malignancy. Adherence was documented to clinically relevant guideline recommendations concerning timely and evidence-based lung cancer management. Of 431 patients, 257 were diagnosed with primary lung cancer, mean age 68 years, 70% men and 90% current smokers or ex-smokers. Only 21% were referred with known malignancy and 28% were asymptomatic. Overall, 51% had stages I and II non-small-cell lung cancer, with this bias towards early-stage disease greatest in patients from rural areas. Histological confirmation of lung cancer was obtained in 92%. There was a high rate of adherence to international guideline recommendations concerning timely lung cancer diagnosis, staging and treatment implementation. Similarly, there was adherence to selected key evidence based recommendations for lung cancer management contained in national guidelines. Within a MDC, patients receive timely diagnosis, staging and treatment according to evidence-based guideline recommendations. The high proportion of patients receiving active treatment has implications for resource allocation. There is a referral bias towards patients with early non-small-cell lung cancer, particularly in rural patients, suggesting that further education about advances in metastatic lung cancer management is required. This study would support the establishment of regional lung cancer services with links to fully resourced MDC.


Relapse of childhood acute lymphoblastic leukemia and outcomes at a reference center in Latin America: organomegaly at diagnosis is a significant clinical predictor.
Relapse is the major cause of treatment failure in acute lymphoblastic leukemia (ALL) of childhood; it is more frequent among high-risk patients from low-middle income than from high-income countries. The frequency, sites and outcome of relapsed ALL in children of northeast Mexico over a decade was documented. A retrospective analysis of 246 children belonging to a low-income group <16 years with de novo ALL during 2004-2015 was performed. Five-year overall survival (OS) and event-free survival was estimated by Kaplan-Meier analysis. Data on time, site, response to therapy and final outcome of relapse were analyzed. Hazard ratios (HRs) of relapse and death were estimated by the Cox regression model. Very early relapse was defined as that occurring in <18 months, early relapse between 18 and 36 months, and late relapse >36 months from diagnosis, respectively. Eighty-seven (35.4%) children relapsed. Five-year OS was 82.6% in children without relapse vs. 42% for relapsed patients. Bone marrow (BM) was the most frequent site of relapse (51.72%). Isolated central nervous system (CNS) relapses occurred in 29.9%. Five-year OS was 11.2% for BM and 15.5% for early relapse. HR of relapse for organomegaly was 3.683, 2.247 for an initial white blood cell count >50 000 × 109/l and 1.169 for positive minimal residual disease status. A high rate of very early, CNS, and BM relapse with a considerably low 5-year OS requiring reassessment of therapy was documented. Organomegaly at diagnosis was a highly significant clinical predictor for relapse.


Appropriateness of self-medication: method development and testing in urban Indonesia.
Most illness episodes are treated by self-medication, however, little is known about the appropriateness of this self-medication. Moreover, tools to evaluate the appropriateness of self-medication still need to be developed. In order to monitor the use of drugs by the general public, we developed methodology (for evaluation of the appropriateness of self-medication) that would be reproducible and would therefore allow comparison over time and between regions. For each complaint, criteria for appropriate treatment were set, based on evaluation of both the efficacy and the risks of the medications used. To keep cost at a minimum and to ensure reproducibility, no use was made of expert panels. Instead, only internationally recognized printed sources were used. This study used data on self-medication collected in urban Indonesia in 1993. After excluding illness episodes first treated only with traditional drugs, non-drug treatments or treated by a health worker, we found that self-medication used as a first action was appropriate in 16% of the cases. Fifty-six per cent combined appropriate and unnecessary components and 8% included unnecessary components only. Sixteen per cent of treatments were considered potentially harmful. Only 4.5% of the illness episodes were not treated. Analysis of these potentially harmful treatments showed that over use of antihistamine in children under 5 years of age, use of prescription drugs and multiple intake of paracetamol or antihistamines in different medicines were the main problems. The results of this analysis enabled us to set priorities and formulate recommendations to rationalize the use of drugs in self-medication. The proposed methodology should allow international comparisons and the evaluation of the impact of future interventions.


