Extended π-conjugated system for fast-charge and -discharge sodium-ion batteries.
Organic sodium-ion batteries (SIBs) are potential alternatives of current commercial inorganic lithium-ion batteries for portable electronics (especially wearable electronics) because of their low cost and flexibility, making them possible to meet the future flexible and large-scale requirements. However, only a few organic SIBs have been reported so far, and most of them either were tested in a very slow rate or suffered significant performance degradation when cycled under high rate. Here, we are focusing on the molecular design for improving the battery performance and addressing the current challenge of fast-charge and -discharge. Through reasonable molecular design strategy, we demonstrate that the extension of the π-conjugated system is an efficient way to improve the high rate performance, leading to much enhanced capacity and cyclability with full recovery even after cycled under current density as high as 10 A g(-1).


THE SPARING EFFECT OF CANINE DISTEMPER ON POLIOMYELITIS IN MACACA MULATTA.
1. Rhesus monkeys inoculated with canine distemper are relatively or completely immune to experimental poliomyelitis during the first 2 weeks of the distemper. 2. Monkeys convalescent from distemper are not resistant to experimental poliomyelitis. 3. Two monkeys vaccinated with distemper virus responded to poliomyelitis in a modified manner. 4. Distemper antiserum did not influence the course of experimental poliomyelitis in rhesus monkeys. 5. Equine encephalomyelitis and vaccinia encephalitis showed no sparing effect on the course of experimental poliomyelitis. 6. The concurrence of distemper and poliomyelitis in monkeys seems to represent a new immunity mechanism in the virus field.


Perspective: is it time for advocacy training in medical education?
As the modern medical system becomes increasingly complex, a debate has arisen over the place of advocacy efforts within the medical profession. The authors argue that advocacy can help physicians fulfill their social contract. For physicians to become competent in patient-centered, clinical, administrative, or legislative advocacy, they require professional training. Many professional organizations have called for curricular reform to meet society's health needs during the past 30 years, and the inclusion of advocacy training in undergraduate, graduate, and continuing medical education is supported on both pragmatic and ethical grounds. Undergraduate medical education, especially, is an ideal time for this training because a standard competency can be instilled across all specialties. Although the Accreditation Council for Graduate Medical Education includes advocacy training in curricula for residency programs, few medical schools or residency programs have advocacy electives. By understanding the challenges of the health care system and how to change it for the better, physicians can experience increased professional satisfaction and effectiveness in improving patient care, systems-based practice, and public health.


The prevalence of autism in Nagoya, Japan: a total population study.
The prevalence rate of autism has been reported as 0.04% to 0.05%, but one recent study in Japan found prevalence of 0.16%. The authors have been involved in routine well-child medical examinations at 18 months of age, at the Midori Public Health Center in Nagoya. A statistical survey of diagnoses was made from April 1979 to March 1984 for the purpose of conducting an epidemiological study of autism. Of 12,263 children examined, 168 were identified as having developmental problems and, of these, 139 underwent a second examination. Autism was diagnosed in 16 of these children and a category called "autism suspected" was defined in an additional 10 of these 139 children. The 16 cases of autism gave a minimum prevalence of 0.13%, three times the usually reported rate. The validity of the higher prevalence rates is discussed.


Variations in perioperative warfarin management: outcomes and practice patterns at nine hospitals.
Before surgery, most patients receiving oral anticoagulation require temporary cessation of treatment. Physicians sometimes substitute heparin or low-molecular-weight heparin for oral anticoagulation in the perioperative setting ("bridging therapy"). We sought to characterize rates of bridging therapy use at 9 clinical centers to determine the extent to which the use of bridging is explained by clinical characteristics of patients (vs physician style) and to determine the 30-day incidence of thrombotic and bleeding complications. This was a prospective, multicenter, observational study. Periprocedural bridging anticoagulation was classified as none, prophylactic-dose heparin/low-molecular-weight heparin, or full-dose heparin/low-molecular-weight heparin. We collected data on patient and surgery characteristics, anticoagulation management, and thromboembolic and bleeding events. A total of 492 of 497 consecutive patients completed the study; 54%, 14%, and 33% of patients had no, prophylactic, and full (therapeutic) doses, respectively, of heparin/low-molecular-weight heparin postprocedure. Two hospitals treated more than 80% of their patients with full-dose heparin, whereas the remaining 7 hospitals used full-dose heparin in an average of 22% of cases (P<.001); this variation persisted after adjustment for patient characteristics. There were 4 thromboembolic events (0.8%) and 16 major bleeding events (3.2%). Full-dose heparin/low-molecular-weight heparin postprocedure was associated with a higher likelihood of major bleeding: adjusted odds ratio 4.4 (95% confidence interval, 1.5-14.7). Management of anticoagulation after an invasive procedure varies widely and is not explained by clinical characteristics of patients alone. The risk of major bleeding is strongly associated with the use of postoperative therapeutic doses of heparin/low-molecular-weight heparin.


Sitting, squatting, and the evolutionary biology of human inactivity.
Recent work suggests human physiology is not well adapted to prolonged periods of inactivity, with time spent sitting increasing cardiovascular disease and mortality risk. Health risks from sitting are generally linked with reduced levels of muscle contractions in chair-sitting postures and associated reductions in muscle metabolism. These inactivity-associated health risks are somewhat paradoxical, since evolutionary pressures tend to favor energy-minimizing strategies, including rest. Here, we examined inactivity in a hunter-gatherer population (the Hadza of Tanzania) to understand how sedentary behaviors occur in a nonindustrial economic context more typical of humans' evolutionary history. We tested the hypothesis that nonambulatory rest in hunter-gatherers involves increased muscle activity that is different from chair-sitting sedentary postures used in industrialized populations. Using a combination of objectively measured inactivity from thigh-worn accelerometers, observational data, and electromygraphic data, we show that hunter-gatherers have high levels of total nonambulatory time (mean ± SD = 9.90 ± 2.36 h/d), similar to those found in industrialized populations. However, nonambulatory time in Hadza adults often occurs in postures like squatting, and we show that these "active rest" postures require higher levels of lower limb muscle activity than chair sitting. Based on our results, we introduce the Inactivity Mismatch Hypothesis and propose that human physiology is likely adapted to more consistently active muscles derived from both physical activity and from nonambulatory postures with higher levels of muscle contraction. Interventions built on this model may help reduce the negative health impacts of inactivity in industrialized populations.


Thermal Preference Ranges Correlate with Stable Signals of Universal Stress Markers in Lake Baikal Endemic and Holarctic Amphipods.
Temperature is the most pervasive abiotic environmental factor for aquatic organisms. Fluctuations in temperature range lead to changes in metabolic performance. Here, we aimed to identify whether surpassing the thermal preference zones is correlated with shifts in universal cellular stress markers of protein integrity, responses to oxidative stress and lactate content, as indicators of anaerobic metabolism. Exposure of the Lake Baikal endemic amphipod species Eulimnogammarus verrucosus (Gerstfeldt, 1858), Ommatogammarus flavus (Dybowski, 1874) and of the Holarctic amphipod Gammarus lacustris Sars 1863 (Amphipoda, Crustacea) to increasing temperatures resulted in elevated heat shock protein 70 (Hsp70) and lactate content, elevated antioxidant enzyme activities (i.e., catalase and peroxidase), and reduced lactate dehydrogenase and glutathione S-transferase activities. Thus, the zone of stability (absence of any significant changes) of the studied molecular and biochemical markers correlated with the behaviorally preferred temperatures. We conclude that the thermal behavioral responses of the studied amphipods are directly related to metabolic processes at the cellular level. Thus, the determined thermal ranges may possibly correspond to the thermal optima. This relationship between species-specific behavioral reactions and stress response metabolism may have significant ecological consequences that result in a thermal zone-specific distribution (i.e., depths, feed spectrum, etc.) of species. As a consequence, by separating species with different temperature preferences, interspecific competition is reduced, which, in turn, increases a species' Darwinian fitness in its environment.


Interferon-dependent IL-10 production by Tregs limits tumor Th17 inflammation.
The capacity of IL-10 and Tregs in the inflammatory tumor microenvironment to impair anticancer Th1 immunity makes them attractive targets for cancer immunotherapy. IL-10 and Tregs also suppress Th17 activity, which is associated with poor prognosis in several cancers. However, previous studies have overlooked their potential contribution to the regulation of pathogenic cancer-associated inflammation. In this study, we investigated the origin and function of IL-10–producing cells in the tumor microenvironment using transplantable tumor models in mice. The majority of tumor-associated IL-10 was produced by an activated Treg population. IL-10 production by Tregs was required to restrain Th17-type inflammation. Accumulation of activated IL-10+ Tregs in the tumor required type I IFN signaling but not inflammatory signaling pathways that depend on TLR adapter protein MyD88 or IL-12 family cytokines. IL-10 production limited Th17 cell numbers in both spleen and tumor. However, type I IFN was required to limit Th17 cells specifically in the tumor microenvironment, reflecting selective control of tumor-associated Tregs by type I IFN. Thus, the interplay of type I IFN, Tregs, and IL-10 is required to negatively regulate Th17 inflammation in the tumor microenvironment. Therapeutic interference of this network could therefore have the undesirable consequence of promoting Th17 inflammation and cancer growth.


Tracking second thoughts: continuous and discrete revision processes during visual lexical decision.
We studied the dynamics of lexical decisions by asking participants to categorize lexical and nonlexical stimuli and recording their mouse movements toward response buttons during the choice. In a previous report we revealed greater trajectory curvature and attraction to competitors for Low Frequency words and Pseudowords. This analysis did not clarify whether the trajectory curvature in the two conditions was due to a continuous dynamic competition between the response alternatives or if a discrete revision process (a "change of mind") took place during the choice from an initially selected response to the opposite one. To disentangle these two possibilities, here we analyse the velocity and acceleration profiles of mouse movements during the choice. Pseudowords' peak movement velocity occurred with 100 ms delay with respect to words and Letters Strings. Acceleration profile for High and Low Frequency words and Letters Strings exhibited a butterfly plot with one acceleration peak at 400 ms and one deceleration peak at 650 ms. Differently, Pseudowords' acceleration profile had double positive peaks (at 400 and 600 ms) followed by movement deceleration, in correspondence with changes in the decision from lexical to nonlexical response buttons. These results speak to different online processes during the categorization of Low Frequency words and Pseudowords, with a continuous competition process for the former and a discrete revision process for the latter.


