Development and validation of the Youth Acute Pain Functional Ability Questionnaire (YAPFAQ).
Physical function and functional recovery are important aspects of the acute pain experience in children and adolescents in hospitalized settings. Measures of function related to pediatric acute pain do not exist currently, limiting understanding of recovery in youth undergoing acute and procedural pain. To address this gap, we developed and assessed the clinical utility and preliminary validity of the Youth Acute Pain Functional Ability Questionnaire (YAPFAQ). We evaluated psychometric properties of this measure in 159 patients with sickle cell disease, ages 7 to 21 years, who were hospitalized for vaso-occlusive episodes at 4 urban children's hospitals. The YAPFAQ demonstrated strong internal reliability and test-retest reliability. An exploratory factor analysis was conducted to examine the preliminary factor structure and to help reduce the number of items for the final scale. Evidence for moderate construct validity was demonstrated among validated measures of pain burden, motor function, functional ability, and quality of life. The YAPFAQ is a new measure of youth functional ability in the acute pain setting. Further evaluation of this measure in additional pediatric populations is needed to understand applicability across a spectrum of youth experiencing acute pain related to illness, trauma, and medical/surgical procedures. Measures of function in response to acute pain are needed in order to more comprehensively evaluate acute pain interventions in pediatrics; however, no specific measures are available. Our preliminary psychometric evaluation of an acute pain functional ability measure for youth indicates that it may be a promising tool for further refinement in additional pediatric acute pain populations.


Comparative genomic analysis identifies small open reading frames (sORFs) with peptide-encoding features in avian 16S rDNA.
The mitochondrial genome (mt-DNA) functional repertoire has recently been enriched in mammals by the identification of functional small open reading frames (sORFs) embedded in ribosomal DNAs. Through comparative genomic analyses the presence of putatively functional sORFs was investigated in birds. Alignment of available avian mt-DNA sequences revealed highly conserved regions containing four putative sORFs that presented low insertion/deletion polymorphism rate (<0.1%) and preserved in frame start/stop codons in >80% of species. Detected sORFs included avian homologs of human Humanin and Short-Humanin-Like-Peptide 6 and two new sORFs not yet described in mammals. The amino-acid sequences of the four putative encoded peptides were strongly conserved among birds, with amino-acid p-distances (5.6 to 25.4%) similar to those calculated for typical avian mt-DNA-encoded proteins (14.8%). Conservation resulted from either drastic conservation of the nucleotide sequence or negative selection pressure. These data extend to birds the possibility that mitochondrial rDNA may encode small bioactive peptides.


Saliva suppresses osteoclastogenesis in murine bone marrow cultures.
Saliva can reach mineralized surfaces in the oral cavity; however, the relationship between saliva and bone resorption is unclear. Herein, we examined whether saliva affects the process of osteoclastogenesis in vitro. We used murine bone marrow cultures to study osteoclast formation. The addition of fresh sterile saliva eliminated the formation of multinucleated cells that stained positive for tartrate-resistant acid phosphatase (TRAP). In line with the histochemical staining, saliva substantially reduced gene expression of cathepsin K, calcitonin receptor, and TRAP. Addition of saliva led to considerably decreased gene expression of receptor activator of nuclear factor kappa-B (RANK) and, to a lesser extent, that of c-fms. The respective master regulators of osteoclastogenesis (c-fos and NFATc1) and the downstream cell fusion genes (DC-STAMP and Atp6v0d2) showed decreased expression after the addition of saliva. Among the costimulatory molecules for osteoclastogenesis, only OSCAR showed decreased expression. In contrast, CD40, CD80, and CD86-all costimulatory molecules of phagocytic cells-were increasingly expressed with saliva. The phagocytic capacity of the cells was confirmed by latex bead ingestion. Based on these in vitro results, it can be concluded that saliva suppresses osteoclastogenesis and leads to the development of a phagocytic cell phenotype.


CD73 Controls Extracellular Adenosine Generation in the Trigeminal Nociceptive Nerves.
Purinergic signaling is involved in pain generation and modulation in the nociceptive sensory nervous system. Adenosine triphosphate (ATP) induces pain via activation of ionotropic P2X receptors while adenosine mediates analgesia via activation of metabotropic P1 receptors. These purinergic signaling are determined by ecto-nucleotidases that control ATP degradation and adenosine generation. Using enzymatic histochemistry, we detected ecto-AMPase activity in dental pulp, trigeminal ganglia (TG) neurons, and their nerve fibers. Using immunofluorescence staining, we confirmed the expression of ecto-5'-nucleotidase (CD73) in trigeminal nociceptive neurons and their axonal fibers, including the nociceptive nerve fibers projecting into the brainstem. In addition, we detected the existence of CD73 and ecto-AMPase activity in the nociceptive lamina of the trigeminal subnucleus caudalis (TSNC) in the brainstem. Furthermore, we demonstrated that incubation with specific anti-CD73 serum significantly reduced the ecto-AMPase activity in the nociceptive lamina in the brainstem. Our results indicate that CD73 might participate in nociceptive modulation by affecting extracellular adenosine generation in the trigeminal nociceptive pathway. Disruption of TG neuronal ecto-nucleotidase expression and axonal terminal localization under certain circumstances such as chronic inflammation, oxidant stress, local constriction, and injury in trigeminal nerves may contribute to the pathogenesis of orofacial neuropathic pain.


[Quantitative study of the effect of occlusal hypofunction on periodontal ligament with and alveolar osteoclastic resorption in rats].
An occlusal hypofunction has been produced by unilateral extraction of the maxillary molars in the rat and its effect has been studied on the antagonistic lower molars during a period of 15 days to 3 months. The quantitative analysis showed that the alveolar width decreased very significantly as early as the fifteen day. This fact was due to a decrease of the periodontal membrane width from the fifteenth day. This decrease was observed until 1 month on the alveolar surface undergoing apposition. The decrease of the alveolar width was also related to a drop of the periodontal membrane width as soon as fifteen days on the surface in resorption. The radicular width remained constant, confirming that it was the bone apposition and not the cementum apposition which caused the narrowing of the periodontal membrane. The quantitative study of the osteoclastic resorption showed that this later decreased but in a non significant on the alveolar surface undergoing remodeling.


Forests, fields, and the edge of sustainability at the ancient Maya city of Tikal.
Tikal has long been viewed as one of the leading polities of the ancient Maya realm, yet how the city was able to maintain its substantial population in the midst of a tropical forest environment has been a topic of unresolved debate among researchers for decades. We present ecological, paleoethnobotanical, hydraulic, remote sensing, edaphic, and isotopic evidence that reveals how the Late Classic Maya at Tikal practiced intensive forms of agriculture (including irrigation, terrace construction, arboriculture, household gardens, and short fallow swidden) coupled with carefully controlled agroforestry and a complex system of water retention and redistribution. Empirical evidence is presented to demonstrate that this assiduously managed anthropogenic ecosystem of the Classic period Maya was a landscape optimized in a way that provided sustenance to a relatively large population in a preindustrial, low-density urban community. This landscape productivity optimization, however, came with a heavy cost of reduced environmental resiliency and a complete reliance on consistent annual rainfall. Recent speleothem data collected from regional caves showed that persistent episodes of unusually low rainfall were prevalent in the mid-9th century A.D., a time period that coincides strikingly with the abandonment of Tikal and the erection of its last dated monument in A.D. 869. The intensified resource management strategy used at Tikal-already operating at the landscape's carrying capacity-ceased to provide adequate food, fuel, and drinking water for the Late Classic populace in the face of extended periods of drought. As a result, social disorder and abandonment ensued.


Lessons from Ebola: Improving infectious disease surveillance to inform outbreak management.
The current Ebola virus disease outbreak in West Africa has revealed serious shortcomings in national and international capacity to detect, monitor, and respond to infectious disease outbreaks as they occur. Recent advances in diagnostics, risk mapping, mathematical modeling, pathogen genome sequencing, phylogenetics, and phylogeography have the potential to improve substantially the quantity and quality of information available to guide the public health response to outbreaks of all kinds.


Transcriptional activators of helper T cell fate are required for establishment but not maintenance of signature cytokine expression.
The stability of helper T cell fates is not well understood. Using conditional introduction of dominant-negative factors, we now show that T-bet and GATA-3 are far more critical in establishment than maintenance of IFN-gamma and IL-4 activity during Th1 and Th2 maturation, respectively. We also show that a genetic interaction between T-bet and its target Hlx seems to be required for Th1 maturation, but that Hlx may also be dispensable for maintenance of a transcriptionally permissive ifng gene. In parallel to progressive activator independence in the permissive lineage, the ifng gene becomes more recalcitrant to switching as the forbidden lineage matures. T-bet plus Hlx can disrupt ifng silencing when introduced into developing Th2 cells, but they fail to perturb ifng silencing in mature Th2 cells. In contrast, a hypermorphic allele of T-bet can reverse silencing of the ifng gene in mature Th2 cells. These results suggest that signature gene activity of helper T cells is initially plastic but later becomes epigenetically fixed and offer an initial strategy for inducing mature cells to switch their fate.


Delivery of wingless to the ventral mesoderm by the developing central nervous system ensures proper patterning of individual slouch-positive muscle progenitors.
During the development of any organism, care must be given to properly pattern gene expression in temporally and spatially regulated manners. This process becomes more complex when the signals that regulate a target tissue are produced in an adjacent tissue and must travel to the target tissue to affect gene expression. We have used the developing somatic mesoderm in Drosophila as a system in which to examine this problem. Our investigation uncovered a novel mechanism by which Wingless (Wg) can travel from its source in the ectoderm to regulate the expression of the somatic muscle founder identity gene, slouch, in the ventral mesoderm. Delivery of Wg to the mesoderm by the developing Central Nervous System (CNS) exploits the stereotypic formation of this tissue to provide high Wg levels to Slouch founder cell cluster II in a temporally specific manner. Coordinated development of these tissues provides a reliable mechanism for delivering high Wg levels to a subset of mesodermal cells. It also provides a means for one signaling pathway to be used reiteratively throughout development to impart unique positional and character information within a target field.