A scanning electron microscopy of subcellular structures of the human hepatic cell.
Human liver specimens obtained by needle biopsy were extensively osmicated by the revised tannin-osmium method of MURAKAMI (1974) and cracked in air after critical point drying, to be observed in the scanning electron microscope. The fracture tended to occur along the membranous elements and exposed beautifully fractured faces of the hepatic cell. The nucleus of the hepatic cell was spherical. The nuclear pores were demonstrated as small pits 0.1 mu in diameter and their total occurrence in one nucleus was estimated to be 2,100. In the spongy framework resembling the endoplasmic reticulum, oval-shaped mitochondria and multivesicular tufts of the Golgi complex were observed. The nucleolus of the hepatic cell nucleus was noticed as a highlighted mass in the cloudy nucleoplasm.


The prevalence and management of asthma in primary-aged schoolchildren in the south of England.
A postal questionnaire survey of headteachers in 149 Infant, Junior and Primary schools (response rate: 63.8%) indicated poor asthma record keeping and a need for regular staff training in asthma. Dealing with an emergency was a major concern of headteachers. In 25 of the schools surveyed, an International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire was distributed to parents of children in Years 3 and 4 (7-9 years). Headteacher-reported asthma prevalence was 11.9% in these schools, while ISAAC parental reports indicated a current or previous diagnosis of asthma in 24.3% children, with 17.8% receiving asthma treatment and 18.9% reporting wheeze in the previous 12 months. Of six wheezing children per Year 3/4 class, one was receiving no treatment for asthma, three had experienced four or more attacks of wheeze in the previous year with one wheezing child per two Year 3/4 classes experiencing more than 12 such attacks. Four in six children experienced exercise-related wheeze, while only one in five schools allowed asthma medication at Physical Education lessons. A whole school policy on asthma together with some regularly updated staff education and training by an asthma-trained nurse would address many of the issues raised in this study.


Estrogen enhances human osteoblast survival and function via promotion of autophagy.
Estrogen increases bone formation by promoting mineralization and prolonging the lifespan of osteoblasts. To understand the underlying molecular mechanism/s, we identified estrogen-regulated proteins at different stages of human osteoblast differentiation using differential proteomics approach. Among the identified proteins, we observed that estrogen upregulated RAB3GAP1 on day 1 and 5 of differentiation. RAB3GAP1 is critically involved in the process of autophagy, a eukaryotic degradative pathway essential for cell survival. We, therefore, investigated the effect of estrogen on autophagy in differentiating human osteoblasts and their precursors, the mesenchymal stem cells (MSCs). MSCs exhibited high autophagic flux which declined during osteoblast differentiation, resulting in high basal apoptosis in osteoblasts. Estrogen reduced apoptosis in differentiating osteoblasts by promoting autophagy, thus contributing towards their longer lifespan. Further, MSCs were resistant against starvation-induced apoptosis, whereas, differentiating osteoblasts showed significant susceptibility towards it. Estrogen, in addition to promoting mineralization, protected differentiating osteoblasts from starvation-induced apoptosis by increasing autophagic flux. Autophagic flux in RAB3GAP1 knockdown osteoblasts appeared diminished, and showed increased apoptosis even in nutrient-rich conditions, and exhibited significantly impaired mineralization. However, irrespective of the presence of estrogen, starvation further enhanced apoptosis in these cells. Furthermore, estrogen failed to promote mineralization in these osteoblasts. Our study illustrates that autophagy is essential for human osteoblast survival and mineralization, and osteoblasts are susceptible to apoptosis due to reduced autophagy during differentiation. Estrogen, via upregulation of RAB3GAP1, promotes autophagy in osteoblasts during differentiation thereby increasing their survival and mineralization capacity. Our study demonstrates the positive role of autophagy in bone homeostasis.