Bile acid kinetics and bile secretion in the pony.
Bile acid pool size and synthesis rate were determined by both isotope-dilution and washout methods in ponies with chronic external biliary fistulas. Bile acid pool size (10.9 mumol/kg) and synthesis rate (11.2 mumol/day per kg) estimated by the isotope-dilution method did not differ significantly from pool size (9.4 mumol/kg) and synthesis rate (9.5 mumol/day per kg) estimated by washout method. Bile acid-dependent and -independent fractions of bile flow, determined by a method that circumvents any inevitable correlation of flow to bile acid secretion due to common factors in both parameters, did not differ from those values obtained by linear regression of bile flow versus bile acid secretion. The choleretic effect of infused chenodeoxycholic acid was higher than that of both endogenous bile acid and infused taurocholic acid.


Robotic-assisted laparoscopy in gynecological surgery.
Laparoscopic surgery has revolutionized the concept of minimally invasive surgery for the last 3 decades. Robotic-assisted surgery is one of the latest innovations in the field of minimally invasive surgery. Already, many procedures have been performed in urology, cardiac surgery, and general surgery. In this article, we attempt to report our preliminary experience with robotic-assisted laparoscopy in a variety of gynecological surgeries. We sought to evaluate the role of robotic-assisted laparoscopy in gynecological surgeries. The study was a case series of 15 patients who underwent various gynecologic surgeries for combined laparoscopic and robotic-assisted laparoscopic surgery. The da Vinci robot was used in each case at a tertiary referral center for laparoscopic gynecologic surgery. An umbilicus, suprapubic, and 2 lateral ports were inserted. These surgeries were performed both using laparoscopic and robotic-assisted laparoscopic techniques. The assembly and disassembly time to switch from laparoscopy to robotic-assisted surgery was measured. Subjective advantages and disadvantages of using robotic-assisted laparoscopy in gynecological surgeries were evaluated. Fifteen patients underwent a variety of gynecologic surgeries, such as myomectomies, treatment of endometriosis, total and supracervical hysterectomy, ovarian cystectomy, sacral colpopexy, and Moskowitz procedure. The assembly time to switch from laparoscopy to robotic-assisted surgery was 18.9 minutes (range, 14 to 27), and the disassembly time was 2.1 minutes (range, 1 to 3). Robotic-assisted laparoscopy acts as a bridge between laparoscopy and laparotomy but has the disadvantage of being costly and bulky. Robotic-assisted laparoscopic surgeries have advantages in providing a 3-dimensional visualization of the operative field, decreasing fatigue and tension tremor of the surgeon, and added wrist motion for improved dexterity and greater surgical precision. The disadvantages include enormous cost and added operating time for assembly and disassembly and the bulkiness of the equipment.


Development and malignant progression of astrocytomas in GFAP-v-src transgenic mice.
We have generated a transgenic mouse model for astrocytoma by expressing the v-src kinase under control of the glial fibrillary acidic protein (GFAP) gene regulatory elements in astrocytes. Abnormal astrogliosis was observed in all transgenic animals already at 2 weeks postnatally, frequently followed by the development of dysplastic changes. Later, small proliferative foci arose, and overt astrocytoma developed in the brain and spinal cord in 14.4% of mice after a follow up time of 65 weeks. While early lesions were histologically consistent with low-grade astrocytoma, at later stages most tumors were highly mitotic and frankly malignant. Vascular endothelial growth factor (VEGF) was expressed by tumor cells already at early stages, suggesting induction by v-src, and it was most pronounced in pseudopalisading cells surrounding necrotic areas, implying additional upregulation by hypoxia. In larger lesions, mitotic activity and expression of flk-1, the cognate receptor of VEGF were induced in endothelial cells. Therefore, end-stage tumors mimicked the morphological and molecular characteristics of human glioblastoma multiforme. Time course and stochastic nature of the process indicate that v-src did not suffice for malignant transformation, and that astrocytomas were the result of a multistep process necessitating co-operation of additional genetic events.


Home blood pressure monitoring: Australian Expert Consensus Statement.
Measurement of blood pressure (BP) by a doctor in the clinic has limitations that may result in an unrepresentative measure of underlying BP which can impact on the appropriate assessment and management of high BP. Home BP monitoring is the self-measurement of BP in the home setting (usually in the morning and evening) over a defined period (e.g. 7 days) under the direction of a healthcare provider. When it may not be feasible to measure 24-h ambulatory BP, home BP may be offered as a method to diagnose and manage patients with high BP. Home BP has good reproducibility, is well tolerated, is relatively inexpensive and is superior to clinic BP for prognosis of cardiovascular morbidity and mortality. Home BP can be used in combination with clinic BP to identify 'white coat' and 'masked' hypertension. An average home BP of at least 135/85 mmHg is an appropriate threshold for the diagnosis of hypertension. Home BP may also offer the advantage of empowering patients with their BP management, with benefits including increased adherence to therapy and lower achieved BP levels. It is recommended that, when feasible, home BP should be considered for routine use in the clinical management of hypertension.


Testing a Model of Functional Impairment in Telephone Crisis Support Workers.
It is well known that helping professionals experience functional impairment related to elevated symptoms of psychological distress as a result of frequent empathic engagement with distressed others. Whether telephone crisis support workers are impacted in a similar way is not currently reported in the literature. The purpose of this study was to test a hypothesized model of factors contributing to functional impairment in telephone crisis support workers. A national sample of 210 telephone crisis support workers completed an online survey including measures of emotion regulation, symptoms of general psychological distress and suicidal ideation, intentions to seek help for symptoms, and functional impairment. Structural equation modeling was used to test the fit of the data to the hypothesized model. Goodness-of-fit indices were adequate and supported the interactive effects of emotion regulation, general psychological distress, suicidal ideation, and intentions to seek help for ideation on functional impairment. These results warrant the deliberate management of telephone crisis support workers' impairment through service selection, training, supervision, and professional development strategies. Future research replicating and extending this model will further inform the modification and/or development of strategies to optimize telephone crisis support workers' well-being and delivery of support to callers.


A conceptual model of patient-professional communication as a self-management skill: A latent growth change modeling.
Patient Communication with healthcare professionals is an integral self-management skill. Yet the underlying mechanisms explaining how such communication might be enhanced across time have not been well studied. Based on the transtheoretical model, the study aimed to develop an across-time Attitude-Social Influence-Efficacy model in order to explain changes in participants' patient-professional communication behaviors in the Chronic Disease Self-management Program (CDSMP). Readiness-to-change construct was hypothesized to be the overall predictors of psychological and behavioral parameters. It was hypothesized that social norm and attitude toward behaviors would be the indirect predictors of communication behavior. One hundred and thirty-six Chinese participants with chronic diseases underwent a 6-week CDSMP. Their attitude toward behavior, self-efficacy, social norm, readiness to change and communication behavior were obtained at 1st, 4th and 6th week of the structured program. A modified latent growth change curve model yielded satisfactory model fit (χ(2)/df = 1.32; RMSEA = 0.063 (90% CI = 0.018-0.96)). The results showed that readiness to change had a positive influence on attitude and self-efficacy. Both attitude and social norm positively affected self-efficacy. Attitude and self-efficacy in turn positively influenced communication behavior at the beginning of the program. Across 6 weeks, self-efficacy imposed a negative influence on communication behavior while social norm exerted a positive influence on the behavior. This study revealed possible underlying mechanisms influencing CDSMP participants' communication with professionals. The results could shed light on further improvement of the structured program.


Urine antigen detection for the diagnosis of human neurocysticercosis.
Neurocysticercosis (NCC) is a major cause of seizures and epilepsy. Diagnosis is based on brain imaging, supported by immunodiagnosis in serum or cerebrospinal fluid (CSF). Lumbar puncture is invasive and painful. Blood sampling is slightly painful and poorly accepted. Urine antigen detection has been used for other parasites and tried in NCC with suboptimal performance. We used a monoclonal antibody-based ELISA to detect Taenia solium antigens in urine from 87 Peruvian neurocysticercosis patients (viable cysts, N = 34; subarachnoid cysticercosis, N = 10; degenerating parasites, N = 7; calcified lesions, N = 36) and 32 volunteers from a non-endemic area of Peru. Overall sensitivity of urine antigen detection for viable parasites was 92%, which decreased to 62.5% in patients with a single cyst. Most patients (30/36, 83%) with only calcified cysticercosis were urine antigen negative. Antigen levels in paired serum/urine samples (evaluated in 19 patients) were strongly correlated. Non-invasive urine testing for T. solium antigens provides a useful alternative for NCC diagnosis.


Terahertz generation by optical rectification in lithium niobate crystal using a shadow mask.
A simple approach to generate high energy, frequency and bandwidth tunable multicycle THz pulses by optical rectification (OR) of spatially shaped femtosecond laser pulses in the lithium niobate (LN) crystal is proposed and demonstrated. A one dimensional binary shadow mask is used as a laser beam shaper. By building the mask's image in the bulk LN crystal with various demagnifications, the frequency of THz generation was tuned in the range of 0.3 - 1.2 THz. There exist also an opportunity to tune the bandwidth of THz generation from 20 GHz to approximately 1 THz by changing the optical beam size on the crystal. The energy spectral density of narrowband THz generation is almost independent of the bandwidth and is typically 0.18 μJ/THz for ~1 W pump power at 1 kHz repetition rate.


Linguistic traces of a scientific fraud: the case of Diederik Stapel.
When scientists report false data, does their writing style reflect their deception? In this study, we investigated the linguistic patterns of fraudulent (N = 24; 170,008 words) and genuine publications (N = 25; 189,705 words) first-authored by social psychologist Diederik Stapel. The analysis revealed that Stapel's fraudulent papers contained linguistic changes in science-related discourse dimensions, including more terms pertaining to methods, investigation, and certainty than his genuine papers. His writing style also matched patterns in other deceptive language, including fewer adjectives in fraudulent publications relative to genuine publications. Using differences in language dimensions we were able to classify Stapel's publications with above chance accuracy. Beyond these discourse dimensions, Stapel included fewer co-authors when reporting fake data than genuine data, although other evidentiary claims (e.g., number of references and experiments) did not differ across the two article types. This research supports recent findings that language cues vary systematically with deception, and that deception can be revealed in fraudulent scientific discourse.