Past and future ozone trends in California's South Coast Air Basin: reconciliation of ambient measurements with past and projected emission inventories.
This paper updates the historic trends (1980-2010) in ambient ozone and ozone precursor concentrations in the South Coast Air Basin (SoCAB) and examines the evolution of the ozone-precursor relationship in the Basin. Whereas reductions in NOx (oxide of nitrogen) emissions have decreased nitrate and PM2.5 (particulate matter with an aerodynamic diameter < or = 2.5 microm) concentrations in the Basin during the past decade, ozone levels have increased at the central basin locations since about 2005 following a reversal in the decline of volatile organic compound (VOC)/NOx ratios during the previous two decades. A chemical box model was used to simulate the effects of changes in precursor concentrations on ozone formation using day-of-week-specific initial precursor concentrations that were derived from measurements and'projected to 2020 based on expected emission reductions from 2005 (-10% VOC and -50% NOx). Results show that peak ozone formation rates in 2020 will increase on weekdays by a factor of 3 relative to 2005 and will be comparable to 1995 weekday and 2005 Sunday rates. Ozone production will become precursor limited on Sundays in 2020, but with higher initial rates than 2005. Although a greater NOx reduction scenario in 2020 of -75% will result in even higher initial ozone formation rates, precursor limitation is reached quickly, leading to a further shift westward in the location of peak ozone levels. However ozone levels will likely be lower in downwind areas where transport is more important than local production of ozone. The ambient versus emission inventory reconciliation indicates a factor of 2 underestimation of VOC emissions in 2009 relative to NOx. Other analyses suggest that there is an overall increase in VOC emissions on hot days that is not fully accounted for by emission inventory estimates. Air quality models using emission inventories that underestimate VOC emissions relative to NOx may lead to inaccurate forecasting of the consequence of emission reductions. The rate and efficiency of ozone formation and accumulation in the SoCAB is more rapid than would be indicated by air quality model simulations based on the current inventory. Projected reductions in NOx emissions without concurrent reductions in VOC emissions will likely cause ozone to increase during the next decade within central regions of the SoCAB compared with a flat or slightly declining trend in far downwind locations. Air quality statistics that are commonly used to track progress toward attainment, such as basin-wide ozone design value and standard exceedances mask these varying trends within the Basin.


The Gastrointestinal Microbiome in Infant Colic: A Scoping Review.
The significant crying of infantile colic adds stress to the infant and their family, yet it has no recognized etiology. Gastrointestinal health problems and dysfunction have been suspected in the etiology of colic. Disruptions to the microbiome colonization of the gastrointestinal system may lead to excess gas and inflammation that are associated with the crying of colic. Infants with colic have increased colonization with gas-producing bacteria, like Escherichia coli and Klebsiella , and they have lower colonization of anti-inflammatory bacteria, like Bifidobacterium and Lactobacillus . Colic is known to self-resolve around 3 months of age. However, few researchers have investigated how the microbiome may be changing at colic's natural resolution without the intervention of a probiotic. With a better understanding of what leads to colic's self-resolution, future researchers may be able to identify more effective therapies for colic prevention or treatment. This scoping review presents the collective evidence from 21 original, primary research articles on what is known about the gastrointestinal microbiome at colic onset and resolution.


Effect of establishing guidelines on appropriate urinary catheter placement.
Avoiding placement of unnecessary urinary catheters (UCs) in the emergency department (ED) affects UC utilization during hospitalization. The authors sought to evaluate the effect of establishing institutional guidelines for appropriate UC placement coupled with emergency physician (EP) education on UC utilization. Urinary catheter utilization was measured before and after the establishment of guidelines and EP education. Data collected included the presence of a UC on ED arrival, placement of a UC in the ED, documentation of a physician order for UC placement, reasons for placement, and compliance with the guidelines. Chi-square analyses were used to study the association between pre- and postintervention time periods and catheter use. A total of 377 (15%) patients had UCs; only 151 (47%) UCs initially placed in the ED had a physician order documented. UC placement was appropriately indicated in 75.5% of patients with a documented physician order, but in only 52% of cases without a documented physician order (p<0.001). The physician intervention was associated with an overall reduction in UC utilization from 16.4% to 13% (p=0.018). Physicians ordered 40% fewer UCs postintervention compared to preintervention. Preintervention, a physician order for UC placement was found indicated in 72.6% patients, compared to 82.2% patients with UC placed postintervention (p=0.21). Establishing guidelines for UC placement and physician education in the ED were associated with a marked reduction in utilization. However, addressing appropriate UC utilization may require evaluating other factors such as nursing influence on utilization.


Heart disease deaths on death certificates re-evaluated by clinical records in a Japanese city.
In order to estimate the number of deaths from ischemic heart disease (IHD) in a Japanese city, we reevaluated heart disease deaths among residents aged 25-74 years by examining their clinical records. During the 2-year period from 1987 to 1988, 271 deaths among this population were attributed to heart disease. The recorded underlying cause of death was IHD in 96 cases, heart failure in 123 cases, and other heart disease in 52 cases. Re-evaluation of the cause of death yielded 57 cases of acute myocardial infarction (AMI), 85 cases of sudden death, 37 cases of heart disease other than IHD, and 63 cases of non-heart disease. In the remaining cases, there was insufficient information for evaluation. According to some autopsy studies, about 50% of sudden deaths are due to IHD. Thus, 50% of the number of sudden death cases may be added to the total number of IHD deaths. Accordingly, the total number of IHD deaths may have been 100, ie, 57 cases of AMI plus 43 cases of sudden death. The difference between the number of IHD deaths after re-evaluation and the number for which IHD was recorded as the underlying cause was small, with the former only 4% higher than the latter. The number of false-positives was equal to the number of false-negatives, and hence the number of IHD deaths recorded in this area seems to be close to the actual figure. We speculate that more accurate death certification will result in a decrease in the total number of deaths attributable to heart disease, as in 23% of deaths attributed to heart disease the underlying cause of death was not in fact heart disease.


Development of Albumin Coupled, Cholesterol Stabilized, Lipid Nanoemulsion of Methotrexate, and TNF-α Inhibitor for Improved In Vivo Efficacy Against Rheumatoid Arthritis.
Methotrexate (MTX; an anti-folate) and etanercept (ET; a TNF-α inhibitor) are used against arthritis; however, limitations like short biological half-life, low cutaneous absorption, and acidic instability limit their clinical relevance. Therefore, the aim of the investigation was to develop albumin coupled lipid nanoemulsion of MTX and ET for improved efficacy by virtue of their controlled release and specificity at the arthritic site. This emulsion was prepared by high-speed homogenization and stabilized using cholesterol. Lipid nanoemulsion of MTX and ET (MTX+ET-LNE) was coupled with albumin (MTX+ET-ALNE). MTX+ET-ALNE was characterized on the basis of particle size (410 ± 25.4 nm), PDI (0.160), and zeta potential (+38.6 ± 5.6 mV) and evaluated for pH (6.15), drug content (97.7 ± 2.17%), entrapment efficiency (76 ± 4.6%), in vitro release, and in vitro cytotoxicity. About 82.6 ± 9.60% release of MTX+ET was observed in 24 h from the developed MTX+ET-ALNE which may help maintain therapeutic level of drugs in blood at least for one day. No toxicity was observed when Raw 264.7 cells were treated with MTX+ET-ALNE, and no causalities of mice were observed at experimental in vivo dose (10 mg/kg BW) of MTX+ET in MTX+ET-ALNE-treated group. MTX+ET-ALNE treatment has alleviated arthritic scores and inflammatory cytokines level in a very significant manner when compared with MTX+ET-LNE and MTX+ET solutions. MTX+ET-ALNE-treated group restored histological alterations (cartilage/bone erosion, inflammatory cell infiltration, synovial hyperplasia, and narrower joint space) as observed in diseased treated groups. In conclusion, MTX+ET-ALNE can be opted as efficacious and clinically pertinent option to the current medication systems of arthritis.


Prevalence of partner violence in same-sex romantic and sexual relationships in a national sample of adolescents.
To present the first national prevalence estimates of psychological and physical intimate partner violence between adolescents in same-sex relationships. Analyses focus on 117 adolescents aged 12-21 years (50% female) from Wave II of the National Longitudinal Study of Adolescent Health who reported exclusively same-sex romantic or sexual relationships in the 18 months before interview. Items from the Conflict Tactics Scale were used to measure partner violence victimization. Data analysis included computation of prevalence estimates and a logistic regression analysis to assess associations between sociodemographic characteristics and violence victimization. Almost one-quarter of adolescents with same-sex romantic or sexual partners reported some type of partner violence victimization; about 1 in 10 reported physical victimization. Significant sex differences were found (OR = .29, CI = 0.08, 1.00), with males being less likely than females to report "any violence." Of six other sociodemographic characteristics examined, importance of religion (OR = .27, CI = 0.07-1.07) and school size (OR = .32, CI = 0.09-1.11) were associated with victimization at the p < .10 level. Adolescents who reported that religion was important to them and adolescents who attended larger schools were at lower risk of "any violence." As with opposite-sex relationships, psychological and minor physical violence victimization is common among adolescents involved in same-sex intimate relationships. Males reporting exclusively same-sex relationships were less likely than females to report experiencing the violence behaviors examined.


Different Clinical Features and Lower Scores in Clinical Scoring Systems for Appendicitis in Preschool Children: Comparison with School Age Onset.
To clarify the clinical features of appendicitis in preschool children and to explore clinical appendicitis scoring systems in this age group. We retrospectively collected data on 142 children, aged 10 years or younger, with confirmed diagnosis of appendicitis based on surgical and pathologic findings. Enrolled subjects were divided into two groups: Group 1 (preschool children aged ≤5 years, n=41) and Group 2 (school children aged >5 to ≤10 years, n=101). Data analyzed included clinical presentation, laboratory findings, the pediatric appendicitis score (PAS), and the modified Alvarado score (MAS). The most common presenting symptom was abdominal pain in both groups (92.7% vs. 97.0%). Other presenting symptoms were as follows: fever (65.9%), vomiting (68.3%), right lower quadrant (RLQ) localization (24.4%), anorexia (14.6%), and diarrhea (7.3%) in Group 1, and RLQ localization (74.3%), vomiting (71.3%), anorexia (52.5%), fever (47.5%), and diarrhea (11.9%) in Group 2. Perforation and abscess occurred more frequently in Group 1 than in Group 2 (43.9% vs. 12.9%, p<0.001; 34.1% vs. 5.0%, p<0.001; respectively). PAS and MAS were lower in Group 1 than in Group 2 (4.09±1.97 vs. 6.91±1.61, p=0.048; 4.65±1.79 vs. 6.51±1.39, p=0.012; respectively). In preschool children, appendicitis often presents with atypical features, more rapid progression, and higher incidence of complications. This age group is more likely to have lower PAS and MAS than those of school children.