Generation of hiPSC-Derived Functional Dopaminergic Neurons in Alginate-Based 3D Culture.
Human induced pluripotent stem cells (hiPSCs) represent an unlimited cell source for the generation of patient-specific dopaminergic (DA) neurons, overcoming the hurdle of restricted accessibility to disease-affected tissue for mechanistic studies on Parkinson's disease (PD). However, the complexity of the human brain is not fully recapitulated by existing monolayer culture methods. Neurons differentiated in a three dimensional (3D) in vitro culture system might better mimic the in vivo cellular environment for basic mechanistic studies and represent better predictors of drug responses in vivo. In this work we established a new in vitro cell culture system based on the microencapsulation of hiPSCs in small alginate/fibronectin beads and their differentiation to DA neurons. Optimization of hydrogel matrix concentrations and composition allowed a high viability of embedded hiPSCs. Neural differentiation competence and efficiency of DA neuronal generation were increased in the 3D cultures compared to a conventional 2D culture methodology. Additionally, electrophysiological parameters and metabolic switching profile confirmed increased functionality and an anticipated metabolic resetting of neurons grown in alginate scaffolds with respect to their 2D counterpart neurons. We also report long-term maintenance of neuronal cultures and preservation of the mature functional properties. Furthermore, our findings indicate that our 3D model system can recapitulate mitochondrial superoxide production as an important mitochondrial phenotype observed in neurons derived from PD patients, and that this phenotype might be detectable earlier during neuronal differentiation. Taken together, these results indicate that our alginate-based 3D culture system offers an advantageous strategy for the reliable and rapid derivation of mature and functional DA neurons from hiPSCs.


Toward genetic counseling practice standards for diagnostic testing in amyotrophic lateral sclerosis and frontotemporal dementia.
Objective: Genetic counseling and diagnostic genetic testing are considered part of the multidisciplinary care of individuals with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). We aimed to investigate the ideal components of genetic counseling for ALS/FTD diagnostic testing amongst various stakeholders using an online, modified Delphi survey. Methods: Experts in genetic counseling and testing for ALS/FTD were purposively then snowball recruited and included genetic health professionals, health professionals outside of genetics and consumer experts (patients, relatives, and staff representatives from ALS/FTD support organizations). First-round items were informed by two systematic literature reviews and qualitative interviews with patients and families who had experienced diagnostic testing. Analysis of each round informed the development of the subsequent round and the final results. Results: Forty-six experts participated in the study, 95.65% completed both rounds. After round one, items were updated based on participant responses and were presented again for consensus in round two. After round two, a high level of consensus (≥80% agreement) was achieved on 16 items covering various topics related to genetic counseling service delivery, before and after diagnostic testing is facilitated. Conclusions: Genetic counseling for individuals with ALS/FTD and their families should include the provision of client-centered counseling, education and support throughout. The items developed are adaptable to varied healthcare settings and may inform a standard of genetic counseling practice for health professionals who facilitate testing and counseling discussions. This area of work is timely, given demand for testing is likely to increase as more genotype-driven clinical trials become available.


Genetic reduction of class IA PI-3 kinase activity alters fetal hematopoiesis and competitive repopulating ability of hematopoietic stem cells in vivo.
Class I(A) phosphatidylinositol-3 kinase (PI-3K) is a lipid kinase, which is activated in blood cells by hematopoietic growth factors. In vitro experiments using chemical inhibitors of PI-3K suggest that this kinase is potentially important for hematopoietic stem and progenitor cell (HSC/P) function, and recent studies identify PI-3K as a therapeutic target in treating different leukemias and lymphomas. However, the role of PI-3K in regulating fetal liver or adult hematopoiesis in vivo is unknown. Therefore, we examined PI-3K-deficient embryos generated by a targeted deletion of the p85alpha and p85beta regulatory subunits of PI-3K (p85alpha-/-p85beta+/-). The absolute frequency and number of hematopoietic progenitor cells were reduced in p85alpha-/- p85beta+/- fetal livers compared with wild-type (WT) controls. Further, p85alpha-/-p85beta+/- fetal liver hematopoietic stem cells (HSCs) had decreased multilineage repopulating ability in vivo compared with WT controls in competitive repopulation assays. Finally, purified p85alpha-/-p85beta+/- c-kit+ cells had a decrease in proliferation in response to kit ligand (kitL), a growth factor important for controlling HSC function in vivo. Collectively, these data identify PI-3K as an important regulator of HSC function and potential therapeutic target in treating leukemic stem cells.