Tropical and Mediterranean biodiversity is disproportionately sensitive to land-use and climate change.
Global biodiversity is undergoing rapid declines, driven in large part by changes to land use and climate. Global models help us to understand the consequences of environmental changes for biodiversity, but tend to neglect important geographical variation in the sensitivity of biodiversity to these changes. Here we test whether biodiversity responses to climate change and land-use change differ among biomes (geographical units that have marked differences in environment and species composition). We find the strongest negative responses to both pressures in tropical biomes and in the Mediterranean. A further analysis points towards similar underlying drivers for the sensitivity to each pressure: we find both greater reductions in species richness in the types of land use most disturbed by humans and more negative predicted responses to climate change in areas of lower climatic seasonality, and in areas where a greater proportion of species are near their upper temperature limit. Within the land most modified by humans, reductions in biodiversity were particularly large in regions where humans have come to dominate the land more recently. Our results will help to improve predictions of how biodiversity is likely to change with ongoing climatic and land-use changes, pointing toward particularly large declines in the tropics where much future agricultural expansion is expected to occur. This finding could help to inform the development of the post-2020 biodiversity framework, by highlighting the under-studied regions where biodiversity losses are likely to be greatest.


Regulation of cell pH by Ca+2-mediated exocytotic insertion of H+-ATPases.
Exposure to CO2 acidifies the cytosol of mitochondria-rich cells in turtle bladder epithelium. The result of the decrease in pH in these, the acid-secreting cells of the epithelium, is a transient increase in cell calcium, which causes exocytosis of vesicles containing proton-translocating ATPase. Because mitochondria-rich cells have rapid luminal membrane turnover, we were able to identify single mitochondria-rich cells by their endocytosis of rhodamine-tagged albumin. Using fluorescence emission of 5,6-carboxyfluorescein at two excitation wavelengths, we measured cell pH in these identified mitochondria-rich cells and found that although the cell pH fell, it recovered within 5 min despite continuous exposure to CO2. This pH recovery also occurred at the same rate in Na+-free media. However, pH recovery did not occur when luminal pH was 5.5, a condition under which the H+-pump does not function, suggesting that recovery of cell pH is due to the luminally located H+ ATPase. Chelation of extracellular calcium by EGTA prevented the CO2-induced rise in cell calcium measured with the intracellular fluorescent dyes Quin 2 or Fura 2 and also prevented recovery of cell pH. When the change in cell calcium was buffered by loading the cells with high concentrations of Quin 2, the CO2-induced decrease in pH did not return back to basal levels. We had found previously that buffering intracellular calcium transients prevented CO2-stimulated exocytosis. Further, we show here that the increased H+ current in voltage-clamped turtle bladders, which is directly proportional to the number of H+-pump-containing vesicles that fuse with the luminal membrane, was significantly reduced in calcium-depleted bladders. These results suggest that pH regulation in these acid-secreting cells occurs by calcium-dependent exocytosis of vesicles containing proton pumps, whose subsequent turnover restores the cell pH to its initial levels.


The role of M2 muscarinic receptor subtypes in mediating contraction of the pig bladder base after cyclic adenosine monophosphate elevation and/or selective M3 inactivation.
In the bladder body M2 muscarinic receptors predominate but a smaller population of M3 receptors mediates direct detrusor contraction. M2 receptors have an indirect role by inhibiting cyclic adenosine monophosphate mediated relaxation in the bladder body. We investigated whether a similar mechanism also exists in the bladder base. Experiments were performed on pig detrusor muscle. In receptor binding studies using l-quinuclidinyl [phenyl-4-(3)H] benzilate ([(3)H]QNB) (NEN Life Science Products, Inc., Boston, Massachusetts) displacement experiments were performed with subtype selective antagonists to determine the M2-to-M3 receptor ratio. In functional studies the affinity of these antagonists against carbachol induced contractions was calculated in normal tissues and in tissues after cyclic adenosine monophosphate elevation by pre-contraction with KCl and relaxation with isoprenaline, and/or selective M3 inactivation by incubation with 4-diphenylacetoxy-N-methyl-piperidine methiodide (4-DAMP) mustard (Sigma Chemical Co., St. Louis, Missouri) in the presence of methoctramine (Sigma Chemical Co.) to protect M2 receptors. In saturation binding studies receptor density was 130.5 of fmol./mg. protein and the dissociation constant for [(3)H]QNB was 0.27 nM. Displacement of [(3)H]QNB by the M3 selective antagonist 4-DAMP and the M2 antagonist methoctramine indicated an M2-to-M3 ratio of about 3:1. In functional studies 4-DAMP and methoctramine caused competitive antagonism of responses with affinity values of 9.5 and 6.3 in normal tissues, and 9.3 and 6.1, respectively, in cyclic adenosine monophosphate elevated tissues, suggesting the involvement of M3 receptors only. In tissues in which M3 receptors were inactivated and cyclic adenosine monophosphate levels were elevated the affinity of 4-DAMP was significantly reduced to 8.5 but that of methoctramine was significantly increased to 6.5, suggesting the involvement of M2 receptors. The M3 subtype appears to mediate contraction of the normal and cyclic adenosine monophosphate elevated tissues of the bladder base. Involvement of M2 receptors was only noted after selective M3 inactivation and cyclic adenosine monophosphate elevation.


Cocaine, MDMA and methamphetamine residues in wastewater: Consumption trends (2009-2015) in South East Queensland, Australia.
Wastewater analysis, or wastewater-based epidemiology, has become a common tool to monitor trends of illicit drug consumption around the world. In this study, we examined trends in cocaine, 3,4-methylenedioxymethamphetamine (MDMA) and methamphetamine consumption by measuring their residues in wastewater from two wastewater treatment plants in Australia (specifically, an urban and a rural catchment, both in South East Queensland) between 2009 and 2015. With direct injection of the samples, target analytes were identified and quantified using liquid chromatography-mass spectrometry. Cocaine and MDMA residues and metabolites were mainly quantifiable in the urban catchment while methamphetamine residues were consistently detected in both urban and rural catchments. There was no consistent trend in the population normalised mass loads observed for cocaine and MDMA at the urban site between 2009 and 2015. In contrast, there was a five-fold increase in methamphetamine consumption over this period in this catchment. For methamphetamine consumption, the rural area showed a very similar trend as the urban catchment starting at a lower baseline. The observed increase in per capita loads of methamphetamine via wastewater analysis over the past six years in South East Queensland provides objective evidence for increased methamphetamine consumption in the Australian population while the use of other illicit stimulants remained relatively stable.


COVID-19 and Cardiovascular Disease.
Coronavirus disease 2019 (COVID-19) is a global pandemic affecting 185 countries and >3 000 000 patients worldwide as of April 28, 2020. COVID-19 is caused by severe acute respiratory syndrome coronavirus 2, which invades cells through the angiotensin-converting enzyme 2 receptor. Among patients with COVID-19, there is a high prevalence of cardiovascular disease, and >7% of patients experience myocardial injury from the infection (22% of critically ill patients). Although angiotensin-converting enzyme 2 serves as the portal for infection, the role of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers requires further investigation. COVID-19 poses a challenge for heart transplantation, affecting donor selection, immunosuppression, and posttransplant management. There are a number of promising therapies under active investigation to treat and prevent COVID-19.


Safety assessment of α-amino acids as used in cosmetics.
The Cosmetic Ingredient Review Expert Panel (Panel) reviewed the safety of α-amino acids, which function primarily as hair- and skin-conditioning agents in cosmetic products. The safety of α-amino acids as direct food additives has been well established based on extensive research through acute and chronic dietary exposures. The Panel focused its review on dermal irritation and sensitization data relevant to the use of these ingredients in topical cosmetics. The Panel concluded that α-amino acids were safe as cosmetic ingredients in the practices of use and concentration of this safety assessment.


Endogenous IRBP can be dispensable for generation of natural CD4+CD25+ regulatory T cells that protect from IRBP-induced retinal autoimmunity.
Susceptibility to experimental autoimmune uveitis (EAU), a model for human uveitis induced in mice with the retinal antigen interphotoreceptor retinoid-binding protein (IRBP), is controlled by "natural" CD4+CD25+ regulatory T (T reg) cells. To examine whether endogenous expression of IRBP is necessary to generate these T reg cells, we studied responses of IRBP knockout (KO) versus wild-type (WT) mice. Unexpectedly, not only WT but also IRBP KO mice immunized with a uveitogenic regimen of IRBP in complete Freund's adjuvant (CFA) exhibited CD25+ regulatory cells that could be depleted by PC61 treatment, which suppressed development of uveitogenic effector T cells and decreased immunological responses to IRBP. These EAU-relevant T reg cells were not IRBP specific, as their activity was not present in IRBP KO mice immunized with IRBP in incomplete Freund's adjuvant (IFA), lacking mycobacteria (whereas the same mice exhibited normal T reg cell activity to retinal arrestin in IFA). We propose that mycobacterial components in CFA activate T reg cells of other specificities to inhibit generation of IRBP-specific effector T cells in a bystander fashion, indicating that effective T reg cells can be antigen nonspecific. Our data also provide the first evidence that generation of specific T reg cells to a native autoantigen in a mouse with a diverse T cell repertoire requires a cognate interaction.


Extended stereopsis evaluation of professional and amateur soccer players and subjects without soccer background.
Stereopsis is one of several visual depth cues. It has been evaluated for athletes of different types of sports in the past. However, most studies do not cover the full range of stereopsis performance. Therefore, we propose computer-supported stereopsis tests that provide an extended assessment and analysis of stereopsis performance including stereo acuity and response times. By providing stationary and moving stimuli they cover static and dynamic stereopsis, respectively. The proposed stereopsis tests were used to compare professional and amateur soccer players with subjects without soccer background. The soccer players could not perform significantly (p ≤ 0.05) superior than the subjects without soccer background. However, the soccer players showed significantly (p ≤ 0.01) superior choice reaction times for monocular stimuli. The results are in congruence with previous findings in literature.


Simultaneous formation of four fringes by using a polarization quadrature phase-shifting interferometer with wave plates and a diffraction grating.
We present a new type of quadrature phase-shifting interferometer, which utilizes wave plates, a diffraction grating, and two lasers with different wavelengths, in order to acquire two sets of two quadrature fringe patterns in each wavelength formed on a single image sensor. This method for calculating with four phase-shifted fringe patterns gives us the phase sum and difference distributions between the phases in two wavelengths. This is also substantiated by results of our experiments.