Screen of five alkyl carbamates for initiating and promoting activity in rat liver.
Five alkyl carbamates, methyl, ethyl, propyl, hydroxypropyl and ethylhexyl, were tested for initiating and promoting activity in rat liver. The test for initiating activity consisted of administering the carbamate by gavage to male Sprague--Dawley rats at either 6 or 18 h after a 2/3 partial hepatectomy. One week later, the rats received 500 ppm sodium phenobarbital in their drinking water until killed 10 weeks later. None of the carbamates at 1/5 the LD50 induced gamma-glutamyltranspeptidase (GGT)-positive foci, indicating the lack of initiating activity. The tumor promoting activity test consisted of initiation with 80 mmol/kg diethylnitrosamine administered 18 h after a partial hepatectomy. One week later, the rats received one of the the carbamates at either 1/10 or 1/20 the LD50 5 days per week until sacrificed 10 weeks later. The alkyl carbamates increased the volume of the foci, the percent of the liver occupied by the foci, the number of foci/cm3 (except ethylhexyl carbamate), and the number of foci/liver (except ethylhexyl carbamate). These results suggest that the alkyl carbamates are tumor promoters and not tumor initiators in rat liver.


Association of ocular toxoplasmosis with type I Toxoplasma gondii strains: direct genotyping from peripheral blood samples.
Toxoplasma gondii strains were genotyped directly from blood samples of patients with ocular toxoplasmosis. Analysis of nontranscribed spacer 2 revealed that all detected strains belonged to type I, suggesting an association of ocular toxoplasmosis with this type. The method shows the usefulness of blood samples for genotyping in ocular toxoplasmosis.


[Analysis of the activity of neuronal populations in the brains of rabbits during adaptive self-regulation].
The multiple unit (of 2 to 10 elements) activity of the somatosensory cortex was studied with the help of autospectral analysis in a rabbit learned with biofeedback technique from changes of the neuronal current discharge frequency. The background activity of neuronal pools is characterized by several basic profiles of frequency spectra. In most neuronal pools, after 4 to 12 min. of stimulation (below-threshold frequency is reinforced), the frequency of neuronal discharges is steadily enhanced, and the number of pain stimulations correspondingly diminishes by 30 to 50% for a few minutes or longer -- the result of learning. The appearance and increase in the autospectra of a relatively higher frequency component (0.35 to 0.6 c/s) during adaptive reorganizations reflects the influence of an effective feedback control; enhancement of the power of oscillations with a 0.05 to 0.07 c/s frequency testifies to a process of search by the system of the state extremum.


The clinical importance of early acute hepatic porphyria diagnosis: a national cohort.
Acute hepatic porphyria (AHP) attacks begin with abdominal pain and can progress to severe life-threatening conditions. Early diagnosis and treatment may prevent these complications. We investigated the difference between the severity of porphyria attacks before and after porphyria diagnosis. A retrospective study including AHP patients hospitalized for an acute attack in Israel during a 15-year period. Diagnosis of an attack was based on typical clinical symptoms accompanied by at least one documented elevated urinary porphobilinogen above fourfold of normal values. The primary outcome was intensive care unit (ICU) admissions. Secondary outcomes included the length of hospital stay, severe hyponatremia, seizures, and psychiatric symptoms. 42 attacks in 9 patients were included. Most attacks occurred in women (78.6%) and in acute intermittent porphyria patients (76.2%). The mean age of attack was 26.5 (± 6.3) years. Attacks following porphyria diagnosis had a lower prevalence of ICU admission (3.3% versus 75.0%, p < 0.001), seizures (0% versus 50.0%, p < 0.001), psychiatric symptoms (23.3% versus 66.7%, p = 0.01), severe hyponatremia (16.7% versus 83.3%, p < 0.001), and median length of hospital stay (5 versus 11.0 days, p < 0.001). These results remained significant after simple univariate logistic regression for ICU admission [odds ratio (OR) 0.01, 95% confidence interval (CI) 0.00-0.12], prolonged hospital stay (OR 0.08, 95% CI 0.01-0.41), seizures or neurological symptoms (OR 0.06, 95% CI 0.01-0.30), and severe hyponatremia (OR 0.02, 95% CI 0.00-0.20). Previously diagnosed AHP patients have a significantly milder attack course as compared to previously undiagnosed patients. Family screening following sentinel cases might prevent severe AHP attacks.


Subcutaneous but not intraluminal epidermal growth factor stimulates colonic growth in normal adult rats.
Epidermal growth factor (EGF) was administered by chronic subcutaneous or intracolonic infusion into normal adult rats to determine the effect on colonic growth. Subcutaneous infusion of 200 micrograms EGF/kg/day for 7 days increased the cross-sectional mass and protein content of the muscularis and mucosal layers of the proximal colon, with the distal colon showing less response. In the mucosa, subcutaneous EGF induced proportional increments in the number of cells per crypt, and in the number of cells positively labelled for PCNA, while maintaining a normal crypt growth fraction. In contrast, an 8-fold higher dose of EGF administered intraluminally had no effect on colonic mucosal or muscularis growth. This lack of bioactivity was unlikely to reflect rapid luminal degradation as radiolabelled EGF remained stable in the colonic lumen for at least 4 h. The results demonstrate that the normal adult colon is responsive to subcutaneously delivered EGF, particularly the proximal colon, whereas EGF may not be active on the normal colon when presented from the luminal direction.


Update: Mode of action (MOA) for liver tumors induced by oral exposure to 1,4-dioxane.
Previous work has shown that the weight of evidence supports the hypothesis that 1,4-dioxane causes liver tumors in rodents through cytotoxicity and subsequent regenerative hyperplasia. Questions regarding a lack of concordant findings for this mode of action (MOA) in mice have not been resolved, however. In the current work, a reanalysis of data from two chronic mouse cancer bioassays on 1,4-dioxane, one 13-week mouse study, seven rat cancer bioassays, coupled with other data such as 1,4-dioxane's negative mutagenicity, its lack of up-regulated DNA repair, and the appearance of liver tumors with a high background incidence, support the conclusion that rodent liver tumors, including those in mice, are evoked by a regenerative hyperplasia MOA. The initiating event for this MOA is metabolic saturation of 1,4-dioxane. Above metabolic saturation, higher doses of the parent compound cause an ever increasing toxicity in the rodent liver as evidenced by higher blood levels of enzymes indicative of liver cell damage and associated histopathology that occurs in a dose and time related manner. Importantly, alternative modes of action can be excluded. The observed liver toxicity has a threshold in the dose scale at or below levels that saturate metabolism, and generally in the range of 9.6-42 mg/kg-day for rats and 57 to 66 mg/kg-day for mice. It follows that threshold approaches to the assessment of this chemical's toxicity are supported by the non-mutagenic, metabolic saturation kinetics, and cytotoxicity-generated regenerative repair information available for 1,4-dioxane promoted rodent liver tumors.


Health-related quality of life and musculoskeletal function in patients with musculoskeletal disorders: after compared to before short-term group-based aqua-exercises.
This study assessed health-related quality of life (HRQoL) and musculoskeletal function in patients with musculoskeletal disorders after participation in group-based aqua-exercising, compared to before participation. Physiotherapists instructed group-based aqua-exercising for 30 min twice a week for 8 weeks in 39 patients (81% women, mean age 55 ± 12 years), with musculoskeletal disorders located in the back (28%), neck (17%), general myalgia (21%), lower extremities (9%), shoulder (7%) and multiple/other regions (18%). Before and after the aqua-exercising, physiotherapists assessed patients' musculoskeletal function categorized using Goal Attainment Scaling, and HRQoL was measured using EuroQol 5 Dimensions (EQ-5D). The median EQ-5D score was 0.36 (25th-75th percentiles 0.09-0.69) at the start, and after the intervention improved to 0.62 (0.09-0.73) (p = 0.038). The EQ-5D score and musculoskeletal function improved in 49% (EQ-5D) and 34% (physiotherapist assessment), were stable in 33% and 63%, and worsened in 18% and 7% of patients, respectively. In conclusion, comparable with improvements previously seen after more time-consuming exercise periods, patients with musculoskeletal disorders had improved HRQoL after 8 weeks of aqua-exercising compared to before exercising. This uncontrolled feasibility study does not reveal whether this was the result of aqua-exercising. The effects and costs need to be evaluated in randomized controlled studies.


Estrogen and Androgen Blockade for Advanced Prostate Cancer in the Era of Precision Medicine.
Androgen deprivation therapy (ADT) has been widely prescribed for patients with advanced prostate cancer (PC) to control key signaling pathways via androgen receptor (AR) and AR-collaborative transcriptional factors; however, PC gradually acquires a lethal phenotype and results in castration-resistant PC (CRPC) during ADT. Therefore, new therapeutic strategies are required in clinical practice. In addition, ARs; estrogen receptors (ERs; ERα and ERβ); and estrogen-related receptors (ERRs; ERRα, ERRβ, and ERRγ) have been reported to be involved in the development or regulation of PC. Recent investigations have revealed the role of associated molecules, such as KLF5, FOXO1, PDGFA, VEGF-A, WNT5A, TGFβ1, and micro-RNA 135a of PC, via ERs and ERRs. Selective ER modulators (SERMs) have been developed. Recently, estrogen and androgen blockade (EAB) using a combination of toremifene and ADT has been demonstrated to improve biochemical recurrence rate in treatment-naïve bone metastatic PC. In the future, the suitability of ADT alone or EAB for individuals may be evaluated by making clinical decisions on the basis of information obtained from RT-PCR, gene-panel, or liquid biopsy to create a "personalized medicine" or "precision medicine". In this review, we summarize ER and ERR signaling pathways, molecular diagnosis, and SERMs as candidates for advanced PC treatment.


Prognostic significance of stem cell-related marker expression and its correlation with histologic subtypes in lung adenocarcinoma.
Cancer stem cells (CSCs) are a small subset of tumor cells that exhibit stem cell-like properties and contribute in treatment failure. To clarify the expression and prognostic significance of several CSC markers in non-small cell lung cancer, we retrospectively analyzed 368 patients with adenocarcinoma (n = 226) or squamous cell carcinoma (n = 142). We correlated the expression of six CSC markers - CD133, CD44, aldehyde dehydrogenase 1 (ALDH1), sex determining region Y-box 2 (SOX2), octamer binding transcription factor 4 (OCT4), and Nanog - with clinicopathologic and molecular variables and survival outcomes. In adenocarcinoma, CD133, ALDH1 and CD44 expression was associated with low pathologic stage and absence of lymphovascular invasion, while Nanog expression correlated with high histologic grade, lymphatic invasion and increased expression of Snail-1, a transcription factor associated with epithelial-mesenchymal transition. CSC marker expression was also associated with histologic subtypes in adenocarcinoma. Multivariate analysis showed that high Nanog expression was an independent factor associated with a poor prognosis in adenocarcinoma. CSC markers had no prognostic value in squamous cell carcinoma. These results suggest that Nanog is an independent negative prognostic factor that may be associated with epithelial-mesenchymal transition in lung adenocarcinoma.