Predictive modeling of emergency cesarean delivery.
To increase discriminatory accuracy (DA) for emergency cesarean sections (ECSs). We prospectively collected data on and studied all 6,157 births occurring in 2014 at four public hospitals located in three different autonomous communities of Spain. To identify risk factors (RFs) for ECS, we used likelihood ratios and logistic regression, fitted a classification tree (CTREE), and analyzed a random forest model (RFM). We used the areas under the receiver-operating-characteristic (ROC) curves (AUCs) to assess their DA. The magnitude of the LR+ for all putative individual RFs and ORs in the logistic regression models was low to moderate. Except for parity, all putative RFs were positively associated with ECS, including hospital fixed-effects and night-shift delivery. The DA of all logistic models ranged from 0.74 to 0.81. The most relevant RFs (pH, induction, and previous C-section) in the CTREEs showed the highest ORs in the logistic models. The DA of the RFM and its most relevant interaction terms was even higher (AUC = 0.94; 95% CI: 0.93-0.95). Putative fetal, maternal, and contextual RFs alone fail to achieve reasonable DA for ECS. It is the combination of these RFs and the interactions between them at each hospital that make it possible to improve the DA for the type of delivery and tailor interventions through prediction to improve the appropriateness of ECS indications.


Epicondylitis and corticosteroid injection: fewer cures at one year.
Corticosteroid injection provides short-term relief for patients with epicondylitis. However, in a trial lasting one year, corticosteroid injection resulted in a lower complete recovery rate and higher recurrence rate. Physiotherapy appears to improve symptoms in the short-term without affecting outcome at one year.


The moderating effect of nutritional status on depressive symptoms in veteran elders with dementia: a spaced retrieval combined with Montessori-based activities.
To examine the long-term effects of fixed/individualized spaced retrieval combined with Montessori-based activities on nutritional status and body mass index and nutritional improvement's moderating effect on depressive symptoms for people with dementia during a specific follow-up period. The decrease in food intake, often combined with poor nutrition, may induce depressive symptoms in people with dementia. A single-blind, quasi-experimental study with repeated measures. Twenty-five fixed group participants received spaced retrieval combined with Montessori-based activities over 24 sessions. Thirty-eight individualized group participants received the same intervention with different sessions, which was adjusted according to each participant's learning response. Twenty-seven control group participants just received routine care. The Chinese version of the Mini-Nutritional Assessment and Cornell Scale for Depression in Dementia scores and body mass index were recorded at pre-test, posttest and 1-, 3- and 6-month follow-ups. Data were collected between July 2008-February 2010. The Mini-Nutritional Assessment scores and body mass index of the fixed and individualized groups could be significantly increased over time. Additionally, the Cornell Scale for Depression in Dementia scores could be significantly reduced as a result of the improvement of the Mini-Nutritional Assessment scores arising from the individualized intervention. The depressive symptoms of residents with dementia could be moderated by the individualized intervention through nutritional improvement. Trained clinical nurse specialists can use this individualized intervention for residents with dementia who also have poor nutrition and depressive symptoms.


Fast and blind chromatic dispersion estimation with one sample per symbol.
We propose a fast and blind chromatic dispersion (CD) estimation method by one sample per symbol after coherent detection. The CD estimation process is non-data aided, without the iterative scanning to obtain the CD values. Moreover, we identify that the proposed CD estimation method is transparent to the used modulation format and robust to the transmission impairments, including amplified spontaneous emission (ASE) noise and fiber nonlinearity. When the 35-GBaud DP-16QAM signal with a roll-off factor of 0.1 is transmitted over standard single mode fiber (SSMF) with a range from 320-km to 560-km, the error of CD estimation is less than 150-ps/nm under the condition of 8192 symbols used.