Hgf/Met activation mediates resistance to BRAF inhibition in murine anaplastic thyroid cancers.
Anaplastic thyroid carcinomas (ATCs) have a high prevalence of BRAF and TP53 mutations. A trial of vemurafenib in nonmelanoma BRAFV600E-mutant cancers showed significant, although short-lived, responses in ATCs, indicating that these virulent tumors remain addicted to BRAF despite their high mutation burden. To explore the mechanisms mediating acquired resistance to BRAF blockade, we generated mice with thyroid-specific deletion of p53 and dox-dependent expression of BRAFV600E, 50% of which developed ATCs after dox treatment. Upon dox withdrawal there was complete regression in all mice, although recurrences were later detected in 85% of animals. The relapsed tumors had elevated MAPK transcriptional output, and retained responses to the MEK/RAF inhibitor CH5126766 in vivo and in vitro. Whole-exome sequencing identified recurrent focal amplifications of chromosome 6, with a minimal region of overlap that included Met. Met-amplified recurrences overexpressed the receptor as well as its ligand Hgf. Growth, signaling, and viability of Met-amplified tumor cells were suppressed in vitro and in vivo by the Met kinase inhibitors PF-04217903 and crizotinib, whereas primary ATCs and Met-diploid relapses were resistant. Hence, recurrences are the rule after BRAF suppression in murine ATCs, most commonly due to activation of HGF/MET signaling, which generates exquisite dependency to MET kinase inhibitors.


Patterns of admission to acute psychiatric in-patient facilities: a national survey in Italy.
A proper understanding of patterns of care represents a crucial step in improving clinical decision making and enhancing service provision. Only a few studies, however, have explored global patterns of psychiatric admissions nationwide, and none have been undertaken in Italy. Sociodemographic, clinical and treatment-related information was collected for 1577 patients admitted to 130 public and 36 private in-patient facilities in Italy during an index period in the year 2004. All patients were also rated using the 24-item Brief Psychiatric Rating Scale (BPRS) and the Personal and Social Performance (PSP) rating scales. Non-affective psychoses (36%) were the most common diagnoses and accounted to a large extent for compulsory admissions. Private facilities were more likely to admit patients with organic mental disorders and substance abuse/dependence and less likely to admit patients with non-affective psychoses. Overall, 77.8% of patients had been receiving treatment by a mental health professional in the month prior to admission. In 54% of cases, the admission was solicited by patients' family members. The main factors preceding admission were impairment in work or social functioning, social withdrawal, and conflict with family members. Agitation, delusions and/or hallucinations, and the presence of multiple problems were associated with compulsory admissions, whereas depressive and anxiety symptoms were associated with voluntary admissions. In a mixed, public-private psychiatric care system, like the Italian one, public and private facilities admit patients with widely different clinical characteristics and needs. Family support represents an important resource for most patients, and interventions specifically addressed to relieving family burden are warranted.


Investigation of environmental and host-related risk factors for tuberculosis in Africa. II. Investigation of host genetic factors.
In an accompanying paper (Am. J. Epidemiol. 2002;155:1066-73), the authors describe the design of a large multicenter study being carried out in three West African countries for investigation of the roles of environmental and host-related factors in the development of tuberculosis. In this paper, the authors review some evidence that host genetic factors play a role in susceptibility to tuberculosis. They describe the three components of the study that are designed to investigate the effect of host genetic factors on the development of tuberculosis: case-control and family-based association studies of candidate genes and analysis of affected relative pairs to screen the human genome for areas of linkage to the disease. The authors also address a number of methodological issues that arise, such as the effects of consanguinity, half-siblings, and nonpaternity. Lastly, they review opportunities to assess gene-environment interaction in the framework of the study, in light of current methodological knowledge. Consideration of these issues may be useful in the design of other studies of genetic susceptibility to infectious diseases, particularly those to be carried out in developing countries.


Highly efficient Q-switched laser operation of Yb:Y3Ga5O12 garnet crystal.
We demonstrate, for the first time, passively Q-switched laser operation of Yb:Y(3)Ga(5)O(12) garnet crystal. An output power of 4.53 W at 1031 nm was generated at a pulse repetition rate of 55.6 kHz, with a Cr(4+):YAG crystal acting as saturable absorber whose initial transmission was 97.5%, the corresponding pulse energy, duration and peak power were respectively 81.5 μJ, 28.5 ns and 2.86 kW. Laser pulses at a lower repetition rate of 18.2 kHz were also achieved at 1025 nm while the initial transmission of the Cr(4+):YAG crystal was 85.0%, with an output power measured to be 2.56 W, the resulting pulse energy, duration, and peak power being 140.8 μJ, 5.9 ns, and 23.9 kW, respectively.


Atomistic simulations of the aggregation of small aromatic molecules in homogenous and heterogenous mixtures.
The relatively weak London dispersion forces are the only interactions that could cause aggregation between simple aromatic molecules. The use of molecular dynamics and high-level ab initio computer simulations has been used to describe the aggregation and interactions between molecular systems containing benzene, naphthalene and anthracene. Mixtures containing one type of molecule (homogenous) and more than one type of molecule (heterogenous) were considered. Our results indicate that as molecular weight increases so does the temperature at which aggregation will occur. In all simulations, the mechanism of aggregation is through small clusters coalescing into larger clusters. The structural analysis of the molecules within the clusters reveals that benzene will orient itself in T-shaped and parallel displaced configurations. Molecules of anthracene prefer to orient themselves in a similar manner to a bulk crystal with no T-shaped configuration observed. The aggregation of these aromatic molecules is discussed in the context of astrochemistry with particular reference to the dust formation region around stars.


Organocatalytic Ring-Opening Polymerization of N-Acylated-1,4-oxazepan-7-ones Toward Well-Defined Poly(ester amide)s: Biodegradable Alternatives to Poly(2-oxazoline)s.
We report a series of poly(ester amide)s (PEAs) synthesized by organocatalytic ring-opening polymerization (ROP) of N-acylated-1,4-oxazepan-7-one (OxP) monomers, produced from N-acylated-4-piperidones using the Baeyer-Villiger oxidation reaction. The ROP of OxPs, conducted in CH2Cl2 at room temperature with benzyl alcohol as initiator and TBD/TU (1,5,7-triazabicyclo[4.4.0]dec-5-ene/thiourea) as a binary organocatalytic system, revealed a controlled/living character. The thermodynamics of the ROP highly depends on the N-acylated substituent of monomers, with the following reactivity order: OxPPh > OxPMe > OxPPr > OxPBn. Based on NMR results, it seems that our system follows the hydrogen bonding bifunctional activation mechanism. All intermediates and final products were characterized by NMR, MALDI-TOF MS, SEC, and DSC techniques. All poly(N-acylated-1,4-oxazepan-7-one) (POxP) polymers are amorphous with different glass transition temperatures (Tg), depending on the N-acylated substituent (Tg: -2.90 to 43.75 °C). Among the synthesized polymers, only POxPMe was water-soluble and it degraded much faster than polycaprolactone in an aqueous phosphate buffer saline solution (pH = 7.4). Therefore, poly(N-acylated-1,4-oxazepan-7-one)s are potential biodegradable alternatives to poly(2-oxazoline)s.


Mucosal endocrine cell micronests and single endocrine cells following neo-adjuvant therapy for adenocarcinoma of the distal oesophagus and oesophagogastric junction.
To determine the frequency of endocrine cell micronests (ECM) and single endocrine cells (SEC) within the glandular mucosa of the distal oesophagus and oesophagogastric junction (OGJ) following neo-adjuvant therapy for adenocarcinoma. The resection specimens from 11 patients with adenocarcinoma of the distal oesophagus or OGJ who had undergone preoperative chemotherapy or chemoradiotherapy (CRT) were reviewed and stained immunohistochemically for cytokeratin and chromogranin. The presence of ECM and/or SEC within the mucosa adjacent to the tumour was noted, and the results correlated with the extent of tumour regression. The corresponding pretreatment endoscopic biopsy specimens were reviewed in 6 cases, and the results were also compared to 10 tumour resections from patients with no history of neo-adjuvant treatment. ECM and/or SEC were identified in 8/11 resection specimens after chemotherapy or CRT. The endocrine cells were typically located within the deep lamina propria or muscularis mucosae and were associated with varying degrees of glandular atrophy and inflammation. The appearances were most consistent with endocrine cell preservation (pseudo-hyperplasia) following treatment. Isolated endocrine elements were not seen in the pretreatment biopsy specimens, while rare SEC without ECM were identified in only 2/10 control resection specimens. Endocrine cell pseudo-hyperplasia may be seen within atrophic glandular mucosa following neo-adjuvant therapy of distal oesophageal/OGJ adenocarcinomas. The changes are analogous to those seen in chronic atrophic gastritis and should not be misinterpreted as those of residual tumour.


Economic conditions of military families.
For military children and their families, the economic news is mostly good. After a period of steady pay increases, James Hosek and Shelley MacDermid Wadsworth write, service members typically earn more than civilians with a comparable level of education. Moreover, they receive many other benefits that civilians often do not, including housing allowances, subsidized child care, tuition assistance, and top-of-the-line comprehensive health care. Of course, service members tend to work longer hours than civilians do, and they are exposed to hazards that civilians rarely, if ever, face. The extra pay they receive when they are deployed to combat zones helps their families cope financially but cannot alleviate the stress. Though service members are relatively well paid, the military lifestyle takes a toll on the earnings of their spouses. Chiefly because the military requires service members to move frequently, spouses' careers are regularly interrupted, and employers are hesitant to offer them jobs that require a large investment in training or a long learning curve. More military spouses than comparable civilian spouses are either unemployed or work fewer hours than they would like, and military spouses overall tend to earn less than their civilian counterparts. Despite the military's relatively high pay, some service members and their families--particularly among the junior enlisted ranks--report financial distress, and a handful even qualify for food stamps. Moreover, precisely because military pay tends to be higher than civilian pay, families may see a drop in income when a service member leaves the armed forces. Finally, the pay increases of recent years have slowed, and force cutbacks are coming; both of these factors will alter the financial picture for service members, possibly for the worse.