Attosecond streak camera.
An electron generated by x-ray photoionization can be deflected by a strong laser field. Its energy and angular distribution depends on the phase of the laser field at the time of ionization. This phase dependence can be used to measure the duration and chirp of single sub100-attosecond x-ray pulses.


Evidence for a magnetically driven superconducting Q phase of CeCoIn5.
We have studied the magnetic order inside the superconducting phase of CeCoIn5 for fields along the [1 0 0] crystallographic direction using neutron diffraction. We find a spin-density wave order with an incommensurate modulation Q=(q,q,1/2) and q=0.45(1), which within our experimental uncertainty is indistinguishable from the spin-density wave found for fields applied along [1 -1 0]. The magnetic order is thus modulated along the lines of nodes of the d{x{2}-y{2}} superconducting order parameter, suggesting that it is driven by the electron nesting along the superconducting line nodes. We postulate that the onset of magnetic order leads to reconstruction of the superconducting gap function and a magnetically induced pair density wave.


Clonal growth of immunocytochemically identified islet beta and alpha cells in culture.
The proliferative capacity of individual immunocytochemically identified islet beta cells was investigated in tissue culture. The pancreatic digest was filtered through a 20-micron filter to eliminate partially digested tissue fragments and islets; it was then cultured at low density to allow assessment of single cells. The type of cell was identified immunocytochemically by reaction with antibody to insulin or glucagon, and DNA synthesis was estimated from autoradiographs after incorporation of tritiated thymidine. Single immunocytochemically reactive beta or alpha cells attached to the culture substratum and then proliferated, directly proportional to time in culture. Single beta cells did not incorporate thymidine after 1 day in culture; nonendocrine cells, presumed to be mainly fibroblasts, readily incorporated thymidine. Beyond the first day, about 10% of the beta cells incorporated thymidine. The number of radioactively labeled, immunocytochemically reactive beta cells increased for 5 days in culture and then remained at the elevated level until experiments were terminated at 12 days. DNA synthesis in beta cells occurred in two waves separated by about 3 days, suggesting a generation time of about 3 days for immunocytochemically identified beta cells. Fetal calf serum was found to be an essential culture medium ingredient to sustain thymidine incorporation; horse serum was found to be an unsuitable substitute. Mitotic figures were recorded in differentiated beta and alpha cells. These studies conclusively show that differentiated beta and alpha cells can proliferate in culture.(ABSTRACT TRUNCATED AT 250 WORDS)


Application of noncollapsing methods to the gene-based association test: a comparison study using Genetic Analysis Workshop 18 data.
Rare variants have been proposed to play a significant role in the onset and development of common diseases. However, traditional analysis methods have difficulties in detecting association signals for rare causal variants because of a lack of statistical power. We propose a two-stage, gene-based method for association mapping of rare variants by applying four different noncollapsing algorithms. Using the Genome Analysis Workshop18 whole genome sequencing data set of simulated blood pressure phenotypes, we studied and contrasted the false-positive rate of each algorithm using receiver operating characteristic curves. The statistical power of these methods was also evaluated and compared through the analysis of 200 simulated replications in a smaller genotype data set. We showed that the Fisher's method was superior to the other 3 noncollapsing methods, but was no better than the standard method implemented with famSKAT. Further investigation is needed to explore the potential statistical properties of these approaches.


Clinical Manifestations, Diagnosis, and Surgery of Inferior Oblique Muscle Ectopia.
To summarize the clinical manifestations, diagnosis, treatment, and prognosis for inferior oblique muscle ectopia (IO-E). Subjects and Methods. Patients diagnosed with IO-E during strabismus surgery from March 2017 to September 2018 were included in this retrospective, cross-sectional study. All patients received preoperative Krimsky test, synoptophore, cycloplegia refraction, fundus torsion, and other strabismus-related specific tests. The anatomic variations of IO-E were always discovered during surgical procedure. Postoperative eye position and binocular visual function (BVF) were all reviewed in early days after operation. A total of 7 patients were enrolled in this study with an average age of 6.4 ± 3.8 yrs. They all presented with significant exotropia and unilateral (or bilateral) overelevation in adduction (OEA). No compensatory head position was detected. Some of them had vertical deviation, V pattern, or excyclotropia, which were indicated by fundus torsion. Monocular or binocular IO-E was distinguished during the surgery, and it could be classified into two types according to its anatomic features. In surgery, the ectopic IO muscle bundle was restored, and different IO weakening methods were employed. Meanwhile, the horizontal deviation was also corrected according to the preoperative examination. Eyes of all patients were properly aligned in the primary position after surgery. Varying degrees of BVF appeared in 3 cases. IO-E is a rare congenital dysplasia variation of the extraocular muscle, which could appear as inferior oblique overaction. It is difficult to diagnose before surgery, and weakening the overactive ectopic inferior oblique was required for better prognosis if this condition was confirmed during surgery.


Single-molecule stepping and structural dynamics of myosin X.
Myosin X is an unconventional myosin with puzzling motility properties. We studied the motility of dimerized myosin X using the single-molecule fluorescence techniques polTIRF, FIONA and Parallax to measure the rotation angles and three-dimensional position of the molecule during its walk. It was found that Myosin X steps processively in a hand-over-hand manner following a left-handed helical path along both single actin filaments and bundles. Its step size and velocity are smaller on actin bundles than individual filaments, suggesting myosin X often steps onto neighboring filaments in a bundle. The data suggest that a previously postulated single alpha-helical domain mechanically extends the lever arm, which has three IQ motifs, and either the neck-tail hinge or the tail is flexible. These structural features, in conjunction with the membrane- and microtubule-binding domains, enable myosin X to perform multiple functions on varied actin structures in cells.


Whole cell patch clamp recording performed on a planar glass chip.
The state of the art technology for the study of ion channels is the patch clamp technique. Ion channels mediate electrical current flow, have crucial roles in cellular physiology, and are important drug targets. The most popular (whole cell) variant of the technique detects the ensemble current over the entire cell membrane. Patch clamping is still a laborious process, requiring a skilled experimenter to micromanipulate a glass pipette under a microscope to record from one cell at a time. Here we report on a planar, microstructured quartz chip for whole cell patch clamp measurements without micromanipulation or visual control. A quartz substrate of 200 microm thickness is perforated by wet etching techniques resulting in apertures with diameters of approximately 1 microm. The apertures replace the tip of glass pipettes commonly used for patch clamp recording. Cells are positioned onto the apertures from suspension by application of suction. Whole cell recordings from different cell types (CHO, N1E-115 neuroblastoma) are performed with microstructured chips studying K(+) channels and voltage gated Ca(2+) channels.


Confocal endomicroscopic imaging of normal and neoplastic human tongue tissue using ALA-induced-PPIX fluorescence: a preliminary study.
Confocal endomicroscopy is a novel and non-invasive microscopic technique that enables surface and subsurface imaging of living tissues or cells in vivo. The purpose of this study was to assess the possibility of utilizing a rigid confocal endomicroscope (RCE) system developed for detecting morphological changes in living normal and neoplastic human tongue tissue in combination with 5-aminolevulinic acid (ALA)-induced endogenous protoporphyrin IX (PPIX) fluorescence. Three patients with squamous cell carcinoma (SCC) of the tongue were examined using the novel RCE system with the excitation wavelength at 488 nm from an argon-ion laser and the detection wavelengths of the tissue fluorescence above 515 nm. Patients were topically applied with 0.4% of 5-ALA rinsing solution to the oral mucosa for approximately 15 min, and then the confocal endomicroscopic imaging of tissue PPIX fluorescence was performed on the lesion sites of the tongue after an optimal incubation period of 90-120 min. For comparison purposes, ALA-PPIX fluorescence confocal endomicroscopic imaging was also carried out on the normal sites of the tongue in vivo from two healthy volunteers. Image distortions due to tissue motion can be minimized using a specially designed tissue stabilizer attached to the RCE probe. Good quality ALA-mediated confocal fluorescence images of the tongue can be acquired in real-time, providing well-defined micro-morphological structures (e.g., filiform papillae, keratinized epithelium and fungiform papillae) of the tongue in vivo. Changes of tissue structures in oral tissue associated with cancer transformation can also be clearly identified using the RCE imaging. Preliminary results obtained in this study suggest that ALA-mediated rigid confocal endomicroscopy may have a significant potential for the rapid, non-invasive diagnosis and evaluation of early oral cancers in vivo.


Sperm harvesting and post-mortem fatherhood.
The motives and consequences of harvesting sperm from brain dead males for the purpose of effecting post mortem fatherhood are examined. I argue that sperm harvesting and post mortem fatherhood raise no harms of a magnitude that would justify forbidding the practice outright. Dead men are not obviously harmed by the practice; children need not be harmed by this kind of birth; and the practice enlarges rather than diminishes the reproductive choices of surviving partners. Certain ethical and legal issues nevertheless require attention. As a matter of consistency with other harvesting protocols, there ought to be a mechanism for respecting the wishes of men who when alive do not wish to become fathers post mortem. Mechanisms governing entitlement to harvest and use sperm will also be required. I note that the law is unlikely to recognize the paternity of children born from harvested sperm, though there may be reasons to recognize that paternity in some instances.


C/EBP, NF-kappa B, and c-Ets family members and transcriptional regulation of the cell-specific and inducible macrophage inflammatory protein 1 alpha immediate-early gene.
Macrophage inflammatory protein 1 alpha (MIP-1 alpha) cytokine gene expression is restricted to a limited number of cells of hemopoietic origin and is rapidly and transiently induced by serum and endotoxin in macrophages. A single nuclear DNase I-hypersensitive site, which maps to the proximal promoter of the MIP-1 alpha gene, was identified in macrophage cells but was absent in cells which do not express basal levels of MIP-1 alpha mRNA. The proximal promoter sequences (+36 to -220 bp) are sufficient to confer cell-specific and inducible transcription in transfection assays. In vitro DNA-binding studies revealed five major nuclear protein binding sites in the proximal promoter which bind C/EBP, NF-kappa B, and/or c-Ets family members. Cell-specific differences in DNA binding by members of the NF-kappa B and c-Ets families correlate with the cell-specificity of MIP-1 alpha gene expression and the chromosomal conformation of the promoter. Changes in promoter binding by members of the C/EBP and NF-kappa B families correlate with the transcriptional up-regulation observed in serum- or endotoxin-stimulated macrophages in functional studies.