Adrenergic effects on exocrine secretion of rat submandibular epidermal growth factor.
The present study was undertaken to investigate the effect of alpha- and beta-adrenergic agonists on secretion of epidermal growth factor (EGF) from the rat submandibular glands and to test the possibility of intestinal absorption of EGF. Alpha-adrenergic agonists increased the concentration of salivary EGF by approximately a hundred times, while the serum concentration of EGF was unchanged. The contents of EGF in the submandibular glands decreased upon administration of the alpha-adrenergic agonist noradrenaline, and this was confirmed on immunohistochemical investigation of the glands. Beta-adrenergic agonists had no effect on secretion of EGF from the submandibular glands. Intestinal absorption of EGF could not be confirmed, as stimulation by noradrenaline with free passage of saliva to the gastrointestinal tract and intrajejunal infusion of EGF had no influence on the concentration of EGF in serum. This study shows that alpha-adrenergic agonists stimulate exocrine secretion of submandibular EGF and that EGF in physiological amounts are not absorbed in the gastrointestinal tract.


Thymomas induced by simple alkylating agents in C57BL/Cbi mice: kinetics of the dose response.
Specific-pathogen-free inbred C57BL/Cbi mice (adult virgin females) were given single sublethal doses of N-methyl-N-nitrosourea or N-ethyl-N-nitrosourea and were studied for a lifetime for the development of thymomas. A fatal lymphocytic lymphoma with a "starry sky" pattern due to the presence of macrophages was induced in the thymuses of treated mice within 250 days of treatment. Control and low-dose treatment groups had up to 70% incidence of a histiocytic lymphoma that was usually primary in mesenteric lymph nodes and nearly always occurred later than 250 days after treatment. A "one-hit" linear relationship existed between the time of appearance of induced thymic lymphomas and the log fraction of non-tumor-bearing mice. The absolute latency period of these tumors was constant and independent of dose. The effect of dose was an exponential increase of the total incidence of induced thymic lymphomas. By mathematical analysis, the best estimate of the exponent from the results was 2 or 3, indicating that the development of these induced tumors may be produced by 2 or 3 "events" in the target cell. Possible candidates for these events are premutagenic alkylation of DNA, inactivation of DNA repair, oncovirus activation, regenerative hyperplasia, development of trisomy No 15, and inhibited immunosurveillance.


[Perioperative enteral nutrition].
Enteral nutrition, as demonstrated by the many published papers, is not only safer and cheaper than parenteral supply of nutrients, but modulates an exaggerated cytokine response related to surgical trauma that leads to an increase in intestinal permeability, bacterial translocation and infection. The aim of enteral nutrition is to reduce the impact of cytokines on surgical patients and the related infectious complications. Via the enteral route the nutrients can reach the bowel lumen where enterocytes draw upon their fuel, preserving the barrier effect and modulating the cytokine response. Parenteral supply does not achieve this target since the blood supply of nutrients is not as important as the luminal supply. It is only via the enteral supply route that we can preserve the barrier effect. Since the cytokine response sets in immediately after a trauma such as surgery, we implement uninterrupted enteral nutrition, which means before, during and after surgery, plus parenteral support till the full calorie intake is achieved. In a hepatic resection study, we have demonstrated that enteral nutrition modulates the interleukin-6 immunological response and shortens both the period to bowel movement resumption and the duration of hospital stay. Aggressive enteral nutrition has also been implemented in severe pancreatitis, allowing control of the disease without the onset of septic complications. The most important target is not to achieve full calorie intake rapidly, but to supply the enteric mucosa continuously with useful immuno-nutrients, such as glutamine and fibres, to preserve the barrier effect, the mucus layer, and immunological status of the mucosa. In this way we have obtained significant results in the surgical treatment of these patients, reducing the infection rate and hospital stay. New prospects may be,possible in the fight against surgical infections by adding probiotics to enteral nutrition in order to improve the microenvironment of the colon.


The diagnosis of "early" pancreatic cancer: the University of Chicago experience.
The results of a prospective study designed to investigate patients suspected of having pancreatic cancer are reported. One hundred and two of 238 patients investigated had pancreatic cancer. Ultrasonography, endoscopic retrograde cholangiopancreatography, and cytology were the most reliable tests for the diagnosis of resectable cancer. Computed tomography had a higher sensitivity for unresectable cancer. Factors responsible for delay in diagnosis are discussed. Cancer of the body and tail of the pancreas cannot be diagnosed early by investigating a symptomatic population. Factors influencing mortality in patients who survive over three years following pancreatic resection are discussed.