Antioxidant and Nephroprotective Activities of the Extract and Fractions of Homonoia riparia Lour.
Homonoia riparia is a plant, which is widely used in the indigenous system of medicine for the treatment of urolithiasis, renal disorders and inflammatory conditions. This is the first report on the antioxidant and nephroprotective activities of whole plant of H. riparia. The present study aims at investigating the in vitro antioxidant and nephroprotective activity of the methanol extract and its different fractions of H. riparia. Petroleum ether (HRPE), Ethyl acetate (HREA), Butanol (HRBU), aqueous fractions (HRAQ) were prepared from the crude methanol extract of H. riparia (HRM) using liquid partitioning. Total phenolic content, flavonoid content and antioxidant activity assay were performed according to suitable methods. Nephroprotective activities were evaluated by MTT assay using Human Embryonic Kidney cells against cisplatin induced toxicity. Quantification of gallic acid was performed using validated HPTLC method. The studies showed that extract and fractions possess significant nephroprotective activity against cisplatin induced renal toxicity. All the extracts/fractions of whole plant of Homonoia riparia was found to be significantly reducing cisplatin induced toxicity (< 0.05). The highest activity was observed with HRBU and HRAQ with a percentage viability of 293.09 ± 4.3 and 345.07 ± 3.2 at a concentration of 200 µg/ml. Gallic acid was detected in the HRM/fractions using HPTLC. Cisplatin (8 μg/ml) exhibited 50 % inhibition in cell viability in HEK 293 cellsButanol and aqueous fractions of Homonoia riparia showed significant nephroprotective activity against cisplatin induced cell damage in HEK cells.Gallic acid was detected and quantified in the extract and fractions of whole plant of Homonoia ripariaAbbreviations used: HPTLC: High Performance Thin Layer Chromatography, DPPH: 1,1-diphenyl-2-picrylhydrazyl, ABTS: 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt, MTT: 3-(4,5-dimethylthiazolyl-2-yl)-2,5- diphenyl tetrazolium bromide, GAE: Gallic acid equivalents, QE: Quercetin equivalents, HEK: Human Embryonic Kidney, HRM: Methanol extract of H. riparia, HRPE: Petroleum ether fraction of H. riparia, HREA: ethyl acetate fraction of H. riparia, HRBU: Butanol fraction of H. riparia, HRAQ: Aqueous fraction of H. riparia, DMEM: Dulbecco's minimum essential medium, FBS: Foetal bovine serum, DMSO: Dimethyl sulfoxide, ANOVA: One way analysis of variance.


Evolutionary Gain of Dbx1 Expression Drives Subplate Identity in the Cerebral Cortex.
Changes in transcriptional regulation through cis-regulatory elements are thought to drive brain evolution. However, how this impacts the identity of primate cortical neurons is still unresolved. Here, we show that primate-specific cis-regulatory sequences upstream of the Dbx1 gene promote human-like expression in the mouse embryonic cerebral cortex, and this imparts cell identity. Indeed, while Dbx1 is expressed in highly restricted cortical progenitors in the mouse ventral pallium, it is maintained in neurons in primates. Phenocopy of the primate-like Dbx1 expression in mouse cortical progenitors induces ectopic Cajal-Retzius and subplate (SP) neurons, which are transient populations playing crucial roles in cortical development. A conditional expression solely in neurons uncouples mitotic and postmitotic activities of Dbx1 and exclusively promotes a SP-like fate. Our results highlight how transcriptional changes of a single fate determinant in postmitotic cells may contribute to the expansion of neuronal diversity during cortical evolution.


Pulsed UV light inactivation of Salmonella enteritidis on eggshells and its effects on egg quality.
The majority of Salmonella Enteritidis outbreaks have been related to the consumption of raw or undercooked eggs or egg-containing foods. Therefore, the U.S. Department of Agriculture mandates egg washing for all graded eggs by use of a detergent solution and sanitizer. These agencies and the egg industry have been investigating alternative decontamination techniques, which could better serve the public, minimize costs, and benefit both the public and the industry. Pulsed UV light is an emerging technology that is used to inactivate microorganisms quickly. In this study, the effectiveness of pulsed UV light was evaluated for the decontamination of eggshells. Eggs inoculated with Salmonella Enteritidis on the top surface at the equator were treated with pulsed UV light 1 to 30 s, at a distance of 9.5 and 14.5 cm from the UV lamp in a laboratory-scale, pulsed UV light chamber. Three eggs were used per treatment in each repetition, except for quality measurements, which involved six eggs per treatment in each repetition. A maximum log reduction of 5.3 CFU/cm2 was obtained after a 20-s treatment at 9.5 cm below the UV lamp at a total dose of 23.6+/-0.1 J/cm2, without any visual damage to the egg. After a 30-s treatment at 9.5 and 14.5 cm, the temperature of eggshell surfaces increased by 16.3 and 13.3 degrees C, respectively. Energy usage increased up to 35.3+/-0.1 and 24.8+/-0.1 J/cm2, after 30-s treatments at 9.5 and 14.5 cm, respectively. The effect of pulsed UV light treatments on egg quality was also evaluated. Pulsed UV-light treatments for 3, 10, and 20s at either 9.5 or 14.5 cm did not change the albumen height, eggshell strength, or cuticle presence significantly (P<0.05). This study demonstrated that pulsed UV light has potential to decontaminate eggshell surfaces.


The relationship between middle-class parents' book-sharing discussion and their preschoolers' abstract language development.
Thirty-five mothers and fathers were videotaped in their homes as they read a familiar and unfamiliar book to their preschoolers aged between 3;6 and 4;1. Parental discussions about the text were coded for four levels of abstraction and correlated with children's gains one year later on a formal test of the same four levels of language abstraction (the Preschool Language Assessment Instrument). Parental input at three of the four levels of abstraction was positively and significantly correlated with their children's gains at the highest level of abstraction. This was also the level at which children's scores were the lowest initially and showed the greatest gains. The results suggest that discussions during book reading with preschoolers may be a positive influence, since it was parents' amount of input at lower as well as higher levels of abstraction that correlated with the children's development of more abstract language. We speculate that more input at lower levels might enhance learning by creating a climate of success in allowing children to display mastered skills, whereas more input at higher levels might enhance learning by challenging children with abstract language skills they are just beginning to acquire. In contrast to previous research, these results suggest that there is a great deal of variability in middle-class families in the amount of input that children receive at various level of abstractions during book sharing.


Improving participant feedback to continuing medical education presenters in internal medicine: a mixed-methods study.
Feedback is essential for improving the skills of continuing medical education (CME) presenters. However, there has been little research on improving the quality of feedback to CME presenters. To validate an instrument for generating balanced and behavior-specific feedback from a national cross-section of participants to presenters at a large internal medicine CME course. A prospective, randomized validation study with qualitative data analysis that included all 317 participants at a Mayo Clinic internal medicine CME course in 2009. An 8-item (5-point Likert scales) CME faculty assessment enhanced study form (ESF) was designed based on literature and expert review. Course participants were randomized to a standard form, a generic study form (GSF), or the ESF. The dimensionality of instrument scores was determined using factor analysis to account for clustered data. Internal consistency and interrater reliabilities were calculated. Associations between overall feedback scores and presenter and presentation variables were identified using generalized estimating equations to account for multiple observations within talk and speaker combinations. Two raters reached consensus on qualitative themes and independently analyzed narrative entries for evidence of balanced and behavior-specific comments. Factor analysis of 5,241 evaluations revealed a uni-dimensional model for measuring CME presenter feedback. Overall internal consistency (Cronbach alpha = 0.94) and internal consistency reliability (ICC range 0.88-0.95) were excellent. Feedback scores were associated with presenters' academic ranks (mean score): Instructor (4.12), Assistant Professor (4.38), Associate Professor (4.56), Professor (4.70) (p = 0.046). Qualitative analysis revealed that the ESF generated the highest numbers of balanced comments (GSF = 11, ESF = 26; p = 0.01) and behavior-specific comments (GSF = 64, ESF = 104; p = 0.001). We describe a practical and validated method for generating balanced and behavior-specific feedback for CME presenters in internal medicine. Our simple method for prompting course participants to give balanced and behavior-specific comments may ultimately provide CME presenters with feedback for improving their presentations.


[Serotype distribution of Streptococcus pneumoniae isolated from invasive infections at the Hospital de Niños of Santa Fe].
The serotype distribution of Streptococcus pneumoniae varies through time. The introduction of pneumococcal conjugate vaccines showed a decreased prevalence of pneumococcal invasive isolates belonging to serotype 14 and an increase of serotypes not therein included. In 1993, the Hospital de Niños of Santa Fe began surveillance of the serotype distribution of invasive S. pneumoniae disease. In the period 2003-2005, 76 isolates were analysed by studying the correlation between serotype and pathology, age and MIC of penicillin. Serotype 14 was the most frequent followed by serotypes 1, 6B, 18C, 7F, 19 F and 5. Serotype 14 showed a statistically significant correlation with MICs of penicillin ranging from 0,5 to 2 mg/l. Although this serotype was more frequently observed in pneumonia than in meningitis, there was not a significant association with any particular pathology. Serotypes 14 and 1, were prevalent among children under and over 2 years old, respectively. Most of these isolates with MICs of penicillin = 2 mg/l, were from patients with pneumonia and not with meningitis. The serotype distribution was similar to that during the period 1993-99, with the exception of serotypes 18C, 4, 12F and 22F which had never been found before. The emergence of these serotypes makes it essential to continue surveillance to determine which conjugated vaccine formulation would be suitable to prevent the most frequent pneumococcal invasive infections.


Awareness of cancer symptoms and anticipated patient interval for healthcare seeking. A comparative study of Denmark and Sweden.
Background Recent epidemiologic data show that Denmark has considerably poorer survival from common cancers than Sweden. This may be related to a lower awareness of cancer symptoms and longer patient intervals in Denmark than in Sweden. The aims of this study were to: 1) compare population awareness of three possible symptoms of cancer (unexplained lump or swelling, unexplained bleeding and persistent cough or hoarseness); 2) compare anticipated patient interval when noticing any breast changes, rectal bleeding and persistent cough; and 3) examine whether potential differences were noticeable in particular age groups or at particular levels of education in a Danish and Swedish population sample. Method Data were derived from Module 2 of the International Cancer Benchmarking Partnership. Telephone interviews using the Awareness and Beliefs about Cancer measure were conducted in 2011 among 3000 adults in Denmark and 3070 adults in Sweden. Results Danish respondents reported a higher awareness of two of three symptoms (i.e. unexplained lump or swelling and persistent cough or hoarseness) and a shorter anticipated patient interval for two of three symptoms studied (i.e. any breast changes and rectal bleeding) than Swedish respondents. Differences in symptom awareness and anticipated patient interval between these countries were most pronounced in highly educated respondents. Conclusion Somewhat paradoxically, the highest awareness of symptoms of cancer and the shortest anticipated patient intervals were found in Denmark, where cancer survival is lower than in Sweden. Thus, it appears that these differences in symptom awareness and anticipated patient interval do not help explain the cancer survival disparity between Denmark and Sweden.