A Focused Observation Tool Using Dreyfus Stages of Skill Acquisition as an Evaluative Scale.
Focused Observartion (FO) is associated with assessing complex skills and differs from generalized observations and evaluations. We've developed a FO assessing clinical procedural skills using Hubert Dreyfus Stages of Skill Acquisition as descriptive anchors. This study sought to analyze the effectiveness of this measure of skill progression. During week 1 and week 4 of training, FO was performed repetitively on 6 residents during endotracheal intubation. Skill stage ratings were converted to numerical scores. A dependent, paired samples t-test was calculated using total mean score (dependent variable) and an effect size. (Cohen's d) was performed to ascertain the standardized mean difference between observations. A significant improvement in mean scores occurred between Week 1 (AVG 1.2, STDV ± 0.1) and Week 4 (AVG 2.0, STDV ± 0.1) (t= -3.9, p<.05) Calculated Chohen's d indicates that this difference was meaningful. This study demonstrates success in adapting a Focused Observation technique and an innovative evaluative scale based upon Dreyfus stages of skill acquisition.


Esophageal Adenocarcinoma in an Active Duty Sailor: A Case Report.
Esophageal adenocarcinoma develops when normal squamous epithelia are replaced by dysplastic intestinal columnar cells in response to chronic gastroesophageal reflux disease (GERD). In addition to squamous cell carcinoma, the two malignancies account for over 95% of esophageal malignancies. This case describes a sailor deployed onboard an aircraft carrier who initially presented with typical GERD symptoms and later developed multifactorial weight loss confounded by the operational environment. Upon return to homeport, he was diagnosed with stage III gastroesophageal junction adenocarcinoma. This case emphasizes the difficulty in identifying and diagnosing a rare and dangerous pathology in the resource-limited, operational environment.


Twinning rates among women at the end of their reproductive span and their relation to age at menopause;.
A review of studies on twinning has shown that dizygotic (DZ) twinning rates among women from general populations characteristically peak at ages 35-39, then decline sharply. Analysis of genealogical data from the Archives of the Mormon Church indicates that women who are dizygous twins themselves or the sibs of dizygous twins have a higher twinning rate among their offspring than do women from the general population. The dizygotic twinning rates of women who are twins or the sibs of twins classified by maternal age also peak at ages 35-39 but remain high at ages 40-44, then decline. It is well known that Negro women have high DZ twinning rates; a less well knwon finding is that the DZ twinning rates of Negro women also remain high after age 39. It has been suggested that high DZ twinning rates at later maternal ages may be related to a delayed age at menopause; However, published reports on age at natural menopause and analysis of our data from contemporary white US women indicate the contrary; Women who have borne unlike-sexed (DZ) twins and Negro women have a lower age at natural menopause then do white women from general populations, and a lower age in comparison with women who have borne like-sexed twins.


Masson's hemangioma of spinal meninges causing cord compression with paraplegia.
Masson's hemangioma is a rare benign pathological entity. A unique case is reported of a 42 year old man with a spinal epidural mass who developed acute cord compression resulting in sudden onset of paraplegia. Histological examination of the resected mass revealed a cystic vascular lesion associated with papillary endothelial cell proliferation, and overlying thrombosis, consistent with Masson's hemangioma. Clinicoradiological correlation is also presented.


A drastic superoxide-dependent oxidative stress is prerequisite for the down-regulation of IRP1: Insights from studies on SOD1-deficient mice and macrophages treated with paraquat.
Iron regulatory protein 1 (IRP1) is a cytosolic bifunctional [4Fe-4S] protein which exhibits aconitase activity or binds iron responsive elements (IREs) in untranslated regions of specific mRNA encoding proteins involved in cellular iron metabolism. Superoxide radical (O2.-) converts IRP1 from a [4Fe-4S] aconitase to a [3Fe-4S] "null" form possessing neither aconitase nor trans-regulatory activity. Genetic ablation of superoxide dismutase 1 (SOD1), an antioxidant enzyme that acts to reduce O2.- concentration, revealed a new O2.--dependent regulation of IRP1 leading to the reduction of IRP1 protein level and in consequence to the diminution of IRP1 enzymatic and IRE-binding activities. Here, we attempted to establish whether developmental changes in SOD1 activity occurring in the mouse liver, impact IRP1 expression. We show no correlation between hepatic SOD1 activity and IRP1 protein level neither in pre- nor postnatal period probably because the magnitude of developmental fluctuations in SOD1 activity is relatively small. The comparison of SOD1 activity in regards to IRP1 protein level in the liver of threeSOD1 genotypes (Sod1+/+, Sod1+/- and Sod1-/-) demonstrates that only drastic SOD1 deficiency leads to the reduction of IRP1 protein level. Importantly, we found that in the liver of fetuses lacking SOD1, IRP1 is not down-regulated. To investigate O2.--dependent regulation of IRP1 in a cellular model, we exposed murine RAW 264.7 and bone marrow-derived macrophages to paraquat, widely used as a redox cycler to stimulate O2.-production in cells. We showed that IRP1 protein level as well as aconitase and IRE-binding activities are strongly reduced in macrophages treated with paraquat. The analysis of the expression of IRP1-target genes revealed the increase in L-ferritin protein level resulting from the enhanced transcriptional regulation of the LFt gene and diminished translational repression of L-ferritin mRNA by IRP1. We propose that O2.--dependent up-regulation of this cellular protectant in paraquat-treated macrophages may counterbalance iron-related toxic effects of O2.-.


Left- and Right-Leaning News Organizations Use Negative Emotional Content and Elicit User Engagement Similarly.
Negativity has historically dominated news content; however, little research has examined how news organizations use affect on social media, where content is generally positive. In the current project we ask a few questions: Do news organizations on Twitter use negative or positive language and which type of affect garners more engagement on social media? Does the political orientation of news organizations impact the affect expressed and engagement tweets receive on social media? The goal of this project is to examine these questions by investigating tweets of 24 left- and 20 right-leaning news organizations (140,358 tweets). Results indicated that negative affect was expressed more than positive affect. Additionally, negativity predicted engagement with news organizations' tweets, but positivity did not. Finally, there were no differences in affect between left- and right-leaning political orientations. Overall, it appears that for news organizations, negativity is more frequent and more impactful than positivity. The online version contains supplementary material available at 10.1007/s42761-021-00046-w.


Ischemic postconditioning inhibits apoptosis after focal cerebral ischemia/reperfusion injury in the rat.
Ischemic postconditioning (Postcond) is defined as a series of intermittent interruptions of blood flow in the early phase of reperfusion that mechanically alters the hydrodynamics of reperfusion. A recent study showed that Postcond reduced infarct size in cerebral ischemia/reperfusion (I/R) injury. However, little is known about the mechanisms of Postcond in cerebral I/R injury. In the present study, we investigated the effects of Postcond in focal cerebral I/R injury in the rat middle cerebral artery occlusion model. Adult male Sprague-Dawley rats were treated with Postcond after 60 minutes of occlusion (beginning of reperfusion). Neurologic scores and infarct volumes were assessed at 24 and 72 hours. Oxidative stress was evaluated by malondialdehyde assay, and apoptosis-related molecules were studied by Western blotting. Postcond treatment upregulated Bcl-2 and heat-shock protein 70 expression and downregulated cytochrome c release to the cytosol, Bax translocation to the mitochondria, and caspase-3 activity. Postcond treatment also reduced infarct volumes and oxidative stress levels and improved neurologic scores compared with the I/R-only group. These findings indicate that Postcond inhibits focal cerebral I/R injury. This neuroprotective effect is likely achieved by antiapoptotic mechanisms.


Impaired respiratory response to resistive loading during sleep in healthy offspring of patients with obstructive sleep apnea.
To evaluate the possibility that healthy offspring of patients with obstructive sleep apnea syndrome (OSAS) may have covert signs of sleep disordered breathing, we compared the respiratory response to inspiratory resistive loads (IRL) in 10 adult offspring of fathers previously diagnosed with OSAS with that of 14 offspring of healthy parents. None of the offspring in either group had any sign of OSAS, and groups were age, weight, and body mass index matched. Both ventilatory response to progressively increasing levels of IRL and the IRL required to produce severe hypopnea (tidal volume [V(T)] < 20% of unloaded magnitude) were determined, during NREM sleep. Offspring of patients with OSAS (OSAS offspring) responded to all levels of IRL with greater decreases in V(T). Their V(T) decreased in the second breath on IRL of 23 cm H2O/l/s by 39 +/- 10%, as compared with a decrease of 19 +/- 4% (mean +/- SD) in the control group (p < 0.05). Severe hypopnea occurred in the OSAS offspring in response to smaller IRL compared to controls (79 +/- 20 and 153 +/- 14 cm H2O/l/s, respectively, p < 0.005). Total upper airway occlusion in response to IRL occurred in three of the OSAS offspring, but in none of the controls. We conclude that apparently healthy offspring of patients with OSAS may inherit subtle defects that reduce their ability to compensate for increased loads and maintain upper airway patency during sleep. We speculate that offspring of OSAS patients with decreased tolerance to IRL may be prone to developing OSAS later on in life.


New molecular targets against cervical cancer.
Cervical cancer is the third most commonly diagnosed cancer worldwide and the fourth leading cause of cancer death in women. Major advances but still insufficient achievements in the treatment of locally advanced and high-risk early stage patients have occurred in the last decade with the incorporation of concurrent cisplatin with radiation and, lately, gemcitabine added to cisplatin chemoradiation. Despite a number of clinical studies incorporating molecular-targeted therapy as radiosensitizers being in progress, so far, only antiangiogenic therapy with bevacizumab added to cisplatin chemoradiation has demonstrated safety and shown encouraging results in a Phase II study. In advanced disease, cisplatin doublets do not have a great impact on the natural history of the disease with median survival rates not exceeding 13 months. The first Phase III study of bevacizumab, added to cisplatin or a non-cisplatin-containing doublet, showed significant increase in both overall survival and progression-free survival. Further studies are needed before bevacizumab plus chemotherapy can be considered the standard of care for advanced disease. Characterization of the mutational landscape of cervical cancer has already been initiated, indicating that, for now, few of these targetable alterations match with available agents. Progress in both the mutational landscape knowledge and developments of novel targeted therapies may result in more effective and individualized treatments for cervical cancer. The potential efficacy of knocking down the key alterations in cervical cancer - E6 and E7 human papillomavirus oncoproteins - must not be overlooked.


Meniscal injury: I. Basic science and evaluation.
The patient with meniscal injury may present with pain, swelling, or mechanical symptoms and often requires surgical intervention for symptom resolution. Treatment of such injuries relies on understanding the gross and microanatomic features of the meniscus that are important in maintaining meniscal function. The ability of the meniscus to participate in load bearing, shock absorption, joint lubrication, and joint stability depends on the maintenance of its structural integrity. The diagnosis of meniscal injury often can be made by clinical evaluation utilizing the history, physical examination, and plain radiographs. Magnetic resonance imaging can be useful in confirming the diagnosis when clinical findings are inconclusive. Treatment depends on tear pattern, vascularity, and an assessment of tissue quality. Surgical decision making for the treatment of meniscal injury is based on patient factors and understanding of the meniscal structure, function, and pathology.