Network confinement and heterogeneity slows nanoparticle diffusion in polymer gels.
Nanoparticle (NP) diffusion was measured in polyacrylamide gels (PAGs) with a mesh size comparable to the NP size, 21 nm. The confinement ratio (CR), NP diameter/mesh size, increased from 0.4 to 3.8 by increasing crosslinker density and from 0.4 to 2.1 by adding acetone, which collapsed the PAGs. In all gels, NPs either became localized, moving less than 200 nm, diffused microns, or exhibited a combination of these behaviors, as measured by single particle tracking. Mean squared displacements (MSDs) of mobile NPs decreased as CR increased. In collapsed gels, the localized NP population increased and MSD of mobile NPs decreased compared to crosslinked PAGs. For all CRs, van Hove distributions exhibited non-Gaussian displacements, consistent with intermittent localization of NPs. The non-Gaussian parameter increased from a maximum of 1.5 for crosslinked PAG to 5 for collapsed PAG, consistent with greater network heterogeneity in these gels. Diffusion coefficients decreased exponentially as CR increased for crosslinked gels; however, in collapsed gels, the diffusion coefficients decreased more strongly, which was attributed to network heterogeneity. Collapsing the gel resulted in an increasingly tortuous pathway for NPs, slowing diffusion at a given CR. Understanding how gel structure affects NP mobility will allow the design and enhanced performance of gels that separate and release molecules in membranes and drug delivery platforms.


Modulation of the biologic activities of IgE-binding factor. V. The role of glycosylation-enhancing factor and glycosylation-inhibiting factor in determining the nature of IgE-binding factors.
Glycosylation-enhancing factor (GEF) and IgE-potentiating factor were detected in culture supernatants of rat mesenteric lymph nodes (MLN) cells obtained 14 days after infection with Nippostrongylus brasiliensis (Nb), but not in supernatants of MLN cells of 8-day Nb-infected rats. Both factors were also released from T cells upon antigenic stimulation of KLH + alum-primed spleen cells. The GEF from the Nb-infected rats and KLH + alum-primed spleen cells had affinity for p-aminobenzamidine agarose and were inactivated by phenylmethylsulfonylfluoride, an inhibitor of serine proteases. These results indicate that the GEF obtained in the two systems is a serine protease and is identical to that obtained by stimulation of normal T cells with lymphocytosis-promoting factor (LPF) from Bordetella pertussis. The concomitant formation of IgE-potentiating factor and GEF by Nb infection, by antigenic simulation of KLH + alum-primed spleen cells, and by treatment of rats with Bordetella pertussis vaccine suggests that the serine protease is involved in a common pathway leading to the selective formation of IgE-potentiating factor. In contrast, glycosylation-inhibiting factor (GIF) is always found during the selective formation of IgE-suppressive factor. IgE-suppressive factor and GIF were formed by MLN cells of 8-day Nb-infected rats and KLH-CFA-primed spleen cells. GIF was detected in culture supernatants of T cell hybridomas 23A4 and 23B6, which form unglycosylated IgE-binding factors upon incubation with IgE. GIF obtained from all of these sources bound to monoclonal anti-lipomodulin. These findings indicate that GIF or lipomodulin is involved in all systems, which leads to the selective formation of IgE-suppressive factor. However, the formation of GIF was not restricted to those conditions in which IgE-suppressive factor was selectively formed. The culture supernatants of MLN cells of 14-day Nb-infected rats and antigen-stimulated KLH + alum-primed spleen cells contained a small amount of GIF, which could be detected after inactivation of GEF. It appears that T cells from these sources formed GEF and GIF, but that GEF overcame the effect of GIF on glycosylation of IgE-binding factors. The results indicate that the nature and biologic activities of IgE-binding factors are decided by the balance between GEF and GIF formed by T cells.


Induction of murine macrophage fungal killing by interleukin 3.
The effect of recombinant interleukin 3 (IL-3) on the function of murine resident peritoneal macrophages was investigated. IL-3 enhanced the phagocytosis of Candida pseudotropicalis and Candida albicans and enhanced killing of the former. The enhanced killing is inhibited by scavengers of oxygen radicals, suggesting that IL-3 primes macrophages for enhanced oxidative metabolism in response to Candida.