[Multiplex PCR for the detection of sea, seb, sec, sed and see genes of Staphylococcus aureus. Characterization of isolates from food].
Multiplex PCR for the detection of sea, seb, sec, sed and see genes of Staphylococcus aureus. Characterization of isolates from food. The presence of Staphylococcus aureus in food represents a potential risk to public health, being its enterotoxins the major virulence factor. Enterotoxin detection can be determined by ELISA, but only for the pool of enterotoxins SEA, SEB, SEC, SED and SEE. The main aims of this study were to optimize two PCR techniques for detection of S. aureus sea, seb, sec, sed and see, and to characterize Staphylococcus spp. isolates associated with food intoxication. Two PCR techniques were optimized and 115 Staphylococcus spp. isolates from Ciudad Aut6noma de Buenos Aires, and Buenos Aires, Córdoba, and Neuquén provinces were characterized. The characterization was performed by biochemical tests, ELISA and PCR. Sixty-eight isolates (59.1%) were positive by ELISA, while 61 (53%) were positive by PCR. Out of the positive PCR isolates, 34 (55.7%) carried the sea gene, 9 (14.8%) the seb gene, 5 (8.1%) the see gene, 4 (6.5%) the sec gene, 6 (9.9%) were positive for sea and seb genes, 2 (3.3%) for sea and sec genes, and 1 (1.7%) for sea and sedgenes. This is the first study of genotypic characterization of S. aureus isolates associated with food intoxication from different provinces of Argentina.


Fast and Selective Post-polymerization Modification of Conjugated Polymers Using Dimethyldioxirane.
Modification of functional groups attached to conjugated polymer backbones can drastically alter the material properties. Oxidation of electron-donating thioalkyl substituents to electron-withdrawing sulfoxides or sulfones is a particularly effective modification. However, so far, this reaction has not been studied for the modification of conjugated polymers used in organic electronics. Crucial questions regarding selectivity and reaction time waited to be addressed. Here, we show that the reaction is highly selective and complete within just a few minutes when using dimethyldioxirane (DMDO) for the oxidation of thioalkyl substituents attached to the well-investigated conjugated polymers poly(9-(1-octylnonyl)carbazole-alt-4,7-dithienylbenzothiadiazole) (PCDTBT) and poly(9,9-dioctylfluorene-alt-benzothiadiazole) (F8BT). The selectivity was confirmed by comparison with polymers obtained from pre-oxidized monomers and by control experiments using related polymers without thioalkyl substituents. Using DMDO, the oxidation yields acetone as the only side-product, which reduces the work-up to mere evaporation of solvents and excessive reagent. Our results show that this oxidation is an exciting method for the preparation of electron-deficient conjugated polymers. It may even allow the preparation of electron acceptors for solar cells directly from the electron donors.


Beneficial effects of cyclosporine and rapamycin in small bowel ischemic injury.
Gut ischemia has been implicated in the pathogenesis of necrotizing enterocolitis. Cyclosporine A and rapamycin, both potent novel immunosuppressants which act on signal transduction pathways in CD4+ T-cells, could potentially modulate immune/inflammatory cellular reactions involved in tissue ischemia/reperfusion injury. We hypothesized that cyclosporine A and rapamycin would preserve mucosal cell function and attenuate inflammatory T-cell-mediated cellular changes associated with small bowel ischemic injury. Forty Sprague-Dawley rats underwent 60 min of gut ischemia by vascular occlusion of the superior mesenteric vessels. Animals were randomized to four groups (n = 10): cyclosporine A (CSA, 5 mg/kg/day SQ), rapamycin (RAP, 2 mg/kg/day SQ), cyclosporine A and rapamycin (C&R), and vehicle given to controls (CON). Following 1 hr of reperfusion, small bowel was harvested for xanthine oxidase (XO, units/mg protein) and maltase (MALT, mM substrate degraded/min/g protein) assays. Blood was obtained from the portal vein for tumor necrosis factor-alpha (TNF-alpha, pg/ml) assay. The results of the study are presented below (mean +/- SEM, *, P < 0.05 versus controls). (Table in text) The results indicate that cyclosporine and rapamycin each play a significant role in attenuating ischemia/reperfusion injury in the gut. These data suggest that there are cytoprotective and anti-inflammatory mechanisms of these drugs independent of T-cell signal transduction that provide some protective effect in small bowel ischemia. Furthermore, T-cell-mediated immune mechanisms may not be associated with the adverse effects of small bowel ischemia/reperfusion injury. Additional investigation will be necessary in order to define the role of T-cell-mediated immune injury in the gut and how this relates to the beneficial effect of immunosuppression in small bowel mucosal ischemic injury.


Detection of Rheumatoid Arthritis-Interstitial Lung Disease Is Enhanced by Serum Biomarkers.
Interstitial lung disease (ILD), a leading cause of morbidity and mortality in rheumatoid arthritis (RA), is highly prevalent, yet RA-ILD is underrecognized. To identify clinical risk factors, autoantibodies, and biomarkers associated with the presence of RA-ILD. Subjects enrolled in Brigham and Women's Hospital Rheumatoid Arthritis Sequential Study (BRASS) and American College of Rheumatology (ACR) cohorts were evaluated for ILD. Regression models were used to assess the association between variables of interest and RA-ILD. Receiver operating characteristic curves were generated in BRASS to determine if a combination of clinical risk factors and autoantibodies can identify RA-ILD and if the addition of investigational biomarkers is informative. This combinatorial signature was subsequently tested in ACR. A total of 113 BRASS subjects with clinically indicated chest computed tomography scans (41% with a spectrum of clinically evident and subclinical RA-ILD) and 76 ACR subjects with research or clinical scans (51% with a spectrum of RA-ILD) were selected. A combination of age, sex, smoking, rheumatoid factor, and anticyclic citrullinated peptide antibodies was strongly associated with RA-ILD (areas under the curve, 0.88 for BRASS and 0.89 for ACR). Importantly, a combinatorial signature including matrix metalloproteinase 7, pulmonary and activation-regulated chemokine, and surfactant protein D significantly increased the areas under the curve to 0.97 (P = 0.002, BRASS) and 1.00 (P = 0.016, ACR). Similar trends were seen for both clinically evident and subclinical RA-ILD. Clinical risk factors and autoantibodies are strongly associated with the presence of clinically evident and subclinical RA-ILD on computed tomography scan in two independent RA cohorts. A biomarker signature composed of matrix metalloproteinase 7, pulmonary and activation-regulated chemokine, and surfactant protein D significantly strengthens this association. These findings may facilitate identification of RA-ILD at an earlier stage, potentially leading to decreased morbidity and mortality.


Chronic sun damage and the perception of age, health and attractiveness.
Young and healthy-looking skin is a feature that is universally admired and considered attractive among humans. However, as we age, skin condition deteriorates due to a variety of intrinsic and extrinsic factors determined not only by genetics and physiological health but also by behaviour and lifestyle choice. As regards the latter, cumulative, repeated exposure to solar ultraviolet radiation (UVR) is linked intrinsically to the induction of specific types of skin cancer and the expression of cutaneous damage markers responsible for the majority of the visible signs of skin ageing. Here we review empirical evidence for skin-specific effects of chronic UVR exposure and relate it to perception of visible skin condition. In contrast to other dermatological accounts, we stress an evolutionary psychology context in understanding the significance of age-related changes in visible skin condition in human social cognition and interaction. We suggest that the "marriage" of the scientific fields of skin biology and evolutionary psychology provides a modern, powerful framework for investigating the causes, mechanisms and perception of chronic sun damage of skin, as it explains the human obsession with a youthful and healthy appearance. Hence, it may be that these insights bring true emotional impetus to the adoption of sun protection strategies, which could conceivably impact skin cancer rates in coming years.


The neural substrate of human empathy: effects of perspective-taking and cognitive appraisal.
Whether observation of distress in others leads to empathic concern and altruistic motivation, or to personal distress and egoistic motivation, seems to depend upon the capacity for self-other differentiation and cognitive appraisal. In this experiment, behavioral measures and event-related functional magnetic resonance imaging were used to investigate the effects of perspective-taking and cognitive appraisal while participants observed the facial expression of pain resulting from medical treatment. Video clips showing the faces of patients were presented either with the instruction to imagine the feelings of the patient ("imagine other") or to imagine oneself to be in the patient's situation ("imagine self"). Cognitive appraisal was manipulated by providing information that the medical treatment had or had not been successful. Behavioral measures demonstrated that perspective-taking and treatment effectiveness instructions affected participants' affective responses to the observed pain. Hemodynamic changes were detected in the insular cortices, anterior medial cingulate cortex (aMCC), amygdala, and in visual areas including the fusiform gyrus. Graded responses related to the perspective-taking instructions were observed in middle insula, aMCC, medial and lateral premotor areas, and selectively in left and right parietal cortices. Treatment effectiveness resulted in signal changes in the perigenual anterior cingulate cortex, in the ventromedial orbito-frontal cortex, in the right lateral middle frontal gyrus, and in the cerebellum. These findings support the view that humans' responses to the pain of others can be modulated by cognitive and motivational processes, which influence whether observing a conspecific in need of help will result in empathic concern, an important instigator for helping behavior.


Crystal structure of a fibrillarin homologue from Methanococcus jannaschii, a hyperthermophile, at 1.6 A resolution.
Fibrillarin is a phylogenetically conserved protein essential for efficient processing of pre-rRNA through its association with a class of small nucleolar RNAs during ribosomal biogenesis. The protein is the antigen for the autoimmune disease scleroderma. Here we report the crystal structure of the fibrillarin homologue from Methanococcus jannaschii, a hyperthermophile, at 1.6 A resolution. The structure consists of two domains, with a novel fold in the N-terminal region and a methyltransferase-like domain in the C-terminal region. Mapping temperature-sensitive mutations found in yeast fibrillarin Nop1 to the Methanococcus homologue structure reveals that many of the mutations cluster in the core of the methyltransferase-like domain.