Effectiveness of thymoquinone in the treatment of experimental asthma.
Thymoquinone (TQ), the main active constituent of the volatile oil extracted from Nigella sativa's seeds, is used for the treatment of inflammatory diseases and exhibits a variety of pharmacological effects. Twenty-eight BALB/c female mice were divided into four groups: I (sham-operated control group), II, III, and IV. All groups except for the sham-operated group were sensitized and challenged with ovalbumin. The sham-operated group received nebulized saline in challenge period. Mice in groups III and IV were administered TQ at a dose of 3 mg/kg and dexamethasone 1 mg/kg, respectively, intraperitoneally once a day for the final 5 days of the challenge period. Animals were sacrificed 24 h after the last drug administration and the airway samples were evaluated histologically by light microscopy. All histological parameters in Group III, similar to Group IV, were improved when compared to Group II. All variables except numbers of goblet cells were found to be significantly better in Group III and Group IV compared to Group II. In our study, we demonstrated that TQ administration alleviates the pathological changes of chronic asthma. TQ might be a promising therapy for asthma in the.


[Locus of the retention benefits of variable practice in the motor learning].
Shea and Kohl (1990) reported that acquisition practice with variations of the criterion task leads to better retention than practice on the criterion task alone. The purpose of this study was to determine the locus of this retention benefits. Experimental task was the speed reproduction task. Eighty undergraduate male students were randomly assigned to eight practice conditions differing in the activities performed during the intertrial intervals. All subjects were administered retention test immediately and twenty-four hours after the practice. Results indicated that the retention benefits demonstrated by subjects provided variable practice was produced by the contextual interference effect not by the formation of motor response schema. Results also suggested that both of reconstruction of action plan and elaborative processing resulted in the retention benefits.


Functional cooperation between c-Cbl and Src-like adaptor protein 2 in the negative regulation of T-cell receptor signaling.
Adaptor proteins assemble multiprotein signaling complexes, enabling the transduction of intracellular signals. While many adaptor proteins positively regulate signaling in this manner, a subgroup of adaptors function as negative regulators. Here we report the identification of a hematopoiesis-specific adaptor protein that we have designated Src-like adaptor protein 2 (SLAP-2). SLAP-2 is most closely related to SLAP and contains a Src homology 3 (SH3) domain and an SH2 domain, as well as an amino-terminal myristoylation site that mediates SLAP-2 association with membranes. Following stimulation of primary thymocytes with anti-CD3 and anti-CD28, SLAP-2 coimmunoprecipitates with tyrosine-phosphorylated c-Cbl and an unidentified protein of approximately 72 kDa. In activated Jurkat T cells, SLAP-2 also binds an additional 70-kDa phosphoprotein, identified as ZAP-70. Binding of SLAP-2 to both p72 and ZAP-70 is dependent on its SH2 domain, while c-Cbl interacts with the carboxy-terminal region. Overexpression of wild-type SLAP-2 alone or in combination with c-Cbl in Jurkat T cells leads to inhibition of T-cell antigen receptor-induced activation of nuclear factor of activated T cells. The inhibitory effect of SLAP-2 requires the carboxy-terminal c-Cbl binding region. Expression of SLAP-2 with SYK or ZAP-70 in COS cells or Jurkat T cells causes the degradation of these kinases, and SLAP-2 overexpression in Jurkat T cells reduces the surface expression of CD3. These results suggest that the mechanism of action of SLAP-2 and the related protein SLAP is to promote c-Cbl-dependent degradation of the tyrosine kinases SYK and ZAP-70 and down-regulation of CD3 at the cell surface.


Macrophages and fibrosis: how resident and infiltrating mononuclear phagocytes account for organ injury, regeneration or atrophy.
Mononuclear phagocytes (MP), i.e., monocytes, macrophages, and dendritic cells (DCs), are essential for immune homeostasis via their capacities to clear pathogens, pathogen components, and non-infectious particles. However, tissue injury-related changes in local microenvironments activate resident and infiltrating MP towards pro-inflammatory phenotypes that contribute to inflammation by secreting additional inflammatory mediators. Efficient control of injurious factors leads to a switch of MP phenotype, which changes the microenvironment towards the resolution of inflammation. In the same way, MP endorses adaptive structural responses leading to either compensatory hypertrophy of surviving cells, tissue regeneration from local tissue progenitor cells, or tissue fibrosis and atrophy. Under certain circumstances, MP contribute to the reversal of tissue fibrosis by clearance of the extracellular matrix. Here we give an update on the tissue microenvironment-related factors that, upon tissue injury, instruct resident and infiltrating MP how to support host defense and recover tissue function and integrity. We propose that MP are not intrinsically active drivers of organ injury and dysfunction but dynamic amplifiers (and biomarkers) of specific tissue microenvironments that vary across spatial and temporal contexts. Therefore, MP receptors are frequently redundant and suboptimal targets for specific therapeutic interventions compared to molecular targets upstream in adaptive humoral or cellular stress response pathways that influence tissue milieus at a contextual level.


Anatomical and Functional Connectivity of Critical Deep Brain Structures and Their Potential Clinical Application in Brain Stimulation.
Subcortical structures, such as the hippocampus, amygdala, and nucleus accumbens (NAcc), play crucial roles in human cognitive, memory, and emotional processing, chronic pain pathophysiology, and are implicated in various psychiatric and neurological diseases. Interventions modulating the activities of these deep brain structures hold promise for improving clinical outcomes. Recently, non-invasive brain stimulation (NIBS) has been applied to modulate brain activity and has demonstrated its potential for treating psychiatric and neurological disorders. However, modulating the above deep brain structures using NIBS may be challenging due to the nature of these stimulations. This study attempts to identify brain surface regions as source targets for NIBS to reach these deep brain structures by integrating functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI). We used resting-state functional connectivity (rsFC) and probabilistic tractography (PTG) analysis to identify brain surface stimulation targets that are functionally and structurally connected to the hippocampus, amygdala, and NAcc in 119 healthy participants. Our results showed that the medial prefrontal cortex (mPFC) is functionally and anatomically connected to all three subcortical regions, while the precuneus is connected to the hippocampus and amygdala. The mPFC and precuneus, two key hubs of the default mode network (DMN), as well as other cortical areas distributed at the prefrontal cortex and the parietal, temporal, and occipital lobes, were identified as potential locations for NIBS to modulate the function of these deep structures. The findings may provide new insights into the NIBS target selections for treating psychiatric and neurological disorders and chronic pain.


Inhibitory effects of human leukocyte and fibroblast interferons on normal and chronic myelogenous leukemic granulocytic progenitor cells.
Inhibitory effects of two human interferon preparations, leukocyte interferon (Le-IF) and fibroblast interferon (F-IF), on granulocytic progenitor cells (CFU-C) from hematologically normal cancer patients and from patients with chronic myelogenous leukemia were evaluated. There was a wide variation in sensitivity of CFU-C to both Le-IF and F-IF. F-IF was mor inhibitory against CFU-C than le-If. Normal CFU-C and chronic myelogenous leukemia CFU-C were equally inhibited by both interferons. Effects of both interferons were neutralized by corresponding specific antisera but not by the other antisera. These observations confirmed that differences in immunogenicity of the interferons may attend their different origins.


Bioactive furonaphtoquinones from Tabebuia barbata (Bignoniaceae).
Tabebuia barbata (E. Mey) Sandw. (Bignoniaceae), locally known as "palo de arco", is indigenous to the upper Orinoco and Amazonas rivers. Brine shrimp lethality-directed fractionation and extensive column chromatography, normal-phase preparative TLC and normal-phase HPLC separation of the ethanol extract of the bark of this previously uninvestigated species has led to the isolation of five active compounds 1-5. The combined spectral evidence (UV, IR, 1H and 13C NMR and mass) identified these compounds as naphthoquinones. These compounds, characterized as lapachol (1), 2-acetylnaphtho-[2,3-b]-furan-4,9-dione (2), 2-acetyl-5-hydroxy-naphtho-[2,3-b]-furan-4,9-dione (3), 2-acetyl-8-hydroxy-naphtho-[2,3-b]-furan-4,9-dione (4), and (+)-8-hydroxy-2(1-hydroxy-ethyl) naphtho-[2,3-b]-furan-4,9-dione (5), were reported previously from other species of the genus Tabebuia but not from T. barbata. Compounds 2-5, reference adriamycin, were significantly cytotoxic against A-549 human lung adeno-carcinoma, MCF-7 human breast carcinoma, and HT-29 human colon carcinoma cells. The compounds isolated (1-5) were also shown to be inhibitors of electron transport in rat liver mitochondria, reference to rotenone, with IC50 values in the range of 15 microM to 82.5 microM. In addition, this study demonstrated that screening and activity-directed fractionation, using brine shrimp lethality as a simple and inexpensive bioassay, can effectively lead to potential antitumor compounds.


Demodex cricetuli: new species of hair follicle mite (Acari: Demodecidae) from the Armenian hamster, Cricetulus migratorius (Rodentia: Cricetidae).
Demodex cricetuli sp. nov. is described, in all life stages, from the Armenian hamster, Cricetulus migratorius. This demodecid inhabits the hair follicles of all body regions of the host. Heavy infestations are associated with dermatitis and alopecia. Demodex cricetuli is most similar to D. aurati, from the Golden hamster, but adults differ in podosomal length, shape of the opisthosomal terminus, genital opening and opisthosomal organ of the male, and overall length-to-width ratios.


How does an implantable cardioverter defibrillator (ICD) affect the lives of patients and their families?
This study aimed to identify the lived experience of patients with implantable cardioverter defibrillators (ICD) and their families. The methodology used was interpretative phenomenology. Unstructured interviews were conducted with three family members and three ICD recipients. Using a methodological approach outlined by van Manen, the participants transcribed texts were analysed looking for similar concepts and ideas that developed into themes that explicated the meaning of this phenomena. The themes that emerged were: dependence, which encompassed their perceptions about the life-saving device; the memory of their first defibrillation experience; lifestyle changes, which incorporated modification techniques; lack of control, which highlighted feelings such as fear, anxiety and powerlessness; mind game, which illustrated psychological challenges; and the issue of security, demonstrating how 'being there' and not 'being there' impacted on their everyday lives. The long-term outcomes of living with an ICD are important considerations for all health-care providers. This research highlights the everyday activities of recipients, the lifestyle changes they have made, the emotional significance of the device and the psychological coping strategies that the participants have adopted. The findings of this research will allow health-care professionals to be better prepared to provide education and support for ICD recipients and their families in regards to issues related to insertion of the device during the postinsertion recovery period and for long-term management after hospital discharge.