Docetaxel-loaded polyglutamic acid-PEG nanocapsules for the treatment of metastatic cancer.
The design of nanomedicines with suitable physicochemical characteristics for the lymphatic targeting of drugs is critical in order to reach the lymph nodes, where metastatic cells often accumulate. Based on the known effect of particle size and surface hydrophilicity on the capacity of nanocarriers to reach the lymph nodes, here we report the formation and characterization of 100nm polyglutamic acid-polyethylene glycol (PGA-PEG) nanocapsules together with the assessment of their potential for the treatment of cancer with lymphatic metastatic spread. To this purpose, we first studied the biodistribution of fluorescently labeled PGA-PEG nanocapsules (100nm), following, either intravenous or subcutaneous administration. The results confirmed the accumulation of nanocapsules in the lymphatic system, especially upon subcutaneous administration. Next, we evaluated the efficacy and toxicity of the docetaxel-loaded nanocapsules in an orthotopic lung cancer model that metastasizes to the lymph nodes. As expected from the rational design, DCX-loaded PGA-PEG nanocapsules exhibited a greatly enhanced antitumoral efficacy and a reduced toxicity when compared with the commercial formulation Taxotere®. Furthermore, the administration of DCX-loaded PGA-PEG nanocapsules resulted in the practical elimination of the metastatic load in the mediastinal lymph nodes, whereas the treatment with the commercial formulation had a minor effect. Overall, these findings underscore the potential of PGA-PEG nanocapsules for the delivery of anticancer drugs to both, the tumor tissue and the metastatic lymph nodes. Therefore, they represent a promising therapy for the treatment of lung metastatic cancer.


An sd2 hybridized transition-metal monolayer with a hexagonal lattice: reconstruction between the Dirac and kagome bands.
Graphene-like two-dimensional materials have garnered tremendous interest as emerging device materials due to their remarkable properties. However, their applications in spintronics have been limited by the lack of intrinsic magnetism. Here, we perform an ab initio simulation on the structural and electronic properties of several transition-metal (TM) monolayers (TM = Cr, Mo and W) with a honeycomb lattice on a 1/3 monolayer Cl-covered Si(111) surface. Due to the template effect from the halogenated Si substrate, the TM-layers will be maintained in an expanded lattice which is nearly 60% larger than that of the freestanding case. All these isolated TM-layers exhibit ferromagnetic coupling with kagome band structures related to sd2 hybridization and a strong interfacial interaction may destroy the topological bands. Interestingly, the W-monolayer on the Cl-covered Si substrate shows a half-metallic behavior. A Dirac point formed at the K point in the spin-down channel is located exactly at the Fermi level which is crucial for the realization of a quantum spin Hall state. Moreover, the reconstruction process between the Dirac and kagome bands is discussed in detail, providing an interesting platform to study the interplay between massless Dirac fermions and heavy fermions.


Dysregulation of host cellular genes targeted by human papillomavirus (HPV) integration contributes to HPV-related cervical carcinogenesis.
Integration of human papillomavirus (HPV) viral DNA into the human genome has been postulated as an important etiological event during cervical carcinogenesis. Several recent reports suggested a possible role for such integration-targeted cellular genes (ITGs) in cervical carcinogenesis. Therefore, a comprehensive analysis of HPV integration events was undertaken using data collected from 14 publications, with 499 integration loci on human chromosomes included. It revealed that HPV DNA preferred to integrate into intragenic regions and gene-dense regions of human chromosomes. Intriguingly, the host cellular genes nearby the integration sites were found to be more transcriptionally active compared with control. Furthermore, analysis of the integration sites in the human genome revealed that there were several integration hotspots although all chromosomes were represented. The ITGs identified were found to be enriched in tumor-related terms and pathways using gene ontology and KEGG analysis. In line with this, three of six ITGs tested were found aberrantly expressed in cervical cancer tissues. Among them, it was demonstrated for the first time that MPPED2 could induce HeLa cell and SiHa cell G1/S transition block and cell proliferation retardation. Moreover, "knocking out" the integrated HPV fragment in HeLa cell line decreased expression of MYC located ∼500 kb downstream of the integration site, which provided the first experimental evidence supporting the hypothesis that integrated HPV fragment influence MYC expression via long distance chromatin interaction. Overall, the results of this comprehensive analysis implicated that dysregulation of ITGs caused by viral integration as possibly having an etiological involvement in cervical carcinogenesis.