The effects of siRNA-mediated RGS4 gene silencing on the whole genome transcription profile: implications for schizophrenia.
The regulator of G-protein signaling (RGS) molecules represent a class of proteins that modulate the signaling activity of G-protein coupled receptors. Regulator of G-protein signaling 4 (RGS4) is of particular interest in schizophrenia due to reported downregulation of RGS4 transcripts in schizophrenia as well as a connection between RGS4 and a number of receptors implicated in schizophrenia. The mechanism of RGS4 involvement in the pathophysiology of this illness is not clear. To elucidate thise role of RGS4 in pathophysiology of schizophrenia, we silenced RGS4 using siRNAs in human neuroblastoma cell lines and we studied the effects of differential RGS4 expression by microarray. The cell lines with downregulated expression of RGS4 showed 67 genes with changed expression (30 underexpressed and 37 overexpressed). We have detected three subgroups of genes which might be implicated in schizophrenia pathophysiology: histone genes, which suggest epigenetic mechanisms of the disease; genes for transcription factors associated with other genes relevant to schizophrenia pathology (BDNF and DISCI1) and a heterogeneous group containing genes for G-proteins (GPR50 and GPR64) and calcium binding proteins.


B-spline modal method: a polynomial approach compared to the Fourier modal method.
A detailed analysis of the B-spline Modal Method (BMM) for one- and two-dimensional diffraction gratings and a comparison to the Fourier Modal Method (FMM) is presented. Owing to its intrinsic capability to accurately resolve discontinuities, BMM avoids the notorious problems of FMM that are associated with the Gibbs phenomenon. As a result, BMM facilitates significantly more efficient eigenmode computations. With regard to BMM-based transmission and reflection computations, it is demonstrated that a novel Galerkin approach (in conjunction with a scattering-matrix algorithm) allows for an improved field matching between different layers. This approach is superior relative to the traditional point-wise field matching. Moreover, only this novel Galerkin approach allows for an competitive extension of BMM to the case of two-dimensional diffraction gratings. These improvements will be very useful for high-accuracy grating computations in general and for the analysis of associated electromagnetic field profiles in particular.


High-Sensitivity Troponin in Patients With Coronary Artery Endothelial Dysfunction.
Coronary endothelial dysfunction (CED) is associated with recurrent ischemia. The role of high-sensitivity cardiac troponin I (hscTnI) levels in patients with CED has not been established. Patients with suspected ischemia, who underwent clinically indicated coronary angiography and were found to have non-obstructive coronary artery disease, were included in the study. CED was defined as ≤50% increase in coronary blood flow from baseline and/or a decrease in epicardial coronary artery diameter >20% in response to maximal dosages of acetylcholine. HscTnI was measured at the time of the procedure using the Architect hscTnI assay (Abbott). Of 299 patients, 60 had normal endothelial function and 239 patients had abnormal endothelial function. The median age of the population was 52 years (interquartile range [IQR], 45-60 years). Patients with abnormal endothelial function had significantly higher log hscTnI values when compared to patients with normal endothelial function (0.9 ng/L [IQR, 0.7-1.4 ng/L] vs 0.7 ng/L [IQR, 0.7-1.1 ng/L]; P=.04). An hscTnI value >12.5 ng/L was 100% specific for the presence of endothelial dysfunction (100% positive predictive value). There were 39 major adverse cardiovascular events during follow-up. In patients with normal endothelial function, hscTnI levels were significantly higher in patients who developed major adverse cardiac events when compared to patients who did not (1.35 ng/L [IQR, 1.1-2.1 ng/L] vs 0.7 ng/L [IQR, 0.7-1.1 ng/L]; P=.02). Our findings suggest that endothelial dysfunction may be associated with higher baseline hscTnI levels, suggesting increased myocardial injury in this population of patients. Additional studies are necessary to further define the role of hscTnI in risk stratification in this population.


Treatment benefit by perindopril in patients with stable coronary artery disease at different levels of risk.
Patients with stable coronary artery disease (CAD) are at increased risk. Estimation of individual risk is difficult. We developed a cardiovascular risk model based on the EUROPA study population and investigated whether benefit of long-term administration of the angiotensin-converting enzyme (ACE)-inhibitor perindopril was modified by risk level. A total of 12 218 patients with stable CAD were treated with 8 mg perindopril or placebo. Baseline patient characteristics were assessed for association with 1091 cardiovascular deaths or non-fatal myocardial infarction (MI). Risk factors were age over 65 years, male gender [hazard ratio (HR) 1.2], previous MI (HR 1.5), previous stroke and/or peripheral vascular disease (HR 1.7), diabetes, smoking, angina (all HR 1.5), and high serum cholesterol and systolic blood pressure. Treatment benefit by perindopril was consistent among high, intermediate, and low risk patients (HRs 0.88, 0.68, and 0.83, respectively). Risk reduction was thus not modified by absolute risk level. Risk factors such as age, male gender, smoking, total cholesterol, and blood pressure continue to play an important role once clinical sequellae of coronary heart disease have developed. Patients at moderate-to-high risk because of uncontrolled risk factors and those with other indications for ACE-inhibitors have the most to gain from ACE-inhibition.


Production and characterization of multiple antigenic peptide antibodies to the adenosine A2b receptor.
A polyclonal antibody to the human adenosine A2b receptor (A2bR) was produced by immunizing a chicken with a multiple antigenic peptide consisting of eight copies of a 16-amino acid peptide, corresponding to the presumed second extracellular loop of the A2bR, linked to a branched lysine core. Western blotting with affinity-purified antibody revealed the human A2bR to be a protein of approximately 50-55 kDa, found in a variety of tissues including thymus, colon, and small intestine. The antibody also recognized mouse and rat A2bRs and revealed heterogeneity in size, with a 35-kDa protein being detected in small intestine in addition to the larger 50-52-kDa species in thymus, colon, and placenta. The chicken anti-human A2bR peptide antibody recognized the receptor in both frozen and formalin-fixed tissue sections. In human colon, the A2bR was highly expressed in epithelial cells of the crypts. A2bR immunoreactivity was also apparent in syncytiotrophoblast cells of human placental villi and in the basal zone of murine chorioallantoic placenta. These cell type-specific patterns of expression are consistent with the hypothesized roles of the A2bR in mediating electrogenic Cl- secretion and the resulting secretory diarrhea caused by colonic crypt abscesses and in regulating morphogenesis of the placenta. Insight into the multiple physiological consequences of A2bR engagement will be forthcoming from an analysis of the cell type-specific expression of this receptor in additional tissues.


Smartphone Allows Capture of Speech Abnormalities Associated With High Risk of Developing Parkinson's Disease.
Although smartphone technology provides new opportunities for the recording of speech samples in everyday life, its ability to capture prodromal speech impairment in persons with a high risk of developing Parkinson's disease (PD) has never been investigated. Speech data were acquired through a smartphone as well as a professional microphone with a linear frequency response from 50 participants with a rapid eye movement sleep behavior disorder that are at a high risk of developing PD and related neurodegenerative disorders. Additionally, recordings of 30 newly diagnosed, untreated PD patients and 30 healthy participants were evaluated. Acoustic assessment of 11 speech dimensions representing the key aspects of hypokinetic dysarthria in the early stages of PD was performed. Smartphone allowed the detection of speech abnormalities in participants with a high risk of developing PD. Acoustic measurements related to fundamental frequency variability, duration of pause intervals, and rate of speech timing extracted from spontaneous speech were sufficiently sensitive to significantly separate groups (area under curve of 0.85 between PD and controls) and showed very strong correlation and reliability between the professional microphone and the smartphone. Speech-based biomarkers collected through smartphones may have the potential to revolutionize the diagnostic process in neurodegenerative diseases and improve stratification for future neuroprotective therapy in PD.


A framework for measuring costs to society of IgE-mediated food allergy.
Both immunoglobulin E (IgE)-mediated food allergy and food intolerance can lead to many changes in personal behaviour and health care resource use which have important economic consequences. These costs will impact directly, indirectly and intangibly on both individuals and society in general. It is important to measure the cost of illness (COI) of food allergy as a first step in developing and evaluating measures to reduce and control the burden of illness. This paper outlines a framework for assessing COI of food allergy from different viewpoints. It offers a structure for identifying the different cost impacts on allergic and nonallergic consumers, food producers and society as a whole, and for scoping, measurement and valuation of relevant costs. Within this structure, the existing literature is reviewed. This review illustrates the lack of information and clear methodology for assessing costs of food allergy. The paper concludes that there is a need for a more structured research programme to generate data essential for future evaluations of procedures and technologies for the diagnosis, treatment and management of food allergy.


MLL tandem duplication and multiple splicing in adult acute myeloid leukemia with normal karyotype.
Rearrangement of the MLL (myeloid-lymphoid or mixed-lineage leukemia) gene through a reciprocal chromosomal translocation is found in 5% of adult acute myeloid (AML) and 10% of pediatric acute lymphoid (ALL) leukemia. More than 25 different reciprocal chromosomal translocations, with an 11q23 breakpoint, fuse the MLL gene (also named ALL-1, HRX and Htrx1) to a second partner gene. These leukemias have poor prognosis and frequently have a monocytic, lymphoid or biphenotypic (myeloid and lymphoid) antigen expression in blast cells. Approximately 20-30% of patients diagnosed as having adult de novo, AML have normal chromosomes by metaphase analysis and the majority of these patients have good prognosis. With the use of reverse transcriptase-polymerase chain reaction (RT-PCR) technique and Southern blot analysis, we found that seven of 34 such patients (21%) had a tandem partial duplication of exons 2 to 6 or 2 to 8 of the MLL gene. These seven patients showed a median survival of 2.7 months, compared to a 6.8 months median survival for all other patients in the study. If confirmed on a large series of patients, our findings may help differentiate AML with normal karyotype and poor prognosis from those with normal karyotype and a more favorable prognosis.