Reduction in the Ratio of Low-density Lipoprotein Cholesterol to Highdensity Lipoprotein Cholesterol is Associated with Increased Risks of Hemorrhagic Transformation in Patients with Acute Ischemic Stroke.
Hemorrhagic transformation (HT) is a potentially serious complication in patients with acute ischemic stroke (AIS). Whether the ratio of low-density lipoprotein cholesterol to high-density lipoprotein cholesterol (LDL-C/HDL-C) is associated with HT remains unclear. Ischemic stroke patients within 7 days of stroke onset from January 2016 to November 2017 were included in this study. Lipid profiles were measured within 24h after admission. HT was determined by a second computed tomography or magnetic resonance imaging within 7 days after admission. Univariate and multivariate logistic regression analysis was used to assess the association between LDL-C/HDL-C and HT. We enrolled 1239 patients with AIS (788 males; mean age, 64 ± 15 years), of whom 129 (10.4%) developed HT. LDL-C/HDL-C was significantly lower on admission in patients with HT than those without HT (2.00 ± 0.89 vs. 2.25 ± 1.02, P=0.009). The unadjusted odds ratio (OR) of low LDL-C/HDL-C for HT was 2.07 (95% confidence interval [CI] 1.42-3.01, P<0.001). After adjustment for possible confounders, lower LDL-C/HDL-C (≤1.52) was significantly associated with HT (OR 1.53, 95% CI: 1.02-2.31, P=0.046). Similar results were observed between lower LDL-C (≤ 4 mmol/L) and HT (OR 4.17, 95% CI: 1.25-13.90, P=0.02). However, no significant association was found between HT and high HDL-C, low triglycerides or low total cholesterol. Lower LDL-C/HDL-C and LDL-C were significantly associated with increased risk of HT after AIS. Further investigations are warranted to confirm these findings and then optimize lipid management in stroke patients with lower LDL/HDL-C or LDL-C.


Direct selection on genetic robustness revealed in the yeast transcriptome.
Evolutionary theory predicts that organisms should evolve the ability to produce high fitness phenotypes in the face of environmental disturbances (environmental robustness) or genetic mutations (genetic robustness). While several studies have uncovered mechanisms that lead to both environmental and genetic robustness, we have yet to understand why some components of the genome are more robust than others. According to evolutionary theory, environmental and genetic robustness will have different responses to selective forces. Selection on environmental robustness for a trait is expected to be strong and related to the fitness costs of altering that trait. In contrast to environmental robustness, selection on genetic robustness for a trait is expected to be largely independent of the fitness cost of altering the trait and instead should correlate with the standing genetic variation for the trait that can potentially be buffered. Several mechanisms that provide both environmental and genetic robustness have been described, and this correlation could be explained by direct selection on both forms of robustness (direct selection hypothesis), or through selection on environmental robustness and a correlated response in genetic robustness (congruence hypothesis). Using both published and novel data on gene expression in the yeast Saccharomyces cerevisiae, we find that genetic robustness is correlated with environmental robustness across the yeast genome as predicted by the congruence hypothesis. However, we also show that environmental robustness, but not genetic robustness, is related to per-gene fitness effects. In contrast, genetic robustness is significantly correlated with network position, suggesting that genetic robustness has been under direct selection. We observed a significant correlation between our measures of genetic and environmental robustness, in agreement with the congruence hypothesis. However, this correlation alone cannot explain the co-variance of genetic robustness with position in the protein interaction network. We therefore conclude that direct selection on robustness has played a role in the evolution of genetic robustness in the transcriptome.


Case report: Post-thoracoscopy pendelluft monitoring.
Asynchronous alveolar ventilation is called pendelluft, which may induce lung injury in spontaneously breathing patients. We report a case that electrical impedance tomography (EIT) was used to assess the pendelluft in a post-thoracoscopy patient. The pendelluft amplitude was as high as 77.5% of the tidal variation. The average regional time shift was 0.5 s. The patient was instructed to adjust the breathing method, symptomatic treatment was performed, and the symptoms were improved. This is the first case reporting pendelluft in a post-thoracoscopy patient. Our case demonstrated that (1) pendelluft may occur in post-thoracoscopy patients and it effects lung function, and (2) early identification of affected patients and implementation of corresponding treatments could improve patient outcomes.


Quantitation of the Borrelia burgdorferi outer surface protein A in Ixodes scapularis: fluctuations during the tick life cycle, doubling times, and loss while feeding.
The presence of outer surface protein A (OspA) as a marker for Borrelia burgdorferi in Ixodes scapularis ticks was monitored with an OspA antigen-capture ELISA. The OspA ELISA, with a sensitivity of 30 spirochetes (8 fg), was not affected by the presence of either recently blood-fed or flat tick homogenates. Median spirochete equivalent levels as high as 16,000 in larvae, 55,000 in attached nymphs, and 10,000 in unfed adults were observed. Estimates of OspA doubling times ranged from a maximum of 140 h in larvae to as short as 17.5 h during nymphal attachment to the host. Spirochete equivalents in nymphs fell by 3 x 10(4) spirochete equivalents (54% of total OspA) in the last 12 h of attachment to mice but rose after detachment. Each OspA-positive I. scapularis nymph, regardless of spirochete equivalent density or length of attachment, successfully transmitted B. burgdorferi to a mouse.


Spin-crossover and high-spin iron(ii) complexes as chemical shift 19F magnetic resonance thermometers.
The potential utility of paramagnetic transition metal complexes as chemical shift 19F magnetic resonance (MR) thermometers is demonstrated. Further, spin-crossover FeII complexes are shown to provide much higher temperature sensitivity than do the high-spin analogues, owing to the variation of spin state with temperature in the former complexes. This approach is illustrated through a series of FeII complexes supported by symmetrically and asymmetrically substituted 1,4,7-triazacyclononane ligand scaffolds bearing 3-fluoro-2-picolyl derivatives as pendent groups (L x ). Variable-temperature magnetic susceptibility measurements, in conjunction with UV-vis and NMR data, show thermally-induced spin-crossover for [Fe(L1)]2+ in H2O, with T1/2 = 52(1) °C. Conversely, [Fe(L2)]2+ remains high-spin in the temperature range 4-61 °C. Variable-temperature 19F NMR spectra reveal the chemical shifts of the complexes to exhibit a linear temperature dependence, with the two peaks of the spin-crossover complex providing temperature sensitivities of +0.52(1) and +0.45(1) ppm per °C in H2O. These values represent more than two-fold higher sensitivity than that afforded by the high-spin analogue, and ca. 40-fold higher sensitivity than diamagnetic perfluorocarbon-based thermometers. Finally, these complexes exhibit excellent stability in a physiological environment, as evidenced by 19F NMR spectra collected in fetal bovine serum.


Morally Relevant Similarities and Differences Between Children and Dementia Patients as Research Subjects: Representation in Legal Documents and Ethical Guidelines.
Children and adults with dementia are vulnerable populations. Both groups are also relatively seldom included in biomedical research. However, including them in clinical trials is necessary, since both groups are in need of scientific innovation and new therapies. Their dependence and limited decision-making capacities increase their vulnerability, necessitating extra precautions when including them in clinical trials. Beside these similarities there are also many differences between the groups. The most obvious one is that children have an entire life ahead of them and will become persons with certain ideals and preferences, while adults with dementia have lived a life in which they have expressed their ideals and preferences. Some of the available research guidelines recognize these differences, setting one list of specific requirements for groups of incapacitated adults and another list for children. Other documents, however, do not differentiate and only set requirements for subjects unable to consent as a single category of subjects. In this article we analyse to what extent the similarities and differences between the two groups are represented in legal documents and ethical guidelines. The article presents an overview and an analysis of the requirements for doing research with children and dementia patients. We conclude with suggestions about how to better incorporate the morally relevant aspects of these two groups in legislation and ethical guidelines.


Non-Planar [n]Cyclo-1,8-carbazolylenes (n=3,4,6) and [3]Cyclo-1,8-carbazolylenyl B, P, PO, SiPh Complexes.
A new family of non-planar heterocyclic molecules consisting of carbazoles was created. A bowl-shaped cyclodimer, a flake-shaped cyclotrimer, a double-decker-ring-shaped cyclotetramer and a cyclohexamer were synthesized by Ni0 -mediated one-shot cyclo-oligomerization of 1,8-dibromocarbazole, and were named [n]cyclo-1,8-carbazolylenes (n=3,4,6). [3]Cyclo-1,8-carbazolylene was found to act as a trivalent tridentate ligand for heteroatoms (B, P, Si), giving flake-shaped complexes. The boron derivative acted as a Lewis acid, and the tetra-coordinated complexes showed an unprecedented red-shift of absorption and emission spectra by the coordination. The synthetic method, the distorted C2 or C1 symmetric shape, the trivalent tridentate coordination ability and the kinds of introduced heteroatoms of [3]cyclo-1,8-carbazolylenes, the electronic structure, the photophysical property, and the Lewis acidity were distinct from those of related subporphyrins/subphthalocyanines.


Compact near-eye display with a wide FOV and a wide eye box using 24 multiple-exposure holograms.
A compact near-eye display with a 60° horizontal field of view, wide eye box of 5 mm, and high resolution of 720 p is proposed and developed by combining a transmission hologram that duplicates the beam of a scanning display and a reflection hologram that reflects duplicated beams toward the user's eye. The feasibility of the proposed near-eye display is demonstrated by examining the specifications and exposure of 24 multiple holograms. A compact NED that can display images with a horizontal FOV of 60° and that has a 6.2 mm × 4.8 mm eye box and 720 pixels vertical resolution is achieved.