Comparison of Body Composition Metrics for United States Air Force Airmen.
The United States Air Force currently uses AFI 36-2905 for cardiovascular fitness standards and evaluation. Regarding its fitness test, the Air Force considers waist circumference (WC) twice as important as push-ups or sit-ups. Because of this weighting, one assumes that the Air Force considers WC relatively correlated with overall fitness or at least cardiovascular fitness. To our knowledge, the Air Force has not considered on a large scale how body mass index (BMI), height-to-weight ratio (H-W), or waist-to-height ratio (WHtR) compares with WC with respect to its fitness test. Using a 5.38 million record database from the Air Force Fitness Management System, we evaluated how WC, BMI, WHtR, and H-W correlate with fitness as assessed by the 1.5-mile run in addition to total fitness, which incorporates the 1.5-mile run time, number of push-ups and sit-ups. As this previously collected data were anonymous to us, this study fell under the definition of exempt status and approved by the institutional review board overseeing Joint Base San Antonio. For each waist metric, we performed a simple ordinary least squares regression to ascertain the correlation between that particular metric and either run time or total fitness; when incorporating more than one explanatory variable or covariate (to control for age and/or sex), we performed multiple ordinary least squares regressions. Due to the large database size and to mitigate against a type I error, we used an alpha of 0.001 for all statistical hypothesis tests. Approximately 18% of the 5.38 million records belonged to women. With respect to sex differences, males appeared noticeably faster and performed more push-ups on average than females. The number of sit-ups completed was more comparable, with males having a slight advantage. Males also appeared to have larger WC, BMI, H-W, and WHtR measurements. We compared the ordinary least squares results between WC, H-W, WHtR, and BMI and ranked them by R2. Models varied in R2 from 1% to 46% depending on the covariates in the model, with sex having a greater effect than age. Whether individually or adjusting for age and sex, WHtR performed better than the other body composition variables with an average rank score of 1.1 and a median improvement of approximately 4% to the current Air Force metric of WC. From our findings, we present a 20-point WHtR scoring system for the Air Force to use in lieu of its traditional usage of WC. We used this assessment chart to score all Airmen in our database and compared the results to their current scores on the abdominal circumference portion of the test with respect to predicting run time, after accounting for sex, age, and number of push-ups and sit-ups. The R2 value improved from 40.3 to 43.6, a relative improvement of approximately 8%, a fairly significant effect given the database consisted of over 5 million records. Future studies should investigate the longitudinal effect of varying waist metrics over time on run time or total fitness performance.


The use of flow microbluorimetry in the analysis of the phenotype expression of mouse histocompatibility antigens.
Quantitation of the expression of cell surface antigens has hitherto been limited to analysis by either cytotoxicity tests or radioimmune assays (5, 15). We report here the use of a new methodology to analyze and quantitate the expression of mouse histocompabililty antigens (H-2 locus) in hybrid clones and parental cell types. The binding of fluorescein-tagged antibody is measured on a cell-to-cell basis in large viable cell populations using flow microfluorimetric techniques. These techniques have been used to measure hapten and immunoglobulin binding to lymphocyte populations (8, 9, 14). However, this is the first report in which these techniques have been used to examine the expression of the H-2 locus. The advantage of this approach is twofold: first, a large and statistically significant sample population may be analyzed one cell at a time, thus revealing the fine detail of heterogeneity in the expression of the cell surface markers within a population. Second, as has been demonstrated for analysis of specific components of the immune system, this method does permit fluorescence-activated sorting of cell types according to their different surface populations (8, 9, 14).


Hereditary xanthinuria: report on three patients and short review of the literature.
Three patients with hereditary xanthinuria are presented and the pertinent literature is reviewed. In two siblings the disease has been asymptomatic; in the third urolithiasis has developed. Xanthine stone formation is the clinical hallmark of the disease. Hereditary xanthinuria seems to be relatively prevalent in Lebanon.