Status and Trends of Physical Activity Surveillance, Policy, and Research in 164 Countries: Findings From the Global Observatory for Physical Activity-GoPA! 2015 and 2020 Surveys.
Physical activity (PA) surveillance, policy, and research efforts need to be periodically appraised to gain insight into national and global capacities for PA promotion. The aim of this paper was to assess the status and trends in PA surveillance, policy, and research in 164 countries. We used data from the Global Observatory for Physical Activity (GoPA!) 2015 and 2020 surveys. Comprehensive searches were performed for each country to determine the level of development of their PA surveillance, policy, and research, and the findings were verified by the GoPA! Country Contacts. Trends were analyzed based on the data available for both survey years. The global 5-year progress in all 3 indicators was modest, with most countries either improving or staying at the same level. PA surveillance, policy, and research improved or remained at a high level in 48.1%, 40.6%, and 42.1% of the countries, respectively. PA surveillance, policy, and research scores decreased or remained at a low level in 8.3%, 15.8%, and 28.6% of the countries, respectively. The highest capacity for PA promotion was found in Europe, the lowest in Africa and low- and lower-middle-income countries. Although a large percentage of the world's population benefit from at least some PA policy, surveillance, and research efforts in their countries, 49.6 million people are without PA surveillance, 629.4 million people are without PA policy, and 108.7 million live in countries without any PA research output. A total of 6.3 billion people or 88.2% of the world's population live in countries where PA promotion capacity should be significantly improved. Despite PA is essential for health, there are large inequalities between countries and world regions in their capacity to promote PA. Coordinated efforts are needed to reduce the inequalities and improve the global capacity for PA promotion.


Characterization of Puerto Rican West Nile Virus isolates in mice.
West Nile virus (WNV) is a neurotropic arbovirus that was first isolated in 1937 in the West Nile District of Uganda. The virus emerged in New York in 1999 and is now endemic in North America (2007). The first virus isolates from Puerto Rico were obtained in 2007 from a chicken (PR20wh) and a mosquito pool (PR423). Our study further characterized these viral isolates using in vitro plaque morphology assays and in vivo using a Balb/c mice pathogenesis model. In the in vitro experiments, PR WNV isolates produced significantly smaller plaques in Vero cells compared to the New York 1999 strain (NY99). For the in vivo experiments, PR WNV isolates were propagated in mammalian (Vero) and insect (C6/36) cell lines and then inoculated in Balb/c mice. When WNV was propagated in Vero cells, we observed a trend towards significance in the survival rate with PR20wh compared to NY99 (log rank, p = 0.092). Regardless of whether the viral isolates were propagated in Vero or C6/36 cells, we found a significantly greater survival in mice infected with PR20wh strain, when compared to NY99 (log rank, p = 0.04), while no statistical difference was detected between PR423 and NY99 (p = 0.84). The average survival time (AST) in mice was significantly lower in C6/36-derived PR423 when compared to C6/36-derived NY99 (t-test, p = 0.013), and Vero-derived PR423 (t-test, p < 0.001). Eight days post infection in mice the viral load in brain tissue for Vero-derived PR423 was significantly higher when compared to NY99 and PR20wh. These results suggest that the PR WNV isolate, PR20wh, is a less pathogenic strain in mice than NY99. Moreover, we found that PR423 is a pathogenic isolate that causes faster mortality than NY99, when propagated in C6/36.


Memory deficits correlating with acetylcholinesterase splice shift and amyloid burden in doubly transgenic mice.
Current mouse models of Alzheimer's disease show brain pathology that correlates to a degree with memory impairment, but underlying molecular mechanisms remained unknown. Here we report studies with three lines of transgenic mice: animals that doubly express mutated human amyloid precursor protein (APPswe) and human acetylcholinesterase (hAChE); and animals transgenic for only the APPswe or the hAChE. Among these genotypes, variations were observed in expression of mRNA for presenilin-1, which was highest in singly transgenic hAChE mice, and the stress-inducible form of AChE, which was elevated when both transgenes were present. At the age of nine months, both double and single transgenic mice displayed working memory impairment in a radial arm water maze. However, as compared with mice expressing amyloid alone, the double transgenic animals exhibited more numerous plaques and greater amyloid burden in brain (both by histochemistry and by ELISA of amyloid protein). Moreover, the amyloid burden in double transgenics was tightly correlated with memory impairment as measured by total maze errors (r2= 0.78, p = .002). This correlation was markedly stronger than observed in mice with amyloid alone. These new findings support the notion of cholinergic-amyloid interrelationships and highlight the double transgenic mice as a promising alternative for testing Alzheimer's therapies.


Cryopreservation of testicular tissue before long-term testicular cell culture does not alter in vitro cell dynamics.
To assess whether testicular cell dynamics are altered during long-term culture after testicular tissue cryopreservation. Experimental basic science study. Reproductive biology laboratory. Testicular tissue with normal spermatogenesis was obtained from six donors. None. Detection and comparison of testicular cells from fresh and frozen tissues during long-term culture. Human testicular cells derived from fresh (n = 3) and cryopreserved (n = 3) tissues were cultured for 2 months and analyzed with quantitative reverse-transcription polymerase chain reaction and immunofluorescence. Spermatogonia including spermatogonial stem cells (SSCs) were reliably detected by combining VASA, a germ cell marker, with UCHL1, a marker expressed by spermatogonia. The established markers STAR, ACTA2, and SOX9 were used to analyze the presence of Leydig cells, peritubular myoid cells, and Sertoli cells, respectively. No obvious differences were found between the cultures initiated from fresh or cryopreserved tissues. Single or small groups of SSCs (VASA(+)/UCHL1(+)) were detected in considerable amounts up to 1 month of culture, but infrequently after 2 months. SSCs were found attached to the feeder monolayer, which expressed markers for Sertoli cells, Leydig cells, and peritubular myoid cells. In addition, VASA(-)/UCHL1(+) cells, most likely originating from the interstitium, also contributed to this monolayer. Apart from Sertoli cells, all somatic cell types could be detected throughout the culture period. Testicular tissue can be cryopreserved before long-term culture without modifying its outcome, which encourages implementation of testicular tissue banking for fertility preservation. However, because of the limited numbers of SSCs available after 2 months, further exploration and optimization of the culture system is needed.


On the production and correction of involuntary prosaccades in a gap antisaccade task.
In an antisaccade task, where saccades in the direction opposite of a suddenly presented stimulus are required, certain numbers of prosaccades can occur. The hypothesis is put forward that poor fixation and poor voluntary saccade control constitute two independent sources for the errors. This possibility is investigated by including the corrections of the errors in the analysis. First, the eye movements of 346 normal subjects (group N) performing a gap antisaccade and an overlap prosaccade task were measured. For each subject the proportion of express saccades in the overlap prosaccade task and the proportion of prosaccades in the gap antisaccade task were determined. The data of 150 subjects with more than 20% proerrors were divided into two groups: group A with relatively many, group B with relatively few express saccades in the overlap prosaccade task. Group A subjects produced their errors after significantly shorter reaction times and they corrected their errors significantly faster and more often than group B subjects. Second, we analysed the data of three groups of subjects: the complete normal group N, a group D of dyslexic subjects (n=343), and a group T containing all subjects irrespective of their cognitive achievements (n=780). A highly significant negative correlation exists between the correction rates and the error rates. A factor analysis of the variables performed for each group separately results in only two factors, one describing prosaccade the other antisaccade control. Only the error rate contributes significantly to both factors indicating that high errors may have two independent reasons.


Ketogenic diet restrains aging-induced exacerbation of coronavirus infection in mice.
Increasing age is the strongest predictor of risk of COVID-19 severity and mortality. Immunometabolic switch from glycolysis to ketolysis protects against inflammatory damage and influenza infection in adults. To investigate how age compromises defense against coronavirus infection, and whether a pro-longevity ketogenic diet (KD) impacts immune surveillance, we developed an aging model of natural murine beta coronavirus (mCoV) infection with mouse hepatitis virus strain-A59 (MHV-A59). When inoculated intranasally, mCoV is pneumotropic and recapitulates several clinical hallmarks of COVID-19 infection. Aged mCoV-A59-infected mice have increased mortality and higher systemic inflammation in the heart, adipose tissue, and hypothalamus, including neutrophilia and loss of γδ T cells in lungs. Activation of ketogenesis in aged mice expands tissue protective γδ T cells, deactivates the NLRP3 inflammasome, and decreases pathogenic monocytes in lungs of infected aged mice. These data establish harnessing of the ketogenic immunometabolic checkpoint as a potential treatment against coronavirus infection in the aged.


Toward quantifying water pollution abatement in response to installing buffers on crop land.
The scientific research literature is reviewed (i) for evidence of how much reduction in nonpoint source pollution can be achieved by installing buffers on crop land, (ii) to summarize important factors that can affect this response, and (iii) to identify remaining major information gaps that limit our ability to make probable estimates. This review is intended to clarify the current scientific foundation of the USDA and similar buffer programs designed in part for water pollution abatement and to highlight important research needs. At this time, research reports are lacking that quantify a change in pollutant amounts (concentration and/or load) in streams or lakes in response to converting portions of cropped land to buffers. Most evidence that such a change should occur is indirect, coming from site-scale studies of individual functions of buffers that act to retain pollutants from runoff: (1) reduce surface runoff from fields, (2) filter surface runoff from fields, (3) filter groundwater runoff from fields, (4) reduce bank erosion, and (5) filter stream water. The term filter is used here to encompass the range of specific processes that act to reduce pollutant amounts in runoff flow. A consensus of experimental research on functions of buffers clearly shows that they can substantially limit sediment runoff from fields, retain sediment and sediment-bound pollutants from surface runoff, and remove nitrate N from groundwater runoff. Less certain is the magnitude of these functions compared to the cultivated crop condition that buffers would replace within the context of buffer installation programs. Other evidence suggests that buffer installation can substantially reduce bank erosion sources of sediment under certain circumstances. Studies have yet to address the degree to which buffer installation can enhance channel processes that remove pollutants from stream flow. Mathematical models offer an alternative way to develop estimates for water quality changes in response to buffer installation. Numerous site conditions and buffer design factors have been identified that can determine the magnitude of each buffer function. Accurate models must be able to account for and integrate these functions and factors over whole watersheds. At this time, only pollutant runoff and surface filtration functions have been modeled to this extent. Capability is increasing as research data is produced, models become more comprehensive, and new techniques provide means to describe variable conditions across watersheds. A great deal of professional judgment is still required to extrapolate current knowledge of buffer functions into broadly accurate estimates of water pollution abatement in response to buffer installation on crop land. Much important research remains to be done to improve this capability. The greatest need is to produce direct quantitative evidence of this response. Such data would confirm the hypothesis and enable direct testing of watershed-scale prediction models as they become available. Further study of individual pollution control functions is also needed, particularly to generate comparative evidence for how much they can be manipulated through buffer installation and management.