Validation of the use of long-term indwelling jugular catheters in a rat model of cardiotoxicity.
Doxorubicin administered to rats induces a dose-dependent cardiomyopathy. Both doxorubicin administration and the presence of indwelling catheters have been associated with thrombus formation. We sought to determine feasibility of drug delivery and degree of thrombogenesis related to long-term indwelling catheter use in a cardiotoxicity model. Rats receiving doxorubicin or saline via jugular catheters coated with end-point immobilized heparin were compared to rats receiving similar treatments via direct jugular intravenous injection (venotomy). Onset of cardiotoxicity, defined by reduction in fractional shortening to 45% or less, was determined by echocardiography. Thrombogenesis was assessed by observation of atrial thrombi and pulmonary emboli as determined by post-mortem and histologic examination. Significantly more of the doxorubicin-treated and catheterized group (87.5%) developed cardiotoxicity relative to the doxorubicin-treated-venotomized group (28.6%), as indicated by an earlier and more precipitous decline in fractional shortening in the doxorubicin-treated-catheterized rats. Despite this change, rats from catheterized groups demonstrated improved weight maintenance relative to venotomy groups. Although the number of pulmonary emboli did not differ significantly between groups, 50% of the doxorubicin-treated-catheterized animals developed vegetative endocarditis. Despite alteration of the model-induced cardiac disease, we submit that the more reliable and early induction of the desired endpoint, in addition to improved weight maintenance, represent model refinements. The ease of drug delivery with minimal restraint and no anesthesia is an additional and important benefit. The development of vegetative endocarditis represents an opportunity to study the formation and prevention of this condition.


A Spin-Active, Electrochromic, Solvent-Free Molecular Liquid Based on Double-Decker Lutetium Phthalocyanine Bearing Long Branched Alkyl Chains.
Synthesis and characterization of a novel, multifunctional, solvent-free room-temperature liquid based on alkylated double-decker lutetium(III) phthalocyanine (Pc2 Lu) are described. Lowering of the melting point and viscosity of intrinsically solid Pc2 Lu compounds has been achieved through the attachment of flexible, bulky, and long branched-alkyl chains, that is, thio-2-octyldodecyl, to the periphery of the Pc2 Lu unit. The embedded Pc2 Lu unit maintains its inherent molecular functions, such as spin-active nature and electrochromic behavior in the liquid state. Comparison of the properties with a solid-like Pc2 Lu derivative, functionalized with shorter alkyl chains, that is, thio-2-ethylhexyl, underlines the importance of the hampering effect on the π-π interactions of neighboring Pc2 Lu molecules by bulkier and longer branched-alkyl chains. This study could possibly pave the way for novel multifunctional liquids whose spin-activities are associated with their rheological or optoelectronic properties.


The Potential Role of Social Media Platforms in Community Awareness of Antibiotic Use in the Gulf Cooperation Council States: Luxury or Necessity?
The increasing emergence and spread of antimicrobial resistance (AMR) is a serious public health issue. Increasing the awareness of the general public about appropriate antibiotic use is a key factor for combating this issue. Several public media campaigns worldwide have been launched; however, such campaigns can be costly and the outcomes are variable and difficult to assess. Social media platforms, including Twitter, Facebook, and YouTube, are now frequently utilized to address health-related issues. In many geographical locations, such as the countries of the Gulf Cooperation Council (GCC) States (Saudi Arabia, United Arab Emirates, Kuwait, Oman, Qatar, and Bahrain), these platforms are becoming increasingly popular. The socioeconomic status of the GCC states and their reliable communication and networking infrastructure has allowed the penetration and scalability of these platforms in the region. This might explain why the Saudi Ministry of Health is using social media platforms alongside various other media platforms in a large-scale public awareness campaign to educate at-risk communities about the recently emerged Middle East respiratory syndrome coronavirus (MERS-CoV). This paper discusses the potential for using social media tools as cost-efficient and mass education platforms to raise awareness of appropriate antibiotic use in the general public and in the medical communities of the Arabian Peninsula.


Evidence for atrial natriuretic factor induced natriuretic peptide receptor subtype switching in rat proximal tubular cells during culture.
Culture and natriuretic peptide dependent changes in the expression of the natriuretic peptides atrial natriuretic factor (ANF), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP) and the natriuretic peptide receptors A, B, and C in primary cultures of rat proximal tubular cells were demonstrated using polymerase chain reaction analysis and cyclic guanosine monophosphate response to ANF and CNP. Freshly isolated cells expressed mRNA coding for the natriuretic peptide receptor C only, with no expression of the natriuretic peptides or the natriuretic peptide receptors A or B. At confluence natriuretic peptide receptor C expression was lost, while mRNA transcripts for both ANF and BNP and the A and B receptors became apparent. The appearance of mRNA transcripts for the natriuretic peptide receptors A and B during cell growth correspond with a significant increase in the cyclic guanosine monophosphate response to both ANF and CNP, confirming the presence of functionally active guanylate cyclase linked A and B natriuretic peptide receptors. The observed changes in peptide receptor expression during culture were preceded by changes in natriuretic peptide mRNA expression, suggesting the possibility that natriuretic peptide receptor subtype switching may be under the control of endogenous peptide release. Incubation of freshly isolated proximal tubular cells with ANF, BNP, or CNP for 3 h induced similar changes in receptor expression. Incubation with ANF induced expression of the natriuretic peptide receptor B and CNP while inhibiting natriuretic peptide receptor C. Incubation with BNP induced expression of the natriuretic peptide receptor B and CNP. Incubation with CNP induced expression of the natriuretic peptide receptors A and B and CNP. These results suggest that primary cultures of rat proximal tubular cells may experience natriuretic peptide and natriuretic peptide receptor subtype switching as they approach confluence under the control of endogenously expressed natriuretic peptides.


Tris-chelated complexes of nickel(II) with bipyridine derivatives: DNA binding and cleavage, BSA binding, molecular docking, and cytotoxicity.
Two nickel(II) complexes with substituted bipyridine ligand of the type [Ni(NN)3](ClO4)2, where NN is 4,4'-dimethyl-2,2'-bipyridine (dimethylbpy) (1) and 4,4'-dimethoxy-2,2'-bipyridine (dimethoxybpy) (2), have been synthesized, characterized, and their interaction with DNA and bovine serum albumin (BSA) studied by different physical methods. X-ray crystal structure of 1 shows a six-coordinate complex in a distorted octahedral geometry. DNA-binding studies of 1 and 2 reveal that both complexes sit in DNA groove and then interact with neighboring nucleotides differently; 2 undergoes a partial intercalation. This is supported by molecular-docking studies, where hydrophobic interactions are apparent between 1 and DNA as compared to hydrogen bonding, hydrophobic, and π-π interactions between 2 and DNA minor groove. Moreover, the two complexes exhibit oxidative cleavage of supercoiled plasmid DNA in the presence of hydrogen peroxide as an activator in the order of 1 > 2. In terms of interaction with BSA, the results of spectroscopic methods and molecular docking show that 1 binds with BSA only via hydrophobic contacts while 2 interacts through hydrophobic and hydrogen bonding. It has been extensively demonstrated that the nature of the methyl- and methoxy-groups in ligands is a strong determinant of the bioactivity of nickel(II) complexes. This may justify the above differences in biomolecular interactions. In addition, the in vitro cytotoxicity of the complexes on human carcinoma cells lines (MCF-7, HT-29, and U-87) has been examined by MTT assay. According to our observations, 1 and 2 display cytotoxicity activity against selected cell lines. Communicated by Ramaswamy H. Sarma.


The pattern of isolated sleep paralysis among Nigerian medical students.
In a cross-sectional study of the patterns of isolated sleep paralysis among 164 Nigerian medical students, 26.1% admitted having experienced this phenomenon. About 31% of the females and 20% of the males had had this experience. Of those with sleep paralysis, 32.6% had hypnogenic hallucinations during the episode, mainly visual. Sleep paralysis was not significantly associated with psychosocial distress or differences in personality profile. Although the rate differs across cultures, the myths associated with sleep paralysis are similar.


The intron 4 polymorphism in the calcium-sensing receptor gene in diabetes mellitus and its chronic complications, diabetic nephropathy and non-diabetic renal disease.
Calcium-Sensing Receptor (CaSR) significantly affects calcium-phosphate metabolism in kidneys, and it is implicated in the pathogenesis of diabetes mellitus (DM) due to its expression in pancreatic β-cells. The role of CaSR as one of the players in pathogenesis of chronic kidney disease (CKD) has been speculated. 158 Type 2 diabetic patients divided into three groups according to occurrence and type of kidney complications, 66 nondiabetic patients CKD, and 93 healthy subjects were enrolled into the study to analyze the role of two CaSR polymorphisms (in the codon 990 and in the intron 4) in ethiopathogenesis of DM and CKD. The Type 2 diabetic groups consisted of 48 patients without any kidney abnormalities, 58 patients with diabetic nephropathy (DN), and 52 patients with nondiabetic renal disease (NDRD). The distribution of genotype and allele frequencies was studied using PCR with the TaqMan Discrimination Assay or followed by the Restriction Fragment Length Polymorphism method, respectively. We have found that the intron 4 polymorphism is a risk factor for the development of DM and CKD, except DN, while the codon 990 does not show any disease association. We conclude that CaSR is a general factor in pancreas and kidney pathologies.


Emergence of Salmonella serotype Enteritidis phage type 4 in Hawaii traced to locally-produced eggs.
In August 1998, the Hawaii Department of Health observed a nine-fold increase in human Salmonella Enteritidis (SE) infections. Isolates were phage type 4 (PT4). An investigation was initiated to determine the source of the outbreak. A matched case-control study enrolled 38 cases. Cases were Hawaii residents with diarrhea and a stool culture yielding SE. Eating eggs was associated with SE illness; 28 cases (74%) ate eggs in the three days before illness compared to 34 (45%) of 76 controls (MOR=3.0, 95% CI=1.4-7.4). Eighteen (47%) of 38 case patients ate eggs from Farm A compared to 11 (14%) of 76 controls (MOR=12.0, 95% CI=3.1-78.0); the eggs were not properly handled or refrigerated. Cultures from Farm A yielded SE. Human illness subsided following selective flock depopulation. This outbreak highlights the importance of proper handling and refrigeration of eggs. The egg industry must implement quality assurance programs to prevent the spread of SE PT4 and human SE illness.


A Highly Efficient All-Solid-State Lithium/Electrolyte Interface Induced by an Energetic Reaction.
The energetic chemical reaction between Zn(NO3 )2 and Li is used to create a solid-state interface between Li metal and Li6.4 La3 Zr1.4 Ta0.6 O12 (LLZTO) electrolyte. This interlayer, composed of Zn, ZnLix alloy, Li3 N, Li2 O, and other species, possesses strong affinities with both Li metal and LLZTO and affords highly efficient conductive pathways for Li+ transport through the interface. The unique structure and properties of the interlayer lead to Li metal anodes with longer cycle life, higher efficiency, and better safety compared to the current best Li metal electrodes operating in liquid electrolytes while retaining comparable capacity, rate, and overpotential. All-solid-state Li||Li cells can operate at very demanding current-capacity conditions of 4 mA cm-2 -8 mAh cm-2 . Thousands of hours of continuous cycling are achieved at Coulombic efficiency >99.5 % without dendrite formation or side reactions with the electrolyte.